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The GlaxoSmithKline group of companies

A randomised, double-blind, double-dummy, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GW685698X 100µg administered once daily either in the morning or the evening and GW685698X 250µg administered once daily in the evening all administered by inhalation via DISKHALER™ for 28 days in subjects with persistent bronchial asthma

Clinical Study Report for Study FFA20001 (Development Phase IIa)

Document Number: GM2004/00341/00 Compound Number: GW685698X

Indication Studied: Asthma

Initiation Date: 24 Sept 2003

Completion Date: 31 Mar 2004

Date of Report: 06 June 2005

Sponsor Signatory: (and Medical Officer)

MD Vice President, Clinical North America Respiratory MDC

This study was performed in compliance with Good Clinical Practices including the archiving of essential documents.

Copyright 2004 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

CONFIDENTIAL GM2004/00341/00 FFA20001

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Synopsis

Document Number: GM2004/00341/00 Study Number: FFA20001

Title: A randomised, double-blind, double-dummy, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GW685698X 100µg administered once daily either in the morning or the evening and GW685698X 250µg administered once daily in the evening all administered by inhalation via DISKHALER™ for 28 days in subjects with persistent bronchial asthma

Investigator(s): This was a multi-centre study.

Study center(s): This study was conducted at 62 sites in 12 countries in Europe, South America, and S Africa.

Publication(s): There were no publications based on this study at the time of this report

Study period: 24 Sep 2003 - 31 Mar 2004 Phase of Development: IIa

Objectives: The primary objective of this study was to evaluate the time of dosing (a.m. vs p.m.) of GW685698X 100µg once daily, administered by inhalation via DISKHALER on the mean change in daily trough (pre-study treatment and pre-bronchodilator) PEF during the 28 day treatment period.

The secondary objectives of this study were to compare the efficacy and safety of GW685698X 250µg with 100µg both given once daily in the evening, and to compare the efficacy and safety of GW685698X 100µg given either in the morning or evening and to compare the safety and efficacy of all three active treatment regimens with placebo.

Methodology:

This was a multi-centre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group study. The study comprised a run-in period of 1-3 weeks, followed by a four week treatment period and a one week follow-up period. Clinic visits took place at the beginning and end of the run-in period (and repeat run-in periods if appropriate) and then at weekly intervals throughout the treatment period. The follow-up visit took place one week after the end of the treatment period. Daily Record Cards (DRC) were completed twice daily throughout the run-in and treatment periods.

During the run-in, subjects took VENTOLIN™ as required for relief of asthma symptoms. If the entry criteria were fulfilled at the end of the run-in (or repeat run-ins), subjects were randomised and given study treatment to be taken as one actuation from the study DISKHALER/ ROTADISK™ each morning and evening throughout the treatment period. In addition subjects continued to take VENTOLIN as required for relief of asthma symptoms throughout the treatment period.


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Number of subjects:

It was planned to screen approximately 600 subjects to achieve 492 randomised subjects (123 per treatment group). A total of 669 subjects were recruited into the study, of whom 578 were randomised to treatment. The Intent-to-Treat (ITT) population comprised 575 subjects, 143 in the placebo group, 144 in the GW685698X 100µg a.m. group, 146 in the GW685698X 100µg p.m. group and 142 in the GW685698X 250µg group. The Per Protocol population comprised 494 subjects, 119 in the placebo group, 128 in each of the GW685698X 100µg a.m. and p.m. groups, and 119 in the GW685698X 250µg p.m. group.

Diagnosis and main criteria for inclusion:

Male and female subjects aged 16 to 55 years inclusive, with a documented history of persistent asthma of at least 6 months duration, who were currently receiving inhaled short-acting β2-agonists as their asthma treatment and had a PEF of 50-90% predicted normal were eligible to enter the run-in. Subjects who had taken inhaled corticosteroids (ICS) within 4 weeks of Visit 1, or systemic, oral or depot corticosteroids within 8 weeks of Visit 1, or who had had a respiratory tract infection or asthma exacerbation within 4 weeks of Visit 1 were not permitted to enter the study. At the end of the run-in period, subjects were required to have demonstrated an increase in PEF of ≥ 15% after 400µg salbutamol, a mean morning PEF of 50-80% predicted normal during the last 7 consecutive days of the run-in, and a daily asthma symptom score of >1 on at least four of the last seven consecutive days of the run-in.

Treatment administration:

• GW685698X 250µg / dose ROTADISK (4 blister): Batch number AX6121/003

• GW685698X 100µg / dose ROTADISK (4 blister): Batch number AX2096/061

• Placebo ROTADISK (4 blister): Batch number AX2096/059A

• DISKHALER (4 place): Batch number SV0136606

Each subject was instructed to take one inhalation from the study DISKHALER/ROTADISK each morning and evening throughout the four-week treatment period. In addition rescue VENTOLIN either formulated as a MDI (100µg /actuation) or DISKUS™/ACCUHALER™ (200µg /actuation) was dispensed to all subjects.


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Criteria for evaluation:

Efficacy Evaluations:

Subjects were given a Daily Record Card (DRC) to complete each morning and evening throughout the run-in and treatment period. The following parameters were recorded in the DRC:- morning and evening PEF; night-time and day-time asthma symptom scores; the use of rescue VENTOLIN each day and night and night-time awakenings due to asthma symptoms. The following lung function measurements were performed at clinic visits: FEV1 and PEF.

The primary efficacy endpoint was mean change from baseline in daily trough (pre-study treatment and pre-bronchodilator) PEF during the 28-day treatment period. The primary comparison was estimation of the treatment difference between GW685698X 100µg once daily in the morning and GW685698X 100µg once daily in the evening. Secondary comparisons were GW685698X 250µg od compared with 100µg od both administered in the evening and each GW685698X group with placebo. The above comparisons were also made for the secondary endpoints which were:- mean change from baseline in pre-bronchodilator clinic lung function (FEV1 and PEF) after 28 days of treatment; percentage of VENTOLIN-free 24-hour periods, days and nights; percentage of symptom-free 24-hour periods, days and nights; percentage of nights with no awakenings and withdrawals due to lack of efficacy during the 28 day treatment period.

Safety Evaluations:

Safety evaluations included the incidence of adverse events (AE), oropharyngeal examinations; haematological, clinical chemistry and urinalysis measurements; 24-hour urinary cortisol measurements, 12-lead ECG evaluations; physical examinations and measurements of vital signs.

Statistical methods:

The primary purpose of this study was the estimation of the difference of effect between GW685698X 100µg od a.m. and p.m.. Similarly the secondary objective of comparing GW685698X 250µg od p.m. and 100µg od p.m. related to treatment differences only. Therefore statistical testing was only performed for the secondary comparisons of each dosing regimen with placebo. The sample size was based on an estimated standard deviation of trough PEF of 40L/min. A sample size of 492 subjects (123/group) was required to ensure the width of the 95% confidence interval for the treatment effect was no larger than 20L/min. The ITT population was the primary population for analyses of efficacy. The safety population was used for analyses of safety parameters. The Per Protocol population was used for confirmatory analysis of trough PEF endpoints.


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Pharmacokinetic methods:

For the pharmacokinetic data, population modelling techniques using non-linear mixed effects methods (NONMEM) were used to estimate the following individual and population pharmacokinetic parameters for GW685698X from the sparse sampling: absorption rate constant; apparent clearance; apparent volume of distribution and area under the concentration time curve over the dosing interval [AUC(0-24)].

Summary: Efficacy Results: For the primary efficacy comparison of mean change from baseline in daily trough PEF during treatment with GW685698X 100µg od a.m. with od p.m., a difference of 13.4L/min was observed, indicating that a.m. dosing with GW685698X 100µg was more effective (95%CI: 2.3, 24.4). However, an unexpectedly large increase in a.m. PEF in the placebo group indicated that not all the improvement observed in the GW685698X 100µg a.m. group was due to the study treatment. Therefore, although the primary comparison was defined as GW685698X 100µg a.m. vs p.m., the results were required to be assessed in the context of this placebo response. GW685698X 100µg a.m. showed the largest improvement from baseline in trough PEF (38.0L/min) compared with GW685698X 250µg p.m. (33.4L/min) or GW685698X 100µg p.m. (24.6L/min). However, when compared with placebo, GW685698X 250µg p.m. had a greater effect on trough PEF (24.6L/min; 95%CI: 13.6, 35.7; p<0.001) than GW685698X 100µg a.m. (19.2L/min; 95%CI: 8.2, 30.2; p<0.001). Trough PEF increased by 15.9L/min in the 100µg p.m. group compared with placebo (95%CI 4.9, 26.9; p=0.005). In this context, a.m. dosing with GW685698X 100µg showed a 3L/min benefit over p.m. dosing indicating that a.m. and p.m. dosing were comparable for this endpoint. All GW685698X dosing regimens demonstrated significant improvements over placebo for all secondary efficacy endpoints (except withdrawals due to lack of efficacy, of which only three occurred). There was a trend to indicate that GW685698X 250µg p.m. had a greater effect on clinic-measured lung function parameters and symptom and rescue medication endpoints than GW685698X 100µg given either in the morning or evening. However the differences between the 250µg and 100µg dose groups were not significant and all three active treatments were statistically significantly better than placebo. Safety Results: The overall incidence of treatment-emergent adverse events was low and similar in all four treatment groups (AEs were reported by 26% subjects in the placebo and GW685698X 100µg p.m. group; 25% subjects in the GW685698X 100µg a.m. group and 23% subjects in the GW685698X 250µg p.m. group). Only three serious adverse events occurred (one subject in each of the GW685698X 100µg and placebo groups experienced worsening asthma and one subject in the GW685698X 100µg a.m. group experienced supraventricular arrhythmia), none of which were related to study treatment. All four treatment groups showed an increase in 24-hour urinary cortisol levels from baseline. There was a statistically significant


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Title: A randomised, double-blind, double-dummy, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GW685698X 100µg administered once daily either in the morning or the evening and GW685698X 250µg administered once daily in the evening all administered by inhalation via DISKHALER™ for 28 days in subjects with persistent bronchial asthma reduction in 24-hour urinary cortisol excretion level relative to placebo of 17% (21% when corrected for creatinine) with GW685698X 250µg. However, there were no downward shifts relative to the normal range and after 4 weeks treatment no subjects in the active treatment groups had urinary cortisol values below the normal range. There were no reductions relative to placebo in either of the GW685698X 100µg groups.

Pharmacokinetic Results: GW685698X plasma concentration-time data were well described by a two compartment model with first order absorption and elimination. Only body weight was a significant demographic covariate on the estimate of apparent clearance. None of the demographic covariates showed a relevant effect on the apparent volume of distribution.

Conclusions:

The findings of this study indicate that treatment with GW685698X once daily was well-tolerated and effective in the treatment of persistent asthma. Although the pre-defined primary comparison appeared to demonstrate greater efficacy of morning dosing over evening dosing, the large morning placebo response needs to be considered. Comparisons of each active dose with placebo is of greater statistical validity in these circumstances and these comparisons for the primary endpoint indicated only a small improvement (approximately 3L/min) in the 100µg a.m. group compared with the 100µg p.m. group . Other efficacy endpoints demonstrated equally small numerical differences between the 100µg a.m. and p.m. groups, with some endpoints showing higher values in the a.m. group and some in the p.m. group.

All three active treatments were well tolerated and there was no evidence of a dose-related increase of any reported adverse event. 24-hour urinary cortisol levels increased in all four treatment groups, which was not anticipated and cannot be adequately explained. Although there was a significant decrease in 24-hour urinary cortisol values in the GW685698X 250µg p.m. group compared with placebo, it is difficult to interpret, because levels at Week 4 actually increased from baseline. This is further supported by the fact that no subject in the GW685698X 250µg p.m. group had a value for 24-hour urinary cortisol excretion that was below the lower limit of the normal range. Taken together, these data suggest that there was no occurrence of reduction in 24-hour urinary cortisol excretion during the study.

Therefore GW685698X given once daily at a dose of 100µg in the morning or evening is a well-tolerated and effective new treatment for persistent asthma and there is no conclusive evidence of superior efficacy or safety relative to the time of dosing. There is some evidence to indicate that efficacy was greater with GW685698X 250µg compared with GW685698X 100µg dosed in the morning or evening.

Date of Report: June 2005


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TABLE OF CONTENTS

Page1. ETHICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

1.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) . 151.2. Ethical Conduct of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151.3. Subject Information and Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE . . . . . . . . . . . 15

3. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

4. STUDY OBJECTIVE(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174.1. Study Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

4.1.1. Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174.1.2. Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174.1.3. Other Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

4.2. Study Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184.2.1. Primary Endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184.2.2. Secondary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

5. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205.1. Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5.1.1. Overall Study Design Description . . . . . . . . . . . . . . . . . . . . . . . . . . . 205.1.2. Discussion of Study Design, Including the Choice of Control

Group(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225.2. Protocol Amendment(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235.3. Selection of Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

5.3.1. Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235.3.2. Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245.3.3. Predetermined Criteria for Subject Withdrawal . . . . . . . . . . . . . . . . . 26

5.4. Investigational Product(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265.4.1. Description of Investigational Product(s) . . . . . . . . . . . . . . . . . . . . . . 265.4.2. Dosages and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275.4.3. Dose Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285.4.4. Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285.4.5. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295.4.6. Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295.4.7. Treatment of Investigational Product Overdose . . . . . . . . . . . . . . . . 29

5.5. Prior and Concomitant Medications and Non-Drug Therapies . . . . . . . . . . . 295.5.1. Permitted Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295.5.2. Prohibited Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305.5.3. Medical Device(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305.5.4. Non-drug Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31


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5.6. Study Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315.6.1. Demographic and Baseline Assessments . . . . . . . . . . . . . . . . . . . . . 315.6.2. Efficacy Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315.6.3. Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345.6.4. Pharmacokinetic Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395.6.5. Pharmacogenetic Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

5.7. Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405.8. Data Analysis Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

5.8.1. Timings of Planned Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415.8.2. Sample Size Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425.8.3. Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435.8.4. Treatment Comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435.8.5. General Considerations for Data Analyses . . . . . . . . . . . . . . . . . . . . 435.8.6. Data Handling Conventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445.8.7. Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495.8.8. Efficacy Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515.8.9. Safety Analyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555.8.10. Extent of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555.8.11. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555.8.12. Deaths and Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . 565.8.13. Clinical Laboratory Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565.8.14. Other Safety Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565.8.15. Pharmacokinetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575.8.16. Pharmacokinetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585.8.17. Pharmacokinetic/Pharmacodynamic Analyses . . . . . . . . . . . . . . . . 615.8.18. Pharmacogenetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

6. STUDY POPULATION RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636.1. Disposition of Subjects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636.2. Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646.3. Populations Analysed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656.4. Demographics and Other Baseline Characteristics . . . . . . . . . . . . . . . . . . . 65

6.4.1. Demographic Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656.4.2. Baseline Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666.4.3. Other Current Medical Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . 686.4.4. Previous Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

6.5. Concomitant Medications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696.5.1. Concomitant Asthma Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . 696.5.2. Concomitant Non-Asthma Medications . . . . . . . . . . . . . . . . . . . . . . . 70

7. EFFICACY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717.1. Primary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71


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7.1.1. 24-hour Duration of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737.1.2. Trough PEF (Per Protocol Population) . . . . . . . . . . . . . . . . . . . . . . . 747.1.3. Trough PEF for Treatment Weeks 1, 2, 3 and 4 . . . . . . . . . . . . . . . . 747.1.4. Results of Covariate Analyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757.1.5. Trough PEF by Baseline Asthma Severity . . . . . . . . . . . . . . . . . . . . 76

7.2. Secondary Efficacy Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767.2.1. Morning PEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767.2.2. Evening PEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767.2.3. Change from Baseline in Pre-bronchodilator FEV1 . . . . . . . . . . . . . . 777.2.4. Change from Baseline in Pre-Bronchodilator Clinic Visit PEF . . . . . . 787.2.5. Asthma Symptom Scores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787.2.6. Rescue Medication Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807.2.7. Withdrawals Due to Lack of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . 827.2.8. Summary of Efficacy Endpoints. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

7.3. Efficacy Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

8. SAFETY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 848.1. Extent of Exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 848.2. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

8.2.1. Pre-Treatment Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 848.2.2. Treatment-Emergent Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . 848.2.3. Post-Treatment Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858.2.4. Treatment-Emergent Adverse Events Related to Study Treatment . 86

8.3. Serious Adverse Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868.3.1. Fatal Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868.3.2. Non-Fatal Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868.3.3. Adverse Events Leading to Premature Discontinuation of

Investigational Product and/or Study . . . . . . . . . . . . . . . . . . . . . . . . 878.4. Pregnancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878.5. Clinical Laboratory Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

8.5.1. 24 hour Urinary Cortisol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878.5.2. Urinary Cortisol Over Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878.5.3. Individual Subject Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

8.6. Other Safety Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898.6.1. Haematology/Clinical Biochemistry Assessments . . . . . . . . . . . . . . . 898.6.2. Urinalysis (Local Analysis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 908.6.3. ECG Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 908.6.4. Oropharyngeal Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 908.6.5. Vital Signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

8.7. Medical Device Incidents, Near-Incidents, Malfunctions and RemedialAction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

8.8. Safety Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91


9

9. PHARMACOKINETIC RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939.1. GW685698X Pharmacokinetic Parameters . . . . . . . . . . . . . . . . . . . . . . . . . 939.2. Pharmacokinetic Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

10. PHARMACOKINETIC/PHARMACODYNAMIC RESULTS . . . . . . . . . . . . . . . . . 9710.1. Pharmacokinetic/Pharmacodynamic Conclusions . . . . . . . . . . . . . . . . . . . 97

11. DISCUSSION AND CONCLUSIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9811.1. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9811.2. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

12. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

13. CASE NARRATIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10413.1. Serious Adverse Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10413.2. Adverse Events Leading to Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . 10613.3. Pregnancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

STUDY POPULATION DATA SOURCE TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

EFFICACY DATA SOURCE FIGURES AND TABLES . . . . . . . . . . . . . . . . . . . . . . . 163

SAFETY DATA SOURCE FIGURES AND TABLES . . . . . . . . . . . . . . . . . . . . . . . . . 206

ATTACHMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505Attachment 1 - PK Tables and Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505Attachment 2 - Listings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522


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LIST OF FIGURES

PageFigure 1 Change from Baseline in Trough PEF (ITT Population) . . . . . . . . . . . . . . . 73Figure 2 Trough and 24-Hour Changes from Baseline in PEF . . . . . . . . . . . . . . . . . 74


11

LIST OF TABLES

PageTable 1 Time and Events Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Table 2 Subject Disposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63Table 3 Reasons for Withdrawal after Randomisation (ITT Population) . . . . . . . . . . 64Table 4 Summary of Demographic Characteristics (ITT Population) . . . . . . . . . . . . . 66Table 5 Summary of Baseline Clinic Lung Function (ITT Population) . . . . . . . . . . . . 67Table 6 Baseline Diary Card Pulmonary Function Data (ITT Population) . . . . . . . . . 68Table 7 Summary of Non-Asthma Medication taken by Greater than or equal to

5% Subjects in any Treatment Group during the Treatment Period (ITTPopulation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Table 8 Analysis of Change from Baseline in Trough PEF (Weeks 1-4) (ITTpopulation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Table 9 Change from Baseline in Trough PEF (ITT Population) . . . . . . . . . . . . . . . . 75Table 10 Analysis of Clinic Visit FEV1 (Change from Baseline at Endpoint) (ITT

Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77Table 11 Analysis of Clinic Visit PEF (Change from Baseline at Endpoint) (ITT

Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78Table 12 Summary of Changes from Baseline (Treatment Differences from

Placebo) in Efficacy Endpoints (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . 82Table 13 Overall Incidence of Adverse Events (Safety population) . . . . . . . . . . . . . . 84Table 14 Summary of the Most Common Treatment-Emergent Adverse Eventsa

(Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85Table 15 Summary of Statistical Analysis of 24-hour Urinary Cortisol Values (with

and without Correction for Creatinine) (Safety Population) . . . . . . . . . . . . . . . . 88Table 16 Population pharmacokinetic parameters for GW685698X in asthmatic

patients No Imputation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Table 17 Population pharmacokinetic parameters for GW685698X in asthmatic

patients Imputation 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95Table 18 GW685698X Pharmacokinetic Parameters in Asthmatics Administered

Repeat Inhaled Doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96


12

Abbreviations

AE Adverse Event a.m. ante meridien (before noon) ANCOVA Analysis of Covariance ATC Anatomical Therapeutic Classification AUC Area under the curve BDS Biomedical Data Sciences CI Confidence Interval cm Centimetre CPDM Clinical Pharmacology and Discovery Medicine CRF Case Report Form CYP Cytochrome P450 ° C Degrees Celsius DNA Deoxyribonucleic Acid DRC Daily Record Card ECG Electrocardiogram EDTA Ethylene Diamine Tetraacetic Acid EISR Expedited Investigator Safety Report FEV1 Forced Expiratory Volume in 1 Second FP Fluticasone Propionate GCO Global Clinical Operations GCP Good Clinical Practice G/dL Grams/Decilitre GI/L Giga/Litre GINA Global Initiative for Asthma GP General Practitioner GSK GlaxoSmithKline GCSP Global Clinical Safety and Pharmacovigilance HPA Hypothalamic-Pituitary-Adrenal hr Hour HVTs Human Volunteers IB Investigator’s Brochure ICH GCP International Code on Harmonisation of Good Clinical

Practice ICS Inhaled Corticosteroid IEC Independent Ethics Committee IRB Institutional Review Board ITT Intent-To-Treat IVRS Interactive Voice Recognition System L Litre LOCF Last Observation Carried Forward L/min Litres/minute LLN Lower Limit of Normal Range µg microgram µmol/L Micromol/L MDI Metered Dose Inhaler MRHA Medicines and Healthcare Products Regulatory Agency


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MedDRA Medical Dictionary for Regulatory Affairs mL millilitre mmol/L Millimole/Litre NCE New Chemical Entity NONMEM Non-linear mixed effects modelling od Once-daily PC20 Concentration of AMP resulting in a 20% fall in FEV1 PD Pharmacodynamic PEF Peak Expiratory Flow Pg/mL Picograms/millilitre PGx Pharmacogenetics PK Pharmacokinetics p.m. post meridian (after noon) PP Per Protocol QC Quality Control RAP Reporting and Analysis Plan RR Reference Range SABA Short-acting β-agonist SAE Serious Adverse Event SCA Standard Clarification Agreement SCAD System for Central Allocation of Drug SNP Single Nucleotide Polymorphism TED Transformer for External Data ULN Upper Limit of Normal Range vs versus

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

DISKHALER ClinTrial ROTADISK DISKUS/ACCUHALER VENTOLIN SERETIDE SEREVENT


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1. ETHICS

1.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB)

The study protocol, and amendments, the informed consent, and other information that required pre-approval were reviewed and approved by a national, regional, or investigational centre ethics committee or institutional review board.

1.2. Ethical Conduct of the Study

This study was conducted in accordance with "good clinical practice" (GCP) and all applicable regulatory requirements, including, where applicable, the 1996 version of the Declaration of Helsinki.

1.3. Subject Information and Consent

Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. Case report forms were provided for each subject’s data to be recorded.

2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

This study was conducted in 12 countries (Bulgaria, Chile, Croatia, Estonia, Germany, Greece, Hungary, Italy, Mexico, Romania, Russian Federation and South Africa). A total of 63 centres were used, of which 62 centres contributed subjects to the Intent-to-Treat (ITT) population. Subjects were recruited by their general practitioner (GP), or were hospital out-patients.

The study administration was performed by GSK in all countries. A System for Central Allocation of Drug (SCAD) using an Interactive Voice Response System (IVRS) was used for treatment allocation and management of supplies. Data management, including data processing and database release was performed by GSK.

The clinical study report was written by (GCO, Respiratory), (BDS) and (CPDM).


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3. INTRODUCTION

Asthma is a chronic disease of the lungs characterised by airway inflammation, bronchoconstriction and increased airway responsiveness. Inhaled corticosteroids (ICS) are considered the most effective anti-inflammatory treatments for all severities of persistent asthma [British Thoracic Society, 1997; National Institutes of Health, 2002]. The benefits of ICS include control of asthma symptoms, improvement in lung function, decrease in airway hyper-responsiveness and possibly, prevention of airway wall remodelling [Pedersen, 1997].

GW685698X is a novel glucocorticoid currently under development as an inhaled treatment for asthma. Pre-clinical data and Phase I studies indicate that GW685698X may have a longer duration of action than fluticasone propionate (FP) and is therefore suitable for development for once daily administration. The availability of a once daily corticosteroid would be expected to improve compliance and therefore improve asthma control. Furthermore, if the molecule is retained in the lung rather than in the systemic circulation, it may give rise to a reduction in the dose required with corresponding improvement in the therapeutic index compared with other available inhaled corticosteroids.

The toxicity of GW685698X has been assessed following single and repeated administration for up to 4 weeks. Safety pharmacology and genetic toxicology have also been evaluated. To date, the compound has exhibited a pharmacological/toxicological profile expected for a corticosteroid and no unexpected safety signals have been identified.

The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of increasing single, inhaled doses of a dry powder formulation of GW685698X have been evaluated in healthy volunteers (HVTs) in studies FFA10001, FFA10003 and FFA10008. Doses up to 4000 µg were given, and the maximum tolerated dose was not reached. Once daily, repeat, inhaled doses of GW685698X 500 µg, 1000 µg, and 2000 µg have been evaluated in a 14-day safety, tolerability and PK/PD study (FFA10002). GW685698X has been found to have a good safety profile and was well tolerated in these completed studies to date. No serious adverse events (SAEs) were reported, and the majority of adverse events (AEs) were mild in intensity. There were no clinically significant changes in safety laboratory parameters, electrocardiogram (ECG) results, heart rate or systolic and diastolic blood pressure reported. Lung function evaluations (performed for safety purposes in these studies) showed no indication of any treatment- or dose-related adverse effects on peak expiratory flow (PEF).

The effect of GW685698X on serum cortisol was investigated following single- and repeat-inhaled doses from 500 µg to 2000 µg once daily for 14 days. Significant reductions in serum cortisol were seen after single doses of 1000 µg and 2000 µg. Reductions of 40%, 81%, and 94% in mean serum cortisol were seen after repeat dosing of 500, 1000, and 2000 µg GW685698X, respectively, in comparison with placebo.

For ICS, the timing of the dose may be an important consideration for a product administered once daily. Afternoon or early evening single daily dosing tends to be


16

superior in efficacy to a morning-only dosing schedule [Gagnon, 1994; Pincus, 1995]. It has also been suggested that the timing of ICS administration may be an important factor in relation to steroid interruption of the inflammatory cascade associated with the nocturnal symptoms of asthma.

ICS are generally devoid of harmful side effects especially when given at low to moderate doses (Global Initiative For Asthma (GINA)) [National Institutes of Health, 2002]. Even in subjects with severe asthma, where there is a need for higher doses, the benefits far outweigh the risks. Studies of adrenocortical suppression with once daily dosing of ICS have not found significant effects (except with high doses) [Wilson, 1998]. Studies do not appear to indicate that time of administration plays a role in determining the safety profile of an IC. However, PK and pharmacodynamic (PD) modelling suggests inhalation of a corticosteroid in the afternoon may have a less significant effect on cortisol suppression than a dose taken in the morning; the optimum time point being determined by the terminal elimination half-life of the drug. For FP, the optimum time is 15.00h and for flunisolide 19.00h [Meibohm, 1997].

The primary objective of this study was to evaluate the effect of time of administration (morning versus evening) on the mean change in daily trough PEF over the 28-day treatment period. Secondary objectives were to assess the effect of time of dosing on safety and other efficacy parameters, and the safety and efficacy of GW685698X compared with placebo. Effects on the hypothalamic-pituitary-adrenal (HPA)-axis (24-hour urinary cortisol) and population PK were evaluated. The higher dose of 250 µg GW685698X was included to provide useful dose response information.

4. STUDY OBJECTIVE(S)

4.1. Study Objectives

4.1.1. Primary Objective

To evaluate the effect of time of dosing (morning vs. evening) of GW685698X 100µg once daily, administered by inhalation via DISKHALER™ on the mean change in daily trough (pre-study treatment and pre-bronchodilator) PEF during the 28-day treatment period.

4.1.2. Secondary Objectives

To compare the efficacy of GW685698X 250µg once daily with GW685698X 100µg once daily, both administered in the evening.

To compare the safety and tolerability of GW685698X 250µg once daily, with GW685698X 100µg once daily both administered in the evening.

To compare the efficacy and safety of the three GW685698X treatment regimens with placebo.


17

To evaluate the effect of time of dosing (morning vs. evening) on the safety and tolerability of 100µg GW685698X once daily.

4.1.3. Other Objectives

To characterise the population PK of GW685698X in subjects with persistent asthma.

If at any time it appears there is potential variability in GW685698X response or handling (e.g., PK, safety, and/or efficacy) in this clinical study or in a series of clinical studies, the following objectives may be investigated (assuming sample number is adequate and the availability of genotyping assays):

Relationship between genetic variants and the PK of GW685698X

Relationship between genetic variants and safety and/or tolerability of GW685698X

Relationship between genetic variants and efficacy of GW685698X

4.2. Study Endpoints

4.2.1. Primary Endpoint

Mean change from baseline in daily trough (pre-study treatment and pre-bronchodilator) PEF (recorded in the daily record card (DRC)) during the 28-day treatment period with GW685698X 100µg once daily in the morning compared with GW685698X 100µg once daily in the evening by inhalation via DISKHALER.

4.2.2. Secondary Endpoints

Efficacy

• Mean change from baseline in daily trough (pre-study treatment and pre-bronchodilator) PEF (recorded in the DRC) during the 28-day treatment period with GW685698X 250µg once daily compared with GW685698X 100µg once daily both administered in the evening by inhalation via DISKHALER.

• Mean change from baseline in daily trough (pre-study treatment and pre-bronchodilator) PEF (recorded in the DRC) during the 28-day treatment period with GW685698X 100µg once daily in the morning, 100µg once daily in the evening, or GW685698X 250µg once daily in the evening, compared with placebo.

• Mean change from baseline in morning PEF (pre-study treatment and pre-bronchodilator). This endpoint was not specified in the protocol but prior to production of the Reporting and Analysis Plan (RAP), it was decided that it would be of significant interest in investigation of the secondary study objectives.

• Mean change from baseline in evening PEF (pre-study treatment and pre-bronchodilator). This endpoint was not specified in the protocol but prior to


18

production of the Reporting and Analysis Plan (RAP), it was decided that it would be of significant interest in investigation of the secondary study objectives.

• Change from baseline in pre-bronchodilator clinic lung function (forced expiratory volume in 1 second [FEV1] and PEF) after 28 days of treatment with GW685698X 250µg once daily in the evening compared with GW685698X 100µg once daily in the evening, and GW685698X 100µg a.m. compared with GW685698X 100µg p.m.

• Change from baseline in pre-bronchodilator clinic lung function (FEV1 and PEF) after 28 days of treatment with GW685698X 100µg once daily in the morning, 100µg once daily in the evening, or GW685698X 250µg once daily in the evening, compared with placebo.

• Comparison of the following asthma symptom scores were made during the 28-day treatment period, as assessed from the DRC, between GW685698X 100µg once daily administered in the evening and in the morning; between GW685698X 250µg once daily administered in the evening and GW685698X 100µg in the evening; and between all active treatments compared with placebo:

• Percentage of symptom-free 24-hour periods, symptom-free days and symptom-free nights.

• Percentage of VENTOLIN™ (salbutamol)-free 24-hour periods, days, and nights.

• Percentage of nights with no awakenings.

• Withdrawals due to lack of efficacy (i.e., Section 5.6.2.5 “Withdrawal Due to Lack of Efficacy”) during the 28-day treatment period with each GW685698X treatment group compared with placebo.

Safety

• Incidence of AEs throughout the 28-day treatment period.

• Examination of oropharynx at clinic visits for candidiasis.

• Haematology, clinical chemistry and dipstick urinalysis parameters before and after 28 days of treatment.

• 24-hour urine cortisol assessment before and after 28 days of treatment.

• 12-lead ECG before and after 28 days of treatment.

• Examination of vital signs at clinic visits.

Other

• Characterisation of subject population PK of GW685698X in subjects with persistent asthma following 250µg or 100µg once daily treatment for 28 days.


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5. INVESTIGATIONAL PLAN

5.1. Study Design

5.1.1. Overall Study Design – Description

This was a Phase IIa randomised, double-blind, double-dummy, placebo-controlled, parallel-group, multi-centre study. Subjects who fulfilled the preliminary inclusion criteria were entered into a one-week run-in period. After one week, eligibility for randomisation to treatment was assessed. Subjects who did not fulfil the eligibility criteria for entry into the treatment period at this point could repeat the run-in up to two times. Therefore the run-in period was of between one and three weeks duration. Subjects who did not fulfil the eligibility criteria after the third one-week run-in period were withdrawn. Subjects who fulfilled the post run-in eligibility criteria for inclusion in the treatment phase, were randomised to receive study treatment for four weeks, during which time they attended clinic visits at the end of each of the four weeks. There was a follow-up period of one week after completion of the treatment period. Subjects therefore participated in the study for between six and eight weeks. A schedule of the assessments made at each clinic visit is given in Table 1.

Male and female subjects were eligible to be included in the run-in period if they were aged between 16 and 55 years inclusive and had a documented history of persistent asthma diagnosed at least six months prior to Visit 1. In addition subjects were required to be currently receiving inhaled short-acting β2-agonists (SABA) alone and to demonstrate a baseline Peak Expiratory Flow (PEF) of 50 –90% of their predicted normal value. In addition subjects were required to demonstrate an increase from their baseline PEF value of ≥ 15%, 20 minutes after inhaling 400µg salbutamol at Visit 1 or subsequent run-in Visits 1a or 1b. Subjects who had received inhaled or intranasal corticosteroids within four weeks of Visit 1 or systemic, oral, parenteral or depot corticosteroids within eight weeks of Visit 1 were not eligible for inclusion in the run-in. Subjects were treated on an out-patient basis.


20

Table 1 Time and Events Schedule

Screening visit (start of run-in period) Treatment period Follow-up

Visit Number 1/1a/1b 2 3 4 5 6 7 Weeks -3 to -1 0 1 ± 2 days 2 ± 2 days 3 ± 2 days 4 ± 2 days 5 ± 2 days Informed Consent X b Demographics X b History of Asthma and Concomitant Conditions X b Physical Examination X b X Xe Vital Signs X X X X X X Xe Haematology/Biochemistry/dipstick Urinalysis X b X Xe Urine Pregnancy Testing X X X 12-lead electrocardiogram X b X Xe Clinic measured Pulmonary Function X c X X X X X Xe Pharmacokinetics Blood Samples a X X X Pharmacogenetics Blood Samples X b Adverse Event Monitoring X X X X X X Concomitant Medication Monitoring X X X X X X X Examination of Oropharynx X X X X X X X 24 hr Urine collection for Cortisol Assessments X X Issue Rescue VENTOLIN X Xd Xd Issue Daily Record Card X X X X X Issue Study Medication X Collect used Rescue VENTOLIN X X Xf Collect Completed Daily Record Card X X X X X X Xf Collect Used Study Medication (Blister Packs) X X X X Xf Check Subjects Taking Correct Medication X X X X a. samples were only collected at centres with appropriate facilities; b. The assessments indicated were performed at Visit 1 only, and were not repeated at Visits 1a and 1b; c. Clinic lung function tests (FEV1 and PEF) were to be performed at Visits 1, 1a, and 1b. Reversibility needed only to be performed once during the screening period to meet the

criterion; d. If required; e. Tests only needed to be performed if abnormal at Visit 6; f. If subject did not to return VENTOLIN, study medication, or daily record card at Visit 6 the subject was to return it at Visit 7.

CO

NFID

ENTIA

LG

M2004/00341/00

FFA20001

21

On entry to the run-in, subjects had their usual short-acting β2-agonists stopped and inhaled salbutamol (VENTOLIN) via a MDI or DISKUS™/ACCUHALER™ was provided for symptomatic relief during the run-in and treatment period. On entry to the treatment period, eligible subjects were randomly assigned in a 1:1:1:1 ratio to receive either GW685698X 100µg once daily in the morning and placebo in the evening, GW685698X 100µg once daily in the evening and placebo in the morning, GW685698X 250µg once daily in the evening and placebo in the morning, or placebo in the morning and evening. All treatments were given via DISKHALER and four-place ROTADISKS.

Paper Daily Record Cards (DRC) were used throughout the run-in and treatment periods. Subjects were asked to enter information in the DRC each morning and evening. Clinic visits took place at the beginning of the run-in (Visit 1) and one week later. If, at this visit, the subject had fulfilled the criteria for entry into the treatment period the subject was randomised to treatment (Visit 2), otherwise the run-in was restarted (Visit 1a). One week later the subject was reassessed and either entered to treatment (Visit 2) or the run-in restarted (Visit 1b). After randomisation to treatment, clinic visits took place after one week (Visit 3), 2 weeks (Visit 4), 3 weeks (Visit 5) and at 4 weeks at the end of the treatment period (Visit 6). A Follow-Up appointment was made (Visit 7) one week after the end of the treatment period. The permitted flexibility around the due date of each clinic visit was ± 2 days.

5.1.2. Discussion of Study Design, Including the Choice of Control Group(s)

The primary purpose of this study was to estimate the difference in the effect of GW685698X 100µg given once daily in the morning and given once daily in the evening on trough PEF. PEF was selected as the primary efficacy endpoint because it is simple to measure on a daily basis in a clinical trial environment and causes little inconvenience to the subject. PEF is recognised as an appropriate objective measurement of lung function, and is recommended by international guidelines [GINA, 1998] for both the diagnosis and monitoring of asthma. Trough values were chosen as the primary endpoint as an appropriate measure of a drug with a 24-hour duration of action. The standard deviation of trough PEF has been estimated at 40L/min based on morning and evening PEF values observed in previous asthma studies. Therefore the required study population was estimated to be 123 subjects in each of the treatment groups to ensure that the width of the 95% confidence interval for the treatment effect was no larger than 20L/min.

The study population was designed to include subjects with persistent asthma and to cover a spectrum of mild to moderate asthmatics. Therefore the eligibility criteria facilitated recruitment of subjects whose pre-study lung function ranged from 50-90% of normal predicted values for PEF and who were able to demonstrate reversibility of ≥ 15% after inhalation of 400µg salbutamol. The study population included male and female subjects aged 16-55 years inclusive. The exclusion to recruitment of older subjects was made to restrict the inclusion of subjects who may have had an increased incidence of concurrent pathophysiologies that may have influenced the study results.


22

Placebo was used as the control in this study in order to establish the magnitude of effect of the new chemical entity (NCE), GW685698X, on efficacy and safety parameters which has not yet been evaluated in this population of asthmatic subjects. In addition, the inclusion of a placebo limb facilitated variability in 24-hour urinary cortisol excretion values to be ascertained for comparison against the active groups.

A treatment period of 4 weeks was selected as an appropriate duration to observe changes in pulmonary function from baseline and to allow for differences between treatments to be seen. A 4-week treatment period also minimised exposure to GW685698X, while allowing dose-ranging effects of the 100µg and 250µg to be observed. In addition a 4-week treatment period also minimised exposure to placebo in this study population in whom regular treatment with ICS is indicated.

5.2. Protocol Amendment(s)

Four country-specific protocol amendments were made to the protocol. Amendment No. 1 (GM2003/00336/01) applied to Germany only, and restricted the age of eligible subjects to 18-55 years in line with local ethics and regulatory requirements. Amendment No. 2 (GM2003/00336/02) applied to Italy only, and excluded subjects in Italy from participation in the pharmacogenetics sub-study. Amendment No. 3 (GW2003/00336/03) applied to Bulgaria only, and restricted the age of eligible subjects to 18-55 years in line with local regulatory requirements. Amendment No. 4 (GM2003/00336/04) applied to Greece only, and excluded subjects in Greece from participation in the pharmacogenetics sub-study.

5.3. Selection of Study Population

Subjects were recruited at GP clinics or hospital out-patient clinics for this study.

5.3.1. Inclusion Criteria

Subjects were eligible for inclusion in the run-in period if all of the following criteria applied:

1. Male or females aged 16 to 55 years inclusive.

2. Females were eligible to enter and participate in the study if they were of:

a. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who is post-menopausal. For the purposes of this study, post-menopausal was defined as 1 year without menses; or

b. Child-bearing potential, had a negative pregnancy test (urine) at entry, and agreed to take contraceptive precautions which were adequate to prevent pregnancy during the trial

3. Subjects who had a documented clinical history of persistent asthma first diagnosed at least 6 months prior to Visit 1.


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4. Subjects who were currently receiving inhaled short-acting β2-agonists for symptom relief.

5. Subjects who were able and willing to give written informed consent to take part in the study.

6. Subjects who were able to comply with all the study requirements.

7. Subjects who could demonstrate lung function of between 50 to 90% predicted (PEF).

8. Subjects who could demonstrate an increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol (if patients did not fulfil this criteria at Visit 1, the test could be repeated at visit 1a/1b/2).

At the end of the run-in period subjects were required to fulfil the following additional criteria from DRC recordings in order to enter the treatment period of the study:

1. Subjects who could demonstrate an increase in PEF of ≥15% 20 minutes after inhalation of 400µg salbutamol, if not demonstrated at Visit 1.

2. Subjects who could demonstrate a mean morning PEF (calculated from the last 7 consecutive days of the final run-in period) of between 50% and 80% of their percent predicted normal.

3. Subjects who could demonstrate a daily asthma symptom score (day-time plus night-time) of >1 on at least four of the last 7 consecutive days of the final run-in period.

Additional Inclusion Criteria for Pharmacogenetic Study

Any subject who gave informed consent to participate in the clinical study, had met all the criteria required for entry into the clinical study, and received investigational product could take part in the PGx research. Any subject who had received a bone marrow transplant was excluded from the PGx research.

Subject participation in the PGx research was voluntary and refusal to participate did not indicate withdrawal from the clinical study. Refusal to participate involved no penalty or loss of benefits to which the subject was otherwise be entitled. No administration of investigational product beyond that detailed in the clinical study was associated with the PGx research. Employees of GSK enrolled in the clinical study were not eligible for participation in disease-based diagnostic research.

5.3.2. Exclusion Criteria

A subject was not eligible for inclusion in the run-in period for this study if any of the following criteria applied:

1. Subjects who had a history of respiratory tract infection and/or exacerbation of asthma within 4 weeks prior to Visit 1.

2. Subjects who had a history of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnoea, respiratory arrest or hypoxia seizures.


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3. Subjects who had a history of two or more asthma exacerbations requiring treatment with oral corticosteroids or hospitalisation in the 6 months before Visit 1.

4. Subjects who were previously enrolled in this study, or who were currently participating or had participated in another study during the previous 3 months.

5. Subjects who had past or current disease that, as judged by the investigator, may have affected the outcome of this study. These diseases included, but were not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematologic disease, neurological disease, endocrine disease or pulmonary disease (including, but not confined to, chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis and bronchopulmonary dysplasia).

6. Subjects who had known or suspected sensitivity to corticosteroids, VENTOLIN, or the constituents of ROTADISKS (e.g., lactose).

7. Subjects who were undergoing allergen desensitisation therapy.

8. Subjects who were likely to be non-compliant with study medication and other study-related requirements (e.g., attendance at clinic visits or completion of DRCs).

9. Subjects who had neurological or psychiatric disease or history of drug or alcohol abuse that would have interfered with the subject’s proper completion of the protocol requirements.

10. Subjects who were current smokers or had a smoking history of 10 pack years or more (e.g., 20 cigarettes/day for 10 years). Note: Current smoker was defined as currently smoking or stopped smoking within 6 months of screening visit.

11. Subjects who were receiving any of the following medications:

Theophyllines, oral β2-agonists, slow-release bronchodilators, anticholinergics, long-acting β2-agonists, or ketotifen, within 2 weeks prior to Visit 1.

Inhaled or intranasal corticosteroids, anti-leukotrienes, combination therapy, or cytochrome P450 (CYP) 3A4 inhibitors within 4 weeks prior to Visit 1

Systemic, oral, parenteral or depot corticosteroids within 8 weeks prior to Visit 1.

At the end of the run-in period subjects were not eligible to enter the treatment period of the study if they met any of the following criteria:

1. Subjects who had evidence of clinically significant abnormality in the haematological, biochemical or dipstick urinalysis screen, or 12-lead ECG at Visit 1.

2. Subjects who had had changes in asthma medication (excluding rescue VENTOLIN provided at Visit 1).

3. Subjects who had had an upper or lower respiratory tract infection during the run-in period.

4. Subjects who had had an exacerbation of asthma symptoms during the run-in period.

5. Subjects who had not been compliant with completion of the DRC; the DRC had to have been completed for 6 out of last 7 days prior to Visit 2 to confirm compliance.


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5.3.3. Predetermined Criteria for Subject Withdrawal

5.3.3.1. Subject withdrawal from the investigational product

Randomised subjects who did not complete the four-week treatment period up to and including Visit 6 were considered to have withdrawn from the investigational product. If a subject permanently discontinued the study drug at any time, they were withdrawn from the study and the date of stopping study medication and the reason for discontinuation were recorded in the CRF. Possible reasons for withdrawal included:- an AE; asthma exacerbation; non-compliance; lack of efficacy; abnormal laboratory results; social reasons; or if it was detrimental for the subject to continue in the study.

Subjects who prematurely discontinued study drug for whatever reason could not be re-entered into the study and were not replaced.

5.3.3.2. Subject withdrawal from the study

Premature discontinuation from the study occurred when a subject discontinued prior to the completion of the 28-day treatment period and 1 week follow-up period, either voluntarily or was withdrawn by the investigator. Subjects could voluntarily discontinue participation in the study at any time. The investigator could also, at his or her discretion, discontinue a subject from participating in this study at any time. If a subject was prematurely discontinued from participation in the study for any reason, the investigator made every effort to perform the following evaluations: - measurement of PEF and FEV1; review of AEs and changes in medication; collection of blood and urine samples for laboratory assessments; ECG; oropharyngeal examination; and prescription of appropriate asthma medication.

The date of withdrawal, reason for withdrawal and all post-treatment assessments were documented in the relevant section of the CRF. If a subject failed to return to the clinic for a scheduled visit, the investigator attempted to contact the subject by telephone or letter. If the subject could be contacted the investigator completed the end of study record section of the CRF and recorded that the subject was lost to follow-up. Subjects who were prematurely discontinued from the study for whatever reason were not be re-entered or replaced.

If a subject who had consented to participate in PGx research withdrew from the clinical study for any reason other than lost to follow-up, the subject was asked to choose either to permit the PGx research to continue or have any remaining samples destroyed.

5.4. Investigational Product(s)

5.4.1. Description of Investigational Product(s)

The Clinical Trials Supplies Department of GSK Research and Development supplied the following study drugs and devices:


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GW685698X ROTADISK™ (4-blister) 100µg per dose. Batch number: AX7048/001

GW685698X ROTADISK (4-blister) 250µg per dose. Batch number: AX6121/003

Placebo ROTADISK (4-blister). Batch number: AX2096/061

Placebo ROTADISK (4-blister) for demonstration purposes. Batch number: AX2096/059A

DISKHALER Batch number: SV13606

Subjects were issued with a treatment pack containing study medication, according to the randomisation schedule, at Visit 2. Subjects were asked to return their inhalers at the end of the treatment period, or at withdrawal, whether or not they had been used. The study medication was stored in a secure area by the investigator or authorised site staff in accordance with the investigational product-specific requirements. The study medications were stored at a temperature of 2 to 30°C.

VENTOLIN for use with the MDI or DISKUS/ACCUHALER was provided as rescue medication for symptomatic relief during the run-in and treatment periods. This was sourced locally from commercial stock by the local GSK operating company.

5.4.2. Dosages and Administration

GW685698X was administered via a dry powder inhaler device (DISKHALER), that contains a circular foil pack (ROTADISK) with 4 regularly distributed blisters, each containing a small quantity of blend of micronised GW685698X and lactose. Each blister contained approximately 25mg of drug/lactose blend providing either 100 or 250µg of GW685698X. These products were intended for oral inhalation.

The placebo medication was administered using the same delivery system as the study medication.

Subjects took one of the following four treatment regimens, according to the randomisation schedule:

• GW685698X 100µg once daily in the morning plus placebo in the evening.

• GW685698X 100µg once daily in the evening plus placebo in the morning.


• Placebo twice daily (in the morning and evening).

Subjects were advised to take the morning dose of study medication on waking, and to take their evening dose just before going to bed. They were also asked to take their morning and evening dose at approximately the same time each day (±2 hours).

Subjects were issued with study medication at Visit 2. All treatments were delivered by inhalation via the DISKHALER for a 28-day treatment period. Subjects were to make


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measurements of evening and morning PEF, and asthma symptoms before taking any study or rescue medication. On the day of the study visits subjects were to take their study medication as usual, but they were advised not to take rescue medication until the lung function tests have been performed at the clinic. If subjects did take any rescue medication the time taken was recorded in the DRC.

VENTOLIN was issued, as required, at Visits 1, 2 and 4.

5.4.3. Dose Rationale

The clinical doses of GW685698X in this study were based on the assumption that it had a similar potency to FP, but had a longer duration of effect due to longer lung retention time. It was anticipated that a 100µg dose of GW685698X once daily would have similar or greater efficacy than 100µg FP twice daily. A higher dose of GW685698X (250µg) was included to provide useful dose response information. Both doses were expected to demonstrate beneficial effects in terms of lung function and asthma control.

GW685698X has been shown to be well-tolerated in HVTs at doses up to 2000 µg for 14 days. In a repeat dosing study with once daily doses of GW685698X 500µg, volunteers experienced a reduction in plasma cortisol levels of around 40%. It was considered therefore that GW685698X doses of 100µg and 250µg would be well tolerated, and were appropriate for this study.

Data generated from this study should provide information on the potential benefits gained from the use of GW685698X and whether further development is warranted. The data will provide information on the appropriate doses for the definitive dose ranging studies in Phase IIB.

5.4.4. Blinding

The study was a double-blind study; both the investigators and the study subjects were blinded to study treatment. Central laboratory staff and local ECG readers were also blinded to study treatment.

Only in the case of an emergency, when knowledge of the investigational product was essential for the clinical management or welfare of the subject, could the investigator unblind a subject’s treatment assignment. If the blind was broken for any reason, the investigator was to notify GSK immediately of the unblinding incident without revealing the subject’s study treatment assignment. In addition, the investigator was to record the date and reason for revealing the blinded treatment assignment for that subject in the appropriate CRF.

If a SAE was reported to GSK, Global Clinical Safety and Pharmacovigilance (GCSP) staff may have unblinded the treatment assignment for the individual subject. If an expedited regulatory report to one or more regulatory agencies was required, the report identified the subject’s treatment assignment. When applicable, a copy of the regulatory report could be sent to investigators in accordance with relevant regulations, GSK policy, or both.


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Subjects whose blind was broken by the investigator were withdrawn from the study immediately

5.4.5. Treatment Assignment

Subjects were assigned to study treatment in accordance with the randomisation schedule, which was generated by GSK using the validated computerised randomisation system RandAll.

Each participating centre in this study was supplied with a list of subject numbers (assigned to each subject at Visit 1). Once the run-in had been completed successfully, eligible subjects were assigned to study treatment in accordance with the central randomisation schedule (Visit 2). Randomisation was centralised at the site level. A System for Central Allocation of Drug (SCAD) using an Interactive Voice Response System (IVRS) was used to allocate treatment packs. Details of the central drug allocation procedure using SCAD were outlined in a separate user manual that was provided to each investigator.

Once a treatment number had been assigned to a subject it could not be re-assigned to any other subject at that centre.

5.4.6. Assessment of Compliance

The returned blister packs were collected at each clinic visit during the treatment period and were used to assess compliance with the treatment regimen.

5.4.7. Treatment of Investigational Product Overdose

Very few data are available on overdose with GW685698X. However, during single dose studies with inhaled GW685698X, decreased mean serum cortisol was observed with doses of 500µg or higher. There are no medications or non-drug therapies recommended for treatment of an overdose. Management was to be supportive, and investigators were to use their clinical judgement in treating any overdose situation.

5.5. Prior and Concomitant Medications and Non-Drug Therapies

5.5.1. Permitted Medications

Asthma Medications

Short-acting β2-agonist asthma medications were permitted until Visit 1 only. At the end of Visit 1 VENTOLIN (for use with the MDI or DISKUS/ACCUHALER) was provided as rescue medication for symptomatic relief during the run-in and treatment periods of the study.

Sodium cromoglycate and nedocromil sodium were permitted, but had to have been taken at a constant dose for the 4 weeks prior to Visit 1 and throughout the study.


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Medication for Concomitant Disorders

All medications for other disorders could be continued throughout the study, provided the dose remained constant and their use was not expected to affect a subject’s lung function.

All concomitant medications taken during the study was recorded in the CRF with indication, dose information, and dates of administration.

5.5.2. Prohibited Medications

The following asthma medications were not permitted during the conduct of the study or within the specified time:

Within 2 weeks of Visit 1:

• Theophyllines.

• Oral β2-agonists (e.g., bambuterol).

• Slow-release bronchodilators.

• Anticholinergics.

• Long-acting β2-agonists (e.g., salmeterol).

• Ketotifen.


• Anti-leukotrienes including suppressers of leukotriene production and antagonists.

• Inhaled corticosteroids.

• Intranasal corticosteroids.

• Combination therapy (containing β2-agonists and/or inhaled corticosteroids for asthma).

• Known inhibitors of CYP 3A4 (e.g. ritonavir).


• Systemic, oral, parenteral or depot corticosteroids

5.5.3. Medical Device(s)

The DISKHALER is a medical device. Any instrument used to make a measurement while physically in contact with a subject is a device and the Medicines and Healthcare products Regulatory Agency (MHRA) regulations of reporting incidents and near-incidents applied.


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5.5.4. Non-drug Therapies

Not applicable.

5.6. Study Assessments and Procedures

A schedule of the measurements made and evaluations performed at each clinic visit is given in Table 1 (Section 5.1).

5.6.1. Demographic and Baseline Assessments

Demographic and baseline data were recorded in the CRF. Demographic information collected at Visit 1 included gender, ethnic origin, date of birth, weight, height and smoking history.

Baseline data collected included details of the subject’s asthma, including duration of asthma and exacerbations in the 6 months prior to Visit 1. In addition details of the subject’s medical history and concurrent conditions and concomitant medications (for asthma and other conditions) were recorded. At each subsequent visit, details of any changes to a subject’s concomitant medications were recorded. A physical examination was conducted at Visit 1 and any concurrent conditions identified and recorded in the CRF. A urinary pregnancy test was performed on all females of childbearing potential. In addition baseline measurements of vital signs were made and a 12-lead ECG and a baseline oropharyngeal examination was performed. At Visit 1 blood and urine samples were taken for routine haematology, clinical chemistry and urinalysis assessments. At Visit 2, measurement of urinary-free cortisol was made from a 24-hour urine collection taken prior to Visit 2.

5.6.2. Efficacy Assessment

Efficacy was assessed by:

• Daily Record Card (DRC) recordings of morning and evening PEF (L/min); day-time and night-time asthma symptom scores; day-time and night-time use of rescue VENTOLIN; night-time awakenings due to asthma and subject withdrawal due to lack of efficacy.

• Clinic lung function measurement of FEV1 and PEF

5.6.2.1. Daily Record Card Data

Subjects were issued with a paper DRC at the start of the run-in and treatment period and were instructed how to complete them. Subjects who did not complete the DRC correctly during the run-in period were not eligible to be randomised to treatment.


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5.6.2.2. Morning and Evening PEF Measurements

Morning and evening PEF was measured using a hand-held Peak Flow Meter (mini-Wright) that was issued to subjects at Visit 1. The best of three attempts was recorded by the subjects in the DRC.

• PEF was measured: - Each morning prior to study medication dose and any rescue VENTOLIN use.

- Each evening prior to study medication dose and any rescue VENTOLIN use.

5.6.2.3. Asthma Symptom Scores During the Day and Night

The following symptom scores were recorded daily before taking any study or rescue medication:

• Day-time Symptom Score: 0 = No symptoms during the day 1 = Symptoms for one short period during the day 2 = Symptoms for two or more short periods during the day 3 = Symptoms for most of the day which did not affect my normal daily activities 4 = Symptoms for most of the day which did affect my normal daily activities 5 = Symptoms so severe that I could not go to work or perform normal daily activities

• Night-time Symptom Score: 0 = No symptoms during the night 1 = Symptoms causing me to wake once (or wake early) 2 = Symptoms causing me to wake twice or more (including waking early) 3 = Symptoms causing me to be awake for most of the night 4 = Symptoms so severe that I did not sleep at all.

5.6.2.4. Rescue VENTOLIN Use

Each morning subjects recorded the number of occasions that VENTOLIN had been used during the night and each evening they recorded the number of occasions that VENTOLIN had been used during that day. The absolute number of inhalations was not recorded, only the number of occasions on which it had been used (e.g. if a subject had taken 2 inhalations of VENTOLIN this was recorded as one occasion).

5.6.2.5. Withdrawal Due to Lack of Efficacy

To assist the subject and/or investigator in identifying a worsening of asthma, ‘ALERT VALUES’ were calculated by the investigator and noted in the subjects DRC. Subjects who met one of the following criteria were withdrawn from the study.

• PEF fall of ≥20% from subject’s baseline value for 3 consecutive days.


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• Clinic FEV1 fall of ≥20% from the value at Visit 2.

• Increase in rescue medication use from mean baseline value (individualised per subject) by ≥2 occasions/day for ≥3 consecutive days.

Plus at least one of the following:

• Increase in symptom score from mean baseline value (individualised per subject) by ≥2 /day for ≥3 consecutive days.

• Increase in night-time awakenings from mean baseline value (individualised per subject) by ≥2 occasions/day for ≥3 consecutive days.

5.6.2.6. Clinic Lung Function Measurements

FEV1 was measured at the clinic visits electronically from flow-volume curves generated by spirometry. The highest of three technically acceptable measurements was recorded in the CRF. FEV1 was measured at Visits 1 to 6, prior to any rescue VENTOLIN use. If there were any clinically significant abnormalities at Visit 6, further examinations were performed at Visit 7 (Follow-up Visit). The spirometry printouts for FEV1 were initialled, and dated, and the subject number, visit number and time of assessment recorded by the person responsible for generating the data. The printouts were retained in the subject’s medical notes. PEF was also measured at clinic visits using a hand-held Peak Flow Meter. The best of three attempts was recorded in the CRF. Subjects were asked to refrain from using their VENTOLIN for 6 hours prior to the clinic visit if possible. Where possible, subjects attended the clinic at the same time of day (±2 hours) for each visit throughout the study.

5.6.2.7. Primary efficacy endpoint

The primary efficacy endpoint was mean change from baseline in daily trough (pre-study treatment and pre-bronchodilator) PEF (recorded in the daily record card (DRC)) during the 28-day treatment period with GW685698X 100µg once daily in the morning compared with GW685698X 100µg once daily in the evening by inhalation via DISKHALER.

5.6.2.8. Secondary efficacy endpoint(s)

Secondary efficacy endpoints were measured from the following DRC and clinic visit assessments:


• Mean change from baseline in daily trough (pre-study treatment and pre-bronchodilator) PEF (recorded in the DRC) during the 28-day treatment period with GW685698X 100µg once daily in the morning, 100µg once daily in


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the evening, or GW685698X 250µg once daily in the evening, compared with placebo.

• Mean change from baseline in morning PEF (pre-study treatment and pre-bronchodilator). This endpoint was not specified in the protocol but prior to production of the Reporting and Analysis Plan (RAP), it was decided that it would be of significant interest in the investigation of the secondary study objectives.

• Mean change from baseline in evening PEF (pre-study treatment and pre-bronchodilator). This endpoint was not specified in the protocol but prior to production of the Reporting and Analysis Plan (RAP), it was decided that it would be of significant interest in the investigation of the secondary study objectives.

• Change from baseline in pre-bronchodilator clinic lung function (forced expiratory volume in 1 second [FEV1] and PEF) after 28 days of treatment with GW685698X 250µg once daily in the evening compared with GW685698X 100µg once daily in the evening and GW685698X 100µg a.m. compared with GW685698X 100µg p.m..


• Comparison of the following asthma symptom scores was made during the 28-day treatment period, as assessed from the DRC, between GW685698X 100µg once daily administered in the evening and in the morning; between GW685698X 250µg once daily administered in the evening and GW685698X 100µg in the evening; and between all active treatments compared with placebo:


• Percentage of VENTOLIN-free 24-hour periods, days, and nights.


• Withdrawals due to lack of efficacy during the 28-day treatment period with each GW685698X treatment group compared with placebo.

5.6.3. Safety Assessments

Safety was assessed by the recording of all adverse events (AE) and serious adverse events (SAE), and by physical and oropharyngeal examinations. The investigator or designee was responsible for the detection and documentation of events meeting the definition of AE or SAE as described in the protocol. Urinary pregnancy tests were carried out at the start and end of the study in all female subjects of childbearing potential. Vital signs were measured at all clinic visits. At Visits 1 and 6 a 12-lead ECG was performed and also blood and urine samples were taken for routine clinical chemistry and haematology analysis and urinalysis. 24-hour urine samples were


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collected at the beginning and end of the treatment period for measurement of urinary-free cortisol.

5.6.3.1. Adverse events

An AE was defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also included failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.

An AE could include:

• Significant or unexpected worsening or exacerbation of the condition/indication under study.

• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition.

• New conditions detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study.

• Signs, symptoms, or the clinical sequelae of a suspected interaction.

• Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a concomitant medication (overdose per se should not be reported as an AE/SAE).

An AE did not include:

• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that lead to the procedure is an AE.

• Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital).

• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that did not worsen.

• The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition.

For GSK clinical studies, AEs may include pre- or post-treatment events that occur as a result of protocol-mandated procedures (i.e., invasive procedures, modification of subject’s previous therapeutic regimen).

Information on the management of an overdose, including drug and non-drug therapies, is described in Section 5.4.6.


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“Lack of efficacy” per se was not recorded as an AE. The signs and symptoms or clinical sequelae that resulted from lack of efficacy were reported if they fulfilled the AE or SAE definition.

From clinic visit 2 onwards, after the subject had had an opportunity to mention spontaneously any changes in his/her medical condition, the investigator enquired whether the subject had any AEs by asking the following standard questions:

• Have you had any (other) medical problems since your last visit/assessment?

• Have you taken any new medicines, other than those given to you within this study since the last visit/assessment?

In addition, the investigator reviewed the subject’s DRC at each clinic visit for evidence of any AEs or changes in concurrent medication. The time period during which AEs were collected and recorded started from the time the subject consented to participate in the study and continued until the end of the final visit.

5.6.3.2. Serious adverse events

A SAE was defined as any untoward medical occurrence that, at any dose:

a. Resulted in death;

b. Was life-threatening;

c. Required hospitalisation or prolongation of existing hospitalisation;

d. Resulted in disability/incapacity; or

e. Was a congenital anomaly/birth defect; f. Medical or scientific judgement was exercised in deciding whether reporting was

appropriate in other situations, such as important medical events that may not have been immediately life-threatening or resulted in death or hospitalisation but may have jeopardised the subject or may have required medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These were also considered serious. Examples of such events were invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalisation, or development of drug dependency or drug abuse.

5.6.3.3. Pregnancies

This study was conducted on male and female subjects who were aged 16 to 55 years inclusive. Urinary pregnancy testing was performed on all females of childbearing potential at Visit 1, 1a or 1b as appropriate, and at Visit 4 and at the end of the study (Visit 7). Pregnancy testing kits were provided locally at each investigator site.

The investigator, or his or her designee, collected details of any pregnancy that occurred between Visits 2 and 7. If a pregnancy occurred prior to Visit 2, and study drug administration, the subject was withdrawn from the study but the outcome of the


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pregnancy was not collected. Any subject who became pregnant between Visit 2 and 7 was followed to determine the outcome of the pregnancy. While pregnancy itself was not considered an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons was to be recorded as an AE or SAE. A spontaneous abortion was always considered to be a SAE.

5.6.3.4. Clinical laboratory evaluations

Abnormal laboratory findings (e.g., clinical chemistry, haematology, dipstick urinalysis) or other abnormal assessments (e.g., 12-lead ECG, vital signs) that were judged by the investigator as clinically significant were recorded as AEs or SAEs if they met the definition of an AE or SAE. Clinically significant abnormal laboratory findings or other abnormal assessments that were detected during the study or were present at baseline and significantly worsened following the start of the study were reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that were associated with the disease being studied, unless judged by the investigator as more severe than expected for the subject’s condition, or that were present or detected at the start of the study and did not worsen, were not reported as AEs or SAEs.

The investigator exercised his or her medical and scientific judgement in deciding whether an abnormal laboratory finding or other abnormal assessment was clinically significant.

5.6.3.5. Other safety assessments

12-Lead ECG

A 12-lead ECG examination was recorded at Visits 1, and 6. If there were any clinically significant abnormalities at Visit 6, further examinations were performed at Visit 7 (Follow-up Visit).

Urinary Cortisol Assessment

Urinary free cortisol from 24-hour urine collections was measured to assess HPA-axis function at Visits 2 and 6.

Twenty-four hour urine sample collection was made on the day prior to Visit 2 and 6, and was as near 24 hours in duration as possible. The total volume of urine collected (in mL) was recorded in the CRF and approximately 20mL was sent to the central laboratory for analysis. If the sample was not collected correctly for any reason (for example, incomplete collection or wrong start and finish times) this was clearly recorded on the CRF.


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Physical Examination

Physical examinations were performed at Visits 1, and 6. If the physical examination showed any clinically significant abnormalities at Visit 6, a further examination was performed at Visit 7 (Follow-up Visit). The physical examination was recorded in the CRF.

Oropharyngeal Examination

Oropharyngeal examinations were carried out at all visits for visual evidence of candidiasis. If there was any clinical evidence of candidiasis, a swab was taken and analysed locally. If the swab was positive, appropriate treatment was to be prescribed (if necessary) and details documented in the concomitant medication and AE sections of the CRF (if there was evidence of a new occurrence of candidiasis, or worsening of the condition from baseline, this was to be recorded as an AE).

Vital Signs

Vital signs (systolic and diastolic blood pressure and pulse rate) were measured after 5 minutes rest in the sitting position at Visits 1 to 6. If there were any clinically significant abnormalities at Visit 6, further examinations were to be performed at Visit 7 (Follow-up Visit). These measurements were to be taken before the clinic lung function tests.

5.6.3.6. Medical device

The GSK medical device provided for this study was:

DISKHALER/ROTADISK

In order to fulfil international reporting obligations the investigator was responsible for the detection and documentation of events meeting the definitions of incident, near-incident, or malfunction that occurred during the study with such devices.

Definitions of a medical device, incident, near-incident, malfunction, or remedial action were as follows:

Medical Device – Any instrument, apparatus, appliance, material or other article, the principal intended action of which is typically fulfilled by physical means (including mechanical action, physical barrier, replacement of, or support to, organs or body functions

Incident – Any medical occurrence that occurred in a study subject, user, or other person with a GSK medical device, provided for use in the study, which resulted in death or a serious deterioration in the state of health whether or not due to a malfunction of the device.


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Near-incident – Any potential incident occurring with a GSK medical device provided for use in the study. Near-incidents are events that could have jeopardized the study subject, user, or other person, causing death or a serious deterioration of health, if medical intervention or other fortunate circumstances had not occurred. This would include deficiencies or inaccuracies in the instructions for use of the device and/or malfunctions.

Malfunction – A failure of a device to perform in accordance with its intended purpose when used in accordance with the manufacturer’s instructions.

Remedial Action – Any action other than routine maintenance or servicing of a device where such action is necessary to prevent recurrence of an incident or near-incident. This includes any amendment to the design to prevent recurrence.

Medical device incidents, near-incidents or malfunctions were detected, documented and reported during all periods of the study in which the GSK medical devices that were provided were available for use.

Any medical device incident or near-incident that occurred during the study was documented in the subject’s medical records, in accordance with the investigator’s normal clinical practice, and on the “Medical Device Incident report Form”. In addition, for incidents and near-incidents that fulfilled the definition of an AE or SAE, the appropriate pages of the CRF were completed as described in Section 5.6.3.1 and Section 5.6.3.2.

All medical device incidents and near-incidents involving an AE were followed up until resolution of the event, until the condition had stabilised, until the condition was otherwise explained, or the subject was lost to follow-up. The investigator was responsible for ensuring that follow-up included any supplemental investigations to elucidate as completely as practical the nature and/or causality of the incident.

5.6.4. Pharmacokinetic Assessments

5.6.4.1. Collection and preparation of samples

A single blood sample was collected from all subjects at Visits 3 and 6 (Weeks 1 and 4). At Visit 4 (Week 2) two blood samples were obtained from each subject; one on arrival at the clinic visit and the other immediately prior to departure. The exact time of the sample, the time of the previous evening dose and the time of the morning dose were recorded on the CRF.

A 4mL blood sample was collected into a potassium EDTA tube by direct venepuncture. Samples were centrifuged, within 1 hour of collection, at approximately 1500g for 10 minutes. Supernatant plasma (approximately 1.2mL) was transferred to a 3.6mL Nunc tube and stored at approximately -20°C prior to shipment. Samples were shipped frozen on dry ice at agreed time points throughout the study.


39

Blood samples for PK analysis were collected at centres where the appropriate facilities were available.

5.6.4.2. Assay methods

Plasma samples were analysed for GW685698X by York Bioanalytical Solutions, UK.

Plasma samples were analysed for GW685698X using solid phase extraction followed by high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS-MS). The lower limit of quantification (LLOQ) of this assay was 10 pg/mL for GW685698X. The upper limit of the quantifiable range was 1000 pg/mL [GlaxoSmithKline Document Number WD2002/01057/00]

Quality controls prepared at three different concentrations were analyzed with each batch of samples against separately prepared calibration standards to assess the day-to-day performance of the assay. For the analysis to be acceptable, no more than one third of the quality control results were to deviate from the nominal concentration by more than 15%, with at least one quality control result acceptable at each concentration. Quality control results from this study met these acceptance criteria. Detailed bioanalytical information and data location for this study is provided in Attachment PK1.

5.6.5. Pharmacogenetic Assessments

In addition to the blood samples taken for the clinical study, a whole blood sample (10mL) was collected for the PGx research using a tube containing EDTA. The PGx sample was labelled (or “coded”) with a study specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples did not carry personal identifiers (e.g., name or social security number). The blood sample was taken on a single occasion (at Visit 1) unless a duplicate sample was required due to inability to utilise the original sample. It was recommended that the blood sample was taken at the first available opportunity, but could be taken at any time while the subject was participating in the clinical study.

5.7. Data Quality Assurance

At the clinical study sites, the investigator or their designee recorded all required subject data in paper Case Report Forms (CRF). Subjects were required to complete Daily Record Cards (DRC) and the investigator checked the information. A screening log with GSK required information, created by the investigator at the site, tracked subjects who were screened prior to entry into the study but not randomised. A centralised monitors meeting was held on 9-10th September, 2003 and investigator meetings were held locally in each participating country between September and December, 2003, where the CRF and CRF completion guidelines were presented.

The completed original CRFs and copies of any subject-completed documents were returned to GSK Data Management for processing. In addition, validated central laboratory data were transmitted electronically to GSK Data Management. The investigators retained copies of the CRFs and original subject-completed documents.


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Data entry applications were designed and validated using a data entry screen software system (i.e. ClinTrial). Data values recorded on the CRF were entered using double dependant data entry.

Computerised data validation was performed on the CRF data using ClinTrial validation checks and study-specific data validation checks. Validation discrepancies, if not covered by a Standard Clarification Agreement (SCA) were queried using the documented data query process for review and resolution by investigators, and if appropriate with reference to the clinical study team members. Any necessary changes were made to both the CRF and the database by data management staff.

Quality Control (QC) tasks were conducted in accordance with existing data management standard operating procedures to ensure database accuracy against the data collected in the CRF and any other subject-completed documents. QC procedures are in alignment with the International Conference on Harmonisation of Good Clinical Practice (ICH GCP). Adverse events and concomitant medications were coded by the autoencoder using company standard dictionaries, GSK-Drug and the industry standard, MedDRA.

SAE data, consistent with the data collected for other adverse events, was entered on to the database and quality assured, including reconciliation with Global Clinical Safety and Pharmacovigilance database.

After all data management QC/QA procedures were completed the database was released on 02 Jun 2004. Unblinding of treatment assignments then occurred for review of protocol violators and statistical review of blinded data. Once these activities were complete, the database was frozen on 08 Jun 2004 at which time access to the data was also restricted (database lock).

Pharmacokinetic plasma concentration-time data were generated by DMPK and captured on SMS2000. The Transformer for External Data (TED) system was used to extract pharmacodynamic data from the CSV file and pharmacokinetic data from SMS2000, merge on CT-GSK keys from the CRF sample time data, and produce pharmacokinetic and pharmacodynamic reporting datasets in CT-GSK data structure on the UNIX reporting environment. In addition, the TED system was used to merge pharmacokinetic data, actual treatment and dosing time data, and calculate actual relative times and time deviations and create a CSV file which was supplied to CPK. A CSV file of the merged pharmacodynamic data, actual treatment and dosing times data, and calculated actual relative times and time deviations was produced in the same way and was also supplied to CPK.

The raw data (CRFs etc) will be archived according to company standard procedures.

5.8. Data Analysis Methods

5.8.1. Timings of Planned Analyses

Data from this study were analysed according to the methods detailed in the Reporting and Analysis Plan (RAP). These methods were agreed and finalised prior to the release


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of any treatment codes. The actual analysis of data took place once all subjects had completed the study, the database was declared frozen and the treatment codes were unblinded.

5.8.1.1. Interim analyses and data monitoring

No interim analyses were performed for this study.

5.8.1.2. Changes in the conduct of the study or planned analyses

In addition to the planned tabulation and analysis of urinary cortisol, values corrected for creatinine were also summarised (Table 8.11, Table 8.13, Table 8.14 and Table 8.15) and analysed (Table 8.12) using ANCOVA as for the uncorrected values.

The planned table of treatment compliance was not produced because it would not have been an accurate reflection of compliance. This was because the quality of the recorded data were generally poor (e.g. some sites recorded the number of ROTADISKS returned instead of the number of blisters.

No other additional analyses were performed, although some minor changes were made some aspects of the programmins as follows:

Section 9.2 of the RAP states that any duplicate DRC data would be dealt with by using the average of the duplicate data for analysis. However, in cases where this occurred, the ‘worst case’ data item was used since the symptom score data were categorical in nature and listed as integers only.

For the purposes of identifying major protocol violations, subjects who had <50% of >80% predicted normal PEF were defined as major protocol violators in the RAP. However, during review of major protocol violators, it was decided to include subjects with <50% predicted normal PEF in the Per Protocol population. Similarly, the requirement for subjects to have a daily (a.m. + p.m.) symptom score >1 on at ,east 4 of the last 7 days of the run-in in order to be included in the Per Protocol population, was originally programmed using 24-hour periods starting with the p.m. recording (as defined by the time windows in Section 9.3.2.2 of the RAP). This was amended to allow inclusion of subjects who met the defined criterion within one calendar day (24-hour period with the a.m. recording).

5.8.2. Sample Size Considerations

The sample size was determined based on a required precision of treatment effect for the primary endpoint, which for this study was the difference in trough PEF between morning and evening doses. The standard deviation of trough PEF has been estimated at 40L/min based on morning and evening PEF values observed in previous asthma studies. A total of 492 randomised subjects (123 subjects per group) were required to ensure the width of the 95% confidence interval for the treatment effect was no larger than 20L/min.


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5.8.3. Analysis Populations

Three subject populations were identified for this study:

The Total Population comprised all subjects screened and for whom a record existed on the study database. This was used for summary of reasons for withdrawal prior to randomisation.

The Intent-to-Treat (ITT) population comprised all subjects randomised to treatment who received at least one dose of trial medication. Randomised subjects were assumed to have received trial medication unless definitive evidence to the contrary existed. This constituted the primary population for all analyses of efficacy and safety measures. However, if there were any occurrences of subjects taking a treatment other than that to which they had been randomised, safety data was analysed according to the treatment actually received (Safety Population).

The Per Protocol (PP) population consisted of all subjects in the ITT population not identified as major protocol violators. The major protocol violations for which patients would be excluded from the PP population are detailed in Section 5.8.7.2 and represent criteria that may affect trough PEF. The decision to exclude a subject from the PP population was made prior to breaking the blind. This population was used for confirmatory analysis of trough PEF endpoints only.

5.8.4. Treatment Comparisons

The primary treatment comparison of interest was between GW685698X 100µg given once daily in the morning and once daily in the evening.

The following treatment comparisons were of secondary interest:

• GW685698X 250µg given once daily in the evening vs. GW685698X 100µg once daily in the evening

• GW685698X 100µg given once daily in the evening vs. placebo

• GW685698X 100µg given once daily in the morning vs. placebo

• GW685698X 250µg given once daily in the evening vs. placebo

5.8.5. General Considerations for Data Analyses

All programming was performed in a Unix environment using SAS Version 8.2. All analysis output used the following treatment group naming conventions:

• GW685698X 100µg p.m. for GW685698X 100µg given once daily in the evening

• GW685698X 100µg a.m. for GW685698X 100µg given once daily in the morning

• GW685698X 250µg p.m. for GW685698X 250µg given once daily in the evening

• PLACEBO for Placebo


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5.8.5.1. Multicentre studies

This study was conducted in 62 centres in 12 countries within Europe, Latin America and South Africa so it was likely that many centres would enrol a small number of subjects. Therefore, centres within a country were combined to give 14 centre groupings.

A separate document detailing the final country pooling strategy was completed after recruitment to the study had ended and before the treatment codes were unblinded. All summaries and analyses were of all countries combined (analysis models included country grouping as a covariate). Results were only presented for different country groupings separately if a significant treatment*country interaction was observed (see Section 5.8.8.1).

5.8.5.2. Other strata and covariates

Covariates expected to influence lung function included age and sex. These covariates were included in the analysis models as detailed under each parameter together with the appropriate baseline value of the endpoint being analysed and country.

5.8.5.3. Examination of subgroups

For the primary efficacy variable only (daily trough PEF), interactions with treatment were assessed at the 10% (2-sided) level of significance, for the four covariates listed above. If any significant treatment by covariate interactions were identified from the ANCOVA model, they were further investigated through the review of summary statistics at each level of the covariate. For the continuous variables of age and baseline value, the median values were used to dichotomise into groups for presentation of these summaries.

In addition to the above, trough PEF was summarised for each treatment group by visit 2 percent predicted PEF (subjects with ≥65% predicted and subjects with <65% predicted) in order to investigate potential differences in disease severity with respect to treatment response.

5.8.5.4. Multiple comparison/multiplicity

A single primary efficacy variable was identified for this study, with all other efficacy variables identified as secondary. Similarly there was only one primary treatment comparison specified for this study, with all other treatment comparisons being secondary. Therefore there were no requirements to adjust for multiple endpoints or multiple treatment comparisons within this study.

5.8.6. Data Handling Conventions

5.8.6.1. Premature discontinuation and missing data

For ITT analyses, daily record card data from subjects who withdrew prematurely were included in the analyses as long as at least 1 assessment of on-treatment data had been


44

recorded. For the PP analysis of the primary endpoint, subjects who withdrew prematurely were included provided at least 7 days of on-treatment data had been recorded. Failure to record this minimum amount of DRC data was considered a major protocol violation.

Clinic visit data from subjects who withdrew prematurely were included in the analyses as long as at least one on-treatment assessment had been provided. Any data from subjects who withdrew from the study prior to providing at least one on-treatment assessment were to be excluded from the analysis.

Analyses of daily record card data were based on the available data i.e. patient means and percentages were calculated using the number of non-missing observations as the denominator.

Missing clinic visit FEV1 and PEF values were imputed using a last observation carried forward (LOCF) approach, only post-baseline measurements could be carried forward.

5.8.6.2. Derived and transformed data

Clinic Visit Data: In all cases the most recent evaluations taken before the first dose of study medication were considered to be the baseline measurement.

Daily record card data: The baseline measurement was defined as the mean of the values recorded in the last 7 days prior to the first dose of medication.

Duplicate information collected on the daily record card was dealt with by taking the average of the information and using it for the analyses.

Peak Expiratory Flow:

The predicted normal PEF, percent predicted normal PEF and percent reversibility were derived and used in place of the values collected in the case report form.

For all subjects aged between 25-55 years the predicted PEF values were determined from the guidelines of the working party of the European Community for Coal and Steel (Quanjer 1993) using the following formula where height is to the nearest cm and age is in whole years attained.

Males: Predicted PEF (L/min) = [(6.14 * height / 100) – (0.043 * age) + 0.15] Females: Predicted PEF (L/min) = [(5.50 * height / 100) – (0.030 * age) – 1.11]

The ECCS formulae above was also used for subjects aged 18-24 years, although the age used for the calculation was 25 in all cases.

For subjects who were under 18 years of age, the predicted PEF values was determined from the Polgar tables using the following regression equation, again height is to the nearest cm and the same formulae is used for both males and females (Polgar, 1971).

Males/Females: Predicted PEF (L/min) = -425.5714 + [5.2428 * height]


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Using these derived predicted PEF values the following were calculated:

Percent predicted normal PEF = (Observed PEF (L/min)/ Predicted PEF (L/min)) * 100

Reversibility (%) = Post-bronchodilator PEF - Pre-bronchodilator PEF *100 Pre-bronchodilator PEF*100

5.8.6.3. Assessment windows

Clinic Visit Data

Visits were scheduled to take place within the following timeframes as stated in the protocol:

Visit Number Scheduled Time Visit 1/1a/1b -3 to –1 weeks

Visit 2 0 weeks Visit 3 1 week ± 2 days Visit 4 2 weeks ± 2 days Visit 5 3 weeks ± 2 days Visit 6 4 weeks ± 2 days Visit 7 5 weeks ± 2 days

If visits took place outside the allowable scheduled time, data collected at these visits were still used in analysis of clinic visit data. If unscheduled or multiple assessments occurred, the one closest to the scheduled visit was used. If two such assessments were equally close to the scheduled visit, the earlier of the assessments was used.

Daily Record Card Data

For the daily record card data, assessments were assigned to a time period based upon when they were recorded. For each subject, daily assessments were assigned a day number relative to the date of start of study medication:

Day number = Date of assessment – Treatment Start Date

Provided subjects started their study medication as instructed on the evening of visit 2, day 0 was the date of randomisation and also the treatment start date. Due to the nature of the study design, subjects randomised to the GW685698Xa.m.dose group received placebo on the evening of day 0 and the start of active treatment for this group was the morning of day 1. As a result, different time periods were defined for different treatment groups and/or different endpoints (see below).

Trough PEF

Although trough PEF was collected twice daily, analysis of these data were performed using only the measurement relating to the time of dosing of GW685698X (data from the


46

placebo group were used according to the corresponding dose time of the group to which it was being compared). Therefore, the baseline and treatment periods for analysis of trough PEF were defined as:

GW685698X 100µg/250µg p.m.

GW685698X 100µg a.m. Placebo

Baseline p.m. Day –7 to p.m. Day -1 a.m. Day –6 to a.m.Day 0 p.m. Day –7 to a.m.Day 0 Treatment p.m. Day 1 to p.m. Day 28 a.m. Day 2 to a.m.Day 29 p.m. Day 1 to a.m. Day 29 Week 1 p.m. Day 1 to p.m. Day 7 a.m. Day 2 to a.m.Day 8 p.m. Day 1 to a.m. Day 8 Week 2 p.m. Day 8 to p.m. Day 14 a.m. Day 9 to a.m. Day 15 p.m. Day 8 to a.m.Day 15 Week 3 p.m. Day 15 to p.m. Day 21 a.m. Day 16 to a.m. Day 22 p.m. Day 15 to a.m.Day 22 Week 4 p.m. Day 22 to p.m. Day 28 a.m. Day 23 to a.m.Day 29 p.m. Day 22 to a.m. Day 29

Assessments recorded beyond p.m. Day 28/a.m. Day 29 were excluded from the analysis.

Morning PEF / Evening PEF / % Symptom-Free / VENTOLIN-Free Time Periods

For the analyses of a.m. PEF and p.m. PEF and also for % symptom free or VENTOLIN-free time periods, all treatment groups were compared using the same assessment times.

% Symptom-Free / VENTOLIN-Free 24-Hour

Periodsa

p.m. PEF/ % Symptom-Free Days / % VENTOLIN-

Free Days

a.m. PEF/ % Symptom-Free Nights / % VENTOLIN-Free Nights / % No Awakening

Nights

Baseline p.m. Day –7 to a.m. Day 0 p.m. Day –7 to p.m. Day -1 a.m. Day –6 to a.m.Day 0

Treatment p.m. Day 1 to a.m.Day 29 p.m. Day 1 to p.m. Day 28 a.m. Day 2 to a.m. Day 29 a. 24-Hour period was defined as the evening assessment of a given day together with the morning assessment

of the following day.

5.8.6.4. Values of Clinical Concern

Laboratory parameters were compared to the following normal ranges, as defined by the central laboratory.


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Parameter Units Sex Age Range (years) Normal Range Haematology

Haemoglobin G/DL M M F F

18-64 65+

18-64 65+

13.8 – 17.2 11.8 – 16.8 12.0 – 15.6 11.1 – 15.5

MCV FL M/F 18-64 65+

80 – 100 82 – 103

Platelets GI/L M/F 1+ 130 – 400 Total WBC GI/L M/F 18+ 3.8 - 10.8 Neutrophils GI/L M/F 3+ 1.8 - 8.0

Lymphocytes GI/L M/F 1+ 0.85 - 4.10 Monocytes GI/L M/F 1+ 0.20 - 1.10 Eosinophils GI/L M/F 0+ 0.05 - 0.55

Basophils GI/L M/F 1+ 0.00 - 0.20 Blood Chemistry

Sodium MMOL/L M/F 0+ 135 - 146 Potassium MMOL/L M/F 13+ 3.5 - 5.3

Bicarbonate MMOL/L M/F 13+ 20 - 32 Glucose MMOL/L M/F 13-49

50+ 3.9 - 6.4 3.9 - 6.9

Albumin G/L M/F 3+ 32 – 50 Creatinine UMOL/L M/F 13+ 44 – 124

Total bilirubin UMOL/L M/F 1+ 0 – 22 Alkaline phosphatase U/L M

F M/F

16-19 16-19 20+

30 – 225 30 – 165 20 – 125

AST U/L M/F 3-64 65+

0 – 42 0 – 55

ALT U/L M/F 13+ 0 – 48 Urine Cortisol

Cortisol NMOL M/F 5.5 - 117 Cortisol corrected for

creatinine NMOL/ NMOL

M/F 1 – 8.7

Sex: M=Male, F=Female

The investigator assessed, on a subject by subject basis, any values that fell outside of these pre-defined normal ranges to determine if they were of clinical concern. In addition laboratory parameter values were compared to the following reference ranges which were defined by the Clinical Respiratory group:


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Haematology Blood Chemistry Parameter Upper RR Lower RR Parameter Upper RR Lower RR Haemoglobin 1.10XulN 0.90xLLN Sodium 1.05xULN 0.95xLLN MCV 1.13xULN 0.90xLLN Potassium 1.10xULN 0.90xLLN Platelets 1.90xULN 0.60xLLN Bicarbonate 1.20xULN 0.75xLLN Total WBC 1.50xULN 0.60xLLN Glucose 1.50xULN 0.80xLLN Neutrophils 2.00xULN 0.60xLLN Albumin 1.20xULN 0.80xLLN Lymphocytes 1.50xULN 0.60xLLN Creatinine 1.30xULN none defined Monocytes 1.50xULN none defined Total bilirubin 1.60xULN none defined Eosinophils 2.20xULN none defined Alkaline

phosphatase 2.75xULN none defined

Basophils 5.00xULN none defined AST 2.75xULN none defined ALT 3.00xULN none defined

5.8.7. Study Population

Tabulations of the study populations were produced using the ITT and Per Protocol populations, when specified.

5.8.7.1. Disposition of subjects

The number of subjects in each analysis population was presented, and the total number of subjects attending each clinic visit was also summarised by treatment group.

The number of subjects that were randomised and either completed or were prematurely withdrawn from the study was presented for each treatment group. The primary reasons for withdrawal both prior to and post randomisation were also presented.

A data display listing and summary of deviations from the inclusion/exclusion criteria was presented for all subjects who were either entered or randomised into the trial.

5.8.7.2. Protocol deviations

All major protocol deviations resulting in full or partial exclusion from the Per Protocol population were listed.

Randomised subjects who met any of the following criteria were considered major protocol violators and were excluded from the Per Protocol analysis population. Subjects were summarised by their reason for exclusion. Major protocol violations were defined as:

• Subject did not comply fully with the following inclusion/exclusion criteria (see Section 5.3.1 and Section 5.3.2): Inclusion to Run-In:

• Documented clinical history of persistent asthma first diagnosed at least 6 months prior to visit 1.


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Inclusion to Treatment Period:

• Increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol (fulfilled at any of visits 1/1a/1b/2)

• Mean morning PEF (calculated from last 7 consecutive days of the final run-in period) of between 50% and 90% predicted normal.

• Daily asthma symptom score (day-time plus night-time) of >1 on at least 4 of the last 7 consecutive days of the final run-in period.

Exclusion to Run-In:

• History of respiratory tract infection and/or exacerbation within a period of 4 weeks prior to visit 1.

• History of 2 or more exacerbations requiring treatment with oral corticosteroids or hospitalisation in the 6 months before visit 1.

• Known or suspected sensitivity to corticosteroids, VENTOLIN, or the constituents of ROTADISKS.

• Undergoing allergen desensitisation therapy.

• Current smoker or has a smoking history of 10 pack years or more.

• Administration of the respiratory medications listed in Section 5.2.2 of the protocol

Exclusion to Treatment Period:

• Changes in asthma medication (excluding rescue VENTOLIN)

• Occurrence of an upper or lower respiratory tract infection during the run-in period

• Non-compliance with completion of the DRC (6 out of the last 7 days prior to visit 2 completed to confirm compliance)

• Exacerbation of asthma symptoms during the run-in

• Subject met criteria for withdrawal but was not withdrawn

• Subject took/received treatment to which they were not randomised

• Starting prohibited asthma medications during the run-in or treatment periods. This information was obtained from the asthma concomitant medication details but was reviewed prior to unblinding the treatment allocations. Subjects for whom these violations occurred during the treatment period were considered partial violators and were included in the Per Protocol analysis up to the time at which the violation occurred.

• Subject was less than 80% compliant with either a.m. or p.m. dose of study medication

• Subject failed to record at least 5 days (morning and evening) of DRC data

• Subject received investigational product past the expiration date


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• Subject had treatment blind broken during study

5.8.7.3. Demographic and baseline characteristics

The following demographic information was listed and summarised for subjects in each treatment group: age, sex, race, height and weight. This was also done for history of tobacco use at screening and current medical conditions.

Asthma and other concomitant medications were coded using the GSK Drug coding dictionary and classified as pre-treatment or on-treatment, using the following definitions:

• Pre-treatment: started prior to randomisation

• On-treatment: taken during the treatment period

Asthma concomitant medications were listed and summarised for each treatment group for both pre-treatment and on-treatment medications. Other concomitant medications were summarised/listed on-treatment only.

Information regarding duration of asthma and asthma history was also presented and pulmonary function test measurements at screening were listed and summarised.

5.8.7.4. Treatment compliance

In a change to the planned method of assessment of treatment compliance (See Section 5.8.1.2), treatment compliance was assessed on the basis of DRC entries. No listings or tables were produced.

5.8.8. Efficacy Analyses

For parameters analysed using an analysis of covariance (ANCOVA) model, the underlying assumptions of normality of data and homogenous variances were confirmed by examining the residuals from the model.

Unless otherwise indicated, all hypothesis tests for main effects used a 2-sided test at the 5% level of significance (performed for comparisons with placebo only). For tests of interaction a 2-sided test was used at the 10% level of significance.

5.8.8.1. Primary efficacy measure(s)

The primary efficacy analysis was carried out using both the ITT and PP populations, with the ITT being the primary population.

Daily Trough (Pre-study treatment and pre-bronchodilator) PEF

Daily trough PEF was taken as the morning PEF measurement for subjects assigned to a treatment arm where the active dose of medication was given in the morning (i.e. GW685698X 100µg a.m.). Daily trough PEF was taken as the evening PEF


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measurement for subjects assigned to a treatment arm where the active dose of medication was given in the evening (i.e. GW685698X 100µg p.m. or GW685698X 250µg p.m.). Daily trough PEF was taken as either the morning or evening PEF measurement for subjects assigned to the Placebo treatment arm, the measure taken was from the same time of day as that used for the treatment arm to which it was being compared.

The mean daily trough PEF was calculated from either the a.m. or p.m. PEF values collected on the daily record card (DRC) during the run-in and treatment phases as follows:

Mean Daily Trough PEF = Sum of daily trough PEF measurements in period Days in period where daily trough PEF measured

For each subject the baseline daily trough PEF was defined as the mean of the relevant PEF values measured over the last 7 consecutive days of the run-in period (see Section 5.8.6.3). The treatment daily trough PEF was defined as the mean of the relevant PEF values measured over the 28-day treatment period. The change from baseline for each subject was determined as the difference between these two values.

The primary efficacy endpoint of mean change from baseline in daily trough PEF during the 28-day treatment period was calculated for each treatment group as the sum of the individual changes from baseline divided by the number of subjects.

Summary statistics of actual and change from baseline daily trough PEF were presented for each treatment group. In addition weekly mean values of trough PEF were displayed in a plot by treatment group. The change from baseline daily trough PEF was compared between treatment groups using an ANCOVA model, with treatment, baseline daily trough PEF, age, sex and country as terms in the model.

The primary comparison of interest was between the GW685698X 100µg a.m. and p.m. treated groups. The estimated treatment difference together with a 95% confidence interval for the difference was presented but a p-value was not since the study objective was not to demonstrate statistical superiority of one treatment over the other.

Interactions with treatment were assessed for all covariates included in the model at the 10% (2-sided) level of significance for the ITT population only. Subgroup summaries were produced to further investigate the source of any significant treatment by covariate interaction.

5.8.8.2. Secondary efficacy measure(s)

All secondary analyses, with the exception of daily trough PEF, were carried out using the ITT population only.


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Daily Trough (Pre-study treatment and pre-bronchodilator) PEF

Summary statistics of actual and change from baseline mean daily trough PEF were presented for each treatment group over the 28-day treatment period and in addition for each of the 4 weeks of the treatment period. In each case the change from baseline daily trough PEF were compared between treatment groups using an ANCOVA model, with treatment, baseline daily trough PEF, age, sex and country as terms in the model. Estimates of the treatment difference, p-values for superiority comparisons only and 95% confidence intervals were presented for each comparison. These analyses were carried out for both the ITT and PP populations, with the former being the population of primary interest.

Interactions with treatment were assessed for all covariates included in the model looking at change from baseline over the 28-day treatment period, these were tested at the 10% (2-sided) level of significance for the ITT population only. Subgroup summaries were performed to further investigate the source of any significant treatment by covariate interaction.

In addition, a summary tabulation of trough PEF was prepared for each asthma severity subgroup (defined by % predicted PEF at visit 2) as follows:

• Moderate (≥65% predicted PEF)

• Severe (<65% predicted).

Morning PEF

Summary statistics of actual and change from baseline mean daily a.m. PEF were presented for each treatment group over the 28-day treatment period. The change from baseline in a.m. PEF was compared between treatment groups using an ANCOVA model, with treatment, baseline a.m. PEF, age, sex and country as terms in the model. Estimates of the treatment difference, p-values for superiority comparisons only and 95% confidence intervals were presented for each comparison. It should be noted, however, that a comparison of morning PEF between the a.m. dose group and either of the p.m. active dose groups was biased and therefore interpreted jointly with the evening PEF results.

Evening PEF

Summary statistics of actual and change from baseline mean daily p.m. PEF were presented for each treatment group over the 28-day treatment period. The change from baseline in p.m. PEF was compared between treatment groups using an ANCOVA model, with treatment, baseline p.m. PEF, age, sex and country as terms in the model. Estimates of the treatment difference, p-values for superiority comparisons only and 95% confidence intervals were presented for each comparison. It should be noted, however, that comparison of evening PEF between the a.m. dose group and either of the p.m. active dose groups was biased and therefore was interpreted jointly with the morning PEF results.


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Pre-bronchodilator FEV1

Summary statistics of actual and change from baseline pre-bronchodilator FEV1 were provided at each visit, as well as being listed. The change from baseline in FEV1 at Visit 6 was compared between treatment groups using an ANCOVA model with treatment, baseline FEV1, age, sex and country included as terms in the model. Estimated treatment differences for all comparisons were presented together with 95% confidence intervals for the difference, p-values were only presented for superiority comparisons of each GW685698X group with placebo.

Clinic Visit PEF

Summary statistics of actual and change from baseline clinic visit PEF were provided at each visit, as well as being listed. The change from baseline in clinic visit PEF at Visit 6 was compared between treatment groups using an ANCOVA model with treatment, baseline clinic visit PEF, age, sex and country included as terms in the model. Estimated treatment differences for all comparisons were presented together with 95% confidence intervals for the difference, p-values were only presented for superiority comparisons of each GW685698X group with placebo.

Daily Record Card Data

Throughout the study, subjects recorded their daytime (p.m.) and night-time (a.m.) asthma symptoms scores, rescue medication use and number of night-time awakenings.

For each subject the following parameters were calculated from the DRC data over the 28-day treatment period:

Percentage of symptom free 24-hr periods: No. days with a.m. and p.m. asthma symptom score of 0 *100 Total number of days in treatment period with completed data

Percentage of symptom free days: No. days with p.m. asthma symptom score of 0 *100 Total number of evenings in treatment period with completed data

Percentage of symptom free nights: No. days with a.m. asthma symptom score of 0 *100 Total number of mornings in treatment period with completed data

Percentage of 24-hr periods with no rescue medication: No. days with no rescue medication use in morning or evening *100 Total number of days in treatment period with completed data

Percentage of days with no rescue medication: No. days with no rescue medication use recorded in the evening *100 Total number of evenings in treatment period with completed data


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Percentage of nights with no rescue medication: No. days with no rescue medication use recorded in the morning*100 Total number of mornings in treatment period with completed data

Percentage of nights with no awakenings: No. days with no awakenings recorded in the morning *100 Total number of mornings in treatment period with completed data

Since normal distributional assumptions held and data were not highly skewed, comparisons between pairs of treatment groups were made using ANCOVA with treatment, baseline %, age, sex and country included as terms in the model. Estimated treatment differences for all comparisons were presented together with 95% confidence intervals for the difference, p-values were only presented for superiority comparisons of each GW685698X group with placebo.

Withdrawals

Withdrawals prior to randomisation and premature withdrawals during the treatment period were listed and summarised. The number and percentage of subjects withdrawing from the study were summarised by their primary reason for withdrawal, for each treatment group. In addition Fisher’s Exact test was used to compare the number of withdrawals due to lack of efficacy between each of the GW685698X treated groups and placebo.

5.8.9. Safety Analyses

All analyses of safety data were carried out using the ITT population. However, if there was an occurrence of subjects taking a different treatment from that to which they were randomised, safety displays were according to the actual treatment taken.

5.8.10. Extent of Exposure

Study drug exposure data were listed. The number of days of exposure to study medication were summarised by treatment group in the following categories <=7, 8-14, 15-21, 22-28 and >28 days. This was calculated as the number of days between the first dose and the last dose of medication inclusive.

5.8.11. Adverse Events

Adverse events (AEs) were coded using the MedDRA coding dictionary (Version 6.0 or a later release) and grouped by system organ class. AEs were classified as pre-treatment, on-treatment and post-treatment using the following definitions:

• Pre-treatment: started prior to first dose of study medication with no change in frequency or severity

• On-treatment: started after first dose of study medication, or prior to first dose of medication but with increased frequency or severity


55

• Post-treatment: started after last dose of study medication. Separate data display listings were presented for each of the above classifications. In addition the number and percentage of subjects experiencing an AE were summarised by system organ class and preferred term for pre, on- and post treatment events. Separate summaries were also provided for on-treatment drug-related AEs, all serious AEs and AEs leading to withdrawal.

