UCB Pharma - Europa

STUDY No.: 9153PROTOCOL No.: MPCE91 L 1802/6D 3q’43.4 of 187

UCB S.A. Pharma SectorAl14e de la Recherche, 60 B-1070 Brussels (Belgium)

UCB Pharma

Study Number: 9153

Protocol : MPCE91 L 1802/6D (June 9, 1992), annotated by the UCB MedicalResponsible on December 12, 1992

Study Report No: MRCE98G020 1/1V

Test Substance: Cetirizine

Study Title: A double blind, parallel, randomized study: cetirizine versus loratadine in themanagement of perennial allergic rhinitis in children (6-12 years old). Studyof the effect on the inhibition of histamine-induced wheals. Assessment ofthe safety of both drugs.

Development Phase : IvGCP statement : The study described within this report was conducted in accordance with

Good Clinical Practices

Date of inclusion of first patient: November 3, 1993

Date of completion of last patient: May 8, 1995The studv was terminated accordimz to the motocol.

Date of report: Decemb& 1, 1998

Report written by: M.-P. Derde, Ph. D.

Sponsor medical responsible: P. Coulie, M.D.

Sponsor contact person: B. Burtin, Ph.D.Tel.: +-32.2.386.23.05Fax: +32.2.386.21.99

Sponsor: UCB S.A., Pharma SectorAllee de la Recherche, 60B-1 070 Brussels - Belgium

Principal Investigators: Dr. J.G. Huerta-Lopez

Instituto National de PediatriaInsurgences Sur 3700-C04530 Mexico D.F.MEXICODr. J.J. Sienra-Monge

Hospital Infantil de MexicoDr. Marquez 16203650 Mexico D.F.MEXICO

Report: 187 pagesAppendixes: 578 pages

Confidential This report is the property of UCB S.A. and may not - in fill or in part -be past on, reproduced, published or otherwise used without theexpress permission of UCB S.A.

REPORT No.: MRCE98G0201/l V Study Report December 1, 1998

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STUDY No.: 9153PROTOCOL No. : MPCE91 L 1802/6D of 187

2. SYNOPSIS

NAME OF COMPANY INDIVIDUAL TABLE REFERRING (FOR NATIONAL

UCB S.A. Pharma Sector TO PART IV OF THE DOSSIER: AUTHORITY USE ONLY)B-1 070 Brussels (Belgium)

NAME OF FINISHED PRODUCT Volume:

Zirtec@

NAME OF ACTIVE Page:

INGREDIENT

Cetirizine

Title of the Study A double blind, parallel, randomized study: cetirizine versus Ioratadine inthe management of perennial allergic rhinitis in children (6- 12 years old).Study of the effect on the inhibition of histamine-induced wheals.Assessment of the safety of both drugs.

Investigators Dr. J.G. Huerta-Lopezj MexicoDr. J.J. Sienra-Monge, Mexico

Study Centers Dr. J.G. Huerta-Lopez: Insituto National de PediatricianInsurgences Sur 3700-C04530 Mexico D.F. (MEXICO)

Dr. J.J. Sienra-Monge: Hospital Infantil de MexicoDr. Marquez 16203650 Mexico D.F. (MEXICO)

Publications None

Study Period Date of first enrollment: November 3, 1993 Phase of Development IV

Date of last patient completed: May 8, 1995

Objectives . To assess the possible difference of effects of cetirizine and

loratadine in the treatment of perennial allergic rhinitis in childrenfrom 6 to 12 years old, and additionally, on the results of nasalbrushing and rhinomanometry

. To study the effects of both drugs at skin level on the potency of

the inhibition of histamine-induced wheals● To assess the safety of both drugs.

Methodology Randomized, double-blind, parallel group study performed in two centers,comparing a 28 day treatment of cetirizine od with loratadine od for thetreatment of perennial allergic rhinitis in children from 6 to 12 years old.

Number of patients Planned to be enrolled: 80 patientsAnalyzed: 76 patients

Diagnosis and main Diagnosis:

Inclusion Criteria Perennial allergic rhinitis, documented by anamnesis and positive skin orRAST test for grass-pollen or house-dust mite.Main criteria for inclusion:● Children of either gender, between 6 and 12 years of age. Informed consent given by the legal representative, and if possible by

the patient,● Suffering from perennial allergic rhinitis, documented by anamnesis and

positive skin or RAST test for grass-pollen or house-dust mite.● Presence of at least 3 of the symptoms sneezing, rhinorrhea, nasal

obstruction, pruritus, eye pruritus, at the moment of the first visit orduring the previous 24 hours, and for whom the total symptom score wasat least 8 at inclusion. This total score was to be calculated by givingeach of the 5 symptoms a score ranging between O (absent) and 3(severe).

REPORT No.: MRCE98G0201/1 V Study Report December 1, 1998

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STUDY No.: 9153PROTOCOL No.: MPCE91 L 1802/6D of 187


UCB S.A. Pharma Sector TO PART IV OF THE DOSSIER: AUTHORITY USE ONLY)

B-1070 Brussels (Belgium)

NAME OF FINISHED Volume:

PRODUCTZirtec@


INGREDIENTCetirizine

●

Test Product CetirizineDose 0.2 mgikglday

Administration Route Oral

Batch # 71

Reference Therapy Loratadine

Dose 0.2 mgikglday

Administration Route Oral

Batch # 89

Treatment Duration 28 days

Criteria for Evaluation

E!@!SY CRF Data

● Sneezing (four point ordinal scale ranging from O = absent to 3 = severe)● Rhinorrhea (four point ordinal scale ranging ‘from O = absent to 3 =

severe)

. Nasal obstruction (four point ordinal scale ranging from O = absent to3 = severe)

● Nasal pruritus (four point ordinal scale ranging from O = absent to 3 =severe)

● Ocular pruritus (four point ordinal scale ranging from O = absent to 3 =severe)

● Maximal symptom score= maximum of the scores of sneezing,rhinorrhea, nasal obstruction, nasal pruritus, and ocular pruritus

. VAS (in mm) of the global status of the nasal condition● Rhinomanometry (I/rein)● Wheal surface area (in mm’, average of 4 measurements). Nasal brushing: absolute and percentage eosinophil count.

Daily Record Car&

For each of the five symptoms separately:. Daily symptom scoreFor all symptoms together:● Percentage of days without symptoms (PDSO)s Percentage of days with at worst mild symptoms (PDS 1). Percentage of days with an at worst moderate intensity of the symptoms

(PDS2)

. Daily total symptom score● Mean daily total symptom score.

Safety . Adverse events● Laboratory tests (erythrocytes, hematocrit, hemoglobin, white blood cell

count and differential white blood cell count, platelets, urea or BUN,creatinine, TGP (ALA-transferases)

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NAME OF COMPANYUCB S.A. Pharma SectorB-1070 Brussels (Belgium)

NAME OF FINISHEDPRODUCT

Zirtec@

NAME OF ACTIVEINGREDIENTCetirizine

Statistical Methods

%mmary ConclusionsEfficacy Results

—

INDIVIDUAL TABLE REFERRING (FOR NATIONALTO PART IV OF THE DOSSIER AUTHORITY USE ONLY)

Volume:

Page:

I

The statistical tests are performed two-tailed at the 5°A level of significance.The protocol did not foresee a primary variable for the evaluation, nor anadjustment for multiple testing. The statistical analysis is both descriptive andinferential. The effect of center is taken into account in the analysis.The statistical evaluation is performed on the basis of the ITT population,consisting of all patients randomized in the study for whom follow-upinformation is available.The comparability of the two groups is evaluated on the basis of theobservations recorded at onset of the study, using two-way analysis ofvariance for the continuous variables and the Cochran-Mantel-Haenszel test

for the discrete variables.For the evaluation of efficacy use is made of two-way analysis of variance,controlled for treatment and center, for the continuous variables, and theCochran-Mantel-Haenszel test stratified by the baseline score for the discretevariables.The evaluation of safety is descriptive.

●

●

●

●

●

●

Investigator Assessments: These revealed a significant difference forrhinorrhea at the last visit which was more ffequent in the loratadinegroup: 65% of the patients versus 33% in the cetirizine treatment group.

No significant differences were found for the other symptoms.Visual Analogue Scale: The VAS of the global status of the nasalcondition decreased on average by 41 mm in the loratadine group and by38 mm in the cetirizine group. These changes are not significantlydifferent.Anterior Rhinomanometty: No significant differences were foundbetween the two treatments on the basis of the rhinomanometrymeasurements, which on average increased by 50 1/rein in the Ioratadinegroup and by 45 llmin in the cetirizine group.Skin Wheal Test: Inhibition of the skin wheal surface area induced by theprick test with histamine was comparable for the two treatments, with anaverage wheal surface area after treatment of 12 mmz in the Ioratadinegroup and of 9 mm’ in the cetirizine group.

Daily Record Cards: On average, patients in the cetirizine group hadabsent or mild symptoms during 39°/0 of the treatment period while in theloratadine group this was the case during 35% of the treatment period.These values are not significantly different.

Nasal Brushings: Data could not be analysed for methodologicalreasons.

Both study medications relieved symptoms after 4 weeks. With the exceptionof the symptom of rhinorrhea, this study failed to differentiate between theactive medications.

REPORT No.: MRCE98G0201 /1 V Study Report December 1, 1998

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STUDY No.: 9153PROTOCOL No.: MPCE91L1802/6D of 187


UCB S.A. Pharma Sector TO PART IV OF THE DOSSIER AUTHORITY USE ONLY)B-107O Brussels (Belgium)

NAME OF FINISHED Volume:

PRODUCTZirtec@


INGREDIENTCetirizine

Summary ConclusionsSafety Results One patient under loratadine suffered fi-om tachycardia and one from

somnolence. For both adverse events the relationship with the study treatmentwas considered possible. In the cetirizine treatment group one patientsuffered from pharyngitis and one patient from somnolence. For thepharyngitis the relationship was considered to be remotelnone and for

somnolence it was assessed as certain. No clinically relevant adverse eventswere reported from laboratory data.

Conclusion Both study medications relieved symptoms after 4 weeks. With the exceptionof the symptom of rhinorrhea, where cetirizine was more effective thanloratadine, this study failed to differentiate between the active medications.The active medications were well tolerated.

Date of the report September 1, 1998

REPORT No.: MRCE98G0201/lV Study Report December 1, 1998

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STUDY No.: 9153PROTOCOL No.: MPCE91 L1802/6D of 187

3. TABLE OF CONTENTS

2. SYNOPSIS ......................... .......................................................................... .............................-..-...-...--..-....-.-...... 2

3. TABLE OF CONTENTS ............................................. ...........................o..... .......................................... ............ 6

4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................... ........ .............................. ...... 9

5. ETHICS .......... ............. ..................................... .................................................................................................. 10

5.1 INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONAL REVIEW BOARD (IRB) ...............105.2 ETHICAL CONDUCT OF THE STUDY .............. .................................................................. ......................... 105.3 PATIENT INFORMATION AND CONSENT ...... ..................................... ............................. ............. .. .......... 10

6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................................... ........... 11

6.16.26.36.46.56.66.7

6.8

TMALCENTERS ........................................................................................... .................................................. 11TRIAL INVESTIGATORS ............. ........ ................. .......... ................................. ...................................... ........ 11SPONSOR .... ............... ....................................................................................................................................... 11FINANCIAL ~SPONSIBILITY ..... .... .. .......................................................... .................. ......... ..................... l]MEDICAL RESPONSIBILITY ............ .......................................................................... .... ........................ ...... 12MONITOR~G ......... ........................... .............................................................. .................. .............................. 12CLINICAL TRIAL SUPPLY MANAGEMENT ....................................................... .... ................................... 12DATA ENTRY AND ANALYSIS ................ .. ....................................... .... ................. ....................... ............... 12

7. INTRODUCTION ........ .............................................................................. .... .................................................... 13

8. STUDY OBJECTIVES ............................................. ...... .. .... ......................... .. ........................................... ....... 13

9. INVESTIGATIONAL PLAN ............ ................................................................................................................ 14

9.1 OVERALL STUDY DESIGN ............ .. .. .............................................................. ............................................. 149.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS ..................... 149.3 SELECTION OF STUDY POPULATION ... ...................................................... ................ ............................... 14

9.3.1 Inclusion Criteria ................................................................. ................. ..................................................... 149,3.2 IZrclusion Criteria ............................................ .................................................................... ...................... 159.3.3 Removal oJPatientsfrom Therapy or Assessment ...... ........................................................ ...................... 16

9.4 TREATMENTS ..... ......................................... .. ......................................... ................. .............. ................. ........ 16

9.4.1 TreatwntAdminktered ..................................... .. .......... ...................................................... ............. ......... 169.4.2 Ident@ofInvestigationa[ Product(s) ............ ...... ....................... ......................................... .................... .. 169.4.3 Method ofAssigning Patients to Treatment Groups ... ........................... .................................................. . 179.4.4 Selection of Doses in the Study ............................ .... ............................... ............................. ......... ............. 199.4.5 Selection and Timing of Dose for Each Patient ......................................... ......................... ...................... 199.4.6 Blinding .................................................................... .... .. ............................................................................ 179.4.7 Prior and C’oncomitant Therapy ............................ .............................................................. ................. .... . 189.4.8 Treatmnt Compliance ............................................. .... ........................... ............................. ...................... 18

9.5 EFFICACY AND SAFETY VARIABLES ............ ........................................................................... ............... 199.5.1 Efficacy and Safety Measurements Assessed and Flow Chart .. ............ ............................. ......... ............. 199.5.2 Appropriateness of Measuremenfi .................... ........ ........................................................ ......... ............... 209.5.3 Primary Efficacy Variable(s) ........................... .. .............. ..................... .. ........................... ......... ............... 219.5.4 Drug Concentration Measurements .................. .. ..................................................................... ................. 21

9.6 DATA QUALITY ASSURANCE ........................ .. .. ................................... ........... ................ ........................... 219.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL AND DETERMINATION OF SAMPLE SIZE22

9.7.1 Statktical andAna@tica[ P[ans ................................... .... ................................................ ....... ................... 229.7.2 Determination of Samp[e Size ........................ .. .................... ................. ......................... ....... ............... ...... 24

9.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLA~EDANALYSES ........... ......... ..................... . 249.8.1 Conduct oft}le Study ........ ............................................................................ .... ................ .......................... 24


,.....


9.8.2 Statktical Metllodolo~ .................................... .... .................................... .................................................. 24

10. STUDY PATIENTS .... ................................................. ................................. ......................... .......................... 35

10.1 DISPOSITION OF PATIENTS ............................ .................................................................. ......................... 3510.2 PROTOCOL DEVIATIONS .......................................................................... ........................ .......... ... ............ 39

11. EFFICACY EVALUATION ............................. ...... ........................................................................................ 41

11.1 DATA SETS ANALYZED ........................... ............................................................................ ............... ......4l11.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ... ................................... ..................... 4111.3 MEASUREMENTS OF TREATMENT COMPLIANCE ............... ........................................... ..................... 4411.4 EFFICACY RESULTS AND TABULATIONS OF INDIVIDUAL PATIENT DATA . . ... . . . . .. . . . . . . . 45

11.4.111.4.211.4.311.4.411.4.511.4.611.4.7

Ana@is of EfJcacy ........................................ .... .......................................................... ............. .............. 45Statktical Issues .............................................. .... .................................. ................................................... 49Tabulation of Individual Rmponse Data .... .... ......................................................................................... 51Drug Dose, Drug Concentration, and Relationship to Response ........ .. ................................... .. ............ 51Drug.drug and Drug.Diseme Interaction .............................................. ........ .................. ....................... 52By.Patient Dkplays ........................................................................ ................. ......................................... 52Efficacy Conclusions .............. ......................................................... .. ................................. ..................... 52

12. SAFETY EVALUATION ................................................................................. ........ ................ ............. .......... 53

12.1 EXTENT OF EXPOSURE ....................................................................... ........... ...................... ........... .... ....... 5312.2 ADVERSE EVENTS .................................................................... ............ ............... .................. ...................... 5512.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS 6012.4 CLINICAL LABORATORY EVALUATION ......................................... .... ................................................... 61

12.4.1 Listing of Individual Laboratory Measurements by Patient and of Abnormal Laboratory Values ..... . 6212.4.2 Evaluation of Each Laborato~Parameter .................................... .......................................... .. .............. 62

12.5 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY ........6312.6 SAFETY CONCLUSIONS ................... ...... .................................................... .......................... ....................... 63

13. DISCUSSION AND OVERALL CONCLUSIONS ................................. ......... ........ ................ .. ............. ....... 64

14. TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT .............66

14.1 DEMOGRAPHIC DATA ............................................................. ..................... .. ............................................. 6614.2 EFFICACY DATA ........................................................................... ................... ...... ....................................... 8514.3 SAFETY DATA ...................................................................................................... ....................................... 158

14.3.1 DkplayofAdverse Events ................... ...... .................................................................. ........................... 18614.3.2 Listing of Deaths, Other Serious and Signl~cantAdverse Even fi . ....... .................... ........... ................ 18614.3.3 Narratives of Deaths, Other Serious and Certain Other Sign@iiant Adverse Events .......... ................186

15. REFERENCE LIST ................................... ...... ...... ................................. ...................................... .................. 187

16. APPENDICES ............. .... ........ ....................................................................... .. ................ .... ........................... 187

16.1 STUDY INFORMATION16.1.1 Protocol and protocol amendments16.1.2 Sample case report form16.1.3 List of IECS or IRBs - Representative written information for patients and sample

consent form16.1.4 List and description of investigators and other important participants in the study16.1,5 Signatures of principle or coordinating investigator(s) or sponsor’s responsible

medical otllcer16.1.6 Listing of patients receiving test drug(s)16.1.7 Randomization scheme and codes16.1.8 Audit certificates16.1.9 Documentation of statistical method16.1.10 Documentation of inter-laboratory standardisation methods and quality assurance

REPORT No.: MRCE98G020 1/1V Study Report December 1, 1998

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STUDY No.: 9153PROTOCOL No.: MPCE9lL1802/6D of 187

16.1.1116.1.12

16.2

16.2.116.2.216.2.316.2.416.2.516.2.616.2.716.2.8

16.316.3.116.3.2

16.4

proceduresPublications based on the studyImportant publications referenced in the report

PATIENT DATA LISTING

Discontinued patientsProtocol deviationsPatients excluded from efficacy evaluationDemographic dataCompliance and/or drug concentration dataIndividual efficacy response dataAdverse events listingListing of individual laboratory measurements by patient when required byregulatory authorities

CASE REPORT FORMSCRFS for deaths, other serious adverse events and withdrawals for AEOther CRFS submitted

INDIVIDUAL PATIENT DATA LISTING



4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS

AE(s) :ALP :ALT :AST :AUC :BMI :BP :c:Cfil relCMH :CRF :DCCF :DRC :EC :ECG :EEC :FDA :GGT :GI :HR :IND :IRB :ITT :LFT :LOCF :MCH :MCHC :MCV :NAED :OD :PP :PR :PRN :RBc :SAP :SAE :SOP :

adverse event(s)alkaline phosphatasealanine aminotransferaseaspartate aminotransferasearea under the curvebody mass indexblood pressurepeak concentrationclinically relevantCochran-Mantel-Haenszelcase report formdata clarification and correction formDaily Record CardEthics CommitteeelectrocardiogramelectroencephalogramFood & Drug Administrationgamma-glutamyltransferasegastrointestinalheart rateinvestigational new druginstitutional review boardintent-to-treatliver fi.mction testlast observation carried forwardmean corpuscular hemoglobinmean corpuscular hemoglobin concentrationmean corpuscular volumenon-antiepileptic drugonce a dayper protocolpulse rateas neededred blood cellstatistical analysis planserious adverse eventstandard operating procedure


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5. ETHICS

5.1 INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONALREVIEW BOARD (IRB)

The study could only be initiated after the protocol received approval from a relevantEthics Committee and the Mexican Health Authorities. A copy of the original of theapprovals was to be sent to the sponsor. Copy of this appendix is added in Appendix16.1.3.

5.2 ETHICAL CONDUCT OF THE STUDY

The study was conducted according to the relevant UCB standard operating procedures (SOPS)which were in application at the time of the study, to Good Clinical Practice (GCP) regulations,to regulations applying in Mexico, and to the Declaration

5.3 PATIENT INFORMATION AND CONSENT

of Helsinki, as amended.

Legal representatives of the subject, and when possible the subject hindherself, were informedabout the purpose of the study, the safety of the experimental drugs and their possible sideeffects, the duration of the drug treatment and the nature of the evaluations. It was to be clearthat participation was free, that the choice to participate would have no influence on any othertherapies the subject would receive, and that they were free to withdraw their consent at anymoment without prejudice to any future care and treatment.

A copy of the ‘subject information sheet’ was given to the legal representative of the subject,and when possible to the subject him/herself.

The legal representative of the subject, and when possible the subject hirdherself, gave theirconsent by signing the Informed Consent Form. This was to be kept by the investigator, while acopy could be attached to the CRF after the identity of the subject was removed by the monitoror the investigator.

Representative written information (missing document) and a sample consent form are providedin Appendix 16.1.3. For all except one patient the informed consent form was signed by a legalrepresentative. For patient 24 in the center of Dr. Huerta-Lopez it was confirmed by theinvestigator that consent was given, but not in a written form.


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STUDYNo.: 9153PROTOCOLNo.: MPCE91L1802/6D of 187

6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

A list of all persons involved in the performance, administration, evaluation, and documentationof the study is provided in Appendix 16.1.4. A signature of the principal investigator isincluded in Appendix 16.1.5.

6.1 TRIAL CENTERS

The study was performed in two different study sites:

Center 1: Instituto National de PediatriaInsurgences Sur 3700-C04530 Mexico D.F., MEXICO

Center 2: Hospital Infantil de MexicoDr. Marquez 16203650 Mexico D.F., MEXICO

6.2 TRIAL INVESTIGATORS

The study was performed by two investigators:

6.3

6.4

Center 1: J.G. HUERTA-LOPEZ, M.D.Instituto National de PediatriaInsurgences Sur 3700-C04530 Mexico D.F., MEXICO

Center 2: J.J. SIENRA-MONGE, M.D.Hospital Infantil de MexicoDr. Marquez 16203650 Mexico D.F., MEXICO

SPONSOR

UCB S.A. Pharrna Sector

Al16e de la Recherche, 60

B-107O Brussels, BELGIUM

FINANCIAL RESPONSIBILITY

Johan DE CLERCQ, M.D.

UCB S.A. Pharma Sector

Allee de la Recherche, 60

B-1 070 Brussels, BELGIUM

REPORTNo.: MRCE98G0201/1V Study Report December1, 1998

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STUDYNo.: 9153PROTOCOLNo.: MPCE91L]802/6D of 187

6.5 MEDICAL RESPONSIBILITY

Patrick COULIE, M.D.


Allee de la Recherche, 60

B-1 070 Brussels, BELGIUM

6.6 MONITORING

Monitoring was supervised by I. Deckers, a monitor of the sponsor, who verified and reviewedthe progress of the study according to the SOPS of the sponsor. The monitoring at theinvestigator’s sites was performed by C. Torres of Hoechst-Mexico Quimica S.A. and P. Santaof Glaxo De Mexico S .A.

6.7

6.8

CLINICAL TRIAL SUPPLY MANAGEMENT

Under supervision of Luc UYLENBROECK, Pharrn.


Chemin du Foriest

B-1420 Braine l’Alleud, BELGIUM

DATA ENTRY AND ANALYSIS

Under supervision of Marie-Paule Derde

D. I.CE. N.V.

Eugene Toussainstraat, 56

B-109O Brussels, BELGIUM

Supervised by Bernard BURTIN, Ph. D.


Chemin du Foriest


REPORTNo.: MRCE98G0201/lV StudyReport December1, 1998

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7. INTRODUCTION

Cetirizine has been fully investigated in adults in seasonal and perennial rhinitis. It is clearlysuperior to placebo in relieving most of the symptoms of the diseases: sneezing, runny nose,nasal itching, watering or redness of the eyes (Berman et al [1988], Broide et al [1988], Fallierset al [1991 ], Van Cauwenberghe et al [1989]).

When compared to terfenadine some advantages could be shown, especially in perennialrhinitis, as far as the investigator’s or the patient’s preferences are concerned (Sabbah et al[1988]). Preference of the patient was also in favor of cetirizine compared to astemizole inseasonal allergic rhinitis (Rijntjes et al [1990]) while some slight advantage of cetirizine overastemizole could be shown in perennial rhinitis (Lobaton et al [1990]). Cetirizine andloratadine were equally effective in seasonal rhinitis (Herman et al,[l 990]).

Cetirizine is generally well tolerated in adults, with a low incidence of side effects, notable atthe CNS level (Seidel et al [1988], Volkerts et al [1990]).

In children, at the dose of 5 to 10 mg per day (depending upon the age), cetirizine is moreeffective than a placebo in relieving most of the symptoms of perennial or seasonal rhinitis, andgenerally well-tolerated (UCB internal reports). No comparative data are available up to now.

At skin level, in adults cetirizine is a potent (Rihoux and Dupont [1987]) and quickly active(Coulieetal[1990]) H]-blocker. This has been confirmed in children, after histamine-inducedwheals and flares which were inhibited as from 0.5 h to 24 h after 5 or 10 mg intake of cetirizine(children between 5 and 12 years of age). No evidence of subsensitivity over 5 weeks treatmentcould be shown (Watson et al [1989]).

8. STUDY OBJECTIVES

The aims of this study are:. To assess the possible difference of effects of cetirizine and loratadine in the treatment

of perennial allergic rhinitis in children from 6 to 12 years old, and additionally, on theresults of nasal brushing and rhinomanometry

. To study the effects of both drugs at skin level on the potency of the inhibition ofhistamine-induced wheals

. To assess the safety of both drugs.

REPORTNo.: MRCE98G0201/lV Study Report December 1, 1998

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9. INVESTIGATIONAL PLAN

9.1 OVERALL STUDY DESIGN

The protocol and sample CRF can be found in Appendices 16.1.1. and 16.1.2.

The trial described in this report has a randomized, double-blind, parallel group design. Two

groups of patients are compared, a first group receiving cetirizine od during 28 days and asecond group receiving Ioratadine od during the same period. Subjects were to receive 0.2mglkgfday.

The study took place in two centers. Forty patients were to be enrolled in each center, 20patients per treatment group. The treatments were allocated to the subjects by means of tworandomization lists prepared by blocks of size 4, one list for each center. The randomizationlists are provided in Appendix 16.1.7.

The study foresaw a recruitment visit (day O) and a final visit (day 28). A diary card was to befilled in each day by the legal representative.

The study was expected to start in October 1992 and finish in June 1993. This time schedulewas consistent with the foreseen expiry date of the drug supply, the expected duration oftreatment and the declared potential rate of entry of eligible subjects by the investigators.

9.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OFCONTROL GROUPS

The study is a controlled parallel trial, using loratadine as active comparator. This is consistentwith the objectives of the trial, e.g. to compare the effects of cetirizine and loratadine in thetreatment of perennial allergic rhinitis in children. The design of the trial: parallel, randomized,and double blind, is the most optimal design in order to study the trial objectives.