5.8.12. Deaths and Serious Adverse Events

There were no deaths in this study. Summary tables are provided for serious adverse events. In addition, all serious AE's are documented in a case narrative format in Section 13.1.

5.8.13. Clinical Laboratory Evaluations

Summary statistics of the clinical chemistry and haematology laboratory measurements and also of urinary cortisol and urinary cortisol adjusted for creatinine, were provided by visit and treatment group for both actual and change from baseline values. These parameters were also presented with respect to shifts from baseline. Evaluations were compared to their normal range and labelled according to whether they were below the lower limit of normal, within the normal limits or above the upper limit of normal. Evaluations were also compared to the reference ranges and labelled according to whether they were above or below the reference range. Each on-treatment value was categorised depending on its change relative to the pre-treatment value. Lab values for all subjects were listed. The investigator identified values of clinical concern and all information relating to these values was also listed.

The results of any positive urinalysis assessments were listed and summarised.

In addition to the above, log-transformed 24-hour urinary cortisol measurements were compared between treatment groups using an ANCOVA model with treatment, baseline value, age, sex and country as terms in the model. The adjusted geometric means, estimated treatment effect and 95% confidence intervals were presented for all comparisons, p-values were only presented for comparisons of active treatment versus placebo. Cortisol values were also plotted for each visit against baseline values by treatment group.

The tabulations and analysis of urinary cortisol values were repeated for urinary cortisol corrected for creatinine (See Section 5.8.1.2).

5.8.14. Other Safety Measures

Examination of the Oropharynx

The incidence of clinical/visual evidence of oral candidiasis was summarised for each treatment group and visit. In addition, the number and percent of subjects with a positive


56

swab were tabulated for each treatment group at each time point. All data relating to this parameter were listed.

ECG Measurements

Any abnormal findings from the 12-lead ECG examination were listed.

Vital Signs Assessments

All vital signs data were listed. Summary statistics of systolic and diastolic blood pressure and pulse rate were presented for each treatment group and visit, for both actual and change from baseline values.

Physical Examination

Physical examination data are not entered onto the database within GSK. Any clinically significant changes from screening were captured as an adverse event.

5.8.15. Pharmacokinetic Analyses

5.8.15.1. Pharmacokinetic Population

Only samples from patients taking GW685698X were analysed. Individuals involved in the bioanalysis of PK samples in WorldWide Bioanalysis, DMPK, and the contract research organisation (YBS) were unblinded as per SOP POL-NPD-0009. The PK population includes all subjects who provided plasma samples for measurement of GW685698X concentration.

5.8.15.2. Interim analyses

No interim analysis was planned.

5.8.15.3. General considerations for data analyses

Concentrations below the lower limit of quantification (LLQ) for the LC-MS-MS assay (10pg/mL) were reported as NQ (Below Quantification Limit). Percent of NQ samples was also calculated for each group following active treatments.

All NQ values were set to missing in the NONMEM datasets. All excluded observations along with reasons of exclusion were listed in the report.

Evaluable patients were to be randomised into two groups, Group A (2/3 of patients) and Group B (1/3 of patients). Randomisation was to be accomplished by assigning a random number to each patient using the ranuni function in SAS. SAS Proc Rank was then to be used to group patients into three equal groups by their random number assignment. Patients in group 0 were to be assigned to group B, while patients in groups 1 and 2 were to be assigned to group A. Data from group A were to be used to build the model and


57

data from group B were to be used to validate the model built using the “model development” dataset. However, due to the large number of NQ values it was not deemed appropriate to split the data and only one dataset was generated that was used for model development.

5.8.15.4. Missing sampling and treatment information

The sampling times were relative to the time of the last dose of GW685698X. A missing dependent variable (DV) was not recorded unless EVID (the dosing event flag) and MDV (the missing dependant variable flag) indicated that DV was really missing.

The event identification (EVID) was coded 0 for a concentration observation, 1 for a dose event, 4 to reset the time at a dosing event. Full details of the file structure were presented in a separate CPDM RAP.

Data from subjects with inadequate dosing histories (no records for dosing time for one and/or both doses – morning dose and the previous evening dose) or missing sample information were discarded from the data file. Concentrations following an obvious missing dosing event were excluded from the PK analysis. All excluded observations or discarded data from the data file along with reasons for exclusion were listed in the report.

It was possible that some concentration results were inconsistent with the expected PK behaviour of GW685698X. These data were excluded from the modelling after investigation about possible sampling/labelling errors. The exclusions were listed.

5.8.15.5. Missing covariates

Only subjects with a complete set of covariates and a GW685698X concentration were included for the first covariate analysis. If some covariates had influence in this analysis, then subjects with a missing value for these covariates were added back into the dataset in order to improve the final parameter estimates. These subjects, however, must have had values for all of the significant covariates in the model.


All subjects providing GW685698X plasma concentration-time data were included in the pharmacokinetic analysis. Population compartmental pharmacokinetic modelling was performed by the Clinical Pharmacokinetics Department, Greenford. Population PK analysis, using non-linear mixed effect modelling, was performed with the computer program NONMEM, version V (NONMEM users guide) (Boeckman, 1992), installed on a personal computer, running on Windows NT. Visual NONMEM5 (VisualNM5) was used as interface software. The NONMEM system combines a pre-processor, NM-TRAN, a library of pharmacokinetic subroutines, PREDPP and the main program, NONMEM. Based on a preliminary analysis of the data, the method selected for minimisation was the first order method (FO). The pharmacokinetic models and the NONMEM control and output files for models evaluated are on file.


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5.8.16.1. NONMEM dataset preparation

Subjects who were randomised to receive GW685698X and provided plasma concentration data were included in the population pharmacokinetic analysis. A total of 1481 samples from 398 subjects were included in the analysis. Because of the low doses 820 of these samples (55.4%) had results which were below the lower limit of quantitation. After initial attempts at developing the model using study data alone it was deemed necessary to include data from previous studies where extensive sampling had been conducted. Additional data were taken following 500µg from study FFA10002 (a.m. dosing) and data for the 3 micron material from study FFA10022 (p.m. dosing). All non-quantifiable (NQ) plasma concentrations were set to missing for the initial analysis. For the final dataset NQ concentrations comprised approximately 46.9% of the final dataset for GW685698X. Following completion of the model building with NQ values set to missing, further analyses were conducted utilising two different imputation methods intended to minimise bias (Beal, 2001).

Imputation 1 set NQ values at times 0 to 2h equal to one-half LLQ (5pg/mL) and those at times after 2h equal to one-quarter LLQ (2.5pg/mL).

Imputation 2 set NQ values at times 0 to 1h equal to the LLQ (10pg/mL), those at times greater than 1h up to 4h equal to one-half LLQ (5pg/mL) and those at times after 4h equal to one-quarter LLQ (2.5pg/mL).

All subjects who had accurate dosing information and consistent sampling were included in the analysis. Each set of data began with a dosing record. Analysis was performed with actual dates and times and actual doses administered. If this information was missing, the subject’s data was omitted. Drug concentration was defined as the dependent variable (DV) for the NONMEM analysis. All missing values (indicated by a blank space or a dot) in NONMEM were to be treated as missing. Consequently, a missing DV should never be recorded unless EVID and MDV (the missing dependant variable flag) indicated that DV was really missing. Due to the short duration of the study (4 weeks) the demographic covariates, age and weight were assumed not to have changed during the study without introducing a bias. No covariate values were missing. The following model-dependent variables were included to the files: patient identifier (ID), record type (EVID: 1 for a dose event, and 0 for an observation event), dose amount (AMT), time relative to treatment start (TIME) and treatment group (TMT). Because samples were not collected until after at least one week of dosing, steady state was assumed and the dosing interval was set to 24 hours. The data specifications for variable names and codes are presented in the Pharmacokinetic Attachment PK1.

5.8.16.2. Pharmacokinetic structural and statistical model

Population pharmacokinetic analysis of GW685698X was performed to:

• Characterise the time course of drug concentrations in plasma, based upon sparse samples collected in the study population.

• Assess the effect of gender, height, weight, age and ethnic origin on the pharmacokinetic parameter estimates.


59

• Calculate AUC as a measure of drug exposure. A two-compartmental model was chosen, based on prior knowledge of the pharmacokinetics of the drug and an appropriate error model was selected. Initially, the simplest error model that appeared to describe the data was evaluated.

The compartmental model was parameterised with CL/F and V/F. The rate constant, k, or the half-life, tl/2, is a hybrid of CL/F over V/F. Intersubject variance (η) was included for all structural PK parameters and only excluded if exclusion improved the model. The criteria for accepting a NONMEM model included: (i) convergence of the objective function, (ii) number of significant digits at least equal to 3, (iii) termination of the covariance step without warning messages, (iv) correlation between model parameters < 0.95, (v) all gradients at the last iteration no greater than 10.

Goodness of fit was assessed by graphical methods based on predicted parameters, residuals and weighted residuals. Predicted versus observed concentrations plot gave an overall sense of the fit, with the concentration-time points falling randomly and close to the line of unity throughout the concentration range. Individual plots were also created. Standard error of the estimates were approximated using the asymptotic covariance matrix.

In accounting for interindividual variability, pharmacokinetic parameters were assumed to be log normally distributed and characterised by a constant coefficient of variation error model.

θi = θ * EXP(ηiθ)

where ηiθ represents the proportional difference between the typical parameter value in the population θ and the parameter value for the subject i, θi. The ηs are assumed to be normally distributed random variables with a mean zero and variance ω2. EXP indicates exponentiation of the parameter.

Random residual variability accounts for additional sources of variation between true and observed values of the dependent variable. The residual error was modelled by the combination of both additive and an exponential component (homoscedastic/heteroscedastic model).

Cp = F * EXP(ε1) + ε2

where Cp is the observed drug concentration, F is the predicted concentration and ε represents the difference in the log domain between the two values. The distribution of εs is assumed to be normal, with a mean of zero and variance σ2. The additive component of the residual error model was used to account for observations near the lower limit of detection of the assay.

Both the first order estimation (FO) and the first order with conditional estimation (FOCE) methods were examined during the modelling approach. A priori estimation of interindividual variability, as determined with FOCE was not feasible with the current


60

dataset due to lack of convergence with FOCE. All evaluations were therefore performed with the first order estimation method (FO).

No formal model validation was performed. The final pharmacokinetic model will be validated against further studies when results are available. Data were analysed pooling all centres. No adjustment was made for any potential effect of centre. No correction was made for multiple testing due to the nature of these analyses.

5.8.16.3. Demographic covariates

The primary objective of the covariate analysis was to explore demographic factors in this population that could explain non-random, interindividual variability in the pharmacokinetic parameters, improve goodness of fit and provide more accurate estimates for the secondary pharmacokinetic parameter AUC(0-24). Pharmacokinetic model discrimination and covariate selection were based on established clinical relevance and statistical criteria. Essentially the influence of height, weight, age, body mass index, gender and ethnic origin were tested on clearance and volume of distribution. However, only forty-eight subjects (12.1% of population) were not white and categorised as other. Therefore ethnic origin was not evaluated. To establish, which, if any, of the other covariates merited further evaluation plots of the covariates versus the intersubject variance (η) were generated. Where trends or correlations were evident, covariates further evaluated in the model using NONMEM.

• The influence of subject’s asthma history (baseline asthma symptom scores), and

• The effects of concurrent asthma medication

5.8.16.4. Individual pharmacokinetic estimates

Following completion of model building, individual post-hoc Bayesian pharmacokinetic parameter estimates were obtained and individal estimates of AUC(0-24) were calculated from the individual clearance values..

Pharmacokinetic parameters have been listed as arithmetic mean, standard deviation (SD), minimum (min), median and maximum (max). In addition, the geometric mean, between subject-variability and the corresponding 95% CIs were calculated where:

geometric mean = exp(mean on loge scale)

between-subject CV=SQRT[exp(SD on loge scale)2-1]x100

Pharmacokinetic data are stored in the GCP archives, GlaxoSmithKline Pharmaceuticals, Greenford, UK under Protocol FFA20001.

5.8.17. Pharmacokinetic/Pharmacodynamic Analyses

As an exploratory exercise, the relationship between GW685698X systemic exposure (AUC(0-24)) and clinical efficacy and safety endpoints were investigated by graphical examination. These endpoints included urinary cortisol excretion, average change from


61

baseline in trough PEF, average change from baseline in daytime and nighttime asthma symptom scores and percentage of symptom-free 24-hour days.

5.8.18. Pharmacogenetic Analyses

If PGx analyses were required, they were to be detailed in a separate report written by the Pharmacogenetics department.


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6. STUDY POPULATION RESULTS

6.1. Disposition of Subjects

A total of 669 subjects were recruited into the study (Table 6.1). Of these, 90 (13%) were withdrawn prior to randomisation. The most common reason for withdrawal prior to randomisation was failure to meet the eligibility criteria for randomisation (51 (8%) subjects) (Table 6.2). Other reasons for withdrawal prior to randomisation were: subject decided not to participate (12 (2%) subjects); protocol violation (10 (1%) subjects); adverse event (9 (1%) subjects); exacerbation (5 (<1%) subjects); lost to follow up (1 (<1%) subject) and other reasons (2 (<1%) subjects). Subject disposition is summarised in Table 2.

Table 2 Subject Disposition

GW685698X dose Number of Subjects Placebo

n (%) 100µg a.m.

n (%) 100µg p.m.

n (%) 250µg p.m.

n (%)

Total

n (%) Screened 669 Randomised1 144 (25) 144 (25) 148 (26) 142 (25) 578 (86) ITT 143 (25)2 144 (25)2 146 (25)2 142 (25)2 575 (86)1 Per Protocol2 119 (24) 128 (26) 128 (26) 119 (24) 494 (74) Completed2,3 124 (87) 133 (92) 135 (92) 134 (94) 526 (91) Withdrew after randomisation2

19 (13) 11 (8) 11 (8) 8 (6) 49 (9)

1. Percentage is based on the number of subjects screened 2. Percentages are based on the number of subjects in the ITT population within each treatment group 3. “Completed” means subjects who took study medication until Visit 6 4. Source: Table 6.1, Table 6.4

Three subjects (one in the placebo group and two in the GW685698X 100µg p.m. group) who were randomised to treatment were not included in the ITT population and reasons for the exclusions are given in Section 6.2. The ITT population comprised 575 subjects, equally distributed between the four treatment groups (Table 6.1). The number of subjects screened and randomised to treatment by each investigator is given in Table 6.3.

A total of 49 (9%) subjects withdrew from the ITT population following randomisation, 19 (13%) in the placebo group, 11 (8%) in each of the GW685698X 100µg a.m. and GW685698X 100µg p.m. groups and 8 (6%) in the GW685698X 250µg p.m. group. Table 3 summarises the reasons for withdrawal after randomisation in the ITT population.


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Table 3 Reasons for Withdrawal after Randomisation (ITT Population)

GW685698X dose Reason for Withdrawal Number (%)

Placebo

(n=143) 100µg a.m.

(n=144) 100µg p.m.

(n=146) 250µg p.m.

(n=142)

Total

(N=575) Asthma Exacerbation 6 (4) 4 (3) 6 (4) 0 16 (3) Subject decided to withdraw

1 (<1) 3 (2) 4 (3) 3 (2) 11 (2)

Adverse Event 6 (4) 1 (<1) 0 1 (<1) 8 (1) Protocol Violation 1 (<1) 1 (<1) 1 (<1) 4 (3) 7 (1) Lack of Efficacy 2 (1) 1 (<1) 0 0 3 (<1) Did not meet eligibility criteria

2 (1) 0 0 0 2 (<1)

Non-compliance 1 (<1) 0 0 0 1 (<1) Other (pregnancy) 0 1 (<1) 0 0 1 (<1) Source: Table 6.4

In the placebo group, 6 (4%) withdrew due to adverse events, whereas only one subject <1%) in the GW685698X 100µg a.m. and one (<1%) subjects in the GW685698X 250µg p.m. groups were withdrawn for this reason (Table 6.3). See Section 13.2 for narratives of the subjects who withdrew due to adverse events. The most common reason for withdrawal from the ITT population was exacerbation of asthma, which occurred in 16 (3%) subjects in the ITT population but did not occur in any subjects in the GW6856989X 250µg p.m. treatment group. Table 6.5 summarises the attendance of the ITT population at each of the clinic visits.

6.2. Protocol Deviations

Three subjects were randomised to treatment but were not included in the ITT population as there was documented evidence that they had not received any study medication.

Eighty-one (14%) subjects were totally excluded from the Per Protocol population due to major protocol violations, 24 (17%) in the placebo group, 16 (11%) in the GW685698X 100µg a.m. group, 18 (12%) in the GW685698X 100µg p.m. group and 23 (16%) in the GW685698X 250µg p.m. group. Table 6.6 summarises the reasons for exclusion from the Per Protocol population. One subject (<1%) in each of the GW685698X 100µg a.m. and GW685698X 250µg p.m. groups were totally excluded from the Per Protocol population because the study medication they were given was different from what they had been randomised to receive. These subjects were included in the ITT population in the treatment groups to which they were randomised, and in the safety population according to the treatment they received and are summarised in Table 6.7. The most commonly violated inclusion criteria for entry into the treatment period was failure to achieve a mean morning PEF of ≤ 80% of predicted normal during the last seven days of the run-in. This violation occurred in 38 (7%) subjects overall with a similar distribution across the four treatment groups (5% to 8%).


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A further 28 (5%) subjects were partially excluded from the Per Protocol population, 11 (8%) in the placebo group, 3 (2%) in the GW685698X 100µg a.m. group, 5 (3%) in the GW685698X 100µg p.m. group and 9 (6%) in the GW685698X 250µg p.m. group. The most common reason for partial exclusion from the Per Protocol population was failure to withdraw subjects from the study when FEV1 values met the criteria for withdrawal. This occurred in 14 (2%) subjects, 5 (3%) in the placebo group, 1 (<1%) in the GW685698X 100µg a.m. group, 2 (1%) in the GW685698X 100µg p.m. group and 6 (4%) in the GW685698X 250µg p.m. group. Data from these subjects were excluded from the Per Protocol analyses from the time point at which the violation had occurred (See Section 5.8.7.2).

No subjects were unblinded during the study.

6.3. Populations Analysed

The total population (669 subjects) comprised all subjects who entered the study. Of these, 578 (86%) subjects were randomised to treatment. The ITT population comprised 575 (86%) subjects who were randomised to treatment and received at least one dose of study medication. The Per Protocol population consisted of 494 (74%) subjects in the ITT population who did not have any major protocol violation that could have impacted treatment effects (Table 6.1).

6.4. Demographics and Other Baseline Characteristics

6.4.1. Demographic Characteristics

Table 4 summarises the demographic characteristics of the ITT population. Demographic characteristics were well matched across the four treatment groups (Table 6.8). The mean age of the study population was 36.6 years. The range of ages was 16-69 years. Although the inclusion criteria stated that the permitted age range was 16-55 years inclusive, three subjects in the GW685698X 100µg a.m. group were 56 years old, and in the GW685698X 250µg p.m. group three subjects were included whose ages were 56, 58 and 69 years. A total of 507 subjects (88%) of the ITT population were white/caucasian and 57% were female. All female subjects of child-bearing potential were documented as using adequate contraception. The majority of subjects (82%) had never smoked or were former smokers (17%). Although the entry criteria excluded current smokers, 2% of the ITT population were current smokers (Table 6.9). Overall the mean smoking history of the current and former smokers was 4.88 pack years with a range of 0.2 to 9.0 pack years.


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Table 4 Summary of Demographic Characteristics (ITT Population)

GW685698X dose Parameter Placebo

(n=143) 100µg a.m.

(n=144) 100µg p.m.

(n=146) 250µg p.m.

(n=142)

Total

(N=575) Age (yr),

mean (range)

36.5 (16-55)

36.0 (16-56)

37.1 (16-55)

36.9 (16-69)

36.6 (16-69) Sex n(%)

Female Male

75 (52) 68 (48)

81 (56) 63 (44)

87 (60) 59 (40)

84 (59) 58 (41)

327 (57) 248 (43)

Ethnic Origin n(%) White/Caucasian

Asian or Other

126 (88) 16 (11)

128 (89) 16 (11)

129 (88) 17 (12)

124 (87) 18 (13)

507 (88) 67 (12)

Height (cm) Mean

(range)

169.7

(143-195)

169.0

(143-197)

167.6

(142-196)

169.0

(139-195)

168.8

(139-197) Weight (kg)

Mean (range)

73.6

(46-115)

75.4

(43-120)

71.2

(40-120)

76.5

(40-124)

74.2

(40-124) Smoking History n(%)

Never Current Former

116 (81) 3 (2)

24 (17)

119 (83) 2 (1)

23 (16)

119 (82) 2 (1)

25 (17)

116 (82) 2 (1)

24 (17)

470 (82) 9 (2)

96 (17) Source: Table 6.8, Table 6.9

6.4.2. Baseline Characteristics

6.4.2.1. Asthma History

All subjects in the ITT population had a documented history of asthma of at least 6 months duration prior to Visit 1. A total of 37% of subjects (36% to 39% across the four groups) had had asthma for between one and five years and a further 58% (56% to 60% across the four groups) in excess of five years (Table 6.10). A total of 75% subjects overall had not experienced an exacerbation of asthma in the previous 6 months. A total of 144 subjects, 43 (30%) subjects in the placebo group, 34 (24%) subjects in the GW685698X 100µg a.m. group, 28 (19%) subjects in the GW685698X 100µg p.m. and 39 (27%) subjects in the GW685698X 250µg p.m. group had had at least one exacerbation in this time frame. A total of 267 asthma exacerbations were reported across the groups in the six months prior to Visit 1. In the placebo group, 70 exacerbations had occurred in the previous 6 months, of which 3 (4%) required hospitalisation and 6 (9%) required treatment with oral corticosteroids. In the GW685698X 100µg a.m. group there had been 68 exacerbations of which none required hospitalisation and 5 (7%) required oral corticosteroids. In the GW685698X 100µg p.m. group, 55 exacerbations had occurred, of which one (2%) required hospitalisation and 4 (7%) required oral corticosteroids. In the GW685698X 250µg p.m. group, 74 exacerbations had occurred of


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which 7 (9%) necessitated hospitalisation and 5 (7%) required treatment with oral corticosteroids.

6.4.2.2. Baseline Clinic Lung Function

Table 6.11 presents the baseline lung function of the ITT population measured at the investigator clinics before randomisation to treatment which is summarised in Table 5.

Table 5 Summary of Baseline Clinic Lung Function (ITT Population)

GW685698X dose Parameter Mean (SD)

Placebo

(n=143) 100µg a.m.

(n=144) 100µg p.m.

(n=146) 250µg p.m.

(n=142)

Total

(N=575) PEF (L/min)

Pre-bronchodilator1

% predicted normal2

% reversibility2

360.1

(92.31)

75.6 (9.59)

24.2 (9.91)

359.5

(86.47)

76.4 (9.88)

25.9 (13.42)

351.7

(83.75)

74.3 (11.24)

26.8 (13.71)

349.9

(83.32)

74.4 (10.62)

25.7 (11.37)

355.3

(86.41)

75.2 (10.37)

25.7 (12.22) FEV1 (L)

Pre-bronchodilator1

% predicted normal2

2.718

(0.910)

81.4 (15.26)

2.791

(0.963)

81.6 (17.12)

2.685

(0.962)

80.6 (16.97)

2.684

(0.866)

80.4 (14.66)

2.720

(0.925)

81.0 (16.01) Source: Table 6.11 1. Measured at Visit 2 2. Measured at Visit 1, 1a, 1b or 2

Overall, baseline function was typical of a mild to moderate asthmatic population and was very similar across the four groups. Baseline values indicated that the study population had PEF values that were reversible to inhaled VENTOLIN and therefore had room to demonstrate improvement to study medication.

6.4.2.3. Baseline Daily Record Card Lung Function Data

Table 6 summarises the baseline DRC lung function (PEF) data measured during the last 7 consecutive days of the run-in period.


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Table 6 Baseline Diary Card Pulmonary Function Data (ITT Population)

GW685698X dose Parameter Mean (SD)

Placebo

(n=143) 100µg a.m.

(n=144) 100µg p.m.

(n=146) 250µg p.m.

(n=142)

Total

(N=575) Morning PEF (L/min) 346.31

(82.39) 336.11 (86.93)

330.3 (82.18)

332.3 (81.64)

336.2 (83.33)

Evening PEF (L/min) 369.61 (90.91)

362.8 (93.64)

350.51 (92.26)

357.11 (90.02)

360.0 (91.76)

Source: Table 6.12 1. Value used for analysis of trough PEF (i.e. measurement taken 24 hours after dosing)

All treatment groups showed diurnal variation in PEF, with evening measurements between 20L/min and 27L/min (6.1% - 7.9%) greater than the corresponding morning values (Table 6.12). Analysis of trough PEF values during the treatment period was performed using the change from baseline trough value for each subject. Hence, for the morning dosed group, the morning PEF baseline and treatment values were used and for the evening dosed groups, the evening values were used. For the placebo group, both morning and evening values were used as baseline and treatment trough values, depending on the comparison being made (i.e. morning values for comparison with GW685698X 100µg a.m.).

6.4.3. Other Current Medical Conditions

A total of 325 (57%) subjects presented with concurrent medical conditions, 81 (57%) in the placebo group, 73 (51%) in the GW685698X 100µg a.m. group, 85 (58%) in the GW685698X 100µg p.m. group and 86 (61%) in the GW685698X 250µg p.m. group (Table 6.13). In general, the distribution of concurrent medical disorders was similar across the treatment groups. The most commonly occurring concurrent medical conditions were disorders of the respiratory, thoracic and mediastinum which affected 167 (29%) subjects overall, and between 24% and 32% subjects across the four treatment groups. A total of 64 (11%) subjects reported concurrent eye disorders (9% to 14% across the four treatment groups) and 57 (10%) subjects reported concurrent cardiac disorders (8% to 13% across the four treatment groups). Skin disorders were reported by 39 (7%) subjects overall with 15 subjects (10%) in the GW685698X 100µg p.m. group compared with 8 (6%) subjects in each of the other three treatment groups. Other concurrent conditions that affected 5% or more subjects in any treatment group were: endocrine disorders (8% subjects in the GW685698X 100µg p.m. group and 6% subjects in the GW685698X 250µg p.m. and placebo groups); gastrointestinal disorders (6% subjects in the GW685698X 100µg a.m. GW685698X 250µg p.m. groups); immune system disorders (5% to 8% subjects across the four treatment groups); metabolism and nutrition disorders (5% subjects in each of the GW685698X 100µg a.m. and GW685698X 100µg p.m. groups); musculoskeletal and connective tissue disorders (6% subjects in the placebo group and 5% subjects in the GW685698X 250µg p.m. groups); reproductive system and breast disorders (5% subjects in the GW685698X 100µg a.m. group) and vascular disorders (5% subjects in the GW685698X 250µg p.m. group). All


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other concurrent medical conditions affected less than 5% subjects in any treatment group (Table 6.13).

6.4.4. Previous Medications

6.4.4.1. Previous Asthma Medications

The protocol clearly defined the permitted and non-permitted use of asthma medications prior to and on entry into the study and the time frames in which non-permitted asthma medications had not to be used before entry to the study (See Section 5.5.1 and Section 5.5.2). All subjects had stopped the use of asthma medications such as inhaled corticosteroids within the appropriate times on entry to the study. At Visit 1 the current use of asthma medications was documented in the CRF. The use of asthma medications in the pre-treatment phase of the study was similar across the groups. A total of 83% subjects in the placebo and GW685698X 100µg a.m. groups, 80% subjects in the GW685698X 100µg p.m. group and 82% subjects in the GW685698X 250µg p.m. group recorded the use of concomitant asthma medications (Table 6.14). The use of salbutamol was recorded by 69% to 73% subjects across the four treatment groups. A total of 4% subjects in the placebo and GW685698X 100µg a.m. groups, <1% in the GW685698X 100µg p.m. and 2% subjects in the GW685698X 250µg p.m. group reported the use of Budesonide. A total of 3% of subjects in the placebo, GW685698X 100µg a.m. and GW685698X 250µg p.m. groups were using sodium cromoglycate. Use of fenoterol hydrobromide was reported by 3% of subjects in the GW685698X 100µg a.m. and 4% of subjects in the GW685698X 100µg p.m. groups. A total of 3% of subjects in the GW685698X 100µg p.m. and GW685698X 250µg p.m. groups were using beclomethasone dipropionate. Fluticasone propionate was reported in 3% of subjects in the GW685698X 100µg p.m. A total of 3% of subjects in the GW685698X 100µg a.m. group reported the use of SERETIDE™, while a further 3% of subjects in the GW685698X 250µg p.m. group used SEREVENT™ and 3% of subjects in the GW685698X 100µg a.m. group reported the use of terbutaline. All other asthma medications were used by 2% or less of subjects in any treatment group.

6.5. Concomitant Medications

6.5.1. Concomitant Asthma Medications

Table 6.15 summarises concomitant asthma medications taken during the treatment period. A total of 10% of subjects in the placebo group, 8% of subjects in the GW685698X 100µg a.m. and GW685698X 250µg p.m. groups and 7% of subjects in the GW685698X 100µg p.m. groups reported the use of concomitant asthma medications. A total of 3% of subjects in the placebo and GW685698X 100µg a.m. groups, 2% of subjects in the GW685698X 100µg p.m. group and 4% of subjects in the GW685698X 250µg p.m. groups reported the use of salbutamol during the treatment period. However, all subjects were supplied with VENTOLIN for use as rescue medication. Some investigators recorded this as concurrent medication and others did not as it was provided as part of the study medication. A total of 3% of subjects in the placebo and


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GW685698X 100µg a.m. groups reported the use of sodium cromoglycate during the treatment period. All other use of asthma medications for the treatment of respiratory conditions was reported in 2% or less of subjects in any treatment group.

6.5.2. Concomitant Non-Asthma Medications

Non-asthma medications were taken by 218 (38%) subjects overall in the ITT population (34% to 41% subjects across the four treatment groups). The most common indications for non-asthma concomitant medication were for nervous system disorders (11% subjects in the ITT population), cardiovascular disorders (10% subjects in the ITT population) and genitourinary and sex hormone disorders (10% subjects in the ITT population) (Table 6.16).

Table 7 summarises the non-asthma concomitant medications taken by ≥ 5% subjects in any treatment group. In general, the use of non-asthma concomitant medications was similar across the four treatment groups. However, a higher percentage (15%) of subjects in the GW685698X 250µg p.m. group took medications for the cardiovascular body system compared with the other treatment groups (8-9%). Similarly, fewer subjects in the placebo group took medications for genitourinary/sex hormone conditions (6%) compared with the three active treatment group (10-14%).

Table 7 Summary of Non-Asthma Medication taken by Greater than or equal to 5% Subjects in any Treatment Group during the Treatment Period (ITT Population)

GW685698X dose ATC Category1 No (%)

Placebo

(n=143) 100µg a.m.

(n=144) 100µg p.m.

(n=146) 250µg p.m.

(n=142)

Total

(N=575) Nervous System 14 (10) 17 (12) 18 (12) 17 (12) 66 (11) Cardiovascular System

12 (8%) 13 (9) 13 (9) 21 (15) 59 (10)

Genito-urinary/Sex hormones

8 (6) 15 (10) 21 (14) 14 (10) 58 (10)

Respiratory System 14 (10) 12 (8) 9 (6) 12 (8) 47 (8) Alimentary Tract and Metabolism

15 (10) 10 (7) 9 (6) 11 (8) 45 (8)

Dermatologicals 10 (7) 6 (4) 8 (5) 7 (5) 31 (5) Musculo-skeletal System

7 (5) 4 (3) 10 (7) 10 (7) 31 (5)

Sensory Organs 8 (6) 4 (3) 3 (2) 6 (4) 21 (4) Source: Table 6.16 1. ATC Level 1 Category


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7. EFFICACY RESULTS

7.1. Primary Efficacy Results

The primary efficacy endpoint was mean change from baseline in daily trough (pre-study treatment and bronchodilator) PEF, as recorded in the DRC, during the 28 day treatment period.

Table 7.1 presents the summary statistics of trough PEF at baseline and at each of the time points during the treatment period for each of the three active treatments and for placebo (a.m. and p.m.) and these are shown graphically in Figure 7.1. The statistical analysis of the results is presented in Table 7.2. These results and the statistical analyses performed are summarised in Table 8.

Table 8 Analysis of Change from Baseline in Trough PEF (Weeks 1-4) (ITT population)

Placebo GW685698X Dose Trough PEF (L/min) a.m. p.m. 100 µg

a.m. 100 µg

p.m 250 µg

p.m. Baseline mean (SD) 346.1

(82.0) 369.7 (91.0)

335.9 (87.2)

350.4 (93.1)

356.7 (90.2)

Adjusted mean change (SE)

18.8 (4.9)

8.8 (4.9)

38.0 (4.6)

24.6 (4.9)

33.4 (4.8)

Statistical Analysis Column - GW685698X p.m. Difference (SE) 95% CL

13.4 (5.62) 2.3, 24.4

8.8 (5.59) (-2.2, 19.7)

Column Treatment-Placebo1 Difference (SE) 95%CL p-value

19.2 (5.60) 8.2, 30.2 <0.001

15.9 (5.60) 4.9, 26.9

0.005

24.6 (5.62) 13.6, 35.7

<0.001 Source: Table 7.2 SD: Standard Deviation; SE: Standard Error 1. GW685698X a.m. values are compared with placebo a.m. values; GW685698X p.m. values are compared with

placebo p.m. values

As discussed in Section 6.4.2.3, trough baseline values for the morning groups were lower than the corresponding trough baseline values for the evening dosing groups, due to inherent diurnal variations in PEF. There was also a slight imbalance between the baseline evening trough measurements (370L/min for placebo and 350L/min and 357L/min for the GW685698X 100µg and 250µg p.m. groups respectively). The placebo a.m. group showed an unexpectedly large response (18.8L/min) during the treatment period. However all active treatments showed a larger treatment response than placebo.

For the primary treatment comparison, the difference between GW685698X 100µg a.m. and GW685698X 100µg p.m. was 13L/min (95%CI: 2, 24) suggesting that a.m. dosing


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resulted in greater improvements in trough PEF than evening dosing. However, in addition to the true treatment effect of GW685698X, the a.m. trough values may be affected by a placebo response that was greater in the morning than evening. Therefore, comparison of a.m. versus p.m. values for trough PEF may be biased. The width of the confidence interval was slightly wider than the 20L/min width that the study was designed to show due to a higher variability in trough PEF (47 L/min) than had been assumed (40L/min).

Both a.m. and p.m. dosing with GW685698X 100µg resulted in statistically significant improvements in trough PEF compared with placebo (19L/min and 16L/min respectively) (Table 7.2). Therefore, in terms of comparison with placebo, the 100µg a.m. group demonstrated a 3L/min improvement over the 100µg p.m. group suggesting that morning and evening dosing were comparable for this endpoint.

Confirmatory analyses of trough PEF using the Per Protocol population are presented in Table 7.3 and Table 7.4. These results support the primary analyses using the ITT population.

Figure 1 presents the results of the change from baseline in trough PEF. The magnitude of active treatment effect over the corresponding placebo response can be seen along with the larger improvement in trough PEF following a.m. dosing compared with p.m. dosing.

The GW685698X 250µg p.m. group demonstrated the largest improvement compared with placebo (25L/min). It also demonstrated a 9L/min improvement over GW685698X 100µg given p.m., although the lower limit of the confidence interval for this difference was –2.


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Figure 1 Change from Baseline in Trough PEF (ITT Population)

0

10

20

30

40

50

60

70

Week 1 Week 2 Week 3 Week 4

PEF

(L/m

in)

GW685698X 100mcg a.m. GW685698X 100mcg p.m.Placebo a.m. Placebo p.m.

7.1.1. 24-hour Duration of Action

Formal assessment of duration of action of GW685698X was not an objective of this study. However the trough (24 hour) changes in PEF are presented in Figure 2 alongside the 12-hour changes in PEF for each group. Taking into account placebo response, the the 12-hour values were approximately 2-5 L/min higher than the trough (24-hour) values. This indicates that GW685698X is effective over 24 hours following dosing.


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Figure 2 Trough and 24-Hour Changes from Baseline in PEF

0

5

10

15

20

25

30

35

PEF

(L/m

in) C

hang

e fr

om

Bas

elin

e W

eeks

1-4

100 a.m. morning 100 a.m. evening100 p.m. morning 100 p.m. evening250 p.m. morning 250 p.m. evening

Trough Trough Trough

4.8

1.7

4.4

7.1.2. Trough PEF (Per Protocol Population)

Confirmatory analyses of trough PEF using the Per Protocol population are presented in Table 7.3 and Table 7.4. These results show the same pattern as the ITT results with only slightly smaller treatment differences relative to placebo for each of the three active groups.

7.1.3. Trough PEF for Treatment Weeks 1, 2, 3 and 4

Table 7.5, Table 7.6, Table 7.7 and Table 7.8 present the statistical analysis of trough PEF expressed as the change from baseline over Weeks 1, 2, 3 and 4. The pattern of results is the same as that for all four weeks of treatment combined, with the differences between GW685698X 100µg a.m. and p.m. being consistently in favour of a.m. dosing rather than p.m. dosing. However the magnitude of this effect is much reduced if placebo responses are taken into account. The GW685698X 250µg p.m. group consistently had the highest improvements relative to placebo. All GW685698X groups showed statistically significant improvements relative to placebo at every week with the exception of the GW685698X 100 a.m. group at week 1 (p=0.054) and GW685698X 100µg p.m. group at Week 3 which narrowly failed to reach statistical signficance (p=0.051). These results are summarised in Table 9.


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Table 9 Change from Baseline in Trough PEF (ITT Population)

Treatment Week PEF L/min Difference (SE)

95% CI 1 2 3 4

GW685698X 100µg a.m. – p.m. 6.8 (4.86) -2.7,16.4

13.7 (5.81) 2.3, 25.1

17.8 (6.32) 5.4, 30.2

17.0 (6.84) 3.6, 30.5

GW685698X 100µg a.m. – placebo 9.4 (4.84) -0.1, 18.9

15.6 (5.84) 4.2, 27.1

19.5 (6.39) 6.9, 32.0

20.9 (6.93) 7.3, 34.5

GW685698X 100µg p.m. – placebo 12.1 (4.85) 2.6, 21.6

11.9 (5.81) 0.5, 23.3

12.4 (6.37) -0.1, 24.9

15.8 (6.92) 2.2, 29.3

GW685698X 250µg p.m. – placebo 14.4 (4.87) 4.9, 24.0

23.1 (5.85) 11.7, 34.6

23.9 (6.40) 11.3, 36.5

21.4 (6.91) 7.8, 34.9

GW685698X 250µg p.m. – 100µg p.m.

2.4 (4.83) -7.1, 11.9

11.2 (5.75) -0.1, 22.5

11.4 (6.25) -0.8, 23.7

5.6 (6.73) -7.6, 18.8

Source: Table 7.5, Table 7.6, Table 7.7, Table 7.8

7.1.4. Results of Covariate Analyses

Table 7.9 presents the p-values associated with tests for treatment-by-covariate interactions in trough PEF analysis model. There were no significant treatment interactions for age, sex and country (p=0.692, p=0.704 and p=0.698 respectively). There was, however, a positive (p<0.1) treatment interaction for baseline trough PEF (p=0.072). Therefore change from baseline trough PEF was summarised for each subgroup using the median value (339L/min) across the ITT population to dichotomise the population. The results are summarised in Table 7.10.

For subjects with a baseline trough PEF of <339L/min, the greatest improvement was observed following treatment with GW685698X 250µg p.m. (44L/min). However this improvement was very similar to that seen following treatment with GW685698X 100µg a.m. (43L/min). GW685698X 100µg a.m. resulted in a larger improvement than that seen following treatment with GW685698X 100µg p.m. (35L/min).

For subjects with a baseline trough PEF of >339L/min, treatment with GW685698X 100µg a.m. resulted in the largest improvement in trough PEF (44L/min) compared with either GW685698X 250µg p.m. (31L/min) or GW685698X 100µg p.m. (23L/min). Therefore, subjects in the GW685698X 100µg a.m. group had consistent improvements in trough PEF from baseline regardless of their baseline values (< or >339L/min), whereas the other active groups demonstrated greater improvements is subjects with lower PEF values at baseline. However, it should also be noted that for subjects with a baseline PEF <339L/min, the placebo response in p.m. values (18L/min) was almost as high as for the a.m. measurements (20.5L/min). But for subjects with a baseline PEF of ≥339 L/min, the p.m. placebo response was much lower than that of the a.m. values. Therefore a substantial amount of the observed improvement in the GW685698X p.m. groups for the milder subgroup could have been due to ‘placebo response’ rather than a real superiority of effect in these subjects.


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7.1.5. Trough PEF by Baseline Asthma Severity

Table 7.11 examined the changes in trough PEF by baseline asthma severity defined by percent predicted normal PEF at Visit 2 (either <65% or >65%). GW685698X 250µg p.m. and 100µg a.m. demonstrated greater improvements in trough PEF in the less severe subgroup (39 – 45L/min) whereas the improvements in the 100µg p.m. group were the same for each subgroup (29L/min). The placebo response for both morning and evening trough PEF were largely restricted to the milder subgroup, with the a.m. trough PEF measurements increasing by 29L/min from baseline (compared with 2L/min in the more severe subgroup). The GW685698X 100µg p.m. placebo response for trough PEF was 17L/min in the milder subgroup and –4L/min in the more severe subgroup. However, there were few subjects enrolled in the study with a percent predicted PEF of <65% (approximately 20 per group) and therefore the results for this subgroup may be unreliable.

7.2. Secondary Efficacy Endpoints

7.2.1. Morning PEF

Table 7.12 summarises the results of mean morning PEF measured at baseline and over Weeks 1-4. The morning versus evening dosing with GW685698X 100µg comparison in the change from baseline in morning PEF was theoretically biased in favour of the evening dosing regimen. This was because morning PEF (which was measured before taking study medication) represented the trough effect for the morning dosing group, but not the evening dosing group (where it represented 12 hours post dosing).

Table 7.13 summarises the statistical analysis of the change from baseline in mean morning PEF (12 hours post-dosing for the p.m. dosed groups). Compared with placebo, all three active groups were statistically significantly superior to placebo over Weeks 1-4 with treatment effects ranging from 17L/min to 29L/min. Despite the endpoint being theoretically biased in favour of the p.m. dosed group, GW685698X 100µg a.m. had a 2L/min improvement relative to 100µg p.m., indicating that morning dosing was at least as efficacious as evening dosing.

7.2.2. Evening PEF

Table 7.14 summarises the results of mean evening PEF measured at baseline and over Weeks 1-4. The morning versus evening dosing with GW685698X 100µg comparison in the change from baseline in morning PEF was theoretically biased in favour of the morning dosing regimen. This was because evening PEF (which was measured before taking study medication) represented the trough effect for the evening dosing group, but not the morning dosing group (where it represented 12 hours post dosing).

Table 7.15 summarises the statistical analysis of the change from baseline in mean evening PEF (12 hours post-dosing for the GW685698X 100µg a.m. group). Compared with placebo, all three active groups were statistically significantly superior to placebo over weeks 1-4, with treatment effects ranging from 16L/min to 24L/min. Although the


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endpoint was theoretically biased in favour of the a.m. dosed groups, GW685698X 100µg a.m. showed a 9L/min improvement relative to the 100µg p.m. group. However, the confidence interval included zero indicating that there may not be a true difference between the groups.

7.2.3. Change from Baseline in Pre-bronchodilator FEV1

Table 7.16 presents the summary statistics of clinic visit measurements of FEV1 at baseline (Visit 2) and at each of clinic visits 3, 4, 5 and 6 and at Endpoint (LOCF for missing data) for the ITT population. Baseline mean FEV1 values were relatively balanced across the groups, although baseline mean FEV1 for the GW685698X 100µg a.m. group was approximately 100ml higher than for the two p.m. groups and approximately 75ml higher than for the placebo group. Mean FEV1 values increased in all active treatment groups during the treatment period, with the active groups showing greater improvements at each successive visit.

Table 10 Analysis of Clinic Visit FEV1 (Change from Baseline at Endpoint) (ITT Population)

GW685698X Dose FEV1 (L) Placebo

(N=143) 100 µg a.m.

(N=144) 100 µg p.m

(N=146) 250 µg p.m.

(N=142) Number of Subjects 137 143 142 140 Baseline mean (SD) 2.756 (0.897) 2.788 (0.996) 2.704 (0.962) 2.684 (0.872) Adjusted mean change (SE)

0.099 (0.043) 0.203 (0.041)

0.265 (0.042)

0.317 (0.042)

Statistical Analysis Column - GW685698X p.m. Difference (SE) 95% CL

-0.062 (0.048) -0.156, 0.032

0.052 (0.048) -0.043, 0.147

Column Treatment-Placebo Difference (SE) 95%CL p-value

0.104 (0.048) 0.009, 0.199 0.032

0.166 (0.049) 0.071, 0.262 <0.001

0.218 (0.049) 0.123, 0.314 <0.001

Source: Table 7.17 SD: Standard Deviation; SE: Standard Error

Table 7.17 presents the results of the treatment comparisons between GW685698X 100µg a.m. and p.m. and 250µg p.m. and placebo for change from baseline in clinic measured FEV1. These results are summarised in Table 10. GW685698X 250µg p.m. showed the greatest improvements relative to placebo and to baseline, followed by the GW685698X 100µg p.m. group. However all confidence intervals for active treatment differences included zero, thereby failing to demonstrate conclusive superiority of any given dose. The point estimate of treatment differences between a.m. and p.m. groups was small.


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7.2.4. Change from Baseline in Pre-Bronchodilator Clinic Visit PEF

Table 7.18 presents the results of clinic visit measurement of PEF at baseline (Visit 2) and at each of clinic visits 3, 4, 5 and 6 and at Endpoint (LOCF for missing data) for the ITT population. Baseline mean PEF values were similar across all groups, varying by 10L/min from the smallest to the largest baseline mean values.

Table 7.19 presents the results of the treatment comparisons between GW685698X 100µg a.m. and p.m., between GW685698X 100µg and 250µg p.m. and between each GW685698X treatment group and placebo for change from baseline in clinic measured PEF. These results are summarised in Table 11. Improvements from baseline were similar across the groups, although there was an indication that GW685698X 250µg p.m. produced larger increases than either of the GW685698X 100µg treatment groups.

Table 11 Analysis of Clinic Visit PEF (Change from Baseline at Endpoint) (ITT Population)

GW685698X Dose PEF (L/min) Placebo

(N=143) 100 µg a.m.

(N=144) 100 µg p.m

(N=146) 250 µg p.m.

(N=142) Number of Subjects 138 143 142 140 Baseline mean (SD) 364.2 (89.8) 359.1 (86.6) 352.1 (84.1) 349.2 (83.6) Adjusted mean change (SE) 31.1 (6.3) 57.3 (6.0) 56.1 (6.3) 62.8 (6.2) Statistical Analysis Column - GW685698X p.m. Difference (SE) 95% CL

1.2 (7.16) -12.9, 15.2

6.7 (7.18) -7.4, 20.8

Column Treatment-Placebo1 Difference (SE) 95%CL p-value

26.2 (7.20) 12.0, 40.3

<0.001

25.0 (7.22) 10.8, 39.2

<0.001

31.7 (7.24) 17.4, 45.9

<0.001 Source: Table 7.19 SD: Standard Deviation; SE: Standard Error

7.2.5. Asthma Symptom Scores

7.2.5.1. Percentage of Symptom-free 24 hour periods

Table 7.20 summarises the results of DRC recordings of the percentage of symptom-free 24-hour periods at baseline and over the 4-week treatment period for the ITT population. Baseline percentages of 24-hour symptom-free periods were low (between 4% and 7% across the groups) as was expected due to the requirement for symptoms for eligibility. During treatment, the percentage of symptom-free 24-hour periods increased in all four treatment groups. The mean percentage of symptom-free 24-hour periods was 29% in the placebo group, 41% in the GW685698X 100µg a.m. group, 43% in the GW685698X 100µg p.m. group and 48% in the GW685698X 250µg p.m. group.


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Table 7.21 presents the statistical analysis of this endpoint. There was no difference between GW685698X 100µg, a.m. or p.m. (0.1% treatment difference). There was a small benefit observed in the GW685698X 250µg group relative to the 100µg groups (4%) but the confidence interval for the difference between GW685698X 250µg p.m. and GW685698X 100µg p.m. was –3, 11, indicating a non-significant effect. When the three active treatments were compared with placebo, the difference in the percentage of symptom-free 24 hour periods was in all cases statistically significant (p<0.001 for all three active treatment groups) and ranged between 14% and 19%.

7.2.5.2. Percentage of Symptom-free Days and Nights

Table 7.22 summarises the percentage of symptom-free days at baseline and over the 4-week treatment period for the ITT population. Baseline values were slightly lower in the GW685698X 100µg a.m. group (9%) compared with the placebo group (13%), the GW685698X 100µg p.m. group (13%) and the GW685698X 250µg p.m. group (13%). During treatment, the mean percentage of symptom-free days increased in all four groups. In the placebo group, the percentage of symptom-free days rose to 36%, while the increases in the GW685698X 100µg a.m., 100µg p.m. and 250µg p.m. groups rose to 48%, 48% and 53% respectively.

Table 7.23 presents the statistical analysis of the percentage of symptom-free days. The adjusted mean change from baseline was slightly higher in the GW685698X 250µg p.m. group (43%) compared with the GW685698X 100µg p.m. group (37%) and the GW685698X 100µg a.m. group (40%). The adjusted mean change from baseline in the placebo group was 26%. The difference between GW685698X 100µg a.m. and p.m. dosing was 3% (95%CI: -4, 10), indicating that there was no real difference between these two groups and therefore time of dosing with GW685698X 100µg did not affect this outcome. The difference between GW685698X 250µg p.m. and GW685698X 100µg p.m. was 6% (95%CI: -1, 13). All three active treatments showed statistically significant differences compared with placebo (p≤0.001).

Table 7.24 presents the results of the percentage of symptom-free nights. Mean baseline values were slightly higher in the placebo group (40%) compared with the GW685698X 100µg a.m. group (38%), GW685698X 100µg p.m. group (38%) and GW685698X 250µg p.m. group (35%). Over weeks 1-4 of the treatment period, these values increased to 59% in the placebo group, 67% in the GW685698X 100µg a.m. group, 71% in the GW685698X 100µg p.m. group and 72% in the GW685698X 250µg p.m. group.

Table 7.25 presents the results of the statistical analysis of percentage of symptom-free nights. The adjusted mean changes from baseline in the percentage of symptom-free nights was slightly higher in the GW685698X 250µg p.m. group (38%) than the GW685698X 100µg p.m. group (36%) and the GW685698X 100µg a.m. group (31%). The adjusted mean change in the placebo groups was 23%. The treatment difference between GW685698X 250µg p.m. and 100µg p.m. was 3% (95%CI: -4, 9) indicating that there was little difference between the two doses for this parameter. The difference between GW685698X 100µg a.m. and p.m. dosing was –4% (95%CI: -10, 2), indicating that morning and evening dosing had similar effects on this endpoint. All differences


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between the three active treatment groups and placebo were statistically significant with treatment differences of 9%, 13% and 16% for GW685698X 100µg a.m., GW685698X 100µg p.m. and GW685698X 250µg p.m. respectively.

7.2.5.3. Percentage of Nights with No Awakenings

Table 7.26 summarises the results of DRC recordings of the percentage of nights with no awakenings due to asthma at baseline and over the 4-week treatment period for the ITT population. Baseline values were similar across the groups: 50% in the placebo group, 47% in the GW685698X 100µg a.m. group, 47% in the GW685698X 100µg p.m. group and 45% in the GW685698X 250µg p.m. group. During treatment, the percentage of nights with no awakenings increased in all four treatment groups. The mean values rose to 65% in the placebo group, 74% in the GW685698X 100µg a.m. group, 76% in the GW685698X 100µg p.m. group and 77% in the GW685698X 250µg p.m. group.

Table 7.27 presents the statistical analysis of this endpoint. For the comparison between GW685698X 100µg a.m. or p.m. dosing, the difference between treatments was –2.5% (95%CI: -8.6, 3.5) indicating that there was little difference between the two treatments. For the comparison between GW685698X 250µg p.m. and GW685698X 100µg p.m., the difference was 2.1% (95%CI: -4.0, 8.2). When the three active treatments were compared with placebo, the difference in the percentage of nights with no awakenings was in all cases statistically significant with treatment differences of between 9% and 14%.

Overall the percentage of nights with no awakenings was slightly higher in the GW685698X 250µg p.m. group; however, the difference was not statistically significant and there was little difference between morning or evening dosing with GW685698X 100µg.

7.2.6. Rescue Medication Use

7.2.6.1. Percentage of VENTOLIN-free 24-hour periods

Table 7.28 summarises the results of DRC recordings of the percentage of rescue-free 24-hour periods at baseline and over the 4-week treatment period for the ITT population. Baseline percentages of 24-hour rescue-free periods were highest in the placebo group (18%) compared with 9% in the GW685698X 100µg a.m. group, 16% in the GW685698X 100µg p.m. group and 14% in the GW685698X 250µg p.m. group. During treatment, the percentage of rescue-free 24-hour periods increased in all four treatment groups. The mean percentage of rescue-free 24-hour periods was 39% in the placebo group, 50% in the GW685698X 100µg a.m. group, 52% in the GW685698X 100µg p.m. group and 54% in the GW685698X 250µg p.m. group.

Table 7.29 presents the statistical analysis of this endpoint. For the comparison between GW685698X 100µg, a.m. or p.m. dosing, the difference between treatments was 2% (95%CI: -5, 10) indicating that there was little difference between the two treatments. For the comparison between GW685698X 250µg and GW685698X100µg p.m., the


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difference was 4% (95%CI: -4, 11). When the three active treatments were compared with placebo, the difference in the percentage of rescue-free 24 hour periods was in all cases statistically significant (with treatment differences of between 14% and 18%).

Overall, the percentage of rescue-free 24-hour periods was slightly higher in the GW685698X 250µg p.m. group. However, the difference between the GW685698X 250µg p.m. group and the GW685698X 100µg p.m. group (4%) was not statistically significant and there was little difference between morning and evening dosing with GW685698X 100µg.

7.2.6.2. Percentage of VENTOLIN-free Days and Nights

Table 7.30 summarises the percentage of rescue-free days at baseline and over the 4-week treatment period for the ITT population. This parameter was theoretically biased towards the GW685698X 100µg a.m. treatment group as the assessments were made 12 hours post-dose for this treatment group compared with 24 hours post dose (trough) for the p.m. dosed groups. Baseline values were somewhat lower in the GW685698X 100µg a.m. group (15%) compared with the placebo group (24%), the GW685698X 100µg p.m. group (22%) and the GW685698X 250µg p.m. group (20%). During treatment, the mean percentage of rescue-free days increased in all four groups. In the placebo group, the percentage of rescue-free days rose to 46%, while the values in the GW685698X 100µg a.m., 100µg p.m. and 250µg p.m. groups rose to 55%, 57% and 59% respectively.

Table 7.31 presents the statistical analysis of the percentage of rescue-free days. The adjusted mean change from baseline was slightly higher in the GW685698X 250µg p.m. group (39%) compared with the GW685698X 100µg p.m. group (36%) and the GW685698X 100µg a.m. group (38%). The adjusted mean change from baseline in the placebo group was 24%. The difference between GW685698X 100µg a.m. and p.m. dosing was 2% (95%CI: -5, 10), indicating that morning and evening dosing with GW685698X 100µg were essentially equally effective. The difference between GW685698X 250µg p.m. and GW685698X100µg p.m. was 4% (95%CI: -4, 11). All three active treatments showed statistically significant differences compared with placebo of between 12 and 15%.

Table 7.32 presents the results of the percentage of rescue-free nights. This endpoint was theoretically biased in favour of the p.m.- treated groups as the assessment was made 12 hours after the evening dose and at 24 hours (trough) after the morning dose. Mean baseline values were similar across the groups, 55%, 53%, 52% and 48% in the placebo group, the GW685698X 100µg a.m. group, the GW685698X 100µg p.m. group and the GW685698X 250µg p.m. group respectively. Over weeks 1-4 of the treatment period, these values increased to 67% in the placebo group, 76% in the GW685698X 100µg a.m. group, 78% in the GW685698X 100µg p.m. group and 77% in the GW685698X 250µg p.m. group.

Table 7.33 presents the results of the statistical analysis of percentage of rescue-free nights. The adjusted mean changes from baseline in the percentage of rescue-free nights was slightly higher in the GW685698X 250µg p.m. group (26%) than the GW685698X


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100µg p.m. group (25%) and the GW685698X 100µg a.m. group (23%). The adjusted mean change in the placebo groups was 12%. The treatment difference between GW685698X 250µg p.m. and 100µg p.m. was 1% (95%CI: -5, 7) indicating that there was little difference between the two doses on this parameter. The difference between GW685698X 100µg a.m. and p.m. dosing was –2% (95%CI: -8, 4), indicating that they were essentially equally effective in improving this parameter. All differences between all three active treatment groups and placebo were statistically significant with treatment differences of between 11% and 14%.

7.2.7. Withdrawals Due to Lack of Efficacy

Table 7.34 presents the statistical analysis of the number of withdrawals due to lack of efficacy. Only three subjects, two in the placebo group and one in the GW685698X 100µg a.m. group withdrew for this reason. Therefore, there was little power to detect any treatment effects.

7.2.8. Summary of Efficacy Endpoints

Table 12 provides an overall summary of the efficacy endpoints, showing the changes from baseline compared with placebo for each of the efficacy endpoints.

Table 12 Summary of Changes from Baseline (Treatment Differences from Placebo) in Efficacy Endpoints (ITT Population)

GW685698X Dose Endpoint 100 µg a.m.

(N=144) 100 µg p.m

(N=146) 250 µg p.m.

(N=142) Trough PEF (L/min) 19.2 15.9 24.6 Morning PEF (L/min) 19.6 17.3 28.8 Evening PEF (L/min) 24.4 15.6 24.4 Clinic FEV1 (L) 0.104 0.166 0.218 Clinic PEF (L/min) 26.2 25.0 31.7 24-hour Symptom-free Periods (%)

14.6 14.4 18.7

Symptom-free Days (%) 14.3 11.5 17.5 Symptom-free Nights (%) 9.0 13.0 15.9 24-hour Rescue-free Periods (%)

16.4 14.0 17.9

Rescue-free Days (%) 13.8 11.5 15.1 Rescue-free Nights (%) 10.5 12.7 13.7 Night-time Awakenings (%) 9.4 11.9 14.0 Source: Table 7.1 to Table 7.33


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7.3. Efficacy Conclusions

• Treatment for 28 days with GW685698X resulted in statistically and clinically significant benefits over placebo for all efficacy measures.

• GW685698X demonstrated a 24-hour duration of effect.

• No clinically important differences were observed on any efficacy measure between morning and evening dosing.

• For the primary efficacy comparison, (mean change from baseline in daily trough PEF during treatment with GW685698X 100µg once daily in the morning compared with once daily in the evening), a difference of 13L/min in favour of morning dosing was observed. However due to the large placebo response in the morning measurements, the placebo effect should be taken into account when drawing conclusions regarding the GW685698X 100µg a.m. group. When this is done, there was only a 3L/min difference between the two GW685698X 100µg groups, thereby indicating that GW685698X 100µg had comparable efficacy when dosed in the morning compared with the evening.

• When compared with placebo, GW685698X 250µg p.m. had a greater effect on change from baseline in trough PEF than GW685698X 100µg a.m. or p.m..

• All GW685698X dosing regimens demonstrated significant improvements over placebo for all secondary efficacy endpoints (except withdrawals due to lack of efficacy, of which only three occurred, two in the placebo group and one in the GW685698X 100µg a.m. group).

• GW685698X 250µg p.m. had a slightly greater effect on clinic-measured FEV1 and PEF than GW685698X 100µg given either in the morning or evening. However these benefits were relatively small and not likely to be clinically relevant.

• For asthma symptom endpoints, there were no apparent differences between morning and evening dosing. The GW685698X 250µg p.m. dose showed slightly greater improvements compared with the 100µg a.m. or p.m. dose, although the differences were not significant and all three active treatments were statistically significantly better than placebo.


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8. SAFETY RESULTS

8.1. Extent of Exposure

Table 8.1 summarises the extent of exposure to study medication. The median (range) exposure to study medication was 29.0 (1-32) days in the GW685698X 100µg a.m. group, 29.0 (2-34) days in the GW685698X 100µg p.m. group and 29.0 (2-45) days in the GW685698X 250µg p.m. group.

8.2. Adverse Events

Table 8.2, Table 8.3 and Table 8.4 provide summaries of the incidence of adverse events in the pre-treatment, treatment and post-treatment phases of the study. These are summarised in Table 13.

Table 13 Overall Incidence of Adverse Events (Safety population)

GW685698X dose Adverse Event No (%)

Placebo

(n=143) 100µg a.m.

(n=143) 100µg p.m.

(n=148) 250µg p.m.

(n=141) Pre-Treatment 6 (4) 4 (3) 8 (5) 1 (<1) On-Treatment

Drug-Related Serious AE

Led to Withdrawal

37 (26) 10 (7) 1 (<1) 11 (8)

36 (25) 8 (6)

1 (<1) 5 (3)

39 (26) 11 (7) 1 (<1) 6 (4)

32 (23) 13 (9)

0 1 (<1)

Post-Treatment 5 (3) 2 (1) 3 (2) 2 (1) Source: Table 8.2, Table 8.3, Table 8.4, Table 8.5, Table 8.6, Table 8.7

8.2.1. Pre-Treatment Adverse Events

During the pre-treatment phase of the study, 19 (3.3%) subjects (of 575 subjects included in the safety population) experienced adverse events, as shown in Table 13. Fewer subjects in the GW685698X 250µg p.m. group experienced adverse events than in the other three treatment groups. The most commonly reported pre-treatment adverse events were disorders of the nervous system, all of which were headache. Gastrointestinal disorders were reported by 2 (1%) subjects in the GW685698X 250µg p.m. group, and 2 subjects (1%) in the GW685698X 250µg group reported infections and infestations (on both occasions this was cystitis). All other pre-treatment adverse events were reported by <1% of subjects in the safety population (Table 8.2).

8.2.2. Treatment-Emergent Adverse Events

Table 8.3 summarises all adverse events that occurred during the treatment period of this study. A total of 144 subjects (25% of the safety population) experienced adverse events during the treatment period. Overall the incidence of treatment-emergent adverse events


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was low and was distributed similarly across the four treatment groups. Adverse events were experienced by 37 (26%) subjects in the placebo group, 36 (25%) subjects in the GW685698X 100µg a.m. group, 39 (26%) subjects in the GW685698X100µg p.m. group and 32 (23%) subjects in the GW 685698X 250µg p.m. group. Table 14 summarises the most commonly occurring treatment-emergent adverse events (i.e. occurred in ≥ 3% subjects in any treatment group). The most commonly occurring treatment-emergent adverse events was headache, which occurred in 4-9% subjects across the four groups. Headache occurred more frequently in the active treatment groups compared with placebo. However the occurrence of headache was similar across the GW685698X treatment groups. Asthma was reported as an adverse event in more subjects in the placebo group (8%) than in subjects who received GW685698X 100µg a.m. or p.m. (3% and 4% respectively), and was not reported by any subject who received the higher dose of GW685698X. Similar numbers of subjects in all treatment groups reported nasopharyngitis (3% - 4% across the groups). Hoarseness was reported more frequently in the GW685698X 250µg p.m. group (3%) than in the GW685698X 100µg p.m. group (1%) and placebo group (<1%) and was not reported by any subject in the GW685698X 100µg a.m. group.

Table 14 Summary of the Most Common Treatment-Emergent Adverse Eventsa (Safety Population)

GW685698X dose Adverse Event No (%)

Placebo

(n=143) 100µg a.m.

(n=143) 100µg p.m.

(n=148) 250µg p.m.

(n=141) Headache 6 (4) 13 (9) 10 (7) 10 (7) Asthma 11 (8) 5 (3) 6 (4) 0 Nasopharyngitis 5 (3) 4 (3) 6 (4) 4 (3) Hoarseness 1 (<1) 0 2 (1) 4 (3) Source: Table 8.3 a. Occurring in 3% or more subjects in any treatment group

8.2.3. Post-Treatment Adverse Events

After completion of the four-week treatment period (or after discontinuation) subjects entered a one-week Follow-Up period during which details of any AEs were recorded. Subjects were prescribed appropriate asthma medications on completion of the treatment period (or discontinuation). Table 8.4 summarises the AEs that occurred during this time. A total of 12 subjects experienced AEs. Five (3%) subjects in the placebo group experienced AEs. Of these, headache was the most commonly reported AE and occurred in 2 (1%) subjects, one subject (<1%) experienced arterial hypertension, one subject (<1%) experienced a decrease in urinary creatinine and one (<1%) subject experienced nausea. AEs were reported by 2 (1%) subjects in the GW685698X 100µg a.m. group, one (<1%) subject experienced urticaria and one (<1%) subject experienced increased alanine aminotransferase, gamma-glutamyltransferase and glucose. A total of 3 (2%) subjects in the GW685698X 100µg p.m. group experienced post-treatment AEs. One subject (<1%) experienced abdominal pain and diarrhoea, one (<1%) subject experienced swelling of the face and one subject (<1%) experienced a common cold and an increase in urinary


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cortisol and cortisol/creatinine. In the GW685698X 250µg p.m. group, 2 (1%) subjects experienced post-treatment AEs. One subject (<1%) experienced nasophayngitis and one (<1%) subject experienced an increase in urinary cortisol and cortisol/creatinine ratio.

8.2.4. Treatment-Emergent Adverse Events Related to Study Treatment

A total of 42 subjects experienced treatment-emergent AEs that were considered possibly related to study treatment by the reporting investigator. These are summarised in Table 8.5. Ten (7%) subjects in the placebo group experienced AEs that were considered possibly related to study treatment. Two (1%) subjects in the placebo treatment group experienced candidiasis and two subjects (1%) experienced asthma exacerbations. Each of the following AEs were experienced by one (<1%) subject: - vasculitis; headache; epistaxis; hoarseness; palpitations and chest pain. In the GW685698X 100µg a.m. group, 8 (6%) subjects experienced AEs considered possibly related to study medications. Two subjects (1%) experienced headache and each of the following AEs were experienced by one (<1%) subject: - increased libido; worsening asthma; pruritis; gastric pain; dry cough and candidiasis. In the GW685698X 100µg p.m. group, 11 (7%) subjects experienced treatment-emergent AEs considered possibly related to study medication. Three subjects (2%) experienced candidiasis and in one subject (<1%) this was accompanied by elevated alkaline phosphatase levels, and in another subject (<1%) this was accompanied by odynophagia and dysphonia). One subject (<1%) experienced erythema with pruritis and rhinnorhea, and one subject (<1%) experienced erythema with headache and low phosphorus levels. One subject (<1%) experienced stomach ache and bruising to the lower limbs. Each of the following AEs were experienced by one (<1%) subject in this treatment group:- dry cough; dizziness and hoarseness; asthma exacerbation; positive urinalysis result (haematuria); and hoarseness.

Thirteen subjects (9%) in the GW685698X 250µg p.m. group experienced treatment-emergent AEs that were considered possibly related to study medication. Four subjects (3%) experienced candidiasis. Four subjects (3%) experienced headache (in one subject (<1%) this was accompanied by myalgia and URTI). Three subjects (2%) experienced hoarseness and one subject (<1%) experienced trachydysphonia. One further subject (<1%) experienced:- absence of voice; throat discomfort; bitter taste in the mouth; decreased taste; sour taste in mouth, cold feeling of tongue; numbness of lower lip; excitement; palpitations and sensitive skin.

8.3. Serious Adverse Events

8.3.1. Fatal Events

No subjects died during the study.

8.3.2. Non-Fatal Events

Three subjects, one (<1%) in each of the placebo, GW685698X 100µg a.m. and GW685698X 100µg p.m. groups experienced serious adverse events during the treatment period of the study (Table 8.6). None of these SAEs were considered related to study


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treatment and all were resolved.

Case narratives for these subjects are presented

in Section 13.1

8.3.3. Adverse Events Leading to Premature Discontinuation of Investigational Product and/or Study

Table 8.7 summarises the treatment-emergent adverse events that lead to withdrawal from the study. A total of 23 (4%) subjects were withdrawn due to adverse events. Of these, 11 (8%) were in the placebo group; 5 (3%) were in the GW685698X 100µg a.m. group; 6 (4%) were in the GW685698X 100µg p.m. group and 1 (<1%) was in the GW685698X 250 µg p.m. group. In the placebo group, 9 (6%) subjects were withdrawn due to asthma, one (<1%) subject was withdrawn due to bronchitis and one subject (<1%) was withdrawn due to vasculitis. In the GW685698X 100µg a.m. group, 4 (3%) subjects were withdrawn due to asthma (in one case in conjunction with a viral respiratory tract infection) and 1 (<1%) subject was withdrawn due to headache. In the GW685698X 100µg p.m. group, 6 (4%) subjects were withdrawn prematurely due to AEs, in all six cases this was because of asthma symptoms. In the GW685698X 250µg p.m. group, the one (<1%) subject who was withdrawn prematurely due to an AE experienced hoarseness. Case narratives for all withdrawals due to AEs are given in Section 13.2

8.4. Pregnancies

Two subjects became pregnant during the course of the study.

Case narratives for these subjects are given in Section 13.3.

8.5. Clinical Laboratory Evaluations

8.5.1. 24 hour Urinary Cortisol

Twenty-four hour urine samples were collected at baseline and at the end of the treatment for measurement of cortisol and cortisol adjusted for creatinine.

8.5.2. Urinary Cortisol Over Time

The summary statistics of the raw values for 24-hour urinary cortisol excretion are given in Table 8.8 which shows an increase in geometric mean values for all four treatment groups. Table 8.9 summarises the changes in urinary cortisol levels from baseline. The geometric mean ratios of the Week 4 values relative to baseline were between 1.00 (GW685698X 250µg p.m. group) and 1.15 (placebo group) indicating that there was no


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occurrence of cortisol reduction during the study. This is also illustrated in Figure 8.1 (Week 4 urinary cortisol levels relative to baseline).

The statistical analysis of 24-hour urinary cortisol excretion is presented in Table 8.10 and summarised in Table 15 below. When adjusted for covariates of baseline value, sex, age and country, the geometric means at Week 4 increased from baseline in all four treatment groups. These increases were 15nmol/L in the placebo group, 12nmol/L in the GW685698X 100µg a.m. group, 11nmol/L in the GW685698X 100µg p.m. group and 6nmol/L in the GW685698X 250µg p.m. group.

Table 15 Summary of Statistical Analysis of 24-hour Urinary Cortisol Values (with and without Correction for Creatinine) (Safety Population)

GW685698X Dose Placebo 100 µg a.m. 100 µg p.m 250 µg p.m.

24-Hour Urinary Cortisol (nmol/24 Hr)

Baseline Geometric Mean 50.56 52.65 51.19 47.67 Raw Geometric Mean 58.04 58.74 55.82 47.86

Adjusted Geometric Mean 65.32 64.44 62.21 54.08 Statistical Analysis

Ratio of Column to Placebo 95% CL p-value

0.99

0.83, 1.18 0.879

0.95

0.80. 1.14 0.585

0.83

0.70, 0.98 0.033

24-Hour Urinary Cortisol corrected for Creatinine

(mmol/24 Hr)

Baseline Geometric Mean 5.17 5.46 5.55 5.20 Raw Geometric Mean 6.06 6.16 5.87 4.88

Adjusted Geometric Mean 6.74 6.59 6.32 5.32 Statistical Analysis

Ratio of Column to Placebo 95% CL p-value

0.98

0.83, 1.15 0.787

0.94

0.80, 1.10 0.436

0.79

0.67, 0.93 0.004

Source: Table 8.12, Table 8.14

Relative to placebo, a 17% reduction in 24-hour urinary cortisol excretion was observed in the GW685698X 250µg p.m. group which was statistically significant (95%CI: 2%, 30%). However this was not associated with any occurences of urinary cortisol levels being below the normal range or shifting downwards relative to the normal range (see Section 8.5.3). There were no statistically significant reductions in either of the GW685698X 100µg groups relative to placebo (ratios = 0.99 and 0.95 for GW685698X 100µg a.m. and p.m. respectively).

The same tables and analysis were also produced for 24-hour urinary cortisol excretion corrected for creatinine (Table 8.11, Table 8.12, Table 8.13, Table 8.14 and Table 8.15 and Figure 8.2). These results are also summarised in Table 15. Similar patterns to the


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uncorrected values were observed when cortisol was adjusted for creatinine with placebo and the two GW685698X 100µg groups showed an increase from baseline. The GW685698X 250µg p.m. group showed a slight decrease of 6% relative to baseline (Table 8.12) in terms of raw geometric mean and ratio. However, when adjusted for the covariates of baseline, age, sex and country in the statistical analysis, there was an increase of 0.12 mmol/24 hr in the GW685698X 250µg p.m. group. Relative to placebo there was a 21% reduction in 24-hour urinary cortisol excretion corrected for creatinine (Table 8.15). However, this was not associated with clinical episodes of reduction (See Section 8.5.3).

8.5.3. Individual Subject Changes

Table 8.16 presents the number of subjects with 24-hour urinary cortisol excretion values in relation to the normal range and Table 8.17 summarises the shifts observed in 24-hour urinary cortisol levels from baseline values relative to the normal range.

At baseline, one (<1%) subject in the GW685698X 100µg p.m. group and one subject in the GW685698X 250µg p.m. group had urinary cortisol values that were below the normal range. At the end of the treatment period, one subject (<1%) who was in the placebo group had a cortisol level below the normal range. This subject had been within the normal range at baseline. The two subjects who had been below the normal range at baseline had values within the normal range at the end of the treatment period. However, no subject in any of the GW685698X treatment groups had values below the lower limit of normal at the end of the treatment period.

Similarly, when the 24-hour urinary cortisol values were corrected for creatinine, only one subject in the GW685698X 250µg p.m. group was below the normal range at Week 4, compared with 2 subjects at baseline. In the placebo group, 2 subjects were below the normal range at Week 4, which was the same as at baseline. Furthermore, in the GW685698X 250µg p.m. group, 19 subjects at Week 4 shifted down a category relative to the normal range from baseline, compared with 17 subjects who shifted up a category. This is very similar to the placebo group where 19 subjects also shifted down a category compared with 25 who shifted upwards (Table 8.16). Therefore, there is no evidence to suggest that any of these treatments had a suppressive effect on HPA axis function during this study.

8.6. Other Safety Evaluations

8.6.1. Haematology/Clinical Biochemistry Assessments

Blood samples were taken at Visit 1 and Visit 6 (and at Visit 7 if abnormal at Visit 6) for routine haematology and clinical biochemistry analysis. Table 8.18 summarises the haematology data results, Table 8.19 presents the changes in haematological parameters from baseline, Table 8.20 summarises the incidence of haematological parameters outside the reference ranges and Table 8.21 summarises shifts in haematological parameters from normal ranges. The corresponding data for the clinical biochemistry assessments are presented in Table 8.22, Table 8.23. Table 8.24 and Table 8.25.


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No significant abnormalities or shifts from baseline or shifts from normal ranges were observed in any of the treatment groups for any haematological or clinical biochemistry parameters.

8.6.2. Urinalysis (Local Analysis)

Urine samples were taken at each investigator site for local urinalysis at Visit 1 and also at the end of the treatment period (Visit 6) and at the end of Follow-Up (Visit 7) if significant abnormalities were observed at Visit 6. The results of these analyses are summarised in Table 8.26.

At Visit 1, positive urinalysis findings were recorded in 17 (12%) subjects in the placebo group, 20 (14%) subjects in the GW685698X 100µg a.m. group, 19 (13%) subjects in the GW685698X 100µg p.m. group and 10 (7%) subjects in the GW685698X 250µg p.m. group. At Visit 6, positive urinalysis tests were recorded in 12 (10%) subjects in the placebo group, 15 (11%) subjects in the GW685698X 100µg a.m. group, 16 (12%) subjects in the GW685698X 100µg p.m. group and 16 (12%) subjects in the GW685698X 250µg a.m. group. Therefore there was a slight reduction in positive urinalysis reports in the placebo and both the GW685698X 100µg groups and a slight increase in the number of positive urinalyses in the GW685698X 250µg group. However, overall there was little difference across the four treatment groups. Further Follow-Up urinalysis samples were taken in 10 subjects in the placebo group, none of which were positive; 10 subjects in the GW685698X 100µg a.m. group, one of which was positive; 14 subjects in the GW685698X 100µg p.m. group, 3 of which were positive and 12 subjects in the GW685698X 250µg p.m. group, two of which were positive.

8.6.3. ECG Data

12-lead ECGs were performed at Visit 1 and at the end of treatment (Visit 6) and at Follow-Up (Visit 7) if abnormal at Visit 6. No clinically significant abnormal results were observed in any subject at any time point in any of the treatment groups (Table 8.27).

8.6.4. Oropharyngeal Examination

Oropharyngeal examinations for evidence of candidiasis were performed at each clinic visit. Table 8.28 summarises the findings of these examinations. At Visit 1 no evidence of oral candidiasis was observed in any subject in any treatment group. At Visit 2, one subject who was in the GW685698X 100µg p.m. group displayed signs of oral candidiasis but no swab was taken to confirm the finding. At Visit 3, one subject who was in the GW685698X 250µg p.m. group displayed signs of oral candidiasis but no swab taken to confirm the finding. At Visit 4, 2 subjects, both in the GW685698X 250µg p.m. group displayed signs of oral candidiasis which were confirmed by a positive swab result. At Visit 5, one subject in each of the placebo and GW685698X 100µg a.m. groups and 3 subjects in each of the GW685698X 100µg p.m. and 250µg p.m. groups displayed signs of oral candidiasis. Positive swab cultures were found in 2 subjects in both of the


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GW685698X 100µg p.m. and the 250µg p.m. groups. At Visit 6, 3 subjects all of whom were in the placebo group, displayed signs of oral candidiasis, none of which were confirmed by swab culture.

Therefore the confirmed incidence of orophayngeal candidiasis was low, with only two subjects in the GW685698X 100µg p.m. group and four subjects in the GW685698X 250µg p.m. group presenting with positive swab culture results for oral candidiasis.

8.6.5. Vital Signs

Table 8.29 summarises the measurements of blood pressure and heart rate at baseline (Visit 2) and at each of the clinic visits during the treatment period (Visits 3-6). No clinically significant changes from baseline were observed in any treatment group at any time point during the treatment period.

8.7. Medical Device Incidents, Near-Incidents, Malfunctions and Remedial Action

No incidents, near incidents or malfunctions were reported with the use of the medical device(s) manufactured or marketed, by GSK or by a third party for GSK, for this study.

8.8. Safety Conclusions

• The overall incidence of adverse events was low and similar in all four treatment groups. Each of the treatments was well-tolerated and there was no evidence of an increased incidence of any adverse event in any of the treatment groups.

• No deaths occurred in this study. Only three serious adverse events occurred, none of which were related to study treatment.

• Total 24-hour urinary cortisol levels increased from baseline in all treatment groups. Although there was statistically significant evidence of a reduction in urinary cortisol levels relative to placebo at the higher dose of GW685698X, no trends were observed in shifts from baseline relative to the normal range.

• Although there was a significant decrease in 24-hour urinary cortisol values in the GW685698X 250µg p.m. group compared with placebo, it is difficult to interpret, because levels at Week 4 actually increased from baseline indicating that GW685698X 250µg p.m. did not affect this parameter. This is further supported by the fact that no subject in the GW685698X 250µg p.m. treatment group had a value for 24-hour urinary cortisol excretion that was below the lower limit of the normal range.

• There was no evidence of cortisol reduction in either of the GW685698X 100µg treatment groups.

• The incidence of oral candidiasis was low. Two subjects in the GW685698X 100µg p.m. group and four subjects in the GW685698X 250µg p.m. group had confirmed diagnoses of oral candidiasis.


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• No significant abnormalities, shifts from baseline or shifts from normal ranges were observed in any of the treatment groups for any haematological or clinical biochemistry parameters.


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9. PHARMACOKINETIC RESULTS

A total of 1481 samples from 398 subjects were included in the analysis. Because of the low doses of GW685698X used in this study, 820 of these samples (55.4%) had results which were below the lower limit of quantitation. Additional data was taken following 500µg from study FFA10002 (a.m. dosing) and data for the 3 micron material from study FFA10022 (p.m. dosing). All non-quantifiable (NQ) plasma concentrations were set to missing for the initial analysis.

For the aggregated dataset NQ concentrations comprised approximately 47.9% of the final dataset for GW685698X. Following completion of the model building with NQ values set to missing, further analyses were conducted using two imputation methods intended to reduce bias. These datasets are described in Section 5.8.16.1 and provided in the Pharmacokinetic Listings. Both methods provided similar results (Figure 9.1) and Imputation 2 was chosen because it more closely mimics the established pharmacokinetic profile based on the pharmacokinetic characteristics of GW685698X.

Five records from 3 patients were excluded from the dataset because of incomplete dosing information.

This value was also 4 times higher than any other values reported for this treatment group. Excluded values are identified by a # next to the ID in the dataset. The demographics for the pharmacokinetic population from this study are summarised in Table 9.1 for the overall population and also by treatment group.

9.1. GW685698X Pharmacokinetic Parameters

The pharmacokinetic disposition of GW685698X was characterised by a two-compartment model with first order absorption and elimination, described by clearance (CL/F), central volume of distribution (V2/F), intercompartmental clearance (Q/F) and peripheral volume of distribution (V3/F). This model used the ADVAN4 subroutine with TRANS4 PK parameterisation from the NONMEM library. The pharmacostatistical model included two components of variability: the interindividual variability and the random residual variability. The between-subject variability was modelled as proportional to the parameter, i.e., assuming a constant coefficient of variation (CCV).

The population pharmacokinetic parameters for GW685698X for the final model without imputation are presented in Table 9.2 and summarised in Table 16. Details of this analysis (control and output files) are presented separately in Listings and graphics used to assess the goodness of fit for the final model and are also presented in Figure 9.2. A listing of the main models evaluated during the development of the model without imputation is presented in Table 9.3. The diagnostic plots (Figure 9.2) show that although the population PK model does not predict all of the observed concentrations, the individual post-hoc predictions were comparable to the observed concentrations. Differences between population and individual estimates were partially explained by


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interindividual variability (η) on apparent clearance, absorption rate constant, peripheral volume and inter-compartmental clearance.

Table 16 Population pharmacokinetic parameters for GW685698X in asthmatic patients – No Imputation

Parameter Estimate 95% CI η (%) TVKA(THETA1) 0.262 0.185, 0.370 44 TVCL/F (THETA2) a.m. for median wt 72kg 262 155, 445 71 TVCL/F(THETA3) p.m. for median wt 72kg 424 249, 723 50 TVV2/F(THETA4) 27.9 10.1, 77.3 ND TVV3/F(THETA5) 16482 11858, 22909 12 TVQ/F (THETA6) 1772 935, 3358 70 Wt on CL/F (THETA7) 2.97 1.82, 4.86 ND 1. Source data: Table 9.2. Parameter estimates from the final GW685698X model (Run019) η = inter-individual variability; ND – Not determined

Absorption: The fraction of the dose absorbed could not be estimated and was considered to remain constant over the dosing period. Drug absorption was according to a first order process with no lag-time. The absorption rate constant (Ka; 0.262 h-1) is suggestive of a rapid absorption phase, with moderate interindividual variability (44%).

Disposition and Elimination: Time of dosing (a.m. or p.m.) had a considerable effect on the estimates of clearance. In addition, body weight showed additional effect on clearance (Figure 9.3). The population clearance (CL/F) for a.m. dosing assuming median body weight (72kg) was 263 L/h, with an inter-subject variability of approximately 71% and the equivalent for p.m. dosing was 424 L/h with an inter-subject of variability of approximately 50%. The central volume of distribution (V2/F) was 27.9 L. Interindividual variability (η) was not determined for this parameter. The data allowed interindividual variability in peripheripheral volume (16482 L) to be estimated (12%). Intercompartmental clearance was 1772 L/h with interindividual variability of 70%.

Residual Error: A model including an exponential and an additive component was used to characterise total residual error. The additive component was used to account for observations near the lower limit of detection of the assay. The model resulted in moderately low levels of residual variability for the exponential component (CV: 13%) but a high value for the additive component (11 pg/mL c.f. LLQ of 10pg/mL).

The population pharmacokinetic parameters for GW685698X for the final model with imputation are presented in Table 9.4 and summarised in Table 17. Details of this analysis (control and output files) are presented separately in Listings and graphics used to assess the goodness of fit for the final model and are also presented in Figure 9.2. A listing of the main models evaluated during the development of the model with imputation is presented in Table 9.5. The diagnostic plots (Figure 9.2) show that although the population PK model does not predict well some of the observed concentrations, the individual post-hoc predictions were comparable to the observed concentrations. Moreover, this analysis showed less bias at low concentrations than that without imputation for NQ values. Differences between population and individual estimates were


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partially explained by interindividual variability (η) on apparent clearance, absorption rate constant, peripheral volume and inter-compartmental clearance.

Table 17 Population pharmacokinetic parameters for GW685698X in asthmatic patients – Imputation 2

Parameter Estimate 95% CI η (%) TVKA(THETA1) 0.210 0.127, 0.348 316 TVCL/F (THETA2) a.m. for median wt 72kg 290 97.7, 861 66 TVCL/F(THETA3) p.m. for median wt 72kg 713 318,1600 94 TVV2/F(THETA4) 13.74 4.967, 37.987 ND TVV3/F(THETA5) 59874 18911, 189564 179 TVQ/F (THETA6) 4447 1022, 19341 913 Wt on CL/F (THETA7) 5.16 2.20, 12.09 ND Source data: Table 9.4 Parameter estimates from the final GW685698X model (Run019IMP2) η = inter-individual variability

Absorption: As with the analysis without imputation, the absorption rate constant (Ka; 0.21 h-1) was suggestive of a rapid absorption phase, although interindividual variability was very high (316%).

Disposition and Elimination: Time of dosing (a.m. or p.m.) and body weight showed a considerable effect on the estimate of clearance. The population clearance (CL/F) for a.m. dosing, assuming median body weight (72kg) was 290 L/h, with an inter-subject variability of approximately 66% and the equivalent for p.m. dosing was 713 L/h with an inter-subject of variability of approximately 94%. The central volume of distribution (V2/F) was 13.74 L. Interindividual variability (η) was not determined for this parameter. The data allowed interindividual variability in peripheral volume (59874 L) to be estimated (179%). Intercompartmental clearance was 4447 L/h with very high interindividual variability of 913%.

Residual Error: A model including an exponential and an additive component was used to characterise total residual error. The additive component was used to account for observations near the lower limit of detection of the assay. The model resulted in high levels of residual variability for the exponential component (CV: 82%), but a lower value for the additive component (5 pg/mL c.f. LLQ of 10pg/mL).

The final population pharmacokinetic model and parameters (mean, variance and residual error) for GW685698X were used to generate AUC(0-24). These are summarised in Table 9.6 with geometric mean and 95% CI values for AUC(0-24) from final models with and without imputation for NQ values are shown in Table 18.


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Table 18 GW685698X Pharmacokinetic Parameters in Asthmatics Administered Repeat Inhaled Doses

Treatment n AUC(0-24) (pg.h/mL) Imputation 2

AUC(0-24) (pg.h/mL) No Imputation

GW685698X 100µg a.m. 132 285 (267, 305)

353 (334, 374)

GW685698X 100µg p.m. 134 140 (130, 150)

250 (240, 260)

GW685698X 250µg p.m. 132 370 (340, 404)

580 (551, 611)

Source data: Table 9.6 Summary of model predicted plasma GW685698X pharmacokinetic parameters

The pharmacokinetics of GW685698X can be described by a two-compartment model with a first order absorption process. Population pharmacokinetic parameters were estimated with good precision, as indicated by 95% CIs and coefficient of variation of the parameter estimates when using the dataset with NQ values set to missing. However, the censoring of NQ produces a biased over estimate of AUC. Hence, further analyses were conducted looking at two imputation methods for NQ values. The method chosen yielded AUC values that were approximately 33% lower that those of the original analysis (Figure 9.4), but resulted in pharmacokinetic parameters being estimated with poorer precision, possibly as a consequence of the error associated with the imputation. Overall, the goodness-of-fit was satisfactory and inter-individual variability accounted for a considerable part of the variation observed in individual concentrations.

9.2. Pharmacokinetic Conclusions

• GW685698X plasma concentration-time data were well described by a two compartment model with first order absorption and elimination

• For GW685698X, only time of dosing and body weight were significant covariates on the estimate of apparent clearance


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10. PHARMACOKINETIC/PHARMACODYNAMIC RESULTS

As an exploratory exercise, the relationship between GW685698X systemic exposure and urinary cortisol excretion was assessed graphically comparing GW685698X AUC(0-24) versus creatinine corrected 24 hour urinary cortisol (Figure 9.5). Although there was a very slight trend towards greater reduction in 24 hour urinary cortisol as GW685698X AUC(0-24) increased, data at the higher AUC(0-24) values were very limited with only small changes from baseline for urinary cortisol. This relationship will need to be investigated further as more data become available. Moreover, the estimated AUC(0-24) values observed in this study would not be predicted to have significant reductions in 24 hour serum cortisol based on a model previously developed using GW685698X repeat dose data.

Systemic exposure and clinical efficacy endpoints were also investigated by graphical means (Figure 9.6). These endpoints included average change from baseline in trough PEF, average change from baseline in daytime and nighttime asthma symptom scores and percentage of symptom-free 24-hour days. All endpoints showed a trend to greater improvement in efficacy with increasing AUC(0-24). Further analysis of the data will be conducted to better understand the relationship between systemic exposure, which can be considered as a surrogate for lung exposure, and these efficacy endpoints. This work will be reported separately.

10.1. Pharmacokinetic/Pharmacodynamic Conclusions

• Graphical evaluation of systemic exposure and efficacy endpoints showed a trend to greater improvement in efficacy as AUC(0-24) increased.


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11. DISCUSSION AND CONCLUSIONS

11.1. Discussion

This study was the first clinical efficacy study with GW685698X in asthmatic patients. The objectives of the study were to compare the efficacy and safety of three different dose groups of GW685698X (100µg given in the morning, 100µg given in the evening and 250µg given in the evening) and placebo. Of primary interest was the comparison of 100µg given in the morning with 100µg given in the evening.

The study population comprised subjects with mild and moderate persistent asthma in whom inhaled corticosteroid treatment is recommended by international guidelines. Subjects were required to demonstrate lung function of between 50% and 80% of predicted normal PEF, and also the potential for improvement as assessed by a demonstrable reversibility in PEF of at least 15% after administration of short-acting beta2-agonists and the occurrence of asthma symptoms. The study population was restricted to subjects who were not currently using inhaled corticosteroids, so that the effects of GW685698X could be clearly evaluated.

The study treatment period was four weeks, which was regarded as sufficient time to assess the effects of treatment, while minimising the exposure to the study drug and also to treatment with placebo. PEF was selected as the primary endpoint because it is a validated and reproducible measure of lung function. The selection of change from baseline in trough values of PEF as the primary endpoint was made to ensure that this endpoint represented the true 24 hour effect of treatment with GW685698X. Due to the inherent diurnal variation in lung function observed in asthma, evening trough values are naturally higher than those measured in the morning. It was therefore important to compare change from baseline rather than absolute trough PEF values in order to assess the effect of time of dosing. It has also been suggested that afternoon or early evening dosing may provide superior efficacy compared with morning dosing with once-daily regimens [Gagnon, 1994; Pincus, 1995]. Therefore it was particularly important in this study to assess the relative benefits of morning or evening dosing.

The size of the study population was determined on the basis of the standard deviation in change from baseline trough PEF values seen in previous studies, which was calculated as 40L/min. On this basis, it was estimated that 123 subjects were required in each treatment group to ensure that the width of the 95% confidence interval was no larger than 20L/min. However, the actual standard deviation of trough PEF in this study was 47L/min, which resulted in a confidence interval of width 22L/min. The ITT population included 575 subjects, while the Per Protocol population included 494 subjects, therefore, 14% of the ITT population were excluded from the Per Protocol population. The most common reason for exclusion from the Per Protocol population was failure to fulfil key eligibility criteria for entry to the treatment period.

The baseline demographics of the study population were similar across the four treatment groups. The mean age of the study population was 37 years overall and over 90% of the study population had had asthma for longer than one year. The mean baseline percent of


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predicted normal PEF was similar across the four groups and was 75% overall. Therefore, the population in this study was on average, relatively mild. Baseline mean values for trough morning PEF were lower in the morning dose group (and a.m. placebo assessments) than in the evening dose groups (and p.m. placebo assessments). As mentioned above, this was expected due to diurnal variation and in theory would be compensated for by using change from baseline trough values rather than absolute values.

All four treatment groups demonstrated an increase from baseline in the primary endpoint over the four week treatment period. The largest of these increases was observed in the GW685698X 100µg a.m. group and resulted in a fairly substantial treatment difference of 13L/min over the 100µg p.m. group, supported by a confidence interval which did not include zero.

However, there was an unexpectedly high placebo response in the a.m. values, (19L/min) and it is likely that a similar proportion of the improvement observed in the GW685698X 100µg a.m. group was also due to a placebo effect rather than the actual effect of GW685698X. Therefore, it is important to consider all treatment effects of GW685698X relative to placebo. The differential between the placebo response for a.m. measurements and that for p.m. measurements was unexpected. However, it is possible that in this relatively mild population, there was more room for improvement in morning values than there was in evening values, and therefore using change from baseline as the endpoint did not compensate entirely for the effect of diurnal variation.

When GW685698X 100µg a.m. was compared with 100µg p.m. using their relative improvement over placebo, the treatment difference was only 3L/min (19L/min – 16L/min), which is not of a clinically relevant magnitude. Consequently, it can be concluded that time of dosing does not have an impact on PEF. The GW685698X 250µg dose demonstrated the largest treatment effect relative to placebo (25L/min) providing some evidence of a dose response between the 100µg and 250µg doses.

The results of the comparisons of the primary efficacy endpoint were similar for both the ITT and Per Protocol populations, therefore endorsing the validity of the findings and conclusions of the study.

Formal assessment of duration of action was not an objective of this study. However, the trough (24 hour) changes in PEF were presented in the form of a bar chart alongside the 12-hour changes in PEF for each group. For the two p.m. dosed groups, the 12 hour values were approximately 10L/min higher than the trough values which is the same differential as that observed between the a.m. and p.m. placebo values. For the 100µg a.m. group, there was only a 4L/min differential between the trough and 12-hour values. Therefore, there is a good indication of a 24-hour duration of action of GW685698X.

Secondary efficacy endpoints of lung function, asthma symptoms and rescue medication use, also supported the conclusion of no effect of time of dosing on efficacy. The mean values observed in the GW685698X 100µg a.m. group were higher in some endpoints than those observed in the 100µg p.m. group and the reverse was true in other endpoints. The confidence interval for the treatment differences between these two groups included zero for all endpoints indicating that it is unlikely that there are true population


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differences of any clinical relevance. All secondary endpoints demonstrated larger improvements in the GW685698X 250µg p.m. treatment group than either of the 100µg groups. Although the magnitude of effect of the 250µg dose over the 100µg dose was often not large, there is some evidence indicative of a dose response between these two doses.

The safety of GW685698X was primarily assessed by the occurrence of adverse events and by laboratory measurements of 24-hour urinary cortisol excretion. The incidence of adverse events was very similar across all four treatment groups and there was no evidence of an increased occurrence of any adverse event in any of the active treatment groups. Only three serious adverse events occurred, none of which were considered related to treatment.

The urinary cortisol results are difficult to interpret due to the unexpected increase in values over the four weeks of treatment. Although some subjects had been washed off steroids prior to entry into the study, the 4-week washout period is considered more than adequate to prevent cortisol increases. It is possible that the observed reduction in 24-hour urinary cortisol excretion in the GW685698X 250µg p.m. group relative to placebo is due to chance, as there is no difference from placebo in shift patterns relative to the normal range. There was no evidence of any cortisol reduction in either of the GW685698X 100µg treatment groups relative to either placebo or baseline.

The use of sparse pharmacokinetic sampling in conjunction with population PK analysis was used to recover steady-state estimates of drug exposure to GW685698X in asthmatic patients. A two-compartment model with first order absorption process could describe the pharmacokinetics of GW685698X. Population pharmacokinetic parameters were estimated with good precision, as indicated by 95% CIs and coefficient of variation of the parameter estimates when using the dataset with NQ values set to missing. However, the censoring produced a biased over estimate of AUC. Hence, further analyses were conducted looking at two imputation methods for NQ values. As expected, the method chosen yielded mean AUC values that were lower that those from the original method, but resulted in pharmacokinetic parameters being estimated with poorer precision probably as a consequence of the error associated with the imputation. Overall the goodness-of-fit was satisfactory and inter-individual variability accounted for a considerable part of the variation observed in individual concentrations. For GW685698X, only body weight was a significant demographic covariate on the estimate of apparent clearance. Time of dosing also had a significant effect on apparent clearance with systemic exposure being estimated to be higher following morning dosing. This may have been a consequence of the sampling schedule, since samples were generally obtained earlier post-dose for morning dosing than for evening dosing. However, this apparent higher exposure did not result in any significant systemic effect in the morning dosing group.

11.2. Conclusions

The findings of this study indicate that treatment with GW685698X once daily was well-tolerated and effective in the treatment of persistent asthma. Although the pre-defined primary comparison appeared to demonstrate greater efficacy of morning dosing over


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evening dosing, the large morning placebo response needs to be considered. Comparisons of each active dose with placebo is of greater statistical validity in these circumstances and these comparisons for the primary endpoint indicated only a small improvement (approximately 3L/min) in the 100µg a.m. group compared with the 100µg p.m. group . Other efficacy endpoints demonstrated equally small numerical differences between the 100µg a.m. and p.m. groups, with some endpoints showing higher values in the a.m. group and some in the p.m. group.

All three active treatments were well tolerated and there was no evidence of a dose-related increase of any reported adverse event. 24-hour urinary cortisol levels increased in all four treatment groups, which was not anticipated and cannot be adequately explained. Although there was a significant decrease in 24-hour urinary cortisol values in the GW685698X 250µg p.m. group compared with placebo, it is difficult to interpret, because the levels at Week 4 actually increased from baseline. This is further supported by the fact that no subject in the GW685698X 250µg p.m. group had a value for 24-hour urinary cortisol excretion that was below the lower limit of the normal range. Taken together, these data suggest that 24-hour urinary cortisol excretion was not suppressed with the once daily 250µg dose of GW685698X.

Therefore GW685698X given once daily at a dose of 100µg in the morning or evening is a well-tolerated and effective new treatment for persistent asthma and there is no conclusive evidence of superior efficacy or safety relative to the time of dosing. There is some evidence to indicate that efficacy was greater with GW685698X 250µg compared with GW685698X 100µg dosed in the morning or evening.


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12. REFERENCES

Beal SL (2001). Ways to fit a PK model with some data below the quantification limit. Journal Pharmacokinetics and Pharmacodynamics 28: 481-504

Boeckman AJ, Sheiner LB and Beal SL (1992 and 1998). NONMEM users guide. NONMEM project group, San Francisco

British Thoracic Society. Guidelines on asthma management 1995: review and position statement. Thorax 1997;52(suppl.1):S1-S21.

Cardon LR, Idury RM, Harris TJR, Witte JS, Elston RC. Testing drug response in the presence of genetic information: sampling issues for clinical trials. Pharmacogenetics 2000;10:503-10.

Gagnon M, Côté M, Milot J, Turcotte H, Boulet LP. Comparative safety and efficacy of single or twice daily administration of inhaled beclomethasone in moderate asthma. Chest 1994;105:1732-37.

GlaxoSmithKline Document Number WD2002/01057/00. Validation of an Analytical Method for the Determination of GW685698X in Human Plasma (Range 10-1000 pg/mL) using Solid Phase Extraction and HPLC with Tandem Mass Spectrometric Detection. (York Bioanalytical Solutions Study No. YAY/010)

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. NHLBI/WHO workshop report March 1993. Bethesda: National Institutes of Health, National Heart, Lung and Blood Institute. Publication number 96-3659B. Revised November 1998.

McCarthy JJ, Hilfiker R. The use of single-nucleotide polymorphism maps in pharmacogenomics. Nat Biotechnol 2000;18:505-8.

Meibohm B, Hochhaus G, Rohatagi S, Mollmann H, Barth J, Wagner M, et al. Dependency of cortisol suppression on the administration time of inhaled corticosteroids. J Clin Pharmacol 1997;37:704-10.

National Institutes of Health. Global Initiative for Asthma. Global strategy for asthma management and prevention. National Institutes of Health National Heart, Lung and Blood Institute Bethesda, MD, NHLBI/WHO workshop report April 2002. Publication number 96-3659.

Palmer LJ, Cookson WO. Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma. Respir Res 2001;2:102-12.

Pedersen S, O’Byrne P. A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy 1997;52(suppl.39):1-34.


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Pincus, DJ, Szefler SJ, Ackerson LM, Martin RJ. Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J. Allergy Clin Immunol 1995;95(6):1172-78.

Polgar G, Promadhat V. Pulmonary function testing in children: techniques and standards. Philadelphia: WB Saunders, 1971.

Quanjer PH, Tammeling GJ, Cotes JS, Pederson OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardisation of Lung Function Tests. European Community for Coal and Steel (ECCS). Official Statement of the European respiratory Society. Eur Respir J 1993; Suppl 16: 5-4.

Wilson AM, Clarke DJ, Devlin MM, McFarlane LC, Lipworth BJ. Adrenocortical activity with repeated administration of one-daily fluticasone propionate and budesonide in asthmatic adults. Eur J Clin Pharmacol 1998;53:317-20.


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This section contained patient narratives which are textual descriptions of medical history,

treatment and outcome for individual patients who experienced a clinically important adverse

event including serious adverse events during the trial. They have been excluded to protect

patient privacy. This data may be made available subject to an approved research proposal and

a determination of the ability to provide information from the specific narratives whilst protecting

the patient’s privacy. For further information please see the Patient Level Data section of

the GSK Clinical Study Register.

Study Population Data Source Tables

PageTable 6.1 Summary of Subject Populations (Total Population) . . . . . . . . . . . . . . . . . 116Table 6.2 Summary of Reasons for Withdrawal Prior to Randomisation (Total

Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117Table 6.3 Summary of Subjects by Investigator (Total Population) . . . . . . . . . . . . . . 118Table 6.4 Summary of End of Study Record (Intent-to-Treat Population) . . . . . . . . . 123Table 6.5 Summary of Attendance at Each Clinic Visit (Intent-to-Treat Population) . 124Table 6.6 Summary of Reasons for Exclusion from the Per Protocol Population

(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125Table 6.7 Summary of Inclusion/Exclusion Deviations (Intent-to-Treat Population) . 128Table 6.8 Summary of Demographic Characteristics (Intent-to-Treat Population) . . 130Table 6.9 Summary of History of Tobacco Use at Visit 1 (Screening)

(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132Table 6.10 Summary of Duration of Asthma and Asthma History (Intent-to-Treat

Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134Table 6.11 Summary of Clinic Pulmonary Function Tests Prior to Treatment

(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135Table 6.12 Summary of Baseline Diary Card Pulmonary Function Tests

(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Table 6.13 Summary of Current Medical Conditions (Intent-to-Treat Population) . . . 139Table 6.14 Summary of Asthma Concomitant Medications - Pre-Treatment

(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Table 6.15 Summary of Asthma Concomitant Medications - On-Treatment

(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145Table 6.16 Summary of Other Concomitant Medications - On-Treatment

(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148


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Protocol: FFA20001 Page 1 of 1 Population: Total Table 6.1 Summary of Subject Populations GW685698X GW685698X GW685698X Population Placebo 100mcg AM 100mcg PM 250mcg PM Total -------------------------------------------------------------------------------------- Total 669 Randomised 144 (25%) 144 (25%) 148 (26%) 142 (25%) 578 (86%) Intent-to-Treat (ITT) 143 (25%) 144 (25%) 146 (25%) 142 (25%) 575 (86%) Safety 143 (25%) 143 (25%) 148 (26%) 141 (25%) 575 (86%) Per Protocol (PP) 119 (24%) 128 (26%) 128 (26%) 119 (24%) 494 (74%) Total: All subjects screened and for whom a record exists on the study database ITT: All randomised subjects who received at least a single dose of trial medication PP: All subjects in the ITT population who have not been identified as major protocol violators Safety: All subjects in the ITT population according to the treatment actually received

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Protocol: FFA20001 Page 1 of 1 Population: Total Table 6.2 Summary of Reasons for Withdrawal Prior to Randomisation Total Reason (N=669) -------------------------------------------------------------- Withdrawals prior to randomisation 90 (13%) Adverse event 9 (1%) Lost to follow-up 1 (<1%) Protocol violation 10 (1%) Subject decided to withdraw from the study 12 (2%) Lack of efficacy 0 Exacerbation 5 (<1%) Non-compliance 0 Did not meet treatment eligibility criteria 51 (8%) Other, specify 2 (<1%)

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Protocol: FFA20001 Page 1 of 5 Population: Total Table 6.3 Summary of Subjects by Investigator Non GW685698X GW685698X GW685698X Country Randomised Placebo 100mcg AM 100mcg PM 250mcg PM Total Investigator (N=91) (N=144) (N=144) (N=148) (N=142) (N=669) ------------------------------------------------------------------------------------------ Bulgaria All Sites 7 (8%) 8 (6%) 9 (6%) 8 (5%) 7 (5%) 39 (6%) 0 3 (2%) 3 (2%) 3 (2%) 3 (2%) 12 (2%) 0 2 (1%) 2 (1%) 2 (1%) 1 (<1%) 7 (1%) 6 (7%) 2 (1%) 2 (1%) 2 (1%) 2 (1%) 14 (2%) 1 (1%) 1 (<1%) 2 (1%) 1 (<1%) 1 (<1%) 6 (<1%) Chile All Sites 1 (1%) 3 (2%) 3 (2%) 3 (2%) 4 (3%) 14 (2%) 1 (1%) 1 (<1%) 2 (1%) 2 (1%) 2 (1%) 8 (1%) 0 2 (1%) 1 (<1%) 1 (<1%) 2 (1%) 6 (<1%) Croatia All Sites 6 (7%) 6 (4%) 7 (5%) 9 (6%) 7 (5%) 35 (5%) 1 (1%) 2 (1%) 2 (1%) 3 (2%) 2 (1%) 10 (1%) 2 (2%) 1 (<1%) 1 (<1%) 2 (1%) 1 (<1%) 7 (1%) 1 (1%) 0 1 (<1%) 1 (<1%) 0 3 (<1%) 2 (2%) 3 (2%) 3 (2%) 3 (2%) 4 (3%) 15 (2%) Estonia All Sites 2 (2%) 6 (4%) 7 (5%) 8 (5%) 7 (5%) 30 (4%) 1 (1%) 1 (<1%) 0 1 (<1%) 1 (<1%) 4 (<1%) Note: 3 subjects (1 Placebo and 2 GW685698X 100mcg PM) were randomised but excluded from the ITT population

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Protocol: FFA20001 Page 2 of 5 Population: Total Table 6.3 Summary of Subjects by Investigator Non GW685698X GW685698X GW685698X Country Randomised Placebo 100mcg AM 100mcg PM 250mcg PM Total Investigator (N=91) (N=144) (N=144) (N=148) (N=142) (N=669) ------------------------------------------------------------------------------------------ 1 (1%) 3 (2%) 3 (2%) 3 (2%) 3 (2%) 13 (2%) 0 1 (<1%) 2 (1%) 2 (1%) 2 (1%) 7 (1%) 0 1 (<1%) 2 (1%) 2 (1%) 1 (<1%) 6 (<1%) Germany All Sites 33 (36%) 32 (22%) 32 (22%) 34 (23%) 36 (25%) 167 (25%) 5 (5%) 6 (4%) 6 (4%) 7 (5%) 6 (4%) 30 (4%) 1 (1%) 1 (<1%) 2 (1%) 1 (<1%) 2 (1%) 7 (1%) 0 2 (1%) 1 (<1%) 2 (1%) 2 (1%) 7 (1%) 1 (1%) 3 (2%) 4 (3%) 4 (3%) 3 (2%) 15 (2%) 2 (2%) 1 (<1%) 1 (<1%) 0 1 (<1%) 5 (<1%) 0 1 (<1%) 0 0 0 1 (<1%) 3 (3%) 2 (1%) 2 (1%) 3 (2%) 3 (2%) 13 (2%) 0 0 0 1 (<1%) 0 1 (<1%) 7 (8%) 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) 11 (2%) 1 (1%) 2 (1%) 2 (1%) 2 (1%) 2 (1%) 9 (1%) 0 3 (2%) 3 (2%) 3 (2%) 3 (2%) 12 (2%) 0 2 (1%) 2 (1%) 1 (<1%) 1 (<1%) 6 (<1%) 0 2 (1%) 2 (1%) 2 (1%) 2 (1%) 8 (1%) 1 (1%) 0 0 0 1 (<1%) 2 (<1%) 3 (3%) 2 (1%) 2 (1%) 2 (1%) 3 (2%) 12 (2%) 3 (3%) 2 (1%) 1 (<1%) 2 (1%) 2 (1%) 10 (1%) Note: 3 subjects (1 Placebo and 2 GW685698X 100mcg PM) were randomised but excluded from the ITT population

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Protocol: FFA20001 Page 3 of 5 Population: Total Table 6.3 Summary of Subjects by Investigator Non GW685698X GW685698X GW685698X Country Randomised Placebo 100mcg AM 100mcg PM 250mcg PM Total Investigator (N=91) (N=144) (N=144) (N=148) (N=142) (N=669) ------------------------------------------------------------------------------------------ 4 (4%) 0 1 (<1%) 0 1 (<1%) 6 (<1%) 1 (1%) 0 0 1 (<1%) 1 (<1%) 3 (<1%) 1 (1%) 2 (1%) 2 (1%) 2 (1%) 2 (1%) 9 (1%) Greece All Sites 1 (1%) 8 (6%) 7 (5%) 6 (4%) 6 (4%) 28 (4%) 0 3 (2%) 2 (1%) 2 (1%) 2 (1%) 9 (1%) 0 3 (2%) 3 (2%) 3 (2%) 2 (1%) 11 (2%) 1 (1%) 2 (1%) 2 (1%) 1 (<1%) 2 (1%) 8 (1%) Hungary All Sites 0 2 (1%) 2 (1%) 2 (1%) 3 (2%) 9 (1%) 0 2 (1%) 2 (1%) 2 (1%) 3 (2%) 9 (1%) Italy All Sites 15 (16%) 10 (7%) 10 (7%) 9 (6%) 7 (5%) 51 (8%) 0 1 (<1%) 2 (1%) 2 (1%) 1 (<1%) 6 (<1%) 0 1 (<1%) 1 (<1%) 2 (1%) 1 (<1%) 5 (<1%) 3 (3%) 1 (<1%) 2 (1%) 1 (<1%) 1 (<1%) 8 (1%) 6 (7%) 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) 10 (1%) 0 1 (<1%) 0 0 0 1 (<1%) 1 (1%) 1 (<1%) 0 1 (<1%) 1 (<1%) 4 (<1%) Note: 3 subjects (1 Placebo and 2 GW685698X 100mcg PM) were randomised but excluded from the ITT population

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Protocol: FFA20001 Page 4 of 5 Population: Total Table 6.3 Summary of Subjects by Investigator Non GW685698X GW685698X GW685698X Country Randomised Placebo 100mcg AM 100mcg PM 250mcg PM Total Investigator (N=91) (N=144) (N=144) (N=148) (N=142) (N=669) ------------------------------------------------------------------------------------------ 0 2 (1%) 2 (1%) 1 (<1%) 1 (<1%) 6 (<1%) 1 (1%) 0 0 0 0 1 (<1%) 1 (1%) 1 (<1%) 1 (<1%) 0 0 3 (<1%) 3 (3%) 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) 7 (1%) Mexico All Sites 1 (1%) 13 (9%) 13 (9%) 14 (9%) 13 (9%) 54 (8%) 0 7 (5%) 7 (5%) 7 (5%) 7 (5%) 28 (4%) 1 (1%) 6 (4%) 6 (4%) 7 (5%) 6 (4%) 26 (4%) Romania All Sites 7 (8%) 11 (8%) 11 (8%) 12 (8%) 10 (7%) 51 (8%) 2 (2%) 2 (1%) 2 (1%) 3 (2%) 2 (1%) 11 (2%) 5 (5%) 4 (3%) 4 (3%) 4 (3%) 3 (2%) 20 (3%) 0 5 (3%) 5 (3%) 5 (3%) 5 (4%) 20 (3%) Russian Federation All Sites 11 (12%) 45 (31%) 41 (28%) 43 (29%) 41 (29%) 181 (27%) 1 (1%) 8 (6%) 7 (5%) 8 (5%) 7 (5%) 31 (5%) 3 (3%) 7 (5%) 6 (4%) 7 (5%) 6 (4%) 29 (4%) 1 (1%) 8 (6%) 7 (5%) 8 (5%) 8 (6%) 32 (5%) 0 2 (1%) 2 (1%) 2 (1%) 2 (1%) 8 (1%) 0 2 (1%) 2 (1%) 2 (1%) 2 (1%) 8 (1%) Note: 3 subjects (1 Placebo and 2 GW685698X 100mcg PM) were randomised but excluded from the ITT population

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Protocol: FFA20001 Page 5 of 5 Population: Total Table 6.3 Summary of Subjects by Investigator Non GW685698X GW685698X GW685698X Country Randomised Placebo 100mcg AM 100mcg PM 250mcg PM Total Investigator (N=91) (N=144) (N=144) (N=148) (N=142) (N=669) ------------------------------------------------------------------------------------------ 1 (1%) 9 (6%) 9 (6%) 8 (5%) 8 (6%) 35 (5%) 5 (5%) 7 (5%) 6 (4%) 6 (4%) 6 (4%) 30 (4%) 0 2 (1%) 2 (1%) 2 (1%) 2 (1%) 8 (1%) South Africa All Sites 7 (8%) 0 2 (1%) 0 1 (<1%) 10 (1%) 6 (7%) 0 1 (<1%) 0 1 (<1%) 8 (1%) 1 (1%) 0 1 (<1%) 0 0 2 (<1%) Note: 3 subjects (1 Placebo and 2 GW685698X 100mcg PM) were randomised but excluded from the ITT population

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 6.4 Summary of End of Study Record GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total (N=143) (N=144) (N=146) (N=142) (N=575) ------------------------------------------------------------------------------------------ Completion Status Completed 124 (87%) 133 (92%) 135 (92%) 134 (94%) 526 (91%) Prematurely Withdrawn [1] 19 (13%) 11 (8%) 11 (8%) 8 (6%) 49 (9%) Primary reason for withdrawal Adverse Event 6 (4%) 1 (<1%) 0 1 (<1%) 8 (1%) Lost to follow-up 0 0 0 0 0 Protocol Violation 1 (<1%) 1 (<1%) 1 (<1%) 4 (3%) 7 (1%) Subject decided to withdraw from study 1 (<1%) 3 (2%) 4 (3%) 3 (2%) 11 (2%) Lack of Efficacy 2 (1%) 1 (<1%) 0 0 3 (<1%) Exacerbation 6 (4%) 4 (3%) 6 (4%) 0 16 (3%) Non-compliance 1 (<1%) 0 0 0 1 (<1%) Treatment period elig. crit. not met 2 (1%) 0 0 0 2 (<1%) Other 0 1 (<1%) 0 0 1 (<1%) [1] Prematurely withdrawn after randomisation

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 6.5 Summary of Attendance at Each Clinic Visit GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total Week (N=143) (N=144) (N=146) (N=142) (N=575) ----------------------------------------------------------------------------------------- Visit 1 (Screen) -3 to -1 143 (100%) 144 (100%) 146 (100%) 142 (100%) 575 (100%) Visit 1a (Screen) -3 to -1 16 (11%) 19 (13%) 26 (18%) 16 (11%) 77 (13%) Visit 1b (Screen) -3 to -1 1 (<1%) 3 (2%) 4 (3%) 1 (<1%) 9 (2%) Visit 2 (Baseline) 0 143 (100%) 143 (>99%) 146 (100%) 142 (100%) 574 (>99%) Visit 3 (Week 1) 1 134 (94%) 140 (97%) 142 (97%) 139 (98%) 555 (97%) Visit 4 (Week 2) 2 131 (92%) 137 (95%) 138 (95%) 136 (96%) 542 (94%) Visit 5 (Week 3) 3 125 (87%) 135 (94%) 138 (95%) 134 (94%) 532 (93%) Visit 6 (Week 4) 4 124 (87%) 133 (92%) 135 (92%) 133 (94%) 525 (91%) Visit 7 (Follow-up) 5 134 (94%) 133 (92%) 137 (94%) 134 (94%) 538 (94%)

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Protocol: FFA20001 Page 1 of 3 Population: Intent-to-Treat Table 6.6 Summary of Reasons for Exclusion from the Per Protocol Population GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total Reason (N=143) (N=144) (N=146) (N=142) (N=575) ------------------------------------------------------------------------------------------ Totally Excluded 24 (17%) 16 (11%) 18 (12%) 23 (16%) 81 (14%) Exacerbation of asthma 1 (<1%) 0 0 0 1 (<1%) symptoms during the run-in Current smoker or has history 3 (2%) 2 (1%) 2 (1%) 2 (1%) 9 (2%) of 10 pack years or more Did not have an increase in 1 (<1%) 0 0 0 1 (<1%) PEF of >= 15%, 20 mins after inhalation of 400ug salbutamol Did not have a mean morning 9 (6%) 9 (6%) 8 (5%) 12 (8%) 38 (7%) PEF (last 7 days of run-in) <= 80% predicted normal Did not have a daily symptom 5 (3%) 2 (1%) 3 (2%) 6 (4%) 16 (3%) score (day+night) > 1 on at least 4 of the last 7 days of run-in Did not complete the diary 0 0 0 1 (<1%) 1 (<1%) card for 6 out of last 7 days prior to Visit 2 [1] Compliance as recorded on the diary card

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Protocol: FFA20001 Page 2 of 3 Population: Intent-to-Treat Table 6.6 Summary of Reasons for Exclusion from the Per Protocol Population GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total Reason (N=143) (N=144) (N=146) (N=142) (N=575) ------------------------------------------------------------------------------------------ Failed to record at least 5 5 (3%) 2 (1%) 4 (3%) 2 (1%) 13 (2%) days of DRC data Less than 80% compliant with 5 (3%) 2 (1%) 4 (3%) 6 (4%) 17 (3%) either am or pm dose of study medication [1] Failed to record at least 5 1 (<1%) 0 0 0 1 (<1%) days of DRC data before meeting criteria for withdrawal Actual medication received 0 1 (<1%) 0 1 (<1%) 2 (<1%) different to Randomised [1] Compliance as recorded on the diary card

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Protocol: FFA20001 Page 3 of 3 Population: Intent-to-Treat Table 6.6 Summary of Reasons for Exclusion from the Per Protocol Population GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total Reason (N=143) (N=144) (N=146) (N=142) (N=575) ------------------------------------------------------------------------------------------ Partially Excluded 11 (8%) 3 (2%) 5 (3%) 9 (6%) 28 (5%) Met the criteria for 2 (1%) 0 1 (<1%) 0 3 (<1%) withdrawal based on PEF Met the criteria for 2 (1%) 0 0 0 2 (<1%) withdrawal based on rescue med and (symptom or night awakenings) Met the criteria for 5 (3%) 1 (<1%) 2 (1%) 6 (4%) 14 (2%) withdrawal based on Clinic FEV1 Took prohibited meds on 4 (3%) 2 (1%) 2 (1%) 3 (2%) 11 (2%) treatment [1] Compliance as recorded on the diary card

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Protocol: FFA20001 Page 1 of 2 Population: Intent-to-Treat Table 6.7 Summary of Inclusion/Exclusion Deviations GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total Criterion (N=143) (N=144) (N=146) (N=142) (N=575) ----------------------------------------------------------------------------------------- Any criteria deviations 5 (3%) 5 (3%) 11 (8%) 8 (6%) 29 (5%) Inclusion to Run-In Male or female aged 16 to 55 0 2 (1%) 0 3 (2%) 5 (<1%) years inclusive A lung function of between 50 to 1 (<1%) 1 (<1%) 2 (1%) 1 (<1%) 5 (<1%) 90% predicted (PEF) Increase in PEF >=15%, 20 1 (<1%) 1 (<1%) 4 (3%) 0 6 (1%) minutes after inhalation of 400ug salbutamol Inclusion to Treatment Period Increase in PEF >=15%, 20 1 (<1%) 0 0 0 1 (<1%) minutes after inhalation of 400ug salbutamol, if not demonstrated at Visit 1, 1a or 1b Note: Deviations as recorded on the Inclusion/Exclusion Pages in the CRF

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Protocol: FFA20001 Page 2 of 2 Population: Intent-to-Treat Table 6.7 Summary of Inclusion/Exclusion Deviations GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total Criterion (N=143) (N=144) (N=146) (N=142) (N=575) ----------------------------------------------------------------------------------------- Mean morning PEF of between 50% 3 (2%) 0 2 (1%) 1 (<1%) 6 (1%) and 80% of their percent predicted normal Daily asthma symptom score of >1 2 (1%) 2 (1%) 2 (1%) 3 (2%) 9 (2%) on at least four of the last 7 consecutive days of the final run-in period Exclusion to Run-In Is a current smoker or has a 1 (<1%) 0 2 (1%) 0 3 (<1%) smoking history of 10 pack years or more Administration of prohibited 0 0 1 (<1%) 0 1 (<1%) medications prior to Visit 1 Exclusion to Treatment Period Exacerbation of asthma symptoms 1 (<1%) 0 0 0 1 (<1%) during the run-in period Note: Deviations as recorded on the Inclusion/Exclusion Pages in the CRF

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Protocol: FFA20001 Page 1 of 2 Population: Intent-to-Treat Table 6.8 Summary of Demographic Characteristics GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total (N=143) (N=144) (N=146) (N=142) (N=575) --------------------------------------------------------------------------------------- Age (yrs) n 143 144 146 142 575 Mean 36.5 36.0 37.1 36.9 36.6 SD 12.05 12.17 12.48 12.28 12.22 Median 36.0 37.0 38.5 37.5 37.0 Min. 16 16 16 16 16 Max. 55 56 55 69 69 Sex n 143 144 146 142 575 Female 75 (52%) 81 (56%) 87 (60%) 84 (59%) 327 (57%) Male 68 (48%) 63 (44%) 59 (40%) 58 (41%) 248 (43%) Race[1] n 143 144 146 142 575 Arabic/N African 0 0 0 0 0 Black 0 0 0 0 0 E & SE Asian 0 0 0 0 0 S Asian 1 (<1%) 0 0 0 1 (<1%) White/Caucasian 126 (88%) 128 (89%) 129 (88%) 124 (87%) 507 (88%) Other 16 (11%) 16 (11%) 17 (12%) 18 (13%) 67 (12%) [1] N=North, E=East, S=South, SE=South East

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Protocol: FFA20001 Page 2 of 2 Population: Intent-to-Treat Table 6.8 Summary of Demographic Characteristics GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total (N=143) (N=144) (N=146) (N=142) (N=575) --------------------------------------------------------------------------------------- Height (cm) n 143 144 146 142 575 Mean 169.7 169.0 167.6 169.0 168.8 SD 10.07 10.78 10.78 10.98 10.66 Median 170.0 168.0 168.0 169.5 168.0 Min. 143 143 142 139 139 Max. 195 197 196 195 197 Weight (kg) n 143 144 146 142 575 Mean 73.6 75.4 71.2 76.5 74.2 SD 14.09 16.29 14.00 17.36 15.59 Median 72.0 73.5 70.0 73.1 72.0 Min. 46 43 40 40 40 Max. 115 120 120 124 124 [1] N=North, E=East, S=South, SE=South East

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Protocol: FFA20001 Page 1 of 2 Population: Intent-to-Treat Table 6.9 Summary of History of Tobacco Use at Visit 1 (Screening) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total (N=143) (N=144) (N=146) (N=142) (N=575) --------------------------------------------------------------------------------------- Smoking Habit n 143 144 146 142 575 Never smoked 116 (81%) 119 (83%) 119 (82%) 116 (82%) 470 (82%) Current smoker 3 (2%) 2 (1%) 2 (1%) 2 (1%) 9 (2%) Former smoker 24 (17%) 23 (16%) 25 (17%) 24 (17%) 96 (17%) Average cigs. n 25 24 25 24 98 smoke/day Mean 9.0 10.3 10.1 11.5 10.2 SD 4.40 5.95 5.33 10.63 6.91 Median 10.0 10.0 10.0 10.0 10.0 Min. 3 1 1 5 1 Max. 20 20 20 60 60 No. years smoked n 25 24 25 24 98 Mean 11.0 10.1 9.4 11.4 10.5 SD 6.74 4.30 4.38 7.66 5.91 Median 10.0 10.0 10.0 10.0 10.0 Min. 3 2 3 3 2 Max. 30 18 18 30 30

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Protocol: FFA20001 Page 2 of 2 Population: Intent-to-Treat Table 6.9 Summary of History of Tobacco Use at Visit 1 (Screening) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total (N=143) (N=144) (N=146) (N=142) (N=575) --------------------------------------------------------------------------------------- No. pack years n 25 24 25 24 98 Mean 4.42 5.11 4.81 5.21 4.88 SD 2.564 2.847 2.823 2.435 2.650 Median 3.15 5.50 5.00 5.00 5.00 Min. 0.9 0.2 0.2 1.5 0.2 Max. 9.0 9.0 9.0 9.0 9.0

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 6.10 Summary of Duration of Asthma and Asthma History GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total (N=143) (N=144) (N=146) (N=142) (N=575) ------------------------------------------------------------------------------------------ Duration of n 143 144 146 142 575 Asthma <6 mns. 0 0 0 0 0 >=6 mns. to <1 yr 10 (7%) 5 (3%) 9 (6%) 6 (4%) 30 (5%) >=1 to <5 yrs 51 (36%) 52 (36%) 55 (38%) 56 (39%) 214 (37%) >=5 to <10 yrs 32 (22%) 40 (28%) 34 (23%) 30 (21%) 136 (24%) >=10 yrs 50 (35%) 47 (33%) 48 (33%) 50 (35%) 195 (34%) Subjects with >0 n 43 (30%) 34 (24%) 28 (19%) 39 (27%) 144 (25%) exacerbations in last 6 months Exacerbations in n [1] 70 68 55 74 267 last 6 months Not hospitalised 61 (87%) 63 (93%) 50 (91%) 62 (84%) 236 (88%) Hospitalised 3 (4%) 0 1 (2%) 7 (9%) 11 (4%) Required OCS[2] 6 (9%) 5 (7%) 4 (7%) 5 (7%) 20 (7%) [1] n is the total number of exacerbations in the last 6 months [2] OCS = Oral Corticosterids

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Protocol: FFA20001 Page 1 of 3 Population: Intent-to-Treat Table 6.11 Summary of Clinic Pulmonary Function Tests Prior to Treatment GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total Visit 1/1a/1b (Screening) (N=143) (N=144) (N=146) (N=142) (N=575) ------------------------------------------------------------------------------------ Reversibility as a % n 142 144 146 142 574 of pre-bronchodilator Mean 24.2 25.9 26.8 25.7 25.7 PEF [1][2] SD 9.91 13.42 13.71 11.37 12.22 Median 21.0 21.0 23.0 23.0 21.5 Min. 15 15 15 15 15 Max. 70 103 119 90 119 % predicted Normal n 142 144 146 142 574 PEF [1][2] Mean 75.6 76.4 74.3 74.4 75.2 SD 9.59 9.88 11.24 10.62 10.37 Median 77.0 78.5 76.0 75.0 76.0 Min. 50 43 28 37 28 Max. 94 100 90 95 100 Post-bronchodilator n 142 144 146 142 574 PEF (L/min) [2] Mean 447.6 448.8 429.2 432.8 439.6 SD 101.95 98.24 98.80 97.45 99.24 Median 429.0 430.0 420.0 410.0 420.0 Min. 230 260 180 250 180 Max. 700 700 694 720 720 [1] Values have been recalculated from raw data [2] Values are from tests performed at Visit 2 if reversibility criteria not met at Visit 1/1a/1b

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Protocol: FFA20001 Page 2 of 3 Population: Intent-to-Treat Table 6.11 Summary of Clinic Pulmonary Function Tests Prior to Treatment GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total Visit 1/1a/1b (Screening) (N=143) (N=144) (N=146) (N=142) (N=575) ------------------------------------------------------------------------------------ % predicted Normal n 142 144 146 142 574 FEV1 [1][2] Mean 81.4 81.6 80.6 80.4 81.0 SD 15.26 17.12 16.97 14.66 16.01 Median 81.0 82.0 82.0 81.0 81.0 Min. 38 43 35 47 35 Max. 124 123 122 111 124 [1] Values have been recalculated from raw data [2] Values are from tests performed at Visit 2 if reversibility criteria not met at Visit 1/1a/1b

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Protocol: FFA20001 Page 3 of 3 Population: Intent-to-Treat Table 6.11 Summary of Clinic Pulmonary Function Tests Prior to Treatment GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total Visit 2 (Randomisation) (N=143) (N=144) (N=146) (N=142) (N=575) ------------------------------------------------------------------------------------ Pre-bronchodilator n 142 144 146 142 574 PEF (L/min) Mean 360.1 359.5 351.7 349.9 355.3 SD 92.31 86.47 83.75 83.32 86.41 Median 355.0 350.0 330.0 330.0 340.0 Min. 150 180 150 170 150 Max. 650 560 560 550 650 Pre-bronchodilator n 142 144 146 142 574 FEV1 (L) Mean 2.718 2.791 2.685 2.684 2.720 SD 0.910 0.963 0.962 0.866 0.925 Median 2.645 2.655 2.510 2.550 2.600 Min. 0.86 1.07 0.99 1.12 0.86 Max. 5.57 5.13 6.24 5.26 6.24 [1] Values have been recalculated from raw data [2] Values are from tests performed at Visit 2 if reversibility criteria not met at Visit 1/1a/1b

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 6.12 Summary of Baseline Diary Card Pulmonary Function Tests Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM Total (N=143) (N=143) (N=144) (N=146) (N=142) (N=575) --------------------------------------------------------------------------------------- Mean Trough n 143 143 144 146 141 574 PEF (L/min) Mean 346.3 369.6 336.1 350.5 357.1 350.4 SD 82.39 90.91 86.93 92.26 90.02 88.81 Median 331.0 353.0 316.5 335.0 340.0 337.0 Min. 179 159 174 157 180 157 Max. 509 619 595 587 593 595 Mean Morning n 143 144 146 141 574 PEF (L/min) Mean 346.3 336.1 330.3 332.3 336.2 SD 82.39 86.93 82.18 81.64 83.33 Median 331.0 316.5 311.0 316.0 320.0 Min. 179 174 144 184 144 Max. 509 595 572 582 595 Mean Evening n 143 143 146 141 573 PEF (L/min) Mean 369.6 362.8 350.5 357.1 360.0 SD 90.91 93.64 92.26 90.02 91.76 Median 353.0 343.0 335.0 340.0 344.0 Min. 159 176 157 180 157 Max. 619 597 587 593 619 Note: Trough PEF is the measurement taken 24 hours after dosing

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Protocol: FFA20001 Page 1 of 2 Population: Intent-to-Treat Table 6.13 Summary of Current Medical Conditions GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total System Organ Class (N=143) (N=144) (N=146) (N=142) (N=575) ------------------------------------------------------------------------------------------ Any Condition 81 (57%) 73 (51%) 85 (58%) 86 (61%) 325 (57%) Blood and lymphatic system 2 (1%) 1 (<1%) 4 (3%) 2 (1%) 9 (2%) disorders Cardiac disorders 12 (8%) 13 (9%) 13 (9%) 19 (13%) 57 (10%) Ear and labyrinth disorders 1 (<1%) 5 (3%) 1 (<1%) 3 (2%) 10 (2%) Endocrine disorders 8 (6%) 6 (4%) 12 (8%) 9 (6%) 35 (6%) Eye disorders 20 (14%) 14 (10%) 13 (9%) 17 (12%) 64 (11%) Gastrointestinal disorders 6 (4%) 8 (6%) 3 (2%) 9 (6%) 26 (5%) Hepatobiliary disorders 4 (3%) 3 (2%) 5 (3%) 5 (4%) 17 (3%) Immune system disorders 9 (6%) 10 (7%) 8 (5%) 11 (8%) 38 (7%) Infections and infestations 1 (<1%) 0 0 1 (<1%) 2 (<1%) Metabolism and nutrition 6 (4%) 7 (5%) 8 (5%) 5 (4%) 26 (5%) disorders Musculoskeletal and connective 8 (6%) 2 (1%) 6 (4%) 7 (5%) 23 (4%) tissue disorders Neoplasms benign, malignant 0 0 0 1 (<1%) 1 (<1%) and unspecified (incl cysts and polyps) Nervous system disorders 2 (1%) 1 (<1%) 3 (2%) 1 (<1%) 7 (1%) Psychiatric disorders 2 (1%) 2 (1%) 1 (<1%) 0 5 (<1%) Renal and urinary disorders 2 (1%) 2 (1%) 4 (3%) 0 8 (1%) Reproductive system and breast 6 (4%) 7 (5%) 3 (2%) 4 (3%) 20 (3%) disorders

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Protocol: FFA20001 Page 2 of 2 Population: Intent-to-Treat Table 6.13 Summary of Current Medical Conditions GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total System Organ Class (N=143) (N=144) (N=146) (N=142) (N=575) ------------------------------------------------------------------------------------------ Respiratory, thoracic and 42 (29%) 35 (24%) 47 (32%) 43 (30%) 167 (29%) mediastinal disorders Skin and subcutaneous tissue 8 (6%) 8 (6%) 15 (10%) 8 (6%) 39 (7%) disorders Vascular disorders 5 (3%) 3 (2%) 4 (3%) 7 (5%) 19 (3%)

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Protocol: FFA20001 Page 1 of 4 Population: Intent-to-Treat Table 6.14 Summary of Asthma Concomitant Medications - Pre-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- Any Medication 118 (83%) 119 (83%) 117 (80%) 116 (82%) RESPIRATORY SYSTEM Any Medication 118 (83%) 119 (83%) 117 (80%) 115 (81%) SALBUTAMOL 104 (73%) 99 (69%) 104 (71%) 101 (71%) SALBUTAMOL SULFATE 10 (7%) 8 (6%) 6 (4%) 12 (8%) BUDESONIDE 6 (4%) 6 (4%) 1 (<1%) 3 (2%) CROMOGLICATE SODIUM 5 (3%) 4 (3%) 2 (1%) 4 (3%) FENOTEROL HYDROBROMIDE 2 (1%) 5 (3%) 6 (4%) 0 BECLOMETASONE DIPROPIONATE 1 (<1%) 3 (2%) 4 (3%) 4 (3%) FLUTICASONE PROPIONATE 2 (1%) 3 (2%) 5 (3%) 2 (1%) SALMETEROL XINAFOATE+FLUTICASONE 2 (1%) 4 (3%) 2 (1%) 0 PROPIONATE SALMETEROL XINAFOATE 0 1 (<1%) 2 (1%) 4 (3%) FORMOTEROL 2 (1%) 2 (1%) 0 2 (1%) TERBUTALINE 1 (<1%) 4 (3%) 1 (<1%) 0 CROMOGLICATE SODIUM+REPROTEROL 1 (<1%) 2 (1%) 0 2 (1%) HYDROCHLORIDE BUDESONIDE+EFORMOTEROL FUMARATE 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) NEDOCROMIL SODIUM 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) EFORMOTEROL FUMARATE 2 (1%) 0 1 (<1%) 0 ORCIPRENALINE SULFATE 0 2 (1%) 0 0 AMINOPHYLLINE 0 0 0 1 (<1%) Note: A medication may be included in more than one ATC Level category and appear more than once

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Protocol: FFA20001 Page 2 of 4 Population: Intent-to-Treat Table 6.14 Summary of Asthma Concomitant Medications - Pre-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- BECLOMETASONE 0 1 (<1%) 0 0 BUDESONIDE+FORMOTEROL 0 0 1 (<1%) 0 CETIRIZINE HYDROCHLORIDE 0 1 (<1%) 0 0 CROMOGLICATE SODIUM+FENOTEROL 0 0 1 (<1%) 0 HYDROBROMIDE FENOTEROL HYDROBROMIDE+IPRATROPIUM 0 0 0 1 (<1%) BROMIDE FEXOFENADINE HYDROCHLORIDE 0 1 (<1%) 0 0 IPRATROPIUM BROMIDE 0 1 (<1%) 0 0 MONTELUKAST SODIUM 0 1 (<1%) 0 0 OXITROPIUM BROMIDE 0 0 0 1 (<1%) SALMETEROL+FLUTICASONE PROPIONATE 1 (<1%) 0 0 0 TERBUTALINE SULFATE 0 0 1 (<1%) 0 THEOPHYLLINE 0 0 0 1 (<1%) TIOTROPIUM BROMIDE 0 1 (<1%) 0 0 DERMATOLOGICALS Any Medication 9 (6%) 13 (9%) 10 (7%) 9 (6%) BUDESONIDE 6 (4%) 6 (4%) 1 (<1%) 3 (2%) BECLOMETASONE DIPROPIONATE 1 (<1%) 3 (2%) 4 (3%) 4 (3%) FLUTICASONE PROPIONATE 2 (1%) 3 (2%) 5 (3%) 2 (1%) BECLOMETASONE 0 1 (<1%) 0 0 METHYLPREDNISOLONE 0 0 1 (<1%) 0 Note: A medication may be included in more than one ATC Level category and appear more than once

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Protocol: FFA20001 Page 3 of 4 Population: Intent-to-Treat Table 6.14 Summary of Asthma Concomitant Medications - Pre-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- ALIMENTARY TRACT AND METABOLISM Any Medication 7 (5%) 10 (7%) 5 (3%) 7 (5%) BUDESONIDE 6 (4%) 6 (4%) 1 (<1%) 3 (2%) BECLOMETASONE DIPROPIONATE 1 (<1%) 3 (2%) 4 (3%) 4 (3%) BECLOMETASONE 0 1 (<1%) 0 0 SENSORY ORGANS Any Medication 6 (4%) 5 (3%) 5 (3%) 5 (4%) CROMOGLICATE SODIUM 5 (3%) 4 (3%) 2 (1%) 4 (3%) NEDOCROMIL SODIUM 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) CROMOGLICATE SODIUM+FENOTEROL 0 0 1 (<1%) 0 HYDROBROMIDE METHYLPREDNISOLONE 0 0 1 (<1%) 0 SYSTEMIC HORMONAL PREP,EXCL SEX HORMONES Any Medication 6 (4%) 6 (4%) 2 (1%) 3 (2%) BUDESONIDE 6 (4%) 6 (4%) 1 (<1%) 3 (2%) METHYLPREDNISOLONE 0 0 1 (<1%) 0 GENITO URINARY SYSTEM AND SEX HORMONES Any Medication 2 (1%) 5 (3%) 6 (4%) 0 FENOTEROL HYDROBROMIDE 2 (1%) 5 (3%) 6 (4%) 0 Note: A medication may be included in more than one ATC Level category and appear more than once

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Protocol: FFA20001 Page 4 of 4 Population: Intent-to-Treat Table 6.14 Summary of Asthma Concomitant Medications - Pre-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- CARDIOVASCULAR SYSTEM Any Medication 0 1 (<1%) 0 0 IPRATROPIUM BROMIDE 0 1 (<1%) 0 0 NERVOUS SYSTEM Any Medication 0 0 0 1 (<1%) BROMAZEPAM 0 0 0 1 (<1%) Note: A medication may be included in more than one ATC Level category and appear more than once

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Protocol: FFA20001 Page 1 of 3 Population: Intent-to-Treat Table 6.15 Summary of Asthma Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------ Any Medication 15 (10%) 11 (8%) 10 (7%) 11 (8%) RESPIRATORY SYSTEM Any Medication 12 (8%) 10 (7%) 10 (7%) 11 (8%) SALBUTAMOL 5 (3%) 4 (3%) 3 (2%) 6 (4%) CROMOGLICATE SODIUM 4 (3%) 4 (3%) 2 (1%) 3 (2%) NEDOCROMIL SODIUM 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) BECLOMETASONE DIPROPIONATE 2 (1%) 1 (<1%) 0 0 THEOPHYLLINE 0 0 2 (1%) 0 AMINOPHYLLINE 0 0 1 (<1%) 0 BUDESONIDE 0 1 (<1%) 0 0 FENOTEROL HYDROBROMIDE+IPRATROPIUM 0 0 1 (<1%) 0 BROMIDE FEXOFENADINE HYDROCHLORIDE 1 (<1%) 0 0 0 FLUTICASONE PROPIONATE 0 0 0 1 (<1%) FORMOTEROL 0 1 (<1%) 0 0 PREDNISOLONE 1 (<1%) 0 0 0 SALBUTAMOL SULFATE+IPRATROPIUM BROMIDE 0 0 1 (<1%) 0 SALMETEROL XINAFOATE+FLUTICASONE 0 0 1 (<1%) 0 PROPIONATE SENSORY ORGANS Any Medication 7 (5%) 5 (3%) 5 (3%) 4 (3%) Note: A medication may be included in more than one ATC Level category and appear more than once

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Protocol: FFA20001 Page 2 of 3 Population: Intent-to-Treat Table 6.15 Summary of Asthma Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------ CROMOGLICATE SODIUM 4 (3%) 4 (3%) 2 (1%) 3 (2%) METHYLPREDNISOLONE 2 (1%) 0 2 (1%) 0 NEDOCROMIL SODIUM 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) CIPROFLOXACIN 0 0 1 (<1%) 0 PREDNISOLONE 1 (<1%) 0 0 0 DERMATOLOGICALS Any Medication 4 (3%) 2 (1%) 2 (1%) 1 (<1%) METHYLPREDNISOLONE 2 (1%) 0 2 (1%) 0 BECLOMETASONE DIPROPIONATE 2 (1%) 1 (<1%) 0 0 BUDESONIDE 0 1 (<1%) 0 0 FLUTICASONE PROPIONATE 0 0 0 1 (<1%) PREDNISOLONE 1 (<1%) 0 0 0 ALIMENTARY TRACT AND METABOLISM Any Medication 4 (3%) 3 (2%) 1 (<1%) 0 BECLOMETASONE DIPROPIONATE 2 (1%) 1 (<1%) 0 0 PREDNISONE 1 (<1%) 1 (<1%) 1 (<1%) 0 BUDESONIDE 0 1 (<1%) 0 0 PREDNISOLONE 1 (<1%) 0 0 0 SYSTEMIC HORMONAL PREP,EXCL SEX HORMONES Any Medication 3 (2%) 2 (1%) 3 (2%) 0 Note: A medication may be included in more than one ATC Level category and appear more than once

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Protocol: FFA20001 Page 3 of 3 Population: Intent-to-Treat Table 6.15 Summary of Asthma Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------ METHYLPREDNISOLONE 2 (1%) 0 2 (1%) 0 PREDNISONE 1 (<1%) 1 (<1%) 1 (<1%) 0 BUDESONIDE 0 1 (<1%) 0 0 PREDNISOLONE 1 (<1%) 0 0 0 GENERAL ANTIINFECTIVES FOR SYSTEMIC USE Any Medication 3 (2%) 0 1 (<1%) 0 AZITHROMYCIN 1 (<1%) 0 0 0 CEFUROXIME AXETIL 1 (<1%) 0 0 0 CIPROFLOXACIN 0 0 1 (<1%) 0 MOXIFLOXACIN 1 (<1%) 0 0 0 CARDIOVASCULAR SYSTEM Any Medication 1 (<1%) 0 1 (<1%) 0 NIMODIPINE 0 0 1 (<1%) 0 PREDNISOLONE 1 (<1%) 0 0 0 MUSCULO-SKELETAL SYSTEM Any Medication 1 (<1%) 0 0 0 NIMESULIDE 1 (<1%) 0 0 0 Note: A medication may be included in more than one ATC Level category and appear more than once

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Protocol: FFA20001 Page 1 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- Any Medication 48 (34%) 52 (36%) 60 (41%) 58 (41%) NERVOUS SYSTEM Any Medication 14 (10%) 17 (12%) 18 (12%) 17 (12%) PARACETAMOL 6 (4%) 8 (6%) 11 (8%) 6 (4%) ACETYLSALICYLIC ACID 2 (1%) 4 (3%) 2 (1%) 3 (2%) METAMIZOLE SODIUM 2 (1%) 2 (1%) 1 (<1%) 4 (3%) ACETYLSALICYLIC 1 (<1%) 1 (<1%) 0 1 (<1%) ACID+PARACETAMOL+CAFFEINE ACETYLSALICYLIC 0 2 (1%) 0 1 (<1%) ACID+PHENACETIN+CAFFEINE+CITRIC ACID RIZATRIPTAN BENZOATE 0 0 2 (1%) 0 ACETYLSALICYLIC ACID+ASCORBIC ACID 0 1 (<1%) 0 0 ACETYLSALICYLIC ACID+CODEINE 0 1 (<1%) 0 0 PHOSPHATE+PARACETAMOL+CAFFEINE ALPRAZOLAM 1 (<1%) 0 0 0 ASCORBIC ACID+PARACETAMOL 1 (<1%) 0 0 0 BROMOCRIPTINE MESILATE 1 (<1%) 0 0 0 CINNARIZINE 0 0 1 (<1%) 0 CODEINE 0 0 1 (<1%) 0 CODEINE PHOSPHATE+DICLOFENAC SODIUM 0 0 1 (<1%) 0 CODEINE PHOSPHATE+PARACETAMOL 0 0 0 1 (<1%) Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 2 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- CODEINE 0 0 1 (<1%) 0 PHOSPHATE+PARACETAMOL+CAFFEINE+PROPYPH ENAZONE DIAZEPAM 0 0 0 1 (<1%) FLUOXETINE HYDROCHLORIDE 1 (<1%) 0 0 0 GINKGO BILOBA 0 0 0 1 (<1%) IBUPROFEN LYSINATE 1 (<1%) 0 0 0 METAMIZOLE SODIUM+CAFFEINE+DROTAVERINE 1 (<1%) 0 0 0 HYDROCHLORIDE PARACETAMOL+CHLORPHENAMINE 1 (<1%) 0 0 0 MALEATE+PSEUDOEPHEDRINE HYDROCHLORIDE PARACETAMOL+PHENYLPROPANOLAMINE 0 1 (<1%) 0 0 HYDROCHLORIDE PYRIDOSTIGMINE BROMIDE 1 (<1%) 0 0 0 TEMPALGIN (NOS) 0 0 1 (<1%) 0 CARDIOVASCULAR SYSTEM Any Medication 12 (8%) 13 (9%) 13 (9%) 21 (15%) ENALAPRIL 1 (<1%) 1 (<1%) 3 (2%) 5 (4%) ENALAPRIL MALEATE 1 (<1%) 1 (<1%) 1 (<1%) 5 (4%) CAPTOPRIL 0 2 (1%) 2 (1%) 3 (2%) INDAPAMIDE 0 0 1 (<1%) 3 (2%) NIFEDIPINE 0 3 (2%) 1 (<1%) 0 Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 3 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- VERAPAMIL 1 (<1%) 1 (<1%) 0 2 (1%) VERAPAMIL HYDROCHLORIDE 1 (<1%) 0 2 (1%) 1 (<1%) LISINOPRIL 0 0 1 (<1%) 2 (1%) RAMIPRIL 0 1 (<1%) 0 2 (1%) SIMVASTATIN 1 (<1%) 2 (1%) 0 0 CANDESARTAN CILEXETIL 1 (<1%) 1 (<1%) 0 0 DILTIAZEM HYDROCHLORIDE 2 (1%) 0 0 0 NITRENDIPINE 0 1 (<1%) 0 1 (<1%) VALSARTAN 2 (1%) 0 0 0 AMLODIPINE 0 0 0 1 (<1%) ATORVASTATIN CALCIUM 0 0 1 (<1%) 0 BETAMETHASONE 1 (<1%) 0 0 0 BISOPROLOL 1 (<1%) 0 0 0 DILTIAZEM 0 0 1 (<1%) 0 FOSINOPRIL SODIUM 0 0 1 (<1%) 0 GINKGO BILOBA 0 0 0 1 (<1%) GLYCERYL TRINITRATE 1 (<1%) 0 0 0 HYDROCHLOROTHIAZIDE 0 1 (<1%) 0 0 HYDROCHLOROTHIAZIDE+TELMISARTAN 0 0 0 1 (<1%) ISOSORBIDE DINITRATE 0 0 1 (<1%) 0 ISOSORBIDE MONONITRATE 0 0 1 (<1%) 0 LACIDIPINE 0 1 (<1%) 0 0 LERCANIDIPINE HYDROCHLORIDE 1 (<1%) 0 0 0 Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 4 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- METOPROLOL TARTRATE 0 0 0 1 (<1%) MOXONIDINE 0 1 (<1%) 0 0 PERINDOPRIL 0 0 1 (<1%) 0 PREDNISOLONE 1 (<1%) 0 0 0 SPIRONOLACTONE 0 0 0 1 (<1%) TIMOLOL 0 1 (<1%) 0 0 TORASEMIDE 1 (<1%) 0 0 0 TRIAMTERENE+HYDROCHLOROTHIAZIDE 0 0 0 1 (<1%) TRIMETAZIDINE HYDROCHLORIDE 1 (<1%) 0 0 0 VERAPAMIL HYDROCHLORIDE+TRANDOLAPRIL 0 1 (<1%) 0 0 GENITO URINARY SYSTEM AND SEX HORMONES Any Medication 8 (6%) 15 (10%) 21 (14%) 14 (10%) ETHINYLOESTRADIOL+LEVONORGESTREL 2 (1%) 4 (3%) 8 (5%) 5 (4%) IBUPROFEN 0 1 (<1%) 4 (3%) 1 (<1%) ETHINYLOESTRADIOL+GESTODENE 0 1 (<1%) 3 (2%) 1 (<1%) ETHINYLOESTRADIOL+CHLORMADINONE 1 (<1%) 0 0 2 (1%) ACETATE ETHINYLOESTRADIOL+DESOGESTREL 1 (<1%) 1 (<1%) 1 (<1%) 0 ETHINYLOESTRADIOL+DIENOGEST 0 1 (<1%) 2 (1%) 0 ETHINYLOESTRADIOL+DROSPIRENONE 0 2 (1%) 1 (<1%) 0 CLOTRIMAZOLE 1 (<1%) 1 (<1%) 0 0 NYSTATIN 0 0 0 2 (1%) Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 5 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- AMPHOTERICIN B 1 (<1%) 0 0 0 BROMOCRIPTINE MESILATE 1 (<1%) 0 0 0 ESTRADIOL VALERATE+LEVONORGESTREL 0 1 (<1%) 0 0 ESTRADIOL 0 1 (<1%) 0 0 VALERATE+ESTRIOL+LEVONORGESTREL ETHINYLOESTRADIOL 1 (<1%) 0 0 0 ETHINYLOESTRADIOL+LYNESTRENOL 0 0 0 1 (<1%) ETHINYLOESTRADIOL+NORETHISTERONE 0 0 0 1 (<1%) GESTODENE 1 (<1%) 0 0 0 HORMONAL CONTRACEPTIVES FOR SYSTEMIC 0 1 (<1%) 0 0 USE IBUPROFEN LYSINATE 1 (<1%) 0 0 0 KETOCONAZOLE 0 0 0 1 (<1%) LEVONORGESTREL 0 0 0 1 (<1%) MEDROXYPROGESTERONE ACETATE 0 1 (<1%) 0 0 METRONIDAZOLE 1 (<1%) 0 0 0 NAPROXEN 0 0 1 (<1%) 0 NITROFURANTOIN 0 0 1 (<1%) 0 PAPAVERINE HYDROCHLORIDE 0 0 1 (<1%) 0 RESPIRATORY SYSTEM Any Medication 14 (10%) 12 (8%) 9 (6%) 12 (8%) BENZALKONIUM CHLORIDE 2 (1%) 1 (<1%) 3 (2%) 2 (1%) Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 6 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- ACETYLCYSTEINE 0 1 (<1%) 1 (<1%) 3 (2%) DESLORATADINE 1 (<1%) 1 (<1%) 0 2 (1%) XYLOMETAZOLINE HYDROCHLORIDE 0 1 (<1%) 0 2 (1%) BROMHEXINE HYDROCHLORIDE 1 (<1%) 0 1 (<1%) 0 CETIRIZINE HYDROCHLORIDE 0 0 0 2 (1%) CHLORPHENAMINE MALEATE 0 1 (<1%) 0 1 (<1%) FEXOFENADINE HYDROCHLORIDE 0 1 (<1%) 1 (<1%) 0 LORATADINE 1 (<1%) 1 (<1%) 0 0 BETAMETHASONE 1 (<1%) 0 0 0 BUDESONIDE 0 0 1 (<1%) 0 CARBOCISTEINE 1 (<1%) 0 0 0 CODEINE 0 0 1 (<1%) 0 CODEINE+CHLORPHENAMINE MALEATE 1 (<1%) 0 0 0 DOXYCYCLINE HYCLATE+AMBROXOL 0 1 (<1%) 0 0 HYDROCHLORIDE DOXYCYCLINE HYDROCHLORIDE+AMBROXOL 0 1 (<1%) 0 0 HYDROCHLORIDE DOXYLAMINE SUCCINATE 0 0 1 (<1%) 0 EPHEDRINE 0 0 0 1 (<1%) HYDROCHLORIDE+HYDROCORTISONE+THIOMERSA L SODIUM+NAPHAZOLINE HYDROCHLORIDE EPINASTINE HYDROCHLORIDE 0 1 (<1%) 0 0 FENSPIRIDE 0 1 (<1%) 0 0 Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 7 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- FLUTICASONE PROPIONATE 0 1 (<1%) 0 0 GUAIFENESIN 0 0 1 (<1%) 0 LEVOCETIRIZINE 0 1 (<1%) 0 0 MOMETASONE FUROATE 0 1 (<1%) 0 0 NAPHAZOLINE 1 (<1%) 0 0 0 NOSCAPINE 0 0 1 (<1%) 0 PALTOMIEL (NOS) 0 0 0 1 (<1%) PARACETAMOL+CHLORPHENAMINE 1 (<1%) 0 0 0 MALEATE+PSEUDOEPHEDRINE HYDROCHLORIDE PARACETAMOL+PHENYLPROPANOLAMINE 0 1 (<1%) 0 0 HYDROCHLORIDE POTASSIUM IODIDE 0 1 (<1%) 0 0 PREDNISOLONE 1 (<1%) 0 0 0 PSEUDOEPHEDRINE 0 0 1 (<1%) 0 PSEUDOEPHEDRINE SULFATE+LORATADINE 0 0 1 (<1%) 0 SALBUTAMOL 0 0 1 (<1%) 0 SALBUTAMOL SULFATE+IPRATROPIUM BROMIDE 1 (<1%) 0 0 0 SALMETEROL XINAFOATE+FLUTICASONE 0 0 1 (<1%) 0 PROPIONATE TIXOCORTOL PIVALATE+BACITRACIN ZINC 1 (<1%) 0 0 0 TRIAMCINOLONE 1 (<1%) 0 0 0 ALIMENTARY TRACT AND METABOLISM Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 8 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- Any Medication 15 (10%) 10 (7%) 9 (6%) 11 (8%) ACETYLSALICYLIC ACID 2 (1%) 4 (3%) 2 (1%) 3 (2%) OMEPRAZOLE 1 (<1%) 1 (<1%) 1 (<1%) 3 (2%) METFORMIN HYDROCHLORIDE 1 (<1%) 1 (<1%) 0 1 (<1%) ASCORBIC ACID 0 1 (<1%) 1 (<1%) 0 CLOTRIMAZOLE 1 (<1%) 1 (<1%) 0 0 ESOMEPRAZOLE MAGNESIUM 0 1 (<1%) 0 1 (<1%) HYOSCINE BUTYLBROMIDE 1 (<1%) 0 1 (<1%) 0 NYSTATIN 0 0 0 2 (1%) ACARBOSE 1 (<1%) 0 0 0 AMPHOTERICIN B 1 (<1%) 0 0 0 BETAMETHASONE 1 (<1%) 0 0 0 BISMUTH SUBCITRATE 1 (<1%) 0 0 0 BUDESONIDE 0 0 1 (<1%) 0 COD-LIVER OIL 0 1 (<1%) 0 0 DROTAVERINE HYDROCHLORIDE 1 (<1%) 0 0 0 GLIMEPIRIDE 0 0 1 (<1%) 0 GLYCEROL+SODIUM BORATE 0 0 0 1 (<1%) INSULIN ASPART 1 (<1%) 0 0 0 INSULIN GLARGINE 1 (<1%) 0 0 0 LEVOMENTHOL+CINEOLE+MENTHA PULEGIUM 1 (<1%) 0 0 0 OIL+CAMPHENE+PINENE+BORNEOL Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 9 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- MAGNESIUM TRISILICATE+CALCIUM 0 0 0 1 (<1%) CARBONATE+MAGNESIUM CARBONATE METFORMIN 0 0 1 (<1%) 0 METOCLOPRAMIDE HYDROCHLORIDE 0 0 1 (<1%) 0 METRONIDAZOLE 1 (<1%) 0 0 0 PAPAVERINE 0 0 0 1 (<1%) PAPAVERINE HYDROCHLORIDE 0 0 1 (<1%) 0 PIOGLITAZONE HYDROCHLORIDE 0 1 (<1%) 0 0 PREDNISOLONE 1 (<1%) 0 0 0 PREDNISONE 0 1 (<1%) 0 0 RABEPRAZOLE SODIUM 1 (<1%) 0 0 0 RANITIDINE 0 0 1 (<1%) 0 ROSIGLITAZONE MALEATE 0 1 (<1%) 0 0 SALICYLIC ACID SODIUM 0 0 1 (<1%) 0 SALT+METHENAMINE+LEVOMENTHOL+BILLIAR SALTS SIBUTRAMINE 0 0 1 (<1%) 0 SIBUTRAMINE HYDROCHLORIDE 0 0 1 (<1%) 0 SODIUM BICARBONATE 1 (<1%) 0 0 0 SULFAGUANIDINE 0 1 (<1%) 0 0 TETRACYCLINE HYDROCHLORIDE 1 (<1%) 0 0 0 TRIAMCINOLONE 1 (<1%) 0 0 0 VITAMINS NOS 0 1 (<1%) 0 0 Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 10 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- DERMATOLOGICALS Any Medication 10 (7%) 6 (4%) 8 (5%) 7 (5%) BENZALKONIUM CHLORIDE 2 (1%) 1 (<1%) 3 (2%) 2 (1%) FLUCONAZOLE 0 0 1 (<1%) 2 (1%) CLOTRIMAZOLE 1 (<1%) 1 (<1%) 0 0 NYSTATIN 0 0 0 2 (1%) BETAMETHASONE 1 (<1%) 0 0 0 BETAMETHASONE VALERATE+GENTAMICIN 0 1 (<1%) 0 0 SULFATE BETAMETHASONE 1 (<1%) 0 0 0 DIPROPIONATE+CLOTRIMAZOLE BUDESONIDE 0 0 1 (<1%) 0 COD-LIVER OIL 0 1 (<1%) 0 0 FLUTICASONE PROPIONATE 0 1 (<1%) 0 0 GENTAMICIN 0 0 1 (<1%) 0 GLYCERYL TRINITRATE 1 (<1%) 0 0 0 ICHTHAMMOL 1 (<1%) 0 0 0 ISOSORBIDE DINITRATE 0 0 1 (<1%) 0 ISOTRETINOIN 0 0 1 (<1%) 0 KETOCONAZOLE 0 0 0 1 (<1%) METRONIDAZOLE 1 (<1%) 0 0 0 MOMETASONE FUROATE 0 1 (<1%) 0 0 Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 11 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- PIMECROLIMUS 0 1 (<1%) 0 0 PREDNISOLONE 1 (<1%) 0 0 0 TETRACYCLINE HYDROCHLORIDE 1 (<1%) 0 0 0 TRIAMCINOLONE 1 (<1%) 0 0 0 MUSCULO-SKELETAL SYSTEM Any Medication 7 (5%) 4 (3%) 10 (7%) 10 (7%) NIMESULIDE 2 (1%) 2 (1%) 2 (1%) 1 (<1%) IBUPROFEN 0 1 (<1%) 4 (3%) 1 (<1%) DICLOFENAC 2 (1%) 0 1 (<1%) 1 (<1%) KETOPROFEN 0 0 1 (<1%) 3 (2%) DICLOFENAC SODIUM 2 (1%) 0 0 1 (<1%) ROFECOXIB 0 0 0 2 (1%) ACECLOFENAC 0 1 (<1%) 0 0 ALENDRONATE SODIUM 0 0 0 1 (<1%) ALLOPURINOL 0 0 1 (<1%) 0 CODEINE PHOSPHATE+DICLOFENAC SODIUM 0 0 1 (<1%) 0 COLCHICINE 0 0 1 (<1%) 0 GLUCOSAMINE SULFATE 0 0 0 1 (<1%) IBUPROFEN LYSINATE 1 (<1%) 0 0 0 NAPROXEN 0 0 1 (<1%) 0 GENERAL ANTIINFECTIVES FOR SYSTEMIC USE Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 12 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- Any Medication 7 (5%) 3 (2%) 5 (3%) 7 (5%) AZITHROMYCIN 1 (<1%) 0 0 2 (1%) FLUCONAZOLE 0 0 1 (<1%) 2 (1%) CLARITHROMYCIN 1 (<1%) 1 (<1%) 0 0 DOXYCYCLINE 1 (<1%) 0 1 (<1%) 0 AMOXICILLIN 0 0 1 (<1%) 0 AMOXICILLIN TRIHYDRATE+CLAVULANATE 0 1 (<1%) 0 0 POTASSIUM AMPHOTERICIN B 1 (<1%) 0 0 0 CEFIXIME 0 0 0 1 (<1%) CEFUROXIME AXETIL 0 0 1 (<1%) 0 DOXYCYCLINE HYCLATE+AMBROXOL 0 1 (<1%) 0 0 HYDROCHLORIDE DOXYCYCLINE HYDROCHLORIDE+AMBROXOL 0 1 (<1%) 0 0 HYDROCHLORIDE GENTAMICIN 0 0 1 (<1%) 0 INFLUENZA VIRUS VACCINE INACTIVATED 0 0 0 1 (<1%) KETOCONAZOLE 0 0 0 1 (<1%) LEVOFLOXACIN 1 (<1%) 0 0 0 METRONIDAZOLE 1 (<1%) 0 0 0 NITROFURANTOIN 0 0 1 (<1%) 0 SULFAMETHOXAZOLE+TRIMETHOPRIM 1 (<1%) 0 0 0 TELITHROMYCIN 0 0 1 (<1%) 0 Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 13 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- TETRACYCLINE HYDROCHLORIDE 1 (<1%) 0 0 0 SENSORY ORGANS Any Medication 8 (6%) 4 (3%) 3 (2%) 6 (4%) ACETYLCYSTEINE 0 1 (<1%) 1 (<1%) 3 (2%) DICLOFENAC 2 (1%) 0 1 (<1%) 1 (<1%) DICLOFENAC SODIUM 2 (1%) 0 0 1 (<1%) XYLOMETAZOLINE HYDROCHLORIDE 0 1 (<1%) 0 2 (1%) CYCLOPENTOLATE HYDROCHLORIDE 0 1 (<1%) 0 0 DEXAMETHASONE+TOBRAMYCIN 0 1 (<1%) 0 0 GENTAMICIN 0 0 1 (<1%) 0 NAPHAZOLINE 1 (<1%) 0 0 0 POTASSIUM IODIDE 0 1 (<1%) 0 0 PREDNISOLONE 1 (<1%) 0 0 0 TETRACYCLINE HYDROCHLORIDE 1 (<1%) 0 0 0 TIMOLOL 0 1 (<1%) 0 0 TRIAMCINOLONE 1 (<1%) 0 0 0 SYSTEMIC HORMONAL PREP,EXCL SEX HORMONES Any Medication 6 (4%) 3 (2%) 5 (3%) 4 (3%) LEVOTHYROXINE SODIUM 2 (1%) 2 (1%) 5 (3%) 4 (3%) BETAMETHASONE 1 (<1%) 0 0 0 BUDESONIDE 0 0 1 (<1%) 0 Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 14 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- DESMOPRESSIN 1 (<1%) 0 0 0 PREDNISOLONE 1 (<1%) 0 0 0 PREDNISONE 0 1 (<1%) 0 0 TRIAMCINOLONE 1 (<1%) 0 0 0 BLOOD AND BLOOD FORMING ORGANS Any Medication 5 (3%) 4 (3%) 2 (1%) 3 (2%) ACETYLSALICYLIC ACID 2 (1%) 4 (3%) 2 (1%) 3 (2%) CYANOCOBALAMIN 1 (<1%) 0 0 0 DEXTRIFERRON 1 (<1%) 0 0 0 SODIUM BICARBONATE 1 (<1%) 0 0 0 VARIOUS Any Medication 0 2 (1%) 2 (1%) 4 (3%) ACETYLCYSTEINE 0 1 (<1%) 1 (<1%) 3 (2%) AMBIGUOUS MEDICATION 0 0 1 (<1%) 1 (<1%) POTASSIUM IODIDE 0 1 (<1%) 0 0 ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS Any Medication 1 (<1%) 1 (<1%) 0 0 ETHINYLOESTRADIOL 1 (<1%) 0 0 0 MEDROXYPROGESTERONE ACETATE 0 1 (<1%) 0 0 Note: A medication may be included in more than one ATC Level category and appear more than once.

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Protocol: FFA20001 Page 15 of 15 Population: Intent-to-Treat Table 6.16 Summary of Other Concomitant Medications - On-Treatment GW685698X GW685698X GW685698X ATC Level 1 Placebo 100mcg AM 100mcg PM 250mcg PM Ingredient (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------------------- ANTIPARASITIC PRODUCTS,INSECTICIDES AND REPELLENTS Any Medication 1 (<1%) 0 0 0 METRONIDAZOLE 1 (<1%) 0 0 0 Note: A medication may be included in more than one ATC Level category and appear more than once.

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Efficacy Data Source Figures and Tables

PageFigure 7.1 Trough PEF (L/min) - Weekly Absolute Mean Change from Baseline . . . 165Table 7.1 Summary of Trough Peak Expiratory Flow Rate (L/min) (Intent-to-Treat

Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166Table 7.2 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From

Baseline Over Weeks 1-4 (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . 168Table 7.3 Summary of Trough Peak Expiratory Flow Rate (L/min) Per Protocol

Population (Per-protocol Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169Table 7.4 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From

Baseline Over Weeks 1-4 Per Protocol Population (Per-protocol Population) . . 171Table 7.5 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From

Baseline Over Week 1 (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . 172Table 7.6 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From




Baseline Over Weeks 1-4 Treatment Treatment by Covariate Interactions(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

Table 7.10 Summary of Trough Peak Expiratory Flow Rate Change From BaselineOver 28 Days Treatment by Baseline Daily Trough PEF (Intent-to-TreatPopulation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

Table 7.11 Summary of Trough Peak Expiratory Flow Rate (L/min) by BaselineAsthma Severity (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

Table 7.12 Summary of Mean Morning Peak Expiratory Flow Rate (L/min)(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

Table 7.13 Statistical Analysis of Mean Morning Peak Expiratory Flow RateChange From Baseline Over Weeks 1-4 (Intent-to-Treat Population) . . . . . . . . 182

Table 7.14 Summary of Mean Evening Peak Expiratory Flow Rate (L/min)(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

Table 7.15 Statistical Analysis of Mean Evening Peak Expiratory Flow RateChange From Baseline Over Weeks 1-4 (Intent-to-Treat Population) . . . . . . . . 184

Table 7.16 Summary of Clinic Visit FEV1 (L) (Intent-to-Treat Population) . . . . . . . . . 185Table 7.17 Statistical Analysis of Clinic Visit FEV1 (L) Change From Baseline at

Endpoint (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187Table 7.18 Summary of Clinic Visit Peak Expiratory Flow Rate (L/min)

(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188


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Table 7.19 Statistical Analysis of Clinic Visit Peak Expiratory Flow Rate (L/min)Change From Baseline at Endpoint (Intent-to-Treat Population) . . . . . . . . . . . . 190

Table 7.20 Summary of Percentage of Symptom Free 24-hour Periods(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Table 7.21 Statistical Analysis of Percentage of Symptom Free 24-hour Periods(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

Table 7.22 Summary of Percentage of Symptom Free Days (Intent-to-TreatPopulation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Table 7.23 Statistical Analysis of Percentage of Symptom Free Days(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

Table 7.24 Summary of Percentage of Symptom Free Nights (Intent-to-TreatPopulation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

Table 7.25 Statistical Analysis of Percentage of Symptom Free Nights(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

Table 7.26 Summary of Percentage of Nights with No Awakenings (Intent-to-TreatPopulation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Table 7.27 Statistical Analysis of Percentage of Nights with No Awakenings(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

Table 7.28 Summary of Percentage of 24-hour Periods with no Rescue Medication(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

Table 7.29 Statistical Analysis of Percentage of 24-hour periods with No RescueMedication (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

Table 7.30 Summary of Percentage of Days with No Rescue Medication(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

Table 7.31 Statistical Analysis of Percentage of Days with No Rescue Medication(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

Table 7.32 Summary of Percentage of Nights with No Rescue Medication(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

Table 7.33 Statistical Analysis of Percentage of Nights with No Rescue Medication(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

Table 7.34 Statistical Analysis of Withdrawals Due to Lack of Efficacy(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205


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Protocol: FFA20001 Page 1 of 2 Population: Intent-to-Treat Table 7.1 Summary of Trough Peak Expiratory Flow Rate (L/min) Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=144) (N=146) (N=142) Change Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] Raw [1] -------------------------------------------------------------------------------------- Baseline n 143 143 144 146 141 Mean 346.3 369.6 336.1 350.5 357.1 SD 82.4 90.9 86.9 92.3 90.0 Median 331.0 353.0 316.5 335.0 340.0 Min. 179 159 174 157 180 Max. 509 619 595 587 593 Weeks 1-4 n 140 140 140 140 143 143 143 143 140 140 Mean 370.6 24.5 382.9 13.2 379.2 43.3 379.3 28.9 393.6 36.9 SD 100.7 47.7 102.4 46.8 98.1 45.5 98.9 48.4 95.5 48.5 Median 351.5 16.0 364.0 6.0 364.0 39.0 373.0 19.0 380.5 28.5 Min. 110 -121 123 -164 186 -92 159 -115 193 -90 Max. 613 204 639 202 626 213 732 243 672 231 Week 1 n 140 140 140 140 143 143 143 143 140 140 Mean 363.9 17.8 377.9 8.2 362.4 26.5 370.2 19.8 378.6 21.9 SD 99.1 42.7 103.4 43.8 96.2 34.8 100.3 41.3 94.2 39.4 Median 347.0 10.5 364.0 6.0 350.0 21.0 364.0 14.0 360.0 14.5 Min. 110 -121 123 -164 170 -79 153 -55 179 -53 Max. 614 202 709 207 599 120 714 225 629 188 [1] Change = post-baseline value minus baseline Note: Trough PEF is the measurement taken 24 hours after dosing

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Protocol: FFA20001 Page 2 of 2 Population: Intent-to-Treat Table 7.1 Summary of Trough Peak Expiratory Flow Rate (L/min) Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=144) (N=146) (N=142) Change Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] Raw [1] -------------------------------------------------------------------------------------- Week 2 n 132 132 132 132 139 139 141 141 137 137 Mean 375.0 27.0 387.4 15.8 379.4 42.5 380.2 27.7 396.9 38.4 SD 100.0 50.1 98.5 45.1 100.3 45.5 97.6 50.7 94.6 50.5 Median 353.5 16.0 377.0 7.5 367.0 38.0 369.0 16.0 380.0 31.0 Min. 154 -63 159 -110 168 -74 167 -122 191 -96 Max. 644 216 634 206 639 239 710 221 684 243 Week 3 n 127 127 127 127 137 137 139 139 135 135 Mean 385.2 34.0 395.8 20.6 392.9 54.1 388.5 34.0 403.9 44.5 SD 95.1 48.3 96.7 46.2 100.4 55.2 96.8 56.5 99.4 58.3 Median 369.0 23.0 374.0 10.0 376.0 44.0 381.0 26.0 384.0 32.0 Min. 194 -65 201 -96 171 -107 171 -138 200 -90 Max. 613 197 620 200 643 273 757 268 693 253 Week 4 n 123 123 123 123 134 134 135 135 135 135 Mean 390.1 38.4 400.3 24.2 397.2 59.6 394.5 40.6 404.7 45.3 SD 100.7 53.7 101.2 53.1 102.4 58.9 97.3 56.9 99.8 60.8 Median 385.0 29.0 388.0 8.0 383.5 54.5 382.0 29.0 392.0 39.0 Min. 174 -59 234 -97 156 -122 212 -156 203 -132 Max. 615 203 660 193 647 263 748 259 693 277 [1] Change = post-baseline value minus baseline Note: Trough PEF is the measurement taken 24 hours after dosing

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.2 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From Baseline Over Weeks 1-4 Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 140 140 143 143 140 Baseline Mean (sd) 346.1 (82.0) 369.7 (91.0) 335.9 (87.2) 350.4 (93.1) 356.7 (90.2) Raw Mean (sd) 370.6 (100.7) 382.9 (102.4) 379.2 (98.1) 379.3 (98.9) 393.6 (95.5) Raw Mean Change (sd) 24.5 (47.7) 13.2 (46.8) 43.3 (45.5) 28.9 (48.4) 36.9 (48.5) Adjusted Mean (se) 370.5 (4.9) 360.5 (4.9) 389.7 (4.6) 376.3 (4.9) 385.1 (4.8) Adjusted Mean Change 18.8 (4.9) 8.8 (4.9) 38.0 (4.6) 24.6 (4.9) 33.4 (4.8) (se) Column Treatment - GW685698X 100mcg pm (se) 13.4 (5.62) 8.8 (5.59) 95% CI (2.3,24.4) (-2.2,19.7) Column Treatment - Placebo (se) 19.2 (5.60) 15.9 (5.60) 24.6 (5.62) 95% CI (8.2,30.2) (4.9,26.9) (13.6,35.7) p-value <0.001 0.005 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline daily trough PEF, age, sex and country Note: Trough PEF is the measurement taken 24 hours after dosing

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Protocol: FFA20001 Page 1 of 2 Population: Per-protocol Table 7.3 Summary of Trough Peak Expiratory Flow Rate (L/min) Per Protocol Population Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=119) (N=119) (N=128) (N=128) (N=119) Change Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] Raw [1] -------------------------------------------------------------------------------------- Baseline n 119 119 128 128 119 Mean 342.9 367.7 330.0 347.7 355.8 SD 82.0 92.5 84.3 92.6 89.5 Median 323.0 353.0 313.0 331.5 339.0 Min. 179 159 174 157 180 Max. 505 619 527 587 557 Weeks 1-4 n 119 119 119 119 128 128 128 128 119 119 Mean 371.2 28.3 384.3 16.6 376.3 46.2 378.3 30.6 394.0 38.2 SD 99.3 44.4 101.8 41.5 97.0 45.3 98.4 49.7 97.0 50.1 Median 348.0 19.0 361.0 8.0 362.5 41.0 366.5 20.5 382.0 29.0 Min. 152 -40 140 -76 186 -92 159 -80 193 -90 Max. 613 204 639 202 626 213 732 243 672 231 Week 1 n 119 119 119 119 128 128 128 128 119 119 Mean 363.8 20.9 379.3 11.6 358.3 28.2 368.7 21.1 378.1 22.3 SD 97.6 40.9 102.3 39.5 94.2 34.8 100.1 42.9 94.0 41.0 Median 347.0 13.0 364.0 6.0 349.5 23.5 361.0 15.5 360.0 15.0 Min. 152 -50 140 -76 170 -79 153 -55 179 -53 Max. 614 202 709 207 586 120 714 225 629 188

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Protocol: FFA20001 Page 2 of 2 Population: Per-protocol Table 7.3 Summary of Trough Peak Expiratory Flow Rate (L/min) Per Protocol Population Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=119) (N=119) (N=128) (N=128) (N=119) Change Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] Raw [1] -------------------------------------------------------------------------------------- Week 2 n 111 111 111 111 125 125 126 126 115 115 Mean 376.5 30.5 389.5 17.9 375.3 44.6 378.4 29.0 396.2 40.0 SD 99.9 49.8 97.6 40.3 99.5 45.6 98.1 53.0 96.5 51.5 Median 353.0 25.0 377.0 8.0 367.0 38.0 367.5 17.5 380.0 33.0 Min. 154 -50 174 -66 168 -74 167 -123 191 -96 Max. 644 216 634 206 639 239 710 221 684 243 Week 3 n 107 107 107 107 123 123 124 124 113 113 Mean 385.1 35.8 396.4 21.4 389.9 57.3 386.6 36.9 404.2 47.1 SD 96.0 48.2 98.1 45.3 100.6 55.6 98.0 56.7 102.2 60.1 Median 367.0 26.0 369.0 10.0 374.0 50.0 376.5 26.0 386.0 34.0 Min. 194 -64 201 -79 171 -107 171 -90 200 -90 Max. 613 197 620 200 643 273 757 268 693 253 Week 4 n 102 102 104 104 121 121 120 120 110 110 Mean 390.7 39.5 400.6 24.8 393.8 62.4 391.7 43.3 407.1 48.8 SD 100.8 53.4 103.2 52.7 101.6 59.7 97.2 57.0 104.3 62.6 Median 373.0 30.0 387.5 9.5 382.0 58.0 381.0 28.0 398.0 39.5 Min. 242 -44 240 -76 156 -122 212 -97 203 -132 Max. 615 203 660 193 647 263 748 259 693 277

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Protocol: FFA20001 Page 1 of 1 Population: Per-protocol Table 7.4 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From Baseline Over Weeks 1-4 Per Protocol Population Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=119) (N=119) (N=128) (N=128) (N=119) ------------------------------------------------------------------------------------------ Number of Subjects 119 119 128 128 119 Baseline Mean (sd) 342.9 (82.0) 367.7 (92.5) 330.0 (84.3) 347.7 (92.6) 355.8 (89.5) Raw Mean (sd) 371.2 (99.3) 384.3 (101.8) 376.3 (97.0) 378.3 (98.4) 394.0 (97.0) Raw Mean Change (sd) 28.3 (44.4) 16.6 (41.5) 46.2 (45.3) 30.6 (49.7) 38.2 (50.1) Adjusted Mean (se) 373.0 (5.1) 362.4 (5.1) 391.6 (4.9) 377.0 (5.0) 385.0 (5.0) Adjusted Mean Change 24.5 (5.1) 13.9 (5.1) 43.0 (4.9) 28.5 (5.0) 36.5 (5.0) (se) Column Treatment - GW685698X 100mcg pm (se) 14.5 (5.87) 8.0 (5.89) 95% CI (3.0,26.0) (-3.5,19.6) Column Treatment - Placebo (se) 18.5 (5.91) 14.6 (5.91) 22.6 (6.00) 95% CI (6.9,30.2) (3.0,26.2) (10.8,34.4) p-value 0.002 0.014 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline daily trough PEF, age, sex and country Note: Trough PEF is the measurement taken 24 hours after dosing

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.5 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From Baseline Over Week 1 Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 140 140 143 143 140 Baseline Mean (sd) 346.1 (82.0) 369.7 (91.0) 335.9 (87.2) 350.4 (93.1) 356.7 (90.2) Raw Mean (sd) 363.9 (99.1) 377.9 (103.4) 362.4 (96.2) 370.2 (100.3) 378.6 (94.2) Raw Mean Change (sd) 17.8 (42.7) 8.2 (43.8) 26.5 (34.8) 19.8 (41.3) 21.9 (39.4) Adjusted Mean (se) 365.6 (4.2) 356.0 (4.3) 375.0 (4.0) 368.1 (4.2) 370.5 (4.1) Adjusted Mean Change 13.9 (4.2) 4.3 (4.3) 23.3 (4.0) 16.4 (4.2) 18.8 (4.1) (se) Column Treatment - GW685698X 100mcg pm (se) 6.8 (4.86) 2.4 (4.83) 95% CI (-2.7,16.4) (-7.1,11.9) Column Treatment - Placebo (se) 9.4 (4.84) 12.1 (4.85) 14.4 (4.87) 95% CI (-0.1,18.9) (2.6,21.6) (4.9,24.0) p-value 0.054 0.013 0.003 Note: Based on ANCOVA model adjusted for treatment, baseline daily trough PEF, age, sex and country Note: Trough PEF is the measurement taken 24 hours after dosing

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.6 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From Baseline Over Week 2 Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 132 132 139 141 137 Baseline Mean (sd) 348.0 (81.8) 371.6 (91.9) 336.9 (87.8) 352.5 (92.0) 358.6 (89.8) Raw Mean (sd) 375.0 (100.0) 387.4 (98.5) 379.4 (100.3) 380.2 (97.6) 396.9 (94.6) Raw Mean Change (sd) 27.0 (50.1) 15.8 (45.1) 42.5 (45.5) 27.7 (50.7) 38.4 (50.5) Adjusted Mean (se) 375.3 (5.1) 365.3 (5.1) 390.9 (4.8) 377.2 (5.0) 388.4 (4.9) Adjusted Mean Change 21.9 (5.1) 11.9 (5.1) 37.5 (4.8) 23.8 (5.0) 35.0 (4.9) (se) Column Treatment - GW685698X 100mcg pm (se) 13.7 (5.81) 11.2 (5.75) 95% CI (2.3,25.1) (-0.1,22.5) Column Treatment - Placebo (se) 15.6 (5.84) 11.9 (5.81) 23.1 (5.85) 95% CI (4.2,27.1) (0.5,23.3) (11.7,34.6) p-value 0.008 0.041 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline daily trough PEF, age, sex and country Note: Trough PEF is the measurement taken 24 hours after dosing

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.7 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From Baseline Over Week 3 Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 127 127 137 139 135 Baseline Mean (sd) 351.3 (80.9) 375.1 (90.4) 338.8 (87.1) 354.6 (90.9) 359.3 (90.0) Raw Mean (sd) 385.2 (95.1) 395.8 (96.7) 392.9 (100.4) 388.5 (96.8) 403.9 (99.4) Raw Mean Change (sd) 34.0 (48.3) 20.6 (46.2) 54.1 (55.2) 34.0 (56.5) 44.5 (58.3) Adjusted Mean (se) 383.9 (5.6) 373.1 (5.6) 403.4 (5.2) 385.6 (5.4) 397.0 (5.3) Adjusted Mean Change 28.3 (5.6) 17.5 (5.6) 47.8 (5.2) 30.0 (5.4) 41.4 (5.3) (se) Column Treatment - GW685698X 100mcg pm (se) 17.8 (6.32) 11.4 (6.25) 95% CI (5.4,30.2) (-0.8,23.7) Column Treatment - Placebo (se) 19.5 (6.39) 12.4 (6.37) 23.9 (6.40) 95% CI (6.9,32.0) (-0.1,24.9) (11.3,36.5) p-value 0.002 0.051 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline daily trough PEF, age, sex and country Note: Trough PEF is the measurement taken 24 hours after dosing

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.8 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From Baseline Over Week 4 Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 123 123 134 135 135 Baseline Mean (sd) 351.8 (82.0) 376.0 (91.7) 337.6 (87.6) 353.9 (91.5) 359.3 (90.0) Raw Mean (sd) 390.1 (100.7) 400.3 (101.2) 397.2 (102.4) 394.5 (97.3) 404.7 (99.8) Raw Mean Change (sd) 38.4 (53.7) 24.2 (53.1) 59.6 (58.9) 40.6 (56.9) 45.3 (60.8) Adjusted Mean (se) 388.6 (6.0) 376.7 (6.1) 409.4 (5.6) 392.4 (5.9) 398.0 (5.7) Adjusted Mean Change 33.1 (6.0) 21.2 (6.1) 54.0 (5.6) 37.0 (5.9) 42.6 (5.7) (se) Column Treatment - GW685698X 100mcg pm (se) 17.0 (6.84) 5.6 (6.73) 95% CI (3.6,30.5) (-7.6,18.8) Column Treatment - Placebo (se) 20.9 (6.93) 15.8 (6.92) 21.4 (6.91) 95% CI (7.3,34.5) (2.2,29.3) (7.8,34.9) p-value 0.003 0.023 0.002 Note: Based on ANCOVA model adjusted for treatment, baseline daily trough PEF, age, sex and country Note: Trough PEF is the measurement taken 24 hours after dosing

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.9 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From Baseline Over Weeks 1-4 Treatment Treatment by Covariate Interactions p-value for Treatment by Covariate Interaction Covariate [1] ----------------------------------------------------------------- Baseline Daily Trough PEF 0.072 Age 0.692 Sex 0.704 Country 0.698 [1] Based on ANCOVA model adjusted for treatment, baseline daily trough PEF, age, sex, country and treatment by covariate interaction

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Protocol: FFA20001 Page 1 of 2 Population: Intent-to-Treat Table 7.10 Summary of Trough Peak Expiratory Flow Rate Change From Baseline Over 28 Days Treatment by Baseline Daily Trough PEF Baseline Daily Trough PEF < 339 Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=144) (N=146) (N=142) Change Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] Raw [1] -------------------------------------------------------------------------------------- Baseline n 77 55 79 75 68 Mean 281.5 281.5 270.1 277.4 282.7 SD 39.3 41.1 40.0 41.0 39.4 Median 287.0 291.0 276.0 284.0 287.0 Min. 179 159 174 157 180 Max. 336 335 337 337 337 Weeks 1-4 n 75 75 53 53 79 79 74 74 68 68 Mean 301.9 20.5 298.2 17.7 313.2 43.1 311.8 34.8 326.4 43.7 SD 63.5 48.5 67.7 55.7 58.9 46.3 61.2 43.8 59.4 52.0 Median 298.0 16.0 295.0 11.0 313.0 37.0 315.0 23.0 327.5 32.0 Min. 110 -121 123 -164 186 -92 159 -37 193 -55 Max. 508 204 499 202 475 166 499 179 472 189 [1] Change = post-baseline value minus baseline Note: Baseline Trough PEF split on median value across all treatment groups, combining am and pm in the placebo group

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Protocol: FFA20001 Page 2 of 2 Population: Intent-to-Treat Table 7.10 Summary of Trough Peak Expiratory Flow Rate Change From Baseline Over 28 Days Treatment by Baseline Daily Trough PEF Baseline Daily Trough PEF >= 339 Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=144) (N=146) (N=142) Change Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] Raw [1] -------------------------------------------------------------------------------------- Baseline n 66 88 65 71 73 Mean 422.0 424.6 416.4 427.7 426.5 SD 47.3 66.9 54.7 63.9 64.9 Median 427.5 411.5 408.0 417.0 406.0 Min. 339 340 339 339 339 Max. 509 619 595 587 593 Weeks 1-4 n 65 65 87 87 64 64 69 69 72 72 Mean 449.8 29.0 434.4 10.5 460.8 43.6 451.7 22.6 457.1 30.5 SD 73.8 46.8 84.2 40.5 72.0 44.8 78.4 52.5 78.2 44.5 Median 438.0 18.0 418.0 3.0 455.5 41.5 439.0 15.0 448.5 25.0 Min. 287 -104 285 -105 332 -37 333 -115 335 -90 Max. 613 135 639 123 626 213 732 243 672 231 [1] Change = post-baseline value minus baseline Note: Baseline Trough PEF split on median value across all treatment groups, combining am and pm in the placebo group

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Protocol: FFA20001 Page 1 of 2 Population: Intent-to-Treat Table 7.11 Summary of Trough Peak Expiratory Flow Rate (L/min) by Baseline Asthma Severity Visit 2 % predicted PEF < 65% Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=144) (N=146) (N=142) Change Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] Raw [1] -------------------------------------------------------------------------------------- Baseline n 26 26 19 21 22 Mean 282.2 298.8 300.8 307.1 309.7 SD 74.8 77.9 90.2 96.4 83.5 Median 287.5 299.0 278.0 284.0 296.5 Min. 179 159 174 171 180 Max. 509 529 516 574 497 Weeks 1-4 n 24 24 24 24 19 19 21 21 22 22 Mean 283.7 1.8 294.0 -4.3 333.9 33.2 336.4 29.3 333.9 24.1 SD 88.6 43.2 90.6 48.7 116.1 59.1 111.4 47.3 77.0 48.2 Median 289.0 2.0 292.5 2.5 301.0 28.0 349.0 16.0 339.5 13.0 Min. 110 -121 123 -164 186 -92 159 -37 193 -27 Max. 472 62 479 63 597 213 638 142 472 189 [1] Change = post-baseline value minus baseline

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Protocol: FFA20001 Page 2 of 2 Population: Intent-to-Treat Table 7.11 Summary of Trough Peak Expiratory Flow Rate (L/min) by Baseline Asthma Severity Visit 2 % predicted PEF >= 65% Placebo Placebo GW685698X GW685698X GW685698X (AM) (PM) 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=144) (N=146) (N=142) Change Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] Raw [1] -------------------------------------------------------------------------------------- Baseline n 116 116 125 125 119 Mean 359.4 384.4 341.5 357.8 365.9 SD 76.6 86.1 85.5 89.9 88.8 Median 349.0 372.0 323.0 341.0 356.0 Min. 210 206 181 157 214 Max. 505 619 595 587 593 Weeks 1-4 n 116 116 116 116 124 124 122 122 118 118 Mean 388.6 29.2 401.3 16.8 386.2 44.9 386.7 28.8 404.8 39.3 SD 93.7 47.4 95.2 45.7 93.7 43.1 95.2 48.8 94.8 48.4 Median 384.0 17.5 380.5 7.0 369.0 39.5 377.0 19.0 388.0 31.0 Min. 233 -104 237 -105 197 -45 189 -115 223 -90 Max. 613 204 639 202 626 166 732 243 672 231 [1] Change = post-baseline value minus baseline

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.12 Summary of Mean Morning Peak Expiratory Flow Rate (L/min) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] ----------------------------------------------------------------------------------------- Baseline n 143 144 146 141 Mean 346.3 336.1 330.3 332.3 SD 82.4 86.9 82.2 81.6 Median 331.0 316.5 311.0 316.0 Min. 179 174 144 184 Max. 509 595 572 582 Weeks 1-4 n 140 140 143 143 143 143 140 140 Mean 370.6 24.5 379.2 43.3 371.2 41.0 383.5 51.8 SD 100.7 47.7 98.1 45.5 96.0 49.3 90.3 50.0 Median 351.5 16.0 364.0 39.0 361.0 31.0 375.0 43.5 Min. 110 -121 186 -92 160 -73 187 -47 Max. 613 204 626 213 681 284 647 252 [1] Change = post-baseline value minus baseline

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.13 Statistical Analysis of Mean Morning Peak Expiratory Flow Rate Change From Baseline Over Weeks 1-4 GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 140 143 143 140 Baseline Mean (sd) 346.1 (82.0) 335.9 (87.2) 330.2 (82.8) 331.7 (81.7) Raw Mean (sd) 370.6 (100.7) 379.2 (98.1) 371.2 (96.0) 383.5 (90.3) Raw Mean Change (sd) 24.5 (47.7) 43.3 (45.5) 41.0 (49.3) 51.8 (50.0) Adjusted Mean (se) 353.9 (5.1) 373.5 (4.8) 371.3 (5.0) 382.7 (4.9) Adjusted Mean Change (se) 18.0 (5.1) 37.6 (4.8) 35.3 (5.0) 46.7 (4.9) Column Treatment - GW685698X 100mcg pm (se) 2.3 (5.63) 11.4 (5.65) 95% CI (-8.8,13.3) (0.3,22.5) Column Treatment - Placebo (se) 19.6 (5.66) 17.3 (5.66) 28.8 (5.69) 95% CI (8.5,30.7) (6.2,28.5) (17.6,39.9) p-value <0.001 0.002 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline daily morning PEF, age, sex and country

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.14 Summary of Mean Evening Peak Expiratory Flow Rate (L/min) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] ----------------------------------------------------------------------------------------- Baseline n 143 143 146 141 Mean 369.6 362.8 350.5 357.1 SD 90.9 93.6 92.3 90.0 Median 353.0 343.0 335.0 340.0 Min. 159 176 157 180 Max. 619 597 587 593 Weeks 1-4 n 140 140 143 142 143 143 140 140 Mean 382.9 13.2 399.8 37.0 379.3 28.9 393.6 36.9 SD 102.4 46.8 100.2 41.1 98.9 48.4 95.5 48.5 Median 364.0 6.0 389.0 35.5 373.0 19.0 380.5 28.5 Min. 123 -164 197 -57 159 -115 193 -90 Max. 639 202 627 157 732 243 672 231 [1] Change = post-baseline value minue baseline

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.15 Statistical Analysis of Mean Evening Peak Expiratory Flow Rate Change From Baseline Over Weeks 1-4 GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 140 142 143 140 Baseline Mean (sd) 369.7 (91.0) 362.3 (93.8) 350.4 (93.1) 356.7 (90.2) Raw Mean (sd) 382.9 (102.4) 399.4 (100.4) 379.3 (98.9) 393.6 (95.5) Raw Mean Change (sd) 13.2 (46.8) 37.0 (41.1) 28.9 (48.4) 36.9 (48.5) Adjusted Mean (se) 369.4 (4.8) 393.9 (4.6) 385.0 (4.7) 393.8 (4.7) Adjusted Mean Change (se) 9.7 (4.8) 34.1 (4.6) 25.2 (4.7) 34.1 (4.7) Column Treatment - GW685698X 100mcg pm (se) 8.9 (5.40) 8.8 (5.40) 95% CI (-1.7,19.5) (-1.8,19.4) Column Treatment - Placebo (se) 24.4 (5.42) 15.6 (5.42) 24.4 (5.44) 95% CI (13.8,35.1) (4.9,26.2) (13.7,35.1) p-value <0.001 0.004 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline daily evening PEF, age, sex and country

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Protocol: FFA20001 Page 1 of 2 Population: Intent-to-Treat Table 7.16 Summary of Clinic Visit FEV1 (L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Visit Raw [1] Raw [1] Raw [1] Raw [1] ------------------------------------------------------------------------------------------ Visit 2 n 142 144 146 142 (Baseline) Mean 2.718 2.791 2.685 2.684 SD 0.910 0.963 0.962 0.866 Median 2.645 2.655 2.510 2.550 Min. 0.86 1.07 0.99 1.12 Max. 5.57 5.13 6.24 5.26 Visit 3 n 134 134 140 140 142 142 139 139 (Week 1) Mean 2.876 0.121 2.901 0.109 2.857 0.153 2.884 0.191 SD 0.909 0.359 0.908 0.347 0.958 0.328 0.873 0.446 Median 2.795 0.090 2.750 0.055 2.660 0.080 2.720 0.130 Min. 0.87 -0.85 1.21 -0.76 0.90 -0.74 1.12 -0.93 Max. 5.68 1.97 5.38 1.26 6.20 1.27 5.30 2.28 Visit 4 n 131 131 137 137 139 139 136 136 (Week 2) Mean 2.893 0.117 3.001 0.195 2.926 0.207 3.010 0.316 SD 0.929 0.405 0.945 0.388 0.904 0.401 0.911 0.480 Median 2.850 0.080 2.860 0.090 2.760 0.150 2.870 0.240 Min. 0.69 -1.64 1.12 -0.88 1.01 -1.35 1.22 -0.67 Max. 4.93 1.47 5.52 1.44 5.31 1.35 5.70 1.88 [1] Change = change from Visit 2 (Baseline)

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Protocol: FFA20001 Page 2 of 2 Population: Intent-to-Treat Table 7.16 Summary of Clinic Visit FEV1 (L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Visit Raw [1] Raw [1] Raw [1] Raw [1] ------------------------------------------------------------------------------------------ Visit 5 n 125 125 135 135 138 138 135 135 (Week 3) Mean 2.969 0.147 3.038 0.225 2.931 0.214 2.989 0.289 SD 0.888 0.391 0.936 0.398 0.888 0.447 0.889 0.482 Median 2.930 0.110 2.880 0.170 2.820 0.135 2.870 0.210 Min. 0.94 -1.06 1.03 -0.78 1.07 -1.76 1.18 -1.00 Max. 5.08 1.74 5.68 1.48 5.23 1.53 5.26 2.11 Visit 6 n 124 124 134 134 135 135 134 134 (Week 4) Mean 2.971 0.147 3.034 0.229 2.977 0.272 3.034 0.340 SD 0.917 0.374 0.910 0.437 0.897 0.442 0.916 0.480 Median 2.845 0.105 2.895 0.165 2.850 0.190 2.875 0.240 Min. 0.89 -0.64 1.31 -0.55 1.10 -1.63 1.20 -1.28 Max. 5.03 1.65 5.52 1.67 5.23 1.65 5.58 1.76 Endpoint n 137 137 143 143 142 142 140 140 Mean 2.872 0.116 2.989 0.201 2.968 0.264 3.014 0.329 SD 0.947 0.406 0.920 0.450 0.902 0.468 0.913 0.475 Median 2.760 0.100 2.840 0.150 2.845 0.190 2.870 0.225 Min. 0.69 -1.06 1.05 -0.88 0.90 -1.63 1.20 -1.28 Max. 5.03 1.65 5.52 1.67 5.23 1.65 5.58 1.76 [1] Change = change from Visit 2 (Baseline)

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.17 Statistical Analysis of Clinic Visit FEV1 (L) Change From Baseline at Endpoint GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 137 143 142 140 Baseline Mean (sd) 2.756 (0.897) 2.788 (0.966) 2.704 (0.962) 2.684 (0.872) Raw Mean (sd) 2.872 (0.947) 2.989 (0.920) 2.968 (0.902) 3.014 (0.913) Raw Mean Change (sd) 0.116 (0.406) 0.201 (0.450) 0.264 (0.468) 0.329 (0.475) Adjusted Mean (se) 2.832 (0.043) 2.936 (0.041) 2.998 (0.042) 3.050 (0.042) Adjusted Mean Change (se) 0.099 (0.043) 0.203 (0.041) 0.265 (0.042) 0.317 (0.042) Column Treatment - GW685698X 100mcg pm (se) -0.062 (0.048) 0.052 (0.048) 95% CI (-0.156,0.032) (-0.043,0.147) Column Treatment - Placebo (se) 0.104 (0.048) 0.166 (0.049) 0.218 (0.049) 95% CI (0.009,0.199) (0.071,0.262) (0.123,0.314) p-value 0.032 <0.001 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline FEV1, age, sex and country

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Protocol: FFA20001 Page 1 of 2 Population: Intent-to-Treat Table 7.18 Summary of Clinic Visit Peak Expiratory Flow Rate (L/min) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Visit Raw [1] Raw [1] Raw [1] Raw [1] ------------------------------------------------------------------------------------------ Visit 2 n 142 144 146 142 (Baseline) Mean 360.1 359.5 351.7 349.9 SD 92.31 86.47 83.75 83.32 Median 355.0 350.0 330.0 330.0 Min. 150 180 150 170 Max. 650 560 560 550 Visit 3 n 134 134 140 140 141 141 139 139 (Week 1) Mean 386.1 21.8 398.5 39.9 384.2 32.4 386.6 36.5 SD 97.58 46.82 96.29 57.19 98.10 52.69 95.20 58.45 Median 380.0 10.0 390.0 30.0 370.0 29.0 370.0 30.0 Min. 160 -80 225 -100 170 -120 160 -150 Max. 640 170 720 310 703 297 660 200 Visit 4 n 131 131 137 137 138 138 136 136 (Week 2) Mean 396.4 31.3 407.5 47.4 397.5 42.9 407.3 56.6 SD 106.66 56.59 100.80 56.93 95.67 60.96 96.44 60.31 Median 389.4 30.0 400.0 40.0 380.0 35.5 400.0 50.0 Min. 120 -110 220 -80 200 -150 170 -130 Max. 640 190 695 280 660 260 720 260 [1] Change = Change from visit 2 (Baseline)