9.3 SELECTION OF STUDY POPULATION

9.3.1 Inclusion Criteria

To be included in the study were children of either gender, between 6 and 12 years of age, forwhom informed consent was given by the legal representative, and if possible by the patient,with well-documented perennial allergic rhinitis (anamnesis and available positive skin test orRAST for grass pollen or house-dust mite), with the presence of at least 3 of the 5 symptoms:sneezing, rhinorrhea, nasal obstruction, pruritus, eye pruritus, at the moment of the first visit orduring the previous 24 hours, and for whom the total symptom score was at least 8 at inclusion.This total score was to be calculated by giving each of the 5 symptoms a score of

. 0 = absent

. 1 = slight (not disturbing)2 = moderate (disturbing but without impairing sleep)

. 3 = severe (impairs daytime activities and sleep).

REPORTNo.: MRCE98G0201/l V Study Report December 1, 1998

..-..,, ,., ... ... - .....


9.3.2 Exclusion Criteria

Exclusion criteria were:

●

●

●

●

●

●

●

Any subject suffering from diabetes, asthma in case the treatment is able to interferewith the nasal condition, atopic dermatitis, renal or hepatic insufficiency, cardiacdysfunction or general infection necessitating antibiotherapy

Known allergy to cetirizine or other piperazines, loratadine or any constituent of thedrug supplies

Obstructive nasal polyposis

Active skin disease at the level of the forearms

Vasomotor, viral or bacterial rhinitis

Upper airway infection (including sinusitis and medium otitis) during the last 3 weeks

Use of, before starting treatment,

A. ketotifen: 2 weeks

B. astemizole: 6 weeks

C. other antihistaminics: 4 days

D. systemic corticosteroids: 2 months

E. topical corticosteroids: 2 weeks

F. topical cromoglycate: one week

G. any other treatment: 2 weeks

H. current desensitization

I. nasal decongestants: 2 days.


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9.3.3 Removal of Patients from Therapy or Assessment

Patients were to be removed from the study in the following situations:

. The patient left the study for any reason not related to the administered drug

. In case of intake of non-authorized concomitant medication

. If the treatment was interrupted:

A. For more than 2 consecutive days

B. During one of the 2 days preceding a visit

C. For more than a total of 3 days

. The appointment for visit 2 was missed by more than 3 days

. The patient did not comply with the foreseen intake of treatment

● The patient interrupted treatment on account of side effects or inefficacy (total therapyfailure).

9.4 TREATMENTS

9.4.1 Treatment Administered

Patients were to receive a single oral daily dose of 0.2 mg/kg of cetirizine or loratadine solutionfor the entire study period.

9.4.2 Identity of Investigational Product(s)

Cetirizine and loratadine were packed at 1 mg/ml in 150 ml bottles. Each subject was to beassigned a box containing two sealed bottles of the liquid form. The legal representative was tobe informed that there could be an excess of liquid form in the bottles.

The following batch number were used:

Cetirizine : batch 71 (expiration date: July 1995)

UCB S.A. Pharrna Sector

Chemin du Foriest


Loratadine: batch 89 (expiration date: July 1995)

Schering Plough


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The investigators were responsible for the storage of the drug packages at the research sites. Nospecial instructions were given.

9.4.3 Method of Assigning Patients to Treatment Groups

The treatments were allocated to patients by means of two randomization lists, one for eachcenter, each prepared using randomization in blocks. All information relevant torandomization is provided in Appendix 16.1.7.

9.4.4 Selection of Doses in the Study

0.2 mg/kg once daily by oral administration was given to each subject.

9.4.5 Selection and Timing of Dose for Each Patient

The treatment, a fixed dose regimen of 0.2 mg/kg cetirizine or loratadine, was randomlyassigned to the patients. The protocol did not provide a specification for the timing of theintake of study medication nor of the relation of the intake of study medication to themeals. No other specific instructions were mentioned in the protocol concerning the intakeof study medication.

9.4.6 Blinding

The two investigational products were indistinguishable (identical appearance, shape,smell, and taste).

Each drug package was identified by a unique code number divided into two parts: A letteridentified the center and a group of digits corresponded to the order of enrollment into thetrial in the center.

The identity of the treatment was contained in sealed envelopes, one for each package, andcarrying the same label as the medication. These envelopes were only to be opened in caseof a medical emergency which justified unbinding. All the envelopes were to be returnedto UCB at the end of the trial. In case one or more envelopes were opened by theinvestigator, the date and justification were to be noted on these envelopes.

Only the numeric part of the center identification was copied onto the CRF. Therefore, theidentification of the center could not be deduced from the patient number. In order tomake it possible to perform the statistical analysis the center from which each CRF was

REPORTNo.: MRCE98G0201/1V Study Report December 1, 1998

. . .. - ...,,,..,,-


obtained was provided by the study monitor, and a variable ‘center’ was added to thedatabase. This variable takes the value 12 for the center of Dr. Sienra-Monge.

9.4.7 Prior and Concomitant Therapy

for the center of Dr. Huerta-Lopez and the value

Use of concomitant medication was not allowed.

9.4.8 Treatment Compliance

At the end of the test period the bottle and remaining samples were to be returned.contents was to be measured and recorded for the determination of the treatmentcompliance.

The


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9.5 EFFICACY AND SAFETY VARIABLES

9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart

During the inclusion visit (day O) inclusion and exclusion criteria were to be checked,demographic data obtained (initials, age, gender, weight, and height), and the anarnnesisrecorded (familial antecedents, anarnnesis specific for rhinitis: time of diagnosis, previoustreatments and results of prick and RAST tests). Before inclusion the informed consentwas to be obtained.

The following efficacy and safety assessments were to be made at each visit:

Assessments by the investigator ofl

. SneezingRhinorrheaNasal obstructionNasal pruritusOcular pruritus

each scored as:O= absent1 = slight (not disturbing)2 = moderate (disturbing but without impairing sleep)3 = severe (impairs daytime activities and sleep)

and of the global status of the nasal condition using a Visual Analog Scalegraded from O= best to 100 = worst.

● A brushing of the nasal secretions for white blood cell count (in particular eosinophils)in absolute number and percentage.

. Anterior rhinomanometry.

. An epicutaneous test with histamine phosphate (1.0 mg/ml) at the level of the forearm.Induced wheals were outlined 10 minutes afterwards, reported onto a transparency andmeasured centrally using a computerized digitizing system.

. Laboratory tests: Red blood cell count, hematocrit, hemoglobin, white blood cell count(and percentage neutrophils, eosinophils, basophils, monocytes, and lymphocytes),platelets, urea, creatinine, and ALA-transferases.

. Adverse events based upon the impression of the investigator as well as the answer to

the question: ‘Do you or did you experience any unusual sensation ?.Adverse events were to be reported in the CRF, regardless of whether the event wasconsidered by the investigator or the investigator’s staff to be related to theexperimental treatment or not. Type, severity and duration of adverse events were tobe recorded, as well as the need for withdrawal of treatment and the evolution aflerwithdrawal.


., . -. r -.+.. s


Serious adverse events were to be immediately reported to UCB. Subsequently themonitor and/or promoter were to inform the UCB regulatory department for follow-up.The following situations are considered as serious adverse events:

A.

B.

c.D.

E.

Death of the subject

Hospitalization, or prolongation of hospitalization

Any event involving persistence of a significant disability or incapacity

Cancer

Any life threatening condition which did not result in death or in hospitalization orprolongation of hospitalization (a ‘life threatening condition’ does not include acondition which could threaten life if it became more severe).

Each overdosage (defined as an intake exceeding the maximal dose allowed by thisprotocol) and each event reported by the investigator to the local authorities was tofollow the same information procedure as the serious adverse events.

The test medication was accompanied by sealed envelopes, identified by thecorresponding treatment number. In case of emergency, opening of the correspondingenvelope reveals the treatment administered.

Furthermore, a diary card was to be filled in every day by the patient’s legal representative,with assessments of sneezing, rhinorrhea, nasal obstruction, nasal pruritus, and ocularpruritus, making use of the same four point ordinal scale as the investigator.

9.5.2 Appropriateness of Measurements

The assessment of the clinical symptoms of rhinitis on a four-point ordinal scale and theassessment of the global status of the nasal condition using a VAS scale are standardapproaches to measure therapeutic responsiveness in allergic rhinitis. Anteriorrhinomanometry is an acceptable direct and quantitative method to assess nasalobstruction.

The protocol did not describe how to report the results of the evaluation of the nasalsecretion. In consequence the results were not reported in a uniform way, even not withineach center.

The wheals and flares induced by a prick test with histamine is an indirect method toevaluate the effect of the treatments. The repeatability and reproducibility of the techniquewere evaluated in the frame of this study. These results are summarized in Section16.1.10.


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9.5.3 Primary Eftlcacy Variable(s)

The protocol does not foresee a primary efficacy variable, since it was designed as a pilotstudy.

9.5.4 Drug Concentration Measurements

No drug concentration measurements were performed.

9.6 DATA QUALITY ASSURANCE

CRFS and other study material were collected at the investigators’ sites by authorized personson the sponsor’s behalf.

Data entry and data management were performed by D. I.C.E. N.V. (E. Toussaint Street, 56,.B-1 090 Brussels, BELGIUM) under the responsibility of M.-P. Derde, Ph. D., according to aplan for data entry and data management dated 18 June 1996 and approved by the sponsor on 19June 1996. This document describes the procedures for creation and verification of the database, for data entry, and for data management. A verification of the final data base wasperformed by D. I.C.E. N.V. by comparing an outprint of the data base with the CRF, DRC,wheal and flare surface areas, and DCCF data. This verification was performed for all CRFS forthe assessments of the nasal symptoms by the investigator and for the VAS assessments, asrecorded at each of the visits. Furthermore, all data of 5 patients (CRF, DRC, wheal and flaresurface areas) were verified. No errors were found. A further quality control of the data basewas performed by the sponsor and described in the internal UCB report dated 23 July 1997(Appendix 16.1. 10).

The statistical analysis was performed by D. I.C.E. N.V. under the responsibility of M.-P. Derde,according to a statistical analysis plan dated 18 August 1997, approved by the sponsor. Aquality control was performed by D. I.C.E. N.V. (by a different statistician than the one incharge), of all programs developed for the statistical analysis, by checking of the programs andverification of some of the frequencies making use of the listed output of the data base.


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9.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL ANDDETERMINATION OF SAMPLE SIZE

9.7.1 Statistical and Analytical Plans

The statistical analysis is performed according to the statistical analysis plan dated 18 August1997. This plan is incorporated in Section 9.8. The original plan is given in Appendix 16.1.9.

9.7.1.1 Variables

Evaluation of Efficacy

●

●

●

●

●

●

Visual Analog ScaleThe two treatments were to be compared on the basis of the change in VAS assessmentbetween visits. In order to make use of the data of the patients discontinuing the studybecause of intolerance or inefficacy and who have no evaluation under treatment, thebaseline was to serve as last available observation. Patients discontinuing the study forother reasons were not to be considered.

Symptom scoresFor each of the 5 symptoms the change between visits was to be used to evaluate theeffect of treatment.

BrushingThe change between visits of the absolute eosinophil count and the percentage ofeosinophils.

RhinomanometryThe change between visits of the nasal resistance.

SkinThe change between visits of the wheal surface area.

Diary CardsFor each subject and each day the highest score recorded on the diary card was to beconsidered. The evaluation of the diary cards was to be based upon the followingvariables:

A. PDSO: Percentage of days with a symptom score of O

B. PDS 1: Percentage of days with a symptom score of <1

C. PDS2: Percentage of days with a symptom score of <2.

REPORT NO.: MRCE98G0201/1 V Study Report December 1, 1998

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Evaluation of Safety

. Blood SamplesThe evaluation of the laboratory recordings was to be based upon their status withrespect to standard values.

. Adverse eventsThe comparison was to be based upon the frequency of patients for whom adverseevents were reported.

9.7.1.2 Statistical Methodology

Comparison at Onset of the Study

The comparability of the two groups was to be evaluated on the basis of the observationsrecorded at onset of the study. For the continuous variables the nonparametric Wilcoxonrank tests was to be used, and for discrete variables the chi-square test.

Evaluation of Efficacy

The two groups were to be compared on the basis of the change between visits ofi

●

●

●

●

●

●

VASAnalyzed using nonparametric tests.

Symptom scoresEach of the 5 symptoms was to be analyzed separately using the Cochran-Mantel-Haenszel test, stratified by the baseline score. Moreover, the highest score recordedwas to be analyzed using the same test.

BrushingThe difference between the percentage of eosinophils recorded at visits 1 and 2 was tobe analyzed using the Wilcoxon rank test.

RhinomanometryThe difference between the nasal resistance recorded at visits 1 and 2 was to beanalyzed using the Wilcoxon rank test.

SkinThe difference between the wheal surface area recorded at visits 1 and 2 was to beanalyzed using the Wilcoxon rank test.

Diary CardsThe distribution of the data was to be analyzed using the Wilcoxon rank test.


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Evaluation of Safety

The number of patients reporting adverse events was to be compared in the two groups bymeans of the chi-square test. In case the number of patients reporting adverse events is toosmall (expected cell frequencies less than 5) the comparisons was to be performed usingthe Fisher Exact test.

9.7.2 Determination of Sample Size

The sample size determination was based upon the change of the VAS assessment of theglobal status of the nasal condition by the investigator. It was assumed that this changefollows a normal distribution with a standard deviation of 20 mm. With 40 evaluablepatients in each of the two treatment groups the probability of showing a difference inmean change of VAS assessment of 15 mm is 92°/0, when performing the test at the 5°/0level of significance. Furthermore, it can be assumed that 10% of the patients will drop-out before the end of the study. It was then estimated that the power would be close to80%.

9.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED

ANALYSES

9.8.1 Conduct of the Study

The legal representative of the subject, and when possible the subject hidherself, gave @eirconsent by signing the Informed Consent Form. This was to be kept by the investigator, while acopy could be attached to the CRF after the identity of the subject was removed by the monitoror the investigator. However, for most patients the original informed consent form was sent toUCB.

An epicutaneous test with histamine phosphate was to be performed at the level of theforearm and the induced wheals were to be outlined 10 minutes afterwards. In center 2 theflares were also recorded.

9.8.2 Statistical Methodology

The statistical analysis plan as foreseen by the protocol was not very detailed and did notalways select the most powerful test for a particular type of variable. Therefore, beforedisclosure of the randomization code, the following analysis plan was developed inagreement with the sponsor.


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9.8.2.1 Hypotheses Tested

The objective of this study is to compare the effects of cetirizine and loratadine in thetreatment of perennial allergic rhinitis in children between 6 and 12 years of age, basedupon:

. Clinical symptoms of the disease (sneezing, rhinorrhea, nasal obstruction, nasalpruritus, ocular pruritus)

. Results of nasal brushing and rhinomanometry

. Inhibition of histamine induced wheals

● Safety.

The statistical tests will be performed two-tailed at the 5% level of significance.

The protocol does not foresee a primary efficacy variable, nor an adjustment for multipletesting.

9.8.2.2 General Considerations

Throughout this document the following terminology is used for indicating the type of .descriptive analysis to be performed:

● ‘Descriptive statistics’ is used to indicate the description to be provided for continuousvariables, and includes the mean, median, standard deviation, 25% percentile (Q I ),75% percentile (Q3), minimum, maximum, number of available observations, andnumber of missing observations.

● ‘Frequency distributions’ is used to indicate the description to be provided for ordinaland nominal variables and includes frequencies and percentages for each of the scoresor categories, and the number of missing observations.

Whenever two-way analysis of variance is applied, the two factors as well as theirinteraction will be incorporated in the statistical model.


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9.8.2.3 Variables Considered in the Analysis

Patient and Disease Characteristics

. Age (in years)= [Datevl (page 5 of CRF) - Date of Birth] / 365.25

● Weight

. Height

. Gender

. Occurrence of familial antecedents (y/n); type of antecedents (ICD- 10 code)

. Previous treatment for rhinitis (y/n); type of previous treatments (WHO-drug)

. Positive prick test (y/n); type of agonist (UCB translation)

. Positive RAST test (y/n); type of agonist (UCB translation)

. Medical history (y/n); type of antecedents (ICD-1 Ocode)

. Surgery (y/n); type of surgery (ICD-1 Ocode).

Will not be described:

Duration of the disease: It is not always evident whether the investigator mentioned theage of onset or the duration of the disease. Therefore, this variable will not be consideredin the analysis.

Study Characteristics

. Number of patients per center

● Rhythm of enrollment

. Period between the two visits

. Study termination (normal/prematurely) and reason for premature discontinuation

● The height of the solution remaining in the bottle (for this variable a histogram will begiven to document the entire distribution)

The following will not be described:

Compliance: The amount of study medication returned is recorded as the height of thesolution remaining in the bottle. However, since no information is available on the shapeof the bottle, this height cannot be transformed into a volume, and thus the amount of studymedication taken cannot be determined.


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Efficacy Variables

CRF Data

●

●

●

●

●

●

●

●

●

●

Sneezing (four point ordinal scale ranging from O = absent to 3 = severe)

Rhinorrhea (four point ordinal scale ranging from O= absent to 3 = severe)

Nasal obstruction (four point ordinal scale ranging from O= absent to3 = severe)

Nasal pruritus (four point ordinal scale ranging from O= absent to 3 = severe)

Ocular pruritus (four point ordinal scale ranging from O= absent to 3 = severe)

Maximal symptom score = maximum of the scores of sneezing, rhinorrhea, nasalobstruction, nasal pruritus, and ocular pruritus

VAS (in mm) of the global status of the nasal condition

Rhinomanometry (l/rein)

Wheal surface area (in mm2, average of 4 measurements)

Flare surface area ((in mm2, average of 4 measurements).patients from center 2 will be considered since in center 1two patients at the baseline visit.


Only the results of theflares were My recorded for

Nasal brushing: The results of the evaluation of the nasal brushing were not reported in auniform way, even not within each center:

- In center 1 results were sometimes provided on a four point ordinal scalenegative, +, ++, +++) and sometimes as a percentage of eosinophils.

- In center 2 results were sometimes provided as a number of eosinophilsper 10 HPF and sometimes as a percentage of eosinophils.

Therefore, this variable will not be considered in the analysis.

Daily Record Cards

For each of the five symptoms separately:

. Daily symptom score

For all symptoms together:

. Percentage of days without symptoms (PDSO)

● Percentage of days with at worst mild symptoms (PDS 1)

. Percentage of days with an at worst moderate intensity of the symptoms (PDS2)

● Mean daily total symptom score.


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Daily measurements of nasal flow: These measurements were only recorded for thepatients in center 2. Mostly, but not always, two measurements were provided, withoutindication to which moment of the day these measurements applied (it was assumed thatthey concerned a morning and an evening measurement). Since these measurements werenot foreseen by the protocol, and since no information is available on the units they areexpressed in andthe analysis.

Safety Variables

how and when they were recorded, these data will not be considered in

Adverse events reported after onset of treatment:

● Frequency of patients for whom adverse events were reported

. Documentation of the reported adverse events.

Laboratory data, for each test:

. Frequency of patients with results below, within or above the reference range

. Frequency of patients with potentially clinically significant abnormalities (PCSA), oncondition that limits for the determination of PCSA are provided by UCB.

9.8.2.4 Patient Population

The statistical evaluation will be performed on the basis of the ITT population which willconsist of all patients randomized in the study for whom follow-up information isavailable.

REPORT No.: MRCE98G0201/I V Study Report December 1, 1998

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9.8.2.5 Sample Description

Sample Size

Number of patients:. Total. Broken down by treatment group● Broken down by center. Broken down by center and treatment group

List of patients with protocolprotocol violation, reason).

Rhvthm of Enrolment

violations (patient number, center, age, sex, time in study,

. Dates of first and last enrolment (page 3 of CRF)

. Cumulative number of patients enrolled for the study per month, total and broken downby center.

Study Termination

. Frequency of patients with premature study termination

. List of patients who terminated prematurely (patient number, center, age, sex, time instudy, reason for early study termination).


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9.8.2.6 Description and Comparison At Baseline

The descriptive analysis will be performed for the following groups of patients:

. Total ITT population

. ITT population broken down by treatment● ITT population broken down by center and treatment (for a selected group of

variables).

Descriptive Analysis

I. Frequency distribution forA.B.c.D.E.F.G.H.I.J.K.L.M.N.

SexOccurrence of familial antecedents (y/n)Type of antecedents 1Previous treatment for rhinitis (y/n)Type of previous treatments ]Positive prick test (y/n)Type of agonist causing a positive prick test 1Positive RAST test (y/n)Type of agonist causing a positive RAST test [Medical history (y/n)Type of medical antecedents 1Surgexy (y/n)Type of surgery ‘Each of the 5 symptoms and the maximal symptom score.

II. Descriptive statistics forA. Age, weight, heightB. VAS of the global status of the nasal conditionC. RhinomanometryD. Wheal and flare surface area.

1 Descriptive analysis not broken down by center


..—.


Statistical Testing

Comparison of the two treatment groups using:

I. Cochran-Mantel-Haenszel test (controlled for center), if applicable, forA.B.c.D.E.F.G.H.

SexOccurrence of familial antecedents (y/n)Previous treatment for rhinitis (y/n)Positive prick test (y/n)Positive RAST test (y/n)Medical history (y/n)Surgery (y/n)Each of the 5 symptoms and the maximal symptom score.

II. Two-way analysis of variance (center, treatment) forA. Age, weight, height.B. VAS of the global status of the nasal conditionC. RhinomanometryD. Wheal and flare surface area.

Changes with respect to the protocol: The protocol foresaw to perform the analysis by meansof the chi-square test for the discrete variables and the Mann-Whitney test ,for the continuousvariables. Deviations from the protocol are proposed in order to control the analysis for thecenter effect. For the continuous variables this implies the use of a parametric instead of a ~nonpararnetric technique. This change is justifiable since the sample size is large enough forparametric techniques to be applicable.

9.8.2.7 Course of the Study

The descriptive analysis of time in study is performed for the following groups of patients:

. Total ITT population● ITT population broken down by treatment● ITT population broken down by center.


Descriptive statistics for period between visits.

Statistical Testing

None.


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9.8.2.8 Evaluation of Efficacy

The descriptive analysis will be performed for the following groups of patients:

. ITT population broken down by treatment

. ITT population broken down by center and treatment.

The descriptive statistics willavailable observation (LOCFobservation.

CRF Data

be provided for the measurements at VI, at V2, for the lastapproach), and for the change between V 1 and the last available


I. Descriptive statistics for:A. VAS of the global status of the nasal conditionB. RhinomanometryC. Wheal surface areaD. Flare surface area.

II. Frequency distribution for each of the 5 symptoms

Statistical Testing

and of the maximtil symptom score.

Two-way analysis of variance on the change between VI and the last available observation,controlled for center and treatment, for:

. VAS of the global status of the nasal condition

. Rhinomanometry

. Wheal surface area● Flare surface area.

Cochran-Mantel-Haenszel test for the last available observation, controlled for the baselinescore, for each of the 5 symptoms.

Changes with respect to the protocol: The protocol foresaw to perform the analysis of thecontinuous variables by means of the Mann-Whitney test. A deviation from the protocol isproposed in order to control the analysis for the center effect. This implies the use of aparametric instead of a nonparametric technique. This change is justifiable since the samplesize is large enough for a parametric technique to be applicable.


,, .“ ., ,, ,+< ., . . . .


Daily Record Cards


Descriptive statistics:

I. For each of the five symptoms separately:A. Daily symptom score

II. For all symptoms together:A. Percentage of days without symptomsB. Percentage of days with at worst mild symptomsC. Percentage of days with at worst moderate symptoms.

Statistical TestingTwo-way analysis of variance, controlled for center and treatment, for:. Percentage of days without symptoms. Percentage of days with at worst mild symptoms. Percentage of days with at worst moderate symptoms.

Changes with respect to the protocol: The protocol foresaw to perform the analysis by meansof the Mann-Whitney test. A deviation from the protocol is proposed in order to control theanalysis for the center effect. For this purpose a parametric approach is to<be taken instead of anonparametric one. This change is justifiable since the sample size is large enough for aparametric technique to be applicable.


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9.8.2.9 Evaluation of Safety

The descriptive analysis is performed for the following groups of patients:

. ITT population broken down by treatment

. ITT population broken down by center and treatment (only for the laboratory data).

Adverse Events

Descriptive AnalysisI. List of all adverse eventsII. Frequency distribution of patients with adverse eventsIII. Frequency distribution of patients with adverse events

A. by system organ classB. by system organ class and WHO prefemed term.

Statistical Testing

None (in view of the small number of patients expected to suffer from adverse events).

Laboratory Tests

It is assumed that limits for PCSA (Potentially Clinically Significant Abnormalities) will beprovided.

Descriptive AnalysisI.

II.

III.

Frequency distribution of the number of patients for whom laboratory tests areperformed at each of the visits.For each test and each visit:A. Frequency distribution of the status (below, within, above the normal range)B. Frequency distribution of PCSAC. List of patients with PCSA, mentioning center, normal range, range for PCSA.For Visit 2:A. Frequency distribution of the shift in status.

Statistical Testing

None.


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10. STUDY PATIENTS

10.1 DISPOSITION OF PATIENTS

CRFS are available for 78 patients, 38 patients from center 1 (Huerta-Lopez) and 40 patientsfrom center 2 (Sienra-Monge). In both centers patients were attributed a treatment numberbetween 1 and 40. In center 1 treatment numbers 30 and 35 were not used. No reason wasprovided for this deviation.

In center 1 the patients frequently did not receive a treatment number in the order of enrollment.In center 2 patients were attributed a treatment number in the order of enrollment, except forpatients 30 and31 (yatient31 was enrolled 2 days before patient 30).

The CRF did not have a section on study termination. The information concerning studydiscontinuation was therefore to be obtained from comments made by the investigator in theCRF. Study discontinuation was noted for 3 patients (see Table 10.1-l). -

TABLE 10.1-1: STUDY DISCONTINUATIONAll randomized Patients

Patient Treatment Specification1/03” Loratadine The patient abandoned the study for family reasons. The only

available follow-up information was provided on the AE form onwhich only the box ‘Did you have any AE since the last visit’ wasticked ‘No’. The AE form was however not signed by theinvestigator.

1/06 Cetirizine The patient discontinued the study for family reasons. At visit 2data were only available on the DRC, on the AE form, andconcerning the assessment of the nasal symptoms.

1/25’ Loratadine The patient did not attend the second visit. No reason wasprovided. There is no follow-up information available.

*Excluded from the intention to treat population since no follow-up information is available.


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STUDY No.: 9153PROTOCOL No.: MPCE9 IL 1802/6D of 187

According to the analysis plan the evaluation of the study was only to be performed on the basisof the ITT population. This population consists of all patients randomized in the study forwhom follow-up information is available. Therefore, patients 1/03 and 1/25 are excluded fromthis population:

- Patient 1/03: The only available follow-up information is provided on theAE form on which the box ‘Did you have any AE since the lastvisit’ was ticked ‘No’, but the AE form was not signed by theinvestigator. It is therefore considered that no reliable follow-up information is available.