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Protocol: FFA20001 Page 2 of 2 Population: Intent-to-Treat Table 7.18 Summary of Clinic Visit Peak Expiratory Flow Rate (L/min) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Visit Raw [1] Raw [1] Raw [1] Raw [1] ------------------------------------------------------------------------------------------ Visit 5 n 125 125 135 135 138 138 135 135 (Week 3) Mean 401.3 33.0 415.5 55.8 398.2 43.9 407.3 56.0 SD 100.68 45.78 98.97 60.70 94.74 62.49 95.76 57.62 Median 390.0 30.0 403.0 40.0 390.0 34.0 390.0 50.0 Min. 200 -60 210 -50 180 -120 210 -100 Max. 640 141 679 260 640 290 680 220 Visit 6 n 124 124 134 134 135 135 134 134 (Week 4) Mean 401.2 32.6 417.6 58.8 407.5 54.2 412.0 60.7 SD 102.32 47.98 99.72 61.29 94.94 66.20 96.32 60.01 Median 400.0 30.0 400.0 50.0 410.0 49.0 403.0 60.0 Min. 190 -100 230 -77 210 -140 200 -130 Max. 650 150 700 290 690 290 680 220 Endpoint n 138 138 143 143 142 142 140 140 Mean 391.2 27.0 412.2 53.1 402.6 50.5 407.7 58.5 SD 105.25 52.18 103.34 67.67 99.99 68.23 97.32 59.93 Median 373.0 24.8 400.0 42.0 402.0 40.5 400.0 59.0 Min. 120 -110 140 -260 140 -140 200 -130 Max. 650 150 700 290 690 290 680 220 [1] Change = Change from visit 2 (Baseline)

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.19 Statistical Analysis of Clinic Visit Peak Expiratory Flow Rate (L/min) Change From Baseline at Endpoint GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 138 143 142 140 Baseline Mean (sd) 364.2 (89.8) 359.1 (86.6) 352.1 (84.1) 349.2 (83.6) Raw Mean (sd) 391.2 (105.3) 412.2 (103.3) 402.6 (100.0) 407.7 (97.3) Raw Mean Change (sd) 27.0 (52.2) 53.1 (67.7) 50.5 (68.2) 58.5 (59.9) Adjusted Mean (se) 387.2 (6.3) 413.4 (6.0) 412.2 (6.3) 418.9 (6.2) Adjusted Mean Change (se) 31.1 (6.3) 57.3 (6.0) 56.1 (6.3) 62.8 (6.2) Column Treatment - GW685698X 100mcg pm (se) 1.2 (7.16) 6.7 (7.18) 95% CI (-12.9,15.2) (-7.4,20.8) Column Treatment - Placebo (se) 26.2 (7.20) 25.0 (7.22) 31.7 (7.24) 95% CI (12.0,40.3) (10.8,39.2) (17.4,45.9) p-value <0.001 <0.001 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline PEF, age, sex and country

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.20 Summary of Percentage of Symptom Free 24-hour Periods GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] ----------------------------------------------------------------------------------------- Baseline n 143 144 146 141 Mean 6.9 4.2 6.6 7.3 SD 12.27 10.25 11.51 13.19 Median 0.0 0.0 0.0 0.0 Min. 0 0 0 0 Max. 50 43 57 57 Weeks 1-4 n 140 140 143 143 143 143 140 140 Mean 29.3 22.6 41.3 37.1 43.4 37.0 48.2 40.9 SD 31.85 28.00 33.11 30.21 35.53 33.86 35.51 32.34 Median 16.5 10.0 46.0 41.0 48.0 33.0 54.0 43.5 Min. 0 -29 0 0 0 -25 0 0 Max. 100 100 100 100 100 100 100 100 [1] Change = post-baseline value minus baseline

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.21 Statistical Analysis of Percentage of Symptom Free 24-hour Periods GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 140 143 143 140 Baseline Mean (sd) 6.7 (12.0) 4.2 (10.3) 6.5 (11.2) 7.3 (13.2) Raw Mean (sd) 29.3 (31.9) 41.3 (33.1) 43.4 (35.5) 48.2 (35.5) Raw Mean Change (sd) 22.6 (28.0) 37.1 (30.2) 37.0 (33.9) 40.9 (32.3) Adjusted Mean (se) 31.3 (3.1) 45.8 (3.0) 45.7 (3.1) 50.0 (3.0) Adjusted Mean Change (se) 25.1 (3.1) 39.6 (3.0) 39.5 (3.1) 43.8 (3.0) Column Treatment - GW685698X 100mcg pm (se) 0.1 (3.52) 4.3 (3.52) 95% CI (-6.8,7.0) (-2.6,11.2) Column Treatment - Placebo (se) 14.6 (3.53) 14.4 (3.53) 18.7 (3.55) 95% CI (7.6,21.5) (7.5,21.4) (11.7,25.7) p-value <0.001 <0.001 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline percentage of symptom free 24-hours, age, sex and country

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.22 Summary of Percentage of Symptom Free Days GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] ----------------------------------------------------------------------------------------- Baseline n 143 144 146 141 Mean 13.1 9.0 13.1 13.0 SD 19.62 15.15 18.68 20.24 Median 0.0 0.0 0.0 0.0 Min. 0 0 0 0 Max. 100 57 86 100 Weeks 1-4 n 140 140 143 143 143 143 140 140 Mean 36.4 23.4 47.8 38.7 48.1 34.9 53.4 40.3 SD 35.25 27.69 34.49 29.69 36.24 34.56 36.31 32.73 Median 32.0 15.0 56.0 42.0 56.0 27.0 63.0 43.0 Min. 0 -29 0 -14 0 -32 0 -29 Max. 100 100 100 96 100 100 100 100 [1] Change = post-baseline value minus baseline

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.23 Statistical Analysis of Percentage of Symptom Free Days GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 140 143 143 140 Baseline Mean (sd) 13.0 (19.4) 9.1 (15.2) 13.1 (18.6) 13.1 (20.3) Raw Mean (sd) 36.4 (35.2) 47.8 (34.5) 48.1 (36.2) 53.4 (36.3) Raw Mean Change (sd) 23.4 (27.7) 38.7 (29.7) 34.9 (34.6) 40.3 (32.7) Adjusted Mean (se) 37.8 (3.1) 52.1 (3.0) 49.4 (3.1) 55.3 (3.1) Adjusted Mean Change (se) 25.8 (3.1) 40.1 (3.0) 37.3 (3.1) 43.2 (3.1) Column Treatment - GW685698X 100mcg pm (se) 2.7 (3.57) 5.9 (3.57) 95% CI (-4.3,9.7) (-1.1,12.9) Column Treatment - Placebo (se) 14.3 (3.58) 11.5 (3.57) 17.5 (3.59) 95% CI (7.2,21.3) (4.5,18.6) (10.4,24.5) p-value <0.001 0.001 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline percentage symptom free days, age, sex and country

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.24 Summary of Percentage of Symptom Free Nights GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] ----------------------------------------------------------------------------------------- Baseline n 143 144 146 141 Mean 40.3 38.2 38.0 34.6 SD 35.60 34.74 33.94 33.36 Median 43.0 29.0 38.0 29.0 Min. 0 0 0 0 Max. 100 100 100 100 Weeks 1-4 n 140 140 143 143 143 143 140 140 Mean 59.2 18.6 67.4 29.0 70.8 32.9 72.0 37.4 SD 34.82 28.84 33.78 34.73 33.75 32.33 32.05 32.89 Median 67.5 10.0 81.0 29.0 85.0 29.0 85.5 32.0 Min. 0 -32 0 -93 0 -39 0 -40 Max. 100 100 100 100 100 100 100 100

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.25 Statistical Analysis of Percentage of Symptom Free Nights GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 140 143 143 140 Baseline Mean (sd) 40.5 (35.8) 38.5 (34.7) 37.9 (33.8) 34.6 (33.5) Raw Mean (sd) 59.2 (34.8) 67.4 (33.8) 70.8 (33.8) 72.0 (32.0) Raw Mean Change (sd) 18.6 (28.8) 29.0 (34.7) 32.9 (32.3) 37.4 (32.9) Adjusted Mean (se) 60.3 (2.9) 69.3 (2.7) 73.4 (2.9) 76.3 (2.8) Adjusted Mean Change (se) 22.5 (2.9) 31.4 (2.7) 35.5 (2.9) 38.4 (2.8) Column Treatment - GW685698X 100mcg pm (se) -4.1 (3.24) 2.9 (3.25) 95% CI (-10.4,2.3) (-3.5,9.3) Column Treatment - Placebo (se) 9.0 (3.26) 13.0 (3.26) 15.9 (3.28) 95% CI (2.6,15.4) (6.6,19.4) (9.5,22.4) p-value 0.006 <0.001 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline percentage of symptom free nights, age, sex and country

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.26 Summary of Percentage of Nights with No Awakenings GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] ----------------------------------------------------------------------------------------- Baseline n 143 144 146 141 Mean 49.5 47.0 47.4 45.3 SD 37.01 35.94 36.36 37.24 Median 50.0 43.0 43.0 43.0 Min. 0 0 0 0 Max. 100 100 100 100 Weeks 1-4 n 140 140 143 143 143 143 140 140 Mean 64.9 15.9 73.7 26.4 76.1 28.8 77.1 32.1 SD 34.32 29.59 32.12 32.56 30.37 33.66 29.83 34.10 Median 74.0 5.5 89.0 22.0 88.0 25.0 89.0 27.5 Min. 0 -31 0 -59 0 -67 0 -69 Max. 100 100 100 100 100 100 100 100 [1] Change = post-baseline value minus baseline

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.27 Statistical Analysis of Percentage of Nights with No Awakenings GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 140 143 143 140 Baseline Mean (sd) 49.0 (37.1) 47.4 (35.8) 47.3 (36.4) 45.0 (37.2) Raw Mean (sd) 64.9 (34.3) 73.7 (32.1) 76.1 (30.4) 77.1 (29.8) Raw Mean Change (sd) 15.9 (29.6) 26.4 (32.6) 28.8 (33.7) 32.1 (34.1) Adjusted Mean (se) 66.0 (2.7) 75.4 (2.6) 78.0 (2.7) 80.1 (2.7) Adjusted Mean Change (se) 18.8 (2.7) 28.2 (2.6) 30.8 (2.7) 32.9 (2.7) Column Treatment - GW685698X 100mcg pm (se) -2.6 (3.10) 2.1 (3.10) 95% CI (-8.7,3.5) (-4.0,8.2) Column Treatment - Placebo (se) 9.4 (3.11) 11.9 (3.11) 14.1 (3.13) 95% CI (3.3,15.5) (5.8,18.1) (7.9,20.2) p-value 0.003 <0.001 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline percentage of nights with no awakenings, age, sex and country

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.28 Summary of Percentage of 24-hour Periods with no Rescue Medication GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] ----------------------------------------------------------------------------------------- Baseline n 142 143 146 141 Mean 17.9 9.4 15.8 13.5 SD 24.36 17.10 24.18 22.48 Median 0.0 0.0 0.0 0.0 Min. 0 0 0 0 Max. 100 71 100 100 Weeks 1-4 n 140 139 143 142 143 143 140 140 Mean 39.4 22.5 50.3 41.1 52.4 36.6 54.4 40.7 SD 35.10 29.57 36.29 32.40 36.61 33.84 37.00 35.59 Median 40.0 14.0 59.0 45.5 62.0 34.0 67.0 46.0 Min. 0 -65 0 -21 0 -63 0 -69 Max. 100 100 100 100 100 100 100 100 [1] Change = post-baseline value minus baseline

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.29 Statistical Analysis of Percentage of 24-hour periods with No Rescue Medication GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 139 142 143 140 Baseline Mean (sd) 17.2 (23.5) 9.5 (17.1) 15.8 (24.3) 13.6 (22.5) Raw Mean (sd) 39.7 (35.1) 50.6 (36.2) 52.4 (36.6) 54.4 (37.0) Raw Mean Change (sd) 22.5 (29.6) 41.1 (32.4) 36.6 (33.8) 40.7 (35.6) Adjusted Mean (se) 36.7 (3.3) 53.1 (3.2) 50.7 (3.3) 54.6 (3.2) Adjusted Mean Change (se) 22.7 (3.3) 39.1 (3.2) 36.7 (3.3) 40.6 (3.2) Column Treatment - GW685698X 100mcg pm (se) 2.4 (3.76) 3.9 (3.75) 95% CI (-5.0,9.7) (-3.5,11.2) Column Treatment - Placebo (se) 16.4 (3.80) 14.1 (3.76) 17.9 (3.78) 95% CI (9.0,23.9) (6.7,21.5) (10.5,25.4) p-value <0.001 <0.001 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline percentage of rescue medication free 24-hours, age, sex and country

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.30 Summary of Percentage of Days with No Rescue Medication GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] ----------------------------------------------------------------------------------------- Baseline n 143 144 146 141 Mean 23.9 15.0 22.0 20.2 SD 28.04 22.92 28.66 27.68 Median 14.0 0.0 14.0 0.0 Min. 0 0 0 0 Max. 100 100 100 100 Weeks 1-4 n 140 140 143 143 143 143 140 140 Mean 46.4 23.0 55.1 40.0 56.8 34.8 58.8 38.5 SD 36.51 29.66 36.99 32.03 36.40 34.81 37.00 36.13 Median 50.0 19.0 67.0 42.0 68.0 28.0 74.0 37.5 Min. 0 -65 0 -17 0 -85 0 -67 Max. 100 100 100 100 100 100 100 100 [1] Change = post-baseline value minus baseline

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.31 Statistical Analysis of Percentage of Days with No Rescue Medication GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 140 143 143 140 Baseline Mean (sd) 23.4 (27.5) 15.2 (23.0) 22.0 (28.8) 20.4 (27.7) Raw Mean (sd) 46.4 (36.5) 55.1 (37.0) 56.8 (36.4) 58.8 (37.0) Raw Mean Change (sd) 23.0 (29.7) 40.0 (32.0) 34.8 (34.8) 38.5 (36.1) Adjusted Mean (se) 44.3 (3.3) 58.2 (3.1) 55.8 (3.3) 59.4 (3.2) Adjusted Mean Change (se) 24.1 (3.3) 37.9 (3.1) 35.6 (3.3) 39.2 (3.2) Column Treatment - GW685698X 100mcg pm (se) 2.3 (3.71) 3.6 (3.71) 95% CI (-5.0,9.6) (-3.7,10.9) Column Treatment - Placebo (se) 13.8 (3.74) 11.5 (3.72) 15.1 (3.73) 95% CI (6.5,21.2) (4.2,18.8) (7.7,22.4) p-value <0.001 0.002 <0.001 Note: BAsed on ANCOVA model adjusted for treatment, baseline percentage of rescue medication free days, age, sex and country

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.32 Summary of Percentage of Nights with No Rescue Medication GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) Change Change Change Change Period Raw [1] Raw [1] Raw [1] Raw [1] ----------------------------------------------------------------------------------------- Baseline n 142 144 146 141 Mean 55.3 53.0 51.7 47.5 SD 36.74 37.41 36.28 36.89 Median 57.0 57.0 57.0 43.0 Min. 0 0 0 0 Max. 100 100 100 100 Weeks 1-4 n 140 139 143 143 143 143 140 140 Mean 67.1 11.6 76.2 23.0 78.0 26.1 76.9 29.1 SD 33.80 30.19 31.27 34.03 28.41 31.74 29.95 34.46 Median 78.0 2.0 89.0 19.0 89.0 22.0 90.5 21.5 Min. 0 -77 0 -70 0 -85 0 -71 Max. 100 100 100 100 100 100 100 100 [1] Change = post-baseline value minus baseline

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.33 Statistical Analysis of Percentage of Nights with No Rescue Medication GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ------------------------------------------------------------------------------------------ Number of Subjects 139 143 143 140 Baseline Mean (sd) 55.3 (36.8) 53.2 (37.5) 51.9 (36.2) 47.9 (36.8) Raw Mean (sd) 66.9 (33.8) 76.2 (31.3) 78.0 (28.4) 76.9 (29.9) Raw Mean Change (sd) 11.6 (30.2) 23.0 (34.0) 26.1 (31.7) 29.1 (34.5) Adjusted Mean (se) 64.1 (2.7) 74.6 (2.5) 76.9 (2.7) 77.9 (2.6) Adjusted Mean Change (se) 12.1 (2.7) 22.6 (2.5) 24.8 (2.7) 25.8 (2.6) Column Treatment - GW685698X 100mcg pm (se) -2.3 (3.01) 1.0 (3.02) 95% CI (-8.2,3.6) (-5.0,6.9) Column Treatment - Placebo (se) 10.5 (3.03) 12.8 (3.03) 13.7 (3.05) 95% CI (4.5,16.4) (6.8,18.7) (7.7,19.7) p-value <0.001 <0.001 <0.001 Note: Based on ANCOVA model adjusted for treatment, baseline percentage of rescue medication free nights, age, sex and country

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Protocol: FFA20001 Page 1 of 1 Population: Intent-to-Treat Table 7.34 Statistical Analysis of Withdrawals Due to Lack of Efficacy GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=144) (N=146) (N=142) ---------------------------------------------------------------------------- Withdrawn due to 2 (1.4%) 1 (0.7%) 0 0 lack of efficacy Column treatment vs Placebo p-value [1] 0.995 0.488 0.502 [1] Based on Fishers Exact Test

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Safety Data Source Figures and Tables

PageFigure 8.1 Plot of 24hr Urinary Cortisol Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208Figure 8.2 Plot of 24hr Urinary Cortisol Adjusted for Creatinine . . . . . . . . . . . . . . . . 209Table 8.1 Summary of Exposure to Study Drug (Safety Population) . . . . . . . . . . . . . 210Table 8.2 Summary of All Adverse Events - Pre Treatment (Safety Population) . . . . 211Table 8.3 Summary of All Adverse Events - On Treatment (Safety Population) . . . . 213Table 8.4 Summary of All Adverse Events - Post Treatment (Safety Population) . . . 219Table 8.5 Summary of Drug-Related Adverse Events - On Treatment (Safety

Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221Table 8.6 Summary of Serious Adverse Events - On Treatment (Safety

Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224Table 8.7 Summary of Adverse Events Leading To Withdrawal (Safety Population) 225Table 8.8 Summary of 24hr Urinary Cortisol Data (nmol/24hr) (Safety Population) . 226Table 8.9 Summary of 24hr Urinary Cortisol Data (nmol/24hr) Change from

Baseline (Safety Population). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227Table 8.10 Statistical Analysis of 24hr Urinary Cortisol Data (nmol/24hr) at Week 4

(Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228Table 8.11 Summary of 24hr Urinary Cortisol Adjusted for Creatinine (nmol/mmol)

(Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229Table 8.12 Statistical Analysis of 24hr Urinary Cortisol adjusted for Creatinine

(nmol/mmol) at Week 4 (Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . 230Table 8.13 Summary of 24hr Urinary Cortisol adjusted for Creatinine (nmol/mmol)

Change from Baseline (Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231Table 8.14 Summary of 24hr Urinary Cortisol adjusted for Creatinine (nmol/mmol)

Outside the Normal Range (Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . 232Table 8.15 Summary of 24hr Urinary Cortisol adjusted for Creatinine (nmol/mmol)

Shifts from Baseline (Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Table 8.16 Summary of 24hr Urinary Cortisol Data (nmol/24hr) Outside the Normal

Range (Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234Table 8.17 Summary of 24hr Urinary Cortisol Data (nmol/24hr) Shifts From

Baseline (Safety Population). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235Table 8.18 Summary of Haematology Data (Safety Population) . . . . . . . . . . . . . . . . 236Table 8.19 Summary of Haematology Data Change from Baseline (Safety

Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254Table 8.20 Summary of Haematology Data Outside the Reference Range (Safety

Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272Table 8.21 Summary of Haematology Laboratory Shifts From Baseline (Safety

Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290Table 8.22 Summary of Clinical Chemistry Data (Safety Population) . . . . . . . . . . . . 366


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Table 8.23 Summary of Clinical Chemistry Data Change from Baseline (SafetyPopulation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range(Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402

Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline(Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420

Table 8.26 Summary of Urinalysis-Local Data (Safety Population) . . . . . . . . . . . . . . 492Table 8.27 Summary of ECG Data (Safety Population) . . . . . . . . . . . . . . . . . . . . . . . 493Table 8.28 Summary of Oropharyngeal Examination (Safety Population). . . . . . . . . 494Table 8.29 Summary of Vital Signs (Safety Population) . . . . . . . . . . . . . . . . . . . . . . 499Table 8.30 Summary of Vital Signs Change from Baseline (Safety Population) . . . . 502


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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.1 Summary of Exposure to Study Drug GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Total (N=143) (N=143) (N=148) (N=141) (N=575) ----------------------------------------------------------------------------------------- Days on study drug [1] n 143 143 148 141 575 Mean 26.7 27.7 27.8 28.5 27.7 SD 6.92 4.74 4.91 4.86 5.46 Median 29.0 29.0 29.0 29.0 29.0 Min. 2 1 2 2 1 Max. 37 32 34 45 45 Range of Exposure n 143 143 148 141 575 <=7 days 7 (5%) 2 (1%) 4 (3%) 1 (<1%) 14 (2%) 8-14 days 5 (3%) 4 (3%) 2 (1%) 4 (3%) 15 (3%) 15-21 days 6 (4%) 2 (1%) 2 (1%) 2 (1%) 12 (2%) 22-28 days 34 (24%) 40 (28%) 39 (26%) 29 (21%) 142 (25%) >28 days 91 (64%) 95 (66%) 101 (68%) 105 (74%) 392 (68%) [1] Calculated as ((date treatment stopped - date treatment started) +1)

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Protocol: FFA20001 Page 1 of 2 Population: Safety Table 8.2 Summary of All Adverse Events - Pre Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- ANY EVENT 6 (4%) 4 (3%) 8 (5%) 1 (<1%) Nervous system disorders Any event 2 (1%) 3 (2%) 4 (3%) 1 (<1%) Headache 2 (1%) 3 (2%) 4 (3%) 1 (<1%) Gastrointestinal disorders Any event 1 (<1%) 1 (<1%) 2 (1%) 0 Gastritis 0 1 (<1%) 1 (<1%) 0 Abdominal pain upper 1 (<1%) 0 0 0 Flatulence 0 0 1 (<1%) 0 Infections and infestations Any event 0 1 (<1%) 2 (1%) 0 Cystitis 0 0 2 (1%) 0 Sinusitis 0 1 (<1%) 0 0 Musculoskeletal and connective tissue disorders Any event 0 2 (1%) 0 0 Muscle cramp 0 1 (<1%) 0 0 Pain in extremity 0 1 (<1%) 0 0 General disorders and administration site conditions

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Protocol: FFA20001 Page 2 of 2 Population: Safety Table 8.2 Summary of All Adverse Events - Pre Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Any event 0 0 1 (<1%) 0 Chest pain 0 0 1 (<1%) 0 Investigations Any event 1 (<1%) 0 0 0 Alanine aminotransferase increased 1 (<1%) 0 0 0 Gamma-glutamyltransferase increased 1 (<1%) 0 0 0 Renal and urinary disorders Any event 1 (<1%) 0 0 0 Nephrolithiasis 1 (<1%) 0 0 0 Respiratory, thoracic and mediastinal disorders Any event 1 (<1%) 0 0 0 Asthma 1 (<1%) 0 0 0

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Protocol: FFA20001 Page 1 of 6 Population: Safety Table 8.3 Summary of All Adverse Events - On Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ---------------------------------------------------------------------------------------- ANY EVENT 37 (26%) 36 (25%) 39 (26%) 32 (23%) Infections and infestations Any event 12 (8%) 9 (6%) 12 (8%) 16 (11%) Nasopharyngitis 5 (3%) 4 (3%) 6 (4%) 4 (3%) Candidiasis 1 (<1%) 0 2 (1%) 1 (<1%) Bronchitis acute 1 (<1%) 0 2 (1%) 0 Influenza 1 (<1%) 0 1 (<1%) 1 (<1%) Oral candidiasis 1 (<1%) 1 (<1%) 0 1 (<1%) Oropharyngeal candidiasis 0 0 1 (<1%) 2 (1%) Respiratory tract infection 1 (<1%) 1 (<1%) 0 1 (<1%) Upper respiratory tract infection 0 1 (<1%) 1 (<1%) 1 (<1%) Vaginal candidiasis 1 (<1%) 1 (<1%) 0 1 (<1%) Viral infection 0 1 (<1%) 1 (<1%) 1 (<1%) Bronchitis 1 (<1%) 0 0 0 Gastroenteritis 0 0 0 1 (<1%) Pharyngitis 0 0 0 1 (<1%) Respiratory tract infection viral 0 1 (<1%) 0 0 Rhinitis 0 0 0 1 (<1%) Subcutaneous abscess 1 (<1%) 0 0 0 Respiratory, thoracic and mediastinal disorders Any event 13 (9%) 13 (9%) 14 (9%) 7 (5%) Asthma 11 (8%) 5 (3%) 6 (4%) 0

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Protocol: FFA20001 Page 2 of 6 Population: Safety Table 8.3 Summary of All Adverse Events - On Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ---------------------------------------------------------------------------------------- Hoarseness 1 (<1%) 0 2 (1%) 4 (3%) Cough 0 2 (1%) 3 (2%) 0 Epistaxis 1 (<1%) 1 (<1%) 0 1 (<1%) Pharyngolaryngeal pain 0 1 (<1%) 1 (<1%) 1 (<1%) Rhinitis allergic 0 2 (1%) 0 0 Dysphonia 0 0 1 (<1%) 0 Dyspnoea 0 0 0 1 (<1%) Nasal congestion 0 1 (<1%) 0 0 Rhinorrhoea 0 0 1 (<1%) 0 Wheezing 0 1 (<1%) 0 0 Nervous system disorders Any event 7 (5%) 14 (10%) 13 (9%) 12 (9%) Headache 6 (4%) 13 (9%) 10 (7%) 10 (7%) Dizziness 0 0 2 (1%) 1 (<1%) Aphonia 0 0 0 1 (<1%) Dysgeusia 0 0 0 1 (<1%) Hyperaesthesia 0 0 0 1 (<1%) Hypogeusia 0 0 0 1 (<1%) Migraine 0 0 1 (<1%) 0 Neuralgia 0 0 0 1 (<1%) Paraesthesia 0 1 (<1%) 0 0 Sciatica 1 (<1%) 0 0 0 Torticollis 0 0 0 1 (<1%)

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Protocol: FFA20001 Page 3 of 6 Population: Safety Table 8.3 Summary of All Adverse Events - On Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ---------------------------------------------------------------------------------------- Gastrointestinal disorders Any event 2 (1%) 4 (3%) 4 (3%) 4 (3%) Abdominal pain upper 0 1 (<1%) 3 (2%) 0 Dyspepsia 0 2 (1%) 0 0 Toothache 1 (<1%) 0 0 1 (<1%) Enterocolitis 0 0 0 1 (<1%) Gastritis 1 (<1%) 0 0 0 Hypoaesthesia oral 0 0 0 1 (<1%) Irritable bowel syndrome 0 0 0 1 (<1%) Nausea 0 1 (<1%) 0 0 Odynophagia 0 0 1 (<1%) 0 Oesophagitis 0 0 0 1 (<1%) General disorders and administration site conditions Any event 2 (1%) 3 (2%) 0 2 (1%) Chest pain 1 (<1%) 1 (<1%) 0 1 (<1%) Pyrexia 0 2 (1%) 0 0 Asthenia 0 0 0 1 (<1%) Discomfort 0 0 0 1 (<1%) Fatigue 1 (<1%) 0 0 0 Feeling cold 0 0 0 1 (<1%) Investigations Any event 0 1 (<1%) 4 (3%) 0

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Protocol: FFA20001 Page 4 of 6 Population: Safety Table 8.3 Summary of All Adverse Events - On Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ---------------------------------------------------------------------------------------- Blood phosphorus decreased 0 1 (<1%) 1 (<1%) 0 Blood alkaline phosphatase increased 0 0 1 (<1%) 0 Blood urine present 0 0 1 (<1%) 0 Cortisol free urine increased 0 0 1 (<1%) 0 Musculoskeletal and connective tissue disorders Any event 1 (<1%) 0 2 (1%) 2 (1%) Back pain 1 (<1%) 0 2 (1%) 0 Myalgia 0 0 0 1 (<1%) Osteochondrosis 0 0 0 1 (<1%) Skin and subcutaneous tissue disorders Any event 0 2 (1%) 3 (2%) 0 Erythema 0 0 2 (1%) 0 Pruritus 0 1 (<1%) 1 (<1%) 0 Exanthem 0 0 1 (<1%) 0 Rash 0 1 (<1%) 0 0 Vascular disorders Any event 2 (1%) 1 (<1%) 1 (<1%) 1 (<1%) Hypertension 1 (<1%) 1 (<1%) 0 0 Hypertensive crisis 0 0 0 1 (<1%) Thrombophlebitis 0 0 1 (<1%) 0 Vasculitis 1 (<1%) 0 0 0

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Protocol: FFA20001 Page 5 of 6 Population: Safety Table 8.3 Summary of All Adverse Events - On Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ---------------------------------------------------------------------------------------- Cardiac disorders Any event 1 (<1%) 2 (1%) 0 1 (<1%) Palpitations 1 (<1%) 1 (<1%) 0 1 (<1%) Arrhythmia supraventricular 0 1 (<1%) 0 0 Injury, poisoning and procedural complications Any event 0 1 (<1%) 2 (1%) 0 Contusion 0 1 (<1%) 2 (1%) 0 Psychiatric disorders Any event 0 1 (<1%) 1 (<1%) 1 (<1%) Excitability 0 0 0 1 (<1%) Insomnia 0 0 1 (<1%) 0 Libido increased 0 1 (<1%) 0 0 Ear and labyrinth disorders Any event 1 (<1%) 0 0 1 (<1%) Vertigo 1 (<1%) 0 0 1 (<1%) Reproductive system and breast disorders Any event 1 (<1%) 0 1 (<1%) 0 Dysmenorrhoea 1 (<1%) 0 1 (<1%) 0

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Protocol: FFA20001 Page 6 of 6 Population: Safety Table 8.3 Summary of All Adverse Events - On Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ---------------------------------------------------------------------------------------- Eye disorders Any event 0 1 (<1%) 0 0 Uveitis 0 1 (<1%) 0 0 Metabolism and nutrition disorders Any event 0 0 1 (<1%) 0 Gout 0 0 1 (<1%) 0 Renal and urinary disorders Any event 1 (<1%) 0 0 0 Nephrolithiasis 1 (<1%) 0 0 0

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Protocol: FFA20001 Page 1 of 2 Population: Safety Table 8.4 Summary of All Adverse Events - Post Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ------------------------------------------------------------------------------------ ANY EVENT 5 (3%) 2 (1%) 3 (2%) 2 (1%) Investigations Any event 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) Cortisol free urine increased 0 0 1 (<1%) 1 (<1%) Urine cortisol/creatinine ratio 0 0 1 (<1%) 1 (<1%) increased Alanine aminotransferase increased 0 1 (<1%) 0 0 Blood glucose increased 0 1 (<1%) 0 0 Creatinine urine decreased 1 (<1%) 0 0 0 Gamma-glutamyltransferase increased 0 1 (<1%) 0 0 Gastrointestinal disorders Any event 1 (<1%) 0 1 (<1%) 0 Abdominal pain 0 0 1 (<1%) 0 Diarrhoea 0 0 1 (<1%) 0 Nausea 1 (<1%) 0 0 0 Infections and infestations Any event 0 0 1 (<1%) 1 (<1%) Nasopharyngitis 0 0 1 (<1%) 1 (<1%) Nervous system disorders Any event 2 (1%) 0 0 0 Headache 2 (1%) 0 0 0

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Protocol: FFA20001 Page 2 of 2 Population: Safety Table 8.4 Summary of All Adverse Events - Post Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ------------------------------------------------------------------------------------ Skin and subcutaneous tissue disorders Any event 0 1 (<1%) 1 (<1%) 0 Swelling face 0 0 1 (<1%) 0 Urticaria 0 1 (<1%) 0 0 Vascular disorders Any event 1 (<1%) 0 0 0 Hypertension 1 (<1%) 0 0 0

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Protocol: FFA20001 Page 1 of 3 Population: Safety Table 8.5 Summary of Drug-Related Adverse Events - On Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ------------------------------------------------------------------------------------ ANY EVENT 10 (7%) 8 (6%) 11 (7%) 13 (9%) Respiratory, thoracic and mediastinal disorders Any event 4 (3%) 2 (1%) 6 (4%) 5 (4%) Hoarseness 1 (<1%) 0 2 (1%) 4 (3%) Asthma 2 (1%) 1 (<1%) 1 (<1%) 0 Cough 0 1 (<1%) 1 (<1%) 0 Dysphonia 0 0 1 (<1%) 0 Epistaxis 1 (<1%) 0 0 0 Pharyngolaryngeal pain 0 0 0 1 (<1%) Rhinorrhoea 0 0 1 (<1%) 0 Infections and infestations Any event 2 (1%) 2 (1%) 3 (2%) 5 (4%) Candidiasis 1 (<1%) 0 2 (1%) 1 (<1%) Oral candidiasis 1 (<1%) 1 (<1%) 0 1 (<1%) Oropharyngeal candidiasis 0 0 1 (<1%) 2 (1%) Upper respiratory tract infection 0 0 0 1 (<1%) Vaginal candidiasis 0 1 (<1%) 0 0 Nervous system disorders Any event 1 (<1%) 2 (1%) 2 (1%) 5 (4%) Headache 1 (<1%) 2 (1%) 1 (<1%) 4 (3%) Aphonia 0 0 0 1 (<1%)

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Protocol: FFA20001 Page 2 of 3 Population: Safety Table 8.5 Summary of Drug-Related Adverse Events - On Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ------------------------------------------------------------------------------------ Dizziness 0 0 1 (<1%) 0 Dysgeusia 0 0 0 1 (<1%) Hyperaesthesia 0 0 0 1 (<1%) Hypogeusia 0 0 0 1 (<1%) Gastrointestinal disorders Any event 0 1 (<1%) 2 (1%) 1 (<1%) Abdominal pain upper 0 1 (<1%) 1 (<1%) 0 Hypoaesthesia oral 0 0 0 1 (<1%) Odynophagia 0 0 1 (<1%) 0 Investigations Any event 0 0 3 (2%) 0 Blood alkaline phosphatase increased 0 0 1 (<1%) 0 Blood phosphorus decreased 0 0 1 (<1%) 0 Blood urine present 0 0 1 (<1%) 0 Skin and subcutaneous tissue disorders Any event 0 1 (<1%) 2 (1%) 0 Erythema 0 0 2 (1%) 0 Pruritus 0 1 (<1%) 1 (<1%) 0 Cardiac disorders Any event 1 (<1%) 0 0 1 (<1%) Palpitations 1 (<1%) 0 0 1 (<1%)

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Protocol: FFA20001 Page 3 of 3 Population: Safety Table 8.5 Summary of Drug-Related Adverse Events - On Treatment GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ------------------------------------------------------------------------------------ General disorders and administration site conditions Any event 1 (<1%) 0 0 1 (<1%) Chest pain 1 (<1%) 0 0 0 Feeling cold 0 0 0 1 (<1%) Psychiatric disorders Any event 0 1 (<1%) 0 1 (<1%) Excitability 0 0 0 1 (<1%) Libido increased 0 1 (<1%) 0 0 Injury, poisoning and procedural complications Any event 0 0 1 (<1%) 0 Contusion 0 0 1 (<1%) 0 Musculoskeletal and connective tissue disorders Any event 0 0 0 1 (<1%) Myalgia 0 0 0 1 (<1%) Vascular disorders Any event 1 (<1%) 0 0 0 Vasculitis 1 (<1%) 0 0 0

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.6 Summary of Serious Adverse Events - On Treatment GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ------------------------------------------------------------------------- ANY EVENT 1 (<1%) 1 (<1%) 1 (<1%) 0 Respiratory, thoracic and mediastinal disorders Any event 1 (<1%) 0 1 (<1%) 0 Asthma 1 (<1%) 0 1 (<1%) 0 Cardiac disorders Any event 0 1 (<1%) 0 0 Arrhythmia supraventricular 0 1 (<1%) 0 0

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.7 Summary of Adverse Events Leading To Withdrawal GW685698X GW685698X GW685698X System Organ Class Placebo 100mcg AM 100mcg PM 250mcg PM Preferred Term (N=143) (N=143) (N=148) (N=141) ------------------------------------------------------------------------------------ ANY EVENT 11 (8%) 5 (3%) 6 (4%) 1 (<1%) Respiratory, thoracic and mediastinal disorders Any event 9 (6%) 4 (3%) 6 (4%) 1 (<1%) Asthma 9 (6%) 4 (3%) 6 (4%) 0 Hoarseness 0 0 0 1 (<1%) Infections and infestations Any event 1 (<1%) 1 (<1%) 0 0 Bronchitis 1 (<1%) 0 0 0 Respiratory tract infection viral 0 1 (<1%) 0 0 Nervous system disorders Any event 0 1 (<1%) 0 0 Headache 0 1 (<1%) 0 0 Vascular disorders Any event 1 (<1%) 0 0 0 Vasculitis 1 (<1%) 0 0 0

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.8 Summary of 24hr Urinary Cortisol Data (nmol/24hr) Geometric Treatment N Visit n Mean CV Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- Placebo 143 Baseline 130 50.87 85.94 64.59 43.385 55.55 6.3 241.6 Week 4 116 56.90 95.17 80.49 101.987 61.10 5.2 969.1 GW685698X 100mcg AM 143 Baseline 137 52.59 75.59 65.29 46.908 53.60 6.3 323.4 Week 4 125 59.05 87.48 76.68 58.139 64.30 7.2 354.6 GW685698X 100mcg PM 148 Baseline 141 50.18 88.55 66.69 62.759 49.20 5.0 621.7 Week 4 126 55.41 74.73 68.46 46.273 55.25 10.8 260.6 GW685698X 250mcg PM 141 Baseline 136 47.52 97.59 65.59 61.194 48.30 5.0 508.7 Week 4 131 47.72 89.06 64.06 58.863 48.40 8.3 459.5 Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.9 Summary of 24hr Urinary Cortisol Data (nmol/24hr) Change from Baseline Geometric Mean Treatment N Visit n Ratio Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- Placebo 143 Week 4 108 1.15 19.03 110.758 10.15 -180.4 929.8 GW685698X 100mcg AM 143 Week 4 124 1.12 10.90 56.907 8.90 -231.4 288.0 GW685698X 100mcg PM 148 Week 4 122 1.09 1.36 69.766 4.65 -531.4 247.4 GW685698X 250mcg PM 141 Week 4 129 1.00 -1.50 67.615 -2.70 -332.8 452.2 Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.10 Statistical Analysis of 24hr Urinary Cortisol Data (nmol/24hr) at Week 4 GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=148) (N=141) ---------------------------------------------------------------------------------------- Number of Subjects 108 124 122 129 Baseline Geometric Mean (cv) 50.56 (82.80) 52.65 (76.17) 51.19 (86.03) 47.67 (98.26) Raw Geometric Mean (cv) 58.04 (97.60) 58.74 (87.58) 55.82 (75.89) 47.86 (89.82) Adjusted Geometric Mean 65.32 64.44 62.21 54.08 Column Treatment / GW685698X 100mcg pm 1.04 0.87 95% CI (0.87,1.23) (0.74,1.03) Column Treatment / Placebo 0.99 0.95 0.83 95% CI (0.83,1.18) (0.80,1.14) (0.70,0.98) p-value 0.879 0.585 0.033 Note: Baseline is the final run-in visit Note: Based on ANCOVA model adjusted for treatment, baseline, age, sex and country

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.11 Summary of 24hr Urinary Cortisol Adjusted for Creatinine (nmol/mmol) Geometric Treatment N Visit n Mean CV Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- Placebo 143 Baseline 130 5.32 89.97 7.07 6.196 5.55 0.6 48.1 Week 4 116 6.05 87.30 8.74 14.817 5.60 0.7 153.8 GW685698X 100mcg AM 143 Baseline 137 5.53 70.03 6.75 4.628 5.60 1.0 26.7 Week 4 125 6.18 74.20 7.65 5.268 6.20 1.3 28.4 GW685698X 100mcg PM 148 Baseline 141 5.44 75.06 6.85 5.897 5.50 0.8 56.0 Week 4 126 5.88 65.26 6.98 4.313 6.40 1.5 25.5 GW685698X 250mcg PM 141 Baseline 136 5.18 81.82 6.76 6.066 4.95 0.6 41.7 Week 4 130 4.87 73.04 6.05 4.628 4.75 0.8 32.6 Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.12 Statistical Analysis of 24hr Urinary Cortisol adjusted for Creatinine (nmol/mmol) at Week 4 GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=148) (N=141) ---------------------------------------------------------------------------------------- Number of Subjects 108 124 122 128 Baseline Geometric Mean (cv) 5.17 (87.16) 5.46 (69.87) 5.55 (75.88) 5.20 (83.40) Raw Geometric Mean (cv) 6.06 (87.99) 6.16 (74.35) 5.87 (65.39) 4.88 (73.65) Adjusted Geometric Mean 6.74 6.59 6.32 5.32 Column Treatment / GW685698X 100mcg pm 1.04 0.84 95% CI (0.89,1.22) (0.72,0.98) Column Treatment / Placebo 0.98 0.94 0.79 95% CI (0.83,1.15) (0.80,1.10) (0.67,0.93) p-value 0.787 0.436 0.004 Note: Baseline is the final run-in visit Note: Based on ANCOVA model adjusted for treatment, baseline, age, sex and country

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.13 Summary of 24hr Urinary Cortisol adjusted for Creatinine (nmol/mmol) Change from Baseline Geometric Mean Treatment N Visit n Ratio Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- Placebo 143 Week 4 108 1.17 1.99 16.383 1.10 -45.3 148.8 GW685698X 100mcg AM 143 Week 4 124 1.13 0.98 5.659 0.50 -13.0 19.3 GW685698X 100mcg PM 148 Week 4 122 1.06 -0.04 6.306 0.40 -41.4 23.3 GW685698X 250mcg PM 141 Week 4 128 0.94 -0.77 6.397 -0.20 -28.5 30.4

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.14 Summary of 24hr Urinary Cortisol adjusted for Creatinine (nmol/mmol) Outside the Normal Range GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ------------------------------------------------------------------------------------------ Baseline n 130 137 141 136 > normal range high 33 (25%) 33 (24%) 34 (24%) 29 (21%) < normal range low 2 (2%) 0 1 (<1%) 2 (1%) Week 4 n 116 125 126 130 > normal range high 34 (29%) 39 (31%) 33 (26%) 25 (19%) < normal range low 2 (2%) 0 0 1 (<1%)

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.15 Summary of 24hr Urinary Cortisol adjusted for Creatinine (nmol/mmol) Shifts from Baseline ______________________Week 4______________________ Baseline Normal Within Normal Treatment n[1] Value Range High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Placebo 116 NR High 7 (6%) 17 (16%) 1 (<1%) 25 (23%) W/in NR 24 (22%) 57 (53%) 1 (<1%) 82 (76%) NR Low 0 1 (<1%) 0 1 (<1%) Total 31 (29%) 75 (69%) 2 (2%) 108 (100%) GW685698X 100mcg AM 125 NR High 16 (13%) 13 (10%) 0 29 (23%) W/in NR 22 (18%) 73 (59%) 0 95 (77%) NR Low 0 0 0 0 Total 38 (31%) 86 (69%) 0 124 (100%) GW685698X 100mcg PM 126 NR High 18 (15%) 12 (10%) 0 30 (25%) W/in NR 14 (11%) 77 (63%) 0 91 (75%) NR Low 0 1 (<1%) 0 1 (<1%) Total 32 (26%) 90 (74%) 0 122 (100%) GW685698X 250mcg PM 130 NR High 10 (8%) 18 (14%) 0 28 (22%) W/in NR 15 (12%) 82 (64%) 1 (<1%) 98 (77%) NR Low 0 2 (2%) 0 2 (2%) Total 25 (20%) 102 (80%) 1 (<1%) 128 (100%) Note: Baseline is the final run-in visit [1] Number of Subjects at Week 4

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.16 Summary of 24hr Urinary Cortisol Data (nmol/24hr) Outside the Normal Range GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ------------------------------------------------------------------------------------------ Baseline n 130 137 141 136 > normal range high 15 (12%) 12 (9%) 21 (15%) 23 (17%) < normal range low 0 0 1 (<1%) 1 (<1%) Week 4 n 116 125 126 131 > normal range high 16 (14%) 19 (15%) 15 (12%) 14 (11%) < normal range low 1 (<1%) 0 0 0 Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.17 Summary of 24hr Urinary Cortisol Data (nmol/24hr) Shifts From Baseline ______________________Week 4______________________ Baseline Normal Within Normal Treatment n[1] Value Range High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Placebo 116 NR High 2 (2%) 9 (8%) 0 11 (10%) W/in NR 14 (13%) 82 (76%) 1 (<1%) 97 (90%) NR Low 0 0 0 0 Total 16 (15%) 91 (84%) 1 (<1%) 108 (100%) GW685698X 100mcg AM 125 NR High 4 (3%) 7 (6%) 0 11 (9%) W/in NR 15 (12%) 98 (79%) 0 113 (91%) NR Low 0 0 0 0 Total 19 (15%) 105 (85%) 0 124 (100%) GW685698X 100mcg PM 126 NR High 6 (5%) 12 (10%) 0 18 (15%) W/in NR 9 (7%) 95 (78%) 0 104 (85%) NR Low 0 0 0 0 Total 15 (12%) 107 (88%) 0 122 (100%) GW685698X 250mcg PM 131 NR High 9 (7%) 13 (10%) 0 22 (17%) W/in NR 5 (4%) 101 (78%) 0 106 (82%) NR Low 0 1 (<1%) 0 1 (<1%) Total 14 (11%) 115 (89%) 0 129 (100%) Note: Baseline is the final run-in visit [1] Number of subjects at Week 4

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Protocol: FFA20001 Page 1 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Basophils (GI/L) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 133 0.018 0.0127 0.020 0.00 0.10 Week 4 106 0.021 0.0169 0.020 0.00 0.10 Visit 7 14 0.023 0.0154 0.020 0.01 0.06 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 0.022 0.0140 0.020 0.00 0.07 Week 4 123 0.020 0.0109 0.020 0.00 0.08 Visit 7 6 0.015 0.0055 0.015 0.01 0.02 (Follow- up) GW685698X 100mcg PM 148 Baseline 142 0.017 0.0108 0.010 0.00 0.06 Week 4 124 0.019 0.0117 0.020 0.00 0.06 Visit 7 11 0.014 0.0081 0.010 0.00 0.03 (Follow- up) GW685698X 250mcg PM 141 Baseline 132 0.017 0.0117 0.020 0.00 0.09 Week 4 120 0.020 0.0222 0.020 0.00 0.22 Visit 7 14 0.018 0.0163 0.015 0.00 0.05 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 2 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Basophils - percentage (%) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 133 0.26 0.158 0.30 0.0 0.8 Week 4 106 0.33 0.249 0.30 0.0 1.4 Visit 7 14 0.31 0.194 0.30 0.1 0.8 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 0.31 0.208 0.30 0.0 1.5 Week 4 123 0.31 0.172 0.30 0.0 1.0 Visit 7 6 0.20 0.110 0.20 0.1 0.4 (Follow- up) GW685698X 100mcg PM 148 Baseline 142 0.25 0.164 0.20 0.0 0.9 Week 4 124 0.28 0.167 0.30 0.0 1.0 Visit 7 11 0.22 0.140 0.20 0.0 0.5 (Follow- up) GW685698X 250mcg PM 141 Baseline 132 0.25 0.143 0.20 0.0 0.8 Week 4 120 0.29 0.268 0.20 0.0 2.0 Visit 7 14 0.26 0.174 0.20 0.0 0.6 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 3 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Eosinophils (GI/L) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 133 0.308 0.2356 0.230 0.01 1.46 Week 4 106 0.323 0.2512 0.255 0.03 1.22 Visit 7 14 0.304 0.2889 0.170 0.04 0.98 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 0.349 0.2517 0.290 0.01 1.25 Week 4 123 0.270 0.2063 0.230 0.01 1.33 Visit 7 6 0.385 0.1607 0.405 0.14 0.56 (Follow- up) GW685698X 100mcg PM 148 Baseline 142 0.313 0.2383 0.240 0.01 1.25 Week 4 124 0.248 0.1687 0.210 0.02 0.81 Visit 7 11 0.317 0.2360 0.270 0.11 0.83 (Follow- up) GW685698X 250mcg PM 141 Baseline 132 0.275 0.1865 0.230 0.00 0.97 Week 4 120 0.253 0.1869 0.215 0.00 1.07 Visit 7 14 0.342 0.3232 0.265 0.04 1.33 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 4 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Eosinophils - percentage (%) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 133 4.46 3.075 3.70 0.2 13.4 Week 4 106 4.97 3.504 3.95 0.7 16.1 Visit 7 14 3.93 3.755 1.95 0.4 12.0 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 5.03 3.688 4.00 0.1 20.2 Week 4 123 4.16 2.914 3.80 0.1 17.1 Visit 7 6 5.78 3.830 4.85 1.6 12.1 (Follow- up) GW685698X 100mcg PM 148 Baseline 142 4.72 3.488 3.60 0.2 17.9 Week 4 124 3.89 2.936 3.15 0.3 22.1 Visit 7 11 4.64 3.317 3.80 1.8 13.4 (Follow- up) GW685698X 250mcg PM 141 Baseline 133 4.06 2.741 3.70 0.0 16.8 Week 4 120 3.71 2.512 3.30 0.0 12.0 Visit 7 14 4.90 3.411 4.85 0.4 13.7 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 5 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Hematocrit (1) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 137 0.4255 0.04296 0.4210 0.328 0.528 Week 4 108 0.4213 0.03998 0.4195 0.344 0.533 Visit 7 14 0.4249 0.04519 0.4215 0.343 0.503 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 0.4252 0.04389 0.4240 0.314 0.535 Week 4 125 0.4164 0.04119 0.4160 0.327 0.522 Visit 7 7 0.4120 0.04576 0.4110 0.355 0.481 (Follow- up) GW685698X 100mcg PM 148 Baseline 144 0.4159 0.04306 0.4150 0.298 0.586 Week 4 127 0.4135 0.03835 0.4170 0.325 0.528 Visit 7 12 0.4163 0.04681 0.4190 0.359 0.513 (Follow- up) GW685698X 250mcg PM 141 Baseline 136 0.4240 0.04098 0.4275 0.339 0.574 Week 4 125 0.4212 0.04608 0.4260 0.316 0.567 Visit 7 14 0.4144 0.04416 0.4135 0.322 0.508 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 6 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Hemoglobin (G/L) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 137 142.9 14.53 142.0 101 176 Week 4 108 141.2 14.14 141.5 105 175 Visit 7 14 143.6 15.55 145.0 115 166 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 143.2 14.62 143.0 101 173 Week 4 125 140.3 13.64 141.0 108 170 Visit 7 7 139.3 15.67 142.0 116 161 (Follow- up) GW685698X 100mcg PM 148 Baseline 144 139.5 13.77 140.0 97 186 Week 4 127 138.8 12.88 140.0 103 170 Visit 7 12 140.8 16.03 141.5 120 172 (Follow- up) GW685698X 250mcg PM 141 Baseline 136 142.9 13.88 144.0 107 189 Week 4 125 141.3 15.67 144.0 99 185 Visit 7 14 140.7 14.02 142.0 109 164 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 7 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Lymphocytes (GI/L) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 133 2.135 0.5723 2.110 0.87 3.92 Week 4 106 2.119 0.5879 2.040 0.97 3.60 Visit 7 14 2.114 0.4903 2.060 1.41 3.23 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 2.200 0.6302 2.110 0.96 4.44 Week 4 123 2.136 0.5981 2.060 0.86 4.45 Visit 7 6 1.902 0.4010 1.885 1.37 2.41 (Follow- up) GW685698X 100mcg PM 148 Baseline 142 2.067 0.5419 2.000 1.06 4.37 Week 4 124 2.039 0.5645 1.920 1.01 3.87 Visit 7 11 1.945 0.6314 1.780 0.85 3.00 (Follow- up) GW685698X 250mcg PM 141 Baseline 132 2.167 0.7205 2.040 1.06 6.42 Week 4 120 2.123 0.6008 2.070 0.78 4.47 Visit 7 14 2.182 0.7501 2.170 0.88 3.93 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 8 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Lymphocytes - percentage (%) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 133 31.73 8.068 31.10 16.7 56.6 Week 4 106 32.96 8.635 32.50 14.5 66.6 Visit 7 14 27.46 7.311 29.40 13.4 35.6 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 31.80 8.835 30.60 11.8 61.0 Week 4 123 33.19 9.308 31.70 12.3 65.1 Visit 7 6 25.82 5.960 28.40 17.0 31.8 (Follow- up) GW685698X 100mcg PM 148 Baseline 142 31.57 7.923 31.05 16.3 75.7 Week 4 124 31.35 7.500 31.85 14.8 53.1 Visit 7 11 28.72 5.383 28.70 18.8 36.5 (Follow- up) GW685698X 250mcg PM 141 Baseline 132 31.58 7.647 30.95 10.8 57.0 Week 4 120 31.29 7.417 31.05 11.5 51.0 Visit 7 14 32.69 9.648 33.05 15.7 48.5 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 9 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Mean Corpuscle Hemoglobin (FMOL (FE)) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 137 1.87 0.127 1.90 1.3 2.2 Week 4 108 1.88 0.127 1.90 1.4 2.1 Visit 7 14 1.87 0.120 1.88 1.6 2.1 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 1.89 0.107 1.90 1.5 2.2 Week 4 125 1.89 0.107 1.90 1.6 2.2 Visit 7 7 1.90 0.119 1.95 1.7 2.0 (Follow- up) GW685698X 100mcg PM 148 Baseline 144 1.87 0.111 1.90 1.4 2.3 Week 4 127 1.87 0.115 1.90 1.4 2.2 Visit 7 12 1.89 0.091 1.90 1.7 2.0 (Follow- up) GW685698X 250mcg PM 141 Baseline 136 1.89 0.108 1.90 1.6 2.1 Week 4 125 1.88 0.120 1.90 1.4 2.2 Visit 7 14 1.92 0.109 1.90 1.7 2.1 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 10 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Mean Corpuscle Hemoglobin Concentration (G/L) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 137 336.03 9.277 338.38 306.2 354.5 Week 4 108 334.80 9.433 338.38 290.0 354.5 Visit 7 14 338.38 8.938 338.38 322.3 354.5 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 336.73 9.015 338.38 306.2 354.5 Week 4 125 336.58 8.491 338.38 322.3 354.5 Visit 7 7 338.38 9.303 338.38 322.3 354.5 (Follow- up) GW685698X 100mcg PM 148 Baseline 144 335.25 8.367 338.38 306.2 354.5 Week 4 127 336.10 7.790 338.38 306.2 354.5 Visit 7 12 338.38 9.717 338.38 322.3 354.5 (Follow- up) GW685698X 250mcg PM 141 Baseline 136 336.84 8.058 338.38 322.3 354.5 Week 4 125 335.55 8.453 338.38 306.2 354.5 Visit 7 14 340.68 10.683 338.38 322.3 354.5 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 11 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Mean Corpuscle Volume (FL) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 137 89.9 5.06 90.0 68 103 Week 4 108 90.2 5.15 91.0 68 102 Visit 7 14 89.3 5.69 89.5 75 97 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 90.5 4.54 91.0 74 101 Week 4 125 90.3 4.34 91.0 75 101 Visit 7 7 90.1 4.10 92.0 83 95 (Follow- up) GW685698X 100mcg PM 148 Baseline 144 89.9 4.79 90.0 69 106 Week 4 127 89.8 4.66 90.0 68 105 Visit 7 12 90.1 3.68 89.5 83 97 (Follow- up) GW685698X 250mcg PM 141 Baseline 136 90.4 4.71 90.5 75 104 Week 4 125 90.5 5.17 91.0 73 104 Visit 7 14 91.2 4.90 91.0 84 99 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 12 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Monocytes (GI/L) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 133 0.412 0.1683 0.400 0.05 0.88 Week 4 106 0.424 0.1599 0.410 0.13 0.87 Visit 7 14 0.402 0.1607 0.365 0.21 0.83 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 0.422 0.1550 0.410 0.09 0.88 Week 4 123 0.437 0.1870 0.420 0.11 1.25 Visit 7 6 0.487 0.1663 0.450 0.28 0.73 (Follow- up) GW685698X 100mcg PM 148 Baseline 142 0.402 0.1347 0.400 0.00 0.78 Week 4 124 0.408 0.1537 0.390 0.11 0.93 Visit 7 11 0.405 0.1451 0.380 0.15 0.59 (Follow- up) GW685698X 250mcg PM 141 Baseline 132 0.421 0.1671 0.405 0.00 0.97 Week 4 120 0.424 0.1718 0.410 0.03 1.09 Visit 7 14 0.443 0.1217 0.445 0.23 0.71 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 13 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Monocytes - percentage (%) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 133 6.18 2.711 5.90 1.0 17.9 Week 4 106 6.55 2.374 6.40 2.4 15.1 Visit 7 14 5.10 1.726 4.55 2.1 7.9 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 6.15 2.326 6.10 1.0 14.8 Week 4 123 6.79 2.851 6.50 1.6 17.4 Visit 7 6 6.60 2.338 6.70 3.2 9.7 (Follow- up) GW685698X 100mcg PM 148 Baseline 142 6.11 1.881 5.85 0.0 12.8 Week 4 124 6.20 2.030 6.20 2.0 13.7 Visit 7 11 6.00 1.570 6.20 2.5 8.6 (Follow- up) GW685698X 250mcg PM 141 Baseline 132 6.11 2.109 6.00 0.1 12.1 Week 4 120 6.31 2.536 6.15 0.3 16.9 Visit 7 14 6.64 1.405 6.50 3.9 8.8 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 14 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Neutrophils (GI/L) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 133 4.116 1.6962 3.810 0.28 11.27 Week 4 106 3.780 1.5955 3.555 0.29 10.98 Visit 7 14 5.596 3.6469 4.255 2.37 16.64 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 4.130 1.5732 3.890 0.73 9.77 Week 4 123 3.763 1.3889 3.740 0.44 9.79 Visit 7 6 4.850 1.7848 5.000 1.98 6.91 (Follow- up) GW685698X 100mcg PM 148 Baseline 142 3.922 1.3562 3.775 0.33 8.64 Week 4 124 3.942 1.3547 3.810 0.36 8.68 Visit 7 11 4.037 1.0996 3.920 3.01 6.52 (Follow- up) GW685698X 250mcg PM 141 Baseline 132 4.143 1.5630 3.865 1.42 11.61 Week 4 120 4.133 1.5400 3.720 0.92 8.80 Visit 7 14 3.882 1.5923 3.525 2.16 6.79 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 15 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Neutrophils - percentage (%) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 133 57.37 10.005 57.90 16.6 78.0 Week 4 106 55.20 10.357 56.75 17.0 76.9 Visit 7 14 63.21 10.064 60.90 50.5 80.4 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 56.70 10.805 57.90 14.9 82.8 Week 4 123 55.55 10.951 56.60 15.3 83.0 Visit 7 6 61.60 10.477 60.95 46.0 73.5 (Follow- up) GW685698X 100mcg PM 148 Baseline 142 57.36 9.515 58.50 8.6 77.1 Week 4 124 58.28 9.666 58.45 11.9 81.1 Visit 7 11 60.43 7.443 58.50 51.0 72.0 (Follow- up) GW685698X 250mcg PM 141 Baseline 132 58.03 8.661 58.30 35.4 82.9 Week 4 120 58.41 8.883 58.00 28.0 81.8 Visit 7 14 55.51 10.566 55.65 36.8 72.6 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 16 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Platelets (GI/L) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 136 254.1 60.47 252.0 113 424 Week 4 106 254.3 56.11 252.5 126 438 Visit 7 14 259.4 75.36 254.5 134 416 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 257.2 49.89 254.0 135 385 Week 4 124 247.0 49.95 244.0 144 387 Visit 7 6 261.0 68.59 271.5 164 343 (Follow- up) GW685698X 100mcg PM 148 Baseline 143 258.6 64.54 246.0 116 508 Week 4 126 256.6 66.04 244.5 158 516 Visit 7 12 241.4 52.70 249.0 140 326 (Follow- up) GW685698X 250mcg PM 141 Baseline 135 257.8 53.72 258.0 128 413 Week 4 124 250.4 49.97 250.5 142 385 Visit 7 14 243.4 64.79 241.5 152 365 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 17 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: Red Blood Cell Count (TI/L) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 137 4.75 0.478 4.70 3.5 6.0 Week 4 108 4.68 0.465 4.70 3.4 6.0 Visit 7 14 4.77 0.327 4.85 4.2 5.3 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 4.71 0.442 4.70 3.6 5.9 Week 4 125 4.62 0.441 4.60 3.5 5.9 Visit 7 7 4.57 0.442 4.50 4.0 5.2 (Follow- up) GW685698X 100mcg PM 148 Baseline 144 4.64 0.506 4.70 3.6 6.3 Week 4 127 4.62 0.459 4.60 3.7 6.2 Visit 7 12 4.64 0.593 4.75 3.9 5.7 (Follow- up) GW685698X 250mcg PM 141 Baseline 136 4.69 0.415 4.70 3.9 5.9 Week 4 125 4.66 0.423 4.70 3.7 5.7 Visit 7 14 4.55 0.416 4.45 3.8 5.4 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 18 of 18 Population: Safety Table 8.18 Summary of Haematology Data Lab Test: White Blood Cell Count (GI/L) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------- Placebo 143 Baseline 133 6.99 2.055 6.70 1.7 15.7 Week 4 106 6.67 1.944 6.50 1.7 14.8 Visit 7 14 8.44 3.981 7.50 4.7 20.7 (Follow- up) GW685698X 100mcg AM 143 Baseline 137 7.12 1.785 6.90 4.0 12.9 Week 4 124 6.60 1.672 6.65 2.9 13.2 Visit 7 6 7.63 1.848 8.15 4.3 9.5 (Follow- up) GW685698X 100mcg PM 148 Baseline 142 6.72 1.647 6.60 3.7 11.5 Week 4 124 6.65 1.600 6.60 3.0 11.4 Visit 7 11 6.72 1.770 6.20 4.5 10.1 (Follow- up) GW685698X 250mcg PM 141 Baseline 132 7.02 2.022 6.70 2.8 14.0 Week 4 121 6.93 1.916 6.40 3.3 12.5 Visit 7 14 6.87 2.025 6.55 4.2 9.9 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 1 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Basophils (GI/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 97 0.003 0.0198 0.000 -0.04 0.08 Visit 7 14 0.004 0.0203 0.000 -0.03 0.05 (Follow- up) GW685698X 100mcg AM 143 Week 4 119 -0.002 0.0172 0.000 -0.05 0.08 Visit 7 5 0.002 0.0084 0.000 -0.01 0.01 (Follow- up) GW685698X 100mcg PM 148 Week 4 119 0.002 0.0133 0.000 -0.03 0.04 Visit 7 11 -0.003 0.0101 0.000 -0.02 0.01 (Follow- up) GW685698X 250mcg PM 141 Week 4 113 0.002 0.0229 0.000 -0.07 0.19 Visit 7 11 0.003 0.0162 0.010 -0.03 0.02 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 2 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Basophils - percentage (%) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 97 0.05 0.275 0.00 -0.7 1.2 Visit 7 14 0.07 0.230 0.10 -0.2 0.5 (Follow- up) GW685698X 100mcg AM 143 Week 4 119 0.00 0.263 0.00 -1.2 1.0 Visit 7 5 -0.02 0.045 0.00 -0.1 0.0 (Follow- up) GW685698X 100mcg PM 148 Week 4 119 0.03 0.199 0.00 -0.5 0.6 Visit 7 11 -0.04 0.157 0.00 -0.2 0.2 (Follow- up) GW685698X 250mcg PM 141 Week 4 113 0.03 0.234 0.00 -0.5 1.8 Visit 7 11 0.01 0.277 0.00 -0.6 0.5 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 3 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Eosinophils (GI/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 97 0.036 0.1560 0.020 -0.25 0.84 Visit 7 14 0.036 0.2476 -0.025 -0.30 0.77 (Follow- up) GW685698X 100mcg AM 143 Week 4 119 -0.082 0.2051 -0.050 -0.75 0.52 Visit 7 5 -0.170 0.2077 -0.180 -0.43 0.06 (Follow- up) GW685698X 100mcg PM 148 Week 4 119 -0.048 0.1713 -0.020 -0.60 0.58 Visit 7 11 -0.040 0.2758 -0.020 -0.70 0.42 (Follow- up) GW685698X 250mcg PM 141 Week 4 113 -0.028 0.1700 -0.020 -0.72 0.51 Visit 7 11 0.164 0.3857 0.060 -0.23 1.23 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 4 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Eosinophils - percentage (%) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 97 0.55 2.325 0.30 -5.1 12.3 Visit 7 14 0.16 3.357 -0.10 -6.7 8.8 (Follow- up) GW685698X 100mcg AM 143 Week 4 119 -0.90 2.621 -0.50 -10.3 5.1 Visit 7 5 -3.26 2.277 -3.70 -5.9 -0.2 (Follow- up) GW685698X 100mcg PM 148 Week 4 119 -0.62 3.067 -0.10 -10.7 15.8 Visit 7 11 -1.15 4.596 0.20 -12.6 4.1 (Follow- up) GW685698X 250mcg PM 141 Week 4 114 -0.43 2.612 -0.30 -9.8 7.3 Visit 7 11 1.40 4.690 0.70 -4.5 12.2 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 5 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Hematocrit (1) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 103 -0.0024 0.01983 -0.0020 -0.073 0.053 Visit 7 14 0.0039 0.01354 0.0065 -0.013 0.033 (Follow- up) GW685698X 100mcg AM 143 Week 4 121 -0.0091 0.02163 -0.0070 -0.069 0.043 Visit 7 6 -0.0122 0.01141 -0.0105 -0.026 0.002 (Follow- up) GW685698X 100mcg PM 148 Week 4 124 -0.0007 0.02080 -0.0010 -0.066 0.055 Visit 7 12 -0.0034 0.01603 -0.0020 -0.029 0.021 (Follow- up) GW685698X 250mcg PM 141 Week 4 121 -0.0025 0.01976 -0.0010 -0.073 0.058 Visit 7 13 -0.0005 0.01924 0.0040 -0.034 0.032 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 6 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Hemoglobin (G/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 103 -1.3 5.84 -1.0 -22 18 Visit 7 14 0.8 4.14 1.5 -6 6 (Follow- up) GW685698X 100mcg AM 143 Week 4 121 -3.0 7.04 -3.0 -24 17 Visit 7 6 -3.3 3.50 -3.0 -8 1 (Follow- up) GW685698X 100mcg PM 148 Week 4 124 -0.1 6.41 -0.5 -21 17 Visit 7 12 -1.4 7.04 -0.5 -11 14 (Follow- up) GW685698X 250mcg PM 141 Week 4 121 -1.2 6.09 -1.0 -23 16 Visit 7 13 0.5 6.20 2.0 -9 8 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 7 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Lymphocytes (GI/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 97 0.004 0.4761 -0.030 -0.93 1.52 Visit 7 14 0.076 0.4053 0.185 -0.61 0.61 (Follow- up) GW685698X 100mcg AM 143 Week 4 119 -0.088 0.4555 -0.060 -1.95 1.20 Visit 7 5 0.188 0.1796 0.180 -0.02 0.47 (Follow- up) GW685698X 100mcg PM 148 Week 4 119 -0.019 0.4161 -0.020 -0.93 1.21 Visit 7 11 -0.194 0.3380 -0.080 -0.89 0.20 (Follow- up) GW685698X 250mcg PM 141 Week 4 113 -0.042 0.5903 -0.010 -2.20 1.28 Visit 7 11 0.272 0.5560 0.170 -0.29 1.79 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 8 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Lymphocytes - percentage (%) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 97 0.51 7.856 0.30 -17.0 24.4 Visit 7 14 -1.66 7.465 -1.60 -14.3 8.7 (Follow- up) GW685698X 100mcg AM 143 Week 4 119 0.81 9.472 1.20 -27.4 44.1 Visit 7 5 -4.00 8.108 -3.20 -17.4 3.6 (Follow- up) GW685698X 100mcg PM 148 Week 4 119 -0.26 8.439 -0.10 -37.0 31.2 Visit 7 11 -4.45 7.588 -2.80 -16.3 5.8 (Follow- up) GW685698X 250mcg PM 141 Week 4 113 -0.35 7.887 -1.00 -20.2 24.2 Visit 7 11 0.71 10.582 1.70 -16.7 15.1 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 9 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Mean Corpuscle Hemoglobin (FMOL (FE)) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 103 -0.00 0.044 0.00 -0.1 0.1 Visit 7 14 -0.00 0.039 0.00 -0.1 0.1 (Follow- up) GW685698X 100mcg AM 143 Week 4 121 -0.00 0.043 0.00 -0.2 0.1 Visit 7 6 0.03 0.052 0.03 -0.1 0.1 (Follow- up) GW685698X 100mcg PM 148 Week 4 124 0.00 0.041 0.00 -0.1 0.1 Visit 7 12 0.00 0.058 0.00 -0.1 0.1 (Follow- up) GW685698X 250mcg PM 141 Week 4 121 -0.00 0.038 0.00 -0.1 0.2 Visit 7 13 0.02 0.032 0.00 -0.1 0.1 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 10 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Mean Corpuscle Hemoglobin Concentration (G/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 103 -1.72 9.279 0.00 -32.2 16.1 Visit 7 14 1.15 9.921 0.00 -16.1 16.1 (Follow- up) GW685698X 100mcg AM 143 Week 4 121 -0.40 9.637 0.00 -16.1 32.2 Visit 7 6 2.69 12.130 0.00 -16.1 16.1 (Follow- up) GW685698X 100mcg PM 148 Week 4 124 1.04 8.152 0.00 -16.1 16.1 Visit 7 12 0.00 11.901 0.00 -16.1 16.1 (Follow- up) GW685698X 250mcg PM 141 Week 4 121 -0.53 7.481 0.00 -16.1 16.1 Visit 7 13 2.48 8.938 0.00 -16.1 16.1 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 11 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Mean Corpuscle Volume (FL) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 103 0.2 1.49 0.0 -4 3 Visit 7 14 0.5 1.83 0.5 -3 4 (Follow- up) GW685698X 100mcg AM 143 Week 4 121 0.0 1.81 0.0 -5 6 Visit 7 6 0.5 1.22 1.0 -1 2 (Follow- up) GW685698X 100mcg PM 148 Week 4 124 0.2 1.41 0.0 -5 6 Visit 7 12 0.8 1.19 0.5 -1 3 (Follow- up) GW685698X 250mcg PM 141 Week 4 121 0.3 1.46 0.0 -4 4 Visit 7 13 0.3 1.60 0.0 -3 3 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 12 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Monocytes (GI/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 97 0.002 0.1674 -0.010 -0.42 0.41 Visit 7 14 -0.029 0.1677 -0.035 -0.30 0.37 (Follow- up) GW685698X 100mcg AM 143 Week 4 119 0.017 0.1748 0.000 -0.43 1.16 Visit 7 5 0.118 0.1866 0.070 -0.08 0.42 (Follow- up) GW685698X 100mcg PM 148 Week 4 119 0.001 0.1169 -0.010 -0.33 0.41 Visit 7 11 0.034 0.1983 0.000 -0.13 0.58 (Follow- up) GW685698X 250mcg PM 141 Week 4 113 -0.020 0.1531 -0.020 -0.56 0.47 Visit 7 11 0.076 0.1757 0.010 -0.08 0.46 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 13 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Monocytes - percentage (%) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 97 0.05 2.382 0.10 -8.0 6.6 Visit 7 14 -1.03 2.065 -1.45 -4.1 2.5 (Follow- up) GW685698X 100mcg AM 143 Week 4 119 0.58 2.765 0.30 -9.0 11.7 Visit 7 5 0.26 1.299 -0.10 -0.9 2.3 (Follow- up) GW685698X 100mcg PM 148 Week 4 119 0.02 1.922 0.00 -6.2 7.2 Visit 7 11 -0.10 2.473 -0.80 -3.1 6.2 (Follow- up) GW685698X 250mcg PM 141 Week 4 113 -0.18 1.830 -0.30 -6.1 5.9 Visit 7 11 0.61 3.120 -0.20 -3.8 7.6 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 14 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Neutrophils (GI/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 97 -0.134 1.7014 -0.120 -5.80 5.84 Visit 7 14 1.194 3.4788 0.395 -2.67 11.50 (Follow- up) GW685698X 100mcg AM 143 Week 4 119 -0.265 1.6365 -0.140 -5.54 7.35 Visit 7 5 1.528 1.2592 1.820 -0.10 3.24 (Follow- up) GW685698X 100mcg PM 148 Week 4 119 0.033 1.4132 0.020 -4.82 6.03 Visit 7 11 0.513 1.1889 0.690 -0.81 3.15 (Follow- up) GW685698X 250mcg PM 141 Week 4 113 -0.008 1.5638 0.000 -8.70 3.78 Visit 7 11 0.196 1.7449 -0.350 -2.09 3.93 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 15 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Neutrophils - percentage (%) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 97 -1.17 9.794 -0.70 -31.2 22.4 Visit 7 14 2.46 9.951 3.95 -12.6 18.2 (Follow- up) GW685698X 100mcg AM 143 Week 4 119 -0.50 11.502 -1.10 -52.9 33.7 Visit 7 5 7.02 8.081 4.30 0.2 19.8 (Follow- up) GW685698X 100mcg PM 148 Week 4 119 0.84 11.207 1.30 -54.8 43.1 Visit 7 11 5.73 9.856 5.30 -5.4 24.1 (Follow- up) GW685698X 250mcg PM 141 Week 4 113 0.89 9.201 1.80 -28.0 23.9 Visit 7 11 -2.91 13.911 -3.50 -24.3 19.5 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 16 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Platelets (GI/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 100 1.8 33.01 -0.5 -110 93 Visit 7 14 10.3 44.54 -0.5 -48 130 (Follow- up) GW685698X 100mcg AM 143 Week 4 120 -8.4 29.49 -5.0 -117 58 Visit 7 5 20.4 37.81 16.0 -14 84 (Follow- up) GW685698X 100mcg PM 148 Week 4 122 0.3 40.19 -2.0 -152 151 Visit 7 12 -2.4 39.77 2.0 -76 62 (Follow- up) GW685698X 250mcg PM 141 Week 4 120 -7.6 33.75 -5.5 -92 85 Visit 7 13 -11.2 33.41 -14.0 -75 55 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 17 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: Red Blood Cell Count (TI/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 103 -0.04 0.209 0.00 -0.8 0.5 Visit 7 14 0.04 0.186 0.10 -0.3 0.3 (Follow- up) GW685698X 100mcg AM 143 Week 4 121 -0.10 0.222 -0.10 -0.8 0.4 Visit 7 6 -0.17 0.103 -0.20 -0.3 0.0 (Follow- up) GW685698X 100mcg PM 148 Week 4 124 -0.01 0.236 0.00 -0.8 0.6 Visit 7 12 -0.07 0.150 -0.05 -0.3 0.2 (Follow- up) GW685698X 250mcg PM 141 Week 4 121 -0.04 0.213 -0.10 -0.8 0.5 Visit 7 13 -0.01 0.210 0.00 -0.4 0.3 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 18 of 18 Population: Safety Table 8.19 Summary of Haematology Data Change from Baseline Lab Test: White Blood Cell Count (GI/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 97 -0.09 1.828 -0.20 -6.1 6.8 Visit 7 14 1.29 3.797 0.65 -2.7 12.7 (Follow- up) GW685698X 100mcg AM 143 Week 4 120 -0.44 1.798 -0.35 -5.9 7.1 Visit 7 5 1.66 1.417 1.40 -0.3 3.6 (Follow- up) GW685698X 100mcg PM 148 Week 4 119 -0.03 1.397 0.00 -4.7 5.8 Visit 7 11 0.31 1.210 0.30 -1.4 3.2 (Follow- up) GW685698X 250mcg PM 141 Week 4 114 -0.11 1.799 0.00 -8.7 4.6 Visit 7 11 0.73 1.777 0.20 -1.3 4.3 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 1 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Basophils (GI/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 133 137 142 132 > ref. range high 0 0 0 0 Week 4 n 106 123 124 120 > ref. range high 0 0 0 0 Visit 7 (Follow-up) n 14 6 11 14 > ref. range high 0 0 0 0 Any Visit Post Baseline n 115 128 129 124 > ref. range high 0 0 0 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 2 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Basophils - percentage (%) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 133 137 142 132 > ref. range high 0 0 0 0 Week 4 n 106 123 124 120 > ref. range high 0 0 0 0 Visit 7 (Follow-up) n 14 6 11 14 > ref. range high 0 0 0 0 Any Visit Post Baseline n 115 128 129 124 > ref. range high 0 0 0 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 3 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Eosinophils (GI/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 133 137 142 132 > ref. range high 1 (<1%) 1 (<1%) 1 (<1%) 0 Week 4 n 106 123 124 120 > ref. range high 1 (<1%) 1 (<1%) 0 0 Visit 7 (Follow-up) n 14 6 11 14 > ref. range high 0 0 0 1 (7%) Any Visit Post Baseline n 115 128 129 124 > ref. range high 1 (<1%) 2 (2%) 0 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 4 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Eosinophils - percentage (%) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 133 137 142 133 > ref. range high 0 4 (3%) 2 (1%) 1 (<1%) Week 4 n 106 123 124 120 > ref. range high 1 (<1%) 1 (<1%) 1 (<1%) 0 Visit 7 (Follow-up) n 14 6 11 14 > ref. range high 0 0 0 0 Any Visit Post Baseline n 115 128 129 124 > ref. range high 1 (<1%) 2 (2%) 1 (<1%) 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 5 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Hematocrit (1) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 137 137 144 136 > ref. range high 1 (<1%) 1 (<1%) 1 (<1%) 2 (1%) < ref. range low 1 (<1%) 1 (<1%) 1 (<1%) 0 Week 4 n 108 125 127 125 > ref. range high 0 0 0 2 (2%) < ref. range low 1 (<1%) 1 (<1%) 0 0 Visit 7 (Follow-up) n 14 7 12 14 > ref. range high 0 0 0 1 (7%) < ref. range low 0 0 0 0 Any Visit Post Baseline n 118 130 132 129 > ref. range high 1 (<1%) 0 0 2 (2%) < ref. range low 1 (<1%) 1 (<1%) 0 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 6 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Hemoglobin (G/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 137 137 144 136 > ref. range high 0 0 1 (<1%) 0 < ref. range low 2 (1%) 1 (<1%) 1 (<1%) 1 (<1%) Week 4 n 108 125 127 125 > ref. range high 0 0 0 1 (<1%) < ref. range low 2 (2%) 1 (<1%) 2 (2%) 2 (2%) Visit 7 (Follow-up) n 14 7 12 14 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 118 130 132 129 > ref. range high 0 0 0 1 (<1%) < ref. range low 2 (2%) 1 (<1%) 2 (2%) 2 (2%) Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 7 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Lymphocytes (GI/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 133 137 142 132 > ref. range high 0 0 0 1 (<1%) < ref. range low 0 0 0 0 Week 4 n 106 123 124 120 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Visit 7 (Follow-up) n 14 6 11 14 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 115 128 129 124 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 8 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Lymphocytes - percentage (%) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 133 137 142 132 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Week 4 n 106 123 124 120 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Visit 7 (Follow-up) n 14 6 11 14 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 115 128 129 124 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 9 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Mean Corpuscle Hemoglobin (FMOL (FE)) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 137 137 144 136 > ref. range high 0 0 0 0 < ref. range low 3 (2%) 1 (<1%) 2 (1%) 0 Week 4 n 108 125 127 125 > ref. range high 0 0 0 0 < ref. range low 3 (3%) 0 2 (2%) 1 (<1%) Visit 7 (Follow-up) n 14 7 12 14 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 118 130 132 129 > ref. range high 0 0 0 0 < ref. range low 3 (3%) 0 2 (2%) 1 (<1%) Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 10 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Mean Corpuscle Hemoglobin Concentration (G/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 137 137 144 136 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Week 4 n 108 125 127 125 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Visit 7 (Follow-up) n 14 7 12 14 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 118 130 132 129 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 11 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Mean Corpuscle Volume (FL) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 137 137 144 136 > ref. range high 0 0 0 0 < ref. range low 2 (1%) 0 1 (<1%) 0 Week 4 n 108 125 127 125 > ref. range high 0 0 0 0 < ref. range low 2 (2%) 0 1 (<1%) 0 Visit 7 (Follow-up) n 14 7 12 14 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 118 130 132 129 > ref. range high 0 0 0 0 < ref. range low 2 (2%) 0 1 (<1%) 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 12 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Monocytes (GI/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 133 137 142 132 > ref. range high 0 0 0 0 Week 4 n 106 123 124 120 > ref. range high 0 0 0 0 Visit 7 (Follow-up) n 14 6 11 14 > ref. range high 0 0 0 0 Any Visit Post Baseline n 115 128 129 124 > ref. range high 0 0 0 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 13 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Monocytes - percentage (%) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 133 137 142 132 > ref. range high 0 0 0 0 Week 4 n 106 123 124 120 > ref. range high 0 0 0 0 Visit 7 (Follow-up) n 14 6 11 14 > ref. range high 0 0 0 0 Any Visit Post Baseline n 115 128 129 124 > ref. range high 0 0 1 (<1%) 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 14 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Neutrophils (GI/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 133 137 142 132 > ref. range high 0 0 0 0 < ref. range low 1 (<1%) 1 (<1%) 1 (<1%) 0 Week 4 n 106 123 124 120 > ref. range high 0 0 0 0 < ref. range low 2 (2%) 3 (2%) 1 (<1%) 1 (<1%) Visit 7 (Follow-up) n 14 6 11 14 > ref. range high 1 (7%) 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 115 128 129 124 > ref. range high 0 0 0 0 < ref. range low 2 (2%) 3 (2%) 1 (<1%) 1 (<1%) Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 15 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Neutrophils - percentage (%) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 133 137 142 132 > ref. range high 0 0 0 0 < ref. range low 1 (<1%) 2 (1%) 1 (<1%) 0 Week 4 n 106 123 124 120 > ref. range high 0 0 0 0 < ref. range low 1 (<1%) 3 (2%) 1 (<1%) 0 Visit 7 (Follow-up) n 14 6 11 14 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 115 128 129 124 > ref. range high 0 0 0 0 < ref. range low 1 (<1%) 3 (2%) 1 (<1%) 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 16 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Platelets (GI/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 136 137 143 135 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Week 4 n 106 124 126 124 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Visit 7 (Follow-up) n 14 6 12 14 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 116 129 131 128 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 17 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: Red Blood Cell Count (TI/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 137 137 144 136 > ref. range high 2 (1%) 0 2 (1%) 0 < ref. range low 2 (1%) 0 0 0 Week 4 n 108 125 127 125 > ref. range high 2 (2%) 0 2 (2%) 0 < ref. range low 1 (<1%) 1 (<1%) 0 0 Visit 7 (Follow-up) n 14 7 12 14 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 118 130 132 129 > ref. range high 2 (2%) 0 2 (2%) 0 < ref. range low 1 (<1%) 1 (<1%) 0 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 18 of 18 Population: Safety Table 8.20 Summary of Haematology Data Outside the Reference Range Lab Test: White Blood Cell Count (GI/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 133 137 142 132 > ref. range high 0 0 0 0 < ref. range low 1 (<1%) 0 0 0 Week 4 n 106 124 124 121 > ref. range high 0 0 0 0 < ref. range low 1 (<1%) 0 0 0 Visit 7 (Follow-up) n 14 6 11 14 > ref. range high 1 (7%) 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 115 129 129 125 > ref. range high 0 0 0 0 < ref. range low 1 (<1%) 0 0 0 Note: Baseline in the final run-in visit Note: Any visit post baseline includes all on-treatment visits including unscheduled visits

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Protocol: FFA20001 Page 1 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Basophils (GI/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 0 0 0 0 W/in NR 0 97 (92%) 0 97 (92%) NR Low 0 0 0 0 Missing 0 9 (8%) 0 9 (8%) Total 0 106 (100%) 0 106 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 14 (100%) 0 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 2 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Basophils (GI/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 123 NR High 0 0 0 0 W/in NR 0 119 (97%) 0 119 (97%) NR Low 0 0 0 0 Missing 0 4 (3%) 0 4 (3%) Total 0 123 (100%) 0 123 (100%) Visit 7 (Follow-up) 6 NR High 0 0 0 0 W/in NR 0 5 (83%) 0 5 (83%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 0 6 (100%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 3 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Basophils (GI/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 0 0 0 W/in NR 0 119 (96%) 0 119 (96%) NR Low 0 0 0 0 Missing 0 5 (4%) 0 5 (4%) Total 0 124 (100%) 0 124 (100%) Visit 7 (Follow-up) 11 NR High 0 0 0 0 W/in NR 0 11 (100%) 0 11 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 11 (100%) 0 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 4 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Basophils (GI/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 120 NR High 0 0 0 0 W/in NR 1 (<1%) 112 (93%) 0 113 (94%) NR Low 0 0 0 0 Missing 0 7 (6%) 0 7 (6%) Total 1 (<1%) 119 (>99%) 0 120 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 11 (79%) 0 11 (79%) NR Low 0 0 0 0 Missing 0 3 (21%) 0 3 (21%) Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 5 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Basophils - percentage (%) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 0 0 0 0 W/in NR 0 97 (92%) 0 97 (92%) NR Low 0 0 0 0 Missing 0 9 (8%) 0 9 (8%) Total 0 106 (100%) 0 106 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 14 (100%) 0 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 6 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Basophils - percentage (%) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 123 NR High 0 0 0 0 W/in NR 0 119 (97%) 0 119 (97%) NR Low 0 0 0 0 Missing 0 4 (3%) 0 4 (3%) Total 0 123 (100%) 0 123 (100%) Visit 7 (Follow-up) 6 NR High 0 0 0 0 W/in NR 0 5 (83%) 0 5 (83%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 0 6 (100%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 7 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Basophils - percentage (%) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 0 0 0 W/in NR 0 119 (96%) 0 119 (96%) NR Low 0 0 0 0 Missing 0 5 (4%) 0 5 (4%) Total 0 124 (100%) 0 124 (100%) Visit 7 (Follow-up) 11 NR High 0 0 0 0 W/in NR 0 11 (100%) 0 11 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 11 (100%) 0 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 8 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Basophils - percentage (%) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 120 NR High 0 0 0 0 W/in NR 0 113 (94%) 0 113 (94%) NR Low 0 0 0 0 Missing 0 7 (6%) 0 7 (6%) Total 0 120 (100%) 0 120 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 11 (79%) 0 11 (79%) NR Low 0 0 0 0 Missing 0 3 (21%) 0 3 (21%) Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 9 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Eosinophils (GI/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 7 (7%) 3 (3%) 0 10 (9%) W/in NR 7 (7%) 74 (70%) 1 (<1%) 82 (77%) NR Low 0 3 (3%) 2 (2%) 5 (5%) Missing 2 (2%) 6 (6%) 1 (<1%) 9 (8%) Total 16 (15%) 86 (81%) 4 (4%) 106 (100%) Visit 7 (Follow-up) 14 NR High 1 (7%) 1 (7%) 0 2 (14%) W/in NR 1 (7%) 9 (64%) 1 (7%) 11 (79%) NR Low 0 1 (7%) 0 1 (7%) Missing 0 0 0 0 Total 2 (14%) 11 (79%) 1 (7%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 10 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Eosinophils (GI/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 123 NR High 10 (8%) 12 (10%) 0 22 (18%) W/in NR 0 90 (73%) 5 (4%) 95 (77%) NR Low 0 2 (2%) 0 2 (2%) Missing 0 3 (2%) 1 (<1%) 4 (3%) Total 10 (8%) 107 (87%) 6 (5%) 123 (100%) Visit 7 (Follow-up) 6 NR High 0 2 (33%) 0 2 (33%) W/in NR 1 (17%) 2 (33%) 0 3 (50%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 1 (17%) 5 (83%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 11 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Eosinophils (GI/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 3 (2%) 12 (10%) 0 15 (12%) W/in NR 4 (3%) 96 (77%) 2 (2%) 102 (82%) NR Low 0 1 (<1%) 1 (<1%) 2 (2%) Missing 2 (2%) 3 (2%) 0 5 (4%) Total 9 (7%) 112 (90%) 3 (2%) 124 (100%) Visit 7 (Follow-up) 11 NR High 1 (9%) 2 (18%) 0 3 (27%) W/in NR 1 (9%) 7 (64%) 0 8 (73%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 2 (18%) 9 (82%) 0 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 12 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Eosinophils (GI/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 120 NR High 3 (3%) 4 (3%) 0 7 (6%) W/in NR 4 (3%) 92 (77%) 6 (5%) 102 (85%) NR Low 0 3 (3%) 1 (<1%) 4 (3%) Missing 2 (2%) 5 (4%) 0 7 (6%) Total 9 (8%) 104 (87%) 7 (6%) 120 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 1 (7%) 8 (57%) 0 9 (64%) NR Low 0 1 (7%) 1 (7%) 2 (14%) Missing 0 3 (21%) 0 3 (21%) Total 1 (7%) 12 (86%) 1 (7%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 13 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Eosinophils - percentage (%) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 11 (10%) 8 (8%) 0 19 (18%) W/in NR 8 (8%) 70 (66%) 0 78 (74%) NR Low 0 0 0 0 Missing 4 (4%) 5 (5%) 0 9 (8%) Total 23 (22%) 83 (78%) 0 106 (100%) Visit 7 (Follow-up) 14 NR High 1 (7%) 1 (7%) 0 2 (14%) W/in NR 3 (21%) 9 (64%) 0 12 (86%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 4 (29%) 10 (71%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 14 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Eosinophils - percentage (%) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 123 NR High 10 (8%) 15 (12%) 0 25 (20%) W/in NR 5 (4%) 89 (72%) 0 94 (76%) NR Low 0 0 0 0 Missing 0 4 (3%) 0 4 (3%) Total 15 (12%) 108 (88%) 0 123 (100%) Visit 7 (Follow-up) 6 NR High 1 (17%) 2 (33%) 0 3 (50%) W/in NR 0 2 (33%) 0 2 (33%) NR Low 0 0 0 0 Missing 1 (17%) 0 0 1 (17%) Total 2 (33%) 4 (67%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 15 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Eosinophils - percentage (%) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 8 (6%) 14 (11%) 0 22 (18%) W/in NR 5 (4%) 92 (74%) 0 97 (78%) NR Low 0 0 0 0 Missing 1 (<1%) 4 (3%) 0 5 (4%) Total 14 (11%) 110 (89%) 0 124 (100%) Visit 7 (Follow-up) 11 NR High 1 (9%) 2 (18%) 0 3 (27%) W/in NR 1 (9%) 7 (64%) 0 8 (73%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 2 (18%) 9 (82%) 0 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 16 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Eosinophils - percentage (%) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 120 NR High 5 (4%) 9 (8%) 0 14 (12%) W/in NR 6 (5%) 94 (78%) 0 100 (83%) NR Low 0 0 0 0 Missing 3 (3%) 3 (3%) 0 6 (5%) Total 14 (12%) 106 (88%) 0 120 (100%) Visit 7 (Follow-up) 14 NR High 1 (7%) 0 0 1 (7%) W/in NR 1 (7%) 9 (64%) 0 10 (71%) NR Low 0 0 0 0 Missing 0 3 (21%) 0 3 (21%) Total 2 (14%) 12 (86%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 17 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Hematocrit (1) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 108 NR High 2 (2%) 2 (2%) 0 4 (4%) W/in NR 1 (<1%) 85 (79%) 6 (6%) 92 (85%) NR Low 0 3 (3%) 4 (4%) 7 (6%) Missing 0 5 (5%) 0 5 (5%) Total 3 (3%) 95 (88%) 10 (9%) 108 (100%) Visit 7 (Follow-up) 14 NR High 1 (7%) 0 0 1 (7%) W/in NR 0 11 (79%) 1 (7%) 12 (86%) NR Low 0 1 (7%) 0 1 (7%) Missing 0 0 0 0 Total 1 (7%) 12 (86%) 1 (7%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 18 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Hematocrit (1) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 4 (3%) 7 (6%) 0 11 (9%) W/in NR 3 (2%) 94 (75%) 3 (2%) 100 (80%) NR Low 0 2 (2%) 8 (6%) 10 (8%) Missing 0 3 (2%) 1 (<1%) 4 (3%) Total 7 (6%) 106 (85%) 12 (10%) 125 (100%) Visit 7 (Follow-up) 7 NR High 0 1 (14%) 0 1 (14%) W/in NR 0 5 (71%) 0 5 (71%) NR Low 0 0 0 0 Missing 0 1 (14%) 0 1 (14%) Total 0 7 (100%) 0 7 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 19 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Hematocrit (1) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 3 (2%) 2 (2%) 0 5 (4%) W/in NR 1 (<1%) 101 (80%) 6 (5%) 108 (85%) NR Low 0 7 (6%) 4 (3%) 11 (9%) Missing 0 3 (2%) 0 3 (2%) Total 4 (3%) 113 (89%) 10 (8%) 127 (100%) Visit 7 (Follow-up) 12 NR High 1 (8%) 0 0 1 (8%) W/in NR 0 10 (83%) 0 10 (83%) NR Low 0 0 1 (8%) 1 (8%) Missing 0 0 0 0 Total 1 (8%) 10 (83%) 1 (8%) 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 20 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Hematocrit (1) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 5 (4%) 5 (4%) 0 10 (8%) W/in NR 4 (3%) 98 (78%) 5 (4%) 107 (86%) NR Low 0 2 (2%) 2 (2%) 4 (3%) Missing 0 2 (2%) 2 (2%) 4 (3%) Total 9 (7%) 107 (86%) 9 (7%) 125 (100%) Visit 7 (Follow-up) 14 NR High 1 (7%) 0 0 1 (7%) W/in NR 0 11 (79%) 0 11 (79%) NR Low 0 0 1 (7%) 1 (7%) Missing 0 0 1 (7%) 1 (7%) Total 1 (7%) 11 (79%) 2 (14%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 21 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Hemoglobin (G/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 108 NR High 2 (2%) 0 0 2 (2%) W/in NR 1 (<1%) 89 (82%) 4 (4%) 94 (87%) NR Low 0 2 (2%) 5 (5%) 7 (6%) Missing 0 4 (4%) 1 (<1%) 5 (5%) Total 3 (3%) 95 (88%) 10 (9%) 108 (100%) Visit 7 (Follow-up) 14 NR High 1 (7%) 0 0 1 (7%) W/in NR 0 12 (86%) 0 12 (86%) NR Low 0 0 1 (7%) 1 (7%) Missing 0 0 0 0 Total 1 (7%) 12 (86%) 1 (7%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 22 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Hemoglobin (G/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 4 (3%) 3 (2%) 0 7 (6%) W/in NR 0 99 (79%) 4 (3%) 103 (82%) NR Low 0 4 (3%) 7 (6%) 11 (9%) Missing 0 2 (2%) 2 (2%) 4 (3%) Total 4 (3%) 108 (86%) 13 (10%) 125 (100%) Visit 7 (Follow-up) 7 NR High 0 0 0 0 W/in NR 0 5 (71%) 1 (14%) 6 (86%) NR Low 0 0 0 0 Missing 0 1 (14%) 0 1 (14%) Total 0 6 (86%) 1 (14%) 7 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 23 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Hemoglobin (G/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 2 (2%) 2 (2%) 0 4 (3%) W/in NR 0 103 (81%) 3 (2%) 106 (83%) NR Low 0 5 (4%) 9 (7%) 14 (11%) Missing 0 3 (2%) 0 3 (2%) Total 2 (2%) 113 (89%) 12 (9%) 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 11 (92%) 0 11 (92%) NR Low 0 1 (8%) 0 1 (8%) Missing 0 0 0 0 Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 24 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Hemoglobin (G/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 4 (3%) 3 (2%) 0 7 (6%) W/in NR 1 (<1%) 100 (80%) 6 (5%) 107 (86%) NR Low 0 1 (<1%) 6 (5%) 7 (6%) Missing 0 2 (2%) 2 (2%) 4 (3%) Total 5 (4%) 106 (85%) 14 (11%) 125 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 1 (7%) 11 (79%) 0 12 (86%) NR Low 0 0 1 (7%) 1 (7%) Missing 0 0 1 (7%) 1 (7%) Total 1 (7%) 11 (79%) 2 (14%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 25 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Lymphocytes (GI/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 0 0 0 0 W/in NR 0 97 (92%) 0 97 (92%) NR Low 0 0 0 0 Missing 0 9 (8%) 0 9 (8%) Total 0 106 (100%) 0 106 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 14 (100%) 0 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 26 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Lymphocytes (GI/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 123 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 1 (<1%) 117 (95%) 0 118 (96%) NR Low 0 0 0 0 Missing 0 4 (3%) 0 4 (3%) Total 1 (<1%) 122 (>99%) 0 123 (100%) Visit 7 (Follow-up) 6 NR High 0 0 0 0 W/in NR 0 5 (83%) 0 5 (83%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 0 6 (100%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 27 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Lymphocytes (GI/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 0 118 (95%) 0 118 (95%) NR Low 0 0 0 0 Missing 0 5 (4%) 0 5 (4%) Total 0 124 (100%) 0 124 (100%) Visit 7 (Follow-up) 11 NR High 0 0 0 0 W/in NR 0 11 (100%) 0 11 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 11 (100%) 0 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 28 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Lymphocytes (GI/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 120 NR High 1 (<1%) 2 (2%) 0 3 (3%) W/in NR 0 109 (91%) 1 (<1%) 110 (92%) NR Low 0 0 0 0 Missing 0 7 (6%) 0 7 (6%) Total 1 (<1%) 118 (98%) 1 (<1%) 120 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 11 (79%) 0 11 (79%) NR Low 0 0 0 0 Missing 0 3 (21%) 0 3 (21%) Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 29 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Lymphocytes - percentage (%) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 3 (3%) 2 (2%) 0 5 (5%) W/in NR 1 (<1%) 90 (85%) 1 (<1%) 92 (87%) NR Low 0 0 0 0 Missing 2 (2%) 7 (7%) 0 9 (8%) Total 6 (6%) 99 (93%) 1 (<1%) 106 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 12 (86%) 2 (14%) 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 12 (86%) 2 (14%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 30 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Lymphocytes - percentage (%) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 123 NR High 4 (3%) 4 (3%) 0 8 (7%) W/in NR 6 (5%) 102 (83%) 2 (2%) 110 (89%) NR Low 0 1 (<1%) 0 1 (<1%) Missing 1 (<1%) 3 (2%) 0 4 (3%) Total 11 (9%) 110 (89%) 2 (2%) 123 (100%) Visit 7 (Follow-up) 6 NR High 0 0 0 0 W/in NR 0 5 (83%) 0 5 (83%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 0 6 (100%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 31 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Lymphocytes - percentage (%) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 4 (3%) 0 4 (3%) W/in NR 3 (2%) 109 (88%) 3 (2%) 115 (93%) NR Low 0 0 0 0 Missing 0 5 (4%) 0 5 (4%) Total 3 (2%) 118 (95%) 3 (2%) 124 (100%) Visit 7 (Follow-up) 11 NR High 0 2 (18%) 0 2 (18%) W/in NR 0 9 (82%) 0 9 (82%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 11 (100%) 0 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 32 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Lymphocytes - percentage (%) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 120 NR High 0 5 (4%) 0 5 (4%) W/in NR 3 (3%) 102 (85%) 1 (<1%) 106 (88%) NR Low 0 1 (<1%) 1 (<1%) 2 (2%) Missing 1 (<1%) 6 (5%) 0 7 (6%) Total 4 (3%) 114 (95%) 2 (2%) 120 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 1 (7%) 10 (71%) 0 11 (79%) NR Low 0 0 0 0 Missing 0 2 (14%) 1 (7%) 3 (21%) Total 1 (7%) 12 (86%) 1 (7%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 33 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Hemoglobin (FMOL (FE)) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 108 NR High 1 (<1%) 1 (<1%) 0 2 (2%) W/in NR 0 96 (89%) 0 96 (89%) NR Low 0 0 5 (5%) 5 (5%) Missing 0 5 (5%) 0 5 (5%) Total 1 (<1%) 102 (94%) 5 (5%) 108 (100%) Visit 7 (Follow-up) 14 NR High 0 1 (7%) 0 1 (7%) W/in NR 0 12 (86%) 0 12 (86%) NR Low 0 0 1 (7%) 1 (7%) Missing 0 0 0 0 Total 0 13 (93%) 1 (7%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 34 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Hemoglobin (FMOL (FE)) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 2 (2%) 1 (<1%) 0 3 (2%) W/in NR 0 110 (88%) 2 (2%) 112 (90%) NR Low 0 1 (<1%) 5 (4%) 6 (5%) Missing 0 3 (2%) 1 (<1%) 4 (3%) Total 2 (2%) 115 (92%) 8 (6%) 125 (100%) Visit 7 (Follow-up) 7 NR High 0 0 0 0 W/in NR 0 6 (86%) 0 6 (86%) NR Low 0 0 0 0 Missing 0 1 (14%) 0 1 (14%) Total 0 7 (100%) 0 7 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 35 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Hemoglobin (FMOL (FE)) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 2 (2%) 0 0 2 (2%) W/in NR 0 117 (92%) 0 117 (92%) NR Low 0 1 (<1%) 4 (3%) 5 (4%) Missing 0 3 (2%) 0 3 (2%) Total 2 (2%) 121 (95%) 4 (3%) 127 (100%) Visit 7 (Follow-up) 12 NR High 0 1 (8%) 0 1 (8%) W/in NR 0 11 (92%) 0 11 (92%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 36 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Hemoglobin (FMOL (FE)) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 2 (2%) 2 (2%) 0 4 (3%) W/in NR 3 (2%) 109 (87%) 0 112 (90%) NR Low 0 1 (<1%) 4 (3%) 5 (4%) Missing 0 3 (2%) 1 (<1%) 4 (3%) Total 5 (4%) 115 (92%) 5 (4%) 125 (100%) Visit 7 (Follow-up) 14 NR High 1 (7%) 0 0 1 (7%) W/in NR 1 (7%) 11 (79%) 0 12 (86%) NR Low 0 0 0 0 Missing 0 1 (7%) 0 1 (7%) Total 2 (14%) 12 (86%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 37 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Hemoglobin Concentration (G/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 108 NR High 0 0 0 0 W/in NR 0 101 (94%) 0 101 (94%) NR Low 0 0 2 (2%) 2 (2%) Missing 0 5 (5%) 0 5 (5%) Total 0 106 (98%) 2 (2%) 108 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 14 (100%) 0 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 38 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Hemoglobin Concentration (G/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 0 0 0 0 W/in NR 0 120 (96%) 0 120 (96%) NR Low 0 1 (<1%) 0 1 (<1%) Missing 0 4 (3%) 0 4 (3%) Total 0 125 (100%) 0 125 (100%) Visit 7 (Follow-up) 7 NR High 0 0 0 0 W/in NR 0 6 (86%) 0 6 (86%) NR Low 0 0 0 0 Missing 0 1 (14%) 0 1 (14%) Total 0 7 (100%) 0 7 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 39 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Hemoglobin Concentration (G/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 0 0 0 0 W/in NR 0 123 (97%) 0 123 (97%) NR Low 0 0 1 (<1%) 1 (<1%) Missing 0 3 (2%) 0 3 (2%) Total 0 126 (>99%) 1 (<1%) 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 12 (100%) 0 12 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 40 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Hemoglobin Concentration (G/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 0 0 0 0 W/in NR 0 121 (97%) 0 121 (97%) NR Low 0 0 0 0 Missing 0 3 (2%) 1 (<1%) 4 (3%) Total 0 124 (>99%) 1 (<1%) 125 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 13 (93%) 0 13 (93%) NR Low 0 0 0 0 Missing 0 1 (7%) 0 1 (7%) Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 41 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Volume (FL) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 108 NR High 1 (<1%) 1 (<1%) 0 2 (2%) W/in NR 0 96 (89%) 1 (<1%) 97 (90%) NR Low 0 0 4 (4%) 4 (4%) Missing 0 5 (5%) 0 5 (5%) Total 1 (<1%) 102 (94%) 5 (5%) 108 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 13 (93%) 0 13 (93%) NR Low 0 0 1 (7%) 1 (7%) Missing 0 0 0 0 Total 0 13 (93%) 1 (7%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 42 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Volume (FL) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 1 (<1%) 116 (93%) 0 117 (94%) NR Low 0 2 (2%) 1 (<1%) 3 (2%) Missing 0 3 (2%) 1 (<1%) 4 (3%) Total 1 (<1%) 122 (98%) 2 (2%) 125 (100%) Visit 7 (Follow-up) 7 NR High 0 0 0 0 W/in NR 0 6 (86%) 0 6 (86%) NR Low 0 0 0 0 Missing 0 1 (14%) 0 1 (14%) Total 0 7 (100%) 0 7 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 43 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Volume (FL) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 1 (<1%) 0 0 1 (<1%) W/in NR 0 121 (95%) 0 121 (95%) NR Low 0 0 2 (2%) 2 (2%) Missing 0 3 (2%) 0 3 (2%) Total 1 (<1%) 124 (98%) 2 (2%) 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 12 (100%) 0 12 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 44 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Mean Corpuscle Volume (FL) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 1 (<1%) 0 0 1 (<1%) W/in NR 1 (<1%) 115 (92%) 1 (<1%) 117 (94%) NR Low 0 0 3 (2%) 3 (2%) Missing 0 3 (2%) 1 (<1%) 4 (3%) Total 2 (2%) 118 (94%) 5 (4%) 125 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 13 (93%) 0 13 (93%) NR Low 0 0 0 0 Missing 0 1 (7%) 0 1 (7%) Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 45 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Monocytes (GI/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 0 0 0 0 W/in NR 0 85 (80%) 7 (7%) 92 (87%) NR Low 0 5 (5%) 0 5 (5%) Missing 0 8 (8%) 1 (<1%) 9 (8%) Total 0 98 (92%) 8 (8%) 106 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 13 (93%) 0 13 (93%) NR Low 0 1 (7%) 0 1 (7%) Missing 0 0 0 0 Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 46 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Monocytes (GI/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 123 NR High 0 0 0 0 W/in NR 0 105 (85%) 5 (4%) 110 (89%) NR Low 1 (<1%) 8 (7%) 0 9 (7%) Missing 0 3 (2%) 1 (<1%) 4 (3%) Total 1 (<1%) 116 (94%) 6 (5%) 123 (100%) Visit 7 (Follow-up) 6 NR High 0 0 0 0 W/in NR 0 5 (83%) 0 5 (83%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 0 6 (100%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 47 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Monocytes (GI/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 0 0 0 W/in NR 0 109 (88%) 7 (6%) 116 (94%) NR Low 0 2 (2%) 1 (<1%) 3 (2%) Missing 0 4 (3%) 1 (<1%) 5 (4%) Total 0 115 (93%) 9 (7%) 124 (100%) Visit 7 (Follow-up) 11 NR High 0 0 0 0 W/in NR 0 9 (82%) 1 (9%) 10 (91%) NR Low 0 1 (9%) 0 1 (9%) Missing 0 0 0 0 Total 0 10 (91%) 1 (9%) 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 48 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Monocytes (GI/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 120 NR High 0 0 0 0 W/in NR 0 102 (85%) 5 (4%) 107 (89%) NR Low 0 3 (3%) 3 (3%) 6 (5%) Missing 0 6 (5%) 1 (<1%) 7 (6%) Total 0 111 (93%) 9 (8%) 120 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 10 (71%) 0 10 (71%) NR Low 0 1 (7%) 0 1 (7%) Missing 0 3 (21%) 0 3 (21%) Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 49 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Monocytes - percentage (%) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 2 (2%) 1 (<1%) 0 3 (3%) W/in NR 3 (3%) 91 (86%) 0 94 (89%) NR Low 0 0 0 0 Missing 0 9 (8%) 0 9 (8%) Total 5 (5%) 101 (95%) 0 106 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 14 (100%) 0 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 50 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Monocytes - percentage (%) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 123 NR High 1 (<1%) 1 (<1%) 0 2 (2%) W/in NR 5 (4%) 112 (91%) 0 117 (95%) NR Low 0 0 0 0 Missing 1 (<1%) 3 (2%) 0 4 (3%) Total 7 (6%) 116 (94%) 0 123 (100%) Visit 7 (Follow-up) 6 NR High 0 0 0 0 W/in NR 0 5 (83%) 0 5 (83%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 0 6 (100%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 51 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Monocytes - percentage (%) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 1 (<1%) 117 (94%) 0 118 (95%) NR Low 0 0 0 0 Missing 0 5 (4%) 0 5 (4%) Total 1 (<1%) 123 (>99%) 0 124 (100%) Visit 7 (Follow-up) 11 NR High 0 0 0 0 W/in NR 0 11 (100%) 0 11 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 11 (100%) 0 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 52 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Monocytes - percentage (%) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 120 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 1 (<1%) 111 (93%) 0 112 (93%) NR Low 0 0 0 0 Missing 3 (3%) 4 (3%) 0 7 (6%) Total 4 (3%) 116 (97%) 0 120 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 11 (79%) 0 11 (79%) NR Low 0 0 0 0 Missing 0 3 (21%) 0 3 (21%) Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 53 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Neutrophils (GI/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 0 3 (3%) 0 3 (3%) W/in NR 3 (3%) 88 (83%) 0 91 (86%) NR Low 0 1 (<1%) 2 (2%) 3 (3%) Missing 0 9 (8%) 0 9 (8%) Total 3 (3%) 101 (95%) 2 (2%) 106 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 2 (14%) 12 (86%) 0 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 2 (14%) 12 (86%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 54 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Neutrophils (GI/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 123 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 2 (2%) 106 (86%) 6 (5%) 114 (93%) NR Low 0 3 (2%) 1 (<1%) 4 (3%) Missing 0 3 (2%) 1 (<1%) 4 (3%) Total 2 (2%) 113 (92%) 8 (7%) 123 (100%) Visit 7 (Follow-up) 6 NR High 0 0 0 0 W/in NR 0 5 (83%) 0 5 (83%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 0 6 (100%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 55 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Neutrophils (GI/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 2 (2%) 0 2 (2%) W/in NR 2 (2%) 107 (86%) 5 (4%) 114 (92%) NR Low 0 3 (2%) 0 3 (2%) Missing 0 5 (4%) 0 5 (4%) Total 2 (2%) 117 (94%) 5 (4%) 124 (100%) Visit 7 (Follow-up) 11 NR High 0 0 0 0 W/in NR 0 11 (100%) 0 11 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 11 (100%) 0 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 56 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Neutrophils (GI/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 120 NR High 1 (<1%) 1 (<1%) 0 2 (2%) W/in NR 2 (2%) 105 (88%) 0 107 (89%) NR Low 0 4 (3%) 0 4 (3%) Missing 0 6 (5%) 1 (<1%) 7 (6%) Total 3 (3%) 116 (97%) 1 (<1%) 120 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 10 (71%) 0 10 (71%) NR Low 0 1 (7%) 0 1 (7%) Missing 0 3 (21%) 0 3 (21%) Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 57 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Neutrophils - percentage (%) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 2 (2%) 88 (83%) 2 (2%) 92 (87%) NR Low 0 1 (<1%) 3 (3%) 4 (4%) Missing 0 7 (7%) 2 (2%) 9 (8%) Total 2 (2%) 97 (92%) 7 (7%) 106 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 3 (21%) 11 (79%) 0 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 3 (21%) 11 (79%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 58 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Neutrophils - percentage (%) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 123 NR High 0 2 (2%) 0 2 (2%) W/in NR 2 (2%) 102 (83%) 6 (5%) 110 (89%) NR Low 0 4 (3%) 3 (2%) 7 (6%) Missing 0 4 (3%) 0 4 (3%) Total 2 (2%) 112 (91%) 9 (7%) 123 (100%) Visit 7 (Follow-up) 6 NR High 0 0 0 0 W/in NR 0 5 (83%) 0 5 (83%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 0 6 (100%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 59 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Neutrophils - percentage (%) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 4 (3%) 109 (88%) 2 (2%) 115 (93%) NR Low 0 2 (2%) 1 (<1%) 3 (2%) Missing 0 5 (4%) 0 5 (4%) Total 4 (3%) 117 (94%) 3 (2%) 124 (100%) Visit 7 (Follow-up) 11 NR High 0 0 0 0 W/in NR 0 10 (91%) 0 10 (91%) NR Low 0 1 (9%) 0 1 (9%) Missing 0 0 0 0 Total 0 11 (100%) 0 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 60 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Neutrophils - percentage (%) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 120 NR High 0 2 (2%) 0 2 (2%) W/in NR 5 (4%) 103 (86%) 0 108 (90%) NR Low 0 3 (3%) 0 3 (3%) Missing 0 6 (5%) 1 (<1%) 7 (6%) Total 5 (4%) 114 (95%) 1 (<1%) 120 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 9 (64%) 1 (7%) 10 (71%) NR Low 0 1 (7%) 0 1 (7%) Missing 0 3 (21%) 0 3 (21%) Total 0 13 (93%) 1 (7%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 61 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Platelets (GI/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 0 2 (2%) 0 2 (2%) W/in NR 1 (<1%) 95 (90%) 0 96 (91%) NR Low 0 1 (<1%) 1 (<1%) 2 (2%) Missing 0 6 (6%) 0 6 (6%) Total 1 (<1%) 104 (98%) 1 (<1%) 106 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 1 (7%) 13 (93%) 0 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 1 (7%) 13 (93%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 62 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Platelets (GI/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 0 0 0 W/in NR 0 120 (97%) 0 120 (97%) NR Low 0 0 0 0 Missing 0 4 (3%) 0 4 (3%) Total 0 124 (100%) 0 124 (100%) Visit 7 (Follow-up) 6 NR High 0 0 0 0 W/in NR 0 5 (83%) 0 5 (83%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 0 6 (100%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 63 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Platelets (GI/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 1 (<1%) 5 (4%) 0 6 (5%) W/in NR 2 (2%) 113 (90%) 0 115 (91%) NR Low 0 1 (<1%) 0 1 (<1%) Missing 0 4 (3%) 0 4 (3%) Total 3 (2%) 123 (98%) 0 126 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 12 (100%) 0 12 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 64 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Platelets (GI/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 0 118 (95%) 0 118 (95%) NR Low 0 1 (<1%) 0 1 (<1%) Missing 0 4 (3%) 0 4 (3%) Total 0 124 (100%) 0 124 (100%) Visit 7 (Follow-up) 14 NR High 0 1 (7%) 0 1 (7%) W/in NR 0 12 (86%) 0 12 (86%) NR Low 0 0 0 0 Missing 0 1 (7%) 0 1 (7%) Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 65 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Red Blood Cell Count (TI/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 108 NR High 2 (2%) 2 (2%) 0 4 (4%) W/in NR 1 (<1%) 90 (83%) 5 (5%) 96 (89%) NR Low 0 1 (<1%) 2 (2%) 3 (3%) Missing 0 5 (5%) 0 5 (5%) Total 3 (3%) 98 (91%) 7 (6%) 108 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 1 (7%) 13 (93%) 0 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 1 (7%) 13 (93%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 66 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Red Blood Cell Count (TI/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 5 (4%) 2 (2%) 0 7 (6%) W/in NR 0 109 (87%) 3 (2%) 112 (90%) NR Low 0 0 2 (2%) 2 (2%) Missing 0 4 (3%) 0 4 (3%) Total 5 (4%) 115 (92%) 5 (4%) 125 (100%) Visit 7 (Follow-up) 7 NR High 0 0 0 0 W/in NR 0 6 (86%) 0 6 (86%) NR Low 0 0 0 0 Missing 0 1 (14%) 0 1 (14%) Total 0 7 (100%) 0 7 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 67 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Red Blood Cell Count (TI/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 3 (2%) 1 (<1%) 0 4 (3%) W/in NR 0 110 (87%) 2 (2%) 112 (88%) NR Low 0 4 (3%) 4 (3%) 8 (6%) Missing 0 3 (2%) 0 3 (2%) Total 3 (2%) 118 (93%) 6 (5%) 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 12 (100%) 0 12 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 68 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Red Blood Cell Count (TI/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 125 NR High 2 (2%) 3 (2%) 0 5 (4%) W/in NR 1 (<1%) 113 (90%) 1 (<1%) 115 (92%) NR Low 0 0 1 (<1%) 1 (<1%) Missing 0 4 (3%) 0 4 (3%) Total 3 (2%) 120 (96%) 2 (2%) 125 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 1 (7%) 10 (71%) 1 (7%) 12 (86%) NR Low 0 1 (7%) 0 1 (7%) Missing 0 1 (7%) 0 1 (7%) Total 1 (7%) 12 (86%) 1 (7%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 69 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Segmented Neutrophils - percentage (%) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 2 (2%) 88 (83%) 2 (2%) 92 (87%) NR Low 0 1 (<1%) 3 (3%) 4 (4%) Missing 0 7 (7%) 2 (2%) 9 (8%) Total 2 (2%) 97 (92%) 7 (7%) 106 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 3 (21%) 11 (79%) 0 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 3 (21%) 11 (79%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 70 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Segmented Neutrophils - percentage (%) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 123 NR High 0 2 (2%) 0 2 (2%) W/in NR 2 (2%) 102 (83%) 6 (5%) 110 (89%) NR Low 0 4 (3%) 3 (2%) 7 (6%) Missing 0 4 (3%) 0 4 (3%) Total 2 (2%) 112 (91%) 9 (7%) 123 (100%) Visit 7 (Follow-up) 6 NR High 0 0 0 0 W/in NR 0 5 (83%) 0 5 (83%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 0 6 (100%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 71 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Segmented Neutrophils - percentage (%) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 4 (3%) 109 (88%) 2 (2%) 115 (93%) NR Low 0 2 (2%) 1 (<1%) 3 (2%) Missing 0 5 (4%) 0 5 (4%) Total 4 (3%) 117 (94%) 3 (2%) 124 (100%) Visit 7 (Follow-up) 11 NR High 0 0 0 0 W/in NR 0 10 (91%) 0 10 (91%) NR Low 0 1 (9%) 0 1 (9%) Missing 0 0 0 0 Total 0 11 (100%) 0 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 72 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: Segmented Neutrophils - percentage (%) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 120 NR High 0 2 (2%) 0 2 (2%) W/in NR 5 (4%) 103 (86%) 0 108 (90%) NR Low 0 3 (3%) 0 3 (3%) Missing 0 6 (5%) 1 (<1%) 7 (6%) Total 5 (4%) 114 (95%) 1 (<1%) 120 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 9 (64%) 1 (7%) 10 (71%) NR Low 0 1 (7%) 0 1 (7%) Missing 0 3 (21%) 0 3 (21%) Total 0 13 (93%) 1 (7%) 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 73 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: White Blood Cell Count (GI/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 106 NR High 0 3 (3%) 0 3 (3%) W/in NR 5 (5%) 87 (82%) 1 (<1%) 93 (88%) NR Low 0 0 1 (<1%) 1 (<1%) Missing 0 9 (8%) 0 9 (8%) Total 5 (5%) 99 (93%) 2 (2%) 106 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 2 (14%) 12 (86%) 0 14 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 2 (14%) 12 (86%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 74 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: White Blood Cell Count (GI/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 2 (2%) 0 2 (2%) W/in NR 2 (2%) 111 (90%) 4 (3%) 117 (94%) NR Low 0 1 (<1%) 0 1 (<1%) Missing 0 4 (3%) 0 4 (3%) Total 2 (2%) 118 (95%) 4 (3%) 124 (100%) Visit 7 (Follow-up) 6 NR High 0 0 0 0 W/in NR 0 5 (83%) 0 5 (83%) NR Low 0 0 0 0 Missing 0 1 (17%) 0 1 (17%) Total 0 6 (100%) 0 6 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 75 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: White Blood Cell Count (GI/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 124 NR High 0 2 (2%) 0 2 (2%) W/in NR 2 (2%) 109 (88%) 3 (2%) 114 (92%) NR Low 0 2 (2%) 1 (<1%) 3 (2%) Missing 0 5 (4%) 0 5 (4%) Total 2 (2%) 118 (95%) 4 (3%) 124 (100%) Visit 7 (Follow-up) 11 NR High 0 0 0 0 W/in NR 0 11 (100%) 0 11 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 11 (100%) 0 11 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 76 of 76 Population: Safety Table 8.21 Summary of Haematology Laboratory Shifts From Baseline Lab Test: White Blood Cell Count (GI/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 121 NR High 2 (2%) 5 (4%) 0 7 (6%) W/in NR 6 (5%) 99 (82%) 0 105 (87%) NR Low 0 1 (<1%) 1 (<1%) 2 (2%) Missing 0 6 (5%) 1 (<1%) 7 (6%) Total 8 (7%) 111 (92%) 2 (2%) 121 (100%) Visit 7 (Follow-up) 14 NR High 0 0 0 0 W/in NR 0 11 (79%) 0 11 (79%) NR Low 0 0 0 0 Missing 0 3 (21%) 0 3 (21%) Total 0 14 (100%) 0 14 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 1 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Alanine Aminotransferase (IU/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 25.0 19.33 20.0 5 136 Week 4 114 24.4 21.12 20.0 6 174 Visit 7 15 22.7 24.92 16.0 11 111 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 22.3 14.14 19.0 4 119 Week 4 126 21.8 13.60 18.0 8 70 Visit 7 8 26.5 14.11 22.0 10 48 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 22.3 16.49 18.0 6 152 Week 4 130 21.6 14.20 17.0 7 81 Visit 7 10 24.0 15.00 16.0 9 46 (Follow- up) GW685698X 250mcg PM 141 Baseline 138 25.1 26.49 19.0 7 282 Week 4 127 24.2 26.23 19.0 6 274 Visit 7 12 24.2 17.80 20.0 10 74 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 2 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Albumin (G/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 46.6 3.09 47.0 40 53 Week 4 115 46.5 3.03 47.0 39 54 Visit 7 15 46.7 3.56 46.0 40 52 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 47.0 3.38 47.0 39 55 Week 4 127 46.6 3.45 46.0 39 63 Visit 7 8 44.6 3.29 45.0 40 49 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 46.4 3.43 46.0 37 57 Week 4 130 46.1 3.30 46.0 38 54 Visit 7 10 46.3 3.47 47.0 37 49 (Follow- up) GW685698X 250mcg PM 141 Baseline 139 46.2 3.17 47.0 36 54 Week 4 127 46.6 2.98 47.0 39 53 Visit 7 12 45.5 1.68 46.0 42 48 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 3 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Alkaline Phosphatase (IU/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 65.2 22.56 62.0 28 163 Week 4 115 63.9 21.20 61.0 27 160 Visit 7 15 65.7 21.79 61.0 40 109 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 67.3 24.92 62.0 33 228 Week 4 126 64.9 22.49 61.0 28 211 Visit 7 8 70.9 22.97 68.0 46 116 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 66.8 23.03 62.0 28 154 Week 4 131 66.9 24.99 62.0 27 161 Visit 7 10 56.0 26.46 51.0 32 127 (Follow- up) GW685698X 250mcg PM 141 Baseline 138 70.1 31.86 63.5 32 338 Week 4 127 70.3 33.76 65.0 31 353 Visit 7 12 61.4 22.12 57.5 30 101 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 4 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Aspartate Aminotransferase (IU/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 22.0 7.62 20.0 10 61 Week 4 115 22.2 9.18 20.0 12 73 Visit 7 15 19.9 6.35 18.0 13 37 (Follow- up) GW685698X 100mcg AM 143 Baseline 142 21.0 7.08 19.0 9 59 Week 4 126 21.0 8.02 19.0 10 48 Visit 7 8 22.1 7.32 20.5 13 34 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 21.4 8.45 19.0 9 81 Week 4 130 20.7 7.04 19.0 9 49 Visit 7 10 21.8 5.37 22.0 13 32 (Follow- up) GW685698X 250mcg PM 141 Baseline 139 22.5 11.18 19.0 10 91 Week 4 127 22.1 11.11 19.0 11 102 Visit 7 12 22.0 6.98 18.5 16 34 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 5 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Bicarbonate (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 21.5 2.40 22.0 15 28 Week 4 115 21.7 2.45 22.0 16 28 Visit 7 15 22.3 3.26 22.0 17 28 (Follow- up) GW685698X 100mcg AM 143 Baseline 142 21.5 2.29 22.0 16 27 Week 4 126 21.9 2.40 22.0 15 26 Visit 7 8 21.5 2.51 21.0 18 26 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 21.7 2.15 22.0 17 25 Week 4 131 21.9 2.03 22.0 17 26 Visit 7 10 21.6 2.50 22.0 19 26 (Follow- up) GW685698X 250mcg PM 141 Baseline 139 21.7 2.41 22.0 15 27 Week 4 127 21.7 2.31 22.0 16 27 Visit 7 12 22.7 2.53 22.5 19 26 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 6 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Calcium (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 2.350 0.1178 2.350 2.02 2.70 Week 4 115 2.306 0.1187 2.320 1.77 2.59 Visit 7 15 2.341 0.1248 2.380 2.07 2.50 (Follow- up) GW685698X 100mcg AM 143 Baseline 142 2.370 0.1210 2.350 2.06 2.72 Week 4 126 2.311 0.1259 2.310 1.88 2.73 Visit 7 8 2.330 0.1309 2.325 2.13 2.55 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 2.349 0.1303 2.360 1.82 2.74 Week 4 131 2.318 0.1159 2.300 1.89 2.72 Visit 7 10 2.360 0.0789 2.350 2.23 2.48 (Follow- up) GW685698X 250mcg PM 141 Baseline 139 2.359 0.1085 2.350 2.09 2.72 Week 4 127 2.330 0.1234 2.320 2.04 2.89 Visit 7 12 2.355 0.1444 2.360 2.05 2.61 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 7 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Chloride (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 105.3 1.95 105.0 101 110 Week 4 115 105.4 2.51 105.0 99 112 Visit 7 15 102.8 2.46 103.0 98 107 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 105.2 2.35 105.0 99 112 Week 4 126 105.0 2.28 105.0 97 112 Visit 7 8 105.0 1.85 105.5 101 107 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 105.2 2.08 105.0 99 111 Week 4 131 104.9 2.23 105.0 92 110 Visit 7 10 104.7 1.16 105.0 103 106 (Follow- up) GW685698X 250mcg PM 141 Baseline 138 105.0 2.34 105.0 99 112 Week 4 127 104.8 2.44 105.0 99 113 Visit 7 12 104.6 2.47 105.0 102 109 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 8 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Creatinine (UMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 79.1 13.84 79.0 52 115 Week 4 114 82.2 14.65 80.5 50 127 Visit 7 15 75.4 10.95 75.0 59 94 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 79.7 15.15 78.0 50 123 Week 4 126 80.4 15.63 79.5 45 120 Visit 7 8 75.4 8.86 71.5 68 95 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 79.4 12.98 77.5 57 114 Week 4 130 79.7 13.36 78.0 53 109 Visit 7 10 78.5 15.23 81.5 57 102 (Follow- up) GW685698X 250mcg PM 141 Baseline 138 80.3 16.24 78.0 44 129 Week 4 127 80.4 16.42 79.0 44 128 Visit 7 12 74.4 12.65 73.5 58 110 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 9 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Gamma Glutamyl Transferase (IU/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 32.1 45.80 21.0 8 493 Week 4 115 33.8 55.36 22.0 6 572 Visit 7 15 24.1 23.18 16.0 8 95 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 25.9 16.28 21.0 7 110 Week 4 127 24.5 15.43 19.0 7 90 Visit 7 8 34.9 15.40 31.5 12 58 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 27.3 23.15 19.0 8 166 Week 4 130 26.2 22.77 19.0 7 155 Visit 7 10 27.7 16.26 23.5 10 56 (Follow- up) GW685698X 250mcg PM 141 Baseline 138 33.3 43.44 22.0 6 418 Week 4 127 32.8 54.33 21.0 8 576 Visit 7 12 91.4 140.16 31.5 8 439 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 10 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Globulin (G/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 28.3 3.82 28.0 20 38 Week 4 115 27.0 3.59 27.0 17 35 Visit 7 15 27.0 4.57 26.0 18 35 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 28.2 4.13 28.0 13 39 Week 4 126 26.9 4.24 27.0 17 37 Visit 7 8 27.6 4.84 27.5 21 35 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 28.3 3.89 28.0 18 40 Week 4 130 28.2 3.80 28.0 19 40 Visit 7 10 26.2 4.69 24.0 20 34 (Follow- up) GW685698X 250mcg PM 141 Baseline 139 29.1 4.42 29.0 16 42 Week 4 127 28.4 4.39 28.0 20 43 Visit 7 12 26.3 3.89 26.0 21 35 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 11 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Glucose (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 5.56 1.186 5.40 2.9 15.0 Week 4 115 5.44 1.491 5.30 2.6 17.5 Visit 7 15 5.17 0.588 5.00 3.9 6.2 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 5.41 0.901 5.30 3.2 11.6 Week 4 126 5.31 0.820 5.20 2.5 10.8 Visit 7 8 5.39 0.951 5.20 4.2 6.8 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 5.47 0.945 5.25 3.9 10.2 Week 4 131 5.30 0.842 5.20 3.2 8.5 Visit 7 10 5.35 0.805 5.50 4.3 6.8 (Follow- up) GW685698X 250mcg PM 141 Baseline 139 5.37 0.707 5.30 3.4 8.6 Week 4 127 5.34 0.892 5.20 3.6 9.0 Visit 7 12 5.83 1.111 5.80 4.1 8.0 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 12 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Phosphorus (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 1.096 0.1932 1.100 0.64 1.52 Week 4 115 1.127 0.2149 1.140 0.63 1.58 Visit 7 15 1.176 0.1563 1.160 0.81 1.46 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 1.128 0.1843 1.130 0.68 1.57 Week 4 126 1.169 0.2926 1.130 0.76 3.35 Visit 7 8 1.069 0.1928 1.075 0.80 1.39 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 1.114 0.1775 1.115 0.68 1.65 Week 4 131 1.148 0.1806 1.150 0.67 1.61 Visit 7 10 1.063 0.2127 1.070 0.66 1.35 (Follow- up) GW685698X 250mcg PM 141 Baseline 138 1.101 0.1846 1.095 0.67 1.77 Week 4 127 1.132 0.1833 1.130 0.75 1.63 Visit 7 12 1.212 0.2384 1.260 0.67 1.54 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 13 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Potassium (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 4.48 0.571 4.40 3.6 9.0 Week 4 115 4.48 0.471 4.40 3.6 5.9 Visit 7 15 4.32 0.468 4.20 3.8 5.3 (Follow- up) GW685698X 100mcg AM 143 Baseline 142 4.44 0.436 4.40 3.7 6.4 Week 4 126 4.51 0.622 4.40 3.4 7.6 Visit 7 8 4.53 0.518 4.35 3.9 5.4 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 4.44 0.438 4.40 3.6 6.1 Week 4 131 4.45 0.377 4.40 3.7 5.4 Visit 7 10 4.39 0.238 4.35 4.0 4.8 (Follow- up) GW685698X 250mcg PM 141 Baseline 139 4.42 0.392 4.40 3.5 5.6 Week 4 127 4.39 0.376 4.30 3.7 5.6 Visit 7 12 4.45 0.493 4.40 3.9 5.8 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 14 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Sodium (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 141.3 1.96 141.0 137 148 Week 4 115 141.1 2.57 141.0 134 150 Visit 7 15 139.5 1.85 140.0 136 142 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 141.6 2.24 141.0 137 152 Week 4 126 140.9 2.33 141.0 136 151 Visit 7 8 140.6 2.72 140.0 137 144 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 141.4 1.98 141.0 137 148 Week 4 131 140.7 2.54 141.0 129 151 Visit 7 10 140.2 1.99 140.0 138 143 (Follow- up) GW685698X 250mcg PM 141 Baseline 137 141.4 2.46 141.0 134 149 Week 4 127 141.1 2.52 141.0 135 150 Visit 7 12 140.5 2.97 139.5 137 147 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 15 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Total Bilirubin (UMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 10.4 4.06 10.0 3 29 Week 4 115 9.9 3.85 9.0 3 29 Visit 7 15 11.3 3.92 10.0 5 20 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 11.6 7.14 10.0 5 62 Week 4 127 10.4 5.34 9.0 3 37 Visit 7 8 9.6 2.67 9.0 6 14 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 10.5 4.22 9.0 3 27 Week 4 131 10.2 4.36 9.0 4 26 Visit 7 10 10.7 5.01 9.0 4 19 (Follow- up) GW685698X 250mcg PM 141 Baseline 138 10.6 5.24 9.0 4 34 Week 4 127 10.9 6.12 9.0 5 54 Visit 7 12 9.4 6.16 8.0 4 26 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 16 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Total Protein (G/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 75.0 4.70 75.0 66 88 Week 4 115 73.5 4.38 74.0 64 84 Visit 7 15 73.7 4.47 74.0 66 80 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 75.2 5.08 75.0 62 89 Week 4 126 73.6 5.23 73.0 62 95 Visit 7 8 72.3 4.33 71.5 68 79 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 74.7 4.74 74.0 63 88 Week 4 131 74.2 4.77 74.0 60 86 Visit 7 10 72.5 4.14 72.0 66 79 (Follow- up) GW685698X 250mcg PM 141 Baseline 139 75.4 4.56 76.0 66 87 Week 4 127 75.0 4.54 75.0 65 91 Visit 7 12 71.8 3.69 71.0 68 81 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 17 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Urea (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 4.83 1.298 4.70 2.2 9.6 Week 4 115 4.83 1.374 4.70 2.0 11.3 Visit 7 15 4.31 1.114 4.20 2.7 6.5 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 4.86 1.380 4.60 2.1 11.0 Week 4 127 4.64 1.395 4.40 2.2 9.1 Visit 7 8 4.04 0.880 4.35 2.4 5.2 (Follow- up) GW685698X 100mcg PM 148 Baseline 146 4.68 1.253 4.50 2.1 8.0 Week 4 131 4.77 1.174 4.80 2.0 8.9 Visit 7 10 5.21 1.190 5.25 2.9 6.6 (Follow- up) GW685698X 250mcg PM 141 Baseline 139 5.03 1.413 4.80 2.0 9.5 Week 4 127 4.96 1.386 4.80 2.3 9.1 Visit 7 12 4.57 1.504 4.80 2.7 7.0 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 18 of 18 Population: Safety Table 8.22 Summary of Clinical Chemistry Data Lab Test: Uric Acid (UMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Baseline 141 287.0 82.08 285.0 110 500 Week 4 115 292.5 82.70 287.0 132 520 Visit 7 15 273.1 98.41 262.0 113 483 (Follow- up) GW685698X 100mcg AM 143 Baseline 143 295.6 85.16 288.0 121 480 Week 4 126 287.2 82.58 277.0 131 502 Visit 7 8 314.8 67.42 322.0 228 412 (Follow- up) GW685698X 100mcg PM 148 Baseline 145 287.4 82.52 285.0 130 514 Week 4 129 284.1 86.71 281.0 139 536 Visit 7 10 254.2 78.60 247.0 160 409 (Follow- up) GW685698X 250mcg PM 141 Baseline 138 303.6 90.39 297.5 119 664 Week 4 127 289.1 79.35 280.0 120 536 Visit 7 12 296.7 104.43 282.0 179 500 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 1 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Alanine Aminotransferase (IU/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 113 -2.0 13.98 -1.0 -83 59 Visit 7 15 -0.9 4.22 -2.0 -8 11 (Follow- up) GW685698X 100mcg AM 143 Week 4 126 -0.8 12.08 -1.0 -50 48 Visit 7 8 2.5 4.75 1.5 -3 10 (Follow- up) GW685698X 100mcg PM 148 Week 4 129 -0.9 11.60 -1.0 -71 56 Visit 7 10 -2.1 5.45 0.0 -12 4 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -1.5 9.51 0.0 -44 29 Visit 7 11 -1.1 5.26 -1.0 -11 7 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 2 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Albumin (G/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -0.2 2.51 0.0 -5 7 Visit 7 15 -0.1 1.64 0.0 -2 4 (Follow- up) GW685698X 100mcg AM 143 Week 4 127 -0.4 2.55 0.0 -11 9 Visit 7 8 -2.1 1.36 -1.5 -4 -1 (Follow- up) GW685698X 100mcg PM 148 Week 4 129 -0.4 2.94 0.0 -10 7 Visit 7 10 -0.6 2.67 -0.5 -4 4 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 0.2 2.30 0.0 -6 8 Visit 7 11 -1.3 2.69 -2.0 -5 3 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 3 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Alkaline Phosphatase (IU/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -1.1 10.91 -1.0 -60 49 Visit 7 15 3.3 7.05 5.0 -11 20 (Follow- up) GW685698X 100mcg AM 143 Week 4 126 -1.7 9.26 -1.0 -45 21 Visit 7 8 1.8 10.07 1.5 -17 18 (Follow- up) GW685698X 100mcg PM 148 Week 4 130 -0.8 10.72 -1.5 -33 35 Visit 7 10 -1.7 7.97 -0.5 -20 8 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.0 8.64 -1.0 -18 54 Visit 7 11 -2.0 8.88 -2.0 -14 15 (Follow- up) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 4 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Aspartate Aminotransferase (IU/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -0.2 6.78 -0.5 -26 31 Visit 7 15 -0.5 3.76 0.0 -5 6 (Follow- up) GW685698X 100mcg AM 143 Week 4 125 -0.2 7.25 0.0 -29 24 Visit 7 8 -0.5 3.82 -0.5 -6 5 (Follow- up) GW685698X 100mcg PM 148 Week 4 129 -0.8 5.90 -1.0 -38 17 Visit 7 10 -2.0 5.10 -1.0 -15 3 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.6 8.12 0.0 -52 46 Visit 7 11 -1.8 4.90 -1.0 -14 5 (Follow- up) Note: Baseline is the final run-in visit

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FFA20001

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Protocol: FFA20001 Page 5 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Bicarbonate (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 0.1 2.58 0.0 -6 8 Visit 7 15 0.2 3.67 0.0 -9 6 (Follow- up) GW685698X 100mcg AM 143 Week 4 125 0.3 2.65 0.0 -6 7 Visit 7 8 0.4 1.51 0.5 -2 3 (Follow- up) GW685698X 100mcg PM 148 Week 4 130 0.2 2.42 0.0 -6 7 Visit 7 10 0.7 2.83 0.5 -4 5 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.2 2.46 0.0 -7 6 Visit 7 11 1.0 1.55 1.0 -1 4 (Follow- up) Note: Baseline is the final run-in visit

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FFA20001

388

Protocol: FFA20001 Page 6 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Calcium (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -0.0 0.14 -0.0 -1 0 Visit 7 15 -0.0 0.14 -0.0 -0 0 (Follow- up) GW685698X 100mcg AM 143 Week 4 125 -0.1 0.14 -0.0 -1 0 Visit 7 8 -0.0 0.14 -0.0 -0 0 (Follow- up) GW685698X 100mcg PM 148 Week 4 130 -0.0 0.12 -0.0 -0 1 Visit 7 10 -0.0 0.10 -0.0 -0 0 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.0 0.10 -0.0 -0 0 Visit 7 11 -0.0 0.09 -0.0 -0 0 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

389

Protocol: FFA20001 Page 7 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Chloride (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 0.0 2.65 0.0 -7 7 Visit 7 15 -2.4 1.55 -2.0 -5 1 (Follow- up) GW685698X 100mcg AM 143 Week 4 126 -0.2 2.62 0.0 -15 4 Visit 7 8 0.3 1.75 0.5 -2 2 (Follow- up) GW685698X 100mcg PM 148 Week 4 130 -0.3 2.48 0.0 -7 6 Visit 7 10 -0.1 2.42 0.0 -4 3 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.1 2.54 0.0 -5 7 Visit 7 11 0.1 2.77 0.0 -5 4 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

390

Protocol: FFA20001 Page 8 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Creatinine (UMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 113 2.1 10.76 2.0 -24 35 Visit 7 15 -3.0 9.35 -2.0 -17 16 (Follow- up) GW685698X 100mcg AM 143 Week 4 126 0.1 10.19 1.0 -47 27 Visit 7 8 2.0 7.17 1.5 -9 11 (Follow- up) GW685698X 100mcg PM 148 Week 4 129 0.2 8.44 0.0 -37 19 Visit 7 10 -1.2 6.43 0.0 -9 11 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.4 8.90 0.0 -27 28 Visit 7 11 -2.9 9.38 -3.0 -19 11 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

391

Protocol: FFA20001 Page 9 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Gamma Glutamyl Transferase (IU/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -0.9 17.46 -0.5 -114 79 Visit 7 15 -2.7 6.45 0.0 -17 3 (Follow- up) GW685698X 100mcg AM 143 Week 4 127 -1.7 12.21 -1.0 -93 37 Visit 7 8 2.9 8.17 1.0 -8 14 (Follow- up) GW685698X 100mcg PM 148 Week 4 129 -1.4 13.21 0.0 -65 49 Visit 7 10 -0.7 5.46 -0.5 -9 11 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.7 22.02 0.0 -146 158 Visit 7 11 5.3 14.71 2.0 -10 41 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

392

Protocol: FFA20001 Page 10 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Globulin (G/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -1.1 3.28 -1.0 -10 8 Visit 7 15 -0.5 3.70 -1.0 -6 9 (Follow- up) GW685698X 100mcg AM 143 Week 4 126 -1.0 3.23 -1.0 -13 7 Visit 7 8 -1.1 1.46 -1.0 -4 1 (Follow- up) GW685698X 100mcg PM 148 Week 4 129 -0.4 3.22 0.0 -9 8 Visit 7 10 -1.7 2.63 -2.5 -5 4 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.9 3.03 -1.0 -8 9 Visit 7 11 -1.1 3.70 -2.0 -7 4 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

393

Protocol: FFA20001 Page 11 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Glucose (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -0.1 1.18 -0.1 -4 9 Visit 7 15 0.1 0.58 0.4 -1 1 (Follow- up) GW685698X 100mcg AM 143 Week 4 126 -0.2 0.62 -0.1 -2 2 Visit 7 8 0.0 0.99 0.3 -2 1 (Follow- up) GW685698X 100mcg PM 148 Week 4 130 -0.2 1.03 -0.1 -4 3 Visit 7 10 -0.5 1.17 -0.1 -3 1 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.0 0.83 -0.1 -2 4 Visit 7 11 0.1 1.10 -0.3 -1 2 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

394

Protocol: FFA20001 Page 12 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Phosphorus (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 0.0 0.18 0.0 -0 1 Visit 7 15 0.1 0.23 0.0 -0 0 (Follow- up) GW685698X 100mcg AM 143 Week 4 126 0.1 0.25 0.0 -0 2 Visit 7 8 -0.0 0.14 -0.0 -0 0 (Follow- up) GW685698X 100mcg PM 148 Week 4 130 0.0 0.16 0.0 -0 1 Visit 7 10 -0.0 0.18 0.0 -0 0 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 0.0 0.18 0.0 -1 0 Visit 7 11 0.1 0.23 0.1 -0 0 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

395

Protocol: FFA20001 Page 13 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Potassium (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -0.0 0.67 0.0 -4 2 Visit 7 15 -0.1 0.23 -0.1 -1 0 (Follow- up) GW685698X 100mcg AM 143 Week 4 125 0.1 0.54 0.0 -2 2 Visit 7 8 -0.2 0.58 -0.3 -1 0 (Follow- up) GW685698X 100mcg PM 148 Week 4 130 -0.0 0.51 0.0 -2 1 Visit 7 10 -0.1 0.33 -0.1 -1 0 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.0 0.46 -0.1 -2 2 Visit 7 11 0.2 0.65 0.2 -1 2 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

396

Protocol: FFA20001 Page 14 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Sodium (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -0.2 2.87 0.0 -9 7 Visit 7 15 -1.7 2.82 -1.0 -9 1 (Follow- up) GW685698X 100mcg AM 143 Week 4 126 -0.7 2.65 0.0 -10 8 Visit 7 8 -0.4 1.69 -1.0 -3 2 (Follow- up) GW685698X 100mcg PM 148 Week 4 130 -0.6 2.87 0.0 -11 8 Visit 7 10 -0.4 1.96 -0.5 -3 3 (Follow- up) GW685698X 250mcg PM 141 Week 4 125 -0.2 2.71 0.0 -9 6 Visit 7 11 -0.5 2.21 -1.0 -4 3 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

397

Protocol: FFA20001 Page 15 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Total Bilirubin (UMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -0.3 3.65 0.0 -13 14 Visit 7 15 0.0 3.84 0.0 -9 8 (Follow- up) GW685698X 100mcg AM 143 Week 4 127 -1.5 7.61 -1.0 -52 26 Visit 7 8 -0.4 2.97 0.0 -6 3 (Follow- up) GW685698X 100mcg PM 148 Week 4 130 -0.3 3.41 0.0 -10 10 Visit 7 10 0.4 3.81 -1.0 -4 8 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 0.1 5.33 0.0 -16 44 Visit 7 11 -0.6 2.91 -2.0 -4 5 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

398

Protocol: FFA20001 Page 16 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Total Protein (G/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -1.4 4.00 -1.0 -15 10 Visit 7 15 -0.6 4.22 0.0 -8 9 (Follow- up) GW685698X 100mcg AM 143 Week 4 126 -1.3 4.17 -1.0 -15 15 Visit 7 8 -3.3 2.55 -3.0 -8 0 (Follow- up) GW685698X 100mcg PM 148 Week 4 130 -0.8 4.47 -1.0 -11 12 Visit 7 10 -2.3 4.16 -2.5 -9 5 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.7 3.82 -1.0 -10 8 Visit 7 11 -2.4 5.41 -2.0 -10 5 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

399

Protocol: FFA20001 Page 17 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Urea (MMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -0.0 1.46 0.0 -4 7 Visit 7 15 -0.2 1.38 -0.4 -3 3 (Follow- up) GW685698X 100mcg AM 143 Week 4 127 -0.2 1.40 -0.2 -7 5 Visit 7 8 0.0 0.88 0.0 -1 2 (Follow- up) GW685698X 100mcg PM 148 Week 4 130 0.1 1.17 0.1 -3 3 Visit 7 10 0.2 1.03 0.0 -1 2 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -0.1 1.24 -0.1 -4 3 Visit 7 11 -0.7 0.96 -0.5 -3 1 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

400

Protocol: FFA20001 Page 18 of 18 Population: Safety Table 8.23 Summary of Clinical Chemistry Data Change from Baseline Lab Test: Uric Acid (UMOL/L) Treatment N Visit n Mean SD Median Min. Max. ---------------------------------------------------------------------------------- Placebo 143 Week 4 114 -0.3 44.24 -0.5 -91 188 Visit 7 15 -15.7 62.44 -16.0 -120 146 (Follow- up) GW685698X 100mcg AM 143 Week 4 126 -9.2 42.96 -9.5 -195 106 Visit 7 8 8.1 27.63 14.0 -50 40 (Follow- up) GW685698X 100mcg PM 148 Week 4 128 -5.2 50.39 -8.5 -234 205 Visit 7 10 -20.8 46.57 -19.5 -87 37 (Follow- up) GW685698X 250mcg PM 141 Week 4 126 -14.6 51.49 -15.0 -249 190 Visit 7 11 -13.6 49.24 -20.0 -100 82 (Follow- up) Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

401

Protocol: FFA20001 Page 1 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Alanine Aminotransferase (IU/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 138 > ref. range high 0 0 1 (<1%) 1 (<1%) Week 4 n 114 126 130 127 > ref. range high 1 (<1%) 0 0 1 (<1%) Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 Any Visit Post Baseline n 124 130 135 131 > ref. range high 1 (<1%) 0 0 1 (<1%) Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

402

Protocol: FFA20001 Page 2 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Albumin (G/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 139 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Week 4 n 115 127 130 127 > ref. range high 0 1 (<1%) 0 0 < ref. range low 0 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 125 131 135 131 > ref. range high 0 1 (<1%) 0 0 < ref. range low 0 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

403

Protocol: FFA20001 Page 3 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Alkaline Phosphatase (IU/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 138 > ref. range high 0 0 0 0 Week 4 n 115 126 131 127 > ref. range high 0 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 Any Visit Post Baseline n 125 130 136 131 > ref. range high 0 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

404

Protocol: FFA20001 Page 4 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Aspartate Aminotransferase (IU/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 142 146 139 > ref. range high 0 0 0 0 Week 4 n 115 126 130 127 > ref. range high 0 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 Any Visit Post Baseline n 125 130 135 131 > ref. range high 0 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

405

Protocol: FFA20001 Page 5 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Bicarbonate (MMOL/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 142 146 139 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Week 4 n 115 126 131 127 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 125 130 136 131 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

406

Protocol: FFA20001 Page 6 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Calcium (MMOL/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 142 146 139 > ref. range high 0 0 0 0 < ref. range low 0 0 1 (<1%) 0 Week 4 n 115 126 131 127 > ref. range high 0 0 0 1 (<1%) < ref. range low 2 (2%) 1 (<1%) 1 (<1%) 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 125 130 136 131 > ref. range high 0 0 0 1 (<1%) < ref. range low 2 (2%) 1 (<1%) 1 (<1%) 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

407

Protocol: FFA20001 Page 7 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Chloride (MMOL/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 138 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Week 4 n 115 126 131 127 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 125 130 136 131 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

408

Protocol: FFA20001 Page 8 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Creatinine (UMOL/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 138 > ref. range high 0 0 0 0 Week 4 n 114 126 130 127 > ref. range high 0 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 Any Visit Post Baseline n 124 130 135 131 > ref. range high 0 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

409

Protocol: FFA20001 Page 9 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Gamma Glutamyl Transferase (IU/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 138 > ref. range high 2 (1%) 0 1 (<1%) 2 (1%) Week 4 n 115 127 130 127 > ref. range high 1 (<1%) 0 1 (<1%) 2 (2%) Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 2 (17%) Any Visit Post Baseline n 125 131 135 131 > ref. range high 1 (<1%) 0 1 (<1%) 2 (2%) Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

410

Protocol: FFA20001 Page 10 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Globulin (G/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 139 > ref. range high 0 0 0 0 < ref. range low 0 2 (1%) 2 (1%) 2 (1%) Week 4 n 115 126 130 127 > ref. range high 0 0 0 0 < ref. range low 2 (2%) 2 (2%) 3 (2%) 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 < ref. range low 1 (7%) 0 0 0 Any Visit Post Baseline n 125 130 135 131 > ref. range high 0 0 0 0 < ref. range low 2 (2%) 3 (2%) 3 (2%) 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

411

Protocol: FFA20001 Page 11 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Glucose (MMOL/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 139 > ref. range high 2 (1%) 1 (<1%) 0 0 < ref. range low 1 (<1%) 0 0 0 Week 4 n 115 126 131 127 > ref. range high 1 (<1%) 1 (<1%) 0 0 < ref. range low 1 (<1%) 1 (<1%) 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 125 130 136 131 > ref. range high 1 (<1%) 1 (<1%) 0 0 < ref. range low 1 (<1%) 1 (<1%) 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

412

Protocol: FFA20001 Page 12 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Phosphorus (MMOL/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 138 > ref. range high 0 0 0 0 < ref. range low 1 (<1%) 0 0 0 Week 4 n 115 126 131 127 > ref. range high 0 2 (2%) 0 0 < ref. range low 1 (<1%) 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 125 130 136 131 > ref. range high 0 2 (2%) 0 0 < ref. range low 1 (<1%) 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

413

Protocol: FFA20001 Page 13 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Potassium (MMOL/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 142 146 139 > ref. range high 2 (1%) 1 (<1%) 2 (1%) 0 < ref. range low 0 0 0 0 Week 4 n 115 126 131 127 > ref. range high 1 (<1%) 4 (3%) 0 0 < ref. range low 0 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 125 130 136 131 > ref. range high 1 (<1%) 4 (3%) 0 0 < ref. range low 0 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

414

Protocol: FFA20001 Page 14 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Sodium (MMOL/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 137 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Week 4 n 115 126 131 127 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 125 130 136 131 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

415

Protocol: FFA20001 Page 15 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Total Bilirubin (UMOL/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 138 > ref. range high 0 2 (1%) 0 0 Week 4 n 115 127 131 127 > ref. range high 0 1 (<1%) 0 1 (<1%) Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 Any Visit Post Baseline n 125 131 136 131 > ref. range high 0 1 (<1%) 0 1 (<1%) Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

416

Protocol: FFA20001 Page 16 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Total Protein (G/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 139 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Week 4 n 115 126 131 127 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Any Visit Post Baseline n 125 130 136 131 > ref. range high 0 0 0 0 < ref. range low 0 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

FFA20001

417

Protocol: FFA20001 Page 17 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Urea (MMOL/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 146 139 > ref. range high 0 1 (<1%) 0 0 Week 4 n 115 127 131 127 > ref. range high 1 (<1%) 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 Any Visit Post Baseline n 125 131 136 131 > ref. range high 1 (<1%) 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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M2004/00341/00

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Protocol: FFA20001 Page 18 of 18 Population: Safety Table 8.24 Summary of Clinical Chemistry Data Outside the Reference Range Lab Test: Uric Acid (UMOL/L) GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) ----------------------------------------------------------------------------------------- Baseline n 141 143 145 138 > ref. range high 0 0 0 1 (<1%) Week 4 n 115 126 129 127 > ref. range high 0 0 0 0 Visit 7 (Follow-up) n 15 8 10 12 > ref. range high 0 0 0 0 Any Visit Post Baseline n 125 130 134 131 > ref. range high 0 0 0 0 Note: Any visit post baseline includes all on-treatment visits including unscheduled visits Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 1 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Alanine Aminotransferase (IU/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 114 NR High 6 (5%) 2 (2%) 0 8 (7%) W/in NR 2 (2%) 103 (90%) 0 105 (92%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 8 (7%) 106 (93%) 0 114 (100%) Visit 7 (Follow-up) 15 NR High 1 (7%) 0 0 1 (7%) W/in NR 0 14 (93%) 0 14 (93%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 1 (7%) 14 (93%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 2 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Alanine Aminotransferase (IU/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 2 (2%) 2 (2%) 0 4 (3%) W/in NR 6 (5%) 116 (92%) 0 122 (97%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 8 (6%) 118 (94%) 0 126 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 8 (100%) 0 8 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 3 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Alanine Aminotransferase (IU/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 130 NR High 5 (4%) 5 (4%) 0 10 (8%) W/in NR 3 (2%) 116 (89%) 0 119 (92%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 8 (6%) 122 (94%) 0 130 (100%) Visit 7 (Follow-up) 10 NR High 0 2 (20%) 0 2 (20%) W/in NR 0 8 (80%) 0 8 (80%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 4 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Alanine Aminotransferase (IU/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 7 (6%) 5 (4%) 0 12 (9%) W/in NR 0 114 (90%) 0 114 (90%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 7 (6%) 120 (94%) 0 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 11 (92%) 0 11 (92%) NR Low 0 0 0 0 Missing 1 (8%) 0 0 1 (8%) Total 1 (8%) 11 (92%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 5 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Albumin (G/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 2 (2%) 12 (10%) 0 14 (12%) W/in NR 8 (7%) 92 (80%) 0 100 (87%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 10 (9%) 105 (91%) 0 115 (100%) Visit 7 (Follow-up) 15 NR High 3 (20%) 2 (13%) 0 5 (33%) W/in NR 0 10 (67%) 0 10 (67%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 3 (20%) 12 (80%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 6 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Albumin (G/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 12 (9%) 8 (6%) 0 20 (16%) W/in NR 6 (5%) 101 (80%) 0 107 (84%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 18 (14%) 109 (86%) 0 127 (100%) Visit 7 (Follow-up) 8 NR High 0 1 (13%) 0 1 (13%) W/in NR 0 7 (88%) 0 7 (88%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 7 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Albumin (G/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 130 NR High 6 (5%) 8 (6%) 0 14 (11%) W/in NR 9 (7%) 106 (82%) 0 115 (88%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 15 (12%) 115 (88%) 0 130 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 10 (100%) 0 10 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 8 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Albumin (G/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 4 (3%) 6 (5%) 0 10 (8%) W/in NR 9 (7%) 107 (84%) 0 116 (91%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 13 (10%) 114 (90%) 0 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 11 (92%) 0 11 (92%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 9 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Alkaline Phosphatase (IU/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 0 0 0 0 W/in NR 0 114 (>99%) 0 114 (>99%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 0 115 (100%) 0 115 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 0 15 (100%) 0 15 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 15 (100%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 10 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Alkaline Phosphatase (IU/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 0 125 (>99%) 0 125 (>99%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 126 (100%) 0 126 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 8 (100%) 0 8 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 11 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Alkaline Phosphatase (IU/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 131 NR High 2 (2%) 0 0 2 (2%) W/in NR 1 (<1%) 127 (97%) 0 128 (98%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 3 (2%) 128 (98%) 0 131 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 1 (10%) 9 (90%) 0 10 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 1 (10%) 9 (90%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 12 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Alkaline Phosphatase (IU/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 2 (2%) 1 (<1%) 0 3 (2%) W/in NR 0 123 (97%) 0 123 (97%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 2 (2%) 125 (98%) 0 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 11 (92%) 0 11 (92%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 13 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Aspartate Aminotransferase (IU/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 2 (2%) 1 (<1%) 0 3 (3%) W/in NR 1 (<1%) 110 (96%) 0 111 (97%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 3 (3%) 112 (97%) 0 115 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 0 15 (100%) 0 15 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 15 (100%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 14 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Aspartate Aminotransferase (IU/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 0 2 (2%) 0 2 (2%) W/in NR 4 (3%) 119 (94%) 0 123 (98%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 4 (3%) 122 (97%) 0 126 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 8 (100%) 0 8 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 15 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Aspartate Aminotransferase (IU/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 130 NR High 3 (2%) 1 (<1%) 0 4 (3%) W/in NR 1 (<1%) 124 (95%) 0 125 (96%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 4 (3%) 126 (97%) 0 130 (100%) Visit 7 (Follow-up) 10 NR High 0 1 (10%) 0 1 (10%) W/in NR 0 9 (90%) 0 9 (90%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 16 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Aspartate Aminotransferase (IU/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 4 (3%) 3 (2%) 0 7 (6%) W/in NR 2 (2%) 117 (92%) 0 119 (94%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 6 (5%) 121 (95%) 0 127 (100%) Visit 7 (Follow-up) 12 NR High 0 1 (8%) 0 1 (8%) W/in NR 0 10 (83%) 0 10 (83%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 17 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Bicarbonate (MMOL/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 0 0 0 0 W/in NR 0 82 (71%) 11 (10%) 93 (81%) NR Low 0 11 (10%) 10 (9%) 21 (18%) Missing 0 1 (<1%) 0 1 (<1%) Total 0 94 (82%) 21 (18%) 115 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 0 11 (73%) 3 (20%) 14 (93%) NR Low 0 1 (7%) 0 1 (7%) Missing 0 0 0 0 Total 0 12 (80%) 3 (20%) 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 18 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Bicarbonate (MMOL/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 0 0 0 0 W/in NR 0 95 (75%) 8 (6%) 103 (82%) NR Low 0 12 (10%) 10 (8%) 22 (17%) Missing 0 1 (<1%) 0 1 (<1%) Total 0 108 (86%) 18 (14%) 126 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 6 (75%) 0 6 (75%) NR Low 0 1 (13%) 1 (13%) 2 (25%) Missing 0 0 0 0 Total 0 7 (88%) 1 (13%) 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 19 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Bicarbonate (MMOL/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 131 NR High 0 0 0 0 W/in NR 0 100 (76%) 8 (6%) 108 (82%) NR Low 0 14 (11%) 8 (6%) 22 (17%) Missing 0 1 (<1%) 0 1 (<1%) Total 0 115 (88%) 16 (12%) 131 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 5 (50%) 2 (20%) 7 (70%) NR Low 0 1 (10%) 2 (20%) 3 (30%) Missing 0 0 0 0 Total 0 6 (60%) 4 (40%) 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 20 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Bicarbonate (MMOL/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 0 0 0 0 W/in NR 0 91 (72%) 11 (9%) 102 (80%) NR Low 0 10 (8%) 14 (11%) 24 (19%) Missing 0 1 (<1%) 0 1 (<1%) Total 0 102 (80%) 25 (20%) 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 6 (50%) 1 (8%) 7 (58%) NR Low 0 4 (33%) 0 4 (33%) Missing 0 1 (8%) 0 1 (8%) Total 0 11 (92%) 1 (8%) 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 21 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Calcium (MMOL/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 1 (<1%) 7 (6%) 0 8 (7%) W/in NR 2 (2%) 96 (83%) 5 (4%) 103 (90%) NR Low 0 3 (3%) 0 3 (3%) Missing 0 1 (<1%) 0 1 (<1%) Total 3 (3%) 107 (93%) 5 (4%) 115 (100%) Visit 7 (Follow-up) 15 NR High 0 1 (7%) 0 1 (7%) W/in NR 0 13 (87%) 1 (7%) 14 (93%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 14 (93%) 1 (7%) 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 22 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Calcium (MMOL/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 1 (<1%) 4 (3%) 1 (<1%) 6 (5%) W/in NR 2 (2%) 110 (87%) 5 (4%) 117 (93%) NR Low 0 2 (2%) 0 2 (2%) Missing 0 1 (<1%) 0 1 (<1%) Total 3 (2%) 117 (93%) 6 (5%) 126 (100%) Visit 7 (Follow-up) 8 NR High 0 1 (13%) 0 1 (13%) W/in NR 0 7 (88%) 0 7 (88%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 23 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Calcium (MMOL/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 131 NR High 3 (2%) 3 (2%) 0 6 (5%) W/in NR 0 118 (90%) 3 (2%) 121 (92%) NR Low 0 2 (2%) 1 (<1%) 3 (2%) Missing 0 1 (<1%) 0 1 (<1%) Total 3 (2%) 124 (95%) 4 (3%) 131 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 10 (100%) 0 10 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 24 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Calcium (MMOL/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 3 (2%) 1 (<1%) 0 4 (3%) W/in NR 2 (2%) 114 (90%) 5 (4%) 121 (95%) NR Low 0 1 (<1%) 0 1 (<1%) Missing 0 1 (<1%) 0 1 (<1%) Total 5 (4%) 117 (92%) 5 (4%) 127 (100%) Visit 7 (Follow-up) 12 NR High 1 (8%) 0 0 1 (8%) W/in NR 0 9 (75%) 1 (8%) 10 (83%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 1 (8%) 10 (83%) 1 (8%) 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 25 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Chloride (MMOL/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 0 5 (4%) 0 5 (4%) W/in NR 10 (9%) 99 (86%) 0 109 (95%) NR Low 0 0 0 0 Missing 1 (<1%) 0 0 1 (<1%) Total 11 (10%) 104 (90%) 0 115 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 0 15 (100%) 0 15 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 15 (100%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 26 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Chloride (MMOL/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 2 (2%) 7 (6%) 0 9 (7%) W/in NR 4 (3%) 113 (90%) 0 117 (93%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 6 (5%) 120 (95%) 0 126 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 8 (100%) 0 8 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 27 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Chloride (MMOL/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 131 NR High 0 9 (7%) 0 9 (7%) W/in NR 5 (4%) 115 (88%) 1 (<1%) 121 (92%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 5 (4%) 125 (95%) 1 (<1%) 131 (100%) Visit 7 (Follow-up) 10 NR High 0 1 (10%) 0 1 (10%) W/in NR 0 9 (90%) 0 9 (90%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 28 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Chloride (MMOL/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 2 (2%) 8 (6%) 0 10 (8%) W/in NR 7 (6%) 109 (86%) 0 116 (91%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 9 (7%) 118 (93%) 0 127 (100%) Visit 7 (Follow-up) 12 NR High 0 1 (8%) 0 1 (8%) W/in NR 1 (8%) 9 (75%) 0 10 (83%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 1 (8%) 11 (92%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 29 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Creatinine (UMOL/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 114 NR High 0 0 0 0 W/in NR 1 (<1%) 112 (98%) 0 113 (>99%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 1 (<1%) 113 (>99%) 0 114 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 0 15 (100%) 0 15 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 15 (100%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 30 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Creatinine (UMOL/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 0 0 0 0 W/in NR 0 126 (100%) 0 126 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 126 (100%) 0 126 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 8 (100%) 0 8 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 31 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Creatinine (UMOL/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 130 NR High 0 0 0 0 W/in NR 0 129 (>99%) 0 129 (>99%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 0 130 (100%) 0 130 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 10 (100%) 0 10 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 32 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Creatinine (UMOL/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 1 (<1%) 1 (<1%) 0 2 (2%) W/in NR 1 (<1%) 123 (97%) 0 124 (98%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 2 (2%) 125 (98%) 0 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 11 (92%) 0 11 (92%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 33 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Gamma Glutamyl Transferase (IU/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 8 (7%) 5 (4%) 0 13 (11%) W/in NR 3 (3%) 98 (85%) 0 101 (88%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 11 (10%) 104 (90%) 0 115 (100%) Visit 7 (Follow-up) 15 NR High 1 (7%) 1 (7%) 0 2 (13%) W/in NR 0 13 (87%) 0 13 (87%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 1 (7%) 14 (93%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 34 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Gamma Glutamyl Transferase (IU/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 5 (4%) 4 (3%) 0 9 (7%) W/in NR 2 (2%) 116 (91%) 0 118 (93%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 7 (6%) 120 (94%) 0 127 (100%) Visit 7 (Follow-up) 8 NR High 1 (13%) 0 0 1 (13%) W/in NR 1 (13%) 6 (75%) 0 7 (88%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 2 (25%) 6 (75%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 35 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Gamma Glutamyl Transferase (IU/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 130 NR High 7 (5%) 5 (4%) 0 12 (9%) W/in NR 2 (2%) 115 (88%) 0 117 (90%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 9 (7%) 121 (93%) 0 130 (100%) Visit 7 (Follow-up) 10 NR High 1 (10%) 0 0 1 (10%) W/in NR 0 9 (90%) 0 9 (90%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 1 (10%) 9 (90%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 36 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Gamma Glutamyl Transferase (IU/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 9 (7%) 6 (5%) 0 15 (12%) W/in NR 1 (<1%) 110 (87%) 0 111 (87%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 10 (8%) 117 (92%) 0 127 (100%) Visit 7 (Follow-up) 12 NR High 2 (17%) 0 0 2 (17%) W/in NR 0 9 (75%) 0 9 (75%) NR Low 0 0 0 0 Missing 1 (8%) 0 0 1 (8%) Total 3 (25%) 9 (75%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 37 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Globulin (G/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 0 0 0 0 W/in NR 0 100 (87%) 8 (7%) 108 (94%) NR Low 0 5 (4%) 1 (<1%) 6 (5%) Missing 0 1 (<1%) 0 1 (<1%) Total 0 106 (92%) 9 (8%) 115 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 0 14 (93%) 0 14 (93%) NR Low 0 0 1 (7%) 1 (7%) Missing 0 0 0 0 Total 0 14 (93%) 1 (7%) 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 38 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Globulin (G/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 0 0 0 0 W/in NR 0 114 (90%) 7 (6%) 121 (96%) NR Low 0 2 (2%) 3 (2%) 5 (4%) Missing 0 0 0 0 Total 0 116 (92%) 10 (8%) 126 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 7 (88%) 1 (13%) 8 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 7 (88%) 1 (13%) 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 39 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Globulin (G/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 130 NR High 0 0 0 0 W/in NR 0 121 (93%) 4 (3%) 125 (96%) NR Low 0 2 (2%) 2 (2%) 4 (3%) Missing 0 1 (<1%) 0 1 (<1%) Total 0 124 (95%) 6 (5%) 130 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 9 (90%) 1 (10%) 10 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 9 (90%) 1 (10%) 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 40 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Globulin (G/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 0 0 0 0 W/in NR 1 (<1%) 119 (94%) 5 (4%) 125 (98%) NR Low 0 1 (<1%) 0 1 (<1%) Missing 0 1 (<1%) 0 1 (<1%) Total 1 (<1%) 121 (95%) 5 (4%) 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 9 (75%) 1 (8%) 10 (83%) NR Low 0 1 (8%) 0 1 (8%) Missing 0 1 (8%) 0 1 (8%) Total 0 11 (92%) 1 (8%) 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 41 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Glucose (MMOL/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 4 (3%) 2 (2%) 1 (<1%) 7 (6%) W/in NR 5 (4%) 100 (87%) 1 (<1%) 106 (92%) NR Low 0 1 (<1%) 0 1 (<1%) Missing 0 1 (<1%) 0 1 (<1%) Total 9 (8%) 104 (90%) 2 (2%) 115 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 0 15 (100%) 0 15 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 15 (100%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 42 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Glucose (MMOL/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 4 (3%) 7 (6%) 0 11 (9%) W/in NR 3 (2%) 110 (87%) 0 113 (90%) NR Low 0 1 (<1%) 1 (<1%) 2 (2%) Missing 0 0 0 0 Total 7 (6%) 118 (94%) 1 (<1%) 126 (100%) Visit 7 (Follow-up) 8 NR High 0 1 (13%) 0 1 (13%) W/in NR 2 (25%) 4 (50%) 0 6 (75%) NR Low 0 1 (13%) 0 1 (13%) Missing 0 0 0 0 Total 2 (25%) 6 (75%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 43 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Glucose (MMOL/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 131 NR High 3 (2%) 10 (8%) 0 13 (10%) W/in NR 6 (5%) 106 (81%) 5 (4%) 117 (89%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 9 (7%) 117 (89%) 5 (4%) 131 (100%) Visit 7 (Follow-up) 10 NR High 0 1 (10%) 0 1 (10%) W/in NR 0 9 (90%) 0 9 (90%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 44 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Glucose (MMOL/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 2 (2%) 3 (2%) 0 5 (4%) W/in NR 8 (6%) 108 (85%) 3 (2%) 119 (94%) NR Low 1 (<1%) 1 (<1%) 0 2 (2%) Missing 0 1 (<1%) 0 1 (<1%) Total 11 (9%) 113 (89%) 3 (2%) 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 1 (8%) 9 (75%) 0 10 (83%) NR Low 0 1 (8%) 0 1 (8%) Missing 1 (8%) 0 0 1 (8%) Total 2 (17%) 10 (83%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 45 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Phosphorus (MMOL/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 0 2 (2%) 0 2 (2%) W/in NR 7 (6%) 92 (80%) 5 (4%) 104 (90%) NR Low 0 4 (3%) 4 (3%) 8 (7%) Missing 0 1 (<1%) 0 1 (<1%) Total 7 (6%) 99 (86%) 9 (8%) 115 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 1 (7%) 13 (87%) 0 14 (93%) NR Low 0 1 (7%) 0 1 (7%) Missing 0 0 0 0 Total 1 (7%) 14 (93%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 46 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Phosphorus (MMOL/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 3 (2%) 3 (2%) 0 6 (5%) W/in NR 5 (4%) 106 (84%) 1 (<1%) 112 (89%) NR Low 0 6 (5%) 2 (2%) 8 (6%) Missing 0 0 0 0 Total 8 (6%) 115 (91%) 3 (2%) 126 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 7 (88%) 0 7 (88%) NR Low 0 1 (13%) 0 1 (13%) Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 47 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Phosphorus (MMOL/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 131 NR High 2 (2%) 1 (<1%) 0 3 (2%) W/in NR 5 (4%) 115 (88%) 2 (2%) 122 (93%) NR Low 0 3 (2%) 2 (2%) 5 (4%) Missing 0 1 (<1%) 0 1 (<1%) Total 7 (5%) 120 (92%) 4 (3%) 131 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 9 (90%) 1 (10%) 10 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 9 (90%) 1 (10%) 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 48 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Phosphorus (MMOL/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 1 (<1%) 3 (2%) 0 4 (3%) W/in NR 4 (3%) 110 (87%) 2 (2%) 116 (91%) NR Low 0 5 (4%) 1 (<1%) 6 (5%) Missing 0 1 (<1%) 0 1 (<1%) Total 5 (4%) 119 (94%) 3 (2%) 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 2 (17%) 8 (67%) 1 (8%) 11 (92%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 2 (17%) 9 (75%) 1 (8%) 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 49 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Potassium (MMOL/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 1 (<1%) 6 (5%) 0 7 (6%) W/in NR 8 (7%) 99 (86%) 0 107 (93%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 9 (8%) 106 (92%) 0 115 (100%) Visit 7 (Follow-up) 15 NR High 0 2 (13%) 0 2 (13%) W/in NR 0 13 (87%) 0 13 (87%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 15 (100%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 50 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Potassium (MMOL/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 2 (2%) 4 (3%) 0 6 (5%) W/in NR 5 (4%) 113 (90%) 1 (<1%) 119 (94%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 7 (6%) 118 (94%) 1 (<1%) 126 (100%) Visit 7 (Follow-up) 8 NR High 1 (13%) 0 0 1 (13%) W/in NR 0 7 (88%) 0 7 (88%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 1 (13%) 7 (88%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 51 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Potassium (MMOL/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 131 NR High 0 5 (4%) 0 5 (4%) W/in NR 2 (2%) 123 (94%) 0 125 (95%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 2 (2%) 129 (98%) 0 131 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 10 (100%) 0 10 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 52 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Potassium (MMOL/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 0 2 (2%) 0 2 (2%) W/in NR 3 (2%) 121 (95%) 0 124 (98%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 3 (2%) 124 (98%) 0 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 1 (8%) 10 (83%) 0 11 (92%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 1 (8%) 11 (92%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 53 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Sodium (MMOL/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 0 3 (3%) 0 3 (3%) W/in NR 3 (3%) 107 (93%) 1 (<1%) 111 (97%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 3 (3%) 111 (97%) 1 (<1%) 115 (100%) Visit 7 (Follow-up) 15 NR High 0 1 (7%) 0 1 (7%) W/in NR 0 14 (93%) 0 14 (93%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 15 (100%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 54 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Sodium (MMOL/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 0 3 (2%) 0 3 (2%) W/in NR 3 (2%) 120 (95%) 0 123 (98%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 3 (2%) 123 (98%) 0 126 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 8 (100%) 0 8 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 55 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Sodium (MMOL/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 131 NR High 0 3 (2%) 0 3 (2%) W/in NR 3 (2%) 123 (94%) 1 (<1%) 127 (97%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 3 (2%) 127 (97%) 1 (<1%) 131 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 10 (100%) 0 10 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 56 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Sodium (MMOL/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 3 (2%) 1 (<1%) 0 4 (3%) W/in NR 1 (<1%) 119 (94%) 0 120 (94%) NR Low 0 1 (<1%) 0 1 (<1%) Missing 0 2 (2%) 0 2 (2%) Total 4 (3%) 123 (97%) 0 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 1 (8%) 10 (83%) 0 11 (92%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 1 (8%) 11 (92%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 57 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Total Bilirubin (UMOL/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 0 2 (2%) 0 2 (2%) W/in NR 3 (3%) 109 (95%) 0 112 (97%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 3 (3%) 112 (97%) 0 115 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 0 15 (100%) 0 15 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 15 (100%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 58 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Total Bilirubin (UMOL/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 1 (<1%) 6 (5%) 0 7 (6%) W/in NR 4 (3%) 116 (91%) 0 120 (94%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 5 (4%) 122 (96%) 0 127 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 8 (100%) 0 8 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 59 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Total Bilirubin (UMOL/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 131 NR High 2 (2%) 1 (<1%) 0 3 (2%) W/in NR 0 127 (97%) 0 127 (97%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 2 (2%) 129 (98%) 0 131 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 10 (100%) 0 10 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 60 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Total Bilirubin (UMOL/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 3 (2%) 2 (2%) 0 5 (4%) W/in NR 1 (<1%) 120 (94%) 0 121 (95%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 4 (3%) 123 (97%) 0 127 (100%) Visit 7 (Follow-up) 12 NR High 1 (8%) 0 0 1 (8%) W/in NR 0 10 (83%) 0 10 (83%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 1 (8%) 11 (92%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 61 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Total Protein (G/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 0 113 (98%) 0 113 (98%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 0 115 (100%) 0 115 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 0 15 (100%) 0 15 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 15 (100%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 62 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Total Protein (G/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 0 5 (4%) 0 5 (4%) W/in NR 2 (2%) 119 (94%) 0 121 (96%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 2 (2%) 124 (98%) 0 126 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 8 (100%) 0 8 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 63 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Total Protein (G/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 131 NR High 0 2 (2%) 0 2 (2%) W/in NR 2 (2%) 126 (96%) 0 128 (98%) NR Low 0 0 0 0 Missing 0 1 (<1%) 0 1 (<1%) Total 2 (2%) 129 (98%) 0 131 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 10 (100%) 0 10 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 64 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Total Protein (G/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 0 3 (2%) 0 3 (2%) W/in NR 1 (<1%) 122 (96%) 0 123 (97%) NR Low 0 0 0 0 Missing 1 (<1%) 0 0 1 (<1%) Total 2 (2%) 125 (98%) 0 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 11 (92%) 0 11 (92%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 65 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Urea (MMOL/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 1 (<1%) 1 (<1%) 0 2 (2%) W/in NR 1 (<1%) 106 (92%) 3 (3%) 110 (96%) NR Low 0 2 (2%) 0 2 (2%) Missing 0 1 (<1%) 0 1 (<1%) Total 2 (2%) 110 (96%) 3 (3%) 115 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 0 15 (100%) 0 15 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 15 (100%) 0 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 66 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Urea (MMOL/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 2 (2%) 120 (94%) 1 (<1%) 123 (97%) NR Low 0 3 (2%) 0 3 (2%) Missing 0 0 0 0 Total 2 (2%) 124 (98%) 1 (<1%) 127 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 7 (88%) 0 7 (88%) NR Low 0 0 1 (13%) 1 (13%) Missing 0 0 0 0 Total 0 7 (88%) 1 (13%) 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 67 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Urea (MMOL/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 131 NR High 0 0 0 0 W/in NR 0 128 (98%) 1 (<1%) 129 (98%) NR Low 0 1 (<1%) 0 1 (<1%) Missing 0 1 (<1%) 0 1 (<1%) Total 0 130 (>99%) 1 (<1%) 131 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 10 (100%) 0 10 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 68 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Urea (MMOL/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 1 (<1%) 1 (<1%) 0 2 (2%) W/in NR 0 121 (95%) 1 (<1%) 122 (96%) NR Low 0 2 (2%) 0 2 (2%) Missing 0 1 (<1%) 0 1 (<1%) Total 1 (<1%) 125 (98%) 1 (<1%) 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 11 (92%) 0 11 (92%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 69 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Uric Acid (UMOL/L) Treatment: Placebo Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 115 NR High 1 (<1%) 0 0 1 (<1%) W/in NR 1 (<1%) 102 (89%) 2 (2%) 105 (91%) NR Low 0 3 (3%) 5 (4%) 8 (7%) Missing 0 1 (<1%) 0 1 (<1%) Total 2 (2%) 106 (92%) 7 (6%) 115 (100%) Visit 7 (Follow-up) 15 NR High 0 0 0 0 W/in NR 0 13 (87%) 1 (7%) 14 (93%) NR Low 0 0 1 (7%) 1 (7%) Missing 0 0 0 0 Total 0 13 (87%) 2 (13%) 15 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 70 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Uric Acid (UMOL/L) Treatment: GW685698X 100mcg AM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 126 NR High 0 1 (<1%) 0 1 (<1%) W/in NR 0 119 (94%) 1 (<1%) 120 (95%) NR Low 0 0 5 (4%) 5 (4%) Missing 0 0 0 0 Total 0 120 (95%) 6 (5%) 126 (100%) Visit 7 (Follow-up) 8 NR High 0 0 0 0 W/in NR 0 8 (100%) 0 8 (100%) NR Low 0 0 0 0 Missing 0 0 0 0 Total 0 8 (100%) 0 8 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 71 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Uric Acid (UMOL/L) Treatment: GW685698X 100mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 129 NR High 2 (2%) 0 0 2 (2%) W/in NR 2 (2%) 109 (84%) 6 (5%) 117 (91%) NR Low 0 7 (5%) 2 (2%) 9 (7%) Missing 0 1 (<1%) 0 1 (<1%) Total 4 (3%) 117 (91%) 8 (6%) 129 (100%) Visit 7 (Follow-up) 10 NR High 0 0 0 0 W/in NR 0 9 (90%) 0 9 (90%) NR Low 0 1 (10%) 0 1 (10%) Missing 0 0 0 0 Total 0 10 (100%) 0 10 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 72 of 72 Population: Safety Table 8.25 Summary of Clinical Chemistry Laboratory Shifts From Baseline Lab Test: Uric Acid (UMOL/L) Treatment: GW685698X 250mcg PM Time Period Value --------------------------------------------------- Baseline Normal Range Within Normal Visit n Value High Norm Range Range Low Total ------------------------------------------------------------------------------------------ Week 4 127 NR High 2 (2%) 1 (<1%) 0 3 (2%) W/in NR 0 111 (87%) 7 (6%) 118 (93%) NR Low 0 2 (2%) 3 (2%) 5 (4%) Missing 0 1 (<1%) 0 1 (<1%) Total 2 (2%) 115 (91%) 10 (8%) 127 (100%) Visit 7 (Follow-up) 12 NR High 0 0 0 0 W/in NR 0 11 (92%) 0 11 (92%) NR Low 0 0 0 0 Missing 0 1 (8%) 0 1 (8%) Total 0 12 (100%) 0 12 (100%) Note: Baseline is the final run-in visit

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.26 Summary of Urinalysis-Local Data GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category (N=143) (N=143) (N=148) (N=141) -------------------------------------------------------------------------------- Visit 1 n 141 142 146 141 Negative 124 (88%) 122 (86%) 127 (87%) 131 (93%) Positive 17 (12%) 20 (14%) 19 (13%) 10 (7%) No result 0 0 0 0 Visit 6 n 123 131 130 133 Negative 111 (90%) 116 (89%) 113 (87%) 117 (88%) Positive 12 (10%) 15 (11%) 16 (12%) 16 (12%) No result 0 0 1 (<1%) 0 Visit 7 n 10 10 14 12 Negative 9 (90%) 8 (80%) 11 (79%) 10 (83%) Positive 0 1 (10%) 3 (21%) 2 (17%) No result 1 (10%) 1 (10%) 0 0

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Protocol: FFA20001 Page 1 of 1 Population: Safety Table 8.27 Summary of ECG Data GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM Visit Category [1] (N=143) (N=143) (N=148) (N=141) ------------------------------------------------------------------------------------ Visit 1 n 143 143 148 141 Normal 130 (91%) 128 (90%) 129 (87%) 124 (88%) Abnormal - not CS 13 (9%) 15 (10%) 18 (12%) 17 (12%) Abnormal - CS 0 0 0 0 No Result 0 0 1 (<1%) 0 Visit 6 n 124 131 136 133 Normal 113 (91%) 114 (87%) 126 (93%) 121 (91%) Abnormal - not CS 11 (9%) 17 (13%) 10 (7%) 11 (8%) Abnormal - CS 0 0 0 0 No Result 0 0 0 1 (<1%) Visit 7 n 6 3 7 5 Normal 6 (100%) 2 (67%) 6 (86%) 4 (80%) Abnormal - not CS 0 1 (33%) 1 (14%) 0 Abnormal - CS 0 0 0 0 No Result 0 0 0 1 (20%) [1] CS = Clinically Significant

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Protocol: FFA20001 Page 1 of 5 Population: Safety Table 8.28 Summary of Oropharyngeal Examination Planned GW685698X GW685698X GW685698X Relative Placebo 100mcg AM 100mcg PM 250mcg PM Time (N=143) (N=143) (N=148) (N=141) --------------------------------------------------------------------------------------- Visit 1 Clinical n 143 143 148 141 (Week -2) evidence of No 143 (100%) 143 (100%) 148 (100%) 141 (100%) candidiasis Yes 0 0 0 0 Result of Neg 0 0 0 0 swab for subjects Pos 0 0 0 0 with clinical N/A 0 0 0 0 evidence No Swab 0 0 0 0 Visit 2 Clinical n 143 143 148 141 (Week 0) evidence of No 143 (100%) 143 (100%) 147 (99%) 141 (100%) candidiasis Yes 0 0 1 (<1%) 0 Result of Neg 0 0 0 0 swab for subjects Pos 0 0 0 0 with clinical N/A 0 0 0 0 evidence No Swab 0 0 1 (<1%) 0 NOTE: Neg=Negative, Pos=Positive, N/A=Not Available [1] Case defined as having clinical evidence of candidiasis and a positive swab, including withdrawal visit [2] Subjects with no candidiasis at baseline and at least one post baseline candidiasis assessment

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Protocol: FFA20001 Page 2 of 5 Population: Safety Table 8.28 Summary of Oropharyngeal Examination Planned GW685698X GW685698X GW685698X Relative Placebo 100mcg AM 100mcg PM 250mcg PM Time (N=143) (N=143) (N=148) (N=141) --------------------------------------------------------------------------------------- Visit 3 Clinical n 134 139 144 138 (Week 1) evidence of No 134 (100%) 139 (100%) 144 (100%) 137 (99%) candidiasis Yes 0 0 0 1 (<1%) Result of Neg 0 0 0 0 swab for subjects Pos 0 0 0 0 with clinical N/A 0 0 0 0 evidence No Swab 0 0 0 1 (<1%) Visit 4 Clinical n 131 136 141 135 (Week 2) evidence of No 131 (100%) 136 (100%) 141 (100%) 133 (99%) candidiasis Yes 0 0 0 2 (1%) Result of Neg 0 0 0 0 swab for subjects Pos 0 0 0 2 (1%) with clinical N/A 0 0 0 0 evidence No Swab 0 0 0 0 NOTE: Neg=Negative, Pos=Positive, N/A=Not Available [1] Case defined as having clinical evidence of candidiasis and a positive swab, including withdrawal visit [2] Subjects with no candidiasis at baseline and at least one post baseline candidiasis assessment

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Protocol: FFA20001 Page 3 of 5 Population: Safety Table 8.28 Summary of Oropharyngeal Examination Planned GW685698X GW685698X GW685698X Relative Placebo 100mcg AM 100mcg PM 250mcg PM Time (N=143) (N=143) (N=148) (N=141) --------------------------------------------------------------------------------------- Visit 5 Clinical n 125 134 139 134 (Week 3) evidence of No 124 (99%) 133 (99%) 136 (98%) 131 (98%) candidiasis Yes 1 (<1%) 1 (<1%) 3 (2%) 3 (2%) Result of Neg 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) swab for subjects Pos 0 0 2 (1%) 2 (1%) with clinical N/A 0 0 0 0 evidence No Swab 0 0 0 0 Visit 6 Clinical n 124 133 137 133 (Week 4) evidence of No 121 (98%) 133 (100%) 137 (100%) 133 (100%) candidiasis Yes 3 (2%) 0 0 0 Result of Neg 3 (2%) 0 0 0 swab for subjects Pos 0 0 0 0 with clinical N/A 0 0 0 0 evidence No Swab 0 0 0 0 NOTE: Neg=Negative, Pos=Positive, N/A=Not Available [1] Case defined as having clinical evidence of candidiasis and a positive swab, including withdrawal visit [2] Subjects with no candidiasis at baseline and at least one post baseline candidiasis assessment

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Protocol: FFA20001 Page 4 of 5 Population: Safety Table 8.28 Summary of Oropharyngeal Examination Planned GW685698X GW685698X GW685698X Relative Placebo 100mcg AM 100mcg PM 250mcg PM Time (N=143) (N=143) (N=148) (N=141) --------------------------------------------------------------------------------------- Visit 7 Clinical n 132 128 137 131 (Follow-up) evidence of No 131 (99%) 128 (100%) 137 (100%) 131 (100%) candidiasis Yes 1 (<1%) 0 0 0 Result of Neg 1 (<1%) 0 0 0 swab for subjects Pos 0 0 0 0 with clinical N/A 0 0 0 0 evidence No Swab 0 0 0 0 NOTE: Neg=Negative, Pos=Positive, N/A=Not Available [1] Case defined as having clinical evidence of candidiasis and a positive swab, including withdrawal visit [2] Subjects with no candidiasis at baseline and at least one post baseline candidiasis assessment

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Protocol: FFA20001 Page 5 of 5 Population: Safety Table 8.28 Summary of Oropharyngeal Examination GW685698X GW685698X GW685698X Placebo 100mcg AM 100mcg PM 250mcg PM (N=143) (N=143) (N=148) (N=141) ------------------------------------------------------------------------------------------ Summary of new cases on treatment[1] Candidiasis at Baseline (Week 0) n 143 143 148 141 No 143 (100%) 143 (100%) 148 (100%) 141 (100%) Yes 0 0 0 0 If no candidiasis at baseline, n[2] 142 142 147 141 candidiasis on treatment No 142 (100%) 142 (100%) 145 (99%) 138 (98%) Yes 0 0 2 (1%) 3 (2%) NOTE: Neg=Negative, Pos=Positive, N/A=Not Available [1] Case defined as having clinical evidence of candidiasis and a positive swab, including withdrawal visit [2] Subjects with no candidiasis at baseline and at least one post baseline candidiasis assessment

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Protocol: FFA20001 Page 1 of 3 Population: Safety Table 8.29 Summary of Vital Signs Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ Systolic BP Placebo 143 Visit 2 (Week 0) 143 120.4 11.28 120.0 87 150 (mmHg) Visit 3 (Week 1) 134 119.9 11.93 120.0 94 159 Visit 4 (Week 2) 131 119.3 10.84 120.0 90 162 Visit 5 (Week 3) 125 120.2 11.74 120.0 90 163 Visit 6 (Week 4) 124 120.2 12.91 120.0 85 164 GW685698X 143 Visit 2 (Week 0) 143 118.9 11.03 120.0 90 150 100mcg AM Visit 3 (Week 1) 139 119.8 12.97 120.0 82 190 Visit 4 (Week 2) 136 120.4 11.83 120.0 85 180 Visit 5 (Week 3) 134 119.9 11.27 120.0 90 165 Visit 6 (Week 4) 133 119.9 12.26 120.0 90 180 GW685698X 148 Visit 2 (Week 0) 148 120.8 12.11 120.0 95 160 100mcg PM Visit 3 (Week 1) 144 120.4 12.34 120.0 90 160 Visit 4 (Week 2) 141 119.9 13.42 120.0 90 160 Visit 5 (Week 3) 139 121.4 12.71 120.0 94 160 Visit 6 (Week 4) 136 120.2 12.62 120.0 95 160 GW685698X 141 Visit 2 (Week 0) 141 122.5 13.45 120.0 94 164 250mcg PM Visit 3 (Week 1) 138 121.4 13.80 120.0 90 195 Visit 4 (Week 2) 135 120.7 15.09 120.0 80 175 Visit 5 (Week 3) 134 119.9 13.84 120.0 81 162 Visit 6 (Week 4) 133 121.2 12.37 120.0 99 150

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Protocol: FFA20001 Page 2 of 3 Population: Safety Table 8.29 Summary of Vital Signs Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ Diastolic BP Placebo 143 Visit 2 (Week 0) 143 75.9 7.70 76.0 57 92 (mmHg) Visit 3 (Week 1) 134 75.7 7.52 75.0 59 100 Visit 4 (Week 2) 131 75.4 7.43 76.0 58 90 Visit 5 (Week 3) 125 76.0 8.16 77.0 46 98 Visit 6 (Week 4) 124 75.3 8.35 75.5 50 100 GW685698X 143 Visit 2 (Week 0) 143 75.4 7.92 75.0 46 104 100mcg AM Visit 3 (Week 1) 139 75.1 8.33 75.0 48 100 Visit 4 (Week 2) 136 76.0 8.41 79.5 51 110 Visit 5 (Week 3) 134 75.7 7.91 75.0 55 100 Visit 6 (Week 4) 133 76.5 7.77 80.0 60 102 GW685698X 148 Visit 2 (Week 0) 148 76.6 8.49 80.0 50 100 100mcg PM Visit 3 (Week 1) 144 76.0 7.68 80.0 57 100 Visit 4 (Week 2) 141 75.9 8.70 75.0 58 100 Visit 5 (Week 3) 139 76.7 8.16 80.0 58 101 Visit 6 (Week 4) 136 77.1 7.62 80.0 58 100 GW685698X 141 Visit 2 (Week 0) 141 77.1 8.92 80.0 52 108 250mcg PM Visit 3 (Week 1) 138 76.0 8.01 77.0 58 100 Visit 4 (Week 2) 135 75.6 9.82 75.0 51 100 Visit 5 (Week 3) 134 75.5 8.99 80.0 52 105 Visit 6 (Week 4) 133 75.5 9.07 75.0 42 95

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Protocol: FFA20001 Page 3 of 3 Population: Safety Table 8.29 Summary of Vital Signs Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ Heart Rate Placebo 143 Visit 2 (Week 0) 143 74.8 7.76 74.0 58 100 (beats/minute) Visit 3 (Week 1) 134 74.4 7.91 74.0 56 105 Visit 4 (Week 2) 131 73.9 7.86 73.0 58 112 Visit 5 (Week 3) 125 74.8 7.80 74.0 56 107 Visit 6 (Week 4) 124 74.8 8.38 75.0 50 100 GW685698X 143 Visit 2 (Week 0) 143 74.2 7.41 74.0 52 105 100mcg AM Visit 3 (Week 1) 139 74.5 8.19 76.0 52 107 Visit 4 (Week 2) 136 74.4 8.17 74.0 52 105 Visit 5 (Week 3) 134 73.9 8.16 73.5 54 108 Visit 6 (Week 4) 133 73.6 9.33 72.0 50 114 GW685698X 148 Visit 2 (Week 0) 148 75.6 8.11 75.0 52 97 100mcg PM Visit 3 (Week 1) 144 75.8 8.16 76.0 57 103 Visit 4 (Week 2) 141 75.2 8.04 76.0 56 102 Visit 5 (Week 3) 139 76.7 7.83 76.0 58 103 Visit 6 (Week 4) 136 74.5 8.84 75.0 56 112 GW685698X 141 Visit 2 (Week 0) 141 75.8 9.36 76.0 52 118 250mcg PM Visit 3 (Week 1) 138 75.5 8.84 76.0 56 128 Visit 4 (Week 2) 135 74.8 9.11 75.0 52 125 Visit 5 (Week 3) 134 74.8 8.81 74.0 60 117 Visit 6 (Week 4) 133 74.6 9.01 76.0 51 105

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Protocol: FFA20001 Page 1 of 3 Population: Safety Table 8.30 Summary of Vital Signs Change from Baseline Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- Systolic BP Placebo 143 Visit 3 (Week 1) 134 -0.3 9.20 0.0 -21 33 (mmHg) Visit 4 (Week 2) 131 -1.0 10.38 0.0 -31 30 Visit 5 (Week 3) 125 -0.1 9.64 0.0 -28 27 Visit 6 (Week 4) 124 0.0 9.85 0.0 -30 30 GW685698X 143 Visit 3 (Week 1) 139 0.9 11.96 0.0 -23 70 100mcg AM Visit 4 (Week 2) 136 1.4 10.27 0.0 -30 45 Visit 5 (Week 3) 134 0.9 10.90 0.0 -25 60 Visit 6 (Week 4) 133 0.7 10.85 0.0 -35 45 GW685698X 148 Visit 3 (Week 1) 144 -0.3 8.97 0.0 -30 30 100mcg PM Visit 4 (Week 2) 141 -0.5 11.26 0.0 -40 51 Visit 5 (Week 3) 139 0.9 11.09 0.0 -30 45 Visit 6 (Week 4) 136 -0.2 9.99 0.0 -20 39 GW685698X 141 Visit 3 (Week 1) 138 -0.9 10.24 0.0 -30 40 250mcg PM Visit 4 (Week 2) 135 -1.4 12.56 0.0 -40 50 Visit 5 (Week 3) 134 -2.1 10.82 0.0 -30 22 Visit 6 (Week 4) 133 -0.9 10.68 0.0 -32 30

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Protocol: FFA20001 Page 2 of 3 Population: Safety Table 8.30 Summary of Vital Signs Change from Baseline Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- Diastolic BP Placebo 143 Visit 3 (Week 1) 134 0.0 6.75 0.0 -20 30 (mmHg) Visit 4 (Week 2) 131 -0.2 7.65 0.0 -20 20 Visit 5 (Week 3) 125 0.6 7.14 0.0 -20 20 Visit 6 (Week 4) 124 -0.0 7.93 0.0 -20 20 GW685698X 143 Visit 3 (Week 1) 139 -0.3 8.29 0.0 -20 20 100mcg AM Visit 4 (Week 2) 136 0.7 7.67 0.0 -21 25 Visit 5 (Week 3) 134 0.2 8.02 0.0 -20 25 Visit 6 (Week 4) 133 1.0 7.80 0.0 -20 25 GW685698X 148 Visit 3 (Week 1) 144 -0.3 7.80 0.0 -30 30 100mcg PM Visit 4 (Week 2) 141 -0.4 7.83 0.0 -20 30 Visit 5 (Week 3) 139 0.4 7.62 0.0 -22 31 Visit 6 (Week 4) 136 0.8 7.80 0.0 -20 34 GW685698X 141 Visit 3 (Week 1) 138 -1.1 7.88 0.0 -29 14 250mcg PM Visit 4 (Week 2) 135 -1.4 8.62 0.0 -25 20 Visit 5 (Week 3) 134 -1.5 8.09 0.0 -25 25 Visit 6 (Week 4) 133 -1.6 8.57 0.0 -25 20

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Protocol: FFA20001 Page 3 of 3 Population: Safety Table 8.30 Summary of Vital Signs Change from Baseline Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- Heart Rate Placebo 143 Visit 3 (Week 1) 134 -0.1 7.10 0.0 -25 28 (beats/min) Visit 4 (Week 2) 131 -0.4 6.56 0.0 -24 14 Visit 5 (Week 3) 125 0.4 7.63 0.0 -32 20 Visit 6 (Week 4) 124 0.5 7.76 0.0 -25 20 GW685698X 143 Visit 3 (Week 1) 139 0.3 6.65 0.0 -27 15 100mcg AM Visit 4 (Week 2) 136 0.2 6.68 0.0 -24 16 Visit 5 (Week 3) 134 -0.3 6.47 0.0 -22 18 Visit 6 (Week 4) 133 -0.7 7.52 0.0 -18 24 GW685698X 148 Visit 3 (Week 1) 144 0.3 6.66 0.0 -19 20 100mcg PM Visit 4 (Week 2) 141 -0.2 8.27 0.0 -24 36 Visit 5 (Week 3) 139 1.2 8.27 0.0 -17 28 Visit 6 (Week 4) 136 -0.8 8.88 -1.5 -28 28 GW685698X 141 Visit 3 (Week 1) 138 -0.3 8.21 0.0 -24 36 250mcg PM Visit 4 (Week 2) 135 -1.0 8.43 -1.0 -35 32 Visit 5 (Week 3) 134 -1.1 7.86 0.0 -24 25 Visit 6 (Week 4) 133 -1.3 8.85 -2.0 -24 30

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Table 9.1: Demographic Summary for Subjects Included in Population Pharmacokinetic Analysis

100 mcg a.m.(n=132)

Demographic Factor Median Range Age (yr) 37 16 – 56 Weight (kg) 73.5 43 – 120 Body Mass Index (kg.m^2)

25.5 16.4 – 45.1

Sex 59 Male : 73 Female Race White = 118, Other = 14

100 mcg p.m. (n=134) Demographic Factor Median Range Age (yr) 38 16 – 55 Weight (kg) 70 40 – 120 Body Mass Index (kg.m^2)

25 16.7 – 41.6

Sex 53 Male: 81 Female Race White = 118, Other = 16

250 mcg p.m. (n=132) Demographic Factor Median Range Age (yr) 37 16 – 69 Weight (kg) 73 40 – 121 Body Mass Index (kg.m^2)

26.3 15.4 – 44.7


PK Population (n=398) Demographic Factor Median Range Age (yr) 37 16 – 69 Weight (kg) 72 40 – 121 Body Mass Index (kg.m^2)

26.2 15.4 – 45.1



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Table 9.2: Estimated Population pharmacokinetic parameters for Final GW685698X Model Without Imputation (Run019)

Final parameter estimatesRun 019

Ka CL/F am CL/F pm V2/F V3/F QWt on CL/F

THETA -1.34 5.57 6.05 3.33 9.71 7.48 1.09SE 0.176 0.269 0.272 0.519 0.168 0.326 0.25CV -13% 5% 4% 16% 2% 4% 23%

Run1 Ka (h-1) CL/F am CL/F pm V2/F V3/F Q Wt on CL/F

MEAN 0.262 262.43 424.11 27.94 16481.60 1772 2.974L95 0.185 154.897 248.857 10.102 11857.549 935.462 1.822U95 0.370 444.629 722.791 77.265 22908.883 3357.527 4.855BSV 44% 71% 50% ND 12% 70% ND

Residuals 13% 11 pg/ml

ETA(1) ETA(2) ETA(3) ETA(4) ETA(5) ETA(6)0.134 0.288 0.165 ND 0.0135 0.2810.0543 0.0783 0.0597 ND 0.0402 0.19641% 27% 36% ND 298% 70%

EPS(1) EPS(2)0.0149 1310.0108 62.472% 48%


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Table 9.3: Models Evaluated During Development of Final GW685698X Model Without Imputation (Run019)

FFA20001

nmdata Model Error LNKa LNCL LNV2 LNV3 LNQ EPS1 EPS2 LL COVRun002

LL-LLRun001* ETA on all P+A 0.431 5.86 -6.82 8.12 8.83 0.326 51.8 4335.318 NRun002 Eta on all P+A -1.33 5.98 3.93 9.75 7.01 0.00912 140 8015.233 YRun003* Eta on all, one compartment P+A 3.33 5.87 8.26 0.329 50.5 4344.204 Y 8.886Run004 Eta on all, one compartment P+A 1.33 6 8.98 0.0269 82.3 8281.003 Y 265.77Run005 ETA on all P 0.974 5.93 8.54 11.5 7.08 0.321 NA 8566.819 N 551.586Run006 Eta on all A -1.49 5.97 4.08 9.75 7.011 NA 159 8029.534 N 14.301Run007 No Eta V2 P+A -1.33 5.98 3.35 9.74 7 0.00976 140 8016.102 Y 0.869Run008 Population on CL, No Eta V2 P+A -1.37 5.96 HVT, 5.98

AS3.26 9.75 6.97 0.00979 140 8009.747 Y -6.355

Run009 Population on V2, No Eta V2 P+A -1.19 5.97 3.39 HVT, 6.93 AS

9.67 7.08 0.0102 145 8008.669 Y -7.433

Run010 Population on V3, No Eta V2 P+A -1.33 5.98 3.36 9.72 HVT, 9.91 AS

7.01 0.00976 140 8015.962 N -0.14

Run011 Population on CL, V2 and V3, No Eta V2

P+A -1.18 5.97 HVT, 5.96 AS

3.48 HVT, 7.02 AS

9.62 HVT, 9.62 AS

7.11 0.0106 143 7998.748 Y -17.354

Run012 Population on CL and V2, No Eta V2

P+A -1.19 5.97 HVT, 5.97 AS

3.44 HVT, 6.93 AS

9.68 7.06 0.0104 143 8000.573 Y -15.529

Run013 Population on CL and V3, No Eta V2

P+A -1.37 5.96 HVT, 5.98 AS

3.27 9.74 HVT, 9.89 AS

6.98 0.00979 140 8009.648 Y -6.454

NONMEM model fitting GW685698XInput file FFA20001_PK_500.prn except runs with * where input file was FFA20001_PK.prn

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Table 9.3 cont'd: Models Evaluated During Development of Final GW685698X Model Without Imputation (Run019) cont'd

FFA20001

nmdata Model Error LNKa LNCL LNV2 LNV3 LNQ EPS1 EPS2 LL COVRun002

LL-LLRun014 Population on V2 and V3, No

Eta V2P+A -1.18 5.97 3.44 HVT,

7.01 AS9.62 HVT,

10.4 AS7.12 0.0103 144 8007.207 Y -8.895

Run015 am v pm on CL, No Eta V2 P+A -1.32 5.96 am, 6.10 pm 3.44 9.75 7.52 0.0087 141 7975.045 Y -41.057

Run016 am v pm on CL and V2, No Eta V2

P+A -1.17 5.87 am, 6.05 pm 3.44 am, 7.60 pm

9.56 7.01 0.0116 132 7935.596 Y -80.506

Run017 am v pm on CL, V2 and V3, No Eta V2

P+A -1.32 5.90 am, 6.05 pm 3.31 am, 7.52 pm

9.64 am, 9.04 pm

6.88 0.0117 131 7932.81 N -83.292

Run018 am v pm on CL and V3, No Eta V2

P+A -1.33 5.59 am, 6.10 pm 3.54 9.76 am, 9.64 pm

7.5 0.00871 141 7974.954 N -41.148

Run019 am v pm and Weight on CL, No Eta V2

P+A -1.34 4.48 am, 4.96 pm 3.33 9.71 7.48 0.0087 141 7928.97 Y -87.132

Run020 am v pm and Age on CL, No Eta V2

P+A -1.32 5.45 am, 5.98 pm 3.41 9.75 7.51 0.00875 141 7973.092 Y -43.01

Run021 am v pm and weight on V3, No Eta V2

P+A -1.31 5.58 am, 6.10 pm 3.41 9.2 7.54 0.00866 142 7974.576 Y -41.526

NONMEM model fitting GW685698XInput file FFA20001_PK_500.prn except runs with * where input file was FFA20001_PK.prn

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Table 9.4: Estimated Population pharmacokinetic parameters for Final GW685698X Model Without Imputation (Run019)

Final parameter estimatesRun 019IMP2

Ka CL/F am CL/F pm V2/F V3/F QWt on CL/F

THETA -1.56 5.67 6.57 2.62 11 8.4 1.64SE 0.258 0.555 0.412 0.519 0.588 0.75 0.435CV -17% 10% 6% 20% 5% 9% 27%

Run1 Ka (h-1) CL/F am CL/F pm V2/F V3/F Q Wt on CL/F

MEAN 0.210 290.03 713.37 13.74 59874.14 4447 5.155L95 0.127 97.729 318.136 4.967 18911.396 1022.494 2.198U95 0.348 860.746 1599.618 37.987 189563.625 19341.339 12.093BSV 316% 66% 94% ND 179% 913% ND

Residuals 82% 5 pg/ml

ETA(1) ETA(2) ETA(3) ETA(4) ETA(5) ETA(6)2.03 0.258 0.442 ND 1.05 5.363.34 0.0774 0.114 ND 1.52 8.14165% 30% 26% ND 145% 152%

EPS(1) EPS(2)0.361 20.70.161 7.5845% 37%


509

Table 9.5: Models Evaluated During Development of Final GW685698X Model With Imputation (Run019IMP2)

FFA20001

nmdata Model Error LNKa LNCL LNV2 LNV3 LNQ EPS1 EPS2 LL COVRun002IMP1

LL-LLRun002IMP1 Eta on all P+A -1.51 6.5 2.92 10.1 6.66 0.0354 89.4 13701.858 YRun007IMP1 No Eta V2 P+A -1.51 6.5 2.92 10.1 6.66 0.0354 89.4 13701.858 Y 0Run015IMP1 am v pm on CL, No Eta V2 P+A -1.58 6.21 am, 6.54 pm 2.64 9.84 6.81 0.0355 87.5 13653.36 Y -48.498

Run019IMP1 am v pm and Weight on CL, No Eta V2

P+A -1.56 4.15 am, 5.04 pm 2.64 11.1 8.43 0.426 15.5 13400.504 Y -301.354

nmdata Model Error LNKa LNCL LNV2 LNV3 LNQ EPS1 EPS2 LL COVRun002IMP2

LL-LLRun002IMP2 Eta on all P+A -1.51 6.5 2.92 10.1 6.66 0.0354 89.4 13701.858 YRun007IMP2 No Eta V2 P+A -1.51 6.5 2.92 10.1 6.66 0.0354 89.4 13701.858 Y 0Run015IMP2 am v pm on CL, No Eta V2 P+A -1.58 6.16 am, 6.54 pm 2.66 9.83 6.8 0.0324 86.2 13606.963 Y -94.895

Run019IMP2 am v pm and Weight on CL, No Eta V2

P+A -1.56 4.03 am, 4.93 pm 2.64 11 8.4 0.361 20.7 13385.386 Y -316.472

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FFA20001 28JUL04 PK Population AUC(0-24) (pg.h/mL) 100 mcg am 100 mcg pm 250 mcg pm Statistic (N=132) (N=134) (N=132) n 132 134 132 Missing 0 0 0 Mean 307.35 154.94 423.34 95% CI of Arithmetic Mean ( 286.26, 328.44) ( 141.1, 168.77) ( 379.69, 466.99) SD 122.485 80.988 253.507 %CV 39.852 52.272 59.883 Median 293.31 125.72 370.425 Minimum 102.66 52.43 100.47 Maximum 717.05 477.69 1660.5 Geometric Mean 285.39 139.56 370.24 95% CI of Geometric Mean ( 267.01, 305.04) ( 129.52, 150.37) ( 339.52, 403.73) SD of Logs 0.387 0.437 0.503

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Table 9.6 cont’d: Summary of AUC(0-24) Values

FFA20001 28JUL04 PK Population AUC(0-24) (no imputation) (pg.h/mL) 100 mcg am 100 mcg pm 250 mcg pm Statistic (N=132) (N=134) (N=132) n 132 134 132 Missing 0 0 0 Mean 376.26 256.49 610.66 95% CI of Arithmetic Mean ( 346.93, 405.6) ( 246.26, 266.72) ( 570.61, 650.71) SD 170.35 59.863 232.575 %CV 45.274 23.34 38.086 Median 334.4 252.07 572.54 Minimum 175.57 113.17 278.65 Maximum 1477.5 473.86 1975.2 Geometric Mean 353.03 249.51 580.24 95% CI of Geometric Mean ( 333.58, 373.62) ( 239.53, 259.9) ( 550.85, 611.2) SD of Logs 0.329 0.239 0.302

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Figure 9.1 Plot of AUC(0-24) comparing Imputation1 versus Imputation 2

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Figure 9.3: Base Model PK (Run 015) Parameter Estimate versus Influential Covariate

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Figure 9.5 Plot of AUC(0-24) against creatinine corrected 24 hour urinary cortisol

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SPONSOR INFORMATION PAGE

Title: A randomised, double-blind, double-dummy, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GW685698X 100µg administered once daily either in the morning or the evening and GW685698X 250µg administered once daily in the evening all administered by inhalation via DISKHALER for 28 days in subjects with persistent bronchial asthma.