- Patient 1/25: No follow-up information is available.

The ITT population thus consists of 76 patients. Table 10.1-2 describes the frequencies ofpatients in the intention to treat population broken down by treatment and by center. Thepatients were enrolled between 3 November 1993 and 8 April 1995. The rhythm of enrolmentis described in Table 10.1-3.

Besides for patients 1/03 and 1/25, missing data were observed for 19 patients (see Table 10.1-4).

TABLE 10.1-2: SAMPLE SIZEIntention to Treat Population

Center 1 Center 2 All Patients(N= 36) (N= 40) (N= 76)

Loratadine group 17 (47.2%) 20 (50. O’YO) 37 (48.7Yo)Cetirizine group 19 (52.8%) 20 (50.0?40) 39 (51.3%)

All patients 36 40 76


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TABLE 10.1-3: RHYTHM OF ENROLMENTIntention to Treat Population

Center I Center 2 All Patients(N= 36) (N= 40) (N= 76)

First enrolment 3 November 1993 9 November 3 November 19931993

Last enrolment 8 April 1995 23 February 1994 8 April 1995

Cumulative number of patients per monthNovember 1993 3 ( 8.3%)December 1993 3 ( 8.3%)January 1994 4(11.1%)February 1994 5 (13.9YO)March 1994 6 (16.7%)April 1994 9 (25.0%)May 1994 16 (44.4%)June 1994 19 (52.8Yo)July 1994 21 (58.3%)August 1994 22 (61.1%)September 1994 23 (63.9%)October 1994 28 (77.8’?40)November 1994 31 (86.1’XO)December 1994 31 (86.1%)January 1995 31 (86.lYO)Februari 1995 31 (86.lYO)March 1995 31 (86.1%)April 1995 36( loo~o)

5 (12.5’Yo)12 (30!OYO)26 (65.0%)40( 100%)40( 100%)40( 100’YO)40( 100%)40( 100%)40( 100%)40( 100%)40( 100’%0)40( 100%)40( 100%)40( 100%)40( 100%)40( 100%)40( 100%)40( 100%)

8 (10.5Yo)15 (19.7%)30 (39.5?ZO)45 (59.2?40)46 (60.5%)49 (64.5%)56 (73 .7Yo)59 (77.6%)61 (80.37.)62(8 1.6%)63 (82.9Yo)68 (89.5%)71 (93.4%)71 (93.4VO)71 (93.4’YO)71 (93.4%)71 (93.4%)76( 100%)


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TABLE 10.1-4: MISSING DATAIntention to Treat Population

Patient (1) (2) (3) (4) (5) (6) (7) (8)

1/061/151/161/171/181/241/291/311/321/331/341/351/361/371/381/391/402/022/40

x

x

x

x

x

x x

x

x

x

x

x

x

x

x

xx

x

x

x x

x x x

x x xx

x x x

xx

xxxx

xxxx

xx

x

(1) = Height(2) = Date visit 2(3) = Assessment of all nasal symptoms by the investigator and of the VAS at visit 2(4) = Assessment of nasal secretions and rhinomanometry at visit 2(5) = Prick test at visit 1 not performed or results not available(6) = Prick test at visit 2 not performed or results not available(7) = Laboratory data at visit 2(8) = DRC


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10.2 PROTOCOL DEVIATIONS

Violation of inclusion and exclusion criteria was evaluated on the basis ofi. The checklist of inclusion and exclusion criteria filled in by the investigator. The age of the patient (6 to 12 years: this was interpretedas>=6and<13). The results of the prick and RAST tests. The documentation of concomitant diseases.

Violation of inclusion or exclusion criteria was observed for 6 patients, 3 patients in eachtreatment group (see Table 10. 1-5).

Furthermore, patient 1/24 gave consent (as was confirmed by the investigator), but not in awritten form.

Violation of study criteria after onset of treatment, that could be checked on the basis of theCRF data, only concern the period between the two visits (was to be 28+/-3 days). Suchviolations were observed for 9 patients, 5 patients in the loratadine group and 4 patients in thecetirizine group (see Table 10.1-5).


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TABLE 10.1-5: VIOLATION OF STUDY CRITERIAAll randomized Patients

Violation of inclusion and exclusion criteria

Patient Treatment Violation

1/07 Cetirizine 5.4 years of age1/15 Loratadine Prohibited concomitant illness (hypoglycemic syndrome)1/32 Loratadine 14.5 years of age2/08 Cetirizine 5.9 years of age2/18 Cetirizine 13.5 years of age2/40 Loratadine 4.4 years of age

Violation of study criteria after onset of treatment

Patient Treatment Violation

1/06 Cetirizine Period between visits =59 days (This patient discontinued thestudy for family reasons. At visit 2 data were only available onthe DRC, on the AE form, and concerning assessment of thenasal symptoms).

1/08 Loratadine Period between visits= 32 days1/17 Cetirizine Period between visits= 33 days

2/0 1 Loratadine Period between visits= 35 days2/05 Cetirizine Period between visits= 56 days (The assessments of nasal

symptoms, nasal brushings, and rhinomanometry wereperformed on 16 December 1993, e.g. 30 days after visit 1).

2/1 1 Loratadine Period between visits= 36 days2/1 7 Loratadine Period between visits= 35 days2/18 Cetirizine Period between visits =35 days2/3 1 Loratadine Period between visits= 33 days


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STUDY No.: 9153PROTOCOL No.: MPCE91 L1802/6D of187

11. EFFICACY EVALUATION

11.1 DATA SETS ANALYZED

The evaluation of efficacy is performed on the basis of the intention to treat population. Thispopulation consists of all patients randomized in the study, for whom follow-up information isavailable. This population consists of 76 patients. Table 10.1-2 provides the frequencies ofpatients in the intention to treat population broken down by treatment and by center.

11.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS

Descriptive statistics of the variables recorded at baseline, for all patients enrolled, broken downby treatment group, are presented in tables 11.2.1. These statistics were also broken down bycenter and treatment and are given in Tables 14.1-1 to 14.1-13. The tables also give the resultsof the comparison of the two treatment groups on the basis of these variab)es.

The patients enrolled in the study, 43 male (57%) and 33 female (43%), were on average 9.1years of age (st. dev. 2.1 years and ranging from 4 to 14 years). Forty-six of the patients (61~0)had familial antecedents and 58 patients (76’Yo)had been treated previously for rhinitis. Allpatients had a positive prick test. For 11 patients (14%) it was mentioned that they also had apositive MST test. For 57 patients (75%) medical antecedents were recorded and 17 patients(22’XO)had underwent surgery.

For 52 patients (68%) the maximal symptom score was severe, for 23 patients (30’%0)it wasmoderate, and for one patient (10/0)it was mild. The VAS used as a global assessment of nasalcondition reached an average value of 73.9 mm, while rhinomanometry reached an averagevalue of 89.8 llmin. The prick test resulted in an average wheal surface area of 44.7 mm2 whilethe average flare surface area was 436 mrn2 (flares were only recorded in center 2).

The two treatment groups were compared on the basis of the demographic and diseasecharacteristics recorded at baseline. A significant difference was found between the twotreatment groups for the frequency of former surgery, which was higher in the cetirizine group

(33?40versus 11% of the patients). For the continuous variables the comparison of the twotreatment groups was performed by means of two-way analysis of variance in which the centereffect and the treatment-center interaction are also evaluated. For several variables (totalsymptom score, VAS of nasal condition, rhinomanometry, and wheal surface area) a significantdifference was found between the two centers, with worse overall assessments in center 2.

REPORT No.: MRCE98G020 l/l V Study Report December 1, 1998

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STUDY No.: 9153PROTOCOL No.: MPCE9 lL 1802/6D of 187

TABLE 11.2-1: BASELINE CHARACTERISTICSIntention to Treat Population

Loratadine Cetirizine All Patients(N= 37) (N= 39) (N= 76)

Age (years)Mean 9.5 8.9 9.1

St. dev. 2.1 2.0 2.1Min - Max 4.4- 14.5 5.4- 13.5 4.4- 14.5

GenderFemale 16 (43%) 17 (44%) 33 (43’?40)

Male 21 (57’XO) 22 (56%) 43 (57%)

Familial antecedents 21 (57%) 25 (64Yo) 46 (61VO)

Previous treatment for rhinitis 31 (84%) 27 (69%) 58 (76VO)

Positive prick test 37 (loo%) 39 (100’?40) ( 76(1 ()()’%0)

Positive RAST test 7 (19YO) 4 (1OYO) 11 (15%)

Medical history 25 (68%) 32 (82VO) 57 (75?40)

Surgery 4(1 170) 13 (33’XO) 17 (22YO)

Maximal symptom scoreAbsent o ( 0.0%) o ( 0.0’%0) o ( 0.0%)

Mild 1 ( 2.7%) o ( 0.0%) 1 ( 1.3?40)

Moderate 11 (29.7%) 12 (30.8%) 23 (30.3?40)

Severe 25 (67.6Yo) 27 (69.2%) 52 (68.4%)

Total symptom scoreAll Patients Mean 10.3 10<2 10.3

St. dev. 2.9 2.4 2.6

Center 1 Mean 7.9 8.3

St. dev. 2.0 1.5

Center2 Mean 12.4 12.0

St. dev. 1.8 1.7

REPORT No,: MRCE98G0201/1 V Study Report December 1, 1998

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TABLE 11.2-1- Continued: BASELINE CHARACTERISTICSIntention to Treat Population


VAS of Global Status of Nasal Condition (mm)All Patients Mean 75.4 72.5 73.9

St. dev. 14.6 14.0 14.3

Center 1 Mean 65.9 63.5St. dev. 12.0 11.0


Rhinomanometry (Umin)All Patients Mean 93.4 86.4 89.8

St. dev. 54.7 43.5 49.1”


Center 2 Mean 72.3 67.5 ‘St. dev. 25.6 20.2

Prick Test - Wheal Surface Area (mm*)All Patients Mean 45.3 44.1 44.7

St. dev. 28.8 34.8 31.8




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STUDY No.: 9153PROTOCOL No. : MPCE91 LI 802/6D of 187

11.3 MEASUREMENTS OF TREATMENT COMPLIANCE

The only information concerning medication intake recorded in the CRF is the heightof thestudy medication remaining in the bottle, as recorded at visit 2. It was decided to consider 2.5cm intervals and to calculate the frequencies of patients in each interval, broken down bytreatment group. These frequencies are given in Table 11.3-1.

TABLE 11.3-1: STUDY MEDICATION REMAINING AFTER VISIT 2 (cm)Intention to Treat Population


o- < 2.5 cm 2 ( 6.9%) 7 (25.OYO) 9 (15.8VO)

2 2.5-< 5 cm 10 (34.570) 7 (25.0%) ‘ 17 (29.8Yo)

25- < 7.5 cm 8 (27.6Yo) 9 (32. lYo) 17 (29.8Yo)

2 7.5 -<10 cm 7 (24.1%) 2 ( 7.1%) 9 (15.8%)>10 - <12.5 cm 1 ( 3.4%) 3 (10.7VO) 4 ( 7.0%)>12.5-<15 cm 1 ( 3.4?40) o ( 0.0%) 1 ( 1.8Yo)

Missing 8 11 19


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11.4 EFFICACY RESULTS AND TABULATIONS OF INDIVIDUALPATIENT DATA

11.4.1 Analysis of Efficacy

The evaluation of efficacy is based upon:

●

●

●

●

●

Assessments by the investigator of five clinical symptoms (sneezing, rhinorrhea, nasalobstruction, nasal pruritus, eye pruritus), each scored on a four point ordinal scaleranging from O (absence of symptoms) to 3 (severe symptoms), the maximal symptomscore, and the total symptom score.

The assessment by the investigator of the global status of the nasal condition using aVisual Analogue Scale ranging from Omm (best condition) to 100 mm (worstcondition).

Anterior rhinomanometry .

An epicutaneous test with histamine phosphate (1.0 mgjml) at the level of the forearm.Induced wheals were outlined 10 minutes afterwards, reported onto a transparency andmeasured using a computerized digitizing system.

A diary card, to be filled in every day by the patient’s legal representative, withassessments of sneezing, rhinorrhea, nasal obstruction, nasal pruritus, and eye pruritus,making use of the same four point ordinal scale as the investigator.

Descriptive statistics of the clinical symptoms recorded at each visit and for the last evaluation,broken down by treatment group, and by center and treatment, are given in Tables 14.2-1 to14.2-5. Table 14.2-6 gives these descriptive statistics for the maximal symptom score. Tables14.2-1 to 14.2-6 also contain the results of the comparison of the two treatment groups for thelast evaluation. These comparisons make use of the Cochran-Mantel-Haenszel test (controllingfor the baseline score). Table 14.2-7 gives the frequencies of patients for whom each of thesymptoms as well as the maximal symptom score improves, stays the same, and worsens duringthe study, as well as the results of the Wilcoxon tests performed in each treatment group, foreach symptom, and for the maximal symptom score. Table 14.2-8 gives descriptive statisticsand the results of the two-way analysis of variance for the total symptom score.

A summary of the results for the clinical symptoms is given in Table 11.4.1. For the lastassessment of rhinorrhea during the study, a significant difference was found between the twotreatment groups. Rhinorrhea is more frequent in the loratadine treatment group: 65% of thepatients versus 33% in the cetirizine treatment group.


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TABLE 11.4-1: CLINICAL SYMPTOMSIntention to Treat Population

Loratadine Cetirizine Significance of the(N= 37) (N= 39) Difference

(CMH test controllingfor baseline score)

Sneezing - Last evaluation p=o.319Absent 13 (35.lYO) 15 (38.5Yo)Mild 18 (48.6%) 21 (51.8’Yo)Moderate 6 (16.2%) 2( 5.1’%0)Severe o ( 0.0’%0) 1 ( 2.6Yo)Missing o 0

Rhinorrhea - Last evaluation p = 0.049Absent 13 (35.lYO) 26 (66.7%)Mild 16 (43.2Yo) 5 (12.8VO)

Moderate 8 (21 .6%) 6 (15.4%)Severe o ( 0.0%) 2( 5.1%)

Nasal obstruction - Last evaluation p = 0.968

Absent 12 (32.4Yo) 10 (25.6Yo)Mild 11 (29.7%) 14 (35.9VO)Moderate 13 (35.1%) 13 (33.3%)Severe 1 ( 2.7%) 2( 5.1%)

Nasal pruritus - Last evaluation p= O.156Absent 15 (40.5YO) 21 (53.8Yo)Mild 16 (43.2%) 13 (33.3%)

Moderate 6 (16.2%) 5 (12.8%)

Severe o ( O.OYO) o ( 0.0’%0)

Ocular pruritus - Last evaluation p = 0.872Absent 25 (67.6Yo) 30 (76.9VO)Mild 8 (21 .6VO) 8 (20.5%)Moderate 4 (10.8%) 1 ( 2.6Yo)

Severe o ( 0.0?40) o ( 0.0%)

Maximal symptom score - Last evaluation p= O.162

Absent 3 ( 8.1?40) 4 (10.3%)Mild 11 (29.7%) 18 (46<2%)Moderate 22 (59.5%) 14 (35.9?40)Severe 1 ( 2.7’?40) 3 ( 7.7?40)


... .... . .,, ,,, ~,. ,-. ,,-,, -.


Tables 14.2-9 to 14.2-12 gives descriptive statistics for the VAS assessment of the nasalcondition, the results of rhinomanometry, and wheals and flares, for the two visits, for the lastevaluation, and for the difference between visit 1 and the last evaluation. These descriptivestatistics are broken down by treatment group, and by center and treatment group. The tablesalso give the results of the analysis of variance tests evaluating the treatment and center effects(and their interaction) on the change between visit 1 and the last evaluation. For the flares thedescriptive statistics are not broken down by center as they were only recorded in center 2.

A summary of the change between visit 1 and the last evaluation is given in Table 11.4.2.

The comparison of the two treatment groups on the basis of these variables was performed bymeans of two-way analysis of variance in which the center effect and the treatment-centerinteraction are also evaluated. For none of the variables was a significant difference foundbetween the two treatments. For each variable a significant difference emerged between the twocenters, with more important improvements for the patients of center 2. This differencebetween the two centers was apparent in both treatment groups.

TABLE 11.4-2: VAS OF GLOBAL STATUS OF NASAL CONDITION -RHINOMANOMETRY - PRICK TESTIntention to Treat Population

Center 1 Center 1 Center 2 Center 2Loratadine Cetirizine Loratadine Cetirizine

(N=17) (N=19) (N= 20) (N= 20)

VAS of global status of nasal condition (mm): Visit 1- Last evaluationMean 15.0 12.2 63.3 62.8St. dev. 18.0 18.8 21.5 19.1

Rhinomanometry: Last evaluation - Visit 1Mean 20.0 26.3 75.0 62.5St. dev. 40.2 37.4 53.8 56.3

Prick test - Wheal surface area (mm2): Visit 1- Last evaluationMean 12.08 7.11 47.92 54.98St. dev. 14.92 8.34 20.72 26.87

RESULT OF THE COMPARISONSTwo-way Analysis of Variance

Center Treatment InteractionVAS global status nasal condition p -=0.001 p=o.714 p = 0.799Rhinomanometry p <0.001 p = 0.782 p = 0.399Wheal surface area p -=0.001 p = 0.836 p = 0.237


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STUDY No.: 9153PROTOCOL No.:MPCE91 L 1802/6D of 187

Tables 14.2-13 to 14.2-15 gives descriptive statistics respectively for the percentage of dayswithout symptoms, with no or mild symptoms, and with at worst moderate symptoms, asderived from the diary cards. These descriptive statistics are given broken down by treatmentgroup, and broken down by center and treatment group. The tables also give the results of theanalysis of variance tests evaluating the treatment and center effects (and their interaction).

A summary of these evaluations is given in Table 11.4.3. The comparison of the two treatmentgroups on the basis of these variables was performed by means of two-way analysis of variancein which the center effect and the treatment-center interaction are also evaluated. For none ofthe variables was a significant difference found between the two treatments. For the percentageof days with at worst moderate symptoms a significant difference emerged between the twocenters, with on average higher values for center 1. The difference between the two centers wasapparent in both treatment groups.

Tables 14.2-16 to 14.2-21 give descriptive statistics for the mean value of each of the symptomsand of the total symptom score over the entire treatment period, and the results of the analysis ofvariance tests evaluating the treatment and center effects (and their interaction). Tables 14.2-22to 14.2-27 give descriptive statistics for the daily assessments of each of the 5 symptoms and forthe total symptom score, broken down by treatment group, and by center and treatment group.

TABLE 11.4-3: DAILY RECORD CARDSIntention to Treat Population

Loratadine Cetirizine(N= 37) (N= 39)

Percentage of days without symptoms (PDSO)Mean 4.7 10.7

St. dev. 9.0 19.6

Missing 3 1

Percentage of days with no or mild symptoms (PDS1)Mean 35.2 39.1St. dev. 33.7 32.6Missing 3 1

Percentage of days with at worst moderate symptoms (PDS2)Mean 82.9 75.6

St. dev. 24.1 23.2

Missing 3 1

RESULT OF THE COMPARISONSTwo-way Analysis of Variance

Center Treatment Interaction

PDSO p = 0.300 p=o.lo5 p = 0.397

PDS1 p = 0.704 p = 0.551 p = 0.258

PDS2 p = 0.049 p=o.175 p = 0.509


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STUDY No.: 9153PROTOCOL No.: MPCE9 1L 1802/6D of 187

11.4.2 Statistical Issues

The statistical analysis plan included in the protocol is not very detailed and does notalways select the most powerful test for a particular type of variable. Therefore, beforedisclosure of the randomization code, a detailed analysis plan was developed in agreementwith the sponsor. Subsequent to the availability of the results of the analysis, somesupplementary analyses were made. These include:

. Clinical symptoms of the disease as assessed by the investigator:

. Descriptive statistics of the total symptom score, defined as the sum of the scores ofthe five individual clinical symptoms (sneezing, rhinorrhe~ nasal obstruction, nasalpruritus, ocular pruritus). These descriptive statistics are given for each of thevisits, for the last visit, and for the change between baseline and the last visit.Comparison of the two treatments, both at baseline and for the change betweenbaseline and the last visit, using two-way analysis of variance controlled for centerand treatment.

. Frequency distribution of the change between baseline and the last visit, for each ofthe five individual clinical symptoms, and for the maximal symptom score.Evaluation of the evolution within each treatment group between baseline and thelast visit, making use of the Wilcoxon test. However, treatment and time effect areconfounded, implying that it cannot be ascertained to which extent a change duringthe study is due to the treatment and to which extent to the natural course of thedisease. Therefore, the results of these tests are not discussed in the report.

. Daily record cards:

● Descriptive statistics of the daily total symptom score

. For each of the five clinical symptoms and for total symptom score: Descriptivestatistics of the mean value for the total evaluation period and comparison of thetwo treatment groups for these variables using two-way analysis of variancecontrolled for center and treatment.


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11.4.2.1 Adjustment for Covariates

For each of the efficacy variables for which a baseline measurement was available, thecomparison of the two treatment groups was performed by taking the baseline value intoaccount. For the continuous variables this was achieved by performing the comparison for thechange between baseline and the last available measurement. For the ordinal variables the twotreatments were compared for the value at the last visit, controlled for the value at baseline.Except for center (Section 11.4.2.4), no other covariates were considered in the analysis.

11.4.2.2 Handling of Dropouts or Missing Data

For assessments performed by the investigator at the two visits, the comparison of the twotreatment groups is performed on the basis of the assessment made on the last visit, which canbe the baseline visit. This approach implies that missing values are estimated by their lastavailable value.

Since missing values were not frequent, no sensitivity analysis was performed on the basis ofcomplete cases.

11.4.2.3 Interim Analyses and Data Monitoring

No interim analysis was performed.

11.4.2.4 Multicenter Studies

The baseline and efficacy parameters were computed by center. For the evaluation of thecontinuous variables, the effect of center was taken into account in the analysis, by applyingtwo-way analysis of variance, controlled for center. Important differences were observedbetween the two centers, both at baseline (Section 11.1) and during the study (Section 11.4.1).On average worse overall assessments were observed in center 2. The improvement during thestudy is also more important in center 2 than in center 1, which is to be expected in view of thelarger room for improvement possible in the center. However, for all variables the effect ofcenter is comparable in the two treatment groups.


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11.4.2.5 Multiple Comparisons - Multiplicity

In agreement with the analysis plan, no adjustment is made for multiple testing.

11.4.2.6 Use of an ‘Efficacy Subset’ of Patients

The evaluation of efficacy was based upon the intention to treat population. No evaluationswere performed on the basis of a per protocol population.

11.4.2.7 Active-Control Studies Intended to Show Equivalence

Not applicable,

11.4.2.8 Examination of Subgroups

No evaluations were performed on subsets of patients.

11.4.3 Tabulation of Individual Response Data

Individual efficacy data are listed in Section 16.2.

11.4.4 Drug Dose, Drug Concentration, and Relationship to Response

Not applicable since there were no different dose groups entered in the study, nor weredrug concentration measurements performed.


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11.4.5 Drug-drug and Drug-Disease Interaction

Not applicable.

11.4.6 By-Patient Displays

Individual patient data are presented in tabular listings provided in Section 16.2. Nographical representations were made of the individual patient profiles.

11.4.7 Efficacy Conclusions

The aims of the present study were to assess the possible difference of effects of cetirizineand loratadine in the treatment of perennial allergic rhinitis in children from 6 to 12 yearsof age. Additionally it was intended to compare the effects of cetirizine with loratadine onthe results of nasal brushing and rhinomanometry, and to study the effects of both drugs atskin level on the potency of the inhibition of histamine-induced wheals.

At the baseline visit, clinical symptoms were observed by the investigator in all patients. Inall but one of the patients, the maximal symptom score was moderate or severe. Theintensity of the clinical symptoms as assessed by the investigator at the follow-up visitdecreased during the study in both treatment groups. At the last visit, no or mild symptomswere observed for 14 patients (3 8°/0) in the loratadine group and for 22 patients (56°/0) inthe cetirizine group. This difference was not statistically significant.

Comparison of the two treatment groups for the intensity of each of the clinical symptomsseparately revealed a significant difference for rhinorrhea at the last visit which was morefrequent in the Ioratadine group: 65’?40of the patients versus 33% in the cetirizine treatmentgroup (p= 0.049). No significant differences were found for the other symptoms.

The VAS of the global status of the nasal condition decreased on average by 41 mm in theloratadine group and by 38 mm in the cetirizine group. These changes are not significantlydifferent.

No significant difference was found between the two treatments on the basis of therhinomanometry measurements, which on average increased by 50 l/rein in the loratadinegroup and by 45 l/rein in the cetirizine group.

Inhibition of the wheal surface area induced by the prick test with histamine wascomparable for the two treatments, with an average wheal surface area after treatment of 12mmz in the Ioratadine group and of 9 mmz in the cetirizine group.



From the daily record cards it appeared that, on average, patients in the cetirizine group hadno or mild symptoms during 39°/0 of the treatment period while in the loratadine group thiswas the case during 35°% of the treatment period. These values are not significantlydifferent.

Due to missing data and methodological differences (use of different units), data fromnasal brushings for changes in eosinophil counts between visits were not analysed.

For several variables (total symptom score, VAS of nasal condition, rhinomanometry,wheal surface area) important differences were observed between the two centres, both atbaseline and during the study. On average, worse overall assessments were observed incentre 2. The improvement during the study is also more important in centre 2 than incentre 1, which is to be expected in view of the larger room for improvement in that centre.However, for all variables the centre effect is comparable in the two treatment groups, sothat this does not jeopardise the conclusions that can be drawn from this trial.

12. SAFETY EVALUATION

12.1 EXTENT OF EXPOSURE

The time in the study @eriod between visit 1 and visit 2) is described in Table 12.1-1, brokendown by treatment group as well as by center and treatment group. The median time ofexposure was 28 days in center 1 and 29 days in center 2.


,.,—,..., ,


TABLE 12.1-1: PERIOD BETWEEN VISIT 1 AND VISIT 2 (days)Intention to Treat Population


All PatientsMean 29.4 30.5 30.0St. dev. 2.2 6.6 5.0Minimum 26 27 2625% percentile 28 28 28Median 29 29 29

75% percentile 29 29 29

Maximum 36 59 59Number 37 38 75Missing o 1 1,

Center 1Mean 28.5 30.4 29.5St. dev. 1.4 7.1 ~ 5.2Minimum 26 27 2625% percentile 28 28 28Median 28 28 28

75% percentile 29 30 29Maximum 32 59 59Number 17 19 36Missing o 0 0

Center 2Mean 30.3 30.6 30.4St. dev. 2.4 6.3 4.7Minimum 28 28 2825?40percentile 29 28 29Median 29 29 29

75% percentile 31 29 30

Maximum 36 56 56

Number 20 19 39Missing o 1 1


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12.2 ADVERSE EVENTS

Adverse events were reported for two patients of the loratadine treatment group and twopatients of the cetirizine treatment group. One patient under loratadine suffered fromtachycardia and one from somnolence. For both adverse events the relationship with the studytreatment was considered possible. In the cetirizine treatment group one patient suffered frompharyngitis and one patient from somnolence. For the pharyngitis the relationship wasconsidered to be remote/none and for somnolence it was assessed as certain.

Table 12.2-1 gives the frequencies of patients with adverse events, the number of adverse eventsper patient, as well as the frequencies of adverse events broken down by system organ class andby WHO preferred term.

Table 12.2-2 contains a patient listing of all the data concerning the adverse events.


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TABLE 12.2-1: ADVERSE EVENTSIntention to Treat Population


Any adverse eventYes 2 ( 5.4%) 2 ( 5.1%)

No 35 (94.6%) 37 (94.9VO)

Missing o 0

Number of adverse events per patiento 35 (94.6%) 37 (94.9’YO)

1 2 ( 5.4%) 2( 5.1%)

Missing o 0

Number of patients with adverse events per system organ classAutonomic nervous system disorders (420) 1 0

Psychiatric disorders (500) 1 1

Heart rate and rhythm disorders (1030) 1 0

Respiratory system disorders (1 100) o ‘1

Resistance mechanism disorders (1830) o 1

Number of patients with adverse events per system organ class and WHO preferred term420

TACHYCARDIA 1 0

500SOMNOLENCE 1 1

1030TACHYCARDIA 1 0

1100PHARYNGITIS o 1

1830PHARYNGITIS o 1


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STUDY No.: 9153

PROTOCOL No.: MPCE91L1802/6D of 187

TABLE 12.2-2ADVERSE EVENTS - INDIVIDUAL DATA LISTING

Part 1

WHO

Treat- Date Included

Center Patient ment Visit 1 AE Description Term

1 15 Loratadine 25MAY94 TACHYCARDIA AND PALPITATIONS TACHYCARD IA

1 16 Cetirizine 25MAY94 INFECTIOUS PHARYNGITIS PHARYNGITIS

1 17 Cetirizine 03NOV93 SOMNOLENCE SOMNOLENCE

1 19 Loratadine 16NOV93 SOMNOLENCE SOMNOLENCE

WHO

Preferred Body Date Date

Term Systems Onset End

TACHYCARDIA 1030 27MAY94 04JUN94420

PHARYNGITIS 1100 02JUN94 07JUN94t830

SOMNOLENCE 500 08NOV93 23NOV93

SOMNOLENCE 500 17NOV93 20NOV93

REPORT No. : MRCE98G0201/lV Study Report December 1, 1998

STUDY No.: 9153PROTOCOL No.: MPCE9 lL1802/6D of 187

ADVERSE EVENTS - INDIVIDUAL DATA LISTINGPart 2

WHO Laboratory AE Present

Treat- Preferred

Relation toTreatment Tests Before the

Center Patient ment Term

AE

Frequency

StudyOrigin Necessary Severity Confirmed AE Study Action Taken Disappeared Outcome Medication

1 15 Lorstadine TACHYCARDIA Reported spontaneously None Moderate No No None Total resolution Possible

1 16 Cetirizine PHARYNGITIS Continuous Reported spontaneously External Moderate No No Discontinuation Yes Total resolution Remote/none

1 17 Cetirizine SOMNOLENCE Continuous Reported spontaneously None Severe No No Discontinuation Yes Total resolution Certain

1 19 Loratadine SOMNOLENCE Recurrent Active question None Mild No No None Total resolution Possible

..



ADVERSE EVENTS - INDIVIDUAL DATA LISTING

Part 3: Comments

Treat -

Center Patient ment COMMENTS

1 15 Loratadine

1 16 Cetirizine PHARYNGITIS DURING THE WEEK SHE WAS RECEIVING THE MEDICINE. THE INFECTION RESOLVED AFTER 5 OAYS OF ANTIMICROBIAL TREATMENT,

1 17 Cetirizine STOPPED TREATMENT WITHOUT SEEKING ADVICE

1 19 Loratadine



12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER

SIGNIFICANT ADVERSE EVENTS

No deaths, serious adverse events, or other significant adverse events were reported.


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12.4 CLINICAL LABORATORY EVALUATION

Laboratory tests were performed for all patients at baseline and for all but 5 patients at the endof the study (Table 12.4-1).

TABLE 12.4-1: NUMBERS OF PATIENTS WITH LABORATORY DATA[ntention to Treat Population

Loratadine Cetirizine

(N= 37) (N= 39)

At least one laboratory testperformed on visit 1

Ml PatientsYes 39 (1OOYO)

No o ( OYO)37 (loo%)

o ( o%)

Center 1YesNo

Center 2YesNo

17 (loo%)o ( o%)

20 (1OO’XO)o ( o%)

19 (loo%)o ( 0’?40)

20 (1OOYO)o ( 0’%0)

At least one laboratory testperformed on visit 2

All PatientsYes 34 (91.9YO) 37 (94.9’?40)

No 3 ( 8.1?40) 2 ( 5.1%)

Center 1Yes 14 (82.4%) 17 (89.5Yo)

No 3 (17.6%) 2 (10.5%)

Center 2Yes 20 (loo%) 20(1 0070)

No o ( o%) o ( o%)


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STUDY NO.: 9153PROTOCOL No. : MPCE91 L 1802/6D of 187

12.4.1 Listing of Individual Laboratory Measurements by Patient and of Abnormal

Laboratory Values

Individual patient data are presented in tabular listing provided in Section 16.2.

12.4.2 Evaluation of Each Laboratory Parameter

For each of the laboratory tests (erythrocytes, hematocrit, hemoglobin, white blood count,white blood count differential, platelets, urea or BUN, creatinine, TGP [ALA-transferases])the frequency of patients with a value below, within and above the reference range werecalculated and a description is given of the shift of this status between visits.

The results are described in Tables 14.3-1 to 14.3-14.

The frequency of patients with potentially clinically significant abnormalities (PCSA) wasnot determined since no limits for the determination of PCSA were available in children.

For all laboratory tests the frequency of patients with values outside the reference rangewere comparable, both at baseline and at visit 2. Also, the shifts between baseline andvisit2 were comparable in the two treatment groups. Both upward and downwardvariations were observed. Most abnormalities were recorded for the white blood celldifferential, which was to be expected in view of the pathology.

REPORT No.: MRCE98G0201/l V StUdy Report December 1, 1998

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12.5 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONSRELATED TO SAFETY

No vital signs, physical examinations, or other safety assessments were made in this study.

12.6 SAFETY CONCLUSIONS

The number of patients reporting adverse events was very limited. Adverse events werereported for two patients of the Ioratadine treatment group and two patients of the cetirizinetreatment group. One patient under loratadine suffered from tachycardia and one fromsomnolence. For both adverse events the relationship with the study treatment wasconsidered possible. In the cetirizine treatment group one patient suffered from pharyngitisand one patient from somnolence. For the pharyngitis the relationship was considered to beremote/none and for somnolence it was assessed as certain. No clinically relevant adverseevents were reported from laboratory data.

REPORT No.: MRCE98G0201/l V ShKIy Report December 1, 1998

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13. DISCUSSION AND OVERALL CONCLUSIONS

Cetirizine has been fully investigated in adults in seasonal and perennial rhinitis, where it hasbeen shown to be clearly superior to placebo in relieving most of the symptoms of thesediseases. When compared to active comparators, either some advantages or comparable efficacyhave been demonstrated in seasonal rhinitis. In adults, cetirizine is a potent and quickly activeH,-blocker at the skin level. Cetirizine is generally well tolerated in adults, with a low incidenceof side effects.

In children, at the dose of 5 to 10 mg per day (depending upon the age), cetirizine is moreeffective than a placebo in relieving most of the symptoms of perennial or seasonal rhinitis, andgenerally well-tolerated. Its effect at the skin level has been confirmed in children, afierhistamine-induction of wheals and flares which were inhibited as from 0.5 h to 24 h after 5 or10 mg intake of cetirizine. No data for the comparison with active comparators were available atthe time the present trial was started.

Comparison of the two treatment groups for the intensity of each of the clinical symptomsseparately revealed a significant difference for rhinorrhea at the last visit which was morefrequent in the loratadine group: 65% of the patients versus 33% in the cetirizine treatmentgroup. No significant differences were found for the other symptoms.

The VAS of the global status of the nasal condition decreased on average by 41 mm in theloratadine group and by 38 mm in the cetirizine group. These changes are not significantlydifferent.

No significant difference was found between the two treatments on the basis of therhinomanometry measurements, which on average increased by 50 l/rein in the loratadine groupand by 45 1/rein in the cetirizine group.

Inhibition of the wheal surface area induced by the prick test with histamine was comparable forthe two treatments, with an average wheal surface area after treatment of 12 mm’ in theloratadine group and of 9 mm’ in the cetirizine group.

From the daily record cards it appeared that, on average, patients in the cetirizine group had noor mild symptoms during 39°/0 of the treatment period while in the loratadine group this was thecase during 35°/0 of the treatment period. These values are not significantly different.

Due to missing data and methodological differences (use of different units), data from nasalbrushings for changes in eosinophil counts between visits were not analysed.

For several variables (total symptom score, VAS of nasal condition, rhinomanometry, whealsurface area) important differences were observed between the two centres, both at baseline andduring the study. On average, worse overall assessments were observed in centre 2. Theimprovement during the study is also more important in centre 2 than in centre 1, which is to beexpected in view of the larger room for improvement in that centre. However, for all variablesthe centre effect is comparable in the two treatment groups, so that this does not jeopardise theconclusions that can be drawn from this trial.

Adverse events were reported for two patients of the loratadine treatment group and two patientsof the cetirizine treatment group. One patient under loratadine suffered from tachycardia and


,., ~,, .”.,,-. M.,,..-. , ., ,


one from somnolence. For both adverse events the relationship with the study treatment wasconsidered possible. In the cetirizine treatment group one patient suffered from pharyngitis andone patient from somnolence. For the pharyngitis the relationship was considered to beremote/none and for somnolence it was assessed as certain. No clinically relevant adverse

events were reported from laboratory data.

Both study medications relieved symptoms after 4 weeks. With the exception of the symptom ofrhinorrhea, where cetirizine was more effective than loratadine, this study failed to differentiatebetween the active medications. The active medications were well tolerated.


,,.-,”,., ,


14. TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOTINCLUDED IN THE TEXT

14.1 DEMOGRAPHIC DATA

TABLE 14.1-1: PATIENT CHARACTERISTICSIntention to Treat Population


Age (years)Mean 9.45 8.85 9.14St. dev. 2.10 1.99 2.05Minimum 4.42 5.36 4.4225% percentile 8.18 7.36 7.49Median 9.51 8.37 8.9575’+’0percentile 10.76 10.29 10.62Maximum 14.51 13.49 14.51Number 37 39 , 76Missing o 0 0

GenderFemale 16 (43.2%) 17 (43.6Yo) 33 (43.4VO)Male 21 (56.8%) 22 (56.4%) 43 (56.6?40)Missing o 0 0

Centre 1 Centre 2Loratadine Cetirizine Loratadine Cetirizine

(N= 17) (-N= 19) (-N= 20) (N= 20)

Age (years)Mean 9.81 8.63 9.14 9.07St. dev. 2.32 1.76 1.90 2.22Minimum 6.02 5.36 4.42 5.9325% percentile 8.68 7.49 8.01 7.33Median 9.80 8.37 9.25 8.2675% percentile 11.21 9.93 10.01 10.70Maximum 14.51 11.84 12.88 13.49Number 17 19 20 20Missing o 0 0 0

3enderFemale 5 (29.4%) 10 (52.6%) 11 (55. O’XO) 7 (35.0%)Male 12 (70.6%) 9 (47.4’XO) 9 (45.0?40) 13 (65.OYO)Missing o 0 0 0


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TABLE 14.1-1- Continued: PATIENT CHARACTERISTICSIntention to Treat Population

Loratadine Cetirizine All Patients

(N=37) (N= 39) (N= 76)

Weight (kg)Mean 31.84 33.62 32.75

St. dev. 9.82 10.69 10.25

Minimum 18.0 16.0 16.0

25’?40percentile 23.0 25.0 24.4

Median 29.5 31.5 30.6

75% percentile 37.0 43.0 40.0

Maximum 52.0 60.0 60.0

Number 37 39 76

Missing o 0 0

Height (cm)Mean 132.4 132.2 132.3

St. dev. 13.0 12.5 , 12.7

Minimum 111 112 111

25’XOpercentile 123 122 123

Median 131 128 129

75% percentile 142 140 142

Maximum 163 165 165

Number 37 38 75

Missing o 1 1

BMI (kg/m’)Mean 17.72 18.66 18.19

St. dev. 2.75 3.35 3.09

Minimum 13.5 12.8 12.8

25?40percentile 15.6 15.4 15.4

Median 17.5 18.7 17.9

75’XOpercentile 19.4 20.9 20.3

Maximum 24.4 27.0 27.0

Number 37 38 75

Missing o 1 1


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Centre 1 Centre 2

Loratadine Cetirizine Loratadine Cetirizine

(N=17) (N=19) (N= 20) (N= 20)

Weight (kg)Mean 33.47 32.05 30.46 35.11

St. dev. 11.85 11.61 7.75 9.80

Minimum 18.0 16.0 19.9 20.0

25% percentile 22.0 23.7 25.5 26.7

Median 35.0 29.0 28.7 32.5

75’% percentile 40.0 40.0 34.5 45.5

Maximum 52.0 60.0 51.0 49.0

Number 17 19 20 20

Missing o 0 0 0

Height (cm)Mean 134.2 131.3 130.9 133.1

St. dev. 14.7 12.2 11.6 ‘ 13.0

Minimum 113 112 111 114

25% percentile 123 125 124 122

Median 134 128 130 131

75V0percentile 145 138 136 144

Maximum 163 165 161 154

Number 17 18 20 20

Missing o 1 0 0

BMI (kg/m’)Mean 17.93 17.77 17.53 19.47St. dev. 3.33 3.69 2.21 2.87Minimum 13.5 12.8 13.9 14.425% percentile 14.5 15.2 15.8 17.1Median 17.4 17.3 17.5 20.275% percentile 19.8 20.2 18.5 21.2Maximum 24.4 27.0 22.7 24.5Number 17 18 20 20Missing o 1 0 0


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RESULT OF THE COMPARISON

Two-way analysis of varianceCentre Treatment Interaction

Age p = 0.809 p=o.188 p = 0.244Weight p = 0.992 p = 0.499 p = 0.204Height p = 0.802 p = 0.901 p = 0.401BMI p = 0.363 p= O.213 p=o.141

Cochran-Mantel-Haenszel test (controlling for centre)Sex p = 0.970


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TABLE 14.1-2: OCCURRENCE OF FAMILIAL ANTECEDENTSIntention to Treat Population


(N= 37) (N= 39) (N= 76)

AntecedentAll Patients

YesNot mentioned

Centre 1YesNot mentioned


Type of familial antecedents*E14110JOOJ30.2J30.4J31.OJ45.OJ45.9L20.9L50.9L57.8

21 (56.8Yo)16 (43.2Yo)

11 (64.7’Yo)

6 (35.3%)

10 (50.0?40)10 (50.0%)

1

1019226311

25 (64.1%)14 (35.970)

13 (68.4?40)6(3 1.6Yo)

12 (60.0%)8 (40.0%)

1011902

12130

46 (60.5%)30 (39.5?40)

24 (66.7%)12 (33.3!XO)

22 (55.OYO)20 (45.0%)

2112

1824

18441

RESULT OF THE COMPARISONCochran-Mantel-Haenszel Test (Controlling for centre)

Occurrence of familial antecedent p = 0.534

E14:110:JOO:J30:J31:J45:L20:L50:L57:

Unspecified diabetes mellitusEssential hypertensionAcute nasopharyngitisVasomotor and allergic rhinitisChronic rhinitis, nasopharyngitis and pharingitisAsthmaAtopic dermatitisUrticariaSkin changes due to chronic exposure to nonionizing radiation

* Several possible per patient.

REPORT No. : MRCE98G020 1/1V Study Report December 1, 1998

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STUDY No.: 9153PROTOCOL No. :MPCE91 L 1802/6D of 187

TABLE 14.1-3: PREVIOUS TREATMENT FOR RHINITISIntention to Treat Population


(N= 37) (N= 39) (N= 76)

Previous treatmentAll Patients

Yes 31 (83.8Yo) 27 (69.2%) 58 (76.3%)Not mentioned 6 (16.2Yo) 12 (30.8VO) 18 (23.7VO)

Centre 1Yes 16 (94.1’Yo) 14 (73.7YO) 30 (83.3%)No mentioned 1 ( 5.9%) 5 (26.3%) 6 (16.7%)

Centre 2Yes 15 (75.0%) 13 (65.OYO) 28 (70. O’YO)No mentioned 5 (25.0%) 7 (35.0’?40) 12 (30.070)

Type of previous treatment”AFRIN 1 0 1

AMBROXOL o 1 1

AMOXICILLIN o 1 1

ASTEMIZOLE 4 9 13

BECLOMETASONE 4 3 7

BECONASE o 2 2

CETIRIZINE 1 1 2

CHLORPHENIRAMINE 2 0 2

CLARITYN o 2 2

CROMOGLICATE SODIUM 11 10 21

DIMETAPP 2 0 2

HISMANAL 1 1 2

KETOTIFEN 2 3 5

LEVOCABASTINE 1 0 1

LORATADINE 17 11 28

OPTICROM 1 0 1

OXACILLIN 1 0 1OXYMETAZOLINE o 1 1

PENICILLIN NOS 1 1 2PSEUDOEPHEDRINE 2 3 5RYNACROM o 3 3SALBUTAMOL o 1 1

SYNALAR 1 0 1TELDANE o 1 1

TERFENADINE 7 6 13

THEOPHYLLINE o 1 1


Previous treatment for rhinitis p= O.126



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TABLE 14.1-4: POSITIVE PRICK TESTIntention to Treat Population


(N= 37) (N= 39) (N= 76)

Positive prick testAll Patients

Yes 37(1 00?40) 39 (100’?40) 76(1 00%)

No o ( 0?40) o ( O’MO) o ( O’YO)

Centre 1Yes 17 (loo%) 19 (loo%) 36 (100%)

No o ( OYO) o ( 0’%0) o ( 070)

Centre 2Yes 20 (loo%) 20 (1OOVO) 40 (100’?40)

No o ( Ovo) o ( o%) o ( 0’?40)

Type of agonist causing a positive prick test*ALTERNARIA 1 2 3AMARANTHUS o 1 1AMBROSIA 1 2 3ASH 1 0 1ASPERGILLUS 1 0 1BERMUDA GRASS 1 0 1BIRCH o 1 1CAT 3 1 4CYNODON DACTYLON o 1 1DERMATOPHAGOIDES 21 19 40DERMATOPHAGOIDES 11 10 21

FARINAEDERMATOPHAGOIDES 12 10 22

PTERONYSSINUSHELIANTUS o 1 1LOLIUM 2 2 4LOLIUM PERENNE o 1 1PHLEUM PRATENSE 5 7 12POLLEN 1 3 4TIMOTHY GRASS o 1 1


Positive prick test Not applicable

*Several possible per patient.

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TABLE 14.1-5: POSITIVE RAST TESTIntention to Treat Population


(N= 37) (N= 39) (N= 76)

Positive RAST testAll Patients

Yes 7 (18.9VO) 4 (10.3YO) 11 (14.5%)

Not mentioned 30 (81.1’Yo) 35 (89.7Yo) 65 (85.5’XO)

Centre 1Yes 7 (41 .270) 4 (21.1%) 11 (30.6%)

Not mentioned 10 (58.8%) 15 (78.9%) 25 (69.4’XO)

Centre 2Yes o ( 0?40) o ( OYO) o ( 0?40)

Not mentioned 20 (100?40) 20 (loo%) 40 (1OOYO)

Type of agonist causing positive RAST test*ALTERNARIA 1 0 1AMBROSIA 1 1 2DERMATOPHAGOIDES 2 2 4DERMATOPHAGOIDES 2 0 2

FARINAEDERMATOPHAGOIDES 1 0 1

FARINAE CLASS 4DERMATOPHAGOIDES 1 0 1

PTERONYSSINU SLOLIUM o 1 1


Positive RAST test p=o.197

● Several possible per patient.


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STUDY No.: 9153PROTOCOL No.: MPCE91 L 1802/6D of187

TABLE 14.1-6: MEDICAL HISTORYIntention to Treat Population


Medical historyAll Patients

Yes 25 (67.6%) 32 (82.1%) 57 (75.0’?40)Not mentioned 12 (32.4?40) 7 (17.9%) 19 (25.0%)

Centre 1Yes 13 (76.5%) 15 (78.9%) 28 (77.8%)Not mentioned 4 (23.5%) 4(21.1%) 8 (22.2%)

Centre 2Yes 12 (60.OYO) 17 (85.0%) 29 (72.5VO)Not mentioned 8 (40.OVO) 3 (15.070) 11 (27.5%)

Type of medical antecedents*A38 o 1 1BO1.9 10 13 ‘ 23B05.9 5 1 6B06.9 1 3 4E16.2 1 0 1E66.8 1 0 1H66.9 1 0 1J02.9 1 0 1J3 1.2 0 2 2J32.9 o 1 1J45.O 8 10 18K1l.2 o 2 2K21.9 1 0 1K37 o 1 1K52.9 o 1 1K75.9 2 1 3L20.9 o 1 1L50.8 o 1 1R05 1 0 1


Medical history p=o.154



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A38: Scarlet fever

BO1: Varicella

B05: Measles

B06: Rubella

E 16: Other disorder of pancreatic internal secretion

E66: ObesityH66: Suppurative and unspecified otitis mediaJ02: Acute pharyngitisJ31: Chronic rhinitis, nasopharyngitis and pharyngitisJ32: Chronic sinusitusJ45: AsthmaK11: Diseases of solivary glandsK21: Gastro-oesophageal reflux diseaseK37: Unspecified appendicitisK52: Other noninfective gastroenteritis and colitisK75: Other inflammatory liver diseasesL20: Atopic dermatitisL50: UrticariaR05 : Cough


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TABLE 14.1-7: SURGERYIntention to Treat Population


(N= 37) (N= 39) (N= 76)

Surgery

All PatientsYesNot mentioned



Type of surgery*J35.9K37K40.9N50.9Q40.O

4 (10.8?40)33 (89.2Yo)

2 (11.8?40)15 (88.2Yo)

2 (10.0%)18 (90.0%)

11110

13 (33.3%) 17 (22.4%)26 (66.7%) 59 (77.6Yo)

8 (42. 1~0) 10 (27.8’-XO)11 (57.970) 26 (72.2?40)

5 (25.0%) 7 (17.5?40)15 (75.OYO) 33 (82.5?40)

7 82 32 31 21 1


Surgery performed p = 0.021

J35: Chronic diseases of tonsils and adenoidsK37: Unspecified appendicitisK40: Inguinal herniaN50: Other disorders of male genital organsQ40: Other congenital malformations of upper alimentary tract



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TABLE 14.1-8: CLINICAL SYMPTOMSIntention to Treat Population


SneezingAbsent o ( 0.0%) o ( 0.0%) o ( 0.0%)Mild 8 (21.6%) 5 (12.8%) 13 (17.1%)Moderate 20 (54.1 ‘YO) 21 (53.8?40) 41 (53.9?40)Severe 9 (24,3Yo) 13 (33.3%) 22 (28.9?40)Missing o 0 0

RhinorrheaAbsent o ( O.OYO) o ( O<OYO) o ( 0.0%)Mild 5 (13.5%) 4 (10.3%) 9(11.8Yo)Moderate 20 (54.1%) 19 (48.7Yo) 39 (51.3:?)Severe 12 (32.4%) 16 (41.OYO) 28 (36.8’XO)Missing o 0 0

Nasal obstructionAbsent 2 ( 5.4%) o ( 0.0%) 2 ( 2.6%)Mild 2 ( 5.4%) 3 ( 7.7?40) 5 ( 6.6%)Moderate 15 (40.5%) 12 (30.8%) 27 (35.5%)Severe 18 (48.6?40) 24 (61.5Yo) 42 (55.3Yo)Missing o 0 0

Nasal pruritisAbsent 2 ( 5.4YO) 2 ( 5.lYO) 4 ( 5.3!40)Mild 3( 8.1Yo) 3 ( 7.7YO) 6 ( 7.9Yo)Moderate 14 (37.8Yo) 19 (48.7%) 33 (43.4%)Severe 18 (48.6%) 15 (38.5%) 33 (43.470)Missing o 0 0

Ocular pruritisAbsent 10 (27.0%) 19 (48.7%) 29 (38.2VO)Mild 10 (27.0?40) 8 (20.5Yo) 18 (23.7%)Moderate 6 (16.2Yo) 8 (20.5Yo) 14 (18.4Yo)Severe 11 (29.7%) 4 (10.3%) 15 (19.7%)Missing o 0 0

Maximal symptom scoreAbsent o ( 0.0%) o ( 0.0%) o ( 0.0%)Mild 1 ( 2.7%) o ( 0.0?40) 1 ( 1.3’?40)Moderate 11 (29.7?40) 12 (30.8!40) 23 (30.3?40)Severe 25 (67.6%) 27 (69.2%) 52 (68.4%)Missing o 0 0


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TABLE 14.1-8- Continued: CLINICAL SYMPTOMSIntention to Treat Population


(N=17) (N=19) (N= 20) (N= 20)

SneezingAbsent o ( O.OYO) o ( 0.070) o ( 0.0?40) o ( 0.070)Mild 5 (29.4%) 5 (26.3%) 3 (15.0%) o ( O.OYO)Moderate 11 (64.7%) 14 (73 .7%) 9 (45.0%) 7 (35.0?40)Severe 1 ( 5.9%) o ( 0.0%) 8 (40.0%) 13 (65.0%)Missing o 0 0 0

RhinorrheaAbsent o ( O.ovo) o ( 0.070) o ( O.OYO) o ( O.OYO)Mild 4 (23.5%) 2 (10.5?40) 1 ( 5.OYO) 2 (1O,OYO)Moderate 12 (70.6%) 14 (73.7%) 8 (40.OYO) 5 (25. O’XO)Severe 1 ( 5.9%) 3 (15.8?40) 11 (55.0%) 13 (65.OVO)Missing o 0 0 0

Nasal obstructionAbsent 1 ( 5.9%) o ( 0.0%) 1 ( 5.070) o ( 0.070)Mild 1 ( 5.970) 3 (15.8Yo) 1 ( 5.0?40) o ( O.OYO)Moderate 11 (64.7Yo) 11 (57.9%) 4 (20.OYO) 1 ( 5.OYO)Severe 4 (23.5%) 5 (26.3VO) 14 (70.0%) 19 (95.070)Missing o 0 0 0

Nasal pruritusAbsent 2 (1 1.8%) 2 (10.5YO) o ( 0.0%) o ( 0.0%)Mild 3 (17.6%) 3 (15.8%) o ( O.OYO) o ( O.OYO)Moderate 12 (70.6%) 13 (68.4%) 2 (10.0%) 6 (30.0%)Severe o ( O.OYO) 1 ( 5.3YO) 18 (90.0?40) 14 (70.OVO)Missing o 0 0 0

lcular pruritusAbsent 8 (47. l~o) 9 (47.4%) 2 (10.0%) 10 (50.0%)Mild 6 (35.3%) 6 (31.6%) 4 (20.0%) 2 (10.0%)Moderate 3 (17.6%) 4 (21.lYO) 3 (15.0?40) 4 (20.OYO)Severe o ( 0.0%) o ( O.OYO) 11 (55.0?40) 4 (20.070)Missing o 0 0 0

vlaximal symptom scoreAbsent o ( O.OYO) o ( 0.0%) o ( o%) o ( o%)Mild 1 ( 5.9YO) o ( O.OYO) o ( o%) o ( 0?40)Moderate 11 (64.7%) 12 (63.2%) o ( 0!40) o ( 0’%0)Severe 5 (29.4Yo) 7 (36.8%) 20 ( 100%) 20 (loo%)Missing o 0 0 0


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TABLE 14.1-8- Continued: CLINICAL SYMPTOMSIntention to Treat Population


Sneezing p= O.178Rhinorrhea p = 0.236Nasal obstruction p= O.187Nasal pruritus p = 0.468Ocular pruritus p = 0.057Maximal symptom score p = 0.496


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TABLE 14.1-9: CLINICAL SYMPTOMS - TOTAL SYMPTOM SCOREIntention to Treat Population


All PatientsMean 10.3 10.2 10.3St. dev. 2.9 2.4 2.6

Minimum 2 4 225% percentile 8 8 8Median 10 10 1075% percentile 12 12 12

Maximum 15 15 15Number 37 39 76Missing o 0 0

Centre 1Mean 7.9 8.3St. dev. 2.0 1.5 ,Minimum 2 425% percentile 8 8Median 8 875% percentile 9 9Maximum 10 10Number 17 19Missing o 0

Centre 2Mean 12.4 12.0St. dev. 1.8 1.7Minimum 9 825?40percentile 11 11Median 12 1275% percentile 14 13Maximum 15 15Number 20 20Missing o 0

RESULT OF THE COMPARISONTwo-way Analysis of Variance

Centre Treatment InteractionTotal symtom score p <0.001 p = 0.975 p = 0.337


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TABLE 14.1-10: VAS OF GLOBAL STATUS OF NASAL CONDITION (mm)Intention to Treat Population

Loratadine Cetirizine All Patients(N= 37) (N “ 39) (N= 76)

All PatientsMeanSt. dev.Minimum25% percentileMedian75% percentileMaximumNumberMissing

Centre 1MeanSt. dev.Minimum25% percentileMedian75’?40percentileMaximumNumberMissing

Centre 2MeanSt. dev.Minimum25% percentileMedian75?40percentileMaximumNumberMissing

75.414.637677490

10037

0

65.912.03764677382170

83.511.460758590

10020

0

72.514.042637080

10039

0

63.511.0 ,4257637285190

81.011.165708090

10020

0

73.914.337657281

10076

0


Centre Treatment Interaction~lobal status (VAS) p -=0.001 p = 0.350 p = 0.986


..-4,.., , ,, ,,. ,, M, .I”.,!””-w,..