Study Identifier: FFA20001

GlaxoSmithKline Greenford Road Greenford, Middlesex, UB6 0HE, UK Telephone:

Sponsor Contact Information:

Dr GlaxoSmithKline Greenford Road Greenford, Middlesex, UB6 0HE, UK Telephone:

GM2003/00336/00 CONFIDENTIAL FFA20001

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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I agree:

• To assume responsibility for the proper conduct of the study at this site.

• To conduct the study in compliance with this protocol, any future amendments, and with any other study conduct procedures provided by GlaxoSmithKline (GSK).

• Not to implement any changes to the protocol without agreement from the sponsor and prior review and written approval from the Institutional Review Board (IRB) or Independent Ethics Committee (IEC), except where necessary to eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory requirements).

• That I am thoroughly familiar with the appropriate use of the investigational product(s), as described in this protocol, and any other information provided by the sponsor including, but not limited to, the following: the current Clinical Investigator’s Brochure / Investigator’s Brochure (CIB/IB) or equivalent document, CIB/IB supplement (if applicable), and approved product label (if the product is marketed in this country and the label is not already provided as an equivalent to a CIB/IB).

• That I am aware of, and will comply with, “good clinical practice” (GCP) and all applicable regulatory requirements.

• To ensure that all persons assisting me with the study are adequately informed about the GSK investigational product(s) and of their study-related duties and functions as described in the protocol.

• That I have been informed that certain regulatory authorities require the sponsor to obtain and supply, as necessary, details about the investigator’s ownership interest in the sponsor or the investigational product, and more generally about his/her financial ties with the sponsor. GSK will use and disclose the information solely for the purpose of complying with regulatory requirements.

Hence I:

• Agree to supply GSK with any necessary information regarding ownership interest and financial ties (including those of my spouse and dependent children);

• Agree to promptly update this information if any relevant changes occur during the course of the study and for 1 year following completion of the study; and

• Agree that GSK may disclose any information it has about such ownership interests and financial ties to regulatory authorities.


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Investigator Name: _____________________________

Investigator Signature Date

The following co-signature is required only when the investigator is not a physician

Physician Name: _______________________________

Physician Signature Date


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TABLE OF CONTENTS

PageABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

PROTOCOL SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171.1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171.2. Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

2. OBJECTIVE(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202.1. Primary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202.2. Secondary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202.3. Other Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

3. ENDPOINT(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203.1. Primary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203.2. Secondary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

3.2.1. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213.2.2. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213.2.3. Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

4. STUDY DESIGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

5. STUDY POPULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245.1. Number of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245.2. Eligibility Criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

5.2.1. Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245.2.2. Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255.2.3. Other Eligibility Criteria Considerations . . . . . . . . . . . . . . . . . . 27

6. STUDY ASSESSMENTS AND PROCEDURES . . . . . . . . . . . . . . . . . . . . . 276.1. Demographic and Baseline Assessments . . . . . . . . . . . . . . . . . . . . . 276.2. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

6.2.1. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276.2.2. Adverse Events and Concomitant Medications . . . . . . . . . . . . 286.2.3. Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286.2.4. Examination of Oropharynx . . . . . . . . . . . . . . . . . . . . . . . . . . . 296.2.5. Vital Signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296.2.6. 12-lead ECG. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296.2.7. Laboratory Safety Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296.2.8. Urinary Cortisol Assessments . . . . . . . . . . . . . . . . . . . . . . . . . 29


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6.3. Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306.3.1. Clinic Lung Function Tests During Study Visits . . . . . . . . . . . . 306.3.2. Daily Record Card Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306.3.3. Withdrawal Criteria for Lack of Efficacy . . . . . . . . . . . . . . . . . . 31

6.4. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326.5. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326.6. Biomarker(s). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326.7. Viral Genotyping and Phenotyping . . . . . . . . . . . . . . . . . . . . . . . . . . 326.8. Health Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336.9. Pharmacogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

7. INVESTIGATIONAL PRODUCT(S). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337.1. Description of Investigational Product . . . . . . . . . . . . . . . . . . . . . . . . 337.2. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337.3. Dose Rationale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347.4. Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357.5. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357.6. Packaging and Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357.7. Preparation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367.8. Handling and Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367.9. Product Accountability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367.10. Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367.11. Treatment of Investigational Product Overdose. . . . . . . . . . . . . . . . 367.12. Occupational Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

8. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES. . . . . . . 378.1. Permitted Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378.2. Prohibited Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378.3. Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388.4. Non-drug Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

9. SUBJECT COMPLETION AND WITHDRAWAL . . . . . . . . . . . . . . . . . . . . . 389.1. Subject Completion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389.2. Subject Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

9.2.1. Subject Withdrawal from Study . . . . . . . . . . . . . . . . . . . . . . . . 399.2.2. Subject Withdrawal from Investigational Product . . . . . . . . . . . 40

9.3. Screen and Baseline Failures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

10. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) . . 4110.1. Definition of an AE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41


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10.2. Definition of a SAE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4210.3. Lack of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4310.4. Clinical Laboratory Abnormalities and Other Abnormal

Assessments as AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4310.5. Time Period, Frequency, and Method of Detecting AEs and SAEs . 4310.6. Recording of AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4410.7. Evaluating AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

10.7.1. Assessment of Intensity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4410.7.2. Assessment of Causality . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

10.8. Follow-up of AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4510.9. Prompt Reporting of SAEs to GSK . . . . . . . . . . . . . . . . . . . . . . . . . 45

10.9.1. Timeframes for Submitting SAE Reports to GSK . . . . . . . . . 4610.9.2. Completion and Transmission of the SAE Reports . . . . . . . . 46

10.10. Regulatory Reporting Requirements For SAEs . . . . . . . . . . . . . . . 4610.11. Post-study AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4710.12. SAEs Related to Study Participation . . . . . . . . . . . . . . . . . . . . . . . 47

11. MEDICAL DEVICES — INCIDENTS AND NEAR—INCIDENTS(INCLUDING MALFUNCTIONS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4711.1. Definitions of a Medical Device, Incident, Near—incident,

Malfunction, and Remedial Action . . . . . . . . . . . . . . . . . . . . . . . . . . . 4711.2. Time Period for Detecting Medical Device Incidents and

Near—incidents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4811.3. Documenting Medical Device Incidents and Near—incidents . . . . . 4911.4. Follow-up of Medical Device Incidents and Near—incidents . . . . . . 4911.5. Prompt Reporting of Medical Device Incidents and

Near—incidents to GSK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4911.5.1. Timeframes for Submitting Medical Device Incident and

Near—incident Reports to GSK. . . . . . . . . . . . . . . . . . . . . . . . 4911.5.2. Transmission of Medical Device Incident and

Near—incident Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5011.6. Regulatory Reporting Requirements For Medical Devices . . . . . . . 5011.7. Post-study Medical Device Incidents and Near—incidents . . . . . . . 50

12. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS . . . . . . . . . . 5012.1. Hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5012.2. Treatment Comparisons of Interest . . . . . . . . . . . . . . . . . . . . . . . . . 51

12.2.1. Primary Comparisons of Interest . . . . . . . . . . . . . . . . . . . . . . 5112.2.2. Other Comparisons of Interest . . . . . . . . . . . . . . . . . . . . . . . . 51


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12.3. Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5112.4. Sample Size Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

12.4.1. Sample Size Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . 5112.4.2. Sample Size Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5112.4.3. Sample Size Re—estimation . . . . . . . . . . . . . . . . . . . . . . . . . 52

12.5. Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5212.5.1. Data Sets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

12.6. General Considerations for Data Analysis . . . . . . . . . . . . . . . . . . . . 5312.6.1. Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5312.6.2. Missing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5312.6.3. Derived and Transformed Data . . . . . . . . . . . . . . . . . . . . . . . 5312.6.4. Assessment Windows . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5312.6.5. Other Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

12.7. Efficacy Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5412.7.1. Primary Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5412.7.2. Secondary Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

12.8. Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5512.8.1. Extent of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5512.8.2. Adverse Events (AEs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5512.8.3. Clinical Laboratory Evaluations . . . . . . . . . . . . . . . . . . . . . . . 5612.8.4. Other Safety Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

12.9. Health Outcomes Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5612.10. Clinical Pharmacology Data Analyses . . . . . . . . . . . . . . . . . . . . . . 57

12.10.1. Pharmacokinetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . 5712.10.2. Pharmacodynamic Analyses . . . . . . . . . . . . . . . . . . . . . . . . 5712.10.3. Pharmacokinetics/Pharmacodynamics Analyses . . . . . . . . 57

12.11. Biomarker(s) Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5712.12. Viral Genotyping/Phenotyping Analyses . . . . . . . . . . . . . . . . . . . . 5712.13. Pharmacogenetics Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

13. STUDY ADMINISTRATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5913.1. Regulatory and Ethical Considerations . . . . . . . . . . . . . . . . . . . . . . 59

13.1.1. Regulatory Authority Approval . . . . . . . . . . . . . . . . . . . . . . . . 5913.1.2. Ethical Conduct of the Study and Ethics Approval . . . . . . . . . 5913.1.3. Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6013.1.4. Investigator Reporting Requirements. . . . . . . . . . . . . . . . . . . 60

13.2. Study Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6013.3. Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62


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13.4. Study and Site Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6213.5. Records Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6313.6. Provision of Study Results and Information to Investigators . . . . . . 6313.7. Information Disclosure and Inventions . . . . . . . . . . . . . . . . . . . . . . . 6313.8. Data Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6513.9. Independent Data Monitoring Committee (IDMC) . . . . . . . . . . . . . . 6513.10. Confidentiality of Subject’s PGx Data . . . . . . . . . . . . . . . . . . . . . . 65

14. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

15. APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6715.1. Appendix 1: Time and Events Schedule . . . . . . . . . . . . . . . . . . . . . 6715.2. Appendix 2: Pharmacogenetic and Population Pharmacokinetic

Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6815.3. Appendix 3: Country Specific Requirements . . . . . . . . . . . . . . . . . 71


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ABBREVIATIONS

AE Adverse Event ANCOVA Analysis of Covariance CRF Case Report Form CYP Cytochrome P450 DNA Deoxyribonucleic Acid DRC Daily Record Card ECG Electrocardiogram EDTA Ethylene Diamine Tetraacetic Acid EISR Expedited Investigator Safety Report FEV1 Forced Expiratory Volume in 1 Second FP Fluticasone Propionate GCP Good Clinical Practice GSK GlaxoSmithKline HPA Hypothalamic-Pituitary-Adrenal HVTs Human Volunteers IB Investigator’s Brochure ICS Inhaled Corticosteroid IEC Independent Ethics Committee IRB Institutional Review Board ITT Intent-To-Treat MDI Metered Dose Inhaler PC20 Concentration of AMP resulting in a 20% fall in FEV1 PEF Peak Expiratory Flow PGx Pharmacogenetics PK Pharmacokinetics PP Per Protocol RAP Reporting Analysis Plan SAE Serious Adverse Event SCAD System for Central Allocation of Drug SNP Single Nucleotide Polymorphism

Trademarks

GSK Trademarks Trademarks not owned by GlaxoSmithKline

DISKHALER NA VENTOLIN ROTADISK DISKUS/ACCUHALER


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PROTOCOL SUMMARY

Rationale

For inhaled corticosteroids (ICS), the timing of the dose may be an important consideration for a product administered once daily. Afternoon or early evening single daily dosing tends to be superior in efficacy to a morning-only dosing schedule. It has also been suggested that the timing of ICS administration may be an important factor in relation to steroid interruption of the inflammatory cascade associated with the nocturnal symptoms of asthma.

ICS are generally devoid of harmful side effects especially when given at low to moderate doses (Global Initiative For Asthma [GINA]). Even in subjects with severe asthma, where there is a need for higher doses, the benefits far out weigh the risks. Studies of adrenocortical suppression with once daily dosing of ICS have not found significant effects (except with high doses). Clinical studies do not appear to indicate that time of administration plays a role in determining the safety profile of an ICS. However, pharmacokinetic (PK) and pharmacodynamic modelling suggests inhalation of a corticosteroid in the afternoon may have a less significant effect on cortisol suppression than a dose taken in the morning; the optimum time point being determined by the terminal elimination half-life of the drug. For fluticasone propionate the best time is 15.00 and for flunisolide 19.00.

The primary objective is to evaluate the effect of time of administration (morning versus evening) on the mean change in daily peak expiratory flow (PEF) over the 28-day treatment period. Secondary objectives assess the effect of time of dosing on safety and other efficacy parameters, and the safety and efficacy of GW685698X compared with placebo. Effects on the hypothalamic-pituitary-adrenal (HPA)-axis (24 hour urinary cortisol) and population pharmacokinetics (PK) will also be evaluated. The higher dose of 250 µg GW685698X has been included to provide useful dose response information.

Data generated from FFA20001 should provide information on the potential benefits gained from the use of GW685698X and whether further development is warranted. The data will provide information on the appropriate doses for the definitive dose ranging studies in Phase IIB.

Objective(s)

Primary

• To evaluate the effect of time of dosing (morning vs. evening) of GW685698X 100µg once daily, administered by inhalation via DISKHALER on the mean change in daily trough (pre-study treatment and pre-bronchodilator) PEF during the 28-day treatment period.


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Secondary

• To compare the efficacy of GW685698X 250µg once daily, with GW685698X 100µg once daily, both administered in the evening.

• To compare the safety and tolerability of GW685698X 250µg once daily, with GW685698X 100µg once daily both administered in the evening.

• To compare the efficacy and safety of the three GW685698X treatment regimens with placebo.

• To evaluate the effect of time of dosing (morning vs. evening) on the safety and tolerability of 100µg GW685698X once daily.

Other

• To characterise the population PK of GW685698X in subjects with persistent asthma.

• If at any time it appears there is potential variability in GW685698X response or handling (e.g., PK, safety, and/or efficacy) in this clinical study or in a series of clinical studies, the pharmacogenetic objectives may be investigated.

Endpoint(s)

Primary

• Mean change from baseline in daily trough (pre-study treatment and pre-bronchodilator) PEF (recorded in the daily record card [DRC]) during the 28-day treatment period with GW685698X 100µg once daily in the morning compared with GW685698X 100µg once daily in the evening by inhalation via DISKHALER.

Secondary

Efficacy



• Change from baseline in pre-bronchodilator clinic lung function (forced expiratory volume in 1 second [FEV1] and PEF) after 28 days of treatment with GW685698X 250µg once daily in the evening compared with GW685698X 100µg once daily in the evening.


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• Comparison of the following asthma symptom scores will be made during the 28-day treatment period, as assessed from the DRC, between GW685698X 100µg once daily administered in the evening and in the morning; between GW685698X 250µg once daily administered in the evening and GW685698X 100µg in the evening; and between all active treatments compared with placebo:


• Percentage of VENTOLIN (salbutamol)-free 24-hour periods, days, and nights.



Safety

• Incidence of adverse events throughout the 28-day treatment period.




• 12-lead electrocardiogram before and after 28 days of treatment.

• Physical examination and before and after 28 days of treatment.


Other


Study Design

This will be a Phase IIa randomised, double-blind, double-dummy, placebo-controlled, parallel-group, multi-centre study. Subjects will attend the clinic at Visit 1 (screening visit), and start a 1-week run-in period. On entry to the run-in period, subjects will have their usual short acting inhaled β2-agonists stopped and inhaled VENTOLIN will be provided for symptomatic relief during both the run-in and treatment periods. Subjects who fail to meet the eligibility criteria after 1 week may continue in the run-in period for a further two one-week periods. At Visit 2 subjects meeting the eligibility criteria will be randomised to the treatment phase of the study. Subjects will then attend 4 on-treatment


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visits at weekly intervals (Visits 3, 4, 5, and 6, weeks 1, 2, 3, and 4, respectively). Subjects will receive treatment for 28 days (4 weeks). A follow-up visit will be performed 1 week after completing study medication (Visit 7, week 5). Subjects will therefore participate in the study for a total of 6 to 8 weeks.

Male or female subjects aged 16 to 55 years with a clinical history of persistent asthma, diagnosed at least 6 months prior to Visit 1, and currently receiving inhaled short-acting β2-agonists will be eligible for the study.

Study Population

Approximately 600 subjects will be screened to achieve 492 randomised subjects (123 per group). The study will be conducted in approximately 14 countries in Europe, Latin America and South Africa.

Study Assessments and Procedures

Efficacy

Throughout the study subjects will record the following parameters in a DRC:

• Morning PEF (L/min).

• Evening PEF (L/min).

• Day-time and night-time asthma symptom scores.

• Number of occasions that rescue VENTOLIN was used during the day and night.

• Night-time awakenings due to asthma symptoms.

FEV1 will be measured at the clinic visits electronically from flow-volume curves generated by spirometry. The highest of three technically acceptable measurements will be recorded in the case report form. FEV1 will be measured at Visits 1 to 6, prior to any rescue VENTOLIN use. At Visit 1 or Visit 2, PEF will be measured before, and again 20 minutes after, inhalation of up to 400µg salbutamol. PEF will also be measured at the other clinic visits using the subject’s Peak Flow Meter.

Safety

The following safety evaluations will be performed:

• Pregnancy tests will be performed in all females of child-bearing potential prior to the subject entering the treatment phase of the study (Visit 1, and 1a and 1b as applicable), at Visit 4, and at the end of the end of the study (Visit 7, Follow-up Visit).


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• Adverse events and concomitant medication will be recorded on an ongoing basis throughout the study.

• Physical examinations, 12-lead ECG, and laboratory safety tests (haematology, biochemistry, and dipstick urinalysis) will be performed at Visits 1 and 6. If there are any clinically significant abnormalities at Visit 6, further examinations will be performed at Visit 7 (Follow-up Visit).

• Vital sign assessments will be carried out at all visits.

• Oropharyngeal examinations will be carried out at all visits for visual evidence of candidiasis.

• Urinary free cortisol from 24-hour urine collections will be measured to assess HPA-axis function at Visits 2 and 6.

Pharmacokinetics

A single blood sample will be collected from all subjects at Visits 3 and 6 (Weeks 1 and 4). At Visit 4 (Week 2) two blood samples will be obtained from each subject; one on arrival at the clinic visit and the other immediately prior to departure. The exact time of the sample, the time of the previous evening dose and the time of the morning dose will be recorded on the case report form.

Samples will only be collected at centres with the appropriate facilities.

Pharmacogenetics

In subjects who have consented, a blood sample should be taken at Visit 1.

Investigational Product(s)

At Visit 2, after the run-in period, subjects will be randomly assigned to one of the following treatments for 28 days:

• GW685698X 100µg administered once daily in the morning plus placebo in the evening.

• GW685698X 100µg administered once daily in the evening plus placebo in the morning.


• Placebo morning and evening. GW685698X will be administered via a dry powder inhaler device (DISKHALER), that contains a circular foil pack (ROTADISK) with 4 regularly distributed blisters, each containing a small quantity of blend of micronised GW685698X and lactose. Each blister contains approximately 25mg of drug/lactose blend providing either 100 or 250µg of GW685698X. These products are intended for oral inhalation.


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The placebo medication will be administered using the same delivery system as the study medication.

VENTOLIN for use with the MDI or DISKUS/ACCUHALER will be provided as rescue medication for symptomatic relief during the run-in and treatment period.


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1. INTRODUCTION

1.1. Background

Asthma is a chronic disease of the lungs characterised by airway inflammation, bronchoconstriction and increased airway responsiveness. Inhaled corticosteroids (ICS) are considered the most effective anti-inflammatory treatments for all severities of persistent asthma [British Thoracic Society, 1997, National Institutes of Health, 2000). The benefits of ICS include control of asthma symptoms, improvement in lung function, decrease in airway hyper-responsiveness and possibly, prevention of airway wall remodelling [Pedersen, 1997].

GW685698X is a novel glucocorticoid currently under development as an inhaled treatment for asthma. Pre-clinical data and Phase I studies indicate that GW685698X may have a longer duration of action than fluticasone propionate (FP) and therefore suitable for development for once daily administration. The availability of a once daily corticosteroid would be expected to improve compliance and therefore improve asthma control. Furthermore, if the molecule is retained in the lung rather than in the systemic circulation, it may give rise to a reduction in the dose required with corresponding improvement in the therapeutic index compared with other available medicines.

Pre-clinical Findings

The toxicity of GW685698X has been assessed following single and repeated administration for up to 4 weeks. Safety pharmacology and genetic toxicology have also been evaluated. To date, the compound has exhibited a pharmacological/toxicological profile expected for a corticosteroid and no unexpected safety signals have been identified.

Clinical Experience

The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of increasing single, inhaled doses of a dry powder formulation of GW685698X have been evaluated in healthy volunteers (HVTs) in studies FFA10001, FFA10003 and FFA10008. Doses up to 4000 µg were given, and the maximum tolerated dose was not reached. Once daily, repeat, inhaled doses of GW685698X 500 µg, 1000 µg, and 2000 µg have been evaluated in a 14-day safety, tolerability and PK/PD study (FFA10002). GW685698X has been found to be safe and well tolerated in these completed studies to date. No serious adverse events (SAEs) were reported, and the majority of adverse events (AEs) were mild in intensity. The most common AEs reported have been cough and headache. From the repeat dose study the incidence of cough was 11%, 11%, and 56% for GW685698X 500, 1000 and 2000µg, respectively, and 0% for placebo. There were no clinically significant changes in safety laboratory parameters, electrocardiogram (ECG) results, heart rate or systolic and diastolic blood pressure were reported. Lung function evaluations (performed for safety purposes in these studies) showed no


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indication of any treatment- or dose-related adverse effects on peak expiratory flow (PEF).

The effect of GW685698X on serum cortisol was investigated following single- and repeat-inhaled doses from 500 µg to 2000 µg once daily for 14 days. Significant reductions in serum cortisol were seen after single doses of 1000 µg and 2000 µg. Reductions of 40%, 81%, and 94% in mean serum cortisol were seen after repeat dosing of 500, 1000, and 2000 µg GW685698X, respectively, in comparison with placebo.

Further details of these studies can be found in the current version of the Investigator’s Brochure (IB).

Pharmacokinetics

The PK of GW685698X has been studied in four studies following inhaled dosing from a DISKHALER (FFA10001, FFA10002, FFA10003 and FFA10008). The dose range for these studies was 50 to 4000µg. Following single inhaled administration, GW685698X was rapidly absorbed with maximum plasma concentrations being observed, on average, 20 to 45 minutes after dosing. Thereafter, plasma concentrations of GW685698X declined biexponentially with an average terminal phase elimination half-life of approximately 27 hours at the highest dose. Further details of these studies can be found in the current version of the IB.

Pharmacogenetics

Pharmacogenetics (PGx) is the study of variability in drug handling or response due to hereditary factors in different populations. Further details about the PGx assessment can be found in Section 15.2, Appendix 2 “Pharmacogenetic and Population Pharmacokinetic Assessments”.

Population Pharmacokinetics

Population PK is the study of the sources and correlates of variability in drug concentrations among individuals who are the target subject population receiving clinically relevant doses of drug of interest. Further details about population PK assessments can be found in Section 15.2, Appendix 2 “Pharmacogenetic and Population Pharmacokinetic Assessments”.

1.2. Rationale

For ICS, the timing of the dose may be an important consideration for a product administered once daily. Afternoon or early evening single daily dosing tends to be superior in efficacy to a morning-only dosing schedule [Gagnon, 1994; Pincus, 1995]. It has also been suggested that the timing of ICS administration may be an important factor in relation to steroid interruption of the inflammatory cascade associated with the nocturnal symptoms of asthma.


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ICS are generally devoid of harmful side effects especially when given at low to moderate doses (Global Initiative For Asthma [GINA]) [National Institutes of Health, 1998]. Even in subjects with severe asthma, where there is a need for higher doses, the benefits far out weigh the risks. Studies of adrenocortical suppression with once daily dosing of ICS have not found significant effects (except with high doses) [Wilson, 1998]. Studies do not appear to indicate that time of administration plays a role in determining the safety profile of an IC. However, PK and pharmacodynamic (PD) modelling suggests inhalation of a corticosteroid in the afternoon may have a less significant effect on cortisol suppression than a dose taken in the morning; the optimum time point being determined by the terminal elimination half-life of the drug. For FP, the optimum time is 15.00h and for flunisolide 19.00h [Meibohm, 1997].

The primary objective is to evaluate the effect of time of administration (morning versus evening) on the mean change in daily PEF over the 28-day treatment period. Secondary objectives assess the effect of time of dosing on safety and other efficacy parameters, and the safety and efficacy of GW685698X compared with placebo. Effects on the hypothalamic-pituitary-adrenal (HPA)-axis (24 hour urinary cortisol) and population PK will also be evaluated. The higher dose of 250 µg GW685698X has been included to provide useful dose response information.


Pharmacokinetics Rationale

This is the first time subjects with persistent asthma will receive GW685698X. This is therefore an important opportunity to obtain PK information in an asthmatic population. It would not be practical to conduct traditional PK in this study and therefore, a population PK approach is appropriate. Moreover, utilisation of a population approach will enable an evaluation of factors that may influence the PK of GW685698X in this subject population and an assessment of the random variability.

Pharmacogenetic Rationale

If at any time it appears that there is a potential unexpected or unexplained variation in response to or handling of GW685698X (e.g., PK, efficacy and/or safety) that may be attributable to genetic variation, then PGx analysis may be conducted. Further details can be found in Section 15.2, Appendix 2 “Pharmacogenetic and Population Pharmacokinetic Assessments”.

Sample Quality Control (QC)

If deoxyribonucleic acid (DNA) is extracted from blood samples taken from the clinical study, the DNA may be subjected to sample QC analysis. This analysis will involve the


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genotyping of several genetic markers to confirm the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed.

2. OBJECTIVE(S)

2.1. Primary

• To evaluate the effect of time of dosing (morning vs. evening) of GW685698X 100µg once daily, administered by inhalation via DISKHALER on the mean change in daily trough (pre-study treatment and pre-bronchodilator) PEF during the 28-day treatment period.

2.2. Secondary





2.3. Other Objectives

• To characterise the population PK of GW685698X in subjects with persistent asthma.

• If at any time it appears there is potential variability in GW685698X response or handling (e.g., PK, safety, and/or efficacy) in this clinical study or in a series of clinical studies, the following objectives may be investigated (assuming sample number is adequate and the availability of genotyping assays):

• Relationship between genetic variants and the PK of GW685698X

• Relationship between genetic variants and safety and/or tolerability of GW685698X

• Relationship between genetic variants and efficacy of GW685698X

3. ENDPOINT(S)

3.1. Primary

• Mean change from baseline in daily trough (pre-study treatment and pre-bronchodilator) PEF (recorded in the daily record card [DRC]) during the 28-day


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treatment period with GW685698X 100µg once daily in the morning compared with GW685698X 100µg once daily in the evening by inhalation via DISKHALER.

3.2. Secondary

3.2.1. Efficacy







• Percentage of VENTOLIN (salbutamol)-free 24-hour periods, days, and nights.


• Withdrawals due to lack of efficacy (i.e., Section 6.3.3 “Withdrawal Criteria for Lack of Efficacy”) during the 28-day treatment period with each GW685698X treatment group compared with placebo.

3.2.2. Safety

• Incidence of AEs throughout the 28-day treatment period.




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• 12-lead ECG before and after 28 days of treatment.

• Physical examination before and after 28 days of treatment.


3.2.3. Other


4. STUDY DESIGN

This will be a Phase IIa randomised, double-blind, double-dummy, placebo-controlled, parallel-group, multi-centre study. Approximately 600 subjects will be screened to achieve 492 randomised subjects (123 per group). The study will be conducted in approximately 14 countries in Europe, Latin America and South Africa. There will be approximately 70 centers and subjects will be randomised on a 1:1:1:1 equal allocation ratio basis at each center. Subjects will be included on an out-patient basis. The study is expected to start in September 2003 and finish in March 2004.

Subjects will attend the clinic on seven to nine occasions according to the following schedule:

GW685698X100µg OD (AM)

GW685698X100µg OD (PM)

GW685698X250µg OD (PM)

PLACEBO

VisitWeek

20

1-3 to -1 weeks

1a 1b 64

53

42

31

7+1

Run-in 4 week treatment 1 week

follow-up

Randomisation

At Visit 1 subjects will be asked to sign the informed consent form before participating in any study related activities. Eligible subjects will then enter the run-in period, at which time they will have their usual short acting inhaled beta2-agonists stopped and inhaled


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VENTOLIN will be provided for symptomatic relief during both the run-in and treatment periods. Subjects will have been free of inhaled and intranasal corticosteroids, and leukotriene antagonists, for at least 4 weeks prior to entry into the run-in period, and ketotifen for 2 weeks prior to the start of the study (for details of other prohibited medications see Section 8.2 “Prohibited Medications”). Any permitted asthma medications should be taken at a constant dose for the 4 weeks prior to Visit 1 and throughout the study. Subjects who meet the eligibility criteria for study treatment at the end of the run-in period will be randomly assigned to receive one of four treatment groups as follows:

• GW685698X 100µg administered once daily in the morning plus placebo in the evening.



• Placebo morning and evening.

Subjects who fail to meet the eligibility criteria after 1 week may continue in the run-in period for a further two 1-week periods. If subjects have not met the criteria for randomisation after 3 weeks they will be withdrawn from the study. There will be a 1-week follow-up period after the treatment period, where appropriate alternative asthma therapy will be prescribed. Subjects will therefore participate in the study for a total of 6 to 8 weeks.

Visit 1: Screening visit (-3 to -1 weeks). Start of run-in period.

Visits 1a and 1b: Additional weeks of run-in period (–2, and –1 weeks) for subjects who fail to meet the randomisation criteria due to lack of symptoms or the required obstruction in lung function.

Visit 2: End of run-in (Week 0). To confirm eligibility to enter the double-blind treatment phase, and to assess baseline measurements of efficacy and safety parameters.

Visits 3, 4 and 5: Weekly intervals after initiating treatment (Weeks 1, 2, and 3, ±2 days). On- treatment visits to measure relevant efficacy and safety parameters.

Visit 6: After 4 weeks of treatment (end of treatment period) (Week 4 ±2 days). To perform end of treatment measurements of efficacy and safety parameters, conclude treatment and prescribe appropriate asthma medication.

Visit 7: End of Follow-up period (7 days ±2 days after end of treatment). To monitor post-treatment AEs, and to assess the results of any outstanding laboratory assessments.

For further details of the specific assessments performed at each visit see Section 15.1. Appendix 1 “Time and Events Schedule”.


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5. STUDY POPULATION

5.1. Number of Subjects

Approximately 600 subjects will be screened to achieve 492 randomised subjects (123 per group).

5.2. Eligibility Criteria

5.2.1. Inclusion Criteria

A subject will be eligible for inclusion in the run-in period for this study only if all of the following criteria apply:


A female is eligible to enter and participate in the study if she is of:

a Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who is post-menopausal. For the purposes of this study, post-menopausal is defined as 1 year without menses; or

b Child-bearing potential, has a negative pregnancy test (urine) at entry, and agrees to one of the following acceptable contraceptive methods when used consistently and correctly (i.e., in accordance with the approved product label and the instructions of a physician for the duration of the study – screening visit to follow-up contact):

• Complete abstinence from intercourse from first visit, throughout the treatment phase, and for 2 weeks following study completion; or

• Sterilisation of male partner; or

• Implants of levonorgestrel inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion; or

• Injectable progestogen administered for at least 1 month prior to the study medication administration and administered for 1 month following study completion; or

• Oral contraceptive (combined or progestogen only) administered for a least one monthly cycle prior to study medication administration; or

• An intrauterine device (IUD), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year; or

• Any other methods with published data showing that the highest expected failure rate is less than 1% per year.

2. Documented clinical history of persistent asthma first diagnosed at least 6 months prior to Visit 1.


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3. Currently receiving inhaled short-acting β2-agonists for symptom relief.

4. Able and willing to give written informed consent to take part in the study.

5. Able to comply with all the study requirements.

6. A lung function of between 50 to 90% predicted (PEF).

7. Increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol (if patients do not fulfil the criteria at Visit 1, the test may be repeated at visit 1a/1b/2).

Additional Inclusion Criteria for Randomisation to Treatment

At the end of the run-in period subjects must fulfil the following additional criteria from DRC recordings in order to enter the treatment period of the study:

1. Increase in PEF of ≥15% 20 minutes after inhalation of 400µg salbutamol, if not demonstrated at Visit 1.

2. Mean morning PEF (calculated from the last 7 consecutive days of the final run-in period) of between 50% and 80% of their percent predicted normal.

3. Daily asthma symptom score (day-time plus night-time) of >1 on at least four of the last 7 consecutive days of the final run-in period.

Additional Inclusion Criteria for Pharmacogenetic Study

Any subject who has given informed consent to participate in the clinical study, has met all the criteria required for entry into the clinical study, and receives investigational product may take part in the PGx research. Any subject who has received a bone marrow transplant must be excluded from the PGx research.

Subject participation in the PGx research is voluntary and refusal to participate will not indicate withdrawal from the clinical study. Refusal to participate will involve no penalty or loss of benefits to which the subject would otherwise be entitled.

No administration of investigational product beyond that detailed in the clinical study is associated with the PGx research.

Employees of GSK enrolled in the clinical study will not be eligible for participation in disease-based diagnostic research.

5.2.2. Exclusion Criteria

A subject will not be eligible for inclusion in the run-in period for this study if any of the following criteria apply:

1. History of respiratory tract infection and/or exacerbation of asthma within a period of 4 weeks prior to Visit 1.

2. History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnoea, respiratory arrest or hypoxia seizures.


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3. A history of two or more asthma exacerbations requiring treatment with oral corticosteroids or hospitalisation in the 6 months before Visit 1.

4. Previously enrolled in this study, or currently participating or has participated in another study during the last 3 months.

5. Past or present disease that, as judged by the investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematologic disease, neurological disease, endocrine disease or pulmonary disease (including, but not confined to, chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis and bronchopulmonary dysplasia).

6. Known or suspected sensitivity to corticosteroids, VENTOLIN, or the constituents of ROTADISKS (e.g., lactose).

7. Undergoing allergen desensitisation therapy.

8. Subjects who are likely to be non-compliant with study medication and other study-related requirements (e.g., attendance at clinic visits or completion of DRCs).

9. Neurological or psychiatric disease or history of drug or alcohol abuse that would interfere with the subject’s proper completion of the protocol requirements.

10. Is a current smoker or has a smoking history of 10 pack years or more (e.g., 20 cigarettes/day for 10 years). Note: Current smoker is defined as currently smoking or stopped smoking within 6 months of screening visit.

11. Administration of the following medications:

Theophyllines, oral β2-agonists, slow-release bronchodilators, anticholinergics, long-acting β2-agonists, or ketotifen, within 2 weeks prior to Visit 1.



Additional Exclusion Criteria for Randomisation to Treatment

At the end of the run-in period subjects will not be eligible to enter the treatment period of the study if they meet any of the following criteria:

1. Evidence of clinically significant abnormality in the haematological, biochemical or dipstick urinalysis screen, or 12-lead ECG at Visit 1.

2. Changes in asthma medication (excluding rescue VENTOLIN provided at Visit 1).

3. Occurrence of an upper or lower respiratory tract infection during the run-in period.

4. Exacerbation of asthma symptoms during the run-in period.

5. Non-compliance with completion of the DRC; the DRC must have been completed for 6 out of last 7 days prior to Visit 2 to confirm compliance.


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5.2.3. Other Eligibility Criteria Considerations

To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document for detailed information regarding warnings, precautions, contraindications, AEs, and other significant data pertaining to the investigational product(s) being used in this study: Investigator’s Brochure.

6. STUDY ASSESSMENTS AND PROCEDURES

A schedule of the measurements and evaluations performed at each of the clinic visits is summarised in Section 15. Appendix 1 “Time and Events Schedule”.

6.1. Demographic and Baseline Assessments

The following will be recorded in the case report form (CRF) at Visit 1:

• Gender, ethnic origin, date of birth, weight, height and smoking history.

• History of asthma including duration of asthma and exacerbations in the 6 months prior to Visit 1.

• History and concurrent conditions.

• Concomitant medication (asthma and non-asthma)

Results of the urine pregnancy test will be recorded separately to the CRF.

At Visit 1 or Visit 2, PEF will be measured before and again 20 minutes after inhalation of up to 400µg salbutamol. Subjects who fail to demonstrate a ≥15% increase in PEF will not be eligible to take part in the study.

Percent reversibility will be calculated as follows:

Post-bronchodilator PEF – Pre-bronchodilator PEF X 100% Pre-bronchodilator PEF

6.2. Safety

6.2.1. Pregnancy

6.2.1.1. Pregnancy Testing

Pregnancy tests will be performed in all females of child-bearing potential prior to the subject entering the treatment phase of the study (Visit 1, and 1a and 1b as applicable), at Visit 4, and at the end of the end of the study (Visit 7, Follow-up Visit).


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6.2.1.2. Time Period for Collecting Pregnancy Information

If pregnancy occurs during the screening/run-in period, prior to study drug administration, the subject should be withdrawn, and the outcome of the pregnancy will not be reported. Information on whether a pregnancy has occurred must be collected and recorded from the start of the treatment period (Visit 2) until the final visit (Visit 7).

6.2.1.3. Action to be Taken if Pregnancy Occurs

The investigator, or his/her designee, will collect pregnancy information on any female subject who becomes pregnant while participating in this study. The investigator, or his/her designee, will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of a subject’s pregnancy. The subject will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or a SAE, as described in Section 10.6., "Recording of AEs and SAEs" and will be followed as described in Section 10.8., "Follow-up of AEs and SAEs."

A spontaneous abortion is always considered to be a SAE and will be reported as described in Section 10, “Adverse Events (AE) and Serious Adverse Events (SAE).” Furthermore, any SAE occurring as a result of a post-study pregnancy and considered reasonably related to the investigational product by the investigator, will be reported to GSK as described in Section 10.11., "Post-study AEs and SAEs." While the investigator is not obligated to actively seek this information in former study participants, he/she may learn of an SAE through spontaneous reporting.

Anybody who becomes pregnant while participating in this study will be withdrawn from the study.

6.2.2. Adverse Events and Concomitant Medications

AEs and concomitant medication will be recorded on an ongoing basis throughout the study. Each AE that occurs during the study must be documented in the CRF (see Section 10. “Adverse Events [AE] and Serious Adverse Events [SAE]”). If there has been a change in the subject’s concomitant medication associated with the AE, this must be documented in the appropriate section of the CRF.

6.2.3. Physical Examination

Physical examinations will be performed at Visits 1, and 6. If the physical examination shows any clinically significant abnormalities at Visit 6, a further examination will be performed at Visit 7 (Follow-up Visit). The physical examinations will be recorded in the CRF.


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6.2.4. Examination of Oropharynx

Oropharyngeal examinations will be carried out at all visits for visual evidence of candidiasis. If there is any clinical evidence of candidiasis, a swab will be taken and analysed locally. If the swab is positive, appropriate treatment should be prescribed (if necessary) and details documented in the concomitant medication and AE sections of the CRF (if there is evidence of a new occurrence of candidiasis, or worsening of the condition from baseline, this is to be recorded as an AE).

6.2.5. Vital Signs

Vital signs (systolic and diastolic blood pressure and pulse rate) will be measured after 5 minutes rest in the sitting position at Visits 1 to 6. If there are any clinically significant abnormalities at Visit 6, further examinations will be performed at Visit 7 (Follow-up Visit). These measurements will be taken before the clinic lung function tests.

6.2.6. 12-lead ECG

A 12-lead ECG examination will be recorded at Visits 1, and 6. If there are any clinically significant abnormalities at Visit 6, further examinations will be performed at Visit 7 (Follow-up Visit).

6.2.7. Laboratory Safety Tests

Blood and urine samples will be taken at Visits 1, and 6. If there are any clinically significant abnormalities at Visit 6, further examinations will be performed at Visit 7 (Follow-up Visit).

Clinical chemistry: a 4mL whole blood sample will be collected into a plain glass tube with a gel activator and the supernatant serum will analysed for: sodium, potassium, phosphate, calcium, chloride, bicarbonate, glucose, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, total protein, globulin, albumin, total bilirubin, creatinine, urea, and uric acid.

Haematology: a 2mL whole blood sample will be collected into a tube containing ethylene diamine tetraacetic acid (EDTA) for analysis of: haemoglobin, red blood cells, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, haematocrit, platelets, white blood cells, differential white cell counts (neutrophils, lymphocytes, monocytes, eosinophils, basophils).

A urine sample will be collected for dipstick urinalysis tests.

Laboratory data will be analysed using a central laboratory.

6.2.8. Urinary Cortisol Assessments

Urinary free cortisol from 24-hour urine collections will be measured to assess HPA-axis function at Visits 2 and 6.


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Collections should be made on the day prior to Visit 2 and 6, and must be as near 24 hours in duration as possible. Subjects should void their bladder just before beginning collection of urine and discard this sample. They will then collect all urine in the containers provided. At the end of the 24-hour collection subjects will void their bladder again, this time keeping the sample. They must then bring the collected samples to the clinic at Visits 2 and 6.

The total volume of urine collected (in mL) will be recorded in the CRF and approximately 20mL will be kept for analysis, appropriately labelled and stored prior to being sent to the central laboratory for analysis. If the sample is not collected correctly for any reason (for example, incomplete collection or wrong start and finish times) this must be clearly recorded on the CRF.

The central laboratory will supply all instructions and necessary containers for collection, storage and transport of the urine samples in a separate manual.

6.3. Efficacy

6.3.1. Clinic Lung Function Tests During Study Visits

FEV1 will be measured at the clinic visits electronically from flow-volume curves generated by spirometry. The highest of three technically acceptable measurements will be recorded in the CRF. FEV1 will be measured at Visits 1 to 6, prior to any rescue VENTOLIN use. If there are any clinically significant abnormalities at Visit 6, further examinations will be performed at Visit 7 (Follow-up Visit). The spirometry printouts for FEV1 should be initialled, and dated, and the subject number, visit number and time of assessment recorded by the person responsible for generating the data. The printouts should be retained in the subject’s medical notes.

PEF will also be measured at clinic visits using a hand-held Peak Flow Meter. The best of three attempts will be recorded in the CRF.

Subjects will be asked to refrain from using their VENTOLIN for 6 hours prior to the clinic visit if possible.

If possible subjects will attend the clinic at the same time of day (±2 hours) for each visit throughout the study.

6.3.2. Daily Record Card Data

Subjects will be issued with a paper DRC at the start of the run-in period and each treatment period and instructed on how to complete them. Throughout the study subjects will record the following parameters in the DRC:

• Morning PEF (L/min).

• Evening PEF (L/min).

• Day-time and night-time asthma symptom scores.


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• Number of occasions that rescue VENTOLIN was used during the day and night.


• Time study medication taken.

6.3.2.1. Morning and Evening PEF

Morning and evening PEF will be measured using a hand-held Peak Flow Meter (mini-Wright) that will be issued to subjects at Visit 1. The best of three attempts will be recorded by the subjects in the DRC.

• PEF will be measured:

- Each morning prior to study medication dose and any rescue VENTOLIN use.

- Each evening prior to study medication dose and any rescue VENTOLIN use.

6.3.2.2. Asthma Symptom Scores During the Day and at Night

The following will be recorded daily before taking any study or rescue medication:

• Day-time Symptom Score:

0 = No symptoms during the day

1 = Symptoms for one short period during the day

2 = Symptoms for two or more short periods during the day

3 = Symptoms for most of the day which did not affect my normal daily activities

4 = Symptoms for most of the day which did affect my normal daily activities

5 = Symptoms so severe that I could not go to work or perform normal daily activities

• Night-time Symptom Score:

0 = No symptoms during the night

1 = Symptoms causing me to wake once (or wake early)

2 = Symptoms causing me to wake twice or more (including waking early)

3 = Symptoms causing me to be awake for most of the night

4 = Symptoms so severe that I did not sleep at all.

6.3.3. Withdrawal Criteria for Lack of Efficacy

To assist the subject and/or investigator in identifying a worsening of asthma, ‘ALERT VALUES’ will be calculated by the investigator and noted in the subjects DRC. Subjects meeting one of the following criteria will be withdrawn from the study.

1. PEF fall of ≥20% from subject’s baseline value for 3 consecutive days.


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2. Clinic FEV1 fall of ≥20% from value at Visit 2.

3. Increase in rescue medication use from mean baseline value (individualised per subject) by ≥2 occasions/day for ≥3 consecutive days.

Plus at least on of the following:

• Increase in symptom score from mean baseline value (individualised per subject) by ≥2 /day for ≥3 consecutive days.

• Increase in night-time awakenings from mean baseline value (individualised per subject) by ≥2 occasions/day for ≥3 consecutive days.

PLEASE NOTE

Subjects should be advised to contact the investigator if they experience any one of the above criteria. The investigator may then review the change in the subject's asthma and decide if further action is required.

6.4. Pharmacokinetics

A single blood sample will be collected from all subjects at Visits 3 and 6 (Weeks 1 and 4). At Visit 4 (Week 2) two blood samples will be obtained from each subject; one on arrival at the clinic visit and the other immediately prior to departure. The exact time of the sample, the time of the previous evening dose and the time of the morning dose will be recorded on the case report form.

A 4mL blood sample will be collected into a potassium EDTA tube by direct venepuncture. Samples will be centrifuged, within 1 hour of collection, at approximately 1500g for 10 minutes. Supernatant plasma (approximately 1.2mL) will be transferred to a 3.6mL Nunc tube and stored at approximately -20°C prior to shipment. Samples will be shipped frozen on dry ice at agreed time points throughout the study.

Blood samples for PK analysis will only be collected at centres where the appropriate facilities are available.

6.5. Pharmacodynamics

Not applicable.

6.6. Biomarker(s)

Not applicable.

6.7. Viral Genotyping and Phenotyping

Not applicable.


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6.8. Health Outcomes

Not applicable.

6.9. Pharmacogenetics

In addition to any blood samples taken for the clinical study, a whole blood sample (10mL) will be collected for the PGx research using a tube containing EDTA. The PGx sample is labelled (or “coded”) with a study specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers (e.g., such as name or social security number). The blood sample will be taken on a single occasion (at Visit 1) unless a duplicate sample is required due to inability to utilise the original sample. It is recommended that the blood sample be taken at the first available opportunity, but may be taken at any time while the subject is participating in the clinical study.

7. INVESTIGATIONAL PRODUCT(S)

7.1. Description of Investigational Product

GW685698X will be supplied by Clinical Trial Supplies, GSK, Stevenage, UK. The placebo is identical to the investigational product, but contains only lactose.

Property Study Drug Placebo DISKHALER GW685698X DISKHALER Formulation Lactose Powder Lactose Blend Dosage Form ROTADISK (4-Blister) ROTADISK (4-Blister) Unit Dose Strength Not applicable 100 or 250µg per Blister Physical Description Dry white powder Dry white powder Manufacturer GSK GSK Route of Administration Inhaled Inhaled

VENTOLIN for use with the MDI or DISKUS/ACCUHALER will be provided as rescue medication for symptomatic relief during the run-in and treatment period. Local GSK operating companies will provide this from commercial stock.

7.2. Dosage and Administration

GW685698X will be administered via a dry powder inhaler device (DISKHALER), that contains a circular foil pack (ROTADISK) with 4 regularly distributed blisters, each containing a small quantity of blend of micronised GW685698X and lactose. Each blister contains approximately 25mg of drug/lactose blend providing either 100 or 250µg of GW685698X. These products are intended for oral inhalation.


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The placebo medication will be administered using the same delivery system as the study medication.

Subjects will take one of the following four treatment regimens, according to the randomisation schedule:

• GW685698X 100µg once daily in the morning plus placebo in the evening.



• Placebo twice daily in the morning and evening.

Subjects will be advised to take the morning dose of study medication on waking, and to take their evening dose just before going to bed. They will also be asked to take their morning and evening dose at approximately the same time each day (±2 hours).

Subjects will be issued with study medication at Visits 2. All treatments will be delivered by inhalation via the DISKHALER for a 28-day treatment period. Subjects should make measurements of evening and morning PEF, and asthma symptoms before taking any study or rescue medication. On the day of the study visits subjects will take their study medication as usual, but they will be advised not to take rescue medication until the lung function tests have been performed (see Section 6.3) at the clinic. If subjects do take any rescue medication the time taken should be recorded in the DRC.

VENTOLIN will be issued, as required, at Visits 1, 2 and 4.

7.3. Dose Rationale

The clinical doses of GW685698X in this study are based on the assumption that it has a similar potency to FP, but has a longer duration of effect due to longer lung retention time. It is anticipated that a 100µg dose of GW685698X once daily will have similar or greater efficacy than 100µg FP twice daily. A higher dose of GW685698X (250µg) will be included to provide useful dose response information. Both doses are expected to demonstrate beneficial effects in terms of lung function and asthma control.

GW685698X has been shown to be well tolerated in HVTs at doses up to 2000 µg for 14 days. In the repeat dosing study with once daily doses of GW685698X 500µg, volunteers experienced a reduction in plasma cortisol levels of around 40%. It is considered therefore that GW685698X doses of 100µg and 250µg will be well tolerated, and are appropriate for this study.



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7.4. Blinding

The study is a double-blind study; both the investigators and the study subjects will be blinded to study treatment. Central laboratory staff and local ECG readers will also be blinded to study treatment.

Only in the case of an emergency, when knowledge of the investigational product is essential for the clinical management or welfare of the subject, the investigator may unblind a subject’s treatment assignment. If the blind is broken for any reason, the investigator must notify GSK immediately of the unblinding incident without revealing the subject’s study treatment assignment. In addition, the investigator will record the date and reason for revealing the blinded treatment assignment for that subject in the appropriate CRF.

If a SAE, as defined in Section 10.2. "Definition of a SAE", is reported to GSK, Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment assignment for the individual subject. If an expedited regulatory report to one or more regulatory agencies is required, the report will identify the subject’s treatment assignment. When applicable, a copy of the regulatory report may be sent to investigators in accordance with relevant regulations, GSK policy, or both.

Subjects whose blind is broken by the investigator must be withdrawn from the study immediately.

7.5. Treatment Assignment

Subjects will be assigned to study treatment in accordance with the randomisation schedule, which will be generated by GSK using the validated computerised randomisation system RandAll.

Each participating centre in this study will be supplied with a list of subject numbers (assigned to each subject at Visit 1). Once the run-in has been completed successfully, eligible subjects will be assigned to study treatment in accordance with the central randomisation schedule (Visit 2). Randomisation will be centralised at the site level. A System for Central Allocation of Drug (SCAD) using an Interactive Voice Response System (IVRS), will be used to allocate treatment packs. Details of the central drug allocation procedure using SCAD will be outlined in a separate user manual that will be provided to each investigator.

Once a treatment number has been assigned to a subject it cannot be re-assigned to any other subject at that centre.

7.6. Packaging and Labelling

Blinded study medication will be packaged and labelled by GSK. Subjects will be issued sufficient inhalers/treatment packs to last for the entire study. Each inhalers/treatment pack will be labelled with the study number, container contents and quantity, storage information and the dosing instructions.


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The contents of the label will be in accordance with all applicable regulatory requirements.

7.7. Preparation

The DISKHALER will require no preparation by the Investigator. Individual DISKHALERS should not be removed from their foil packs until the day of dosing.

7.8. Handling and Storage

Investigational product must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive investigational product, in accordance with all applicable regulatory requirements. Only authorized site staff may supply or administer investigational product. All investigational products must be stored in a secure area with access limited to the investigator and authorized site staff and under physical conditions that are consistent with investigational product-specific requirements.

The study medication should be stored between 2 to 30°C.

All used and unused study medication and VENTOLIN should be returned to GSK (or designee of GSK) at or before the end of the study.

7.9. Product Accountability

The investigator is responsible for investigational product accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the investigator or designated site staff must maintain investigational product accountability records throughout the course of the study. This person(s) will document the amount of investigational product received from GSK, the amount supplied and/or administered to and returned by subjects, if applicable.

A drug dispensing and accountability log will be provided and the investigator or designee must record the number of inhalers/treatment packs dispensed to and returned by each subject. The subject must return all used blister packs at Visits 3, 4, 5, and 6, and the investigator or designee must reconcile or resolve any discrepancies. At Visit 6 the subject should also return any unused blister packs.

7.10. Assessment of Compliance

The returned blister packs collected at each visit will be used to assess compliance with the treatment regimen.

7.11. Treatment of Investigational Product Overdose

Very few data are available on overdose with GW685698X. However, during single dose studies with inhaled GW685698X, decreased mean serum cortisol was observed with


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doses of 500µg or higher. There are no recommended medications or non-drug therapies recommended for treatment of an overdose. Management should be supportive, and investigators should use their clinical judgement in treating any overdose situation.

7.12. Occupational Safety

GW685698X is not expected to pose significant occupational safety risk to site staff under normal conditions of use and administration. However, precautions are to be taken to avoid direct skin contact, eye contact, and generating aerosols or mists. In the case of unintentional occupational exposure, treat as if the substance contains the active pharmaceutical even though it is absent from placebo formulations, and notify the monitor. A Material Safety Data Sheet (MSDS) describing occupational hazards and recommended handling precautions either will be provided to the investigator, where this is required by local laws, or is available upon request from GSK.

8. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES

8.1. Permitted Medications

Asthma Medications

Short-acting β2-agonist asthma medications are permitted until Visit 1 only. At the end of Visit 1 VENTOLIN (for use with the MDI or DISKUS/ACCUHALER) will be provided as rescue medication for symptomatic relief during the run-in and treatment periods of the study.

Sodium cromoglycate and nedocromil sodium are permitted, but must be taken at a constant dose for the 4 weeks prior to Visit 1 and throughout the study.

Medication for Concomitant Disorders

All medications for other disorders may be continued throughout the study, provided the dose remains constant and their use would not be expected to affect a subject’s lung function.

All concomitant medications taken during the study will be recorded in the CRF with indication, dose information, and dates of administration.

8.2. Prohibited Medications

The following asthma medications are not permitted during the conduct of the study or within the specified time:


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• Theophyllines.

• Oral β2-agonists (e.g., bambuterol).

• Slow-release bronchodilators.

• Anticholinergics.

• Long-acting β2-agonists (e.g., salmeterol).

• Ketotifen.


• Anti-leukotrienes including suppressers of leukotriene production and antagonists.

• Inhaled corticosteroids.

• Intranasal corticosteroids.

• Combination therapy (containing β2-agonists and/or inhaled corticosteroids for asthma).

• Known inhibitors of CYP 3A4 (e.g. ritonavir).


• Systemic, oral, parenteral or depot corticosteroids

8.3. Medical Devices

The DISKHALER is a medical device. Any instrument used to make a measurement while physically in contact with a subject is a device and the Medicines and Healthcare products Regulatory Agency (MHRA) regulations of reporting incidents and near-incidents apply.

8.4. Non-drug Therapies

Not applicable.

9. SUBJECT COMPLETION AND WITHDRAWAL

9.1. Subject Completion

All subjects who attend all study visits, including the follow-up visit (Visit 7) are considered to have completed the study.


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9.2. Subject Withdrawal

9.2.1. Subject Withdrawal from Study

Premature discontinuation from the study occurs when a subject discontinues prior to the completion of the 28-day treatment period and 1 week follow-up period either voluntarily or is withdrawn by the investigator.

A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his or her discretion, discontinue the subject from participating in this study at any time. If a subject is prematurely discontinued from participation in the study for any reason, the investigator must make every effort to perform the following evaluations:

• Measure PEF (highest of three measurements).

• Measure FEV1 (highest of three measurements).

• Collect their DRC and review for AEs and changes in medication. Transcribe any AE and concomitant medication documented in the paper DRC to the relevant sections of the CRF.

• Review AEs and changes in concomitant medication. Check for any unresolved AEs.

• Collect blood samples for laboratory assessments.

• Conduct an ECG.

• Collect sample for assessment of urinary cortisol (if possible).

• Perform an oropharyngeal examination.

• Prescribe appropriate asthma therapy and record the start date in the CRF.

• If the subject withdraws or is withdrawn following an unscheduled/emergency visit, the unscheduled/emergency visit section of the CRF must also be completed.

• The date of withdrawal, reason for withdrawal and all post-treatment assessments must be documented in the relevant section of the CRF.

• If a subject fails to return to the clinic for a scheduled visit, the investigator should contact the subject by telephone or letter, asking him/her to return to the clinic as soon as possible. If the subject cannot be contacted the investigator should complete the end of study record section of the CRF and record that the subject is lost to follow-up.

These data will be recorded, as they comprise an essential evaluation that needs to be done prior to discharging any subject from the study.

Subjects who are prematurely discontinued from the study for whatever reason must not be re-entered or replaced.


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To facilitate identification for the subject and /or investigator of deterioration of asthma, ‘ALERT VALUES’ will be calculated by the investigator and noted on the subjects DRC (see Section 6.3.3 “Withdrawal Criteria for Lack of Efficacy” for further details).

If a subject who has consented to participate in PGx research withdraws from the clinical study for any reason other than lost to follow-up, the subject will be given the following options concerning the PGx sample:

• PGx research continues per the subject’s consent; or,

• Any remaining sample is destroyed.

If a subject withdraws consent from the PGx research or requests sample destruction, the investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by GSK and maintain the documentation in the site study records. GSK will only keep and study information collected/generated up to that point.

9.2.2. Subject Withdrawal from Investigational Product

Premature discontinuation of the study drug occurs when a subject discontinues study drug before completion of the treatment period i.e., before the end of Visit 6. Reasons for withdrawal include: an AE; asthma exacerbation; non-compliance; lack of efficacy; abnormal laboratory results; social reasons; or if it would be detrimental for the subject to continue in the study.

In the event that a subject is prematurely discontinued from the study at any time due to an AE (as defined in Section 10.1, “Definition of an AE”) or SAE (as defined in Section 10.2, “Definition of a SAE”), the procedures stated in Section 10, “Adverse Events (AE) and Serious Adverse Events (SAE)” must be followed.

The date of stopping study drug must be entered in the CRF and also the reason for premature discontinuation. If the subject discontinues the study drug at any time, then they must be withdrawn from the study and the reason for discontinuation recorded in the “End of Study Record” page of the CRF. Every effort should be made to follow-up subjects who withdraw from the study. The evaluations described in Section 9.2.1 should be performed, if possible.

Subjects who prematurely discontinue study drug for whatever reason must not be re-entered or replaced.

9.3. Screen and Baseline Failures

A screening log will be completed to track subjects who are screened for entry into the run-in period, and the reasons for subjects not entering the run-in will be recorded.

If a blood sample for PGx research has been collected and it is determined that the subject does not meet the inclusion and exclusion criteria for participation in the clinical study, then the investigator must complete the appropriate documentation to request


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sample destruction within the timeframe specified by GSK and maintain the documentation in the site study records.

10. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE)

The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE as provided in this protocol. During the study, when there is a safety evaluation, the investigator or site staff will be responsible for detecting AEs and SAEs, as detailed in this section of the protocol.

10.1. Definition of an AE

Any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.

Examples of an AE include:

• Significant or unexpected worsening or exacerbation of the condition/indication under study. See Section 10.3, “Lack of Efficacy”, for additional information.


• New conditions detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study.



Examples of an AE does not include a/an:

• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE.

• Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital).

• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.


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For GSK clinical studies, AEs may include pre- or post-treatment events that occur as a result of protocol-mandated procedures (i.e., invasive procedures, modification of subject’s previous therapeutic regimen).

10.2. Definition of a SAE

A SAE is any untoward medical occurrence that, at any dose:

a) results in death;

b) is life-threatening;

NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

c) requires hospitalisation or prolongation of existing hospitalisation;

NOTE: In general, hospitalisation signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils any other serious criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred or was necessary, the AE should be considered serious.

Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

d) results in disability/incapacity; or

NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g., sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

e) is a congenital anomaly/birth defect;

f) Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood


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dyscrasias or convulsions that do not result in hospitalisation, or development of drug dependency or drug abuse.

10.3. Lack of Efficacy

“Lack of efficacy” per se will not be reported as an AE. The signs and symptoms or clinical sequelae resulting from lack of efficacy will be reported if they fulfil the AE or SAE definition (including clarifications).

10.4. Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs

Abnormal laboratory findings (e.g., clinical chemistry, haematology, dipstick urinalysis) or other abnormal assessments (e.g., 12-lead ECG, vital signs) that are judged by the investigator as clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE, as defined in Section 10.1 ("Definition of an AE"), or SAE, as defined in Section 10.2 ("Definition of a SAE"). Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that are associated with the disease being studied, unless judged by the investigator as more severe than expected for the subject’s condition, or that are present or detected at the start of the study and do not worsen, will not be reported as AEs or SAEs.

The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant.

10.5. Time Period, Frequency, and Method of Detecting AEs and SAEs

From Visit 2 onwards, after the subject has had an opportunity to spontaneously mention any changes in their medical condition, the investigator should enquire whether the subject has had any AEs by asking the subject the following standard questions:

• “Have you had any (other) medical problems since your last visit/assessment?”

• “Have you taken any new medicines, other than those given to you within this study since the last visit/assessment?”

In addition, the investigator should review the subject’s DRC at each clinic visit for evidence of any AEs or changes in concomitant medication.

The time period during which AEs will be collected and recorded starts from the time the subject consents to participate in the study until the end of the final visit.


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10.6. Recording of AEs and SAEs

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event. The investigator will then record all relevant information regarding an AE/SAE on the CRF. It is not acceptable for the investigator to send photocopies of the subject’s medical records to GSK in lieu of completion of the appropriate AE/SAE CRF pages. However, there may be instances when copies of medical records for certain cases are requested by GSK. In this instance, all subject identifiers will be blinded on the copies of the medical records prior to submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be documented as the AE/SAE and not the individual signs/symptoms.

AEs and subject-completed questionnaires are independent components of the study. Responses to each question in the questionnaires will be treated in accordance with standard scoring and statistical procedures detailed by the scale’s developer. The use of a single question from a multidimensional health survey to designate a cause-effect relationship to an AE is inappropriate.

10.7. Evaluating AEs and SAEs

10.7.1. Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE reported during the study. The assessment will be based on the investigator’s clinical judgement. The intensity of each AE and SAE recorded in the CRF should be assigned to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities.

Severe: An event that prevents normal everyday activities.

An AE that is assessed as severe should not be confused with a SAE. Severity is a category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as described in Section 10.2., “Definition of a SAE”.

10.7.2. Assessment of Causality

The investigator is obligated to assess the relationship between investigational product and the occurrence of each AE/SAE. The investigator will use clinical judgement to determine the relationship. Alternative causes, such as natural history of the underlying


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diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the investigational product will be considered and investigated. The investigator will also consult the CIB/IB and/or Product Information, for marketed products, in the determination of his/her assessment.

There may be situations when an SAE has occurred and the investigator has minimal information to include in the initial report to GSK. However, it is very important that the investigator always make an assessment of causality for every event prior to transmission of the SAE CRF to GSK. The investigator may change his/her opinion of causality in light of follow-up information, amending the SAE CRF accordingly. The causality assessment is one of the criteria used when determining regulatory reporting requirements.

The investigator will provide the assessment of causality as per instructions on the SAE form in the CRF.

10.8. Follow-up of AEs and SAEs

After the initial AE/SAE report, the investigator is required to proactively follow each subject and provide further information to GSK on the subject’s condition.

All AEs and SAEs documented at a previous visit/contact and are designated as ongoing, will be reviewed at subsequent visits/contacts.

All AEs and SAEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up. Once resolved, the appropriate AE/SAE CRF page(s) will be updated. The investigator will ensure that follow-up includes any supplemental investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. This may include additional laboratory tests or investigations, histopathological examinations, or consultation with other health care professionals.

GSK may request that the investigator perform or arrange for the conduct of supplemental measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of the AE or SAE. The investigator is obligated to assist. If a subject dies during participation in the study or during a recognized follow-up period, GSK will be provided with a copy of any post-mortem findings, including histopathology.

New or updated information will be recorded on the originally completed “SAE” CRF, with all changes signed and dated by the investigator. The updated SAE CRF should be resent to GSK within the time frames outlined in Section 10.9. “Prompt Reporting of SAEs to GSK”.

10.9. Prompt Reporting of SAEs to GSK

SAEs will be reported promptly to GSK as described in the following table once the investigator determines that the event meets the protocol definition of an SAE.


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10.9.1. Timeframes for Submitting SAE Reports to GSK

Initial SAE Reports Follow-up Information on a Previously Reported SAE

Type of SAE Time Frame Documents Time Frame Documents All SAEs 24 hrs "SAE" CRF

pages 24 hrs Updated "SAE"

CRF pages

10.9.2. Completion and Transmission of the SAE Reports

Once an investigator becomes aware that an SAE has occurred in a study subject, she/he will report the information to GSK within 24 hours as outlined in Section 10.9., “Prompt Reporting of SAEs to GSK”. The SAE CRF will always be completed as thoroughly as possible with all available details of the event, signed by the investigator (or designee), and forwarded to GSK within the designated time frames. If the investigator does not have all information regarding an SAE, he/she will not wait to receive additional information before notifying GSK of the event and completing the form. The form will be updated when additional information is received.

The investigator will always provide an assessment of causality at the time of the initial report as described in Section 10.7.2., “Assessment of Causality”.

Facsimile transmission of the “SAE” CRF is the preferred method to transmit this information to the project contact for SAE receipt. In rare circumstances and in the absence of facsimile equipment, notification by telephone is acceptable, with a copy of the "SAE" CRF sent by overnight mail. Initial notification via the telephone does not replace the need for the investigator to complete and sign the SAE CRF within the time frames outlined in Section 10.9.1., “Timeframes for Submitting SAE Reports to GSK”.

GSK will provide a list of project contacts for SAE receipt, fax numbers, telephone numbers, and mailing addresses.

10.10. Regulatory Reporting Requirements For SAEs

The investigator will promptly report all SAEs to GSK in accordance with the procedures detailed in Section 10.9., "Prompt Reporting of SAEs to GSK." GSK has a legal responsibility to notify, as appropriate, both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. Prompt notification of SAEs by the investigator to the appropriate project contact for SAE receipt is essential so that legal obligations and ethical responsibilities towards the safety of other subjects are met.

The investigator, or responsible person according to local requirements, will comply with the applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities and the IRB/IEC.


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Expedited Investigator Safety Reports (EISRs) are prepared according to GSK policy and are forwarded to investigators as necessary. An EISR is prepared for a SAE that is both attributable to investigational product and unexpected. The purpose of the EISR is to fulfil specific regulatory and GCP requirements, regarding the product under investigation.

An investigator who receives an EISR describing a SAE or other specific safety information from GSK will file it with the Investigator’s Brochure and will notify the IRB or IEC, if appropriate according to local requirements.

10.11. Post-study AEs and SAEs

A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE detection period defined in Section 10.5., “Time Period, Frequency, and Method of Detecting AEs and SAEs”, of the protocol.

Investigators are not obligated to actively seek AEs or SAEs in former study participants. However, if the investigator learns of any SAE, including a death, at any time after a subject has been discharged from the study, and he/she considers the event reasonably related to the investigational product, the investigator will promptly notify GSK.

10.12. SAEs Related to Study Participation

An SAE considered related to study participation (e.g., procedures, invasive tests, a change in existing therapy), even if it occurs during the pre- or post-treatment period, will be reported promptly to GSK (see Section 10.9., "Prompt Reporting of SAEs to GSK").

11. MEDICAL DEVICES - INCIDENTS AND NEAR-INCIDENTS (INCLUDING MALFUNCTIONS)

GSK medical devices are being provided for use in this study. In order to fulfil international reporting obligations the investigator is responsible for the detection and documentation of events meeting the definitions of incident, near-incident, or malfunction that occur during the study with such devices.

11.1. Definitions of a Medical Device, Incident, Near-incident, Malfunction, and Remedial Action

Medical Device – Any instrument, apparatus, appliance, material or other article, the principal intended action of which is typically fulfilled by physical means (including mechanical action, physical barrier, replacement of, or support to, organs or body functions). Examples of medical devices include measuring spoons, syringes, spacers and spring-loaded auto-injectors.

The detection and documentation procedures described in this protocol apply to all GSK medical devices provided for use in the study.


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Incident – Any medical occurrence that occurs in a study subject, user, or other person with a GSK medical device, provided for use in the study, which results in death or a serious deterioration in the state of health whether or not due to a malfunction of the device.

Incidents include for example:

• Inhalation of an object that has accidentally entered a spacer device and resulted in tracheal obstruction.

Incidents do not include for example:

• Medical occurrences associated with metered-dose inhalers that do not fulfill the definition of a medical device (such events will be reported as medicinal product AEs)

• Non-serious medical occurrences which have no further safety implications for the subject or the device.

Near-incident – Any potential incident occurring with a GSK medical device provided for use in the study. Near-incidents are events that could have jeopardized the study subject, user, or other person, causing death or a serious deterioration of health, if medical intervention or other fortunate circumstances had not occurred. This would include deficiencies or inaccuracies in the instructions for use of the device and/or malfunctions.

Near-incidents include for example:

• Discovery of caustic damage to the plastic parts of a device caused by contamination with an ointment, where no actual injury to a subject occurred but the reporter recognized that such an event could happen in normal medical use of the device and could kill or seriously harm a subject.

Malfunction – A failure of a device to perform in accordance with its intended purpose when used in accordance with the manufacturer’s instructions.

Remedial Action – Any action other than routine maintenance or servicing of a device where such action is necessary to prevent recurrence of an incident or near-incident. This includes any amendment to the design to prevent recurrence.

11.2. Time Period for Detecting Medical Device Incidents and Near-incidents

Medical device incidents, near-incidents or malfunctions will be detected, documented and reported during all periods of the study in which the GSK medical devices that are provided are available for use.


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11.3. Documenting Medical Device Incidents and Near-incidents

Any medical device incident or near-incident occurring during the study will be documented in the subject’s medical records, in accordance with the investigator’s normal clinical practice, and on the "Medical Device Incident Report Form". In addition, for incidents and near-incidents fulfilling the definition of an AE or an SAE, the appropriate pages of the CRF will be completed as described in Section 10, “Adverse Events (AEs) and Serious Adverse Events (SAEs).

The "Medical Device Incident Report Form" will be completed as thoroughly as possible and signed by the investigator or his/her designee before transmittal to GSK, or designee. It is very important that the investigator provides his/her assessment of causality to the medical device provided by GSK at the time of the initial report, and describes any corrective or remedial actions taken to prevent recurrence of the incident.

11.4. Follow-up of Medical Device Incidents and Near-incidents

All medical device incidents, and near-incidents involving an AE, will be followed until resolution of the event, until the condition stabilizes, until the condition is otherwise explained, or until the subject is lost to follow-up. The investigator is responsible for ensuring that follow-up includes any supplemental investigations as may be indicated to elucidate as completely as practical the nature and/or causality of the incident.

New or updated information will be recorded on the originally completed "Medical Device Incident Report Form", with all changes signed and dated by the investigator.

11.5. Prompt Reporting of Medical Device Incidents and Near-incidents to GSK

Medical device incidents and near-incidents will be reported promptly to GSK as described below once the investigator determines that the event meets the protocol definition of a medical device incident or near-incident.

11.5.1. Timeframes for Submitting Medical Device Incident and Near-incident Reports to GSK

Initial Medical Device Incident/Near-incident Reports Additional Information on a Previously Reported Medical Device Incident/Near-incident

Type of Event Time Frame Documents Time Frame Documents Incident and Near-incident

24 hrs "Medical Device Incident Report Form"

24 hrs Updated "Medical Device Incident Report Form"


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11.5.2. Transmission of Medical Device Incident and Near-incident Reports

Facsimile transmission of the "Medical Device Incident Report Form" is the preferred method to transmit this information to the GSK project contact. The same individual will be the GSK project contact for receipt of medical device reports and SAEs. In the absence of facsimile equipment, notification by telephone is acceptable for incidents, with a copy of the "Medical Device Incident Report Form" sent by overnight mail. For near-incidents, telephone notification, in the absence of facsimile equipment, is not acceptable. Instead, a copy of the "Medical Device Incident Report Form" will be sent by overnight mail.

11.6. Regulatory Reporting Requirements For Medical Devices

The investigator will promptly report all incidents and near-incidents occurring with any GSK medical device provided for use in the study, in accordance with the procedures detailed in Section 11.5., “Prompt Reporting of Medical Device Incidents and Near-Incidents to GSK”. GSK has a legal responsibility to notify appropriate regulatory bodies and other entities about certain safety information relating to medical devices being used in clinical studies. Prompt notification of incidents and near-incidents by the investigator to the appropriate project contact is essential in order to meet legal obligations and ethical responsibility towards the safety of other subjects.

The investigator, or responsible person according to local requirements, will comply with the applicable local regulatory requirements relating to the reporting of incidents and near-incidents to regulatory bodies, and the IRB/IEC.

11.7. Post-study Medical Device Incidents and Near-incidents

Investigators are not obligated to actively seek reports of medical device incidents or near-incidents in former study participants. However, if the investigator learns of any incident or near-incident at any time after a subject has been discharged from the study, and such incident/near-incident is reasonably related to a GSK medical device provided for the study, the investigator will promptly notify GSK.

12. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

12.1. Hypotheses

The primary purpose of this estimation study is to evaluate the difference in effect on the mean daily PEF of subjects with persistent asthma given GW685698X 100µg once daily in the morning vs. once daily in the evening, as assessed over a 28-day treatment period.


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12.2. Treatment Comparisons of Interest

12.2.1. Primary Comparisons of Interest

The primary comparison of interest will be between GW685698X 100µg given once daily in the morning and once daily in the evening.

12.2.2. Other Comparisons of Interest

Other comparisons of interest are:

GW685698X 250µg given once daily in the evening vs. GW685698X 100µg once daily in the evening

GW685698X 100µg given once daily in the evening vs. placebo

GW685698X 100µg given once daily in the morning vs. placebo


12.3. Interim Analysis

There are no interim analyses planned for this study.

12.4. Sample Size Considerations

12.4.1. Sample Size Assumptions

The sample size has been determined based on required precision of treatment effect, which for this study is the difference in trough PEF between morning and evening doses. The standard deviation of trough PEF has been estimated at 40L/min based on morning and evening PEF values observed in previous asthma studies. A total of 492 randomised subjects (123 subjects per group) are required to ensure the width of the 95% confidence interval for the treatment effect is no larger than 20L/min. Randomisation will be halted once the required number of randomised patients has been achieved.

12.4.2. Sample Size Sensitivity

To demonstrate the sensitivity of the sample size the following tables show the changes in precision that would be observed should the assumptions around the standard deviation of the data change in any way:


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Standard Deviation Precision of Estimate (Width of 95% CI)

Number of Subjects (per group)

37 18.5 123 38 19 123 39 19.5 123 40 20 123 41 20.5 123 42 21 123 43 21.5 123

In addition the following table shows the effect on the sample size for different levels of the precision of treatment effect.

Standard Deviation Precision of Estimate (Width of 95% CI)

Number of Subjects (per group)

40 18.5 144 40 19 137 40 19.5 130 40 20 123 40 20.5 118 40 21 112 40 21.5 107

12.4.3. Sample Size Re-estimation

A sample size re-estimation is not currently planned for this study.

12.5. Analysis Populations

Three subject populations will be identified.

Total Population: This population will comprise of all subjects screened and for whom a record exists on the study database.

Intent-to-treat Population: The Intent-to-treat (ITT) population will comprise of all subjects randomised to treatment and who received at least one dose of trial medication. Randomised subjects will be assumed to have received trial medication unless definitive evidence to the contrary exists. This will constitute the primary population for all analyses of efficacy measures.

Per Protocol population: The Per Protocol (PP) population will consist of all subjects in the ITT population not identified as protocol violators. The decision to exclude a subject from the PP population will be made prior to breaking the blind. This population will be used for confirmatory analyses of primary efficacy measures.


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12.5.1. Data Sets

Full details of the data sets to be created will be given in the Reporting Analysis Plan (RAP).

12.6. General Considerations for Data Analysis

12.6.1. Withdrawal

Where possible, data from subjects who withdraw prematurely from the study will be included in any analyses. Specific details for inclusion will be detailed in the RAP, but in general the minimum data required will be a baseline evaluation and at least one post-baseline evaluation.

12.6.2. Missing Data

Daily PEF values will be taken from the DRC data, mean daily PEF values will be calculated from all available data over the period of interest, no imputations will be performed on DRC data. Missing FEV1 and clinic visit PEF values will be imputed using a last observation carried forward (LOCF) approach, using post-baseline measurements only.

12.6.3. Derived and Transformed Data

Details of all derived and/or transformed data will be presented in the RAP.

12.6.4. Assessment Windows

Details of assessment windows will be provided in the RAP.

12.6.5. Other Issues

Any changes that may be required to the planned analyses detailed in this protocol will be documented in the RAP and final study report.

If the study is terminated prior to completion, the full planned analyses will be performed if at least 12 subjects have completed the study by the time of termination. If fewer than 12 subjects have completed by that time then reporting will be limited to summaries of the demography and safety data.

All hypothesis tests for main effects will use a 2-sided test at the 5% level of significance. Any tests for interactions will be 2-sided at the 10% level of significance. In all cases if any assumptions of the proposed method of analyses are not met, alternative methods of analyses will be used.

If required, centres will be amalgamated by pooling with larger centres within the same country/region. These amalgamations will be used wherever pooled centre is


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incorporated into the analysis. All amalgamations will be finalised in the RAP prior to unblinding the treatment codes.

12.7. Efficacy Analyses

12.7.1. Primary Analysis

The primary endpoint is the mean change from baseline in daily trough (pre-study treatment and pre-bronchdilator) PEF (recorded in DRC) during the 28-day treatment period. Baseline daily PEF is defined as the mean of the last 7 consecutive days of the run-in period (prior to first dose of study treatment), and treatment daily PEF is defined as the mean of all PEF data available over the 28-day treatment period.

The change from baseline in daily PEF during the 28-day treatment period will be compared between GW685698X 100µg given once daily in the morning and once daily in the evening using an analysis of covariance (ANCOVA) model. Treatment, mean baseline PEF, age, sex and pooled centre will be included as terms in the model. Estimated treatment differences and 95% confidence intervals will be presented. This analysis will be carried out for both the ITT and PP populations, with the former being the primary population.

Interactions with treatment will be investigated for terms included in the model; this will be for the ITT population only. Subgroup analyses will be carried out for any terms identified as having a statistically significant interaction with treatment.

12.7.2. Secondary Analysis

12.7.2.1. Trough (Pre-study Treatment, Pre-bronchodilator) PEF

The change from baseline in daily PEF (recorded in the DRC) during the 28-day treatment period will be compared between treatment groups for all comparisons detailed in Section 12.2.2 using an ANCOVA model. Treatment, mean baseline PEF, age, sex and pooled centre will be included as terms in the model. Estimated treatment differences, together with p-values for superiority comparisons and 95% confidence intervals will be presented. This analysis will be carried out for both the ITT and PP populations, with the former being the primary population.

Interactions with treatment will be investigated for terms included in the model; this will be for the ITT population only. Subgroup analyses will be carried out for any terms identified as having a statistically significant interaction with treatment.

The change from baseline in daily PEF will also be compared between treatment groups for each of the 4 weeks of the treatment period, using the same methods as described above.


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12.7.2.2. Pre-bronchodilator FEV1

Summary statistics of actual and change from baseline pre-bronchodilator FEV1 values will be provided at each visit. The change from baseline in FEV1 at Visit 6 will be compared between treatment groups using an ANCOVA model with treatment, baseline FEV1, age, sex and pooled centre included as terms in the model. Estimated treatment differences for all comparisons detailed in Section 12.2, together with p-values and 95% confidence intervals will be presented.

12.7.2.3. Clinic Visit PEF

Summary statistics of actual and change from baseline PEF values will be provided at each visit. The change from baseline in PEF at Visit 6 will be compared between treatment groups using an ANCOVA model with treatment, baseline PEF, age, sex and pooled centre included as terms in the model. Estimated treatment differences for all comparisons detailed in Section 12.2, together with p-values for superiority comparisons and 95% confidence intervals will be presented.

12.7.2.4. Daily Record Card Data

The percentage of symptom-free 24 hour periods, symptom-free days, symptom-free nights, rescue medication-free days, rescue medication-free nights and nights with no awakenings will be calculated for each subject and assigned to one of the following categories: 0-25%, >25-50%, >50-75% and >75%. The number of subjects in each category will be compared between treatment groups using a logistic proportional odds model. Treatment, baseline values, age, sex and pooled centre will be included as terms in the model. Estimated treatment differences, expressed as odds ratios, for all comparisons in Section 12.2, together with p-values for superiority comparisons and 95% confidence intervals will be presented.

12.7.2.5. Withdrawals

The number of withdrawals will be summarised, by reason, for each treatment group. In addition, Fisher’s Exact test will be used to compare the number of withdrawals due to lack of efficacy between each GW685698X treatment group and placebo.

12.8. Safety Analyses

12.8.1. Extent of Exposure

The extent of exposure to study drug will be summarised by treatment group.

12.8.2. Adverse Events (AEs)

AEs will be coded using the standard GSK dictionary, Medical Dictionary for Regulatory Activities (MedDRA), and grouped by body system. AEs occurring pre-treatment, during active treatment and post-treatment will be summarised separately. The number


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and percentage of subjects experiencing at least one AE of any type, AEs within each body system and AEs within each preferred term will be presented for each treatment group. Separate summaries will be provided for all AEs, AEs by maximum severity, drug related AEs, SAEs, and for AEs leading to withdrawal.

12.8.3. Clinical Laboratory Evaluations

Clinical laboratory evaluations, including haematological, clinical chemistry and dipstick urinalysis parameters, will be summarised by treatment group using shift tables and summary statistics for each visit.

For 24-hour urinary cortisol, differences between treatment groups will be compared using an ANCOVA model with treatment, baseline values, age, sex and pooled centre as factors in the model. Estimated treatment differences for all comparisons detailed in Section 12.2, together with p-values for superiority comparisons and 95% confidence intervals will be presented.

12.8.4. Other Safety Measures

12.8.4.1. Examination of Oropharynx

The incidence of clinical/visual evidence of oral candidiasis will be summarised for each treatment group. In addition, the number and percent of subjects with a positive swab will be tabulated for each treatment group at each time point.

12.8.4.2. ECG Measurements

12-lead ECG data will be summarised by treatment group.

12.8.4.3. Vital Signs Assessments

Vital signs will be summarised using shift tables and summary tables for each clinic visit.

12.8.4.4. Physical Examination

This data will be summarised by treatment group.

12.8.4.5. Deaths and SAEs

All SAEs will be tabulated and listed by treatment group. Deaths and SAEs will be documented in case narrative format.

12.9. Health Outcomes Analyses

Not applicable.


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12.10. Clinical Pharmacology Data Analyses


Characterisation of patient population PK of GW685698X in subjects with persistent asthma following 250µg or 100µg once daily treatment for 28 days. GW685698X plasma concentration-time data will be subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The goal of this analysis will be to determine the systemic exposure following evening dosing to asthmatic patients. The effects of patient demographic characteristics such as gender, age, weight, body mass index (BMI) will also be examined. Individual predicted PK parameters will be summarised descriptively.

12.10.2. Pharmacodynamic Analyses

Not applicable.

12.10.3. Pharmacokinetics/Pharmacodynamics Analyses

Not applicable.

12.11. Biomarker(s) Analyses

Not applicable.

12.12. Viral Genotyping/Phenotyping Analyses

Not applicable.

12.13. Pharmacogenetics Analyses

Generally GSK will utilise two approaches to explore genetic variation in drug handling or response.

1. Hypothesis driven approach: A specific hypothesis is generated about sections of DNA (or individual SNPs or other genetic markers) that may be associated with differential drug handling or response. Specific sections of DNA may be selected from areas of the genome (e.g., candidate genes) known to encode the drug target, drug metabolising enzymes, areas associated with mechanisms underlying AEs, and those linked to study disease and, thus, linked to drug response.

2. Genome-wide approach utilizing polymorphic markers (e.g., SNPs): By evaluating large numbers of polymorphic markers throughout the genome, sets of markers may be identified that correspond to differential drug response or handling.

Analysis of genetic markers (e.g., whether within candidate genes or SNPs studied in a genome-wide analysis) will include the following considerations. The genotypic frequencies of each polymorphism will be evaluated for conformity to those expected


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under normal conditions by employing Hardy-Weinberg Equilibrium testing. Any departure from expectation will be taken into account, possibly signalling a data error or alternatively a connection between the polymorphism and asthma.

For pairs of polymorphisms, the degree to which alleles from the two sites are correlated (linkage disequilibrium) may also be evaluated. If the genotypes at two polymorphic sites within a gene are shown to be statistically associated with a response to investigational product, the degree of linkage disequilibrium will aid interpretation in that it will indicate the extent to which the two sites are exerting independent effects.

A decision regarding the construction and analysis of marker haplotypes -- combinations of alleles from different polymorphic sites that are inherited from one parent -- may be guided by the assessment of linkage disequilibrium. For example, if there is no linkage disequilibrium between polymorphic sites, then haplotype construction will be uninformative.

Differences in baseline clinical characteristics and potential contributing covariates may be summarized and compared among genotype (or haplotype) subgroups.

Analyses may be carried out to evaluate the degree of association between subject genotype (or haplotype) and selected parameters (e.g., PK, efficacy and safety). Where such genotypic tests are inappropriate (for example, where the number of marker genotypes is too large and/or the frequency of individual genotypes too small), allelic tests may be conducted. Allelic tests evaluate whether the frequency of each marker allele is the same in responders and non-responders.

In addition to evaluating the main effects of the genotypes (haplotypes or alleles) on the selected parameters, the possibility of a treatment group by genotype (haplotype or allele) interaction may also be explored. If appropriate, the joint effects of multiple markers (gene-gene interactions) may also be evaluated.

Sample Size Considerations

The ability to detect differential drug response or handling among genotypes at a polymorphic site depends on the total number of subjects genotyped and the frequency distribution of the different genotypes. Consequently, genotyping analyses are plausible for those polymorphic sites where the number of subjects comprising the genotypic groups is sufficiently large; however, these frequencies will not be known until sufficient samples have been collected and genotyping is complete.

Estimates of sample sizes required to demonstrate genotype effects vary considerably, depending on the assumptions made about allele frequency, genetic effect size, and mechanism of inheritance [Cardon, 2000]. In the work by Palmer and Cookson [Palmer, 2001], which assumed a genotype relative risk of 1.5, it was estimated that more than 300 cases and 600 controls would be needed to conduct a genetic association analysis. In contrast, McCarthy and Hilfiker [McCarthy, 2000] showed that with a genotype relative risk of 2.16 and a relatively commonly occurring genotype, only 30 cases and 30 controls would be needed to demonstrate an association. Consequently, it is quite possible that


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effects with relatively large genotype relative risks may be detectable in individual Phase I or Phase II studies. A range of examples exist to demonstrate robust and clinically relevant PGx data may be generated from PGx studies with sample sizes far less than the sizes proposed by Palmer and Cookson.

Published PGx examples include abacavir hypersensitivity reaction [Hetherington, 2002 and Mallal, 2002] and tranilast induced hyperbilirubinaemia [Roses, 2002] where genetic markers have been found to significantly associate with hypersensitivity reaction (abacavir) and hyperbilirubinaemia (tranilast). These examples show that small sample sizes typically encountered in Phase I and Phase II studies may be sufficient to identify clinically relevant genetic associations.

13. STUDY ADMINISTRATION

13.1. Regulatory and Ethical Considerations

13.1.1. Regulatory Authority Approval

GSK will obtain approval to conduct the study from the appropriate regulatory agency in accordance with any applicable country-specific regulatory requirements prior to a site initiating the study in that country.

13.1.2. Ethical Conduct of the Study and Ethics Approval

This study will be conducted in accordance with GCP and all applicable regulatory requirements, including, where applicable, the 1996 version of the Declaration of Helsinki.

The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the site’s informed consent form, and any other information that will be presented to potential subjects (e.g., advertisements or information that supports or supplements the informed consent) are reviewed and approved by the appropriate IEC/IRB. The investigator agrees to allow the IEC/IRB direct access to all relevant documents. The IEC/IRB must be constituted in accordance with all applicable regulatory requirements. GSK will provide the investigator with relevant document(s)/data that are needed for IEC/IRB review and approval of the study. Before investigational product(s) and CRFs can be shipped to the site, GSK must receive copies of the IEC/IRB approval, the approved informed consent form, and any other information that the IEC/IRB has approved for presentation to potential subjects.

If the protocol, the informed consent form, or any other information that the IEC/IRB has approved for presentation to potential subjects is amended during the study, the investigator is responsible for ensuring the IEC/IRB reviews and approves, where applicable, these amended documents. The investigator must follow all applicable regulatory requirements pertaining to the use of an amended informed consent form including obtaining IEC/IRB approval of the amended form before new subjects consent to take part in the study using this version of the form. Copies of the IEC/IRB approval


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of the amended informed consent form/other information and the approved amended informed consent form/other information must be forwarded to GSK promptly.

IEC/IRB approval of the PGx consent forms must be obtained in addition to the approval given for the clinical study. Regulatory review and approval may be required in some countries before IEC/IRB approval can be sought.

13.1.3. Informed Consent

Informed consent will be obtained before the subject can participate in the study. The contents and process of obtaining informed consent will be in accordance with all applicable regulatory requirements.

Subjects who do not wish to participate in the PGx research may still participate in the clinical study. For each subject, informed consent must be obtained prior to any blood being taken for PGx research. The informed consent for the PGx research must be obtained in addition to the subject’s consent to participate in the clinical study.