TABLE 14.1-11: RHINOMANOMETRY (l/rein)Intention to Treat Population


All PatientsMean 93.4 86.4 89.8St. dev. 54.7 43.5 49.1Minimum 30 30 3025’XOpercentile 60 50 60Median 80 80 8075’?40percentile 100 100 100Maximum 310 210 310Number 37 39 76Missing o 0 0

Centre 1Mean 118.2 106.3St. dev. 68.9 52.5Minimum 60 40 ‘25?40percentile 70 60Median 100 10075% percentile 120 150Maximum 310 210Number 17 19Missing o 0

Centre 2Mean 72.3 67.5St. dev. 25.6 20.2Minimum 30 3025% percentile 58 50Median 68 7875?40percentile 83 80Maximum 130 90Number 20 20

Missing o 0


Centre Treatment InteractionRhinomanometry p <0.001 p = 0.422 p = 0.732


“!”-,.,., ~, ,,! ,, .,, ,, ““ ,.,!,,,-!-.

STUDY No.: 9153

,PROTOCOLNo.: MPCE91L1802/6D of 187

TABLE 14.1-12: PRICK TEST - WHEAL SURFACE AREA (mm*)Intention to Treat Population


All PatientsMean 45.26 44.11 44.67St. dev. 28.80 34.77 31.78Minimum 4.1 6.1 4.125% percentile 16.3 14.1 14.1Median 48.8 35.3 43.275% percentile 69.2 66.6 67.9Maximum 100.9 134.8 134.8Number 32 34 66Missing 5 5 10

Centre 1Mean 18.09 12.25St. dev. 14.03 7.20 ,Minimum 4.1 6.125% percentile 10.0 7.1Median 12.7 10.175% percentile 18.6 14.6Maximum 53.0 33.4Number 13 14Missing 4 5

Centre 2Mean 63.85 66.42St. dev. 19.99 28.15Minimum 27.4 14.525% percentile 50.4 56.2Median 62.8 66.17570 percentile 75.5 85.6Maximum 100.9 134.8Number 19 20Missing 1 0


Centre Treatment InteractionWheal surface area p <0.001 p = 0.747 p = 0.409


..-,,,.,, ,, ., .“ “-.1l..


TABLE 14.1-13: PRICK TEST - FLARE SURFACE AREA (mmz)Intention to Treat Population (Centre 2)


Centre 2MeanSt. dev.Minimum25% percentileMedian7570 percentileMaximumNumberMissing

437.8149.8236308422566761

191

435.0139.0169352431509669

200

436.3142.5169341425529761

391

RESULT OF THE COMPARISONOne-way Analysis of Variance

Treatment

Flare surface area p = 0.952 ‘


,,--,,.,., ,..4 ,. ,,,.,,,,-.,. , .


14.2 EFFICACY DATA

TABLE 14.2-1: CLINICAL SYMPTOMS - SNEEZINGIntention to Treat Population

Loratadine Cetirizine(N= 37) (-N= 39)

Visit 1Absent o ( O.OYO) o ( O.OYO)Mild 8 (21 .6Yo) 5 (12.8%)Moderate 20 (54.1 ‘XO) 21 (53.8%)Severe 9 (24.3Yo) 13 (33.3%)Missing o 0

Visit 2Absent 13 (36.1%) 15 (38.5?40)Mild 18 (50. O’YO) 21 (53.8Yo)Moderate 5 (13.9%) ‘2( 5.170)Severe o ( O.ovo) 1 ( 2.6Yo)Missing 1 0

Last EvaluationAbsent 13 (35.1%) 15 (38.5Yo)Mild 18 (48.6%) 21 (51.8%)Moderate 6 (16.2Yo) 2 ( 5.lYO)Severe o ( 0.0!40) 1 ( 2.6Yo)Missing o 0

RESULT OF THE COMPARISONCochran-Mantel-Haenszel Test (Controlling for baseline score)

Last evaluation p=o.319


“.....,,,.,., .,, ., “““ .-. ,,~..,%..


TABLE 14.2-1- Continued: CLINICAL SYMPTOMS - SNEEZINGIntention to Treat Population


(N= 17) (N=19) (N= 20) (N= 20)

Visit 1Absent o ( 0.0%) o ( 0.0?40) o ( 0.0%) o ( 0.0%)Mild 5 (29.4%) 5 (26.3’?40) 3 (15.OVO) o ( 0.0?40)Moderate 11 (64.7%) 14 (73 .770) 9 (45.0’?40) 7 (35.OYO)Severe 1 ( 5.9%) o ( 0.0’%0) 8 (40.0%) 13 (65. O’XO)

Missing o 0 0 0

Visit 2Absent 9 (56.3Yo) 8 (42.1%) 4 (20. O’YO) 7 (35.0%)Mild 6 (37.5Yo) 10 (52.6%) 12 (60.0%) 11 (55.0%)Moderate 1 ( 6.3Yo) 1 ( 5.3%) 4 (20.0%) 1 ( 5.0%)Severe o ( 0.0?40) o ( O.OYO) o ( 0.0?40) 1 ( 5.0%)Missing 1 0 0 0

Last EvaluationAbsent 9 (52.9Yo) 8 (42.1%) 4 (20.0’?40) 7 (35.0%)

Mild 6 (35.3?40) 10 (52.6%) 12 (60.0%) 11 (55.0?40)Moderate 2 (11.8’?40) 1 ( 5.3%) 4 (20.0%) 1 ( 5.0%)

Severe o ( 0.0%) o ( 0.0%) o ( 0.0%) 1 ( 5.0%)Missing o 0 0 0


.,-.,,,,.., ! ,“, ,,, ,., ,,M.,...


TABLE 14.2-2: CLINICAL SYMPTOMS - RHINORRHEAIntention to Treat Population


(N= 37) (N= 39)

Visit 1Absent o ( 0.0%) o ( O.OYO)Mild 5 (13.5%) 4 (10.3YO)

Moderate 20 (54. lYO) 19 (48.7%)Severe 12 (32.4%) 16 (41.0?40)Missing o 0

Visit 2Absent 13 (36.lYo) 26 (66.7%)

Mild 16 (44.4%) 5 (12.8%)

Moderate 7 (19.4%) 6 (15.4Yo).

Severe o ( 0.0%) 2( 5.1%)

Missing 1 0

Last EvaluationAbsent 13 (35.lYO) 26 (66.7%)

Mild 16 (43.2%) 5 (12.8%)

Moderate 8 (21 .6Yo) 6 (15.4VO)Severe o ( 0.0?40) 2 ( 5.1%)Missing o 0


Last evaluation p = 0.049


,“,--, ,., ,,, “. - ,,-..,-


TABLE 14.2-2- Continued: CLINICAL SYMPTOMS - RHINORRHEAIntention to Treat Population


(N=17) (N=19) (N= 20) (N= 20)

Visit 1Absent o ( 0.0’70) o ( O.OYO) o ( 0.0?’40) o ( 0.0%)Mild 4 (23.5Yo) 2 (10.5’YO) 1 ( 5.0%) 2 (10.OYO)Moderate 12 (70.6?40) 14 (73.7%) 8 (40.0?40) 5 (25.0%)Severe 1 ( 5.9?40) 3 (15.8%) 11 (55.0%) 13 (65.0%)Missing o 0 0 0

Visit 2Absent 9 (56.3Yo) 15 (78.9?40) 4 (20.0%) 11 (55.0%)Mild 5 (3 1.3%) 2 (10.5YO) 11 (55.OYO) 3 (15.,OYO)Moderate 2 (12.5Yo) 2 (10.5YO) 5 (25.0?40) 4 (20.0?40)Severe o ( 0.0?40) o ( O.OYO) o ( 0.0%) 2 (10.OYO)Missing 1 0 0 0

Last EvaluationAbsent 9 (52.9?40) 15 (78.9Yo) 4 (20.0%) 11 (55.OYO)Mild 5 (29.4%) 2 (10.5%) 11 (55.0%) 3 (15.OYO)Moderate 3 (17.6%) 2 (10.5%) 5 (25.0%) 4 (20.0%)Severe o ( O.ovo) o ( 0.0’%0) o ( O.ovo) 2 (10.OVO)Missing o 0 0 0


,4.-4.,., , ,, ,. ,,. ,,.# ,, .- !!-.!-.


TABLE 14.2-3: CLINICAL SYMPTOMS - NASAL OBSTRUCTIONIntention to Treat Population


(N= 37) (N= 39)

Visit 1Absent 2 ( 5.4’%0) o ( 0.0%)Mild 2 ( 5.4VO) 3 ( 7.770)

Moderate 15 (40.5%) 12 (30.8%)

Severe 18 (48.6Yo) 24 (61 .5%)

Missing o 0

Visit 2Absent 12 (33.3YO) 10 (25.6%)

Mild 11 (30.6%) 14 (35.9%)

Moderate 12 (33.3%) 13 (33.3%).

Severe 1 ( 2.8Yo) 2( 5.1’%0)Missing 1 0

Last EvaluationAbsent 12 (32.4%) 10 (25.6%)

Mild 11 (29.7%) 14 (35.9%)

Moderate 13 (35.1%) 13 (33.370)

Severe 1 ( 2.7Yo) 2 ( 5.1?40)Missing o 0




“.-, .,., , ,.,

STUDY No.: 9153PROTOCOL No.: MPCE91 L 1802/6D . of 187

TABLE 14.2-3- Continued: CLINICAL SYMPTOMS - NASAL OBSTRUCTIONIntention to Treat Population


(N=17) (N=19) (N= 20) (N= 20)

Visit 1Absent 1 ( 5.9?40) o ( 0.0%) 1 ( 5.OVO) o ( 0.0%)Mild 1 ( 5.9%) 3 (15.8Yo) 1 ( 5.0?40) o ( O.OYO)Moderate 11 (64.7%) 11 (57.9’-XO) 4 (20.0%) 1 ( 5.0?40)Severe 4 (23.5Yo) 5 (26.3Yo) 14 (70.OYO) 19 (95.0%)Missing o 0 0 0

Visit 2Absent 3 (18.8’YO) 3 (15.8%) 9 (45.OYO) 7 (35.0%)Mild 4 (25.0%) 9 (47.4%) 7 (35.OYO) 5 (25.,OVO)Moderate 8 (50.0%) 6 (3 1.6%) 4 (20.0%) 7 (35.0%)Severe 1 ( 6.3%) 1 ( 5.3YO) o ( 0.0%) 1 ( 5.0%)Missing 1 0 0 0

Last EvaluationAbsent 3 (17.6Yo) 3 (15.8Yo) 9 (45.070) 7 (35.OVO)

Mild 4 (23.5Yo) 9 (47.4?40) 7 (35.0%) 5 (25.0%)Moderate 9 (52.9%) 6 (31.6%) 4 (20.0%) 7 (35.0%)Severe 1 ( 5.9%) 1 ( 5.3%) o ( 0.0%) 1 ( 5.0?40)Missing o 0 0 0


“,-w,,. .! ., w.!,.. ....


TABLE 14.2-4: CLINICAL SYMPTOMS - NASAL PRURITUSIntention to Treat Population


Visit 1Absent 2 ( 5.4%) 2( 5.1’XO)

Mild 3 ( 8.1°/0) 3 ( 7.7%)

Moderate 14 (37.8Yo) 19 (48.7%)Severe 18 (48.6Yo) 15 (38.5Yo)

Missing o 0

Visit 2Absent 15 (41.7%) 21 (53.8%)

Mild 16 (44.4%) 13 (33.3%)

Moderate 5 (13.9’YO) 5 (12.8Yo),

Severe o ( 0.0%) o ( 0.0%)

Missing 1 0

Last EvaluationAbsent 15 (40.5%) 21 (53.8%)

Mild 16 (43.2%) 13 (33.370)

Moderate 6 (16.2%) 5 (12.8%)

Severe o ( O.OYO) o ( 0.0?40)

Missing o 0


Last evaluation p= O.156


M-..# l.).! . ,,. ,,w ,. .“. !! ,-<..


TABLE 14.2-4- Continued: CLINICAL SYMPTOMS - NASAL PRURITUSIntention to Treat Population

Centre 1 Centre 2Loratadine Cetirizine Loratadine Cetirizine(N=17) (N=19) (N ‘ 20) (N= 20)

Visit 1Absent 2 (11.8%) 2 (10.5YO) o ( 0.0%) o ( O.OYO)Mild 3 (17.6Yo) 3 (15.8!XO) o ( 0.070) o ( O.OYO)Moderate 12 (70.6%) 13 (68.4%) 2 (10.0%) 6 (30.OYO)

Severe o ( O.ovo) 1 ( 5.3%) 18 (90.070) 14 (70.0%)

Missing o 0 0 0

Visit 2Absent 6 (37.5%) 10 (52.6Yo) 9 (45. O?ZO) 11 (55.070)

Mild 7 (43.8 !!40) 6 (3 1.6Yo) 9 (45.0%) 7 (35.y??)Moderate 3 (18.8%0) 3 (15.8?40) 2 (10.OYO) 2 (10.OYO)

Severe o ( 0.0?40) o ( 0.0%) o ( 0.0%) o ( 0.0%)Missing 1 0 0 0

Last EvaluationAbsent 6 (35.370) 10 (52.6?40) 9 (45.OYO) 11 (55.0?40)

Mild 7 (41 .2%) 6 (3 1.6Yo) 9 (45.OVO) 7 (35.0%)

Moderate 4 (23.5?40) 3 (15.8%) 2 (10.0%) 2 (10.OYO)

Severe o ( 0.0?40) o ( 0.0’?40) o ( O.ovo) o ( 0.0%)

Missing o 0 0 0


.,—,,., , ,“, ... ,.” m,,!!-4.!,


TABLE 14.2-5: CLINICAL SYMPTOMS - OCULAR PRURITUSIntention to Treat Population


Visit 1AbsentMildModerateSevereMissing


Last EvaluationAbsentMildModerateSevereMissing

10 (27.0%)10 (27.OYO)6 (16.2%)

11 (29.7%)o

25 (69.4Yo)8 (22.270)3 ( 8.3?40)o ( 0.0%)1

25 (67.6%)8 (21.6%)4 (10.8%)o ( 0.0’%0)o

19 (48.7%)8 (20.5Yo)8 (20.5%)4 (10.3%)o

30 (76.9%)8 (20.5%)1 ( 2.6?40)o ( O.OYO)o

30 (76.9%)8 (20.5%)1 ( 2.6%)o ( O.ovo)o




..—,. ., .,, . -..4!. . .. .


TABLE 14.2-5- Continued: CLINICAL SYMPTOMS - OCULAR PRURITUSIntention to Treat Population


(N=17) (N=19) (N= 20) (N= 20)

Visit 1Absent 8 (47.1%) 9 (47.4VO) 2 (10. O’YO) 10 (50.0%)Mild 6 (35.3%) 6 (3 1.6Yo) 4 (20.0%) 2 (10.0’?40)Moderate 3 (17.6Yo) 4 (21.lYO) 3 (15.OYO) 4 (20.0%)Severe o ( O.ovo) o ( 0.0’%0) 11 (55.0%) 4 (20.0?40)Missing o 0 0 0

Visit 2Absent 14 (87.5%) 14 (73.7%) 11 (55.0%) 16 (80.0%)Mild 2 (12.5%) 4 (21.l!ZO) 6 (30.0%) 4 (20.0%)Moderate o ( O.OYO) 1 ( 5.3%) 3 (15.OYO) o ( 0.0’%0)Severe o ( O.OYO) o ( O.OYO) o ( O.OYO) o ( 0.070)Missing 1 0 0 0

Last EvaluationAbsent 14 (82.4Yo) 14 (73.7YO) 11 (55.0%) 16 (80.0%)Mild 2 (11.8’%0) 4 (21.1%) 6 (30.OYO) 4 (20.OVO)Moderate 1 ( 5.9?40) 1 ( 5.3%) 3 (15.0%) o ( 0.0%)Severe o ( 0.0%) o ( O.OYO) o ( 0.0%) o ( O.OYO)Missing o 0 0 0



TABLE 14.2-6: CLINICAL SYMPTOMSMAXIMAL SYMPTOM SCOREIntention to Treat Population




Last EvaluationAbsentMildModerateSevereMissing

o ( O.OYO)1 ( 2.7%)

11 (29.7?40)25 (67.6?40)

o

3 ( 8.3Yo)11 (30.6VO)21 (58.3%)

1 ( 2.8Yo)1

3 ( 8.lYo)11 (29.7%)22 (59.5%)

1 ( 2.7Yo)o

0 ( O.OYO)o ( 0.0’%0)

12 (30.8VO)27 (69.2Yo)

o

4 (10.3YO)18 (46.2%)14 (35.970)3 ( 7.7%)o

4 (10.3YO)18 (46.2Yo)14 (35.9%)

3 ( 7.7%)o

RESULT OF THE COMPARISON

Cochran-Mantel-Haenszel Test (Controlling for baseline score)

Last evaluation p= O.162


.!--,,,., , ., ,, w..,,w..,,---- ,.


TABLE 14.2-6- Continued: CLINICAL SYMPTOMSMAXIMAL SYMPTOM SCOREIntention to Treat Population


(N=17) (N=19) (N= 20) (N= 20)

Visit 1Absent o ( O.ovo) o ( 0.0%) o ( o%) o ( OYO)Mild 1 ( 5.9?40) o ( 0.0?40) o ( o%) o ( o%)Moderate 11 (64.7%) 12 (63 .2?Ao) o ( OYO) o ( 0’?40)Severe 5 (29.4?40) 7 (36.8Yo) 20 (1OOYO) 20 (1OOYO)Missing o 0 0 0

Visit 2Absent 1 ( 6.3Yo) 1 ( 5.3%) 2 (10.0%) 3 (15.OYO)Mild 4 (25.0%) 10 (52.6?40) 7 (35.0%) 8 (40.OVO)Moderate 10 (62.5%) 7 (36.8%) 11 (55.OYO) 7 (35.0%)Severe 1 ( 6.3%) 1 ( 5.3’?40) o ( O.OYO) 2 (10.0?40)Missing 1 0 0 0

Last EvaluationAbsent 1 ( 5.9?40) 1 ( 5.3%) 2 (10. O’YO) 3 (15.OYO)Mild 4 (23.5Yo) 10 (52.6%) 7 (35.0%) 8 (40.0?40)Moderate 11 (64.7%) 7 (36.8Yo) 11 (55.OYO) 7 (35.0!40)Severe 1 ( 5.9%) 1 ( 5.3%) o ( O.OYO) 2 (10.0%)Missing o 0 0 0

REPORT No.: MRCE98G0201/1 V Stody Report December 1, 1998

..G=,.,., ,,, .1 w,,1,-, ”..

STUDY No.: 9153PROTOCOL Iio.: MPCE91 L 1802/6D of 187

TABLE 14.2-7: CLINICAL SYMPTOMSEVOLUTION BETWEEN BASELINE AND LAST VISITIntention to Treat Population


(N= 37)

SneezingWorsening 1 ( 2.7Yo)

No change 5 (13.5%)

Improvement 31 (83.8%)

Number 37

Missing o

RhinorrheaWorsening o ( 0.070)

No change 9 (24.3%)

Improvement 28 (75.7Yo)

Number 37

Missing o

Nasal obstructionWorsening o ( O.ovo)

No change 10 (27.0%)

Improvement 27 (73.OYO)

Number 37

Missing o

Nasal pruritusWorsening o ( 0.0%)

No change 6 (16.2Yo)

Improvement 31 (83.8VO)

Number 37

Missing o

Ocular pruritusWorsening 1 ( 2.7%)

No change 11 (29.7%)


Number 37

Missing o

Maximal symptom scoreWorsening o ( 0.0%)

No change 8 (21.6%)


Number 37

Missing o

(N= 39)

1 ( 2.6%)3 ( 7.7YO)

35 (89.7%)39

0

0 ( 0.0%)5 (12.8%)

34 (87.2Yo)39

0

2( 5.1?40)5 (12.8%)

32 (82. lYo)39

0

0 ( 0.0%)4 (10.3YO)

35 (89.7VO)39

0

0 ( O.OYO)24 (61.5%)15 (38.5%)39

0

0 ( 0.0%)8 (20.5%)

31 (79.5%)39

0

REPORT No. : MRCE98G0201 /1 V Study Report December 1, 1998

,. ,W. ,, !&,,,,, ,.

.’ -”,...,


TABLE 14.2-7 Continued: CLINICAL SYMPTOMSEVOLUTION BETWEEN BASELINE AND LAST VISITIntention to Treat Population

RESULTS OF THE COMPARISONSWilcoxon Test

Loratadine CetirizineSneezing p <0.001 p <0.001Rhinorrhea p <0.001 p <0.001Nasal obstruction p <0.001 p <0.001Nasal pruritus p <0.001 p <0.001Ocular pruritus p <0.001 p <0.001Maximal symptom score p <0.001 p <0.001


“.--< ,. ,., . ..,, -, ... . ..! ,,


TABLE 14.2-8: CLINICAL SYMPTOMSTOTAL SYMPTOM SCORE - Intention to Treat Population

Loratadine (N = 37) Cetirizine (N = 39)

Visit 1Mean 10.3 10.2

St. dev. 2.9 2.4

Minimum 2 4

25% percentile 8 8

Median 10 10

75?40percentile 12 12

Maximum 15 15

Number 37 39

Missing o 0

Visit 2Mean 3.8 3.3

St. dev. 2.3 2.7

Minimum o 0

25% percentile 2 1

Median 4 2

75% percentile 6 5

Maximum 9 10

Number 36 39

Missing 1 0

Last EvaluationMean 3.9 3.3

St. dev. 2.5 2.7

Minimum o 025?40percentile 2 1

Median 4 2

75?40percentile 6 5

Maximum 10 10Number 37 39

Missing o 0

Visit 1- Last EvaluationMean 6.4 6.8

St. dev. 3.4 3.0

Minimum o 0

25% percentile 4 5

Median 5 7

75% percentile 9 9Maximum 14 13Number 37 39Missing o 0


.- !..,< ,, ,!, . . . ,-.! .,- .--...,,


TABLE 14.2-8- Continued: CLINICAL SYMPTOMSTOTAL SYMPTOM SCORE - Intention to Treat Population

Centre 1 Centre 1 Centre 2 Centre 2Loratadine Cetirizine Loratadine Cetirizine(N=17) (N=19) (N= 20) (N= 20)

Visit 1Mean 8.3 12.4 12.0St. dev. ;:: 1.5 1.8 1.7Minimum 2 425% percentile 8 8 1? 1!Median 12 1275% percentile ; ! 14 13MaximumNumber 1; !: ;; ;;Missing o 0 0 0

Visit 2Mean 3.4 3.2 4.1St. dev. 1.8 2.6 2.6 ;:;Minimum o 0 025% percentile 2 ;Median : 2 4 ;75% percentile 4 6. 6Maximum 2Number 16 ;! 2; 2:Missing 1 0 0 0

Last EvaluationMean 4.1St. dev. ;:: ;:: 2.6 ;:;Minimum o 025% percentile ; :Median 4 : i75?40percentile : 6 6Maximum 1: 10Number 17 19 2; 2:Missing o 0 0 0

Visit 1 – Last EvaluationMean 4.1 8.3St. dev. 1.7 ;:; 3.4 ;:2Minimum o 0 3 425% percentile 4 3 6 6Median 4 575% percentile 1; 1!Maximum ; 1:Number 17 19 ;: ;;Missing o 0 0 0


,.-, . . . ,. ,, ., !, . . ,W ,- ,..>.,.”,,


TABLE 14.2-8- Continued: CLINICAL SYMPTOMSTOTAL SYMPTOM SCOREIntention to Treat Population


Centre Treatment Interaction

Last Evaluation - Visit 1 p <0.001 p = 0.330 p = 0.466

REPORT No.: MRCE98G0201/1 V

m.. . . . .. .

Study Report December 1, 1998

., ,, ,,,. ,. .,, ,W .,.-. . ..-...”. .4.

STUDY No.: 9153PROTOCOL No.: MPCE91L1802/6D of187

TABLE 14.2-9: VAS OF GLOBAL STATUS OF NASAL CONDITION (mm)Intention to Treat Population


(N=37) (N= 39)


St. dev. 14.6 14.0

Minimum 37 42

25% percentile 67 63

Median 74 70


Maximum 100 100

Number 37 39

Missing o 0Visit 2

Mean 33.4 34.3

St. dev. 25.2 27.9

Minimum o 025% percentile 11 ‘ 10

Median 30 30

75’?40percentile 53 60

Maximum 80 79

Number 36 39

Missing 1 0


St. dev. 25.5 27.9

Minimum o 0


Median 30 30

75’XOpercentile 54 60

Maximum 80 79

Number 37 39

Missing o 0


St. dev. 31.3 31.7

Minimum -6 -lo

25’?40percentile 14 7

Median 40 38

75?40percentile 70 70

Maximum 90 90

Number 37 39

Missing o 0


,“+. ,.. . ,. 1, ,,. ,, ,. .,.! - ......-.


TABLE 14.2-9- Continued: VAS OF GLOBAL STATUS OF NASAL CONDITION (mm)Intention to Treat Population

Centre 1 Centre 1 Centre 2 Centre 2Loratadine Cetirizine Loratadine Cetirizine(N=17) (N= 19) (N= 20) (N= 20)

Visit 1Mean 65.9 63.5 83.5 81.0St. dev. 12.0 11.0 11.4 11.1Minimum 42 60 6525940percentile :: 75 70Median 67 i;75940percentile 73 72 ;; ;;Maximum 82 85 100 100Number 17 19 20 20Missing o 0 0 0

Visit 2Mean 49.9 51.3 20.3 18.3St. dev. 25.6 23.6 15.7 2~.7Minimum o25’% percentile 3; 2:Median 2: 1:75% percentile ;: 2; 30 , 30Maximum 80 79Number 16 19 ;: 1Missing 1 0 0 0

Last EvaluationMean 50.9 51.3 20.3 18.3St. dev. 25.1 23.6 15.7 21.7Minimum o 025?40percentile 4: 2:Median 2: 1:75% percentile ;; X 30Maximum 80 79 50 ;:Number 17 19 20 20Missing o 0 0 0

Visit 1- Last EvaluationMean 15.0 12.2 63.3 62.8St. dev. 18.0 18.8 21.5 19.1Minimum -6 -lo 20 2025% percentile 3 -1 50 60Median 7 65 707570 percentile ;: 80 73Maximum 54 ::Number 17 19 ;: ;;Missing o 0 0 0

REPORT No. : MRCE98G0201/ 1V Study Report December 1, 1998

,.,qu, ,.” .,. 1 ,., .,,, ,x,“..,..”.,,.

STUDY No.: 9153

PROTOCOL No.: MPCE91L1802/6D of 187

TABLE 14.2-9- Continued: VAS OF GLOBAL STATUS OF NASAL CONDITION (mm)

Intention to Treat Population



Visit 1- Last Evaluation p <0.001 p=o.714 p = 0.799


,,,-.,,” . ,...,. .,., . ,H. ,.-,.,. ,


TABLE 14.2-10: RHINOMANOMETRY (l/rein)Intention to Treat Population


Visit 1MeanSt. dev.Minimum25% percentileMedian75% percentileMaximumNumberMissing

Visit 2MeanSt. dev.Minimum25’XOpercentileMedian75?40percentileMaximumNumberMissing

Last EvaluationMeanSt. dev.Minimum25% percentileMedian75’%0percentileMaximumNumberMissing

Last Evaluation - Visit 1Mean

St. dev.Minimum25% percentileMedian75% percentileMaximumNumberMissing

93.454.7306080

100310

370

140.753.260

100130180270

352

143.160.360

100130180310

370

49.7

54.9-40104080

19037

0

86.443.5305080

100210

390

128.655.040

‘ 90125155250

363

131.355.64090

130180250

390

44.950.8

-400

4080

18039

0


,.-. . ,, I ,. ., ., ., ., ,- ...m..m,


TABLE 14.2-10- Continued: RHINOMANOMETRY (l/rein)Intention to Treat Population

Centre 1 Centre 1 Centre 2 Centre2Loratadine Cetirizine Loratadine Cetirizine

(N= 17) (N= 19) (N= 20) (N= 20)

Visit 1Mean 118.2 106.3 72.3 67.5St. dev. 68.9 52.5 25.6 20.2Minimum 60 40 30 3025% percentile 58 50Median 1:: 1:: 68 7875% percentile 120 150Maximum 310 210 1:: $;Number 17 19 20 20Missing o 0 0 0

Visit 2Mean 132.0 126.9 147.3 130.0St. dev. 60.0 53.6 47.9 57.4Minimum 60 4025?40percentile 1:! XMedian 1!!: 1!! 140 12075% percentile 190 180 170 ‘ 150Maximum 250 200 270 250Number 15 16 20 20Missing 2 3 0 0

Last EvaluationMean 138.2 132.6 147.3 130.0St. dev. 73.6 55.2 47.9 57.4Minimum 60 4025% percentile 1:! ?:Median 1;: 1:: 140 12075% percentile 190 180 170 150Maximum 310 210 270 250Number 17 19 20 20Missing o 0 0 0

Last Evaluation - Visit 1Mean 20.0 26.3 75.0 62.5St. dev. 40.2 37.4 53.8 56.3Minimum -40 -20 -lo -4025% percentile -lo 0 40 30Median 10 5575% percentile ;: 1::Maximum 1:: 100 190 1::Number 17 19 20 20Missing o 0 0 0


,..-., . , 1 ,., ., ., “..,., ,,=M,. .... . .... . . L


TABLE 14.2-10- Continued: RHINOMANOMETRY (l/rein)Intention to Treat Population


Centre Treatment InteractionLast Evaluation - Visit 1 p <0.001 p = 0.782 p = 0.399


.W-.. ,! ,,, , ,.. . ., ,., .. .“., 4 . ..’ . ...’- .,!


TABLE 14.2-11: PRICK TEST - WHEAL SURFACE AREA (mm)Intention to Treat Population


Visit 1Mean 45.26 44.11

St. dev. 28.80 34.77

Minimum 4.1 6.1

25% percentile 16.3 14.1

Median 48.8 35.3

75V0 percentile 69.2 66.6

Maximum 100.9 134.8

Number 32 34

Missing 5 5


St. dev. 11.39 9.82

Minimum 0.1 0.1

25% percentile 5.0 ‘ 1.3

Median 7.0 4.4


Maximum 39.4 38.6

Number 30 31

Missing 7 8


St. dev. 11.04 9.56

Minimum 0.1 0.1

25?40percentile 5.0 2.0

Median 7.6 5.2


Maximum 39.4 38.6

Number 32 34

Missing 5 5


St. dev. 25.60 31.86

Minimum -6.0 -1.9


Median 29.9 32.9

750/0percentile 52.6 59.4

Maximum 83.6 106.5

Number 32 34

Missing 5 5


.,,-<. ,, ., ,.. ,- ... ......

STUDY No.: 9153PROTOCOL No.: MPCE91L 1802/6D of 187

TABLE 14.2-11- Continued: PRICK TEST - WHEAL SURFACE AREA (mm’)Intention to Treat Population

Centre 1 Centre 1 Centre 2 Centre 2

Loratadine Cetirizine Loratadine Cetirizine(N=17) (N=19) (N= 20) (N= 20)

Visit 1Mean 18.09 12.25 63.85 66.42St. dev. 14.03 7.20 19.99 28.15Minimum 4.1 6.1 27.4 14.525% percentile 10.0 50.4 56.2Median 12.7 1::1 62.8 66.175% percentile 18.6 14.6 75.5 85.6Maximum 53.0 33.4 100.9 134.8Number 13 14 19 20Missing 4 5 1 0

Visit 2Mean 5.09 2.89 15.93 11.44St. dev. 3.21 2.33 12.56 lj.y5Minimum 0.8 0.5 0.125% percentile 3.0 2:1Median 5.0 ;:: 1!:75’% percentile 3.6 27.1 1::;Maximum 1!:; 7.8 39.4 ‘ 38.6Number 11 11 19 20Missing 6 8 1 0

Last EvaluationMean 6.01 5.13 15.93 11.44St. dev. 3.88 5.33 12.56 11.05Minimum 0.8 0.125?40percentile 3.1 !:; $;Median 5.4 2.7 1!::75% percentile 27.1 1!:;Maximum 1!:: 1;:: 39.4 38.6Number 13 14 19 20Missing 4 5 1 0

Visit 1- Last EvaluationMean 12.08 7.11 47.92 54.98St. dev. 14.92 8.34 20.72 26.87Minimum -6.0 -1.7 -1.925% percentile 2.4 0.0 2::! 39.9Median 50.2 56.775% percentile 1::: 1[:? 63.7 69.7Maximum 47.4 31.3 83.6 106.5Number 13 14 19 20Missing 4 5 1 0


,.~-., - ,, ,,, .,. ., ., .,., ,Mw . . . ..- .-.-..

STUDY NO.: 9153PROTOCOL No.: MPCE91L1802/6D Page llOof 187

TABLE 14.2-11- Continued: PRICK TEST - WHEAL SURFACE AREA (mm*)Intention to Treat Population



Visit 1- Last Evaluation p <0.001 p = 0.836 p = 0.237

REPORT No.: MRCE98G0201/1 V

,,m”., ,

Study Report

,., ,,

December 1, 1998

. .. .- ... ..- .”.

STUDY No.: 9153PROTOCOL No.: MPCE91L1802/6D Page lllof 187

TABLE 14.2-12: PRICK TEST - FLARE SURFACE AREA (mm*)Intention to Treat Population (Centre 2)


(N= 20) (N=20)

Visit 1MeanSt. dev.Minimum25?/o percentileMedian75% percentileMaximumNumberMissing

Visit 2MeanSt. dev.Minimum25?40percentileMedian75% percentileMaximumNumberMissing

Last EvaluationMeanSt. dev.Minimum25’?40percentileMedian75% percentileMaximumNumberMissing

Visit 1- Last EvaluationMeanSt. dev.Minimum25’%0percentileMedian75% percentileMaximumNumberMissing

437.8149.8236308422566761

191

154.290.83089

123235384

191

154.290.83089

123235384

191

283.6187.9-23125252450644

191

435.0139.0169352431509669

200

142.896.23166

105216344

200

142.896.23166

105216344

200

292.2154.753

154316387617

200


,.-.,.. ., I ., ,, ,. . ,.,.,“. - .... .. $,


TABLE 14.2-12- Continued: PRICK TEST - FLARE SURFACE AREA (mm*)Intention to Treat Population

RESULT OF THE COMPARISONAnalysis of Variance

Treatment

Visit 1- Last Evaluation p = 0.876


,..--,! “ ., ,. ,,. .“ ~-. -.-..-.!!


TABLE 14.2-13: DRC - PERCENTAGE OF DAYS WITHOUT SYMPTOMS (PDSO) IIntention to Treat Population


(N= 37) (N= 39)


Centre 1MeanSt. dev.Minimum25% percentileMedian75% percentileMaximumNumberMissing

4.688.980.000.000.007.14

32.1434

3

5.108.370.000.000.00

10.7125.00143

10.6519.610.000.000.00

11.7667.8638

1

14.3421.84

, 0.000.001.79

25.0067.8618

1

Centre 2Mean 4.39 7.32

St. dev. 9.58 17.24

Minimum 0.00 0.00

25?A0percentile 0.00 0.00

Median 0.00 0.00


Maximum 32,14 60.71

Number 20 20

Missing o 0



PDSO p = 0.300 p=o.lo5 p = 0.397


., . . .,, ,.=,....... .

STUDY No.: 9153PROTOCOL No.: MPCE9lL1802/6D 0f 187

TABLE 14.2-14: DRCPERCENTAGE OF DAYS WITH NO OR MILD SYMPTOMS (PDS 1)Intention to Treat Population


All PatientsMeanSt. dev.Minimum25% percentile

Median75°A percentileMaximumNumberMissing

Centre 1MeanSt. dev.Minimum25°4 percentileMedian75’XOpercentileMaximumNumberMissing


35.2033.68

0.003.57

23.2160.71

100.0034

3

31.6729.26

0.0014.8121.4342.8692.86143

37.6737.00

0.000.00

28.5769.64

100.0020

0

39.1032.59

0.007.14

28.5764.29

100.0038

1

45.44, 32.22

0.0017.8650.0064.29

100.0018

1

33.3932.68

0.005.36

25.0057.14

100.0020

0



PDS1 p = 0.704 p = 0.551 p = 0.258


---,....,,, ., , ,., , ,. ., ..., . ... . . . ,.,.”A..+,.,

STUDY No.: 9153PROTOCOL No.: MPCE91 L 1802/6D 0f 187

TABLE 14.2-15: DRCPERCENTAGE OF DAYS WITH AT WORST MODERATE SYMPTOMS (PDS2)Intention to Treat Population


All PatientsMeanSt. dev.Minimum25’% percentileMedian75% percentileMaximumNumberMissing

Centre 1MeanSt. dev.Minimum25’?AopercentileMedian75’?40percentileMaximumNumberMissing


82.8824.11

7.1475.0094.64

100.00100.0034

3

87.2415.0057.1478.5791.07

100.00100.00

143

79.8228.84

7.1466.0798.21

100.00100.0020

0

75.5623.2021.4360.7178.57

100.00100.0038

1.

83.33, 21.88

25.0064.2996.43

100.00100.00

181

68.5722.6121.4355.3666.0789.29

100.0020

0



PDS2 p = 0.049 p=o.175 p = 0.509

REPORT No.:MRCE98G0201/l V Study Report December 1, 1998

,“””,-$!.,,, ,, , ,, ., -, .,,..-,.

STUDY No.: 9153PROTOCOL No.: MPCE9lL1802/6D 0f 187

TABLE 14.2-16: DAILY RECORD CARD - MEAN SNEEZING SCOREIntention to Treat Population


(N= 37) (N= 39)

All PatientsMeanSt. dev.Minimum25’% percentileMedian75?40percentileMaximumNumberMissing



0.980.550.000.500.981.322.04

343

0.810.480.000.430.891.071.57

143

1.110.570.180.661.051.572.04

200

0.890.580.000.320.981.361.86

381

0.780.59

, 0.070.250.661.321.75

181

0.990.570.000.501.091.411.86

200

RESULTS OF THE COMPARISONSTwo-way Analysis of Variance


Mean sneezing score p = 0.063 p = 0.590 p = 0.721


,--s, ,. .,, ,,, .,! .-. .”...”it

STUDY No.: 9153PROTOCOL No.:MPCE9lL1802/6D 0f 187

TABLE 14.2-17: DAILY RECORD CARD - MEAN RHINORRHEA SCOREIntention to Treat Population


(N= 37) (N= 39)

All PatientsMeanSt. dev.Minimum25’?40percentileMedian75% percentileMaximumNumberMissing


Centre 2MeanSt. dev.Minimum25’?40percentileMedian75% percentileMaximumNumberMissing

1.100.600.000.711.161.542.29

343

0.910.560.000.430.981.251.75

143

1.230.610.090.861.271.572.29

200

0.970.820.000.111.131.572.75

381

0.690.690.00

‘ 0.110.381.292.04

181

1.220.870.000.271.341.982.75

200



Mean rhinorrhea score p = 0.013 p = 0.485 p = 0.524


,-,--?#,,., . “,. . . .,, , ., . ,“, .--..-$,’ ,,

STUDY No.: 9153PROTOCOL No.: MPCE91L 1802/6D 0f 187

TABLE 14.2-18: DAILY RECORD CARD - MEAN NASAL OBSTRUCTION SCOREIntention to Treat Population


(N= 37) (N= 39)

All PatientsMeanSt. dev.Minimum25’?40percentileMedian75% percentileMaximumNumberMissing

Centre 1MeanSt. dev.Minimum25V0 percentileMedian75’?40percentileMaximumNumberMissing

Centre 2MeanSt. dev.Minimum25’?40percentileMedian75?40percentileMaximumNumberMissing

1.210.690.000.791.291.752.50

343

1.380.600.141.071.411.792.25

143

1.100.740.000.490.961.632.50

200

1.420.770.000.791.552.002.64

381

1.220.780.040.431.321.962.57

181

1.600.730.001.111.802.042.64

200



Mean nasal obstruction score p = 0.784 p = 0.334 p = 0.058


,-, , .,,,

STUDY No.: 9153PROTOCOL No.: MPCE91 L 1802/6D 0f 187

TABLE 14.2-19: DAILY RECORD CARD - MEAN NASAL PRURITUS SCOREIntention to Treat Population


(N= 37) (N= 39)

All PatientsMean 1.01 0.80

St. dev. 0.68 0.69

Minimum 0.04 0.00

25°A percentile 0.39 0.29

Median 0.95 0.61


Maximum 2.50 2.43

Number 34 38

Missing 3 1

Centre 1Mean 0.92 0.81

St. dev. 0.70 0.56

Minimum 0.04 0.00


Median 0.75 0.61


Maximum 2.21 2.14

Number 14 18

Missing 3 1

Centre 2Mean 1.07 0,79

St. dev. 0.67 0.80

Minimum 0.17 0.00


Median 1.14 0,48


Maximum 2.50 2.43

Number 20 20

Missing o 0



Mean nasal pruritus score p = 0.733 p = 0.239 p = 0.607


!..-+!..’, ,, ,,, , ,, ,. ”... , .,. ,-. .Ie,.e,,,,,


TABLE 14.2-20: DAILY RECORD CARD - MEAN OCULAR PRURITUS SCOREIntention to Treat Population


(N= 37) (N= 39)

All PatientsMeanSt. dev.Minimum25% percentileMedian75?40percentileMaximumNumberMissing


Centre 2MeanSt. dev.Minimum25% percentileMedian75’?40percentileMaximumNumberMissing

0.590.630.000.110.431.002.68

343

0.340.380.000.040.240.611.07

143

0.770.710.000.220.521.202.68

200

0.370.450.000.040.200.541.39

381

0.350.390.000.070.210.541.29

181

0.380.500.000.000.130.771.39

200



Mean ocular pruritus score p = 0.073 p = 0.144 p= O.116


..”-.. ,. .“, ,, ., . . . . . . ,.,,-.-X . ..!..!


TABLE 14.2-21: DAILY RECORD CARD - MEAN TOTAL SYMPTOM SCOREIntention to Treat Population




Centre 2MeanSt. dev.Minimum25V0percentileMedian75% percentileMaximumNumberMissing

4.892.380.953.144.616.54

11.6834

3

4.361.681.963.544.125.217.79

143

5.272.750.952.935.237.48

11.6820

0

4.442.470.962.394.596.079.89

381

3.852.441.001.963.265.619.61

181

4.972.450.963.235.206.189.89

200



Mean total symptom score p = 0.083 p = 0.485 p = 0.852


,.-,!. ,,, ,,, ,. ,,. ,, -, ... .. .


TABLE i 4.2-22: DAILY REcOf+O CARDS - SNEEZING


All patients

\ Mean lSt. dev

w 118 090\Ceti [ 1.16/ 1.00

Lora I 1.12 0.91

Ceti I 1.13 1.02

I 1- I 4 096Ceti I 1.05 0.96

‘=--+=++) \ Lora I 1.061 0.85

Ceti 1.08 0.94

1 Lora 1.06 0.89

Ceti 1.24 0.97

Lora 1.00 0.85

Ceti 1.26 0.98

I Lora 1.15 1.08

Ceti 0.87 0.81

I Lora 1.09 1.00

Ceti 1.16 0.86

‘H1 I Lora I 1.031 0.94

3 lLora / 1.091 0.71

\Ceti I 0.821 0.80

4 Lora 1.06 0.60

Ceti 0.97 0.94

( CONTINUEO )

0.0 1.0 1.0 2.0 3.0 34

0.0 0.0 1.0 2.0 3.0 38

0.0 0.0 1.0 2.0 3.0 34

0.0 0.0 1.0 2.0 3.0 38

0.0 1.0 1.0 2.0 3.0 34

0.0 0.0 1.0 2.0 3.0 38

0.0 1.0 1.0 2.0 3.0 34

0.0 0.0 1.0 2.0 3.0 38

0.0 0.0 1.0 2.0 3.0 34

0.0 0.0 1.0 2.0 3.0 38

0.0 0.0 1.0 1.0 3.0 {34

0.0 0.0 1.0 2.0 3.0 38

0.0 0.0 1.0 2.0 3.0 34

0.0 1.0 1.0 2.0 3.0 38

0.0 0.0 1.0 2.0 3.0 34

0.0 0.0 1.0 2.0 2.0 38

0.0 0.0 1.0 1.0 3.0 34

0.0 0.0 1,0 2.0 3.0 38

0.0 0.0 1.0 2.0 3.0 34

0.0 0.0 1.0 2.0 3.0 38

0.0 0.0 1.0 2.0 3.0 34

0.0 0.0 1.0 2.0 3.0 38

0.0 1.0 1.0 1.0 3.0 34

0.0 0.0 1.0 1.0 3.0 38

0.0 1.0 1.0 1.0 3.0 34

0.0 0.0 1.0 1.0 2.0 38

0.01 1.0/ 1.01 1.01 2.01 34

0.01 0.01 1.01 2.0/ 4.01 38

Missing

3

1

3

1

3

1

3

1

3

1

3

1

3

1

3

1

----13

‘11 3

11

3

1

3

1

-13

1


,, ,, ,.. , .,.,, .e, ~--., ,


TABLE I 4.2-22: DAILY RECORD CARDS - SNEEZING


All patients

Day

15

16

17

18

19

20

21

22

23

24

25

26

27

28

‘=ti I ‘4 4 001 0(

Lora 1.00 0.85 0.0 0.(

Cet i 0.95 0.87 0.0 0.(

Lora 0.88 0.81 0.0 0.(

Ceti 0.95 0.80 0.0 0.(

Lora 1.06 0.85 0.0 0.(

Ceti 0.78 0.75 0.0 ().1

Lora 0.85 0.74 0.0 0.(

Cet i 0.78 0.67 0.0 0.(

Lora 0.88 0.89 0.0 0.(

Ceti 0.70 0.74 0.0 0.(

Lora 0.76 0.79 0.0 0.(

Ceti 0.70 0.70 0.0 0.(

Lora 0.85 0.76 0.0 0.(

Ceti 0.68 0.63 0.0 0.(

Lora 0.88 0.78 0.0 0.(

Ceti 0.62 0.68 0.0 O.c

Lora 0.97 0.85 0.0 O.c

>et i 0.70 0.81 0.0 O.c

-era 0.79 0.82 0.0 O.c

ora I 0.71\ 0.721 0.01 O.C

:eti 0.51 0.65 0.0 O.c

-era 0.75 0.72 0.0 O.c

>eti I 0.641 0.721 O.O\ O.C

1.0 1.0 2.0 34 :

1.0 2.0 2.0 38 1

1.0 2.0 3.0 34 :

1.0 1.0 3.0 38 1

1.0 2.0 2.0 34 :

1.0 1.0 3.0 38 1

1.0 2.0 3.0 34 :

1.0 1.0 2.0 37 :

1.0 1.0 2.0 34 :

1.0 1.0 2.0 37 :

1.0 1.0 3.0 33 L

1.0 1.0 3.0 37 2

1.0 1.0 3.0 33 d

1.0 1.0 2.0 37 :

1.0 1.0 3.0 33 f

1.0 1.0 2.0 37 2

1.0 1.0 3.0 33 4

1.0 1.0 2.0 37 2

1.0 1<0 3.0 33 4

1.0 1.0 3.0 37 2

1.0 1.0 2.0 33 4

0.0 1.0 2.0 37 2

1.0 1.0 2.0 34 3

1.0 1.0 2.0 37 2

1.0 1.0 2.0 34 3

0.0 1.0 3.0 37 2

1.0 1.0 2.0 32 5

1.0I I 301 361 31.0


..-, ,.... ,, ,., .,” ,,, as,...... ~,,.,


TABLE 14.2-22: DAILY RECORD CARDS - SNEEZING


Centre 1

Mean St. dev Minimum P25

Day Treatment

1 Lora 1.00 0.96 0.0 0.0

Ceti 1.11 1.1s 0.0 0.0

2 Lora 1.14 0.B6 0.0 1.0

Ceti 1.11 1.13 0.0 0.0

3 Lora 1.21 1.05 0.0 0.0

Ceti 1.00 1.08 0.0 0.0

4 Lora 1.21 0.89 0.0 1.D

Ceti 0.94 0.87 0.0 0.0

5 Lora 1,00 0.88 0.0 0.0

Ceti 0.94 1.00 0.0 0.0

6 Lora 1.14 1.03 0.0 0.0

Ceti 1.28 l.l B 0.0 0.0

7 Lora 1.00 0.B8 0.0 0.0

Ceti 1.39 1.14 0.0 0.0

1 Lora 1.14 1.03 0.0 0.0

Ceti 0.72 0.83 0.0 0.0

3 Lora 0.93 0.92 0.0 0.0

Ceti 1.06 1.00 0.0 0.0

10 Lora 1,14 1.03 0.0 0.0

Ceti 1.06 1.16 0.0 0.0

II Lora 1.00 0.96 0.0 0.0

Ceti 1.06 0.87 0.0 0.0

12 Lora 0.79 0.80 0.0 0.0

Cet i 0.83 0.99 0.0 0.0

13 Lora 1.00 0.68 0.0 1.0

Cet i 0.78 0.88 0.0 0.0

14 Lora 0.86 0.66 0.0 0.0

Cet i 1.00 1.14 0.0 0.0

fledian P75 Maximum Number Missing

1.0 2.0 3.0 14 3

1.0 2.0 3.0 18 1

1.0 2.0 3.0 14 3

1.0 2.0 3.0 18 1

1.0 2.0 3.0 14 3

1.0 2.0 3.0 18 1

1.0 2.0 3.0 14 3

1.0 1.0 3.0 18 1

1.0/ 2.01 2.o\ 141 31I I I I1 /

1.01 2.01 3.01 181 III I I I

1.0 2.0 3.0 ’14 3! I I I

1.0 2.0 3.0 18 1

I I

I I I I

1.01 2.01 3.01 141 3

0.5 1.0 2.0 18 1

1.0 i.o 3.0 14 3

1.0 2.0 3.0 18 1

1.0 2.0 3.0 14 3

1.0 2.0 3.0 18 1

1.0 2.0 3.0 14 3

1.0 2.0 3.0 18 1

1.0 1.0 2.0 14 3

1.0 1.0 3.0 18 1I I

1.0 1.0 2.0 14 3

0.51 2.01 2.01 181 1I I I I

1.0 1.0 2.0 14 3

I 1 I I

1.0 + 401 181 1

(CONTINUED)


,“, ,, . ,., ,,. ,“, ..,. .,=4,,


TABLE 14.2-22: DAILY RECORO CAROS - SNEEZING


Centre 1

Mean

Day Treatment

15 Lora 0.86

Ceti 0.89

16 Lora 0.86

Ceti 0.89

17 Lora 0.57

Ceti 0.83

18 Lora 0.71

Ceti 0.59

19 Lora 0.64

Ceti 0.71

20 Lora 0.43

Ceti 0.53

21 Lora 0.50

Ceti 0.53

22 Lora 0.57

Ceti 0.59

23 Lora 0.64

Ceti 0.35

24 Lora 0.64

Ceti 0.53

25 Lora 0.36

Ceti 0.24

26 Lora 0.43

Cet i 0.53

27 Lora 0.36

R. dev Minimum P25 Medien P75 Maximum Number Missing

0.77 0.0 0.0 1.0 1.0 2.0 14 3

0.90 0.0 0.0 1.0 2.0 2.0 18 1

0.86 0.0 0.0 1.0 2.0 2.0 14 3

0.96 0.0 0.0 1.0 1.0 3.0 18 1

0.76 0.0 0.0 0.0 1.0 2.0 14 3

0.92 0.0 0.0 1.0 1.0 3.0 18 1

0.73 0.0 0.0 1,0 1.0 2.0 14 3

0.62 0.0 0.0 1.0 1.0 2.0 17 2

0.74 0.0 0.0 0.5 1.0 2.0 14 3

0.59 0.0 0.0 1,0 1.0 2.0 17 2

0.65 0.0 0.0 0.0 1.0 2.0 >14 3

0.62 0.0 0.0 0.0 1.0 2.0 17 2

0.65 0.0 0.0 0.0 1.0 2.0 14 3

0.72 0.0 0.0 0.0 1.0 2.0 17 2

0.76 0.0 0.0 0.0 1.0 2.0 14 3

0.62 0.0 0.0 1.0 1.0 2.0 17 2

0.74 0.0 0.0 0.5 1.0 2.0 14 3

0.49 0.0 0.0 0.0 1.0 1.0 17 2

0.63 0.0 0.0 1.0 1.0 2.0 14 3

0.72 0.0 0.0 0.0 1.0 2.0 17 2

0.63 0.0 0.0 0.0 1.0 2.0 14 3

0,44 0.0 0.0 0.0 0.0 1.0 17 2

0.65 0.0 0.0 0.0 1.0 2.0 14 3

0.62 0.0 0.0 0.0 1.0 2.0 17 2

0.63 0.0 0.0 0.0 1.0 2.0 14 3

0.44 0.0 0.0 0.0 0.0 1.0 17 2

0.66 0.0 0.0 0.0 1.0 2.0 13 4

0.63 0.0 0.0 0.0 1.0 2.0 16 3


.--,4 ,., .,., ,... ......-!.