13.1.4. Investigator Reporting Requirements

As indicated in Section 10.10, “Regulatory Reporting Requirements For SAEs” the investigator (or sponsor, where applicable) is responsible for reporting SAEs to the IEC/IRB, in accordance with all applicable regulations. Furthermore, the investigator may be required to provide periodic safety updates on the conduct of the study at his or her site and notification of study closure to the IEC/IRB. Such periodic safety updates and notifications are the responsibility of the investigator and not of GSK.

13.2. Study Monitoring

In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the subject enrolment to review the protocol and data collection procedures with site staff. In addition, the monitor will periodically contact the site, including conducting on-site visits. The extent, nature and frequency of on-site visits will be based on such considerations as the study objective and/or endpoints, the purpose of the study, study design complexity, and enrolment rate.

During these contacts, the monitor will:

• Check the progress of the study.

• Review study data collected.

• Conduct source document verification.

• Identify any issues and address their resolution.

This will be done in order to verify that the:

• Data are authentic, accurate, and complete.


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• Safety and rights of subjects are being protected.

• Study is conducted in accordance with the currently approved protocol (and any amendments), GCP, and all applicable regulatory requirements.

The investigator agrees to allow the monitor direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the monitor to discuss findings and any relevant issues.

At study closure, monitors will also conduct all activities described in Section 13.4, "Study and Site Closure."

Source documents should be available for verification of the following data, which must be recorded in the subject’s notes (computer printouts or hand written):

• Subject identification (initials, date of birth, sex, height, weight, treatment number).

• Subject’s participation in the trial.

• Dates of each of the subject’s visits.

• Medical history and concomitant diseases.

• Previous and concomitant medication.

• AEs (only recorded in subject’s notes in line with the investigator’s normal practice, but must be recorded in CRF) and all SAEs.

• Final outcome: trial completion or withdrawal of subject.

Some data might be recorded directly in the CRF. In this case, it will be considered as source documentation. The investigator is free to transcribe this data to the subject’s notes.

Data that might be generated by a third party:

• Laboratory reports: these will contain all laboratory results.

• DRCs.

• Drug accountability logs.

The original document is the source documentation. The investigator will transcribe this data onto the CRF if required by the CRF design.

All of the following data will be verified 100%:

• Informed consent form, subject identification and demography (initials, date of birth, sex, height, weight), treatment numbers, subject’s participation in the trial, visit dates, inclusion and exclusion criteria, distribution of study medication.

• Previous and concomitant medication, concomitant diseases, oropharyngeal examination, AEs and SAEs, laboratory results, date and reason for withdrawal.

• Medical history.


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13.3. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this study. Such audits/inspections can occur at any time during or after completion of the study. If an audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and any relevant issues.

13.4. Study and Site Closure

Upon completion of the study, the monitor will conduct the following activities in conjunction with the investigator or site staff, as appropriate:

• Return of all study data to GSK.

• Data queries.

• Accountability, reconciliation, and arrangements for unused investigational product(s).

• Review of site study records for completeness.

• Return of treatment codes to GSK.

• Shipment of PK/PGx samples to assay laboratory(ies).

In addition, GSK reserves the right to temporarily suspend or prematurely discontinue this study either at a single site or at all sites at any time for reasons including, but are not limited to, safety or ethical issues or severe non-compliance. If GSK determines such action is needed, GSK will discuss this with the investigator (including the reasons for taking such action) at that time. When feasible, GSK will provide advance notification to the investigator of the impending action prior to it taking effect.

GSK will promptly inform all other investigators and/or institutions conducting the study if the study is suspended or terminated for safety reasons, and will also inform the regulatory authorities of the suspension or termination of the study and the reason(s) for the action. If required by applicable regulations, the investigator must inform the IEC/IRB promptly and provide the reason for the suspension or termination.

If the study is prematurely discontinued, all study data must be returned to GSK. In addition, arrangements will be made for all unused investigational product(s) in accordance with the applicable GSK procedures for the study.

Financial compensation to investigators and/or institutions will be in accordance with the agreement established between the investigator and GSK.


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13.5. Records Retention

Following closure of the study, the investigator must maintain all site study records in a safe and secure location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The investigator must assure that all reproductions are legible and are a true and accurate copy of the original, and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to that site for the study, as dictated by any institutional requirements or local laws or regulations, or GSK standards/procedures; otherwise, the retention period will default to 15 years.

The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, the following: archival at an off-site facility, transfer of ownership of the records in the event the investigator leaves the site.

13.6. Provision of Study Results and Information to Investigators

When a clinical study report is completed, GSK will provide the major findings of the study to the investigator. In addition, details of the study treatment assignment will be provided to the investigator to enable him/her to review the data to determine the outcome of the study for his/her subject.

GSK may list and summarize the PGx research results from coded samples by subject number in the clinical study report. In this event, the investigator and study staff would have access to the research results and would be able to link the results to a particular subject. The investigator and study staff would be directed to hold this information confidentially.

13.7. Information Disclosure and Inventions

Ownership:

All information provided by GSK and all data and information generated by the site as part of the study (other than a subject’s medical records) are the sole property of GSK. This includes the results of the PGx assessments included in the study and all samples collected for those assessments.


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All rights, title, and interests in any inventions, know-how or other intellectual or industrial property rights which are conceived or reduced to practice by site staff during the course of or as a result of the study are the sole property of GSK, and are hereby assigned to GSK.

If a written contract for the conduct of the study which includes ownership provisions inconsistent with this statement is executed between GSK and the study site, that contract’s ownership provisions shall apply rather than this statement.

Confidentiality:

All information provided by GSK and all data and information generated by the site as part of the study (other than a subject’s medical records) will be kept confidential by the investigator and other site staff. This information and data will not be used by the investigator or other site personnel for any purpose other than conducting the study. These restrictions do not apply to: (1) information which becomes publicly available through no fault of the investigator or site staff; (2) information which it is necessary to disclose in confidence to an IEC or IRB solely for the evaluation of the study; (3) information which it is necessary to disclose in order to provide appropriate medical care to a study subject; or (4) study results which may be published as described in the next paragraph. If a written contract for the conduct of the study which includes confidentiality provisions inconsistent with this statement is executed, that contract’s confidentiality provisions shall apply rather than this statement.

Publication:

For multicentre studies, the first publication or disclosure of study results shall be a complete, joint multicentre publication or disclosure coordinated by GSK. Thereafter, any secondary publications will reference the original publication(s).

Prior to submitting for publication, presentation, use for instructional purposes, or otherwise disclosing the study results generated by the site (collectively, a “Publication”), the investigator shall provide GSK with a copy of the proposed Publication and allow GSK a period of at least thirty (30) days [or, for abstracts, at least five (5) working days] to review the proposed Publication. Proposed Publications shall not include either GSK confidential information other than the study results or personal data on any subject, such as name or initials.

At GSK’s request, the submission or other disclosure of a proposed Publication will be delayed a sufficient time to allow GSK to seek patent or similar protection of any inventions, know-how or other intellectual or industrial property rights disclosed in the proposed Publication.

If a written contract for the conduct of the study, which includes publication provisions inconsistent with this statement is executed, that contract’s publication provisions shall apply rather than this statement.


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13.8. Data Management

Subject data are collected by the investigator or designee using the CRF defined by GSK. DRC will also be used to collect data. Subject data necessary for analysis and reporting will be entered/transmitted into a validated database or data system. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures. Database freeze will occur when data management quality control procedures are completed. Original CRFs and DRCs will be retained by GSK, while the investigator will retain a copy.

Data collection will also include a screening log to track subjects who are screened for entry into the run-in period and the reasons for subjects not entering the run-in will be recorded.

All laboratory data will be sent directly from the central laboratory to data management.

Data from the CRFs and PGx research using the coded sample will be stored electronically. International regulations for information on computers and relevant laws on processing personal information will be followed.

13.9. Independent Data Monitoring Committee (IDMC)

Not applicable.

13.10. Confidentiality of Subject’s PGx Data

GSK advises that participation in this PGx research, withdrawal from this research, sample destruction, and/or PGx results should not be documented in the subject’s medical records. Storage of information regarding the PGx research with source documents for the study is permissible if stored in the investigator study files.

Coded PGx samples and results will be associated with the subject’s study specific number in computer databases. Coded PGx research results may be submitted to regulatory agencies as part of an investigational product submission and/or included in a research publication.

Individual genotype results will only be shared with a subject through the investigator if the subject requests to see their results and it is a requirement of a governmental agency or other legal authority that GSK make these results available. GSK will not release individual PGx results to anyone else (e.g., family members, primary care physicians, insurers, or employers) under any circumstance, unless required by law.


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14. REFERENCES

British Thoracic Society. Guidelines on asthma management 1995: review and position statement. Thorax 1997;52(suppl.1):S1-S21.

Cardon LR, Idury RM, Harris TJR, Witte JS, Elston RC. Testing drug response in the presence of genetic information: sampling issues for clinical trials. Pharmacogenetics 2000;10:503-10.

Gagnon M, Côté M, Milot J, Turcotte H, Boulet LP. Comparative safety and efficacy of single or twice daily administration of inhaled beclomethasone in moderate asthma. Chest 1994;105:1732-37.

McCarthy JJ, Hilfiker R. The use of single-nucleotide polymorphism maps in pharmacogenomics. Nat Biotechnol 2000;18:505-8.

Meibohm B, Hochhaus G, Rohatagi S, Mollmann H, Barth J, Wagner M, et al. Dependency of cortisol suppression on the administration time of inhaled corticosteroids. J Clin Pharmacol 1997;37:704-10.

National Institutes of Health. Global Initiative for Asthma. Global strategy for asthma management and prevention. National Institutes of Health National Heart, Lung and Blood Institute Bethesda, MD, NHLBI/WHO workshop report March 1993. Publication number 96-3659B. Revised November 1998.

National Institutes of Health. Global Initiative for Asthma. Global strategy for asthma management and prevention. National Institutes of Health National Heart, Lung and Blood Institute Bethesda, MD, NHLBI/WHO workshop report April 2002. Publication number 96-3659.

Palmer LJ, Cookson WO. Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma. Respir Res 2001;2:102-12.

Pincus, DJ, Szefler SJ, Ackerson LM, Martin RJ. Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J. Allergy Clin Immunol 1995;95(6):1172-78.

Pedersen S, O’Byrne P. A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy 1997;52(suppl.39):1-34.

Wilson AM, Clarke DJ, Devlin MM, McFarlane LC, Lipworth BJ. Adrenocortical activity with repeated administration of one-daily fluticasone propionate and budesonide in asthmatic adults. Eur J Clin Pharmacol 1998;53:317-20.


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15. APPENDICES 15.1. Appendix 1: Time and Events Schedule

Screening visit (start of run-in period) Treatment period Follow-up

Visit Number 1/1a/1b 2 3 4 5 6 7 Weeks -3 to -1 0 1 ± 2 days 2 ± 2 days 3 ± 2 days 4 ± 2 days 5 ± 2 days Informed Consent X b Demographics X b History of Asthma and Concomitant Conditions X b Physical Examination X b X Xe Vital Signs X X X X X X Xe Haematology/Biochemistry/dipstick Urinalysis X b X Xe Urine Pregnancy Testing X X X 12-lead electrocardiogram X b X Xe Clinic measured Pulmonary Function X c X X X X X Xe Pharmacokinetics Blood Samples a X X X Pharmacogenetics Blood Samples X b Adverse Event Monitoring X X X X X X Concomitant Medication Monitoring X X X X X X X Examination of Oropharynx X X X X X X X 24 hr Urine collection for Cortisol Assessments X X Issue Rescue VENTOLIN X Xd Xd Issue Daily Record Card X X X X X Issue Study Medication X Collect used Rescue VENTOLIN X X Xf Collect Completed Daily Record Card X X X X X X Xf Collect Used Study Medication (Blister Packs) X X X X Xf Check Subjects Taking Correct Medication X X X X a samples will only be collected at centres with appropriate facilities; b The assessments indicated will be performed at Visit 1 only, and will not be repeated at Visits 1a and 1b; c Clinic lung function tests (FEV1 and PEF) should be performed at Visits 1, 1a, and 1b. Reversibility need only be performed once during the screening period to meet the criterion; d If required; e Tests only need to be performed if abnormal at Visit 6; f If subject did not to return VENTOLIN, study medication, or daily record card at Visit 6 the subject should return it at Visit 7.

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15.2. Appendix 2: Pharmacogenetic and Population Pharmacokinetic Assessments

Pharmacogenetics

Background

Pharmacogenetics (PGx) is the study of variability in drug handling or response due to hereditary factors in different populations. There is increasing evidence that an individual’s genetic composition (i.e. his or her genotype) may impact product response, or clinical outcome as well as disease susceptibility and progression of that disease.

Genetic markers may be used to help understand and predict drug handling or response in terms of efficacy and/or safety and tolerability. Some reported examples of PGx analysis include:

Drug Disease Gene Outcome

Clozapine Schizophrenia [Arranz, 1995]

5HT2A Subjects homozygous for the C102 allele appear more frequently in the non-responder (53%) than in the responder group (26%)

Pravastatin Coronary Atherosclerosis [Kuivenhoven, 1998]

Cholesteryl ester transfer protein (CETP)

Progression of coronary atherosclerosis slowed in B1/B1 homozygotes but not in B2/B2 homozygotes receiving pravastatin

Desipramine Depression [Daly, 1995]

CYP2D6 Poor metabolizing genotypes at risk of drug accumulation and associated toxicity

Isoniazid Tuberculosis [Nebert, 1997]

NAT-2 (N-acetyl transferase)

High incidence of peripheral neuropathy in subjects with slow acetylator genotypes

Abacavir HIV [Hetherington, 2002; Mallal, 2002]

HLA (human leukocyte antigen)

Caucasian males with HLA B57 variant were at increased risk for experiencing hypersensitivity to abacavir

Tranilast Restenosis prevention following coronary bypass [Roses, 2002]

UGT1A1 Drug induced hyperbilirubinaemia explained by high proportion of affected subjects having 7/7 TA repeat genotype, consistent with clinically benign Gilbert’s Syndrome

ABT-761 Asthma [Drazen, 1999]

ALOX5 ALOX5 Sp1 promoter genotype (x,x) associated with reduced response to 5-lipoxygenase inhibitor ABT-761

A key component to successful PGx research is the collection of samples during the conduct of clinical studies. Collection of whole blood samples, even when no a priori hypothesis has been identified, may enable PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in handling or response to GW685698X.


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Scope of PGx Analysis

If at any time it appears that there is a potential unexpected or unexplained variation in response to or handling of GW685698X (e.g., PK, efficacy and/or safety) that may be attributable to genetic variation, then PGx analysis may be conducted. In these circumstances, the analysis undertaken will be limited to PGx analysis of GW685698X handling or response and may include the evaluation of specific candidate genes, the conduct of a whole genome SNP scan or other marker scan.

For the whole genome SNP scan approach, SNP or other genetic marker sets across the genome may be evaluated to identify those markers associated with differential drug handling or response.

The need to conduct PGx analysis may be identified after a study (or set of studies) of GW685698X has been completed and the study data reviewed. For this reason, samples may be kept for up to 15 years after the last subject completes the study or GSK may destroy the samples before then. In special cases, the samples may not be studied. This might happen if there are not enough subjects, if the study is stopped for other reasons, or if no questions are raised about how people respond to or handle GW685698X.

In the performance of the PGx analysis, GSK may use subjects’ medical information, samples and/or research results. This PGx research is not designed to determine whether other members of the subject’s family are at risk of developing asthma or their response to or handling of GW685698X. Neither is the research designed to generate information relevant to the subject’s decision regarding whether or not to have children.

A whole blood sample will be collected (in addition to any blood samples to be taken for the clinical study) at the start or during the study. A duplicate sample is only required due to inability to utilise the original sample.

Population Pharmacokinetics

Population PK is the study of the sources and correlates of variability in drug concentrations among individuals who are the target subject population receiving clinically relevant doses of drug of interest. Using the population PK approach in drug development offers the possibility of gaining integrated information on PK, not only from relatively sparse data, but also from relatively dense data or a combination of sparse and dense data. The population PK approach allows the analysis of data from a variety of unbalanced designs as well as from studies that do not lend themselves to traditional PK analysis (i.e., requiring dense sampling), such as paediatric or elderly populations, or as in this case, data obtained during the evaluation of the relationship between dosing regimen and efficacy. The subjects of traditional PK studies are usually healthy volunteers or highly selected subjects, and the average behaviour of the group has been the main focus of interest. Inter-individual variability in PK has been minimised through design and restrictive inclusion/exclusion criteria. In contrast to traditional PK methods, the population PK approach allows collection of relevant PK information in subjects representative of the target population, identification and measurement of variability, and the explanation of that variability by identifying factors that may influence the PK


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behaviour of the drug. This approach also allows estimation of the unexplained (random) variability in the subject population, which is important since an increase in this may result in reduced efficacy and/or safety. Defining the optimum dosing strategy for later stages of development can be made more efficient by understanding the variability in the PK of a drug. A recent survey by the Food and Drug Administration (FDA) concluded that population PK is a useful tool in drug development and should be considered where appropriate.

References

Arranz M, Collier D, Sodhi M, Ball D, Roberts G, Price J, et al. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet 1995;346:281-2.

Daly AK. Molecular basis of polymorphic drug metabolism. J Mol Med 1995;73:539-53.

Drazen JM, Yandava CN, Dube L, Szczerback N, Hippensteel R, Pillari A, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet 1999;22:168-70.

Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002;359:1121-2.

Kuivenhoven JA, Jukema JW, Zwinderman AH, de Knijff P, McPherson R, Bruschke AVG, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. New Eng J Med 1998;338:86-93.

Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359:727-32.

Nebert DW. Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am J Hum Genet 1997;60:265-71.

Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Discov 2002;1:541-9.


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15.3. Appendix 3: Country Specific Requirements


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Title:

Country specific amendment for a randomised, double-blind, double-dummy, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GW685698X 100ug administered once daily either in the morning or the evening and GW685698X 250ug administered once daily in the evening by inhalation via DISKHALER for 28 days in subjects with persistent bronchial asthma

Document Number: GM2003/00336/01 Study Identifier: FFA20001 GSK Compound Number: GW685698 Issue Date: 03 Sep 2003 Protocol Amendment Number: 01 Author(s): CDMA Europe Respiratory

Revision Chronology:

GM2003/00336/00 2003-Jul-25 Original

GM2003/00336/01 2003-Sep-03 Amendment No.1: Country specific amendment for Germany. Restricting age range of subjects to 18-55 years due to local ethics/regulatory requirement.



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INVESTIGATOR AGREEMENT PAGE

I agree:


• To conduct the study in compliance with this protocol amendment and with any other study conduct procedures provided by GlaxoSmithKline (GSK).

• Not to implement this protocol amendment without agreement from the sponsor and prior submission to and written approval from (where required) the Institutional Review Board (IRB) or Independent Ethics Committee (IEC), except when necessary to eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory requirements).

• Note to implement any other changes to the protocol without agreement from the sponsor and prior review and written approval from the IRB or IEC, except where necessary to eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory requirements).

• That I am thoroughly familiar with the appropriate use of the investigational product(s), as described herein, and any other information provided by the sponsor including, but not limited to, the following: the current Investigator’s Brochure (IB) or equivalent document, IB supplement (if applicable), and approved product label (if the product is marketed in this country and the label is not already provided as an equivalent to an IB).

• That I am aware of, and will comply with, “good clinical practices” (GCP) and all applicable regulatory requirements.

• To ensure that all persons assisting me with the study are adequately informed about the GSK investigational product(s) and of their study-related duties and functions as described herein.

• That I have been informed that certain regulatory authorities require the Sponsor to obtain and supply, as necessary, details about the investigator’s ownership interest in the Sponsor or the investigational product, and more generally about his/her financial ties with the Sponsor. GSK will use and disclose the information solely for the purpose of complying with regulatory requirements.

Hence I:





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3



The following co-signature is required only when the investigator is not a physician.

Physician Name: _______________________________



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4

ABBREVIATIONS

AE Adverse Event ANCOVA Analysis of Covariance CRF Case Report Form CYP Cytochrome P450 DNA Deoxyribonucleic Acid DRC Daily Record Card ECG Electrocardiogram EDTA Ethylene Diamine Tetraacetic Acid EISR Expedited Investigator Safety Report FEV1 Forced Expiratory Volume in 1 Second FP Fluticasone Propionate GCP Good Clinical Practice GSK GlaxoSmithKline HPA Hypothalamic-Pituitary-Adrenal HVTs Human Volunteers IB Investigator’s Brochure ICS Inhaled Corticosteroid IEC Independent Ethics Committee IRB Institutional Review Board ITT Intent-To-Treat MDI Metered Dose Inhaler PC20 Concentration of AMP resulting in a 20% fall in FEV1 PEF Peak Expiratory Flow PGx Pharmacogenetics PK Pharmacokinetics PP Per Protocol RAP Reporting Analysis Plan SAE Serious Adverse Event SCAD System for Central Allocation of Drug SNP Single Nucleotide Polymorphism Trademarks


DISKHALER NA


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5

STATEMENT OF INTENT

This protocol amendment number 01 applies only in Germany.

RATIONALE

The age range of subjects for this study is defined in the original protocol as 16-55 years. The German Independent Ethics Committee has requested that the age range of subjects is restricted locally to 18-55 years.

LOCATION OF THE CHANGES

All sections.

Original text

16 to 55 years

Amended text

18 to 55 years

Section ‘Protocol Summary, Study design’

Original text


Amended text


Section 5.2.1 Inclusion Criteria

Original text




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6












3. Currently receiving inhaled short-acting β2-agonists for symptom relief. 4. Able and willing to give written informed consent to take part in the study.




Amended text





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7
















8


8

Title:


Document Number: GM2003/00336/02 Study Identifier: FFA20001 GSK Compound Number: GW685698 Issue Date: 19 Sep 2003 Protocol Amendment Number: 02 Author(s): CDMA Europe Respiratory


GM2003/00336/00 2003-Jul-25 Original


GM2003/00336/02 2003-Sep-19 Amendment No.2: Country specific amendment for Italy. Excludes subjects in Italy from participation in pharmacogenetics sub-study.


GM2003/00336/02 CONFIDENTIAL The GlaxoSmithKline group of companies FFA20001

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GM2004/00341/00


I agree:









Hence I:





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Physician Name: _______________________________



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ABBREVIATIONS



DISKHALER NA


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STATEMENT OF INTENT

This protocol amendment number 02 applies only in Italy.

RATIONALE

For this study, GSK may list and summarize the PGx research results from coded samples by subject number in the clinical study report. In this event, the investigator and study staff would have access to the research results and would be able to link the results to a particular subject.

The Italian guidelines require that individual genotype results are only shared with an investigator if a subject requests to see his/her results.

To ensure these local guidelines are not contravened, all subjects in Italy will be excluded from participation in the pharmacogenetics sub-study.


All sections

Pharmacogenetics samples will not be collected from subjects in Italy. All sections in the protocol which refer to enrollment into or participation in the pharmacogenetics sub-study will not apply in Italy.


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Title:


Document Number: GM2003/00336/03 Study Identifier: FFA20001 GSK Compound Number: GW685698 Issue Date: 04 December 2003 Protocol Amendment Number: 03 Author(s): CDMA Europe Respiratory


GM2003/00336/00 2003-Jul-25 Original



GM2003/00336/03 2003-Dec-04 Amendment No.3: Country specific amendment for Bulgaria. Restricting age range of subjects to 18-55 years due to local regulatory requirement.



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GM2004/00341/00


I agree:









Hence I:





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Physician Name: _______________________________



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4

ABBREVIATIONS



DISKHALER NA


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STATEMENT OF INTENT

This protocol amendment number 03 applies only in Bulgaria.

RATIONALE

The age range of subjects for this study is defined in the original protocol as 16-55 years. The Regulatory Commission in Bulgaria has requested that the age range of subjects is restricted locally to 18-55 years.


All sections.

Original text

16 to 55 years

Amended text

18 to 55 years

Section ‘Protocol Summary, Study design’

Original text


Amended text


Section 5.2.1 Inclusion Criteria

Original text





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Amended text






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Title:


Document Number: GM2003/00336/04 Study Identifier: FFA20001 GSK Compound Number: GW685698 Issue Date: 15 December 2003 Protocol Amendment Number: 04 Author(s): CDMA Europe Respiratory


GM2003/00336/00 2003-Jul-25 Original



GM2003/00336/03 2003-Dec-04 Amendment No.3: Country specific amendment for Bulgaria. Restricting age range of subjects to 18-55 years due to local regulatory requirement.

GM2003/00336/04 2003-Dec-15 Amendment No.4: Country specific amendment for Greece. Excludes subjects in Greece from participation in pharmacogenetics sub-study.



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I agree:









Hence I:





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Physician Name: _______________________________



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ABBREVIATIONS

GSK GlaxoSmithKline PGx Pharmacogenetics

Trademarks


DISKHALER NA


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STATEMENT OF INTENT

This protocol amendment number 04 applies only in Greece.

RATIONALE

Regulatory authorities in Greece have required that all subjects in this country are excluded from participation in the pharmacogenetics sub-study.


All sections.

Pharmacogenetics samples will not be collected from subjects in Greece. All sections in the protocol which refer to enrollment into or participation in the pharmacogenetics sub-study will not apply in Greece.


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Title:

Reporting and Analysis Plan for FFA20001 A randomised, double-blind, double-dummy, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GW685698X 100ug administered once daily either in the morning or the evening and GW685698X 250ug administered once daily in the evening all administered by inhalation via DISKHALER for 28 days in subjects with persistent bronchial asthma.

GM2003/00516/00

Author(s):

BDS, Statistics, Respiratory, UK

CPDM, UK

Document/Version Number: GM2003/00516/00

Date of Issue: 21st January 2004



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TABLE OF CONTENTS

Page1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2. STUDY OBJECTIVE(S) AND ENDPOINT(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.1. Study Objective(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.2. Study Endpoint(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62.3. Statistical Hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

3. STUDY DESIGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

4. PLANNED ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84.1. Interim Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

5. SAMPLE SIZE CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

6. ANALYSIS POPULATIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

7. TREATMENT COMPARISONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES . . . . . . . . . . . . . . . . . . . 108.1. Multicentre Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108.2. Other Strata and Covariates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108.3. Examination of Subgroups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108.4. Multiple Comparisons and Multiplicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

9. DATA HANDLING CONVENTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119.1. Premature Withdrawal and Missing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

9.1.1. Withdrawals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119.1.2. Missing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

9.2. Derived and Transformed Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119.3. Assessment Windows . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

9.3.1. Clinic Visit Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129.3.2. Daily Record Card Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

9.4. Values of Clinical Concern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

10. STUDY POPULATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1510.1. Disposition of Subjects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1510.2. Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1510.3. Demographic and Baseline Characteristics . . . . . . . . . . . . . . . . . . . . . . . . 1710.4. Treatment Compliance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

11. EFFICACY ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1811.1. Primary Efficacy Analysis(es) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

11.1.1. Daily Trough (Pre-study treatment and pre-bronchodilator) PEF . . 1811.2. Secondary Efficacy Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

11.2.1. Daily Trough (Pre-study treatment and pre-bronchodilator) PEF . . 19


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11.2.2. Morning PEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2011.2.3. Evening PEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2011.2.4. Pre-bronchodilator FEV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2011.2.5. Clinic Visit PEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2011.2.6. Daily Record Card Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2111.2.7. Withdrawals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

12. SAFETY ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2212.1. Extent of Exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2212.2. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2212.3. Deaths and Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2312.4. Clinical Laboratory Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2312.5. Other Safety Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

12.5.1. Examination of the Oropharynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2312.5.2. ECG Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2312.5.3. Vital Signs Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2412.5.4. Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2412.5.5. Deaths and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

13. HEALTH OUTCOMES ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2413.1. Resource Utilisation Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

14. CLINICAL PHARMACOLOGY DATA ANALYSES. . . . . . . . . . . . . . . . . . . . . . . . 2414.1. Pharmacokinetic Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2414.2. Interim analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2414.3. General considerations for data analyses . . . . . . . . . . . . . . . . . . . . . . . . . 2414.4. Covariates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2514.5. Missing sampling and treatment information . . . . . . . . . . . . . . . . . . . . . . . 2514.6. Missing covariates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2514.7. Derived and transformed data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2614.8. Pharmacokinetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

15. PHARMACOGENETIC DATA ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

16. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

17. ATTACHMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2917.1. Table of Contents for Data Display Specifications . . . . . . . . . . . . . . . . . . . 29

17.1.1. Listings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2917.1.2. Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3017.1.3. Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

17.2. Data Display Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33


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List of Abbreviations

AE ANCOVA AUC CPSP DRC DV ECCS EVID FEV1 GSK ITT IVRS MDV NONMEM NQ OD PEF Pharmacokinetics PP RAP

Adverse Event Analysis of Covariance Area under the curve Clinical Pharmacology Statistics & Programming Daily Record Card Dependent variable European Community for Coal and Steel Event identification Forced Expiratory Volume in 1 second GlaxoSmithKline Intent to Treat Interactive Voice Response System Missing dependent variable A nonlinear mixed effect modeling software Below lower limit of quantification Once Daily Peak Expiratory Flow Per Protocol Reporting and Analysis Plan

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

DISKHALER VENTOLIN


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1. INTRODUCTION

This reporting and analysis plan (RAP) documents the planned statistical analyses for the FFA20001 study which will be used for internal decision making relating to further phase II and III clinical development. The RAP is based on the protocol issued 25th July 2003 [GlaxoSmithKline Document Number GM2003/00336/00], together with any subsequent amendments.

This RAP is intended for the use of project team members within GlaxoSmithKline (GSK) and should be read in conjunction with the aforementioned protocol.

2. STUDY OBJECTIVE(S) AND ENDPOINT(S)

2.1. Study Objective(s)

Primary

• To evaluate the effect of time of dosing (morning vs. evening) of GW685698X 100µg once daily, administered by inhalation via DISKHALER™ on the mean change in daily trough (pre-study treatment and pre-bronchodilator) peak expiratory flow (PEF) during the 28-day treatment period.

Secondary





Other

• To characterise the population pharmacokinetics (PK) of GW685698X in subjects with persistent asthma.

• If at any time it appears there is potential variability in GW685698X response or handling (e.g., PK, safety, and/or efficacy) in this clinical study or in a series of clinical studies, the pharmacogenetic objectives may be investigated.


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2.2. Study Endpoint(s)

Primary

• Mean change from baseline in daily trough (pre-study treatment and pre-bronchodilator) PEF (recorded in the daily record card [DRC]) during the 28-day treatment period with GW685698X 100µg once daily in the morning compared with GW685698X 100µg once daily in the evening by inhalation via DISKHALER.

Secondary

The endpoints marked * were not explicitly defined in the protocol but are of significant interest in investigation of the secondary study objectives.

Efficacy



• * Mean change from baseline in daily trough PEF (recorded in the DRC) over each of the four treatment weeks for the following comparisons:

- GW685698X 100µg once daily administered in the evening with the same dose given in the morning

- GW685698X 250µg once daily administered in the evening with GW685698X 100µg in the evening

- each active treatment compared with placebo.

• * Mean change from baseline in morning PEF (recorded in the DRC) during the 28-day treatment period, for the following comparisons:



- Each active treatment compared with placebo.

• * Mean change from baseline in evening PEF (recorded in the DRC) during the 28-day treatment period, for the following comparisons:



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- Each active treatment compared with placebo.





• Percentage of VENTOLIN™ (salbutamol)-free 24-hour periods, days, and nights.



Safety

• Incidence of adverse events (AEs) throughout the 28-day treatment period.




• 12-lead electrocardiogram before and after 28 days of treatment.

• Physical examination before and after 28 days of treatment.


Other



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2.3. Statistical Hypotheses

The primary purpose of this study is estimation of the difference in the effect of GW685698X 100µg given once daily in the morning and given once daily in the evening on trough PEF. Similarly, the secondary objective of comparing evening dosing of GW685698X 100µg with evening dosing of GW685698X 250µg relates to estimation of treatment difference only. Therefore, statistical hypotheses will only be tested for the secondary comparisons of each dosing regimen of GW685698X with placebo.

The null hypothesis is that the effect of each dose regimen of GW685698X and placebo on trough PEF (or other secondary endpoints) is identical:

H0 : Ti – Tj = 0

(where i = 100µg PM, 100µg AM, 250µg PM GW685698X and j = placebo)

The alternative hypothesis is that the dose regimens of GW685698X and placebo have different effects on trough PEF:

Ha : Ti – Tj ≠ 0

3. STUDY DESIGN

This is a Phase IIa randomised, double-blind, double-dummy, placebo-controlled, parallel-group, multi-centre study evaluating different dosing regimens of GW685698X (100ug od in the morning, 100ug od in the evening and 250ug od in the evening) during a 28-day treatment period.

The randomisation code has been generated using the validated computerised system RandAll and randomisation is centralised at the site level via an IVRS system.

4. PLANNED ANALYSES

Data from this study will be analysed according to the methods detailed in this RAP, these methods were agreed and finalised prior to the release of any treatment codes. The actual analysis of data will take place once all subjects have completed the study, the database is declared frozen and the treatment codes are unblinded.

4.1. Interim Analyses

No interim analyses are planned for this study.

5. SAMPLE SIZE CONSIDERATIONS

The sample size has been determined based on a required precision of treatment effect, which for this study is the difference in trough PEF between morning and evening doses. The standard deviation of trough PEF has been estimated at 40L/min based on morning


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and evening PEF values observed in previous asthma studies. A total of 492 randomised subjects (123 subjects per group) are required to ensure the width of the 95% confidence interval for the treatment effect is no larger than 20L/min. Randomisation will be halted once the required number of randomised patients has been achieved.

6. ANALYSIS POPULATIONS

Three subject populations have been identified for this study:

The Total Population will comprise of all subjects screened and for whom a record exists on the study database. This will be used for summary of reasons for withdrawal prior to randomisation.

The Intent-to-Treat (ITT) population will comprise of all subjects randomised to treatment who received at least one dose of trial medication. Randomised subjects will be assumed to have received trial medication unless definitive evidence to the contrary exists. This will constitute the primary population for all analyses of efficacy and safety measures. However, if there are any occurrences of subjects taking a treatment other than that to which they were randomised, safety data will be analysed according to the treatment actually received.

The Per Protocol (PP) population will consist of all subjects in the ITT population not identified as major protocol violators. The major protocol violations for which patients would be excluded from the PP population are detailed in Section 10.2 of this RAP and represent criteria that may affect trough PEF. The decision to exclude a subject from the PP population will be made prior to breaking the blind. This population will be used for confirmatory analysis of trough PEF endpoints only.

7. TREATMENT COMPARISONS

The primary treatment comparison of interest is between GW685698X 100µg given once daily in the morning and once daily in the evening.

The following treatment comparisons are of secondary interest:

GW685698X 250µg given once daily in the evening vs. GW685698X 100µg once daily in the evening


GW685698X 100µg given once daily in the morning vs. placebo



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8. GENERAL CONSIDERATIONS FOR DATA ANALYSES

All programming will be performed in a Unix environment using SAS Version 8.2 or a later release. All analysis output will use the following treatment group naming conventions:

GW685698X 100mcg pm for GW685698X 100µg given once daily in the evening

GW685698X 100mcg am for GW685698X 100µg given once daily in the morning

GW685698X 250mcg pm for GW685698X 250µg given once daily in the evening

PLACEBO for Placebo

8.1. Multicentre Studies

This study of 492 subjects is to be conducted in approximately 78 centres in 14 countries within Europe, Latin America and South Africa so it is likely that many centres will enrol a small number of subjects. Therefore, centres within a country will be combined to give 14 centre groupings. If there are less than 12 subjects within a country, these centres will be combined with another country according to geographical location and/or similarity of clinical practice.

A separate document detailing the final country pooling strategy will be completed after recruitment to the study has ended and before the treatment codes are unblinded. All summaries and analyses will be of all countries combined (analysis models will include country grouping as a covariate). Results will only be presented for different country groupings separately if a significant treatment*country interaction is observed (see Section 11.1.1).

8.2. Other Strata and Covariates

Covariates expected to influence lung function include age and sex. These covariates will be included in the analysis models as detailed under each parameter together with the appropriate baseline value of the endpoint being analysed and country.

8.3. Examination of Subgroups

For the primary efficacy variable only (daily trough PEF), interactions with treatment will be assessed at the 10% (2-sided) level of significance, for the four covariates listed above. If any significant treatment by covariate interactions are identified from the ANCOVA model, they will be further investigated through the review of summary statistics at each level of the covariate. For the continuous variables of age and baseline value, the median values will be used to dichotomise into groups for presentation of these summaries.


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In addition to the above, trough PEF will be summarised for each treatment group by visit 2 percent predicted PEF (subjects with ≥65% predicted and subjects with <65% predicted).

8.4. Multiple Comparisons and Multiplicity

A single primary efficacy variable has been identified for this study, with all other efficacy variables identified as secondary. Similarly there is only one primary treatment comparison specified for this study, with all other treatment comparisons being secondary. Therefore there are no requirements to adjust for multiple endpoints or multiple treatment comparisons within this study.

9. DATA HANDLING CONVENTIONS

9.1. Premature Withdrawal and Missing Data

9.1.1. Withdrawals

For ITT analyses, daily record card data from subjects who withdrew prematurely will be included in the analyses as long as at least 1 assessment of on-treatment data has been recorded (see Section 9.3.2 for definition of on-treatment).

For the PP analysis of the primary endpoint, subjects who withdrew prematurely will be included provided at least 7 days of on-treatment data have been recorded. Failure to record this minimum amount of DRC data will be considered a major protocol violation.

Clinic visit data from subjects who withdrew prematurely will be included in the analyses as long as at least one on-treatment assessment has been provided. Any data from subjects who withdrew from the study prior to providing at least one on-treatment assessment will be excluded from the analysis.

9.1.2. Missing Data

Analyses of daily record card data will be based on the available data ie patient means and percentages will be calculated using the number of non-missing observations as the denominator.

Missing clinic visit FEV1 and PEF values will be imputed using a last observation carried forward (LOCF) approach, only post-baseline measurements can be carried forward.

9.2. Derived and Transformed Data

Clinic Visit Data: In all cases the most recent evaluations taken before the first dose of study medication will be considered to be the baseline measurement.


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Daily record card data: The baseline measurement will be defined as the mean of the values recorded in the last 7 days prior to the first dose of medication (see Section 9.3.2). Derivations of patient means and percentages relating to DRC endpoints are provided in Section 11.1.1 and Section 11.2.4.

Duplicate information collected on the daily record card will be dealt with by taking the average of the information and using it for the analyses.

Peak Expiratory Flow:

The predicted normal PEF, percent predicted normal PEF and percent reversibility will be derived and used in place of the values collected in the case report form.

For all subjects aged between 25-55 years the predicted PEF values will be determined from the guidelines of the working party of the European Community for Coal and Steel [Quanjer, 1993] using the following formula where height is to the nearest cm and age is in whole years attained.

Males: Predicted PEF (L/min) = [(6.14 * height / 100) – (0.043 * age) + 0.15] Females: Predicted PEF (L/min) = [(5.50 * height / 100) – (0.030 * age) – 1.11]

The ECCS formulae above will also be used for subjects aged 18-24 years, although the age used for the calculation will be 25 in all cases.

For subjects who are under 18 years of age, the predicted PEF values will be determined from the Polgar tables [Polgar, 1971] using the following regression equation, again height is to the nearest cm and the same formulae is used for both males and females.

Males/Females: Predicted PEF (L/min) = -425.5714 + [5.2428 * height]

Using these derived predicted PEF values the following will be calculated:

Percent predicted normal PEF = (Observed PEF (L/min)/ Predicted PEF (L/min)) * 100

Reversibility (%) = Post-bronchodilator PEF - Pre-bronchodilator PEF *100 Pre-bronchodilator PEF*100

9.3. Assessment Windows

9.3.1. Clinic Visit Data

Visits are scheduled to take place within the following timeframes as stated in the protocol:


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Visit Number Scheduled Time Visit 1/1a/1b -3 to –1 weeks Visit 2 0 weeks Visit 3 1 week ± 2 days Visit 4 2 weeks ± 2 days Visit 5 3 weeks ± 2 days Visit 6 4 weeks ± 2 days Visit 7 5 weeks ± 2 days

If visits take place outside the allowable scheduled time, data collected at these visits will still be used in analysis of clinic visit data. If unscheduled or multiple assessments occur, the one closest to the scheduled visit will be used. If two such assessments are equally close to the scheduled visit, the earlier of the assessments will be used.


For the daily record card data, assessments will be assigned to a time period based upon when they were recorded. For each subject, daily assessments will be assigned a day number relative to the date of start of study medication:

Day number = Date of assessment – Treatment Start Date

Provided subjects started their study medication as instructed on the evening of visit 2, day 0 should be the date of randomisation and also the treatment start date. Due to the nature of the study design, subjects randomised to the GW685698X AM dose group will receive placebo on the evening of day 0 and the start of active treatment for this group will be the morning of day 1. As a result, different time periods have been defined for different treatment groups and/or different endpoints (see below).

9.3.2.1. Trough PEF

Although trough PEF is collected twice daily, analysis of these data are performed using only the measurement relating to the time of dosing of GW685698X (data from the placebo group will be used according to the corresponding dose time of the group to which it is being compared). Therefore, the baseline and treatment periods for analysis of trough PEF are defined as:

GW685698X 100µg/250µg PM GW685698X 100µg AM Placebo Baseline PM Day –7 to PM Day -1 AM Day –6 to AM Day 0 PM Day –7 to AM Day 0 Treatment PM Day 1 to PM Day 28 AM Day 2 to AM Day 29 PM Day 1 to AM Day 29 Week 1 PM Day 1 to PM Day 7 AM Day 2 to AM Day 8 PM Day 1 to AM Day 8 Week 2 PM Day 8 to PM Day 14 AM Day 9 to AM Day 15 PM Day 8 to AM Day 15 Week 3 PM Day 15 to PM Day 21 AM Day 16 to AM Day 22 PM Day 15 to AM Day 22 Week 4 PM Day 22 to PM Day 28 AM Day 23 to AM Day 29 PM Day 22 to AM Day 29 Assessments recorded beyond PM Day 28/AM Day 29 will be excluded from the analysis.


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9.3.2.2. Morning PEF / Evening PEF / % Symptom-Free / VENTOLIN-Free Time Periods

For the analyses of AM PEF and PM PEF and also for % symptom free or VENTOLIN-free time periods, all treatment groups will be compared using the same assessment times.

% Symptom-Free / VENTOLIN-Free 24-Hour Periods*

PM PEF/ % Symptom-Free Days / %

VENTOLIN-Free Days

AM PEF/ % Symptom-Free Nights / % VENTOLIN-Free Nights / %

No Awakening Nights Baseline PM Day –7 to AM Day 0 PM Day –7 to PM Day -1 AM Day –6 to AM Day 0 Treatment PM Day 1 to AM Day 29 PM Day 1 to PM Day 28 AM Day 2 to AM Day 29 * 24-Hour period is defined as the evening assessment of a given day together with the morning assessment of the following day.

9.4. Values of Clinical Concern

Laboratory parameters will be compared to the following normal ranges, as defined by the central laboratory.

Parameter Units Sex Age Range (years) Normal Range Haematology Haemoglobin G/DL M

M F F

18-64 65+ 18-64 65+

13.8 – 17.2 11.8 – 16.8 12.0 – 15.6 11.1 – 15.5

MCV FL M/F 18-64 65+

80 – 100 82 – 103

Platelets GI/L M/F 1+ 130 – 400 Total WBC GI/L M/F 18+ 3.8 - 10.8 Neutrophils GI/L M/F 3+ 1.8 - 8.0 Lymphocytes GI/L M/F 1+ 0.85 - 4.10 Monocytes GI/L M/F 1+ 0.20 - 1.10 Eosinophils GI/L M/F 0+ 0.05 - 0.55 Basophils GI/L M/F 1+ 0.00 - 0.20 Blood Chemistry Sodium MMOL/L M/F 0+ 135 - 146 Potassium MMOL/L M/F 13+ 3.5 - 5.3 Bicarbonate MMOL/L M/F 13+ 20 - 32 Glucose MMOL/L M/F 13-49

50+ 3.9 - 6.4 3.9 - 6.9

Albumin G/L M/F 3+ 32 – 50 Creatinine UMOL/L M/F 13+ 44 – 124 Total bilirubin UMOL/L M/F 1+ 0 – 22 Alkaline phosphatase U/L M

F M/F

16-19 16-19 20+

30 – 225 30 – 165 20 – 125

AST U/L M/F 3-64 65+

0 – 42 0 – 55

ALT U/L M/F 13+ 0 – 48 Sex: M=Male, F=Female


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The investigator will assess, on a subject by subject basis, any values that fall outside of these pre-defined normal ranges to determine if they are of clinical concern. In addition laboratory parameter values will be compared to the following reference ranges which were defined by the Clinical Respiratory group:

Haematology Blood Chemistry Parameter Upper RR Lower RR Parameter Upper RR Lower RR Haemoglobin 1.10XulN 0.90xLLN Sodium 1.05xULN 0.95xLLN MCV 1.13xULN 0.90xLLN Potassium 1.10xULN 0.90xLLN Platelets 1.90xULN 0.60xLLN Bicarbonate 1.20xULN 0.75xLLN Total WBC 1.50xULN 0.60xLLN Glucose 1.50xULN 0.80xLLN Neutrophils 2.00xULN 0.60xLLN Albumin 1.20xULN 0.80xLLN Lymphocytes 1.50xULN 0.60xLLN Creatinine 1.30xULN none defined Monocytes 1.50xULN none defined Total bilirubin 1.60xULN none defined Eosinophils 2.20xULN none defined Alkaline

phosphatase 2.75xULN none defined

Basophils 5.00xULN none defined AST 2.75xULN none defined ALT 3.00xULN none defined

10. STUDY POPULATION

10.1. Disposition of Subjects

The number of subjects in each analysis population will be presented, and the total number of subjects attending each clinic visit will also be summarised by treatment group.

The number of subjects that were randomised and either completed or were prematurely withdrawn from the study will be presented for each treatment group. The primary reasons for withdrawal both prior to and post randomisation will also be presented.

A data display listing and summary of deviations from the inclusion/exclusion criteria will be presented for all subjects who were either entered or randomised into the trial.

10.2. Protocol Deviations

All major protocol deviations resulting in full or partial exclusion from the Per Protocol population will be listed.

Randomised subjects who meet any of the following criteria will be considered major protocol violators and will be excluded from the Per Protocol analysis population. Subjects will be summarised by their reason for exclusion. Major protocol violations are defined as:

• Subject did not comply fully with the following inclusion/exclusion criteria (see Protocol Section 5.2):


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Inclusion to Run-In:

Documented clinical history of persistent asthma first diagnosed at least 6 months prior to visit 1.

Inclusion to Treatment Period:

Increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol (fulfilled at any of visits 1/1a/1b/2)

Mean morning PEF (calculated from last 7 consecutive days of the final run-in period) of between 50% and 80% predicted normal.

Daily asthma symptom score (day-time plus night-time) of >1 on at least 4 of the last 7 consecutive days of the final run-in period.

Exclusion to Run-In:

History of respiratory tract infection and/or exacerbation within a period of 4 weeks prior to visit 1.

History of 2 or more exacerbations requiring treatment with oral corticosteroids or hospitalisation in the 6 months before visit 1.

Known or suspected sensitivity to corticosteroids, VENTOLIN, or the constituents of Rotadisks.

Undergoing allergen desensitisation therapy.

Current smoker or has a smoking history of 10 pack years or more.

Administration of the respiratory medications listed in Section 5.2.2 of the Protocol

Exclusion to Treatment Period:

Changes in asthma medication (excluding rescue VENTOLIN)

Occurrence of an upper or lower respiratory tract infection during the run-in period

Non-compliance with completion of the DRC (6 out of the last 7 days prior to visit 2 completed to confirm compliance)

Exacerbation of asthma symptoms during the run-in

• Subject met criteria for withdrawal but was not withdrawn (see Protocol Section 6.3.3)

• Subject took/received treatment to which they were not randomised


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• Starting prohibited asthma medications during the run-in or treatment periods (see Section 8.2 of Protocol). This information will be obtained from the asthma concomitant medication details but will be reviewed prior to unblinding the treatment allocations. Subjects for whom these violations occur during the treatment period will be considered partial violators and will be included in the Per Protocol analysis up to the time at which the violation occurred.

• Subject was less than 80% compliant with either am or pm dose of study medication

• Subject failed to record at least 5 days (morning and evening) of DRC data

• Subject received investigational product past the expiration date

• Subject had treatment blind broken during study

10.3. Demographic and Baseline Characteristics

The following demographic information will be listed and summarised for subjects in each treatment group: age, sex, race, height and weight. This will also be done for history of tobacco use at screening and current medical conditions.

Asthma and other concomitant medications will be coded using the GSK Drug coding dictionary and classified as pre-treatment or on-treatment, using the following definitions:

• Pre-treatment: started prior to randomisation

• On-treatment: taken during the treatment period

Asthma concomitant medications will be listed and summarised for each treatment group for both pre-treatment and on-treatment medications. Other concomitant medications will be summarised/listed on-treatment only.

Information regarding duration of asthma and asthma history will also be presented and pulmonary function test measurements at screening will be listed and summarised.

10.4. Treatment Compliance

The overall percentage compliance will be calculated separately for the morning and evening doses of study medication using the following formula:

Actual number blisters used *100 Expected number of blisters to be used

The expected number of blisters to be used will be calculated as follows for both AM and PM doses: Expected number = Stop date of treatment – Treatment Start Date

Note: Subjects should start study medication on the evening of Visit 2, but it is possible that some will start the day after or later. In these cases, it will not be clear from the information provided on the case report form as to whether they started with the morning


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dose or the evening dose. To allow for this inconsistency the above formulae will be used for all subjects.

These data will be listed and summarised for all subjects.

11. EFFICACY ANALYSES

For parameters being analysed using an analysis of covariance (ANCOVA) model, the underlying assumptions of normality of data and homogenous variances will be confirmed by examining the residuals from the model. If any of the assumptions are violated, an appropriate transformation will be applied to the data. If a suitable transformation cannot be found then non-parametric analysis methods will be employed to ascertain differences between treatments.

Unless otherwise indicated, all hypothesis tests for main effects will use a 2-sided test at the 5% level of significance (performed for comparisons with placebo only). For tests of interaction a 2-sided test will be used at the 10% level of significance.

11.1. Primary Efficacy Analysis(es)

The primary efficacy analysis will be carried out using both the ITT and PP populations, with the ITT being the primary population (see Section 6 for definitions).

11.1.1. Daily Trough (Pre-study treatment and pre-bronchodilator) PEF

Daily trough PEF will be taken as the morning PEF measurement for subjects assigned to a treatment arm where the active dose of medication was given in the morning (i.e. GW685698X 100µg am). Daily trough PEF will be taken as the evening PEF measurement for subjects assigned to a treatment arm where the active dose of medication is given in the evening (i.e. GW685698X 100µg pm or GW685698X 250µg pm). Daily trough PEF will be will be taken as either the morning or evening PEF measurement for subjects assigned to the Placebo treatment arm, the measure taken will be from the same time of day as that used for the treatment arm to which it is being compared.

The mean daily trough PEF will be calculated from either the am or pm PEF values collected on the daily record card (DRC) during the run-in and treatment phases as follows:

Mean Daily Trough PEF = Sum of daily trough PEF measurements in period Days in period where daily trough PEF measured

For each subject the baseline daily trough PEF is defined as the mean of the PEF values measured over the last 7 consecutive days of the run-in period (see Section 9.3.2.1). The treatment daily trough PEF is defined as the mean of the PEF values measured over the 28-day treatment period. The change from baseline for each subject will be determined as the difference between these two values.


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The primary efficacy endpoint of mean change from baseline in daily trough PEF during the 28-day treatment period will be calculated for each treatment group as the sum of the individual changes from baseline divided by the number of subjects.

Summary statistics of actual and change from baseline daily trough PEF will be presented for each treatment group. In addition weekly mean values of trough PEF will be displayed in a plot by treatment group. The change from baseline daily trough PEF will be compared between treatment groups using an ANCOVA model, with treatment, baseline daily trough PEF, age, sex and country as terms in the model.

The primary comparison of interest is between the GW685698X 100µg am and pm treated groups. The estimated treatment difference together with a 95% confidence interval for the difference will be presented but a p-value will not since the study objective is not to demonstrate statistical superiority of one treatment over the other.

Interactions with treatment will be assessed for all covariates included in the model at the 10% (2-sided) level of significance for the ITT population only. Subgroup summaries will be produced to further investigate the source of any significant treatment by covariate interaction (see Section 8.3 for further details).

11.2. Secondary Efficacy Analysis

All secondary analyses, with the exception of daily trough PEF, will be carried out using the ITT population only (see Section 6 for definitions).

11.2.1. Daily Trough (Pre-study treatment and pre-bronchodilator) PEF

Summary statistics of actual and change from baseline mean daily trough PEF will be presented for each treatment group over the 28-day treatment period (as stated in Section 11.1.1) and in addition for each of the 4 weeks of the treatment period. In each case the change from baseline daily trough PEF will be compared between treatment groups using an ANCOVA model, with treatment, baseline daily trough PEF, age, sex and country as terms in the model. This will be done for all comparisons listed in Section 7 that have not already been stated in Section 11.1.1. Estimates of the treatment difference, p-values for superiority comparisons only and 95% confidence intervals will be presented for each comparison. These analyses will be carried out for both the ITT and PP populations, with the former being the population of primary interest.

Interactions with treatment will be assessed for all covariates included in the model looking at change from baseline over the 28-day treatment period, these will be tested at the 10% (2-sided) level of significance for the ITT population only. Subgroup summaries will be performed to further investigate the source of any significant treatment by covariate interaction (see Section 8.3 for further details).

In addition, a summary tabulation of trough PEF will also be prepared for each asthma severity subgroup (defined by % predicted PEF at visit 2) as follows:

• Moderate (≥65% predicted PEF)


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• Severe (<65% predicted).

11.2.2. Morning PEF

Summary statistics of actual and change from baseline mean daily AM PEF will be presented for each treatment group over the 28-day treatment period. The change from baseline in AM PEF will be compared between treatment groups using an ANCOVA model, with treatment, baseline AM PEF, age, sex and country as terms in the model. This will be done for all comparisons listed in Section 7. Estimates of the treatment difference, p-values for superiority comparisons only and 95% confidence intervals will be presented for each comparison. It should be noted, however, that a comparison of morning PEF between the AM dose group and either of the PM active dose groups will be biased and should be interpreted jointly with the evening PEF results.

11.2.3. Evening PEF

Summary statistics of actual and change from baseline mean daily PM PEF will be presented for each treatment group over the 28-day treatment period. The change from baseline in PM PEF will be compared between treatment groups using an ANCOVA model, with treatment, baseline PM PEF, age, sex and country as terms in the model. This will be done for all comparisons listed in Section 7. Estimates of the treatment difference, p-values for superiority comparisons only and 95% confidence intervals will be presented for each comparison. It should be noted, however, that a comparison of evening PEF between the AM dose group and either of the PM active dose groups will be biased and should be interpreted jointly with the morning PEF results.

11.2.4. Pre-bronchodilator FEV1

Summary statistics of actual and change from baseline pre-bronchodilator FEV1 will be provided at each visit, as well as being listed. The change from baseline in FEV1 at Visit 6 will be compared between treatment groups using an ANCOVA model with treatment, baseline FEV1, age, sex and country included as terms in the model. Estimated treatment differences for all comparisons will be presented together with 95% confidence intervals for the difference, p-values will only be presented for superiority comparisons of each GW685698X group with placebo.

11.2.5. Clinic Visit PEF

Summary statistics of actual and change from baseline clinic visit PEF will be provided at each visit, as well as being listed. The change from baseline in clinic visit PEF at Visit 6 will be compared between treatment groups using an ANCOVA model with treatment, baseline clinic visit PEF, age, sex and country included as terms in the model. Estimated treatment differences for all comparisons will be presented together with 95% confidence intervals for the difference, p-values will only be presented for superiority comparisons of each GW685698X group with placebo.


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Throughout the study, subjects will have recorded their daytime (PM) and night-time (AM) asthma symptoms scores, rescue medication use and number of night-time awakenings.

For each subject the following parameters will be calculated from the DRC data over the 28-day treatment period:

Percentage of symptom free 24-hr periods: No. days with AM and PM asthma symptom score of 0 *100 Total number of days in treatment period with completed data

Percentage of symptom free days: No. days with PM asthma symptom score of 0 *100 Total number of evenings in treatment period with completed data

Percentage of symptom free nights: No. days with AM asthma symptom score of 0 *100 Total number of mornings in treatment period with completed data

Percentage of 24-hr periods with no rescue medication: No. days with no rescue medication use in morning or evening *100 Total number of days in treatment period with completed data

Percentage of days with no rescue medication: No. days with no rescue medication use recorded in the evening *100 Total number of evenings in treatment period with completed data

Percentage of nights with no rescue medication: No. days with no rescue medication use recorded in the morning*100 Total number of mornings in treatment period with completed data

Percentage of nights with no awakenings: No. days with no awakenings recorded in the morning *100 Total number of mornings in treatment period with completed data

Provided normal distributional assumptions hold and data are not highly skewed, comparisons between pairs of treatment groups (as detailed in Section 7) will be made using ANCOVA with treatment, baseline %, age, sex and country included as terms in the model. Estimated treatment differences for all comparisons will be presented together with 95% confidence intervals for the difference, p-values will only be presented for superiority comparisons of each GW685698X group with placebo.

If the distributional properties of these data do not allow analysis using ANCOVA, each parameter will be categorised as follows: 0%-25%, >25%-50%, >50%-75% and >75% and the number and percent of subjects falling into each category will be displayed. This categorisation will be checked for appropriateness prior to unblinding. These data will be analysed using a logistic proportional odds model with treatment, baseline value, age, sex


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and country included as terms in the model. The baseline value used will be the mean value of the relevant parameter over the baseline period rather than the percentage symptom free etc because the denominator for the percentage would be small (last 7 days of run-in) and patients are likely to be symptomatic at this time.

If the logistic model is used, the estimated treatment difference will be displayed as an odds ratio with 95% confidence intervals, p-values will only be displayed for superiority comparisons of each GW685698X group with placebo.

11.2.7. Withdrawals

Withdrawals prior to randomisation and premature withdrawals during the treatment period will be listed and summarised. The number and percentage of subjects withdrawing from the study will be summarised by their primary reason for withdrawal, for each treatment group. In addition Fisher’s Exact test will be used to compare the number of withdrawals due to lack of efficacy between each of the GW685698X treated groups and placebo.

12. SAFETY ANALYSES

All analyses of safety data will be carried out using the ITT population (see Section 6 for definitions). However, if there is an occurrence of subjects taking a different treatment to which they were randomised, safety displays will be according to the actual treatment taken.

12.1. Extent of Exposure

Study drug exposure data will be listed. The number of days of exposure to study medication will be summarised by treatment group in the following categories <=7, 8-14, 15-21, 22-28 and >28 days. This will be calculated as the number of days between the first dose and the last dose of medication inclusive.

12.2. Adverse Events

Adverse events (AEs) will be coded using the MedDRA coding dictionary (Version 6.0 or a later release) and grouped by system organ class. AEs will be classified as pre-treatment, on-treatment and post-treatment using the following definitions:

• Pre-treatment: started prior to first dose of study medication with no change in frequency or severity

• On-treatment: started after first dose of study medication, or prior to first dose of medication but with increased frequency or severity

• Post-treatment: started after last dose of study medication.

Separate data display listings will be presented for each of the above classifications. In addition the number and percentage of subjects experiencing an AE will be summarised


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by system organ class and preferred term for pre, on- and post treatment events. Separate summaries will also be provided for on-treatment drug-related AEs, all serious AEs and AEs leading to withdrawal.

12.3. Deaths and Serious Adverse Events

Summary tables will be provided for serious adverse events (See Section 12.2). In addition, all deaths and serious AE's will be documented in a case narrative format in the clinical study report.

12.4. Clinical Laboratory Evaluations

Summary statistics of the clinical chemistry and haematology laboratory measurements and also of urinary cortisol, will be provided by visit and treatment group for both actual and change from baseline values. These parameters will also be presented with respect to shifts from baseline. Evaluations will be compared to their normal range (see Section 9.4) and labelled according to whether they are below the lower limit of normal, within the normal limits or above the upper limit of normal. Evaluations will also be compared to the reference ranges (see Section 9.4) and labelled according to whether they are above or below the reference range. Each on-treatment value will be categorised depending on its change relative to the pre-treatment value. Lab values for all subjects will be listed. The investigator will identify values of clinical concern and all information relating to these values will also be listed.

The results of any positive urinalysis assessments will be listed and summarised.

In addition to the above, log-transformed 24-hour urinary cortisol measurements will be compared between treatment groups using an ANCOVA model with treatment, baseline value, age, sex and country as terms in the model. The adjusted geometric means, estimated treatment effect and 95% confidence intervals will presented for all comparisons detailed in Section 7, p-values will only be presented for comparisons of active treatment versus placebo. Cortisol values will also be plotted for each visit against baseline values by treatment group.

12.5. Other Safety Measures

12.5.1. Examination of the Oropharynx

The incidence of clinical/visual evidence of oral candidiasis will be summarised for each treatment group and visit. In addition, the number and percent of subjects with a positive swab will be tabulated for each treatment group at each time point. All data relating to this parameter will be listed.

12.5.2. ECG Measurements

Any abnormal findings from the 12-lead ECG examination will be listed.


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12.5.3. Vital Signs Assessments

All vital signs data will be listed. Summary statistics of systolic and diastolic blood pressure and pulse rate will be presented for each treatment group and visit, for both actual and change from baseline values.

12.5.4. Physical Examination

Physical examination data are not entered onto the database within GSK. Any abnormal findings will be captured as an adverse event.

12.5.5. Deaths and SAEs

See Section 12.3 of this RAP.

13. HEALTH OUTCOMES ANALYSES

13.1. Resource Utilisation Measures

Unscheduled, emergency, or telephone contact information will be listed.

14. CLINICAL PHARMACOLOGY DATA ANALYSES

Clinical pharmacology analyses will be performed by CPSP, BDS.

14.1. Pharmacokinetic Population

Only samples from patients taking GW685698X will be analyzed. Individuals involved in the bioanalysis of PK samples in WorldWide Bioanalysis, DMPK, and the contract research organization will be unblinded as per SOP POL-NPD-0009. The PK population includes all subjects who provided plasma samples for measurement of GW685698X concentration.

14.2. Interim analyses

No interim analysis is planned.

14.3. General considerations for data analyses

Concentrations below the lower limit of quantification (LLQ) for the LC-MS-MS assay (10pg/mL) will be reported as NQ (Below Quantification Limit). Percent of NQ samples will also be calculated for each time interval following active treatments.

All NQ values will be set to missing in the NONMEM datasets. All excluded observations along with reasons of exclusion will be listed in the report.


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14.4. Covariates

The effect of the following covariates on the PK of GW685698X will be investigated:

• demographic data (age, race, gender, weight, body mass index),

• the influence of subject’s asthma history (baseline asthma symptom scores) , and

• the effects of concurrent asthma medication.

Evaluable patients will be randomized into two groups, Group A (2/3 of patients) and Group B (1/3 of patients). Randomization will be accomplished by assigning a random number to each patient using the ranuni function in SAS. SAS Proc Rank then will be used to group patients into three equal groups by their random number assignment. Patients in group 0 will be assigned to group B, while patients in groups 1 and 2 will be assigned to group A. Data from group A will be used to build the model. This dataset will be the “model development” dataset. Data from group B will be used to validate the model built using the “model development” dataset. This dataset will be called “model validation” dataset.

14.5. Missing sampling and treatment information

The sampling times are relative to the time of the last dose of GW685698X. A missing dependent variable (DV) should never be recorded unless EVID (the dosing event flag) and MDV (the missing dependant variable flag) indicate that DV is really missing.

The event identification (EVID) will be coded 0 for a concentration observation, 1 for a dose event, 4 to reset the time at a dosing event. Full details of the file structure will be presented in a separate CPDM RAP.

Data from subjects with inadequate dosing histories (no records for dosing time for one and/or both doses – morning dose and the previous evening dose) or missing sample information will be discarded from the data file. Concentrations following an obvious missing dosing event will be excluded from the PK analysis. All excluded observations or discarded data from the data file along with reasons for exclusion will be listed in the report.

Some concentration results may be inconsistent with the expected PK behavior of GW685698X. These data may be excluded from the modeling after investigation about possible sampling/labeling errors. The exclusions will be listed.

14.6. Missing covariates

Only subjects with a complete set of covariates and a GW685698X concentration will be included for the first covariate analysis. If some covariates have no influence in this analysis, then subjects with a missing value for these covariates may be added back into the dataset in order to improve the final parameter estimates. These subjects, however, must have values for all of the significant covariates in the model.


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14.7. Derived and transformed data

Primary pharmacokinetic parameters will be computed by substituting the fitted values of those fixed effects determined to be influential during the modeling process and the typical values of covariates representing the population of interest into the functional expression of the parameter as defined in any given model. Secondary PK parameters will be computed from the estimated values of the primary PK parameters. The expressions used to calculate the secondary parameters are dependent upon the model that is finally selected during the PK analysis.

14.8. Pharmacokinetic Analyses

Characterisation of patient population PK of GW685698X in subjects with persistent asthma following 250µg or 100µg once daily treatment for 28 days. GW685698X plasma concentration-time data will be subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The goal of this analysis will be to determine the systemic exposure following evening dosing to asthmatic patients. The effects of patient demographic characteristics such as gender, age, weight, body mass index (BMI) will also be examined. Individual predicted PK parameters will be summarised descriptively.

Population modeling will be conducted utilising the software NONMEM, version V, (Non-linear mixed effects model, UCSF, CA) which needs specific data formats and a number of indicator variables identifying each task. A summary of possible indicator variables and their description is given in Attachment 1. Variables included in the final dataset will depend upon the best fit population PK model and influential covariates in this population. Therefore all indicator variables in the Attachment 1 may not be included in the final model and final model may include variables, which are not listed in the Attachment 1.

Evaluable patients from both studies will be randomized into two groups, Group A (2/3 of patients) and Group B (1/3 of patients). Data from group A will be used to build the model. This dataset will be the “model development” dataset. Data from group B will be used to validate the model built using the “model development” dataset. This dataset will be called “model validation” dataset.

The PK analysis will begin with the development of a basic structural model. This model will be defined in terms of the number of compartments, the inter-compartment transfer rate constants, and, if necessary, lag-times between compartments. Various models for residual error will be tested, each serving as a starting point for examining the nature and significance of the available covariates.

Effects of covariates will be assessed by examining the minimum value of the objective function (MVOF) before and after its inclusion in the model. In addition, the estimated model parameters are associated with standard errors. These are used to construct 95% confidence interval (CI) for the parameter. Therefore, the influence of a covariate can also be evaluated by determining whether or not the CI for the associated model parameters includes a value (i.e. zero for additive effects) that would nullify its


26

contribution to the model. Other covariates may be considered in the analysis if diagnostic plots indicate that they might explain residual variability in the model.

Relationships between the PK parameters and demographic variables will be explored by examining the effects of these variables on the residual error when they are included in the model as covariates. In a typical population-based PK analysis, estimates of the population variance of the PK parameters are used to calculate bayesian, post-hoc estimates of the PK parameters for individual subjects. This is possible because the data being analyzed normally contains two or more observed concentrations per subject. These post-hoc estimates can then be related to clinical measures of efficacy and safety endpoints using pharmacodynamic models.

As an exploratory exercise, the relationship between GW685698X systemic exposure and clinical efficacy and safety endpoints will be investigated. These endpoints include urinary cortisol excretion, average change from baseline in trough PEF, average change from baseline in daytime and nighttime asthma symptom scores and percentage of symptom-free 24-hour days.

15. PHARMACOGENETIC DATA ANALYSES

If PGx analyses are required, they will be detailed in a separate analysis plan written by the Pharmacogenetics department.


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16. REFERENCES

GlaxoSmithKline Document Number GM2003/00336/00 Study ID FFA20001. A randomised, double-blind, double-dummy, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GW685698X 100µg administered once daily either in the morning or the evening and GW685698X 250µg administered once daily in the evening all administered by inhalation via DISKHALER. for 28 days in subjects with persistent bronchial asthma.

Polgar G, Promadhat V. Pulmonary function testing in children: techniques and standards. Philadelphia: WB Saunders, 1971.

Quanjer PH, Tammeling GJ, Cotes JS, Pedersen OF, Peslin R, Yernault JC. Lung Volumes and Forced Ventilatory Flows. Report Working Party Standardisation of Lung Function Tests. European Community for Coal and Steel (ECCS). Official statement of the European Respiratory Society. European Respiratory Journal 1993; Suppl. 16, 5-4


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17. ATTACHMENTS

17.1. Table of Contents for Data Display Specifications

17.1.1. Listings

Listing 1 Listing of Randomisation Data Listing 2 Listing of Subjects with Inclusion/Exclusion Criteria Deviations Listing 3 Listing of Withdrawals Prior to Randomisation Listing 4 Listing of End of Study Record Listing 5 Listing of Major Protocol Violators (Excluded from Per Protocol

Population) Listing 6 Listing of Subjects for Whom the Treatment Blind was Broken

During the Study Listing 7 Listing of Demographic Characteristics Listing 8 Listing of History of Tobacco Use Listing 9 Listing of Current Medical Conditions Listing 10 Listing of Duration of Asthma and Asthma History Listing 11.1 Listing of Asthma Concomitant Medications – Pre-treatment Listing 11.2 Listing of Asthma Concomitant Medications – On-treatment Listing 12 Listing of Other Concomitant Medications – On-treatment Listing 13 Relationship between ATC Level 1, Preferred Term and Verbatim

Text Listing 14 Listing of Investigational Product and Investigational Product

Compliance Listing 15 Listing of Pre-Treatment Lung Function Listing 16 Listing of Daily Record Card Mean Peak Expiratory Flow Rate

(L/min) Listing 17 Listing of Diary Card Symptom and VENTOLIN-Use Data Days Listing 18 Listing of Clinic Visit Pulmonary Function Tests Listing 19 Listing of Exposure Data Listing 20 Listing of Subject Numbers for Individual Adverse Events Listing 21.1 Listing of All Adverse Events – Pre-Treatment Listing 21.2 Listing of All Adverse Events – On-Treatment Listing 21.3 Listing of All Adverse Events – Post-Treatment Listing 22 Listing of Serious Adverse Events Listing 23 Listing of Fatal Adverse Events Listing 24 Relationship of Adverse Event System Organ Classes, Preferred

Terms, and Verbatim Text Listing 25 Listing of Haematology Data for Subjects with Abnormalities of

Clinical Concern Listing 26 Listing of Haematology Data for All Subjects Listing 27 Listing of Clinical Chemistry Data for Subjects with Abnormalities

of Clinical Concern Listing 28 Listing of Clinical Chemistry Data for All Subjects Listing 29 Listing of 24-hour Urinary Cortisol Data for Subjects with

Abnormalities of Clinical Concern


29

Listing 30 Listing of Urinary Cortisol Data for All Subjects Listing 31 Listing of Urinalysis-Local Data for Subjects with Positive Results Listing 32 Listing of Oropharyngeal Examination Listing 33 Listing of Abnormal ECG Findings Listing 34 Listing of Vital Signs Listing 35 Listing of Unscheduled/Emergency Contact Information Listing 36 Key of all the variables used in the model development dataset Listing 37 Listing of NONMEM primary dataset Listing 38 Listing of the validation dataset Listing 39 Listing of all control files used for selection of primary model

(base model, intermediate model and final control file) Listing 40 NONMEM output file from the final primary PK model Listing 41 Listing of all validation control files used. Listing 42 NONMEM output file from the validation PK model. Listing 43 Estimated Population Pharmacokinetic Parameters for

GW685698X

17.1.2. Tables

Table 19.1 Summary of Subject Populations Table 19.2 Summary of Reasons For Withdrawal Prior to Randomisation Table 19.3 Summary of End of Study Record Table 19.4 Summary of Attendance at Each Clinic Visit Table 19.5 Summary of Reasons for Exclusion from Per Protocol Population Table 19.6 Summary of Inclusion/Exclusion Criteria Deviations Table 19.7 Summary of Demographic Characteristics Table 19.8 Summary of History of Tobacco Use at Visit 1 (Screening) Table 19.9 Summary of Current Medical Conditions Table 19.10 Summary of Duration of Asthma and Asthma History Table 19.11 Summary of Asthma Concomitant Medications – Pre-Treatment Table 19.12 Summary of Asthma Concomitant Medications – On-Treatment Table 19.13 Summary of Other Concomitant Medications Table 19.14 Summary of Overall Treatment Compliance Table 19.15 Summary of Clinic Pulmonary Function Tests Prior to Treatment Table 19.16 Summary of Baseline Diary Card Pulmonary Function Tests Table 20.1 Summary of Trough Peak Expiratory Flow Rate (L/min) Table 20.2 Statistical Analysis of Trough Peak Expiratory Flow Rate Change

From Baseline Over 28 Days Treatment Table 20.3 Statistical Analysis of Trough Peak Expiratory Flow Rate Change

From Baseline Over 28 Days Treatment: Treatment by Covariate Interactions

Table 20.4 Summary of Trough Peak Expiratory Flow Rate Change From Baseline Over 28 Days Treatment by Covariate

Table 20.5 Summary of Trough Peak Expiratory Flow Rate (L/min) – Per Protocol Population

Table 20.6 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From Baseline Over 28 Days Treatment - Per Protocol Population


30

Table 20.7 Statistical Analysis of Trough Peak Expiratory Flow Rate Change From Baseline Over Week 1




Table 20.11 Summary of Trough Peak Expiratory Flow Rate (L/min) By Screening Asthma Severity

Table 20.12 Summary of Mean Morning Peak Expiratory Flow Rate (L/min) Table 20.13 Statistical Analysis of Mean Morning Peak Expiratory Flow Rate

(L/min) Change from Baseline Over 28 Days Treatment Table 20.14 Summary of Mean Evening Peak Expiratory Flow Rate (L/min) Table 20.15 Statistical Analysis of Mean Evening Peak Expiratory Flow Rate

(L/min) Change from Baseline Over 28 Days Treatment Table 20.16 Summary of Clinic Visit FEV1 (L) Table 20.17 Statistical Analysis of Clinic Visit FEV1 (L) Change from

Baseline at Visit 6 (LOCF) Table 20.18 Summary of Clinic Visit Peak Expiratory Flow Rate (L/min) Table 20.19 Statistical Analysis of Clinic Visit Peak Expiratory Flow Rate

(L/min) Change from Baseline at Visit 6 (LOCF) Table 20.20 Summary of Diary Card Information: Percentage of Symptom Free

24-hour Periods Table 20.21 Statistical Analysis of Diary Card Information: Percentage of

Symptom Free 24-hour Periods Table 20.22 Summary of Diary Card Information: Percentage of Symptom Free

Days Table 20.23 Statistical Analysis of Diary Card Information: Percentage of

Symptom Free Days Table 20.24 Summary of Diary Card Information: Percentage of Symptom Free

Nights Table 20.25 Statistical Analysis of Daily Record Card Information: Percentage

of Symptom Free Nights Table 20.26 Summary of Diary Card Information: Percentage of 24-Hour

Periods with no Rescue Medication Table 20.27 Statistical Analysis of Daily Record Card Information: Percentage

of 24-Hour Periods with no Rescue Medication Table 20.28 Summary of Daily Record Card Information: Percentage of Days

with no Rescue Medication Table 20.29 Statistical Analysis of Daily Record Card Information: Percentage

of Days with no Rescue Medication Table 20.30 Summary of Daily Record Card Information: Percentage of Nights

with no Rescue Medication Table 20.31 Statistical Analysis of Daily Record Card Information: Percentage

of Nights with no Rescue Medication Table 20.32 Summary of Daily Record Card Information: Percentage of Nights

with No Awakenings


31

Table 20.33 Statistical Analysis of Daily Record Card Information: Percentage of Nights with No Awakenings

Table 20.34 Statistical Analysis of Withdrawals Due to Lack of Efficacy Table 21.1 Summary of Exposure to Study Drug Table 21.2 Summary of All Adverse Events – Pre Treatment Table 21.3 Summary of All Adverse Events – On Treatment Table 21.4 Summary of All Adverse Events – Post Treatment Table 21.5 Summary of Drug-Related Adverse Events – On Treatment Table 21.6 Summary of Serious Adverse Events – Pre Treatment Table 21.7 Summary of Serious Adverse Events – On Treatment Table 21.8 Summary of Serious Adverse Events – Post Treatment Table 21.9 Summary of Adverse Events Leading To Withdrawal Table 22.1 Summary of Haematology Data Table 22.2 Summary of Haematology Data Change From Visit 2 (Baseline) Table 22.3 Summary of Haematology Data Outside the Reference Range Table 22.4 Summary of Haematology Laboratory Shifts From Baseline Table 22.5 Summary of Clinical Chemistry Data Table 22.6 Summary of Clinical Chemistry Data Change From Visit 2

(Baseline) Table 22.7 Summary of Clinical Chemistry Data Outside the Reference Range Table 22.8 Summary of Clinical Chemistry Laboratory Shifts From Baseline Table 22.9 Summary of 24hr Urinary Cortisol Data Table 22.10 Summary of 24hr Urinary Cortisol Data Change From Visit 2

(Baseline) Table 22.11 Summary of 24hr Urinary Cortisol Data Outside the Reference

Range Table 22.12 Summary of 24hr Urinary Cortisol Shifts From Baseline Table 22.13 Statistical Analysis of 24hr Urinary Cortisols at Visit 6 Table 22.14 Summary of Urinalysis-Local Data Table 22.15 Summary of ECG Data Table 22.16 Summary of Oropharyngeal Examination Table 22.17 Summary of Vital Signs Table 22.18 Summary of Vital Signs Change From Visit 2 (Baseline) Table 23.1 Summary statistics for demographic characteristics for subjects in

the PK dataset by treatment Table 23.2 Estimated population PK parameter means and their 95% CI Table 23.3 Description of all intermediate models tested in the report.

17.1.3. Figures

Figure 1 Plot of Change from Baseline in Weekly Mean Trough PEF by Treatment Group

Figure 2 Plot of Urinary Cortisol Values Figure 3 Goodness of fit plots of basic and final PK model (Prediction vs

dependent variable, Time vs Residual, Time vs Weighted residual, Prediction vs residual, Prediction vs Weighted residual)

Figure 4 Plots of base model PK parameter estimates versus influential covariates.


32

Figure 5 Exploratory plots between GW685698X systemic exposure and some of the clinical efficacy and safety endpoints.

17.2. Data Display Specifications

Available on Request


33

Protocol Identifier Subject Identifier Centre Number

FFA20001 {{{{{{} {{{{{{}

Final - 05 SEP 03CONFIDENTIAL

*FFA20001* Page

COVER SHEET - TRACKING DETAILS

A Randomised, Double-blind, Double-dummy, Placebo-controlled, Parallel-group Study to Evaluate The Efficacy and Safety of GW685698X 100µg

Administered Once Daily Either In The Morning or The Evening and GW685698X 250µg Administered Once Daily In The Evening All

Administered by Inhalation Via DISKHALER for 28 Days In Subjects With Persistent Bronchial Asthma.

Visits included in this CRF - Visits 1-6, Visit 7 Follow-up and Withdrawal. Investigational Product, InvestigationalProduct Compliance, Status of Treatment Blind, Unscheduled/Emergency Contact, Pharmacogenetic Research, Concomitant Medications, Non-Serious Adverse Events, Serious Adverse Event, Study Conclusion, Investigator Comment Log, Investigator’s Signature.

*1* 1


1

Final - 05 SEP 03Protocol Identifier FFA20001

CONFIDENTIAL

COMPLETION GUIDELINES FOR CASE REPORT FORMS (CRFS) GENERAL INSTRUCTIONS FOR CRF COMPLETION

• Complete CRFs in English; answer all questions on every page unless directed otherwise.• Print neatly and legibly; use a black ballpoint pen and press firmly so that all copies are legible.• Do not write information on page margins.• Avoid use of abbreviations and acronyms whenever possible. If abbreviations must be used, use only clear

abbreviations that are in standard medical use, or those supplied on instructional pages in this CRF.• Enter Subject Number in the space provided at the top of each CRF page.• Do not write the Subject’s name or initials anywhere inside the CRF.• Record all values in the units indicated on the CRF (e.g., Height in centimetres, Weight in kilograms).• Where boxes are provided in the CRF to record numbers, complete as follows, using leading zeroes if

necessary: 6 recorded as )^}.• Ensure that information classified as "Other, specify" does not fit into one of the listed categories. Record a

concise reason in the "specify" field that accompanies "Other", if "Other" is ✔.• If extra pages need to be inserted between numbered CRF pages, do the following: insert the first extra page

after the last numbered page in the section of the CRF affected (e.g., Concomitant Medications) and number the extra page as nn.01. Subsequent extra pages are then numbered nn.02, nn.03 etc.

DATE

• If the CRF is not completed at time of subject assessment, record date of assessment, not date of CRF completion.

• Use the first three letters of each month as the abbreviation for the months (e.g., JAN, FEB, MAR).

Day Month Year= 1st January 2002

TIME

• Record time in 24-hour clock format unless specified otherwise, per conversion chart below.

a.m. p.m.

Midnight = 00:001:00 = 01:002:00 = 02:003:00 = 03:004:00 = 04:005:00 = 05:00

6:00 = 06:007:00 = 07:008:00 = 08:009:00 = 09:0010:00 = 10:0011:00 = 11:00

Noon = 12:001:00 = 13:002:00 = 14:003:00 = 15:004:00 = 16:005:00 = 17:00

6:00 = 18:007:00 = 19:008:00 = 20:009:00 = 21:0010:00 = 22:0011:00 = 23:00

Note: Midnight = 00:00 is the start of the new day, not the end of the previous day.

MISSING INFORMATION

• Use the following abbreviations for missing information.

• NA• ND• UNK• NR

not available/not applicablenot doneunknownno result (to be used only for missing data recorded on Local Lab pages)

CRF CORRECTION PROCESS

• Draw a single line through an incorrect entry and write the correct information nearby.• Initial and date all corrections, additions or deletions.• DO NOT erase, write over, use correction fluid or tape, or re-copy the original page to correct errors.

0 1 J A N 0 2


2

Final - 05 SEP 03Protocol Identifier FFA20001 CONFIDENTIAL

TIME AND EVENTS SCHEDULE Screening visit (start

of run-in period)Treatment period Follow-up

Visit Number 1/1a/1b 2 3 4 5 6 7

Weeks -3 to -1 0 1 ± 2 days 2 ± 2 days 3 ± 2 days 4 ± 2 days 5 ± 2 days

Informed Consent X b

Demographics X b

History of Asthma and Concomitant Conditions X b

Physical Examination X b X Xe

Vital Signs X X X X X X Xe

Haematology/Biochemistry/dipstick Urinalysis X b X Xe

Urine Pregnancy Testing X X X

12-lead electrocardiogram X b X Xe

Clinic measured Pulmonary Function X c X X X X X Xe

Pharmacokinetics Blood Samples a X X X

Pharmacogenetics Blood Samples X b

Adverse Event Monitoring X X X X X X

Concomitant Medication Monitoring X X X X X X X

Examination of Oropharynx X X X X X X X

24 hr Urine collection for Cortisol Assessments X X

Issue Rescue Ventolin X Xd Xd

Issue Daily Record Card X X X X X

Issue Study Medication X

Collect used Rescue Ventolin X X Xf

Collect Completed Daily Record Card X X X X X X Xf

Collect Used Study Medication (Blister Packs) X X X X Xf

Check Subjects Taking Correct Medication X X X X

a samples will only be collected at centres with appropriate facilities; b The assessments indicated will be performed at Visit 1 only, and will not be repeated at Visits 1a and 1b; c Clinic lung function tests (FEV1 and PEF) should be performed at Visits 1, 1a, and 1b. Reversibility need only be performed once during the screening period to meet the criterion; d If required; e Tests only need to be performed if abnormal at Visit 6; f If subject did not return Ventolin, study medication, or daily record card at Visit 6 the subject should return it at Visit 7.

CO

NFID

ENTIA

LG

M2004/00341/00

FFA20001

3


CONFIDENTIAL

INCLUSION AND EXCLUSION CRITERIAMONITOR DATA VALIDATION CHECK

• Confirm that the subject is eligible to participate in the study and if not, that all the failed criteria have been marked.


4

Protocol Identifier Subject Identifier Visit DateDay Month Year

Visit Description

FFA20001 {{{{{{}Screening

Visit 1


*FFA20001* Page

ELIGIBILITY QUESTION

INCLUSION CRITERIA

Did the subject meet all the entry criteria?

[Y]by [N]bn

If No, ✔ all boxes corresponding to violations of any inclusion/exclusion criteria.

Do not enter the subject into the study if they failed any inclusion or exclusion criteria below.

✔ the boxes corresponding to any of the inclusion criteria the subject failed.

1. b Male or female, aged 16 to 55 years inclusive.


a) Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who is post-menopausal. For the purposes of this study, post-menopausal is defined as 1 year without menses; or

b) Child-bearing potential, has a negative pregnancy test (urine) at entry, and agrees to one of the following acceptable contraceptive methods when used consistently and correctly (i.e., in accordance with the approved product label and the instructions of a physician for the duration of the study - screening visit to follow-up contact):








2. b Documented clinical history of persistent asthma first diagnosed at least 6 months prior to Visit 1.

3. b Currently receiving inhaled short-acting β2-agonists for symptom relief.

4. b Able and willing to give written informed consent to take part in the study.

5. b Able to comply with all the study requirements.

*2* 2


5


Protocol Identifier Subject Identifier Visit Description


Visit 1

*FFA20001* Page

INCLUSION CRITERIA (Continued)

EXCLUSION CRITERIA


6. b A lung function of between 50 to 90% predicted (PEF).

7. b Increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol (if subjects do not fulfil the criteria at Visit 1, the test may be repeated at visit 1a/1b/2).

✔ the boxes corresponding to any of the exclusion criteria that disqualified the subject from entry.

1. b History of respiratory tract infection and/or exacerbation of asthma within a period of 4 weeks prior to Visit 1.

2. b History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnoea, respiratory arrest or hypoxia seizures.

3. b A history of two or more asthma exacerbations requiring treatment with oral corticosteroids or hospitalisation in the 6 months before Visit 1.

4. b Previously enrolled in this study, or currently participating or has participated in another study during the last 3 months.

5. b Past or present disease that, as judged by the investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematologic disease, neurological disease, endocrine disease or pulmonary disease (including, but not confined to, chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis and bronchopulmonary dysplasia).

6. b Known or suspected sensitivity to corticosteroids, VENTOLIN, or the constituents of ROTADISKS (e.g., lactose).

7. b Undergoing allergen desensitisation therapy.

8. b Subjects who are likely to be non-compliant with study medication and other study-related requirements (e.g., attendance at clinic visits or completion of DRCs).

9. b Neurological or psychiatric disease or history of drug or alcohol abuse that would interfere with the subject’s proper completion of the protocol requirements.

10. b Is a current smoker or has a smoking history of 10 pack years or more (e.g., 20 cigarettes/day for 10 years).Note: Current smoker is defined as currently smoking or stopped smoking within 6 months of

screening visit.

11. b Administration of the following medications:

Theophyllines, oral β2-agonists, slow-release bronchodilators, anticholinergics, long-acting β2-agonists or ketotifen within 2 weeks prior to Visit 1.



*3* 3


6


CONFIDENTIAL

DEMOGRAPHYINVESTIGATOR INSTRUCTIONS

The racial groups below are based on the subject’s genotypical racial origin, not nationality or where they currently reside.

✔ the racial group which best describes the subject’s racial origin.

• Arabic/North African

• Black

• East and South East Asian

• South Asian

• White/Caucasian

• Other

With racial origin in North Africa/Middle East

With racial origin in Central, East or West Africa

With racial origin in East and South East Asia, e.g., Chinese, Korean, Thai, Vietnamese

With racial origin in South Asia e.g., Indian, Pakistani

With racial origin in Europe

With racial origin not represented above or whose predominate origin can not be determined


7




Visit 1

*FFA20001* Page

DEMOGRAPHY

Date of birth Day Month Year

Sex [M]bMale

[F]bFemale

Race * [2]bArabic/North African

[3]bBlack

[4]bEast & South East Asian

[6]bSouth Asian

[7]bWhite/Caucasian

[Z]bOther

* See facing page for race definitions .

*4* 4


8

Protocol Identifier Subject Identifier

WORKSHEET

Visit Description


Visit 1


PHYSICAL EXAMINATION WORKSHEET

Indicate current physical findings by ✔ the appropriate box(es) below and if ABNORMAL, describe concisely: [different findings should be separated by either a (;) or a (/)].

NotDone

Normal Abnormal If Abnormal, specify:

1. Hair and Skin {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

2. Lymph nodes {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

3. Eyes {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

4.Ears, Nose and Throat {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

5. Breast {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

6. Respiratory {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

7. Cardiovascular {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

8. Abdomen {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

9. Urogenital {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

10. Pelvic {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

11. Rectal {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

12. Musculoskeletal {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

13. Neurological {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

14. Mental Status {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


9


CONFIDENTIAL

CURRENT MEDICAL CONDITIONS DEFINITIONS

CURRENT MEDICAL CONDITIONS

Conditions from which the subject is currently suffering, regardless of how long they have been present. If the subject has had a recurring condition that is not present at the time of the assessment, it can be classed as current if, in the Investigator’s opinion it is likely to recur during the study.


10




Visit 1

*FFA20001* Page

CURRENT MEDICAL CONDITIONS If the subject is suffering from any significant medical condition(s), other than the condition under study, specify the condition(s) next to the appropriate category.

Only provide conditions related to the categories below.

Record multiple conditions on the same line, separated by commas.

1. Blood and lymphatic system disorders

2. Cardiac disorders

3. Ear and labyrinth disorders

4. Endocrine disorders

5. Eye disorders

6. Gastrointestinal disorders

7. Hepatobiliary disorders

8. Immune system disorders

9. Metabolism and nutrition disorders

10. Musculoskeletal and connective tissuedisorders

11. Neoplasms benign, malignant andunspecified (inc. cysts and polyps)

12. Nervous system disorders

13. Psychiatric disorders

14. Renal and urinary disorders

15. Reproductive system and breast disorders

16. Respiratory, thoracic and mediastinaldisorders

17. Skin and subcutaneous tissue disorders

18. Vascular disorders

19. Infections and Infestations

*5* 5


11


CONFIDENTIAL

DURATION OF ASTHMA MONITOR DATA VALIDATION CHECKS

• Ensure that only one box is ✔ for range of duration.

• Ensure that the bottom of the range is not greater than the subject’s age.


12




Visit 1

*FFA20001* Page

DURATION OF ASTHMA

ASTHMA HISTORY

✔ one box only:

[ 1]b< 6 months [ 2]b≥ 6 months to < 1 year [ 6]b≥ 1 year to < 5 years

[11]b≥ 5 years to < 10 years [12]b≥ 10 years

Note: Subject must have documented clinical history of persistent asthma first diagnosed at least 6 months prior to Visit 1 to be eligible for the study.

Record number of exacerbations of asthma in the 6 months prior to Visit 1.

Number of episodes in the last 6 months(not involving hospitalisation) {{} If none, enter ’00’.

Number of episodes in the last 6 monthsthat required hospitalisation {{} If none, enter ’00’.

Number of exacerbations requiring treatment withoral corticosteroids in the 6 months before Visit 1 {{} If none, enter ’00’.

Note: Subjects with a history of two or more asthma exacerbations requiring treatment with oral corticosteroids or hospitalisation in the 6 months before Visit 1 are NOT eligible for the study.

*6* 6


13


CONFIDENTIAL

HISTORY OF TOBACCO USEINVESTIGATOR INSTRUCTIONS

DEFINITIONS

• Never smoked

• Current smoker

• Former smoker

Never smoked

Currently smoking or stopped smoking within 6 months of screening visit(Current smokers are not eligible for inclusion in this study)

Previously smoked and stopped smoking at least 6 months prior to screening visit

CONVERTER FOR TOBACCO PRODUCTS

1 cigar

1 gram (or 0.03 oz.) of tobacco

= 7 cigarettes

= 1 cigarette

CALCULATION FOR NUMBER OF PACK YEARS

Average number of cigarettes smoked per dayx number of years smoked

20

Note: If more than >10 pack years subject’s are not eligible for the study


14




Visit 1

*FFA20001* Page

HISTORY OF TOBACCO USE

What is the subject’s history of tobacco use (includes all tobacco products)?

[1]bNever smoked1

[2]bCurrent smoker1

[3]bFormer smoker1 aWhen did the subject last smoke?Day Month Year

If former smoker, answer the following questions:

Average number of cigarettes2 smoked per day? {{{} per day

Number of years during which the subject has smoked? {{{} years

Number of pack years?3 {{{} pack years

1 See facing page for definitions.2 For cigar and pipe smokers and smokeless tobacco use the conversion on the facing page.3 See facing page for calculation guidelines.

*7* 7


15


CONFIDENTIAL

OROPHARYNGEAL CANDIDIASIS EXAMINATIONINVESTIGATOR INSTRUCTIONS

MONITOR DATA VALIDATION CHECKS

CENTRAL LABORATORYMONITOR DATA VALIDATION CHECK

• Swab need only be taken if there is clinical evidence of Oropharyngeal Candidiasis.

If there is clinical evidence of oropharyngeal candidiasis:

• Take a swab and send to a local laboratory for analysis.

• Complete the Current Medical Conditions page if the swab is positive.

• Complete the Concomitant Medications page if treatment is prescribed.

• Ensure that either the Yes or No box is ✔ for evidence of oropharyngeal candidiasis.


• Ensure that a swab has been taken.

• Ensure that only one result of the swab has been recorded and is correct.

• If swab result will never be known ensure that ’Not Available’ is ✔.

• Ensure that all medications used to treat the infection are recorded on the Concomitant Medications page.

• Ensure that oropharyngeal candidiasis when present is recorded on the Current Medical Conditions page.

• Ensure that the appropriate lab samples have been couriered to the Central Laboratory for processing if appropriate.


16




Visit 1

*FFA20001* Page

OROPHARYNGEAL CANDIDIASIS EXAMINATION

CENTRAL LABORATORY - Blood

Does the subject have clinical evidence of oropharyngeal candidiasis? [Y]by [N]bn

Note: Swab need only be taken if there is clinical evidence of oropharyngeal candidiasis.

Was a swab taken? [Y]by [N]bn

If Yes, result of swab,

✔only one:

[1]bNegative

[2]bPositive

[4]bNot available

Complete the Concomitant Medications page and Current Medical Conditions page(s) if applicable.

Date and time sample taken Day Month Year

:

(00:00-23:59)Hr:Min

*8* 8


17


CONFIDENTIAL

URINALYSIS - LOCALINVESTIGATOR INSTRUCTIONS

URINALYSISMONITOR DATA VALIDATION CHECK

• If the laboratory results are not available to report or if a lab error occurred, enter "NR" (the abbreviation for ’NoResult’).

Code Results as:

NEGTRA1+2+3+4+5+

=======

none or negativetrace+ or 1+++ or 2++++ or 3+++++ or 4++++++ or 5+ (include this code if dipstick used requires it)

• Check that results are provided using appropriate codes as outlined in the instructions above.


18




Visit 1

*FFA20001* Page

URINALYSIS - LOCAL

PREGNANCY TEST

PHARMACOGENETIC RESEARCH

Date and time sample takenDay Month Year

:

(00:00-23:59)Hr:Min

Result of dipstick [NEG]bNegative

[POS]bPositive a If positive, record results of individual tests below.

[NR]bNo result

Urinalysis Test Result 1

Leucocytes

Nitrite

Urobilinogen

Protein

pH

Blood

Specific gravity

Ketone

Bilirubin

Glucose

1 See facing page for results codes

Complete the Non-Serious Adverse Events (AE) or Serious Adverse Event (SAE) page(s) if clinically significant abnormalities meet the protocol definition for an AE or SAE.

• Ensure a urinary pregnancy test has been performed (for females of childbearing potential only).

Note: Subjects who have a positive pregnancy test result at Visit 1 must be excluded from the study.

• In addition to any blood samples taken for the clinical study, if the subject is eligible to enter the run-in period, collect a whole blood sample (10mL) for the PGx research using a tube containing EDTA.

Note: Subject must give informed consent for pharmacogenetic research.

*9* 9


19


CONFIDENTIAL

VITAL SIGNSINVESTIGATOR INSTRUCTIONS

• Blood pressure and heart rate must be measured after 5 minutes rest in the sitting position and prior to the clinic lung function tests.


20




Visit 1

*FFA20001* Page*10* 10

VITAL SIGNS

12-LEAD ECG

Height {{{} cm

Weight {{{}.{} kg

Blood pressure {{{}/{{{} mmHg

Systolic / DiastolicPosition: Sitting

Heart rate {{{} beats/minute

Date of ECGDay Month Year

Result of the ECG

[1]bNormal

[2]bAbnormal - not clinically significant

[3]bAbnormal - clinically significant

[4]bNo result (not available)

Record medical conditions in the Current Medical Conditions page.


21


CONFIDENTIAL

PULMONARY FUNCTION TESTINGMONITOR DATA VALIDATION CHECKS

• Ensure that the appropriate test is within the protocol defined range.

• Ensure that predicted normal(s) is/are correct from the table provided.

• Ensure that % Predicted Normal(s) calculation(s) is/are correct and within theprotocol specified range(s).

• Ensure that the % Reversibility calculation is correct.

• Ensure that % Predicted Normal has been rounded accurately to 1 decimal place.

• Ensure that % Reversibility has been rounded accurately to 1 decimal place.

• Ensure that PEF (L/min) has been rounded accurately to a whole number.

• Ensure that FEV1 has been rounded accurately to 2 decimal places.

• Ensure that all spirometry printouts are signed and dated by the responsible person and clearly indicate the clinic visit, the date of the visit, the time of assessment and the GlaxoSmithKline subject number.

• The spirometry printouts must be stored in the subject medical notes.

• If spirometry printouts are on thermal paper the pages must be copied.

AB

x 100( )

C - AA

x 100 )(


22




Visit 1

*FFA20001* Page*11* 11

PULMONARY FUNCTION TESTING

Has the subject taken a bronchodilator in the last 6 hours? [Y]by [N]bn

Test Time of AssessmentPre-400mg salbutamol

ActualMeasurement

Pre-400mg salbutamol

(highest of 3 measurements)

PredictedNormal

% PredictedNormal

ActualMeasurement

20 minutesPost-400mg salbutamol


%Reversibility

Hr : Min(00:00 - 23:59)

A B C

e.g., PEF (L/min) 08:00 340 440 77.3 400 17.6

PEF (L/min)(hand held meter)

: . .

e.g., FEV1 (L) 08:00 1.75 3.25 53.8 1.82 4.0

FEV1 (L) : .

Note: An increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol must be demonstrated. If the subject does not fulfil this criteria at Visit 1, the test must be repeated at Visit 1a, 1b or Visit 2.

x 100BA ( x 100 )A

C - A


23


CONFIDENTIAL

INVESTIGATOR’S CHECKLIST

• Ensure written informed consent has been obtained.

• Perform a physical examination and record on the physical examination worksheet in the CRF.


• Issue the hand held peak flow meter to the subject and explain how to measure their peak flow.

• Issue VENTOLIN relief medication for use on an ‘as required’ basis.

Note: The use of this medication must not be recorded in the Concomitant Medication section of this CRF.

• Issue the Run-in Daily Record Card (DRC) and instruct the subject on the correct completion. Inform the subject of the importance of completing the DRC correctly.

• Issue the container for the 24 hour urine sample to be collected prior to the next clinic visit.

• Record details of the subject’s ongoing concomitant medications in the appropriate Concomitant Medicationssection.

• Review inclusion/exclusion criteria and ensure all Visit 1 sections have been completed.

• Complete the ’Consent for Pharmacogenetic Research’ and the ’Blood Sample Collection’ sections of thePharmacogenetic Research page in this CRF.