Centre 2

Mean St. dev Minimum P25 Median P75 Maximum Number

Day Treatment

1 Lora 1.30 0.86 0.0 1.0 1.0 2.0 3.0 20

Ceti 1.20 0.83 0.0 1.0 1.0 2.0 3.0 20

2 Lora 1.10 0.97 0.0 0.0 1.0 2.0 3.0 20

Ceti 1.15 0.93 0.0 0.0 1.0 2.0 3.0 20

3 Lora 1.25 0.91 0.0 1.0 1.0 1.5 3.0 20

Ceti 1.10 0.85 0.0 0.0 1.0 2.0 2.0 20

4 Lora 1.30 0.98 0.0 1.0 1.0 2.0 3.0 20

Ceti 1.20 0.83 0.0 0.5 1.0 2.0 2.0 20

5 Lora 1.10 0.85 0.0 0.5 1.0 2.0 3.0 20

Ceti 1.20 0.89 0.0 0.5 1.0 2.0 3.0 20

6 Lora 1.00 0.79 0.0 0.5 1.0 1.0 3.0 ’20

Cet i 1.20 0.77 0.0 1.0 1.0 2.0 2.0 20

7 Lora 1.00 0.86 0.0 0.0 1.0 1.5 3.0 20

Ceti 1.15 0.81 0.0 1.0 1.0 2.0 3.0 20

8 Lora 1.15 1.14 0.0 0.0 1.0 2.0 3.0 20

Ceti 1.00 0.79 0.0 0.0 1.0 2.0 2.0 20

9 Lora 1.20 1.06 0.0 0.5 1,0 1.5 3.0 20

Cati 1.25 0.72 0.0 1.0 1.0 2.0 2.0 20

10 Lora 1.25 1.16 0.0 0.0 1.0 2.5 3.0 20

Cet i 1.20 0.83 0.0 1.0 1.0 2.0 3.0 20

11 Lora 1.05 0.94 0.0 0.0 1.0 1.5 3.0 20

Ceti 1.10 0.85 0.0 0.5 1.0 2.0 3.0 20

12 Lora 1.20 0.70 0.0 1.0 1.0 1.5 3.0 20

Ceti 1.05 0.89 0.0 0.0 1.0 2.0 3.0 20

13 Lora 1.15 0.75 0.0 1.0 1.0 1.5 3.0 20

Ceti 0.85 0.75 0.0 0.0 1.0 1.0 2.0 20

14 Lora 1.20 0.52 0.0 1.0 1.0 1.5 2.0 20

Ceti 0.95 0.76 0.0 0.0 1.0 1.5 2.0 20

(CONTINUEO)

Missin(

c

[

c

c

c

c

c

c

c

c

c

c

c

c

c

o

0

0

0

0

0

0

0

0

0

0

0

0


,--, . ...




Centre 2

Mean St. dev Minimum P25 Median P75 Maximum Number Missing

Day Treatment

15 Lora 0.95 0.69 0.0 0.5 1.0 1.0 2.0 20 0

Ceti 0.90 0.72 0.0 0.0 1.0 1.0 2.0 20 0

16 Lora 1.10 0.85 0.0 0.5 1.0 2.0 3.0 20 0

Cet i 1.00 0.79 0.0 0.0 1.0 2.0 2.0 20 0

17 Lora 1.10 0.79 0.0 0.5 1.0 2.0 2.0 20 0

Ceti 1.05 0.69 0.0 1.0 1.0 1.5 2.0 20 0

18 Lora 1.30 0.86 0.0 1.0 1.0 2.0 3.0 20 0

Ceti 0.95 0.83 0.0 0.0 1.0 2.0 2.0 20 0

19 Lora 1.00 0.73 0!0 0.5 1.0 1.5 2.0 20 0

Ceti 0.85 0.75 0.0 0.0 1.0 1.0 2.0 20 0

20 Lora 1.21 0.92 0.0 1.0 1.0 2.0 3.0 ‘19 1

Cet i 0.85 0.81 0.0 0.0 1.0 1.0 3.0 20 0

21 Lora 0.95 0.85 0.0 0.0 1.0 1.0 3.0 19 1

Ceti 0.85 0.67 0.0 0.0 1.0 1.0 2.0 20 0

22 Lora 1.05 0.71 0.0 1.0 1.0 1.0 3.0 19 1

Ceti 0.75 0.64 0.0 0.0 1.0 1.0 2.0 20 0

23 Lora 1.05 0.78 0.0 1.0 1.0 1.0 3.0 19 1

Cet i 0.65 0.75 0.0 0.0 1.0 1.0 2.0 20 0

24 Lora 1.21 0.92 0.0 1.0 1.0 2.0 3.0 19 1

Ceti 0.85 0.88 0.0 0.0 1.0 1.0 3.0 20 0

25 Lora 1.11 0.81 0.0 0.0 1.0 2.0 2.0 19 1:

Ceti 0.85 0.75 0.0 0.0 1.0 1.0 2.0 20 0

26 Lora 1.10 0.72 0.0 1.0 1.0 2.0 2.0 20 0

Ceti 0.75 0.64 0.0 0.0 1.0 1.0 2.0 20 0

27 Lora 0.95 0.69 0.0 0.5 1.0 1.0 2.0 20 0

Ceti 0.75 0.72 0.0 0.0 1.0 1.0 3.0 20 0

28 Lora 0.95 0.71 0.0 0.0 1.0 1.0 2.0 19 1

Ceti 0.80 0.77 0.0 0.0 1.0 1.0 3.0 20 0


,.--, ,,,. ,, ,, ,,, ,. . ‘,. ,, ,.., ,., ,.. >, e,,,


TABLE 14.2-23: DAILY RECORD CARDS - RHINORRHEA


All Datients

Oay

1

2

3

4

5

6

7

9

10

11

12

13

14

( CONTINUED)


Treatment

Lora 1.44 0.93 0.0 1,0 1.5 2.0 3.0 34 3

Ceti 1.42 1.27 0.0 0.0 1.5 3.0 3.0 38 1

Lora 1.32 0.B4 0.0 1.0 1.0 2.0 3.0 34 3

Get i 1,18 1.18 0.0 0.0 1.0 2.0 3.0 38 1

Lora 1.35 0.95 0.0 1.0 1.0 2.0 3.0 34 3

Ceti 1.26 1.20 0.0 0.0 1.5 2.0 3.0 38 1

Lora 1.29 1.03 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 1.24 1.20 0.0 0.0 1.0 2.0 3.0 38 1

Lora 1.26 0.99 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 1.32 1.23 0.0 0.0 2.0 2.0 3.0 38 1

Lora 1.18 1.00 0.0 0.0 1.0 2.0 3.0 ?34 3

Get i 1.21 1.12 0.0 0.0 1.0 2.0 3.0 38 1

Lora 1.26 0.93 0.0 1.0 1.0 2.0 3.0 34 3

Ceti 1.18 0.95 0.0 0.0 1.0 2.0 3.0 38 1

Lora 1.09 0.93 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 1.24 1.OB 0.0 0.0 1.0 2.0 3.0 38 1

Lora 1.24 0.85 0.0 1.0 1.0 2.0 3.0 34 3

Ceti 1.05 1.01 0.0 0.0 1.0 2.0 3.0 38 1

Lora 1.21 0.88 0.0 1.0 1.0 2.0 3.0 34 3

Ceti 1.21 1.09 0.0 0.0 1.0 2.0 3.0 38 1

Lora 1.00 0.B5 0.0 0.0 1.0 1.0 3.0 34 3

Ceti 1.08 1.05 0.0 0.0 1.0 2.0 3.0 38 1

Lora 0.97 0.80 0.0 0.0 1.0 1.0 3.0 34 3

Cet i 1.08 1.05 0.0 0.0 1.0 2.0 3.0 38 1

Lora 1.00 0.85 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.95 1.01 0.0 0.0 1.0 2.0 3.0 38 1

Lora 1.21 0.77 0.0 1.0 1.0 2.0 3.0 34 3

Ceti 1.00 0.96 0.0 0.0 1.0 2.0 3.0 38 1


!--4.. . . . ,. ,., ,, .,, ....,,-, .,,,,.-,,,,


TABLE 14.2-23: DAILY RECORO CARDS - RHINORRHEA


All patients


Day Treatment

15 Lora 1.06 0.78 0.0 0.0 1.0 2.0 2.0 34 3

Ceti 1.03 0.94 0.0 0.0 1.0 2.0 3.0 38 1

16 Lora 0.97 0.76 0.0 0.0 1.0 2.0 2.0 34 3

Ceti 0.84 0.89 0.0 0.0 1.0 2.0 3.0 38 1

17 Lora 1.03 0.87 0.0 0.0 1.0 2.0 3.0 34 3

Cet i 0.89 0.92 0.0 0.0 1.0 2.0 3.0 38 1

18 Lora 1.12 0.91 0.0 0.0 1.0 2.0 3.0 34 3

Cet i 0.84 0.96 0.0 0.0 1.0 1.0 3.0 37 2

19 Lora 1.03 0.87 0.0 0.0 1.0 2.0 3.0 34 3

Cet i 0.81 1.00 0.0 0.0 0.0 1.0 3.0 37 2

20 Lora 1.09 0.80 0.0 1.0 1.0 2.0 3.0 .33 4

Cet i 0.86 1.06 0.0 0.0 0.0 2.0 3.0 37 2

21 Lora 1.09 0.98 0.0 0.0 1.0 2.0 3.0 33 4

Cet i 0.76 1.01 0.0 0.0 0.0 1.0 3.0 37 2

?2 Lora 1.18 0.81 0.0 1.0 1.0 2.0 3.0 33 4

Cet i 0.78 0.95 0.0 0.0 0.0 1.0 3.0 37 2

?3 Lora 1.06 0.90 0.0 0.0 1.0 2.0 3.0 33 4

Ceti 0.73 0.87 0.0 0.0 1.0 1.0 3.0 37 2

!4 Lora 1.00 0.87 0.0 0.0 1.0 1.0 3.0 33 4

Ceti 0.70 0.91 0.0 0.0 0.0 1.0 3.0 37 2

?5 Lora 0.94 0.79 0.0 0.0 1.0 2.0 2.0 33 4

Ceti 0.70 0.91 0.0 0.0 0.0 1.0 3.0 37 2

!6 Lora 0.85 0.70 0.0 0.0 1.0 1.0 2.0 34 3

Cet i 0.68 0.75 0.0 0.0 1.0 1.0 3.0 37 2

?7 Lora 0.91 0.79 0,0 0.0 1.0 2.0 2.0 34 3

Ceti 0.65 0.82 0.0 0.0 0.0 1.0 3.0 37 2

?8 Lora 0.81 0.69 0.0 0.0 1.0 1.0 2.0 32 5

Ceti 0.64 0.90 0.0 0.0 0.0 1.0 3.0 36 3


,, ,.-, ..,., ,, ,.. .,,-, .,~.“-,, ,,




Centre 1


Day Treatment

1 Lora 1.14 1.03 0.0 0.0 1.0 2.0 3.0 14 3

Ceti 1.11 1.28 0.0 0.0 0.5 2.0 3.0 18 1

2 Lora 1.07 0.92 0.0 0.0 1.0 2.0 2.0 14 3

Ceti 0.89 1.13 0.0 0.0 0.0 2.0 3.0 18 1

3 Lora 1.14 0.86 0.0 1.0 1.0 2.0 3.0 14 3

Ceti 1.00 1.24 0.0 0.0 0.0 2.0 3.0 18 1

4 Lora 1.07 0.92 0.0 0.0 1.0 2.0 2.0 14 3

Ceti 0.94 1.21 0.0 0.0 0.0 2.0 3.0 18 1

5 Lora 0.93 0.92 0.0 0.0 1.0 2.0 2.0 14 3

Ceti 0.83 1.15 0.0 0.0 0.0 2.0 3.0 18 1

6 Lora 1.07 1.27 0.0 0.0 0.5 2.0 3.0 ,14 3

Cet i 0.89 1.18 0.0 0.0 0.0 2.0 3.0 18 1

7 Lora 1.07 1.07 0.0 0.0 1.0 2.0 3.0 14 3

Ceti 0.94 1.00 0.0 0.0 1.0 2.0 3.0 18 1

8 Lora 1.00 1.04 0.0 0.0 1.0 2.0 3.0 14 3

Cet i 0.89 1.13 0.0 0.0 0.0 2.0 3.0 18 1

9 Lora 1.07 0.92 0.0 0.0 1.0 2.0 3.0 14 3

Ceti 0.67 0.91 0.0 0.0 0.0 2.0 2.0 18 1

10 Lora 1.21 0.80 0.0 1.0 1.0 2.0 3.0 14 3

Ceti 1.00 1.14 0.0 0,0 0.5 2.0 3.0 18 1

11 Lora 1.00 0.96 0.0 0.0 1.0 2.0 3.0 14 3

Cet i 0.78 0.94 0.0 0.0 0.5 1.0 3.0 18 1

12 Lora 0.93 0.83 0.0 0.0 1.0 2.0 2.0 14 3

Cet i 0.89 1.02 0.0 0.0 0.5 2.0 3.0 18 1

13 Lora 0.93 0.83 0.0 0.0 1.0 2.0 2.0 14 3

Cet i 0.78 1.06 0.0 0.0 0.0 1.0 3.0 18 1

14 Lora 1.14 0.53 0.0 1.0 1.0 1.0 2.0 14 3

Cet i 0.89 0.96 0.0 0.0 1.0 2.0 3.0 18 1


( CONTINUEO )

...-.,. ,., ., ,,. . . ... ,-. ..,.””,”,,.




. Centre 1

Mean St. dev Minimum P25 Median P75 Maximum Number

3ay Treatment

15 Lora 0.93 0.73 0.0 0.0 1.0 1.0 2.0 14

Ceti 0.83 0.86 0.0 0.0 1.0 2.0 2.0 18

16 Lora 0.86 0.77 0.0 0.0 1.0 1.0 2.0 14

Ceti 0.72 0.83 0.0 0.0 0.5 1.0 2.0 18

17 Lora 0.79 0.70 0.0 0.0 1.0 1.0 2.0 14

Cet i 0.61 0.70 0.0 0.0 0.5 1.0 2.0 18

18 Lora 0.79 0.80 0.0 0<0 1.0 1.0 2.0 14

Ceti 0.65 0.70 0.0 0.0 1.0 1.0 2.0 17

19 Lora 0.71 0.73 0.0 0.0 1.0 1.0 2.0 14

Ceti 0.53 0.72 0.0 0.0 0.0 1.0 2.0 17

20 Lora 0.86 0.77 0.0 0.0 1.0 1.0 2.0 ,14

Cet i 0.53 0.72 0.0 0.0 0.0 1.0 2.0 17

21 Lora 0.79 0.97 0.0 0.0 0.5 1.0 3.0 14

Cet i 0.35 0.61 0.0 0.0 0.0 1.0 2.0 17

22 Lora 1.07 0.92 0.0 0.0 1.0 2.0 3.0 14

Cet i 0.41 0.62 0.0 0.0 0.0 1.0 2.0 17

!3 Lora 0.86 1.03 0.0 0.0 0.5 2.0 3.0 14

Ceti 0.53 0.80 0.0 0.0 0.0 1.0 3.0 17

!4 Lora 0.71 0.73 0.0 0.0 1.0 1.0 2.0 14

Ceti 0.29 0.47 0.0 0.0 0.0 1.0 1.0 17

!5 Lora 0.64 0.74 0.0 0.0 0.5 1.0 2.0 14

Ceti 0.29 0.47 0.0 0.0 0.0 1.0 1.0 17

!6 Lora 0.64 0.74 0.0 0.0 0.5 1.0 2.0 14

Ceti 0.53 0.51 0.0 0.0 1.0 1.0 1.0 17

!7 Lora 0.64 0.74 0.0 0.0 0.5 1.0 2.0 14

Ceti 0.35 0.49 0.0 0.0 0.0 1.0 1.0 17

!8 Lora 0.38 0.51 0.0 0.0 0.0 1.0 1.0 13

Cet i 0.38 0.50 0.0 0.0 0.0 1.0 1.0 16

Missin(

1

1

:

3

2

3

2

3

2

3

2

3

2

4

3

December 1, 1998REPORT No.: MRCE98G020 1/1 V Study Report

.,--,<.,. ,., .,, . ,,-, ,.,W., ..,,


TABLE 14.2-23: DAILY RECORO CARDS - RHINORRHEA


Centre 2

I I Mean I St. dev lMinimum I P25 lMedian I P75 lMaximun ilNumber lMissing\

Day Treatment

1 Lora 1.65 0.81 0.0 1.0 2.0 2.0 3.0 20 0

Ceti 1.70 1.22 0.0 0.5 2.0 3.0 3.0 20 0

2 Lora 1.50 0,76 0.0 1.0 1.0 2.0 3.0 20 0

Ceti 1.45 1.19 0.0 0.0 1.5 2.5 3.0 20 0

3 Lora 1.50 1.00 0.0 1.0 1.0 2.0 3.0 20 0

Cet i 1.50 1.15 0.0 0.0 2.0 2.0 3.0 20 0

4 Lora 1.45 1.10 0.0 1.0 1.0 2.5 3.0 20 0

Ceti 1.50 1.15 0.0 0.0 2.0 2.0 3.0 20 0

5 Lora 1.50 1.00 0.0 1.0 1,0 2.0 3.0 20 0

Ceti 1.75 1.16 0.0 0.5 2,0 3.0 3.0 20 0

6 Lora 1.25 0.79 0.0 1.0 1.0 1.5 3.0 ,20 0

Cet i 1.50 1.00 0.0 1.0 2.0 2.0 3.0 20 0

7 Lora 1.40 0.82 0.0 1.0 1.0 2.0 3.0 20 0

Ceti 1.40 0.88 0.0 1.0 2.0 2.0 3.0 20 0

8 Lora 1.15 0.88 0.0 0.5 1.0 2.0 3.0 20 0

Ceti 1.55 0.94 0.0 1.0 2.0 2.0 3.0 20 0

9 Lora 1.35 0.81 0.0 1.0 1.0 2.0 3.0 20 0

Ceti 1.40 0.99 0.0 0.5 2.0 2.0 3.0 20 0

10 Lora 1.20 0.95 0.0 0.5 1.0 2.0 3.0 20 0

Ceti 1.40 1.05 0.0 0,5 1.5 2.0 3.0 20 0

11 Lora 1.00 0.79 0.0 0.5 1.0 1.0 3.0 20 0

Cet i 1.35 1.09 0.0 0.0 1.5 2.0 3.0 20 0

12 Lora 1.00 0.79 0.0 0.5 1.0 1.0 3.0 20 0

Cet i 1.25 1.07 0.0 0.0 1.0 2.0 3.0 20 0

13 Lora 1.05 0.89 0.0 0.0 1.0 2.0 3.0 20 0

Cet i 1.10 0.97 0.0 0.0 1.0 2.0 3.0 20 0

14 Lora 1.25 0.91 0.0 1.0 1.0 2.0 3.0 20 0

Ceti 1.10 0.97 0.0 0.0 1.0 2.0 3.0 20 0

(CONTINUED)


,.-”, . ,. ., ,,, , ,, . , ... ,-, ........ . ,,


TABLE 14.2-23: DAILY RECORD CAROS - RHINORRHEA


Centre 2


Day Treatment

15 Lora 1.15 0.81 0.0 0.5 1.0 2.0 2.0 20 0

Ceti 1.20 1.01 0.0 0.5 1.0 2.0 3.0 20 0

16 Lo ra 1.05 0.76 0.0 0.5 1.0 2.0 2.0 20 0

Cet i 0.95 0.94 0.0 0.0 1.0 2.0 3.0 20 0

17 Lora 1.20 0.95 0.0 0.0 1.0 2.0 3.0 20 0

Ceti 1.15 1.04 0.0 0.0 1.0 2.0 3.0 20 0

18 Lora 1.35 0.93 0.0 1.0 1.0 2.0 3.0 20 0

Ceti 1.00 1.12 0.0 0.0 1.0 2.0 3.D 20 0

19 Lora 1.25 0.91 0.0 1.0 1.0 2.0 3.0 20 0

Ceti 1.05 1.15 0.0 0.0 1.0 2.0 3.0 20 0

20 Lora 1.26 O.el 0.0 1.0 1.0 2.0 3.0 ,19 1

Cet i 1.15 1.23 0.0 0.0 1.0 2.0 3.0 20 0

21 Lora 1.32 0.95 0.0 1.0 1.0 2.0 3.0 19 1

Ceti 1.10 1.17 0.0 0.0 1.0 2.0 3.0 20 0

22 Lora 1.26 0.73 0.0 1.0 1.0 2.0 3.0 19 1

Ceti 1.10 1.07 0.0 0.0 1.0 2.0 3.0 20 0

23 Lora 1.21 0.79 0.0 1.0 1.0 2.0 3.0 19 1

Ceti 0.90 0.91 0.0 0.0 1.0 1.5 3.0 20 0

Z4 Lora 1.21 0.92 0.0 1,0 1.0 2.0 3.0 19 1

Cet i 1.05 1.05 0.0 0.0 1.0 2.0 3.0 20 0

?5 Lora 1.16 0.76 0.0 1.0 1.0 2.0 2.0 19 1~

Cet i 1.05 1.05 0.0 0.0 1.0 2.0 3.0 20 0

?6 Lora 1.00 0.65 0.0 1.0 1.0 1.0 2.0 20 0

Ceti 0.80 0.89 0.0 0.0 1.0 1.0 3.0 20 0

?7 Lora 1.10 0.79 0,0 0.5 1.0 2.0 2.0 20 0

Ceti 0.90 0.97 0.0 0.0 1.0 2.0 3.0 20 0

?8 Lora 1.11 0.66 0.0 1.0 1.0 2.0 2.0 19 1

Ceti 0.85 1.09 0.0 0.0 0.0 2.0 3.0 20 0


,--, !. ,., ., ,,, ,, . . ~,.,,. . ...... -,,,,, .


TABLE 14.2-24: DAILY RECORO CARDS . NASAL OBSTRUCTION


All patients


Day Treatment

1 Lora 1.26 0.90 0.0 1.0 1.0 2.0 3.0 34 3

Ceti 1.95 1.04 0.0 1.0 2.0 3.0 3.0 3B 1

2 Lora 1.44 0.99 0.0 1.0 1.5 2.0 3.0 34 3

Ceti 1.B2 1.11 0.0 1.0 2.0 3.0 3.0 3B 1

3 Lora 1.41 0.86 0.0 1.0 1.0 2.0 3.0 34 3

Ceti 1.84 1.10 0.0 1.0 2.0 3.0 3.0 3B 1

$ Lora 1.35 0.92 0.0 1.0 1.0 2.0 3.0 34 3

Ceti 1.82 0.98 0.0 1.0 2.0 3.0 3.0 38 1

5 Lora 1.35 0.92 0.0 1.0 1.0 2.0 3.0 34 3

Ceti 1.84 0.97 0.0 1.0 2.0 3.0 3.0 38 1

j Lora 1.26 0.99 0.0 0.0 1.0 2.0 3.0 ,34 3

Ceti 1.71 1.09 0.0 1.0 2.0 3.0 3.0 38 1

7 Lora 1.15 0.93 0.0 0.0 1.0 2.0 3.0 34 3’

Ceti 1.53 1.08 0.0 1.0 1.5 2.0 3.0 38 1

) Lora 1.21 0.95 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 1.66 1.02 0.0 1.0 2.0 3.0 3.0 38 1

1 Lora 1.21 1.07 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 1.5B 0.95 0.0 1.0 2.0 2.0 3.0 3B 1

0 Lora 1.3B 0.99 0.0 0.0 2.0 2.0 3.0 34 3

Ceti 1.50 1.11 0.0 1.0 1.5 2.0 3.0 3B 1

1 Lora 1.38 1.04 0.0 0.0 2.0 2.0 3.0 34 3

Ceti 1.37 1.02 0.0 0.0 1.5 2.0 3.0 3B 1

2 Lora 1.3B 1.02 0.0 0.0 2.0 2.0 3.0 34 3

c eti 1.42 1.03 0.0 1.0 1.5 2.0 3.0 3B 1

3 L ora 1.24 0.96 0.0 0.0 1.0 2.0 3.0 34 3

c eti 1.34 0.99 0.0 0.0 1.5 2.0 3.0 3B 1

4 L ora 1.15 1.05 0,0 0.0 1.0 2.0 3.0 34 3

c eti 1.34 1.07 0.0 0.0 1.0 2.0 3.0 38 1

(CONTINUED)

REPORT No. : MRCE98G0201 /1 V

,.,

Study Report December 1, 1998

, ,.’ ,,., ., -! . . . . . .