• Make an appointment for the subject to return in 7 days(± 2 days) time for the next clinic visit.

Remind the subject of the following:

• To stop taking their usual short-acting inhaled β2-agonists and use inhaled VENTOLIN provided for 'prn' use during all phases of the study (run-in and treatment periods).

• To refrain from using their VENTOLIN medication for at least 6 hours immediately before the next clinic visit.

• Urine collection must be as near 24 hours in duration as possible.

• Bring their urine collection to the clinic visit.

• To record time of VENTOLIN use on the DRC if Ventolin is used on the morning of the next clinic visit.

• To attend the clinic for the next visit at the same time of day.

• To bring the peak flow meter to the next clinic visit.

• To bring the Run-In Daily Record Card and any remaining VENTOLIN to the next clinic visit.


24


CONFIDENTIAL

START OF VISIT 1AINVESTIGATOR INSTRUCTIONS

The pages included in this visit must only be completed for subjects who are repeating the Run-in due to lack of daily asthma symptoms or Daily Record Card PEF was not between 50% and 80% of their predicted normal, during the Visit 1 run-in period.

Note: See the investigator guidelines at the front of Visit 2 before completing Visit 1A.


25


CONFIDENTIAL

DAILY RECORD CARDINVESTIGATOR INSTRUCTIONS


ADVERSE EVENTS / CONCOMITANT MEDICATIONSINVESTIGATOR INSTRUCTIONS


• Check the Run-in Daily Record Card.

• Transcribe any medications (if applicable) from the medication section into the appropriate Concomitant Medication page in this Case Report Form.

• Transcribe any Adverse Events that have been reported into the appropriate Adverse Event page(s) of this CRF and subject medical notes.

• Any changes, corrections or explanations that you have made regarding dates must be initialled and dated in the presence of the subject.

• Check the Run-In Daily Record Card entries since the last visit. Ensure that any adverse events and changes in medication reported in the Run-In Daily Record Card have been transcribed to the appropriate Adverse Event,and Concomitant Medication section(s) of the Case Report Form.

• If any corrections are made, the investigator must initial and date them.

• Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

• Check that any adverse events are recorded in the Adverse Event section and any changes/new medications are recorded in the Concomitant Medication section(s) of the Case Report Form.

NOTE: "✔ if done" box should always be completed to confirm these questions have been asked, regardless of whether an adverse event has occurred or new medicine has been taken.


26


WORKSHEET

Visit Description

FFA20001 {{{{{{}Repeat Run-in

Visit 1A


DAILY RECORD CARD

ADVERSE EVENTS / CONCOMITANT MEDICATIONS

PREGNANCY TEST

Confirm the Daily Record Card has been collected and reviewed {} ✔ if done

Check the subject’s Daily Record Card to determine whether they have experienced an adverse event.

Ask the following questions:

(a) "Have you had any (other) medical problems since your last clinic visit?"

(b) "Have you taken any new medicines, other than those given to you within this study, since your last clinic visit?"

Adverse events must be recorded on the appropriate Adverse Events page(s).

Concomitant medications must be recorded on the appropriate Concomitant Medications page(s).

Confirm these adverse event and concomitant medication questions have been asked. {} ✔ if done


Note: Subjects who have a positive pregnancy test result at Visit 1A must be withdrawn from the study.


27


CONFIDENTIAL



OROPHARYNGEAL CANDIDIASIS EXAMINATIONMONITOR DATA VALIDATION CHECKS




• Complete the Non-serious Adverse Events or Serious Adverse Events page(s) page if the swab is positive.









• Ensure that oropharyngeal candidiasis when present is recorded on the Non-Serious Adverse Events or Serious Adverse Events page(s) if applicable.

• Ensure that results of any previous swab have been recorded at the appropriate visit.


28


Visit Description


Visit 1A


*FFA20001* Page*12* 12


VITAL SIGNS





✔only one:

[1]bNegative

[2]bPositive

[4]bNot available

Complete the Concomitant Medications page and the Non-Serious Adverse Events or Serious Adverse Events page(s) if applicable.





29




Visit 1A

Page

*FFA20001*

24 HOUR URINE COLLECTION Note: Collections should be made on the day prior to Visit 1A and must be as near 24 hours in duration as possible.

Planned Relative Time Interval

Start Date Actual Start Time Stop Date Actual Stop Time

Total Sample Volume

Was all of the sample collected for this interval?

Day Month YearHr : Min

(00:00 - 23:59) Day Month YearHr : Min

(00:00 - 23:59) mLY=YesN=No

e.g., 0-24 hrs 06 JUN 03 08:00 07 JUN 03 08:00 20 Y

0-24 hours : :

Attach Sample Identifier Here

*13*

13

CO

NFID

ENTIA

LG

M2004/00341/00

FFA20001

30


CONFIDENTIAL









• Ensure that PEF (L/sec) has been rounded accurately to 2 decimal places.





AB

x 100( )

C - AA

x 100 )(


31




Visit 1A

*FFA20001* Page




ActualMeasurementPre - 400mg salbutamol


Hr : Min(00:00 - 23:59)

A

e.g., PEF (L/min) 08:00 340


:

e.g., FEV1 (L) 08:00 1.75

FEV1 (L) : .

Note: Reversibility in PEF (increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol), only needs to be repeated if reversibility was not met at Visit 1.

Test PredictedNormal

% PredictedNormal

ActualMeasurement



%Reversibility

B C

e.g., PEF (L/min) 440 77.3 400 17.6


Note: An increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol must be demonstrated. If the subject does not fulfil this criteria at this visit, the test must be repeated at Visit 1b or at Visit 2.

x 100BA ( x 100 )A

C - A

*14* 14


32


CONFIDENTIAL


• Collect and review Run-in DRC.

• Return the Run-in Daily Record Card (DRC) and remind the subject on the correct completion. Inform the subject of the importance of completing the DRC correctly.

• Record any changes to the subject’s concomitant medications or any new medications taken since the last visit in the appropriate Concomitant Medications section.

• Record details of any new non-serious adverse events/serious adverse events observed or reported by the subject or any changes to ongoing non-serious adverse events in the appropriate Non-Serious Adverse Events/Serious Adverse Events section.

• Collect the container with the 24 hour urine sample.

• Ensure all Visit 1A sections have been completed.

• Make an appointment for the subject to return in 7 days (± 2 days) time for the next clinic visit.


• To continue to use inhaled VENTOLIN provided for 'prn' use during all phases of the study (run-in and treatment periods).

• To refrain from using their VENTOLIN medication for at least 6 hours immediately before the next clinic visit .


• To attend the next clinic visit at the same time of day.

• To bring the peak flow meter to the next clinic visit.

• To bring the Daily Record Card and any remaining VENTOLIN to the next clinic visit.


33


CONFIDENTIAL

START OF VISIT 1BINVESTIGATOR INSTRUCTIONS

The pages included in this visit must only be completed for subjects who are repeating the Run-in due to lack of daily asthma symptoms or Daily Record Card PEF was not between 50% and 80% of their predicted normal, during the Visit 1A run-in period.

Note: See the investigator guidelines at the front of Visit 2 before completing Visit 1B.


34


CONFIDENTIAL















35


WORKSHEET

Visit Description


Visit 1B


DAILY RECORD CARD


PREGNANCY TEST










Note: Subjects who have a positive pregnancy test result at Visit 1B must be withdrawn from the study.


36


CONFIDENTIAL



















37


Visit Description


Visit 1B


*FFA20001* Page*15* 15


VITAL SIGNS





✔only one:

[1]bNegative

[2]bPositive

[4]bNot available






38


CONFIDENTIAL









• Ensure that PEF (L/sec) has been rounded accurately to 2 decimal places.





AB

x 100( )

C - AA

x 100 )(


39




Visit 1B

*FFA20001* Page*16* 16






Hr : Min(00:00 - 23:59)

A

e.g., PEF (L/min) 08:00 340


:

e.g., FEV1 (L) 08:00 1.75

FEV1 (L) : .

Note: Reversibility in PEF (increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol), only needs to be repeated if reversibility was not met at Visit 1 or 1A.


% PredictedNormal

ActualMeasurement



%Reversibility

B C

e.g., PEF (L/min) 440 77.3 400 17.6


Note: An increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol must be demonstrated. If the subject does not fulfil this criteria at this visit, the test must be repeated at Visit 2.

x 100BA ( x 100 )A

C - A


40


CONFIDENTIAL



• Return the Run-in Daily Record Card (DRC) and remind the subject on the correct completion. Inform the subject of the importance of completing the DRC correctly.



• Ensure all Visit 1B sections have been completed.

• Make an appointment for the subject to return in 7 days (± 2 days) time for Visit 2.



• To refrain from using their VENTOLIN medication for at least 6 hours immediately before the Visit 2.


• To attend the clinic for Visit 2 at the same time of day.

• To bring the peak flow meter to the clinic for Visit 2.

• To bring the Daily Record Card and any remaining VENTOLIN to clinic Visit 2.


41


WORKSHEET

Visit Description

FFA20001 {{{{{{}Randomisation

Visit 2


INVESTIGATOR GUIDELINES PRIOR TO START OF VISIT 1A OR VISIT 2 ASSESSMENTS

INVESTIGATOR GUIDELINES PRIOR TO START OF VISIT 1B OR VISIT 2 ASSESSMENTS

Note: Review the Daily Record Card data to enable you to make a decision as to whether the subject is to repeat the Run-in (Visit 1A) or to be randomised at this visit (Visit 2).

Was the mean morning PEF (calculated from the last 7 consecutive days of the Visit 1 run-in period) between 50% and 80% of their percent predicted normal?

[Y]by [N]bn

Was the asthma symptom score (day-time plus night-time) >1 on at least four of the last 7 consecutive days of the Visit 1 run-in period?

[Y]by [N]bn

Note: If the questions above are answered YES, the subject can be further assessed for randomisation at Visit 2.

If either of the above questions are answered NO, the subject may repeat the Run-in (Visit 1A).

Note: Review the Daily Record Card data to enable you to make a decision as to whether the subject is to repeat the Run-in (Visit 1B) or to be randomised at this visit (Visit 2).

Was the mean morning PEF (calculated from the last 7 consecutive days of the Visit 1A run-in period) between 50% and 80% of their percent predicted normal?

[Y]by [N]bn

Was the asthma symptom score (day-time plus night-time) >1 on at least four of the last 7 consecutive days of the Visit 1A run-in period?

[Y]by [N]bn

Note: If the questions above are answered YES, the subject can be further assessed for randomisation at Visit 2.

If either of the above questions are answered NO, the subject may repeat the Run-in (Visit 1B).


42


CONFIDENTIAL















43


WORKSHEET

Visit Description


Visit 2


DAILY RECORD CARD











44


CONFIDENTIAL

ELIGIBILITY QUESTIONINVESTIGATOR INSTRUCTIONS

INCLUSION AND EXCLUSION CRITERIAMONITOR DATA VALIDATION CHECK

• If the subject is not entering the treatment phase of the study (e.g., failed randomisation criteria), complete the Study Conclusion page.

• Confirm that the subject is eligible to participate in the study and if not, that all the failed criteria have been marked.


45


Visit Description


Visit 2


*FFA20001* Page

ELIGIBILITY QUESTION

INCLUSION CRITERIA

EXCLUSION CRITERIA

Did the subject meet all the randomisation criteria?

[Y]by [N]bn

If No, ✔ all boxes corresponding to violations of any inclusion/exclusion criteria.

Do not enter the subject into the study if they failed any inclusion or exclusion criteria below.


1. b Increase in PEF of ≥15% 20 minutes after inhalation of 400µg salbutamol, if not demonstrated at Visit 1, 1a or 1b.

2. b Mean morning PEF (calculated from the last 7 consecutive days of the final run-in period) of between 50% and 80% of their percent predicted normal.

3. b Daily asthma symptom score (day-time plus night-time) of >1 on at least four of the last 7 consecutive days of the final run-in period.

✔ the boxes corresponding to any of the exclusion criteria that disqualified the subject from entry.

1. b Evidence of clinically significant abnormality in the haematological, biochemical ordipstick urinalysis screen, or 12-lead ECG at Visit 1.

2. b Changes in asthma medication (excluding rescue VENTOLIN provided at Visit 1).

3. b Occurrence of an upper or lower respiratory tract infection during the run-in period.

4. b Exacerbation of asthma symptoms during the run-in period.

5. b Non-compliance with completion of the DRC; the DRC must have been completed for 6 out of last 7 days prior to Visit 2 to confirm compliance.

*17* 17


46


CONFIDENTIAL



















47




Visit 2

*FFA20001* Page*18* 18


VITAL SIGNS





✔only one:

[1]bNegative

[2]bPositive

[4]bNot available






48


CONFIDENTIAL










• The spirometry printouts must be stored in the subject medical notes


AB

x 100( )

C - AA

x 100 )(


49




Visit 2

*FFA20001* Page






Hr : Min(00:00 - 23:59)

A

e.g., PEF (L/min) 08:00 340


:

e.g., FEV1 (L) 08:00 1.75

FEV1 (L) : .

Note: Reversibility in PEF (increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol), only needs to be repeated if reversibility was not met at Visit 1, 1a or 1b.


% PredictedNormal

ActualMeasurement



%Reversibility

B C

e.g., PEF (L/min) 440 77.3 400 17.6


Note: Subjects who failed to demonstrate an increase in PEF of ≥15%, 20 minutes after inhalation of 400µg salbutamol at Visit 1, 1a, 1b or Visit 2, will not be eligible for randomisation and must be withdrawn from the study.

x 100BA ( x 100 )A

C - A

*19* 19


50


WORKSHEET

Visit Description


Visit 2


ALERT VALUESINVESTIGATOR INSTRUCTIONS


For all Randomised subjects:

• Calculate PEF alert value

Baseline mean morning PEF = (total morning PEF recorded in the last 7 days of the run-in period)(number of days of recorded morning PEF)

Note: There should be at least 6 days of data from the last 7 days of the run-in period (this should not include PEF from morning of this clinic visit) - the denominator should be number of non-missing days counted.

Baseline mean morning PEF = {{{} L/min

• Calculate 20% reduction in baseline mean morning PEF using the following formula:

Baseline mean morning PEF x 0.8

20% reduction in baseline mean morning PEF = {{{} L/min

• Calculate VENTOLIN alert value

Baseline VENTOLIN relief occasions = (total over 24 hours for the last 7 days of the run-in period)(number of 24 hours of relief occasions data)

Note: There should be at least 6 days of data from the last 7 days of the run-in period (this should not include relief use from morning of this clinic visit) - the denominator should be number of non-missing days counted.

Baseline VENTOLIN relief occasions = {{}.{}

Add 2 occasions to this baseline = VENTOLIN alert value

VENTOLIN alert value = {{} occasions

• Write the PEF and VENTOLIN Alert Value on the front of the Daily Record Card for the treatment period.

• Calculate FEV1 alert value

Baseline FEV1 (take from Visit 2 FEV1 measurement) = {{{} L

• Calculate 20% reduction in baseline FEV1 using the following formula:

Baseline FEV1 x 0.8

20% reduction in baseline FEV1 = {{{} L

If the subject enters the Treatment Period:

• Check that all boxes for the inclusion criteria are ticked ‘YES’.

• Check all calculations.


51


24 HOUR URINE COLLECTIONINVESTIGATOR INSTRUCTIONS

• This page must not be completed if urine sample was collected at V1A.

• Collections should be made on the day prior to Visit 2 and must be as near 24 hours in duration as possible.

CO

NFID

ENTIA

LG

M2004/00341/00

FFA20001

52




Visit 2

Page

*FFA20001*

*20*

20

24 HOUR URINE COLLECTION Planned Relative

Time Interval Start Date Actual Start Time Stop Date Actual Stop

TimeTotal Sample

VolumeWas all of the

sample collected for this interval?



(00:00 - 23:59) mLY=YesN=No

e.g., 0-24 hrs 06 JUN 03 08:00 07 JUN 03 08:00 20 Y

0-24 hours : :


CO

NFID

ENTIA

LG

M2004/00341/00

FFA20001

53




Visit 2

*FFA20001* Page

RANDOMISATION NUMBER

INVESTIGATIONAL PRODUCT CONTAINER NUMBER

Record randomisation number.

{{{{{{}

Record the identifying number from the investigational product container dispensed at this visit.

{{{{{{}

*21* 21


54


CONFIDENTIAL



• Collect used VENTOLIN and if required, issue new VENTOLIN relief medication for use on an ‘as required’basis


• Randomise the subject, and issue study medication. Instruct the subject on how and when to take study medication.

• Enter study medication start date on the Investigational Product page in this CRF and enter details on the Investigational Product Compliance page.

• Issue the Treatment Daily Record Card (DRC) and remind the subject on the correct completion. Inform the subject of the importance of completing the DRC correctly.

• Ensure Alert Values are entered on the front cover of the DRC.

• Collect the container with the 24 hour urine sample (if applicable).



• Review inclusion/exclusion criteria and ensure all Visit 2 sections have been completed.

• Make an appointment for the subject to return in 7 days time (± 2 days) for Visit 3.



• To take only the study medication provided for use during the treatment period.

• To contact the investigator if the alert values on the front of the DRC are reached.

• To refrain from using their VENTOLIN medication for at least 6 hours immediately before Visit 3.

• To record time of VENTOLIN use on the DRC if Ventolin is used on the morning of Visit 3.

• To take their study medication as usual on the day of clinic Visit 3.


• To bring the Treatment Daily Record Card, any remaining VENTOLIN and all study medication blister packs (used and unused) to the clinic for Visit 3.

NOTE: If the subject is not eligible for entry into the treatment period, complete the Study Conclusion section in this Case Report Form.


55


CONFIDENTIAL





• Check the Treatment Daily Record Card.




• Check the Treatment Record Card entries since the last visit. Ensure that any adverse events and changes in medication reported in the Daily Record Card have been transcribed to the appropriate Adverse Event, and Concomitant Medication section(s) of the Case Report Form.






56


WORKSHEET

Visit Description

FFA20001 {{{{{{}Treatment Period

Visit 3


DAILY RECORD CARD











57


CONFIDENTIAL



















58


Visit Description


Visit 3


*FFA20001* Page


VITAL SIGNS





✔only one:

[1]bNegative

[2]bPositive

[4]bNot available





*22* 22


59


CONFIDENTIAL








60




Visit 3

*FFA20001* Page


Has the subject taken VENTOLIN in the last 6 hours? [Y]by [N]bn

Test Time ofAssessment

ActualMeasurement(highest of 3

measurements)

Hr : Min(00:00 - 23:59)

e.g., PEF (L/min) 08:00 340


:

e.g., FEV1 (L) 08:00 1.75

FEV1 (L) : .

Note: Subjects who obtain a clinic FEV1 fall of ≥20% from value at Visit 2, must be withdrawn from the study.

*23* 23


61


CONFIDENTIAL

PHARMACOKINETICS - BLOODINVESTIGATOR INSTRUCTIONS

Note: Blood samples for PK analysis will only be collected at centres where the appropriate facilities are available.

• If sample is missed or lost, write "NA" in the Date Sample Taken column.


62




Visit 3

*FFA20001* Page

INVESTIGATIONAL PRODUCT (PRIOR TO PHARMACOKINETIC SAMPLE)

PHARMACOKINETICS - BLOOD

Record the date and time of the previous evening dose and the date and time of the morning dose.

Date ofprevious evening dose

Time ofprevious evening

dose

Date ofmorning dose

Time ofmorning dose

Day Month Year Hr : Min(00:00 - 23:59)


: :

Planned RelativeTime

Date Sample Taken

Day Month Year

Actual TimeHr : Min

(00:00 - 23:59)

Attach Sample Identifier Label Here

On arrival at the clinic visit

:

*24* 24


63


CONFIDENTIAL


• Collect and review Treatment DRC.

• Collect and keep used study medication blister packs and return partially used blisters to the subject.

• Issue a new Treatment Daily Record Card (DRC) and remind the subject on the correct completion. Inform the subject of the importance of completing the DRC correctly.




• Ensure all Visit 3 sections have been completed.





• To contact the investigator if the alert values on the front of the DRC are reached.






NOTE: If the subject is withdrawing at this visit, complete the assessments in the Withdrawal section of this CRF and schedule a safety Follow-up visit for 1 week (± 2 days) after withdrawal. Complete the Study Conclusion page in the Case Report Form.


64


CONFIDENTIAL









• Check the Treatment Daily Record Card entries since the last visit. Ensure that any adverse events and changes in medication reported in the Daily Record Card have been transcribed to the appropriate Adverse Event, and Concomitant Medication section(s) of the Case Report Form.






65


WORKSHEET

Visit Description


Visit 4


DAILY RECORD CARD


PREGNANCY TEST










Note: Subjects who have a positive pregnancy test result at Visit 4 must be withdrawn from the study.


66


CONFIDENTIAL



















67


Visit Description


Visit 4


*FFA20001* Page


VITAL SIGNS





✔only one:

[1]bNegative

[2]bPositive

[4]bNot available





*25* 25


68


CONFIDENTIAL








69




Visit 4

*FFA20001* Page





measurements)

Hr : Min(00:00 - 23:59)

e.g., PEF (L/min) 08:00 340


:

e.g., FEV1 (L) 08:00 1.75

FEV1 (L) : .


*26* 26


70


CONFIDENTIAL





71




Visit 4

*FFA20001* Page



Record the date and time of the previous evening dose and the date and time of the morning dose.



dose

Date ofmorning dose

Time ofmorning dose



: :


Date Sample Taken

Day Month Year

Actual TimeHr : Min

(00:00 - 23:59)


1. On arrival at the clinic visit

:

2. Immediately prior to clinic departure

:

*27* 27


72


CONFIDENTIAL





• Collect used VENTOLIN and if required, issue new VENTOLIN relief medication for use on an ‘as required’basis






• Explain to the subject the procedure to be adopted in the event of alert values criteria being met.













73


CONFIDENTIAL















74


WORKSHEET

Visit Description


Visit 5


DAILY RECORD CARD











75


CONFIDENTIAL



















76


Visit Description


Visit 5


*FFA20001* Page


VITAL SIGNS





✔only one:

[1]bNegative

[2]bPositive

[4]bNot available





*28* 28


77


CONFIDENTIAL








78




Visit 5

*FFA20001* Page





measurements)

Hr : Min(00:00 - 23:59)

e.g., PEF (L/min) 08:00 340


:

e.g., FEV1 (L) 08:00 1.75

FEV1 (L) : .


*29* 29


79


CONFIDENTIAL






• Issue the container for the 24 hour urine sample to be collected prior to Visit 6.



• Explain to the subject the procedure to be adopted in the event of alert values criteria being met.









• Urine collection may start and finish 1 hour earlier or later than the times advised but must be as near 24 hours in duration as possible.

• Bring their urine collection to the clinic visit.





80


CONFIDENTIAL















81


WORKSHEET

Visit Description

FFA20001 {{{{{{}End of Treatment Period

Visit 6


DAILY RECORD CARD











82


WORKSHEET

Visit Description


Visit 6




NotDone


1. Hair and Skin {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

2. Lymph nodes {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

3. Eyes {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


5. Breast {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

6. Respiratory {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

7. Cardiovascular {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

8. Abdomen {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

9. Urogenital {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

10. Pelvic {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

11. Rectal {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


13. Neurological {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

14. Mental Status {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


83


CONFIDENTIAL


MONITOR DATA VALIDATION CHECKSMONITOR DATA VALIDATION CHECKS















84


Visit Description


Visit 6


*FFA20001* Page







✔only one:

[1]bNegative

[2]bPositive

[4]bNot available



:

(00:00-23:59)Hr:Min

*30* 30


85


CONFIDENTIAL




Code Results as:

NEGTRA1+2+3+4+5+

=======




86




Visit 6

*FFA20001* Page

URINALYSIS - LOCAL


:

(00:00-23:59)Hr:Min



[NR]bNo result


Leucocytes

Nitrite

Urobilinogen

Protein

pH

Blood

Specific gravity

Ketone

Bilirubin

Glucose



*31* 31


87




Visit 6

Page

*FFA20001*

24 HOUR URINE COLLECTION Note: Collections should be made on the day prior to Visit 6 and must be as near 24 hours in duration as possible.

Planned Relative Time Interval

Start Date Actual Start Time Stop Date Actual Stop Time

Total Sample Volume

Was all of the sample collected for this interval?



(00:00 - 23:59) mLY=YesN=No

e.g., 0-24 hrs 06 JUN 03 08:00 07 JUN 03 08:00 20 Y

0-24 hours : :


*32*

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CONFIDENTIAL




89




Visit 6

*FFA20001* Page

VITAL SIGNS

12-LEAD ECG





Result of the ECG

[1]bNormal


[3]bAbnormal - clinically significant a Complete the Non-Serious Adverse Events (AE) or Serious Adverse Event (SAE) page(s) if clinically significant abnormalities meet the protocol definition for an AE or SAE.


*33* 33


90


CONFIDENTIAL








91




Visit 6

*FFA20001* Page





measurements)

Hr : Min(00:00 - 23:59)

e.g., PEF (L/min) 08:00 340


:

e.g., FEV1 (L) 08:00 1.75

FEV1 (L) : .

*34* 34


92


CONFIDENTIAL





93




Visit 6

*FFA20001* Page



Record the time of the previous evening dose and the time of the morning dose.



dose

Date ofmorning dose

Time ofmorning dose



: :


Date Sample Taken

Day Month Year

Actual TimeHr : Min

(00:00 - 23:59)


On arrival at the clinic visit

:

*35* 35


94


CONFIDENTIAL



• Collect all study medication, review blister packs and complete the Investigational Product and Investigational Product Compliance section in this CRF.

• Collect VENTOLIN.

• Collect the container with the 24 hour urine sample.




• Complete the ’Withdrawal of Consent’ and the ’Blood Sample Destruction’ sections of the Pharmacogenetic Research page in this CRF.

• Make an appointment for the subject to return in 7 days time (± 2 days) for Visit 7, Follow-up.


• To attend the clinic for Visit 7 at the same time of day (± 2 hours).

• To bring the Treatment Daily Record Card, VENTOLIN and all study medication to the clinic for Visit 7 (if not returned at Visit 6).


95


CONFIDENTIAL





• Check the Treatment Daily Record Card (If not returned at Visit 6 or Withdrawal).










96


WORKSHEET

Visit Description

FFA20001 {{{{{{}Follow-up

Visit 7


DAILY RECORD CARD


PREGNANCY TEST

Confirm the Daily Record Card has been collected and reviewedif not returned at Visit 6 or Withdrawal

{} ✔ if done










97


WORKSHEET

Visit Description


Visit 7



Note: Examination need only be performed if clinically significant abnormalities were detected at Visit 6 or Withdrawal.


NotDone


1. Hair and Skin {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

2. Lymph nodes {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

3. Eyes {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


5. Breast {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

6. Respiratory {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

7. Cardiovascular {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

8. Abdomen {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

9. Urogenital {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

10. Pelvic {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

11. Rectal {} {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


13. Neurological {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

14. Mental Status {} {} _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


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CENTRAL LABORATORY - BloodINVESTIGATOR INSTRUCTIONS







Note: Test need only be performed if clinically significant abnormalities were detected at Visit 6 or Withdrawal.










99


Visit Description


Visit 7


*FFA20001* Page







✔only one:

[1]bNegative

[2]bPositive

[4]bNot available



:

(00:00-23:59)Hr:Min

*36* 36


100


CONFIDENTIAL





Code Results as:

NEGTRA1+2+3+4+5+

=======




101




Visit 7

*FFA20001* Page

URINALYSIS - LOCAL


:

(00:00-23:59)Hr:Min



[NR]bNo result


Leucocytes

Nitrite

Urobilinogen

Protein

pH

Blood

Specific gravity

Ketone

Bilirubin

Glucose



*37* 37


102


CONFIDENTIAL


12-LEAD ECGINVESTIGATOR INSTRUCTIONS





103




Visit 7

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VITAL SIGNS

12-LEAD ECG





Result of the ECG

[1]bNormal




*38* 38


104


CONFIDENTIAL








105




Visit 7

*FFA20001* Page






measurements)

Hr : Min(00:00 - 23:59)

e.g., PEF (L/min) 08:00 340


:

e.g., FEV1 (L) 08:00 1.75

FEV1 (L) : .

*39* 39


106


CONFIDENTIAL


• Collect and review Treatment DRC if not returned at Visit 6 or Withdrawal.

• Collect all study medication, review blister packs and complete the Investigational Product Compliance in this CRF, if not returned at Visit 6 or Withdrawal.

• Collect VENTOLIN, if not returned at Visit 6 or Withdrawal.



• Ensure all appropriate Visit 7 sections have been completed.

• Complete the Study Conclusion page in the Case Report Form.


107


CONFIDENTIAL















108


WORKSHEET

Visit Description

FFA20001 {{{{{{} Withdrawal


DAILY RECORD CARD


PREGNANCY TEST

URINE COLLECTION










• Collect sample for assessment of urinary cortisol (if posible).


109


CONFIDENTIAL

















110


Visit Description



*FFA20001* Page







✔only one:

[1]bNegative

[2]bPositive

[4]bNot available



:

(00:00-23:59)Hr:Min

*40* 40


111


CONFIDENTIAL




112




*FFA20001* Page*41* 41

VITAL SIGNS

12-LEAD ECG





Result of the ECG

[1]bNormal





113


CONFIDENTIAL








114




*FFA20001* Page*42* 42





measurements)

Hr : Min(00:00 - 23:59)

e.g., PEF (L/min) 08:00 340


:

e.g., FEV1 (L) 08:00 1.75

FEV1 (L) : .


115


CONFIDENTIAL



• Collect all study medication, review blister packs and complete the Investigational Product page and the Investigational Product Compliance in this CRF.

• Collect VENTOLIN.



• Ensure all Withdrawal sections have been completed.

• Complete the ’Withdrawal of Consent’ and the ’Blood Sample Destruction’ sections of the Pharmacogenetic Research page in this CRF.

• If the subject withdraws or is withdrawn following an unscheduled/emergency visit, the unscheduled/emergency visit section of the CRF must also be completed.

• Prescribe appropriate asthma therapy and record the start date on the Asthma Concomitant Medication page of the CRF.

• Make an appointment for the subject to return in 7 days time (± 2 days) for Visit 7, Follow-up.


• To take their asthma therapy as prescribed.

• To attend the clinic for Visit 7 at the same time of day (± 2 hours).

• To bring the Treatment Daily Record Card, VENTOLIN and all study medication to the clinic for Visit 7 if not returned at Withdrawal.


116


CONFIDENTIAL

INVESTIGATIONAL PRODUCT COMPLIANCE MONITOR DATA VALIDATION CHECKS

• Ensure the date the investigational product was dispensed has been recorded.

• Ensure the number of blisters dispensed has been recorded.

• Ensure the number of unused blisters returned has been recorded.


117


FFA20001 {{{{{{}


*FFA20001* Page

INVESTIGATIONAL PRODUCT

INVESTIGATIONAL PRODUCT COMPLIANCE

InvestigationalProduct

Start Date Stop Date

Day Month Year Day Month Year

e.g., DISKHALER 05 JUN 03 08 JUN 03

Double blind DISKHALER

InvestigationalProduct

Timepoint VisitInvestigational

Product Dispensed

DateInvestigational Product

Dispensed

Number ofBlisters

Dispensed

Number ofUnused Blisters Returned

Day Month Year

e.g., [10] Double-Blind DISKUS 2 05 JUN 03 200 20

Double-blind diskhaler AM 2

Double-blind diskhaler PM

Double-blind diskhaler AMReplacement

(if used)Double-blind diskhaler PM

*43* 43


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*FFA20001* Page

STATUS OF TREATMENT BLIND

Was the treatment blind broken during the study?

[Y]by [N]bn

If Yes, complete the following

Date blind broken Day Month Year

Reason blind broken, ✔ one:

[1]bMedical emergency requiring identification of investigational product for further treatment

[Z]bOther, specify _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Complete Non-Serious Adverse Event, Serious Adverse Event and/or Investigational Product pages, as appropriate.

*44* 44


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CONFIDENTIAL

UNSCHEDULED / EMERGENCY CONTACTINVESTIGATOR INSTRUCTIONS

MONITOR VALIDATION CHECKS

• If the unscheduled visit / contact is due to an adverse event, complete the appropriate Non-serious Adverse Events or Serious Adverse Event page(s). If study medication is withdrawn at the unscheduled visit, complete the Withdrawal section and make an appointment for the subject to return for a follow-up visit in 1 week (±2 days) time.

• Check either the YES or NO box has been ✔.

• If the YES box has been ✔, ensure that at least one unscheduled contact has been recorded.

• Check that data is within the time period of subject’s participation in the study.

• Check that type of contact has been recorded as either V or P.

• Check that reason for contact is in precise and legible text.


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*FFA20001* Page

UNSCHEDULED / EMERGENCY CONTACT

This page should be completed each time the subject makes an Unscheduled / Emergency Visit or Telephone Contact.

Did the subject make any unscheduled emergency visits or contacts during the study?

[Y]by [N]bn

If Yes, indicate below.

Ensure that any Adverse Events, Asthma Medications and/or changes in Concomitant Medications are also documented on the appropriate pages of the CRF.

If the subject is withdrawn, complete Withdrawal section, and make an appointment for the subject to return for a follow-up visit in 1 week (± 2 days) time.

Date Type of Contact

Reason for Contact SubjectWithdrawn?

Day Month YearV = Visit

P = TelephoneY =YesN =No

e.g., 06 JUN 03 V N

1.

2.

3.

4.

5.

6.

7.

8.

*45* 45


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CONFIDENTIAL

PHARMACOGENETIC RESEARCHINVESTIGATOR INSTRUCTIONS

Note: Any subject who has received a bone marrow transplant must be excluded from the PGx research.

CONSENT FOR PHARMACOGENETIC RESEARCH

The question "Has informed consent been obtained for pharmacogenetic research?" should be completed at the beginning of the study.

• If the question is answered No, ✔ one of the boxes for reason and do not complete the remainder of the page.

WITHDRAWAL OF CONSENT

The question "Has the subject withdrawn consent for pharmacogenetic research?" must be completed immediately if the subject withdraws consent. Otherwise, it must be completed when the subject leaves the study. It must be completed for all subjects for whom informed consent was obtained for pharmacogenetic research.

• If consent is withdrawn, a request for destruction must be made and Blood Sample Destruction section below completed.

BLOOD SAMPLE DESTRUCTION

Do not complete this section if a blood sample was not collected.

The question "Has a request been made for sample destruction?" must be completed immediately if there is a request for sample destruction. Otherwise, it must be completed when the subject leaves the study. It must be completed for all subjects for whom a blood sample was obtained for pharmacogenetic research.

• If the question is answered Yes, ✔one of the boxes for reason.


122


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*FFA20001* Page

PHARMACOGENETIC RESEARCH

CONSENT FOR PHARMACOGENETIC RESEARCH

Has informed consent been obtained for pharmacogenetic research?

[Y]by [N]bn

If Yes, record the date informed consent obtained for pharmacogenetic research Day Month Year

If No, ✔ one reason: [1]bSubject declined

[2]bSubject not asked by Investigator

[Z]bOther, specify _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

BLOOD SAMPLE COLLECTION

Has a blood sample been collected for pharmacogenetic research?

[Y]by [N]bn

If Yes, record the date sample takenDay Month Year

WITHDRAWAL OF CONSENT

Has subject withdrawn consent for pharmacogenetic research?

[Y]by [N]bn

BLOOD SAMPLE DESTRUCTION

Has a request been made for sample destruction?

[Y]by [N]bn

If Yes, ✔ one reason: [1]bSubject requested

[2]bScreen failure

[Z]bOther, specify _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

*46* 46


123


ASTHMA CONCOMITANT MEDICATIONSMONITOR VALIDATION CHECKS

• Ensure that either the Yes or No box is checked for the leading question"Were any asthma concomitant medications taken by the subject during the study?" If Yes, check that at least one drug is recorded.

• Ensure that the spelling of the Drug Name(s) is correct (use of Trade Names is preferred).

• Ensure that combination drugs are recorded as shown in the example row.

• Ensure that the Unit Dose is recorded as a single unit.

• Ensure that the Units, Frequency, and Route are correctly abbreviated. See Asthma Concomitant Medications facing page for Units, Frequency, and Route abbreviations.

• Ensure that Start Date is accurate and complete.

• Check that either medication start date is completed or ’Taken Prior to Study?’ is ’Yes’.• It is acceptable for start date to be missing if ’Taken Prior to Study?’ is ’Yes’.• It is acceptable if ’Taken Prior to Study?’ is ’Yes’ and a start date is present, as long as the start date is prior to the date of the subject’s initial visit.

• Check that either medication stop date is completed or ’Ongoing Medication?’ is ’Yes’.• It is acceptable for stop date to be missing if ’ongoing Medication?’ is ’Yes’.

• It is acceptable if ’Ongoing medication?’ is ’Yes’ and an end date is present, as long as the stop date is after the date of the subject’s final

• Ensure that Ongoing Medication? is answered Yes or No.

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ASTHMA CONCOMITANT MEDICATIONSINVESTIGATOR INSTRUCTIONS

• Record unknown months as UNK.• The following lists of abbreviations are examples which can be used to aid the completion of the appropriate items on the Concomitant Medication page. These

are not all inclusive lists and are for guidance only, other abbreviations not listed may be used if necessary.

UNITS Frequency Route

Abbreviation Label Abbreviation Label Abbreviation Label

% = Percent OD/QD = 1 x Daily IM = Intramuscular

AMP = Ampoule(s) BID = 2 x Daily IH = Inhalation

APP = Application(s) TID = 3 x Daily IV = Intravenous

CAP = Capsule(s) QID = 4 x Daily NS = Nasal

G = Gram(s) PRN = As required PO = Oral

GTT = Drop(s) CONT = Continuous SC = Subcutaneous

IU = International unit(s) CUM = Cumulative dose TP = Topical

L = Litre(s) D = Daily VG = Vaginal

MCG = Microgram(s) INT = Intermittent

MCG/KG/MIN = Microgram per kilogram per minute NA = Not available

MCL = Microlitre(s) NOCT = At night

MG = Milligram(s) OTH = Other

ML = Milliltre QH = Every hour (quaque hora)

PUFF = Puff(s) QOD = Every other day

TAB = Tablet(s) QN = Every night (quaque nocte)

TBLSP = Tablespoon(s) SD = Single dose

TSP = Teaspoon(s) STAT = Immediately

RED = Reduce

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FFA20001 {{{{{{}

Page

*FFA20001*

ASTHMA CONCOMITANT MEDICATIONS

Were any asthma concomitant medications taken by the subject prior to screening and/or during the study? [Y]by [N]bn

If Yes, record each medication on a separate line using Trade Names where possible. If the medication is related to a Non-Serious Adverse Event or Serious Adverse Event, details should be expressed using the same terminology.

Drug Name

(Trade Name preferred)

Unit Dose Units1 Freq-uency1

Route1 Start Date Taken Prior to Study?

Stop Date Ongoing Medi-

cation?

Day Month YearY=YesN=No Day Month Year

Y=YesN=No

e.g., DUOVENT (100 / 40 mcg) 1 PUFF BID IH Y 07 AUG 03 N

BRICANYL 250 MCG PRN IH Y 28 AUG 03 N

1.

2.

3.

4.

5.

6.

7.

8.

1 For Units, Frequency and Route see facing page for examples of acceptable abbreviations.

*47*

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CONCOMITANT MEDICATIONSMONITOR DATA VALIDATION CHECKS

• Check that either ’Yes’ or ’No’ box at the top of the page has been completed.

• Ensure that the spelling of the Drug Name(s) is correct (use of Trade Names is preferred).

• Ensure that combination drugs are recorded as shown in the investigator instructions.

• Check that either medication start date is completed or ’Taken Prior to Study?’ is ’Yes’.• It is acceptable for start date to be missing if ’Taken Prior to Study?’ is ’Yes’.• It is acceptable if ’Taken Prior to Study?’ is ’Yes’ and a start date is present, as long as the start date is prior to the date of the subject’s initial visit.

• Check that either medication stop date is completed or ’Ongoing Medication?’ is ’Yes’.• It is acceptable for stop date to be missing if ’ongoing Medication?’ is ’Yes’.• It is acceptable if ’Ongoing medication?’ is ’Yes’ and an end date is present, as long as the stop date is after the date of the subject’s final visit.

• Ensure that the ’Reason for Medication’ is recorded on one of the following pages using the same terms:• Current Medical Conditions• Non-Serious Adverse Events• Serious Adverse Events Form

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FFA20001 {{{{{{}

Page

*FFA20001*

CONCOMITANT MEDICATIONS

Were any concomitant medications taken by the subject during the study?

[Y]by [N]bn

If Yes, record each medication on a separate line using Trade Names where possible. If the medication is related to a Non-Serious Adverse Event or Serious Adverse Event, details should be expressed using the same terminology.

Drug Name

(Trade Name preferred)

Unit Dose

Units1 Freq-uency1

Route1 Reason for Medication Start Date

Day Month Year

Taken Prior to Study?

Y=Yes N=No

Stop Date

Day Month Year

Ongoing Medi-

cation?

Y=YesN=No

e.g., Aspirin 200 mg BID PO Headache 31 MAY 02 N 31 MAY 02 N

1.

2.

3.

4.

5.

6.

7.

8.

1 For Units, Frequency and Route see facing page for examples of acceptable abbreviations.

*48*

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DEFINITION OF A NON-SERIOUS ADVERSE EVENT (AE) (Page 1 of 3)

Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

Examples of an AE includes Examples of an AE does NOT include a/an

• Significant or unexpected worsening or exacerbation of the condition/indication under study.


• New condition(s) detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study.



• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE.

• Situations where an untoward medical occurrence did not occur(social and/or convenience admission to a hospital).

• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.


For GSK clinical studies, AEs may include pre- or post-treatment events that occur as a result of protocol-mandated procedures (i.e., invasive procedures, modification of subject’s previous therapeutic regimen). See protocol for clarification.

IF THIS EVENT MEETS THE DEFINITION OF SERIOUS, COMPLETE THE SERIOUS ADVERSE EVENT SECTION

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NON-SERIOUS ADVERSE EVENTS (AE) (Page 2 of 3)MONITOR DATA VALIDATION CHECKS

• Check that either ’Yes’ or ’No’ box at the top of the page has been completed.

• Start dates must be provided for the reporting of adverse event data. If the exact date is not known, liaise with the investigator to ensure that a best estimate is provided.

• Ensure that no medical or investigational procedures are captured on Non-Serious Adverse Events pages.

• Non-serious adverse event terms should be reviewed for potential SAEs per protocol.•• Confirm that any adverse events marked as Recovering/Resolving or Not recovered/Not resolved have been followed up for details of resolution.

• If the subject was withdrawn from the study due to an adverse event, confirm that the following variables are consistent for the adverse event which resulted in withdrawal:

• If investigational product was permanently withdrawn due to an adverse event ...• ’Primary Reason for Withdrawal’ on the Study Conclusion page is recorded as ’Adverse Event’

• If the subject was withdrawn from the study for an adverse event ...• ’Withdrawal’ on the Non-Serious Adverse Events page is recorded as ’Yes’.• ’Action Taken with Investigational Product(s) as a Result of the Non-Serious AE’ on the Non-Serious Adverse Events page is recorded as ’Investigational

Product Withdrawn’. Check that the <24 hours duration column has been completed if applicable.

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INSTRUCTIONS FOR COMPLETING NON-SERIOUS ADVERSE EVENTS (AE) (Page 3 of 3)Diagnosis Enter only the diagnosis (if known); otherwise enter sign or symptom. If a diagnosis subsequently becomes available, then this should be entered and the sign or

symptom crossed out, initialled and dated by the investigator.

Start Date Record the start date of the first occurrence of the AE.

Outcome All AEs must be followed until the events are resolved, the condition stabilises, the events are otherwise explained, or the subject is lost to follow-up. Indicate if the event was ’Recovered/Resolved’ or ’Recovered/Resolved with sequelae’. If the AE is ongoing at the time the subject completes the study or becomes lost to follow-up, the outcome must be recorded as ’Not recovered/Not resolved’ or ’Recovering/Resolving’. Also enter ’Not recovered/Not resolved’ if the AE was ongoing at the time of death, but was not the cause of death.

End Date Record the end date. This is the date the AE Recovered/Resolved. If the event Recovered/Resolved with sequelae, enter the date the subject’s medical condition resolved or stabilised. Leave blank if the AE is ’Not recovered/Not resolved’ or ’Recovering/Resolving’.

Frequency Select either single episode or intermittent.Intermittent should be used if the subject experiences the same AE on multiple occasions over a period of time (e.g., dizziness). In these circumstances, the start date will be the start date of the first episode and the end date will be the date of resolution.

Maximum Intensity

Record the maximum intensity that occurred over the duration of the event. Amend the intensity if it increases.

Mild = An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.

Moderate = An event that is sufficiently discomforting to interfere with normal everyday activities.

Severe = An event that prevents normal everyday activities.

Not applicable = those event(s) where intensity is meaningless or impossible to determine (i.e., blindness and coma).

ActionTaken with Investigational Product(s) as a

Result of the Non-Serious AE

Investigational product(s) withdrawn =

Dose reduced =

Dose increased =

Dose not changed =

Dose interrupted =

Not applicable =

Administration of investigational product(s) was permanently discontinued.

Dose is reduced for one or more investigational product(s).

Dose increased for one or more investigational product(s).

Investigational product(s) continues even though an adverse event has occurred.

Administration of one or more investigational product(s) was stopped temporarily but then restarted.

Subject was not receiving investigational product(s) when the event occurred (e.g., pre-or post-dosing).

Withdrawal Indicate ’Yes’ if the event(s) were directly responsible for the subject’s withdrawal as indicated on the Study Conclusion page, otherwise indicate ’No’.

Relationship toInvestigational

Product(s)

It is a regulatory requirement for investigators to assess relationship to investigational product(s) based on information available. The assessment should be reviewed on receipt of any new information and amended if necessary. ’A reasonable possibility’ is meant to convey that there are facts/evidence or arguments to suggest a causal relationship. Facts/evidence or arguments that may support ’a reasonable possibility’ include, e.g., a temporal relationship, a pharmacologically-predicted event, or positive dechallenge or rechallenge. Confounding factors, such as concomitant medication, a concurrent illness, or relevant medical history, should also be considered.

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NON-SERIOUS ADVERSE EVENTS (AE) Note: If this is a Serious Adverse Event (SAE), do not complete this form, go to the SAE section and complete the SAE form.

Did the subject experience any non-serious adverse events during the study? [Y]by [N]bn If Yes, record details below.

Event Start Date Outcome End Date Frequency Maximum Intensity

Action Taken with Investigational Product(s) as a

Result of the Non-Serious AE

With-drawal

Relation-ship to

Investigational Product(s)

Diagnosis Only(if known) Otherwise

Sign/Symptom

Day Month Year

1=Recovered/Resolved

2=Recovering/Resolving

3=Not recovered/Not resolved

4=Recovered/Resolved withsequelae

Day Month Year

1=Singleepisode

2=Intermit-tent

1=Mild2=Moderate3=SevereX=Not

appli-cable

1=Investigationalproduct(s) withdrawn

2=Dose reduced3=Dose increased4=Dose

not changed5=Dose interruptedX=Not applicable

Did the subject

withdraw from

study as a result of this AE?

Y=Yes1

N=No

Is there a reasonable

possibility that the AE may have been

caused by the investigational

product?

Y=YesN=No

e.g., Headache 25 JAN 02 1 27 JAN 02 1 1 4 Y Y

1.

2.

3.

4.

5.

6.

1 Complete Study Conclusion page and ✔ Adverse event as reason for withdrawal.

*49*

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DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) (Page 1 of 5)

A serious adverse event is any untoward medical occurrence that, at any dose:

a) results in death.

b) is life-threatening.

Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

c) requires hospitalisation or prolongation of existing hospitalisation.

Note: In general, hospitalisation signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils any other serious criteria, the event is ’serious’.

When in doubt as to whether ’hospitalisation’ occurred or was necessary, the AE should be considered ’serious’. Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

d) results in disability/incapacity, or

Note: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g., sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

e) is a congenital anomaly/birth defect.

f) other.

Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug dependency or drug abuse.

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SERIOUS ADVERSE EVENTS (SAE) (Page 2 of 5)MONITOR DATA VALIDATION CHECKS

• Check that either ’Yes’ or ’no’ box at the top of the page has been completed.

• Start dates must be provided for the reporting of serious adverse event data. If the exact date is not known, liaise with the investigator to ensure that a best estimate is provided.

• Ensure that no medical or investigational procedures are captured on Serious Adverse Events pages.

• Death should not be recorded as an SAE but should be recorded as the outcome of an SAE. The condition that resulted in the death should be recorded as the SAE.

• Confirm that any SAEs marked as Recovering/Resolving or Not recovered/Not resolved have been followed up for details of resolution.

• If the subject was withdrawn from the study due to an SAE, confirm that the following variables are consistent for the SAE which resulted in withdrawal:

• If investigational product was permanently withdrawn due to an adverse event ...• ’Primary Reason for Withdrawal’ on the Study Conclusion page is recorded as ’Adverse Event’

• If the subject was withdrawn from the study for an adverse event ...• ’Withdrawal’ on the SAE page is recorded as ’Yes’.• ’Action Taken with Investigational Product(s) as a Result of the SAE’ on the SAE page is recorded as ’Investigational Product Withdrawn’.

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THE INVESTIGATOR MUST INFORM GSK OF SERIOUS ADVERSE EVENTS BY FAX OR TELEPHONE (FAX PREFERRED) WITHIN 24 HOURS OF BECOMING AWARE OF THE EVENT. (The original pages must remain in the Case Report Form)

INSTRUCTIONS FOR COMPLETING SERIOUS ADVERSE EVENT FORMS (SAE) (Page 3 of 5)

Diagnosis Record one SAE diagnosis per line, or a sign/symptom if the diagnosis is not available. If a diagnosis subsequently becomes available, this then should be entered and the sign/symptom crossed out, initialled and dated by the investigator. A separate form should be used for each SAE however if multiple SAEs which are temporally or clinically related are apparent at the time of initial reporting then these may be reported on the same page.

Start Date Record the start date of the first occurrence of the SAE.

Outcome All SAEs must be followed until the events are resolved, the condition stabilises, the events are otherwise explained, or the subject is lost to follow-up. Indicate if the event was ’Recovered/Resolved’ or ’Recovered/Resolved with sequelae’. If the SAE is ongoing at the time the subject completes the study or becomes lost to follow-up, the outcome must be recorded as ’Not recovered/Not resolved’ or ’Recovering/Resolving’. Also enter ’Not recovered/Not resolved’ if the SAE was ongoing at the time of death, but was not the cause of death, enter fatal for the SAE which was the direct cause of death.

End Date Record the end date. This is the date the SAE Recovered/Resolved, or if the outcome was fatal, record the date the subject died. If the event Recovered/Resolved with sequelae, enter the date the subject’s medical condition resolved or stabilised. Leave blank if the SAE is ’Not recovered/Not resolved’ or ’Recovering/Resolving’.

Maximum Intensity

Record the maximum intensity that occurred over the duration of the event. Amend the intensity if it increases.Mild = An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.Moderate = An event that is sufficiently discomforting to interfere with everyday activities.Severe = An event that prevents normal everyday activities.Not applicable = Those event(s) where intensity is meaningless or impossible to determine (i.e., blindness and coma).

Action Taken with Investigational Product(s) as a

Result of the SAE

Investigational product(s) withdrawn =

Dose reduced =

Dose increased =

Dose not changed =

Dose interrupted =

Not applicable =

Administration of investigational product(s) was permanently discontinued.

Dose is reduced for one or more investigational product(s).

Dose increased for one or more investigational product(s).

Investigational product(s) continues even though an adverse event has occurred.

Administration of one or more investigational product(s) was temporarily interrupted but then restarted.

Subject was not receiving investigational product(s) when the event occurred (e.g., pre-or post-dosing) or the subject died and there was no prior decision to discontinue IP(s).

Withdrawal Indicate ’Yes’ if the event(s) were directly responsible for the subject’s withdrawal as indicated on the Study Conclusion page, otherwise indicate ’No’.

Relationship toInvestigational

Product(s)

It is a regulatory requirement for investigators to assess relationship to investigational product(s) based on information available. The assessment should be reviewed on receipt of any new information and amended if necessary. ’A reasonable possibility’ is meant to convey that there are facts/evidence or arguments to suggest a causal relationship. Facts/evidence or arguments that may support ’a reasonable possibility’ include, e.g., a temporal relationship, a pharmacologically-predicted event, or positive dechallenge or rechallenge. Confounding factors, such as concomitant medication, a concurrent illness, or relevant medical history, should also be considered.

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Protocol Identifier Subject Identifier Randomisation Number

FFA20001 {{{{{{} {{{{{{} {{{{{{}


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*FFA20001*

SERIOUS ADVERSE EVENT (SAE)

Did the subject experience a serious adverse event during the study? [Y]by [N]bn If Yes, record details below.

SECTION 1Event Start Date Outcome End date Maximum

IntensityAction Taken with

Investigational Product(s) as a

Result of the SAE

With-drawal

Relationship to Investi-gational

Product(s)Diagnosis Only

(if known) OtherwiseSign/Symptom

1=Recovered/ Resolved

2=Recovering/Resolving

3=Notrecovered/Not resolved

4=Recovered/Resolved withsequelae

5=Fatal

If fatal, record date of death.

1=Mild2=Moderate3=SevereX=Not applicable

1=Investigational product(s)

withdrawn2=Dose reduced3=Dose increased4=Dose not

changed5=Dose interruptedX=Not applicable

Did the subject

withdraw from study as a result

of this SAE?

Is there a reasonable

possibility the SAE may have been caused by the investi-

gational product?

Day Month Year Day Month YearY=Yes1

N=NoY=YesN=No

e.g., Anaphylaxis 25 Jan 02 1 27 Jan 02 1 4 Y Y

1 Complete Study Conclusion page and ✔ Adverse event as reason for withdrawal.

If fatal, was a post-mortem/autopsy performed? [Y]bYes [N]bNo If Yes, summarise findings in Section 11 Narrative Remarks of this SAE form.

SECTION 2 Seriousness (specify reason(s) for considering this a SAE, ✔ all that apply:

[A]bResults in death [D]bResults in disability/incapacity

[B]bIs life-threatening [E]bCongenital anomaly/birth defect

[C]bRequires hospitalisation or prolongation of existing hospitalisation

[F]bOther, specify _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (see definition of SAE)

*50*

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SECTION 4

If Investigational Product was Stopped, Did the Reported

Event(s) Recur After Further Investigational Product(s)

Were Administered?

If deliberate or inadvertant administration of further dose(s) of investigational product(s) to the subject occurred, did the reported adverse event recur?

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FFA20001 {{{{{{}


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*FFA20001*

SERIOUS ADVERSE EVENT (SAE) (Continued) SECTION 3 Demography Data

Date of birthDay Month Year

Sex bMale bFemale Weight {{{}.{} kg

SECTION 4 If Investigational Product(s) was Stopped, Did the Reported Event(s) Recur After Further Investigational Product(s) were Administered?

bYes bNo bUnknown at this time bNot applicable

SECTION 5 Possible Causes of SAE Other Than Investigational Product(s), ✔ all that apply:

bDisease under study

bMedical condition(s) (record in Section 6)

bLack of efficacy

bWithdrawal of investigational product(s)

bConcomitant medication (record in Section 8)

bActivity related to study participation (e.g., procedures)

bOther, specify _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

SECTION 6 RELEVANT Medical Conditions

Specify any RELEVANT past or current medical disorders, allergies, surgeries, etc. that can help explain the SAE

Date of Onset

Day Month Year

Condition Present at Time of the SAE?

Y= Yes N=No

If No, Date of Last Occurrence

Day Month Year

*51*

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SECTION 9

Details of Investigational Product(s)

Complete this section using the information in the Investigational Product page. Details of all investigational product(s) taken until the time of the SAE should be included. Provide specific details in Section 11 Narrative Remarks if the subject has taken an overdose of investigational product(s), including whether it was accidental or intentional.

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SERIOUS ADVERSE EVENT (SAE) (Continued) SECTION 7 Other RELEVANT Risk Factors (provide any family or social history (e.g., smoking, alcohol, diet, drug abuse, occupational hazard) relevant to the SAE)

SECTION 8 RELEVANT Concomitant Medications (include details of any concomitant medication(s) which may have contributed to the event)

Drug Name(Trade Name preferred)

Dose Unit Frequency Route Taken Prior to Study?

Start Date Stop Date OngoingMedication?

Reason for Medication

Y=YesN=No Day Month Year Day Month Year

Y=YesN=No

e.g., Zantac 150 mg BID PO N 25 Jan 02 27 Jan 02 N Gastric ulcer

SECTION 9 Details of Investigational Product(s)

Was randomisation code broken at investigational site? bYes bNo bNot applicable

Start Date Stop Date

Day Month Year Day Month Year

Run-in

Investigational product

*52*

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SERIOUS ADVERSE EVENT (SAE) (Continued)

SECTION 10 Details of RELEVANT Assessments (provide details of any other tests/procedures which were carried out to diagnose or confirm the SAE e.g., laboratory data with units and normal range)

SECTION 11 Narrative Remarks (provide a brief narrative description of the SAE and details of treatment given)

Investigator’s signature _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (confirming that the data on the SAE pages are accurate and complete)

DateDay Month Year

Investigator’s name (print) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

*53*

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CONFIDENTIAL

PREGNANCY INFORMATIONMONITOR DATA VALIDATION CHECK

STUDY CONCLUSION INVESTIGATOR INSTRUCTIONS


• Check that responses provided correspond with the sex of the subject.

• If the answer to the subject pregnancy question is ’Yes’, ensure that a Pregnancy Notification Form has been completed for the subject.

• Refer to protocol sections 9.0 - 9.2.1 to evaluate subject completion or withdrawal from the study.

• If subject completed study:Date of subject completion or withdrawal must match the last scheduled study visit date.

• If subject withdrew and a withdrawal visit was conducted:Date of subject completion or withdrawal must match the date of subject withdrawal.

• If subject lost to follow-up: Date of subject completion or withdrawal must match the last actual contact with the subject whether or not the contact was a clinic visit. Do not record dates of unsuccessful attempts to contact the subject.

Note: An ’actual contact’ is defined as an interaction between the subject and the investigator or investigator’sdesignee, where the investigator/designee has the opportunity to query the subject about the subject’sstatus. This would include clinic visits and telephone contacts, but normally would not include mail correspondence or third party reports.

• If the investigational product was discontinued at the same time as the subject was withdrawn from the study, ensure the reasons for the two discontinuations are consistent.

• If the subject was withdrawn due to an adverse event, confirm that details recorded correspond with details on the Adverse Event:• ’Withdrawal’ on the AE/SAE page is recorded as ’Yes’.• ’Action Taken with Investigational Product(s) as a Result of the Non-Serious AE’ on the AE/SAE page is

recorded as ’Investigational Product Withdrawn’.• ’Primary Reason for Withdrawal’ on the Study Conclusion page is recorded as ’Adverse Event’.


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PREGNANCY INFORMATION

MEDICAL DEVICE QUESTION

STUDY CONCLUSION

Did the subject become pregnant during the study?

[Y]by [N]bn [X]bNot Applicable (not of childbearing potential or male)

If Yes, complete Pregnancy Notification form.

Did the subject experience an incident or near-incident with GSK medical devices provided for use during this study?

[Y]by [N]bn

If Yes, complete the Medical Device Incident Report Form.

Date of subject completion or withdrawal Day Month Year

Was the subject withdrawn from the study?

[Y]by [N]bn

If Yes, ✔ the primary reason for withdrawal:

[1]bAdverse event (record details on the Non-Serious Adverse Event or Serious Adverse Event pages as appropriate)

[2]bLost to follow-up

[3]bProtocol violation

[4]bSubject decided to withdraw from the study

[5]bLack of efficacy

[14]bExacerbation

[17]bNon-compliance

[24]bDid not meet treatment period eligibility criteria

[Z]bOther, specify _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


143


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*FFA20001* Page

INVESTIGATOR COMMENT LOG Only use this form to record explanatory information on anomalies such as missing data, sponsor waiver of inclusion/exclusion criteria, departures from planned investigational product administration or missed visits.

CRF page number if applicable

Comment

*55* 55


144


CONFIDENTIAL

INVESTIGATOR’S SIGNATUREINVESTIGATOR INSTRUCTIONS

The Investigator is accountable for CRF data. However, the Principal Investigator may delegate CRF signature authority to a medically qualified Sub-investigator (as indicated on the Site Staff Signature Sheet).


145


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*FFA20001* Page

INVESTIGATOR’S SIGNATURE

I confirm that I have reviewed the data in this Case Report Form for this subject. All information entered by myself or my colleagues is, to the best of my knowledge, complete and accurate, as of the date below.

Investigator’s Signature : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ DateDay Month Year

Investigator’s name (print) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

*56* 56


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WORKSHEET

Visit Description

FFA20001 {{{{{{}


CRF PAGE COUNT (For GlaxoSmithKline Use Only)

• Complete this page for all subjects.• Return this page with the CRF transmission.• Indicate below, if the subject was a screen failure.• Place an “X” through the page number of pages that have no data recorded on them and will not be transmitted.• Enter any additional page numbers in the empty boxes below.

Notes: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _

_ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _

_ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _

_ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _

__ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ GlaxoSmithKline clinical monitor’s signature

DateDay Month Year

11

2 103 4 5 6 7 8 9

1612 13 14 15 17 2018 19

21 2622 23 24 25 27 3028 29

31 3632 33 34 35 37 4038 39

41 4642 43 44 45 47 5048 49

51 5652 53 54 55

1


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Visit Description

FFA20001 {{{{{{}


DAILY RECORD CARD PAGE COUNT (For GlaxoSmithKline Use Only)RUN-IN

TREATMENT

Visit 2-3

Visit 3-4

Visit 4-5

Visit 5-6

Notes: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _

_ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _

_ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _

_ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _

__ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ GlaxoSmithKline clinical monitor’s signature

DateDay Month Year

2 3 4 5 61

2 3 41

2 3 41

2 3 41

2 3 41


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Final - 28 AUG 03CONFIDENTIAL


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Run-in

DAILY RECORD CARDRUN-IN PERIOD

Visit 1, 1A and 1B

Doctor’s name: _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Hospital/Clinic address:_ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Hospital/Clinic telephone number: _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

This Daily Record Card should be filled in by the subject.

Important:If this Daily Record Card is found, please return immediately to the above address.

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Final - 28 AUG 03Protocol Identifier FFA20001 CONFIDENTIAL

UK:ENG (United Kingdom/English) Run-in

SUBJECT INSTRUCTIONS FOR COMPLETION OF DAILY RECORD CARD

Use the following information to help you fill out this daily record card:

• Make all the entries in black ink with a ball point pen

• Do not write your full name anywhere on the Daily Record Card

• Complete dates as Day Month Year e.g. for 06 JULY 2003 write 06 JUL 03.

How to correct a mistake:

• Draw a single line through the incorrect entry and initial and date the correction

• Write the correct entry nearby

• If the correct answer is outside the box circle the correct answer and draw an arrow to the correct box

• Do not use correction fluid/tape, write over the entry or recopy any pages.

Subject reminders:

• Fill in the Daily Record Card every day, each morning and each evening.

• Use the Day-Time and Night-Time symptom scores in this daily record card to rate your asthma.

• Refrain from using your VENTOLIN for at least 6 hours prior to the next clinic visit.

• If you do take VENTOLIN on the morning of your clinic visit, record the time VENTOLIN was taken on the Medical Problems / Concomitant Medication /Ventolin Use page of this Daily Record Card. Record the time using the 24 hour clock e.g., 07:50.

• Bring this Run-In Daily Record Card and any remaining VENTOLIN to the next clinic visit.

• Attend the clinic for the next visit at the same time of day.

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If you have a feeling of chest tightness, feel wheezy or breathless, please use the VentolinTM Inhaler provided, to relieve your symptoms.

Try not to take the Ventolin for 6 hours before your next clinic visit.

Relief Medication Device Dose Frequency

VentolinTM When needed

1. How to fill in the diary:

• Fill in one row each day at the following times:

- Morning section: (immediately after waking)- Evening section: (shortly before going to bed)

• As far as possible, keep to the same times each day.

2. Peak Flow

• Always measure your peak flow each morning when you get up, and each evening before going to bed, before taking any medicine, including rescue medication.

• Your doctor will explain how to measure and record your peak flow

• If you have not made a measurement, put a * in the appropriate box

• Remember to bring your peak flow meter to your next clinic visit

3. VENTOLIN Use:

• If you have not used your VENTOLIN, please enter a zero. DO NOT leave the box blank or enter any other symbols

• Record the number of occasions (not puffs or sucks) on which rescue medication was used, e.g., if at midday 2 inhalations of rescue medication was taken, this should be recorded as 1 occasion.

If you have any medical problems, please make a note of them in the table provided in this Daily Record Card.

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DAY-TIME ASTHMA SYMPTOM SCORES

NIGHT-TIME ASTHMA SYMPTOM SCORES











4 = Symptoms so severe that I did not sleep at all

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Day Date COMPLETE EACH MORNINGComplete this section when you wake up each morning, before

taking relief medication (Ventolin).

COMPLETE EACH EVENINGComplete this section in the evening, before taking

relief medication (Ventolin).

Measure your Peak Flow three times and enter the highest value

On how many occasions during the night did you

use your VENTOLIN to relieve your

asthma symptoms?

How was your asthma during the

night?(Use the Night-

time asthma symptom scores)

How many times during the night did you wake due

to your asthma

symptoms?


On how many occasions during the day did you


asthma symptoms?


day?(Use the Day-time asthma

symptom scores)

Day Month Year Score (0-4) Score (0-5)

e.g., 0 06 JUL 03 210 0 0 0 210 1 1

1

2

3

4

5

6

7

2

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Page




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asthma symptoms?





to your asthma

symptoms?




asthma symptoms?



symptom scores)


e.g., 0 06 JUL 03 210 0 0 0 210 1 1

8

9

10

11

12

13

14

3

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Page




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Run-in

4








asthma symptoms?





to your asthma

symptoms?




asthma symptoms?



symptom scores)


e.g., 0 06 JUL 03 210 0 0 0 210 1 1

15

16

17

18

19

20

21

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asthma symptoms?





to your asthma

symptoms?




asthma symptoms?



symptom scores)


e.g., 0 06 JUL 03 210 0 0 0 210 1 1

22

23

24

25

26

27

28

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MEDICAL PROBLEMS / CONCOMITANT MEDICATION / VENTOLIN USEIf you have any medical problems or need to take any new medications during the study, make a note of them below. Also, If you take VENTOLIN on the morning of your clinic visit, record the time below.

Medical Problem Treatment(if taken)

Start Date ofTreatment

Stop Date ofTreatment

VENTOLIN Use

Did you take VENTOLIN on the

morning of the clinic visit?

If Yes,Time

VENTOLIN taken?

Day Month Year Day Month YearY=YesN=No

Hr : Min(00:00 - 23:59)

e.g., Headache Paracetamol 01 JUN 03 02 JUN 03 Y 07 : 50

:

:

:

FOR OFFICE USE ONLYAll adverse events and medications have been reported in the Case Report Form

Monitor’s Signature: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _Date

Day Month Year

6

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DAILY RECORD CARDTREATMENT PERIOD

Daily Record Card issued at:

✔ appropriate box

Visit 2 {} Visit 3 {} Visit 4 {} Visit 5 {}

Doctor’s name: _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Hospital/Clinic address:_ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Hospital/Clinic telephone number: _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Date of next clinic visitDay Month Year

Time of next clinic visit :

(00:00-23:59)Hr:Min

PEF alert value {{{} L/min VENTOLIN alert value {{} Occasions

This Daily Record Card should be filled in by the subject.

Important:If this Daily Record Card is found, please return immediately to the above address.

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UK:ENG (United Kingdom/English) Treatment

SUBJECT INSTRUCTIONS FOR COMPLETION OF DAILY RECORD CARD

Use the following information to help you fill out this daily record card:

• Make all the entries in black ink with a ball point pen

• Do not write your full name anywhere on the Daily Record Card

• Complete dates as Day Month Year e.g. for 06 JULY 2003 write 06 JUL 03.

How to correct a mistake:

• Draw a single line through the incorrect entry and initial and date the correction

• Write the correct entry nearby

• If the correct answer is outside the box circle the correct answer and draw an arrow to the correct box

• Do not use correction fluid/tape, write over the entry or recopy any pages.

Subject reminders:

• Fill in the Daily Record Card every day, each morning and each evening.

• Use the Day-Time and Night-Time symptom scores in this daily record card to rate your asthma.

• Take your study medication as normal on the morning of the clinic visit.

• Refrain from using your VENTOLIN for at least 6 hours prior to the next clinic visit.

• If you do take VENTOLIN on the morning of your clinic visit, record the time VENTOLIN was taken on the Medical Problems / Concomitant Medication /Ventolin Use page of this Daily Record Card. Record the time using the 24 hour clock e.g., 07:50.

• Bring this Treatment Daily Record Card and any remaining VENTOLIN to the next clinic visit.

• Attend the clinic for the next visit at the same time of day.

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If you have a feeling of chest tightness, feel wheezy or breathless, please use the VentolinTM Inhaler provided, to relieve your symptoms.

Try not to take the Ventolin for 6 hours before your next clinic visit.

Relief Medication Device Dose Frequency

VentolinTM When needed

1. How to fill in the diary:

• Fill in one row each day at the following times:

- Morning section: (immediately after waking)- Evening section: (shortly before going to bed)

• As far as possible, keep to the same times each day.

2. Peak Flow

• Always measure your peak flow each morning when you get up, and each evening before going to bed, before taking any medicine, including rescue medication.

• Your doctor will explain how to measure and record your peak flow

• If you have not made a measurement, put a * in the appropriate box

• Remember to bring your peak flow meter to your next clinic visit

3. VENTOLIN Use:

• If you have not used your VENTOLIN, please enter a zero. DO NOT leave the box blank or enter any other symbols

• Record the number of occasions (not puffs or sucks) on which rescue medication was used, e.g., if at midday 2 inhalations of rescue medication was taken, this should be recorded as 1 occasion.

If you have any medical problems, please make a note of them in the table provided in this Daily Record Card.

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DAY-TIME ASTHMA SYMPTOM SCORES

NIGHT-TIME ASTHMA SYMPTOM SCORES











4 = Symptoms so severe that I did not sleep at all

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2

Note: Contact the investigator if your Peak Flow falls below the ’PEF alert value’ recorded on the front of this Daily Record Card.

Day Date COMPLETE EACH MORNINGComplete this section when you wake up each morning, before taking

your study medication or relief medication (Ventolin).

COMPLETE EACH EVENINGComplete this section in the evening, before taking your

study medication or relief medication (Ventolin).


On how many occasions

during the night did you use your

VENTOLIN to relieve your

asthma symptoms?

How was your

asthma during the



How many times

during the night did you wake

due to your asthma

symptoms?

Time morning dose of study

medication taken?




asthma symptoms?

How was your

asthma during the


symptom scores)

Time evening dose of study

medication taken?

Day Month YearScore (0-4)

Hr : Min(00:00 - 23:59) Score (0-5)

Hr : Min(00:00 - 23:59)

e.g., 0 06 JUL 03 210 0 0 0 08 : 00 210 1 1 22 : 30

1 : :

2 : :

3 : :

4 : :

5 : :

6 : :

7 : :

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Note: Contact the investigator if your Peak Flow falls below the ’PEF alert value’ recorded on the front of this Daily Record Card.

Day Date COMPLETE EACH MORNINGComplete this section when you wake up each morning, before taking

your study medication or relief medication (Ventolin).

COMPLETE EACH EVENINGComplete this section in the evening, before taking your

study medication or relief medication (Ventolin).


On how many occasions

during the night did you use your

VENTOLIN to relieve your

asthma symptoms?

How was your

asthma during the



How many times

during the night did you wake

due to your asthma

symptoms?

Time morning dose of study

medication taken?




asthma symptoms?

How was your

asthma during the


symptom scores)

Time evening dose of study

medication taken?

Day Month YearScore (0-4)

Hr : Min(00:00 - 23:59) Score (0-5)

Hr : Min(00:00 - 23:59)

e.g., 0 06 JUL 03 210 0 0 0 08 : 00 210 1 1 22 : 30

8 : :

9 : :

10 : :

11 : :

12 : :

13 : :

14 : :

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4

MEDICAL PROBLEMS / CONCOMITANT MEDICATION / VENTOLIN USEIf you have any medical problems or need to take any new medications during the study, make a note of them below. Also, If you take VENTOLIN on the morning of your clinic visit, record the time below.

Medical Problem Treatment(if taken)

Start Date ofTreatment

Stop Date ofTreatment

VENTOLIN Use

Did you take VENTOLIN on the

morning of the clinic visit?

If Yes,Time

VENTOLIN taken?

Day Month Year Day Month YearY=YesN=No

Hr : Min(00:00 - 23:59)

e.g., Headache Paracetamol 01 JUN 03 02 JUN 03 Y 07 : 50

:

FOR OFFICE USE ONLYAll adverse events and medications have been reported in the Case Report Form

Monitor’s Signature: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _Date

Day Month Year

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LIST OF INVESTIGATORS, SUBINVESTIGATORS AND IECS/IRBS FOR FFA20001

Investigator Sub-investigator(s) Hospital/Institution and Address IEC/IRB Committee Chair and Name of Committee

Bulgaria

BULGARIA

Assoc. Prof.

BULGARIA

BULGARIA

Assoc. Prof.

BULGARIA

BULGARIA

Prof.

BULGARIA

BULGARIA

Prof.

BULGARIA

BULGARIA

Assoc. Prof.

BULGARIA

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Chile

CHILE

Dr.

Chile

CHILE

Dr.

Chile

Croatia

CROATIA

Prof. dr.

CROATIA

CROATIA

dr.

CROATIA

CROATIA

Dipl.iur.

CROATIA

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CROATIA

Prof dr.

CROATIA

Estonia Dr Dr

Dr. Dr Dr

Estonia

Estonia Professor Professor

Dr Dr. Dr Dr

Estonia


Dr Dr Dr

Estonia


Dr Dr Dr

Estonia


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Germany

GERMANY

Prof. Dr.

med.

GERMANY

Prof. Dr.

med.

GERMANY

Prof. Dr. med. habil.

GERMANY

Prof. Dr.

med.

Dr.

GERMANY

Dr. iur.

GERMANY

Prof. Dr. med. Dr. rer. nat.

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GERMANY

PD Dr. med.

GERMANY

Prof. Dr. med. habil.

GERMANY

PD Dr. med.

GERMANY

Dipl.-Oek.

GERMANY

Prof. Dr.

med.

GERMANY

Dipl.-Oek.

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GERMANY

Dr. iur.

GERMANY

Prof. Dr.

med.

GERMANY

Dr. iur.

GERMANY

PD Dr. med.

GERMANY

Dipl.-Oek.

GERMANY

Prof. Dr.

med.

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GERMANY

Prof. Dr. med.

Greece

GREECE

Dr

Greece

GREECE

Dr

Greece

GREECE

Dr

Greece

Hungary

HUNGARY

Hungary

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Italy

ITALY

Dott.

Dr. Dr. Dr

ITALY

Dott.

Dr. Dr. Dr.

ITALY

Dott.

Dr.

ITALY

Prof.

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Dr.

ITALY

Dott. Dr. Dr.

ITALY

Prof.

ITALY

Prof.

ITALY

Prof.

Dr.

ITALY

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Mexico

MEXICO

MD

México,

MEXICO

MD

Dr. México.

Romania

ROMANIA

Prof. Dr.

Romania

Romania

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ROMANIA

Prof. Dr.

Romania

Romania

ROMANIA

Prof. Dr.

Romania

Romania

Russia

RUSSIA

Russia

RUSSIA

Russia

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RUSSIA

Russia

RUSSIA

Russia

RUSSIA

Russia

RUSSIA

Russia

RUSSIA

Russia

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RUSSIA

Russia

South Africa

SOUTH AFRICA

Dr

South Africa

SOUTH AFRICA

Dr

South Africa

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This section contained Principal Investigator’s Curriculum Vitae and has been excluded to

protect Principal Investigator privacy.

CONFIDENTIAL

1

Written Informed Consent Form

Study Identification: FFA20001

A randomised, double-blind, double-dummy, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GW685698X 100µg administered once daily either in the morning or the evening and GW685698X 250µg administered once daily in the evening all administered by inhalation via DISKHALER† for 28 days in subjects with persistent bronchial asthma.

Short Title - Investigation of the best time of day (morning or evening) to take a once daily medication of GW685698X to treat patients with persistent asthma.

The safety and effectiveness of a new asthma medication called GW685698X is being tested. Different doses, taken at different times of the day are being tested against an inactive medication (known as a placebo), and you will be randomly chosen to receive one of these different treatments in place of your normal asthma treatment.

Version Number: 1 Date: 31/07/03

Company Name: GlaxoSmithKline

Subject Identification: Insert subject ID here

Purpose/Description/Procedures/Duration

Purpose of the Study

You have been asked to take part in a clinical research study testing a medication called GW685698X for the treatment/prophylaxis of asthma. Before you decide whether to participate it is important for you to know why the research is being done and what it will involve. Please take time to read the following information carefully and discuss it if you wish with friends, relatives and your general practitioner. Ask us if there is anything that is not clear or if you would like more information. Take time to decide whether or not you wish to take part.

The study doctor and/or the institution is /are paid to conduct this research study by GlaxoSmithKline. The study has been reviewed an independent ethical committee or review board.

The purpose of this study is to test the safety and effectiveness of two different doses of GW685698X, taken either in the morning or evening, for the treatment of asthma.

GM2004/00341/00 FFA20001

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Description of the Study

You will be randomised into one of the study groups described below. Randomisation means that you are put into a group by chance, like flipping a coin. A computer is used to decide which group you are put into. Participants in each group have a different medication and their responses are then compared. You will have a three in four chance of receiving the study medication at one of the two doses. You will be provided with VENTOLIN to relieve your asthma symptoms.

You will be randomised to be in one of the following treatment groups:

• Group 1: GW685698X 100µg taken once daily in the morning plus placebo in the evening.

• Group 2: GW685698X 100µg taken once daily in the evening plus placebo in the morning.

• Group 3: GW685698X 250µg taken once daily in the evening plus placebo in the morning.

• Group 4: placebo morning and evening.

In a blinded study, the medication provided will be concealed so you will not know which medication you will receive. In this research study, neither you nor your study doctor will know which treatment group you are in; this is called “double blind” (although if your doctor needs to find out he/she can do so).

A placebo is a dummy treatment such as a pill, or an inhaler, which looks like the real thing but is not. Placebo medications do not contain active medicine.

If you agree to take part in this study you will be given either GW685698X, or placebo in a pack that looks identical to GW685698X but contains no active medication.

Study Procedures

The study will involve tests that are done specifically for the purposes of this research. However, some of the tests may be familiar to you, as you may have had them before to assess your asthma. All subjects will undergo the same tests, regardless of which medication they receive. The tests, which will be performed during out-patient visits to the hospital, are described below:

Screening Visit (Visit 1) – Before Treatment is Started

At this visit you will be given this Informed Consent Form to read, sign, and date to confirm you want to take part in the study. You will have some tests, and be asked some questions to find out if you are eligible to take part in the study.

• You will be asked about the history of your asthma, any other medical conditions that you have, and any medications that you are taking at this time.

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• You will have a complete physical examination, including assessments of vital signs (heart rate, and blood pressure), and an examination of the back of your throat.

• An electrocardiogram (ECG) test will be done, which measures how well your heart is working.

• You will be asked to provide a blood sample (about 1 tablespoon).

• You will be asked to provide a urine sample (for routine safety tests, as well as pregnancy tests if you are a woman of childbearing potential). Women who are capable of becoming pregnant must have a negative pregnancy test before study medication is given.

• Lung function tests will be performed to assess how your asthma affects your lungs. These tests will be used throughout the study to see if the medication is improving your asthma. There are 2 types of tests that will be done:

• The first test involves blowing into a simple hand-held tube called a Peak Flow Meter, you will be asked to do this yourself at home every day (morning and night) throughout the study.

• The second test (performed only at hospital visits) uses a different machine to assess how much air you can blow from your lungs in one second.

At the end of this visit if you meet all the necessary conditions to enter the study the following will take place:

• Your usual asthma medication may be stopped, and inhaled VENTOLIN† (salbutamol) will be provided for you to use to relieve any asthma symptoms throughout the study.

• You will be asked to collect a sample of your urine at home for 24-hours, just before the next scheduled visit (Visit 2).

Baseline Visit (Visit 2) – Start of Treatment

After a week, you be asked some questions to find out if you are still suitable to take part in the study. Some more tests will be done before you are given any medication:

• Lung function tests.

• Vital signs

• You will be asked if you have had any new illnesses or symptoms since the Screening Visit, and if you have taken any medications other than VENTOLIN.

• An examination of the back of your throat will be made. If you are still found to be suitable for the study, you will then be assigned one of the treatments. You will be given your medication to take home with you.

† VENTOLIN and DISKHALER are Trade Mark of the GlaxoSmithKline group of companies.

Registered in US Patent and Trademark Office.

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Treatment Visits (Visits 3, 4, 5 and 6) – Whilst Treatment is Being Taken

The following tests will be done at each visit, which are 1, 2, 3, and 4 weeks after you start study medication:

• Lung function tests.

• Blood samples (about a teaspoon in total) will be taken at Visit 3, 4 and 5, for tests that assess how the study medication is absorbed by your body.

• You will be asked to collect a sample of your urine at home for 24-hours, just before Visit 6.

• You will be asked if you have had any new illnesses or symptoms since the last visit, and if you have taken any medications other than VENTOLIN.

• An examination of the back of your throat will be made.

• At Visit 6 (at the end of treatment) some additional tests will be done which are the same as those done at the Screening Visit (physical examination, ECG, urine pregnancy test, blood and urine for routine safety tests, and a blood test to assess how the medication is absorbed by your body).

• At the end of Visit 6 you will be prescribed an appropriate asthma treatment to take instead of study medication.

Follow-up Visit (Visit 7) – After Treatment

You will attend the clinic one week after finishing your medication to check if you have had any new illnesses or symptoms since the last visit. If you had any abnormal tests at the last visit you may have some further tests to ensure that things have returned to normal.

Duration of the Study

You are being asked to participate in the study for approximately 6 to 8 weeks. During this time, you will need to visit the out-patient clinic at least 7 times.

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Summary of Procedures and Study Schedule

Visit 1 (1a/1b, as needed)

and run-in period

Visit 2 (Week

0) Visit 3

(Week 1) Visit 4

(Week 2) Visit 5

(Week 3) Visit 6

(Week 4) Visit 7

(Follow-up)

Weeks -3 to -1 0 1 ±2 days 2 ±2 days 3 ±2 days 4 ±2 days 5 ±2 days Complete Informed Consent Form Xa

Physical Examination Xa X Xb Blood sample for Haematology/ Biochemistry

Xa X Xb

Urine sample for Urinalysis X X

Urine pregnancy testing X X X 12-lead electrocardiogram Xa X Xb

Lung Function Measured in the Clinic X X X X X X Xb

Examination of Mouth and Throat X X X X X X Xb

Pharmacokinetics Blood Samples X X X

Pharmacogenetics Blood Samples X

24 hr urine collection for cortisol assessments (urine to be collected before Visit 2 and Visit 6)

X X

Measure Lung Function Morning and Evening with Peak Flow Meter

X X X X X X

Ventolin use as needed X X X X X X Complete Daily Record Card X X

Take Study Medication X X a The assessments indicated will be performed at Visit 1 only, and will not be repeated at Visits 1a and 1b; b Tests only need to be performed if abnormal at Visit 6

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Your Responsibilities

The Daily Record Card

You will be given a Daily Record Card, or DRC, which is like a diary, which you must complete twice daily (i.e. when you get up in he morning and before going to bed in the evening). You will be asked to record the following information:

• Morning and evening lung function using a hand-held Peak Flow Meter. This should be done before you take your study medication, or any VENTOLIN.

• Day-time and night-time asthma symptom scores. This should be done before you take your study medication, or any VENTOLIN.

• Number of times you needed to take VENTOLIN during the day and night.


• The time you took your study medication.

Medications You Should Not Take

Your doctor may ask you to stop taking your current asthma medication from the end of the Screening Visit through to Visit 6. This is necessary so we can fully measure the effects of GW685698X without any interference from your current medication. You must not take any medications for your asthma other than the VENTOLIN that you are given at the Screening Visit or the study medication given at Visit 2. If you do take any other medications it is vital that you tell the study doctor or nurse.

Number of Subjects

This study will involve a total of 492 subjects at approximately 75 hospitals/clinics. Your study doctor will inform you if this total is reached for the study and whether your participation in the study will be required.

Risks/Inconveniences

All drugs may cause side effects in some people. You may experience some of the following with GW685698X: coughing, headaches and stomach complaints. In an earlier study, where double the top dose used in this study was given, coughing was the most commonly experienced side effect. This happened in approximately 1 in every 10 people

You may experience some of the following with VENTOLIN: fine trembling (usually hands), nervous tension, headache, flushing of the skin and palpitations.

In addition to the side effects of these drugs, giving blood samples may cause pain, bruising and rarely, infection at the site where the blood is drawn.

There may be risks, inconveniences or side effects that are not known at this time.

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Because the effects of GW685698X on the unborn foetus (baby) or nursing baby are uncertain, you will not be allowed to enter this study if you are pregnant or breastfeeding.

If you choose to participate in this study, you must use one of the allowed contraceptive methods (a way to prevent you from becoming pregnant) from the Screening Visit (Visit 1) to last Follow-up Visit (Visit 7). Ask your doctor if you have any questions about these choices and which might be best for you (complete abstinence, sterilisation of male partner, implants of levonorgestrel, injectable progestogen, oral contraceptive, or an intrauterine device).

Even when you use one of the allowed contraceptive methods, there may be a small risk that you could become pregnant. Because of this, you will be tested during the study to see if you are pregnant. If one of these tests shows that you have become pregnant, your unborn baby may have been exposed to GW685698X even if you stop taking the medication right away. So, if you think you are pregnant or may become pregnant, you must tell Dr. [ ] at the earliest opportunity. If you should become pregnant during the study we will need to monitor your pregnancy for up to 6 to 8 weeks following the birth, to check that both you and your baby are well. Any premature termination, or spontaneous abortion of the pregnancy will be reported.

There may be other risks, inconveniences and side effects to the embryo, foetus (unborn child), or nursing infant that are unknown at this time.

Benefits

If you agree to participate in this study, no direct clinical benefit to you can be guaranteed, but you will be seen by the study doctor or staff at regular intervals.

Your participation in this study may add to the medical knowledge about the use of this medicine.

If you agree to participate in this study GW685698X may or may not be beneficial in treating your condition or improving your symptoms. The information learned from this study may help to establish a new medication for the treatment of asthma.

Alternative Treatment

Before you decide whether or not to take part in this study, you may wish to consider other treatment options that include medicines to prevent inflammation in your breathing tubes (such as inhaled steroids or tablets containing a medicine known as a leukotriene receptor antagonist), treatments to open up your breathing tubes (known as bronchodilators, e.g. theophylline tablets), or combined treatment with an inhaled steroid and an inhaled bronchodilator. Your study doctor will describe these to you based on your medical history and the treatment you have received to date: [list country specific alternatives].

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Compensation for Study-Related Injury

In the event that you suffer any injury attributable to the administration of a medicinal product within the study or any clinical intervention or procedure required under the study that would not have occurred but for your inclusion in the study, you will be compensated. A copy of the guidelines covering compensation for any such injury can be obtained from your study doctor.

Payment to Subjects

You will receive no payment for taking part in this study.

Expenses/Costs

GlaxoSmithKline has made provisions with the study doctor to reimburse you for the cost of travelling to and from study visits and for other miscellaneous costs (such as expense for a meal), up to a maximum of CMDs to add figure as appropriate.

Taking part in the study may lead to added cost to you. Please ask the study doctor/staff about the likely added costs and reimbursement.

Contact(s) for Answers to Pertinent Questions about Research and Subject's Rights and Contact(s) in the Event of an Injury

You have the right to ask [Name] at [contact details] any questions concerning this study at any time.

If you have any questions concerning your rights as a subject in a research study, you should contact [Name] at [contact details] at any time.

If you believe you have sustained a research-related injury, you should contact [Name] at [telephone number] at any time.

Termination of Subjects’ Study Participation

Your participation in the study may be stopped for any of the following reasons:

i. If you don’t follow the investigator's instructions.

ii. The investigator decides it is in the best interest of your health and welfare to stop.

iii. There aren’t enough patients in the study, or the study has reached the required number of patients

iv. GlaxoSmithKline stops the study at this study site for other reasons not known now.

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v. GlaxoSmithKline stops enrolling new subjects into the study for any reason, and you are in the screening or run-in phase of the study not yet assigned to a treatment group.

Voluntary Participation and Subjects Right to End Participation

Your participation in this study is voluntary. If you do decide to take part, you will be given this information to keep and be asked to sign this consent form. You may refuse to take part in this study, or once in the study you may decide to stop taking part at any time. You must inform your study doctor if you decide to do this. Your decision not to take part in the study or to stop taking part in the study will not affect your current or future medical care, or any benefits to which you may otherwise be entitled.

Contact your study doctor or clinic should you decide not to continue your participation in the study. He/she will explain the best way for you to do this.

GlaxoSmithKline will be allowed to use any information and study data that were collected before you decided withdraw from the study.

Confidentiality and Data Privacy

Maintaining confidentiality is important to GlaxoSmithKline. Your personal information (for example, your gender, age, the details of your medical conditions) and other information (the data collected by GlaxoSmithKline as part of the study) will be identified by a number (i.e., coded). Your name will not appear in any publications or reports produced from this study.

GlaxoSmithKline will keep the information and the results collected about you in this study. Your name and address are not included in the information kept by GlaxoSmithKline - only your study doctor will keep this information. GlaxoSmithKline has told your study doctor to keep the information about you in a secure place. GlaxoSmithKline will comply with internal procedures to protect personal and other information even in countries where data privacy laws are less strict than in Europe/US.

By agreeing to take part in this research study you will be allowing certain persons to see the information about you (both personal, including your name, and other information) held by the study doctor. Your information will be looked at to confirm that it is correct and that it is related to you. This will be done by selected people working for GlaxoSmithKline and organisations acting on behalf of GlaxoSmithKline and the government regulatory authorities. These persons are required to maintain the confidentiality of your information.

Your information will be processed electronically (i.e., by a computer) or manually and analysed to determine the outcome of this study. GlaxoSmithKline may use your information for other medical/health care purposes related to development of GW685698X. For this purpose only your coded information will be used.

GM2004/00341/00 FFA20001

CONFIDENTIAL

10

Your information could be sent to regulatory authorities, to the IEC/IRB, to other doctors and/or organisations working with GlaxoSmithKline. It may also be sent to other GlaxoSmithKline sites in this country and in other countries where there may be different or lesser standards for looking after it. GlaxoSmithKline will apply the same standard in the protection of your information to the extent permitted by law.

You have the right to ask the study doctor about the data being collected on you for the study and about the purpose of this data. You have the right to ask the study doctor to allow you to see your personal information and to have any needed corrections to it made.

Tissue Samples (Including Blood)

As part of the study, blood and urine samples will be collected. A total of approximately 40 mL (about 2 tablespoons) of blood will be taken during the whole study at the clinic visits. The blood samples will be used for routine safety tests, and to assess how your body absorbs the study medication. Giving blood samples may cause pain, bruising and rarely, infection at the site where the blood is drawn. Urine samples will also be taken: two 24 hour collections to assess a hormone in your urine (called cortisol); two samples for routine safety tests; and two samples for pregnancy tests (females of child-bearing potential only).

The samples stored will not be labelled with information that directly identifies you, but a connection to your information will be kept.

Collected samples may be transferred to the GlaxoSmithKline or to other researchers working with GlaxoSmithKline.

Notification of New Information

Sometimes during the course of a research project, new information becomes available about the treatment/medication that is being studied. If this happens, we will tell you about new information that may affect your willingness to stay in this study.

GM2004/00341/00 FFA20001

CONFIDENTIAL

11

I confirm that I have read the statements in the informed consent form dated 19 June 2003 (Version 1) for this study. I confirm that the study information and procedures have been explained to me by name(s) on date during the consent process for this study.

I confirm that I have had the opportunity to ask questions about this study and I am satisfied with the answers and explanations that have been provided.

I have been given time and opportunity to read the information carefully, to discuss it with others and to decide whether or not to take part in this study.

I agree to take part in this study.

I do/do not agree to my general practitioner being notified of my participation in this study.

Subject's Signature _____________________________ Date: _________

Printed name of Subject

_____________________________

*Signature of Legally Acceptable Representative

_____________________________ Date: _________

*Printed name of Legally Acceptable Representative

_____________________________

Signature of Person conducting Consent

_____________________________ Date:

Printed Name of Person conducting Consent

_____________________________

*Signature of Legally Acceptable Representative is required if the patient to be included in the study is below the age of legal consent

GM2004/00341/00 FFA20001

F-GRD-003 v03 Subject Initials __________ 17 Feb 2003 Page 1 of 4

DIRECTIONS Preferred Wording is provided in this consent form. Text in blue italics may be customized to meet local requirements. To ensure consistency and accuracy, changes/deletions made to the consent must be checked against the protocol. When finalizing the consent, ensure that signature lines are on one page. Check lines and page breaks. Report any significant changes proposed by sites or IRBs/IECs to your contact in Applied Pharmacogenetics.

Subject Informed Consent Form for Pharmacogenetic Research GlaxoSmithKline Protocol Title: A randomised, double-blind, double-dummy, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GW685698X 100µg administered once daily either in the morning or the evening and GW685698X 250µg administered once daily in the evening all administered by inhalation via DISKHALER for 28 days in subjects with persistent bronchial asthma. Short Title - Investigation of the best time of day (morning or evening) to take a once daily medication of GW685698X to treat patients with persistent asthma. GlaxoSmithKline Protocol Number: FFA20001 Study Doctor: _________________________________________________________ Site Address: _________________________________________________________ _________________________________________________________ _________________________________________________________ Site Phone Number: _________________________________________________________ Subject Number: _________________________________________________________ This form is in addition to the consent form you signed for the clinical study for GW685698X. Purpose and Description of the Research The purpose of this consent form is to explain what pharmacogenetic research is and to ask you to give a blood sample that may be used in this research. The sponsor of the research is the GlaxoSmithKline group of companies [referred to as GSK in this consent]. Pharmacogenetics is the study of differences in how our bodies react to or handle medicines. Your genes, pieces of genes, or genetic material may have an effect on how your body responds to or handles a medicine. If it appears that there is a difference in response to or handling of GW685698X, GSK may study these differences using your genes, pieces of genes, or genetic material taken from your blood sample. In special cases, your sample may not be used. This might happen if there are not enough subjects, if the study is stopped for other reasons, or if no questions are raised about how people respond to or GW685698X. The study doctor and/or institution are paid by GSK to conduct this research. This study will have 492 subjects taking part at about 75 sites in 14 countries.


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Procedures If you agree to take part in this research, a trained person will take about 10 ml (or 2 teaspoons) of your blood. If there is a problem processing your sample, then we may ask you to give another sample. Voluntary Participation Participation in this pharmacogenetic research is voluntary. You may withdraw from this research at any time. GSK may keep your sample for up to 15 years after the last subject completes the study or GSK may destroy your sample before then. You may decide not to take part now or you may decide to take part and then change your mind. If you decide not to take part or to withdraw after starting the study, you do not have to give a reason and there will be no change to your medical treatment or to your participation in the GW685698X study. If you withdraw from this research, your sample will be destroyed and GSK will only keep and study information collected/generated up to that point. Alternatives You have the choice not to take part in this research. Benefits You may help scientists understand why people react to or handle GW685698X differently. This may help identify people who are more likely to respond to or experience side effects GW685698X. Risks and Discomfort The physical risks of giving this blood sample are the same as those for any blood sample taken from a vein. You may feel faint, experience mild pain, bruising, irritation or redness at the site of puncture. In rare cases, you may develop an infection. Compensation for Study-Related Injury (ROW – Use language approved by operating company.) Privacy To protect your privacy, your sample and medical information will be labeled (or “coded”) with your study subject number, not your name. Your study doctor and his or her staff will keep the link between your subject number and your name. Your study doctor has been told to keep your pharmacogenetic information including your consent in a separate, secure file, which is not part of your medical records. GSK will control access to its files that hold your information and results. Your name will not be in any publications or reports about this research. GSK or those working with GSK (for example, other researchers) will only work with your sample for the use stated in this consent. Samples will be stored securely. GSK will require anyone who works with your sample to agree to hold the research information and any individual results in confidence.


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If your sample is studied, your study doctor and his or her staff may have access to your pharmacogenetic research results. Your individual results will only be shared with you through the study doctor if you request to see the results and it is a requirement of a governmental agency or other legal authority that GSK make these results available. GSK will not release individual results to anyone else (e.g., family members, primary care physicians, insurers, or employers) under any circumstance, unless required by law. Your results are not for clinical diagnosis or treatment. Medical information, samples and research results from you and other research participants may be studied by GSK to make medicines or tests to determine the body’s response to or handling of medicine. Your information and any results will be put on a computer and stored in electronic databases. International regulations for information on computers and relevant laws on processing personal information will be followed. Your information, sample, and results could be sent to other researchers working with GSK and to other GSK sites. By agreeing to take part in this research, you will allow your medical information, sample, and pharmacogenetic results to be checked as part of collecting and analyzing study results. The people who may check this research include GSK, people working with GSK on this research, ethics committees or institutional review boards, IRBs, and regulatory authorities (such as the EMEA). Compensation You will not receive any payment for taking part in this pharmacogenetic research. OR You will be paid £X/$X for your time and travel related expenses. Commercial Issues GSK and/or others intend to claim sole ownership of any research results consistent with this consent. The results of this research may have commercial or intellectual property value. You agree that GSK can apply for patents. You will not receive any financial benefit that might come from the research. Contact Name Contact __________ at telephone number __________ at any time if you have questions about this study, an injury related to the blood draw for this research, or withdrawal from this research. For questions about your rights as a research subject, contact __________ of the Institutional Review Board/Ethics Committee at telephone number __________.


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CONSENT

A copy of this Consent Form (signed and dated) must be given to the subject or legal representative.

My signature below indicates that: 1. I have read this form and the research has been explained to me. 2. I have been able to discuss the research and ask questions. I am satisfied with the answers. 3. I have been given the time to consider whether or not to take part in this research. 4. I voluntarily agree to take part in this research. Subject’s Name: __________________________________ (Please Print) Subject’s Signature: __________________________________ Date: ________________ (or that of Legal Representative) (Day/Month/Year)

(Written by Subject or Legal Representative) Individual Obtaining the Subject’s Consent: Name: _________________________________ (Please Print) Signature: _________________________________ Date: _______________

(Day/Month/Year)


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Randomization Code

1

Treatments and Sequences defined for studyTreatments

Sequence Code Description Period

GW685698X 100ug am od A GW685698X 100ug am od 1

GW685698X 100ug pm od B GW685698X 100ug pm od 1

GW685698X 250ug pm od C GW685698X 250ug pm od 1

Placebo D Placebo 1

Master Schedule Report

StudyID: FFA20001Description: A randomised, double-blind, double-dummy, placebo-controlled, parallel-group

study to evaluate the efficacy and safety of GW685698X 100ug OD given eitheram or pm and GW685698X 250ug OD given pm for 28 days in subjects withpersistent bronchial asthma

Report generated by: on: 17-FEB-2005 Page 1 of 34


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Schedule No: 1Stratum None

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This section contained data from each individual patient, rather than in aggregate. They have

been excluded to protect patient privacy. Anonymized data from each patient may be made

available subject to an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clinical Study Register.

In February 2013, GlaxoSmithKline (GSK) announced …...Study period: 24 Sep 2003 - 31 Mar 2004...

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Transcript of In February 2013, GlaxoSmithKline (GSK) announced …...Study period: 24 Sep 2003 - 31 Mar 2004...