TABLE 14.2-24: DAILY RECORD CARDS - NASAL OBSTRUCTION


All patients

I ‘can l= ‘e’

* 126 099

]ceti I 1.37[ I.10

XEEE?0 =!3=

Ceti 1.32 1.00

Lora 1.32 1.01

Ceti 1.30 0.91

Lora 1.09 1.01

]Ceti I 1.24] 1.01

“ k-l-++%

Minimum P25 Median P75 Maximum Number Missing

0.0 0.0 1.0 2.0 3.0 34 3

0.0 0.0 1.0 2.0 3.0 38 1

0.0 0.0 2.0 2.0 3.0 34 3

0.0 1.0 1.0 2.0 3.0 38 1

0.0 0.0 1.0 2.0 3.0 34 3

0.0 1.0 1.0 2.0 3.0 37 2

0.0 0.0 1.0 2.0 3.0 34 3

0.0 1.0 1.0 2.0 3.0 37 2

0.0 0.0 1.0 2.0 3.0 34 3

0.0 1.0 1.0 2.0 3.0 37 2

0,0 0.0 1.0 2.0 3.0 ,33 i

0.0 0.0 1.0 2.0 3.0 37 2

0.0 0.0 1.0 2.0 3.0 33 4

0.0 0.0 1.0 2.0 3.0 37 ~

0.0 0.0 1,0 2.0 3.0 33 4

0.0 1.0 1.0 2.0 3.0 37 2

‘3 Lora 1.24 0.87 0.0 1.0 1.0 2.0 3.0 33 4

Ceti 1.19 0.97 0.0 0.0 1.0 2.0 3.0 37 2

4 Lora 1.03 0.77 0.0 1.0 1.0 1.0 3.0 33 4

Ceti 1.22 0.98 0.0 0.0 1.0 2.0 3.0 37 2

?5 Lora 1.18 0.81 0.0 1.0 1.0 2.0 3.0 33 4

Ceti 1.22 0.95 0.0 0.0 1.0 2.0 3.0 37 2

?6 Lora 1.00 0.70 0.0 1.0 1.0 1.0 2.0 34 3

Ceti 1.00 0.97 0.0 0.0 1.0 2.0 3.0 37 2

!7 Lora 1.06 0.85 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.95 0.91 0.0 0.0 1.0 2.0 3.0 37 2

!8 Lo ra 0.84 0.69 0.0 0.0 1.0 1.0 2.0 31 6

Ceti 0.92 0.84 0.0 0,0 1.0 1.5 3.0 36 3


.-, ... ,,, ,. ,,. ... -, .....” .4.!..




Centre 1


Day Treatment

1 Lora 1.43 1.02 0.0 1.0 1.5 2.0 3.0 14 3

Ceti 1.72 1.07 0.0 1.0 2.0 3.0 3.0 18 1

2 Lora 1.43 1.02 0.0 1.0 1.5 2.0 3.0 14 3

Cet i 1.56 1.10 0.0 1.0 2.0 2.0 3.0 lB 1

3 Lora 1.43 0.85 0.0 1.0 1.5 2.0 3.0 14 3

Cet i 1.67 1,14 0.0 1.0 1.5 3.0 3.0 18 1

4 Lora 1.36 0.93 0.0 1.0 1.5 2.0 3.0 14 3

Ceti 1.78 1.06 0.0 1.0 2.D 3.0 3.0 18 1

5 Lora 1.64 0.93 0.0 1.0 2.0 2.0 3.0 14 3

Ceti 1.61 0.9B 0.0 1.0 2.0 2.0 3.0 18 1

6 Lora 1.50 1.02 0.0 1.0 2.0 2.0 3.0 ’14 3

Cet i 1.50 1.15 0.0 0.0 2.0 2.0 3.0 18 1

7 Lora 1.29 0.99 0.0 0.0 1.5 2.0 3.0 14 3

Ceti 1.39 1.14 0.0 0.0 1.0 2.0 3.0 18 1

8 Lo ra 1.29 0.99 0.0 0.0 1.5 2.0 3.0 14 3,

Cet i 1.44 1.10 0.0 1.0 1.0 2.0 3.0 18 1~

9 Lora 1.57 1.09 0.0 1.0 2.0 2.0 3.0 14 3

Ceti 1.39 1.04 0.0 1.0 1.0 2.0 3.0 18 1

10 Lora 1.79 0.70 0.0 2.0 2.0 2.0 3.0 14 3

Ceti 1.28 1.07 0.0 0.0 1.0 2.0 3.0 18 1

11 Lora 1.71 1.07 0.0 1.0 2.0 2.0 3.0 14 3

Ceti 1.06 1.00 0.0 0,0 1.0 2.0 3.0 18 1

12 Lora 1.71 0.73 0.0 1.0 2.0 2.0 3.0 14 3

Ceti 1.28 1.23 0.0 0.0 1.0 2.0 3.0 18 1

13 Lora 1.43 0.94 0.0 1.0 2.0 2.0 3.0 14 3

Ceti 1.22 1.06 0.0 0.0 1.0 2.0 3.0 lB 1

14 Lora 1.43 0.94 0.0 1.0 2.0 2.0 3.0 14 3

Cet i 1.11 1.OB 0.0 0.0 1.0 2.0 3.0 18 1

(CONTINUEO)


--. ! ~. .,. ,q..,,.”., ..#,

STUDY NO.: 9153PROTOCOL No.: MPCE91 L 1802/6D of 187

TABLE 14.2-24: DAILY RECORD CAROS - NASAL OBSTRUCTION


Centre 1


Day Treatment

15 Lora 1.29 0.91 0.0 1.0 1.0 2.0 3.0 14 3

Ceti 1.22 1.17 0.0 0.0 1.0 2.0 3.0 18 1

16 Lora 1.50 1.02 0.0 0.0 2.0 2.0 3.0 14 3

Ceti 1.28 1.02 0.0 0.0 1.0 2.0 3.0 18 1

17 Lora 1.43 0.94 0.0 1.0 2.0 2.0 3.0 14 3

Ceti 1.44 1.10 0.0 1.0 1.0 2.0 3.0 18 1

18 Lora 1.43 0.76 0.0 1.0 2.0 2.0 2.0 14 3

Ceti 1.18 0.95 0.0 0.0 1.0 2.0 3.0 17 2

19 Lora 1.29 0.73 0.0 1.0 1.0 2.0 2.0 14 3

Ceti 1.12 0.93 0.0 0.0 1.0 2.0 3.0 f7 2

20 Lora 1.21 0.89 0.0 1.0 1.0 2.0 3.0 ’14 3

Ceti 1.12 1.05 0.0 0.0 1.0 2.0 3.0 17 2

21 Lora 1.14 0.77 0.0 1.0 1.0 2.0 2.0 14 3

Ceti 1.00 1.00 0.0 0.0 1.0 2.0 3.0 17 2

22 Lora 1.36 0.93 0.0 1.0 1.5 2.0 3.0 14 3

Ceti 0,94 0.75 0.0 0.0 1.0 1.0 2.0 17 2

23 Lora 1.36 0.74 0.0 1.0 1.0 2.0 3.0 14 3

Ceti 0.94 0.90 0.0 0.0 1.0 2.0 2.0 47 2

24 Lora 1.21 0.58 0.0 1.0 1.0 2.0 2.0 14 3

Cet i 0.82 0.73 0.0 0.0 1.0 1.0 2.0 17 2

25 Lora 1.21 0.70 0.0 1.0 1.0 2.0 2.0 14 3

Ceti 1.00 0.87 0.0 0.0 1.0 2.0 2.0 17 2

26 Lora 1.00 0.55 0.0 1.0 1.0 1.0 2.0 14 3

Ceti 0.65 0.79 0.0 0.0 0.0 1.0 2.0 17 2

27 Lora 1.21 0.70 0.0 1.0 1.0 2.0 2.0 14 3

Cet i 0.76 0.83 0.0 0.0 1.0 1.0 2.0 17 2

28 Lora 0.92 0.51 0.0 1.0 1.0 1.0 2.0 12 5

Cet i 0.69 0.60 0.0 0.0 1.0 1.0 2.0 16 3


. ,--4 , ,.,,,




Centre 2


Day Treatment

1 Lora 1.15 O.B1 0.0 1.0 1.0 2.0 3.0 20 0

Ceti 2.15 0.99 0.0 2.0 2.0 3.0 3.0 20 0

2 Lora 1.45 1.00 0.0 1.0 1.5 2.0 3.0 20 0

Ceti 2.05 1.10 0.0 1,5 2.0 3.0 3.0 20 0

3 Lora 1.40 0.88 0.0 1.0 1.0 2.0 3.0 20 0

Cet i 2.00 1.08 0.0 1.0 2.0 3.0 3.0 20 0

4 Lora 1.35 0.93 0.0 1.0 1.0 2.0 3.0 20 0

Cet i 1.85 0.93 0.0 1.0 2.0 2.5 3.0 20 0

5 Lora 1.15 0.88 0.0 0.5 1.0 2.0 3.0 20 0

Ceti 2.05 0.94 0.0 2.0 2.0 3.0 3.0 20 0

? Lora 1.10 0.97 0.0 0.0 1.0 2.0 3.0 ’20 0

Cet i 1.90 1.02 0.0 1.5 2.0 3.0 3.0 20 0

7 Lora 1.05 0.89 0.0 0.0 1.0 2.0 3.0 20 0

Cet i 1.65 1.04 0.0 1.0 2.0 2.5 3.0 20 0

3 Lora 1.15 0.93 0.0 0.0 1.0 2.0 3.0 20 0

Ceti 1.85 0.93 0.0 1.0 2.0 3.0 3.0 20 0

3 Lora 0.95 1.00 0.0 0.0 1.0 2.0 3.0 20 0

Ceti 1.75 0.85 0.0 1.0 2.0 2.0 3.0 20 0

10 Lora 1.10 1.07 0.0 0.0 1.0 2.0 3.0 20 0

Ceti 1.70 1.13 0.0 1.0 2.0 3.0 3.0 20 0

11 Lora 1.15 0.99 0.0 0.0 1.0 2.0 3.0 20 0

Ceti 1.65 0.99 0.0 1.0 2.0 2.0 3.0 20 0

12 Lora 1.15 1.14 0.0 0.0 1.0 2.0 3.0 20 0

Ceti 1.55 0.83 0.0 1.0 2.0 2.0 3.0 20 0

13 Lora 1.10 0.97 0.0 0.0 1.0 2.0 3.0 20 0

Ceti 1.45 0.94 0.0 1.0 2.0 2.0 3.0 20 0

14 Lora 0.95 1.10 0.0 0.0 0.5 2.0 3.0 20 0

Ceti 1.55 1.05 0.0 1.0 1.0 2.5 3.0 20 0

(CONTINUEO)


-“. . . . . . ,,, ,, ,., ,,” ,,, ,, -,, .,, .”.-,,,

STUDY NO.: 9153PROTOCOL No.: MPCE91 L1802/6D of 187



Centre 2

Iissing

o

0

0

0

0

1

0

0

0

0

1

0

1

0

1

0

1

0

1

0

1

0

0

0

0

0

1

0

I Mean St, dew

Treatment

Lora 1.25 1.07

Day

15

0.0 1.0 1.5 2.0 3.0 20

0.0 0.0 1.0 2.0 3.0 20

Ceti I 1.501 1.05

16 Lora I 1.05/ 1.00

Ceti I 1.351 1.04 0.0 1.0 1.0 2.0 3.0 20

0.0 0.0 1.0 1.5 3.0 2017 w 0.01 1.0/ 1.01 2.01 3.01 19

18 Lora 1 1.051 1.15 0,0 0.0 1.0 2.0 3.0 20

0.0 1.0 1.0 2.0 3.0 20

0.0 0.0 1.5 2.0 3.0 20

0.0 1.0 1.5 2.0 3.0 20

0.0 0.0 1.0 2.0 3.0 ’19

0.0 1.0 1.0 2.0 3.0 20

0.0 0.0 1.0 2.0 3.0 19

0.0 1.0 1.0 2.0 3.0 20

0.0 0.0 1.0 2.0 3.0 19

0.0 1.0 1.5 2.0 3.0 20

0.0 0.0 1.0 2.0 3.0 19

0.0 1.0 1.0 2.0 3.0 20

Ceti 1.45 1.05

Lora 1.35 1.18

Cet i 1.45 0.89

Lora 1.00 1.11

Ceti 1.35 0.99

Lora 1.05 1.03

Ceti 1.50 1.00

19

20

21

22 LoraI

1.21/ 1.03

=-+-++=23

#

:eti 1.40 0.99

Lora 0.89 0.88

;eti 1.55 1.05

24 0.0 I I ‘4 ‘.O1 3“01 190.0

0.0 1.01 2.01 2.01 3.01 20

25 0.0 II 0.0 1.01 2.01 3.01 19

=--+++= 0.0 0.5 2.0 2.0 3.0 20

0.0 0.0 1.0 2.0 2.0 20

0.0 0.0 1.5 2.0 3.0 20

0.0 0.0 1.0 2.0 3.0 20

26 Lora I 1.00 0.79

>et i [ 1.30\ 1.03

27

*

_ora 0.95 0.94

2et i 1.10 0.97

.ora 0.79 0.79

0.0 0.0 1.0 2.0 3.0 20

28 0.0 0.0 1.0 1.0 2.0 19

0.0 0.0 1.0 2.0 3.0 20>eti 1.10 0.97


,..-, ,,... ,, ,. ,,, ., ..,,, “.,,,,-,”,”. “., ,,, ,,


TABLE 14.2-25: DAILY RECORD CARDS - NASAL PRURITUS


All patients


Day Treatment

1 Lora 1.48 0.94 0.0 1.0 1.0 2.0 3.0 33 4

Cet i 1.24 1.08 0.0 0.0 1.0 2.0 3.0 38 1

2 Lora 1.18 1.04 0.0 0.0 1.0 2,0 3.0 33 4

Ceti 1.05 1.09 0.0 0.0 1.0 2.0 3.0 38 1

3 Lora 1.44 1.05 0.0 1.0 1.0 2.0 3.0 34 3

Ceti 0.95 1.01 0.0 0.0 1.0 2.0 3.0 38 1

4 Lora 1.12 1.04 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.87 0.91 0.0 0.0 1.0 1.0 3.0 38 1

5 Lora 1.18 0.94 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.82 0.93 0.0 0.0 1.0 1.0 3.0 38 1

6 Lora 1.21 0.95 0.0 0.0 1.0 2.0 3.0 “34 3

Cet i 0.82 0.95 0.0 0,0 0.5 2.0 3.0 38 1

7 Lora 1.15 0.89 0.0 1.0 1.0 2.0 3.0 34 3

Ceti 0.82 0.90 0.0 0.0 1.0 2.0 3.0 38 1

8 Lora 1.03 1.03 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.68 0.81 0.0 0.0 0.0 1.0 2.0 38 1

9 Lora 1.15 0.89 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.74 0.76 0.0 0.0 1.0 1.0 2.0 38 1

10 Lora 1.03 0.83 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.82 0.80 0.0 0.0 1.0 1.0 2.0 38 1

11 Lora 1.18 0.90 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.71 0.90 0.0 0.0 0.0 1.0 3.0 38 1

12 Lora 1.09 0.87 O.D 0.0 1.0 2.0 3.0 34 3

Ceti 0.79 0.84 0.0 0.0 1.0 1.0 3.0 38 1

13 Lora 1.09 0.93 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.87 0.84 0.0 0.0 1.0 1.0 3.0 38 1

14 Lora 0.97 0.97 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.79 0.84 0.0 0.0 1.0 1.0 3.0 38 1


.,. ,+,.,,z. -<.


TABLE 14.2-25: DAILY RECORD CARDS NASAL PRURITUS


All patients


Day Treatment

15 Lora 1.00 0.85 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.89 0.83 0.0 0.0 1.0 1.0 3.0 38 1

16 Lora 0.94 0.85 0.0 0.0 1.0 1.0 3.0 34 3

Ceti 0.68 0.84 0.0 0.0 0.0 1.0 3.0 38 1

17 Lora 0.82 0.87 0.0 0.0 1.0 1.0 3.0 34 3

Ceti 0.76 0.88 0.0 0.0 0.5 1.0 3.0 38 1

18 Lora 0.88 0.84 0.0 0.0 1.0 1.0 3.0 34 3

Ceti 0.81 1.02 0.0 0.0 0.0 1.0 4.0 37 2

19 Lora 0.79 0.91 0.0 0.0 1.0 1.0 3.0 34 3

Cet i 0.84 0.90 0.0 0.0 1.0 1.0 3.0 37 2

20 Lora 0.85 0.82 0.0 0.0 1.0 1.0 3,0 ’34 3

Ceti 0.81 0.84 0.0 0.0 1.0 1.0 3.0 37 2

21 Lora 0.88 0.82 0.0 0.0 1.0 1.0 3.0 33 4

Ceti 0.92 0.92 0.0 0.0 1.0 2.0 3.0 37 2

22 Lora 0.94 0.86 0.0 0.0 1.0 1.0 3.0 33 4

Ceti 0.89 0.94 0.0 0.0 1.0 2.0 3.0 37 2

23 Lora 0.88 0.70 0.0 0.0 1.0 1.0 2.0 33 4

Ceti 0.78 0.85 0.0 0.0 1.0 1.0 3.0 37 2

24 Lora 0.88 0.74 0.0 0.0 1.0 1.0 2.0 33 4

Ceti 0.73 0.87 0.0 0.0 1.0 1.0 3.0 37 2

25 Lora 0.88 0.78 0.0 0.0 1.0 1.0 2.0 33 4

Ceti 0.62 0.72 0.0 0.0 0.0 1.0 2.0 37 2

!6 Lora 0.82 0.72 0.0 0.0 1.0 1.0 2.0 34 3

Ceti 0.65 0.75 0.0 0.0 0.0 1.0 2.0 37 2

!7 Lora 0.88 0.98 0.0 0.0 1.0 2.0 3.0 34 3

Ceti 0.62 0.72 0.0 0.0 0.0 1.0 2.0 37 2

!8 Lora 0.66 0.75 0.0 0.0 1.0 1,0 3.0 32 5

Ceti 0.53 0.70 0.0 0.0 0.0 1.0 2.0 36 3


. ..--..... ., -) . ..”. ..4,, ,,




Centre 1


Day Treatment

1 Lora 1.31 0.95 0.0 1.0 1.0 2.0 3.0 13 4

Ceti 1.11 1.02 0.0 0.0 1.0 2.0 3.0 18 1

2 Lora 1.15 0.90 0.0 1.0 1.0 2.0 3.0 13 4

Ceti 0.94 1.00 0.0 0.0 1.0 2.0 3.0 18 1

3 Lora 1.07 0.92 0.0 0.0 1.0 2.0 3.0 14 3

Cet i 0.72 0.89 0.0 0.0 0.5 1.0 3.0 lB 1

4 Lora 0.93 1.07 0.0 0.0 0.5 2.0 3.0 14 3

Ceti 0.B9 1.02 0.0 0.0 1.0 1.0 3.0 18 1

5 Lora 1.07 0.92 0.0 0.0 1.0 2.0 3.0 14 3

Ceti 0.72 0.89 0.0 0,0 0.5 1.0 3.0 18 1

6 Lora 1.14 1.10 0.0 0.0 1.0 2.0 3.0 ‘14 3

Ceti 0.83 0.92 0.0 0.0 1.0 1.0 3.0 18 1

7 Lora 0.86 0.77 0.0 0.0 1.0 1.0 2.0 14 3

Ceti 0.94 0.80 0.0 0.0 1.0 2.0 2.0 lB 1

8 Lora 0.86 1.03 0.0 0.0 0.5 2.0 3.0 14 3

Ceti 0.67 0.77 0.0 0.0 0.5 1.0 2.0 Is 1

9 Lora 1.07 0.92 0.0 0.0 1.0 2.0 3.0 14 3

Ceti 0.83 0.71 0.0 0.0 1.0 1.0 2.0 18 1

10 Lora 0.86 0.86 0.0 0.0 1.0 2.0 2.0 14 3

Ceti 1.00 0.77 0.0 0.0 1.0 2.0 2.0 18 1

11 Lora 1.14 0.95 0.0 0.0 1.0 2.0 3.0 14 3

Ceti 0.78 0.81 0.0 0.0 1.0 1.0 3.0 18 1

12 Lora 1.00 0.78 0.0 0.0 1.0 2.0 2.0 14 3

Ceti 0.78 0.81 0.0 0.0 1.0 1.0 3.0 18 1

[3 Lora 1.14 0.95 0.0 0.0 1.0 2.0 3.0 14 3

Cet i 0.94 0.80 0.0 0.0 1.0 2.0 2.0 18 1

[4 Lora 1.07 1.00 0.0 0.0 1.0 2.0 3.0 14 3

Ceti 0.63 0.79 0.0 0.0 1,0 1.0 2.0 18 1

( CONTINUEO )


--”<..,”, ., ,, ,,, ~. -, ,.~......

‘. .: -..:.-

,, ,


TABLE 14.2-25: DAILY RECORD CAROS - NASAL PRURITUS


Centre 1

7=)-ey Treatment

1.5 Lora

Ceti

%

16 Lora

Cet i

17 Lora

Cet i

lB

9

!1

?2

?3

?4

7

8

l--Lora

Ceti

Lora

Ceti

Lora

Ceti

Lora

Ceti

Lora

Ceti

Lora

Ceti

Lora

Cet i

Lora

Ceti

Lora

Cet i

Mean St. dev Minimum P25 Median P75 Maximum Number Missing.

.. ‘j(~; ,’ I<C9(J~ .

1.14 0.86 0.0 0.0 1.0 2.0 2.0 14 3

1.00 0.77 0.0 0.0 1.0 2.0 2.0 18 1

1.00 0.78 0.0 0.0 1.0 2.0 2.0 14 3

0.61 0.78 0.0 0.0 0.0 1.0 2.0 lB 1

0.86 0.77 0.0 0.0 1.0 1.0 2.0 14 3

0.72 0.83 0.0 0.0 0.5 1.0 2.0 18 1

0.79 0.80 0.0 0.0 1.0 1.0 2.0 14 3

0.8B 1.17 0.0 0.0 0.0 2.0 4.0 17 2

0.86 0.86 0.0 0.0 1.0 2.0 2.0 14 3

0.82 0.81 0.0 0.0 1.0 1.0 2.0 17 2

0.88 0.86 0.0 0.0 1.0 2.0 2.0 ‘14 3

0.82 0.81 0.0 0.0 1.0 1.0 2.0 17 2

0.86 0.95 0.0 0.0 1.0 1.0 3.0 14 3

0.94 0.90 0.0 0.0 1.0 2.0 2.0 17 2

0.B6 0.95 0.0 0.0 1.0 1.0 3.0 14 3

0.94 0.83 0.0 0.0 1.0 2.0 2.0 17 2

0.64 0.63 0.0 0.0 1.0 1.0 2.0 14 3

0.76 0.66 0.0 0.0 1.0 1.0 2.0 17 2

0.86 0.77 0.0 0.0 1.0 1.0 2.0 14 3

0.82 0.73 0.0 0.0 1.0 1.0 2.0 17 2

0.64 0.74 0.0 0.0 0.5 1.0 2.0 14 3

0.71 0.69 0.0 0.0 1.0 1.0 2.0 17 2

0.71 0.73 0.0 0.0 1.0 1.0 2.0 14 3

0.82 0.73 0.0 0.0 1.0 1.0 2.0 17 2

Lora 0.71 0.91 0.0 0.0 0.0 2.0 2.0 14 3

Ceti 0.71 0.69 0.0 0.0 1.0 1.0 2.0 17 2

Lora 0.54 0.8B 0.0 0.0 0.0 1.0 3.0 13 4

Ceti 0.50 0.73 0.0 0.0 0.0 1.0 2.0 16 3


..=-,,,.“, ,,




Centre 2

Day

1

2

3

4

5

6

7

10

11

12

13

14

(CONTINUED)


Treatment

Lora 1.60 0.94 0.0 1.0 1.5 2.0 3.0 20 0

Ceti 1.35 1.14 0.0 0.0 1.0 2.0 3.0 20 0

Lo ra 1.20 1.15 0.0 0.0 1.0 2.0 3.0 20 0

Ceti 1.15 1.18 0.0 0.0 1.0 2.0 3.0 20 0

Lo ra 1.70 1.08 0.0 1.0 2.0 3.0 3.0 20 0

Cet i 1.15 1.09 0.0 0.0 1.0 2.0 3.0 20 0

Lora 1.25 1.02 0.0 0,5 1.0 2.0 3.0 20 0

Ceti 0.B5 0.81 0.0 0.0 1.0 1.5 2.0 20 0

Lora 1.25 0.97 0.0 0.5 1.0 2.0 3.0 20 0

Ceti 0<90 0.97 0.0 0.0 1.0 2.0 3.0 20 0

Lora 1.25 0.85 0.0 1.0 1.0 2.0 3.0 ’20 0

Cet i 0.80 1.01 0.0 0.0 0.0 2.0 3.0 20 0

Lora 1.35 0.93 0.0 1.0 1.0 2.0 3.0 20 0

Ceti 0.70 0.98 0.0 0.0 0.0 1.5 3.0 20 0

Lora 1.15 1.04 0.0 0.0 1.0 2.0 3.0 20 0

Cet i 0.70 0.86 0.0 0.0 0.0 1.5 2.0 20 0

Lora 1.20 0.89 0.0 0.5 1.0 2.0 3.0 20 0

Cet i 0.65 0.81 0.0 0.0 0.0 1.0 2.0 20 0

Lora 1.15 0.81 0.0 1.0 1.0 2.0 3.0 20 0

Ceti 0.65 0.81 0.0 0.0 0.0 1.0 2.0 20 0

Lora 1.20 0.89 0.0 0.5 1.0 2.0 3.0 20 0

Ceti 0.65 0.99 0.0 0.0 0.0 1.5 3.0 20 0

Lora 1.15 0.93 0.0 0.5 1.0 2.0 3.0 20 0

Ceti 0.80 0.89 0.0 0.0 1.0 1.0 3.0 20 0

Lora 1.05 0.94 0.0 D.O 1.0 1.5 3.0 20 0

Ceti 0.80 0.89 0.0 0.0 1.0 1.0 3.0 20 0

Lora 0.90 0.97 0.0 0.0 1.0 1.0 3.0 20 0

Ceti 0.75 0.91 0.0 0.0 0.5 1.0 3.0 20 0


--, ,.,“, . .! ,-. ., P-.. W!,. ,,

STUDY No.: 9153PROTOCOL No.: MPCE9lL1802/6D of187



Centre 2

Day

15

16

18

19

20

?1

?2

?3

?4


Treatment

Lora 0.90 0.85 0.0 0,0 1.0 1.0 3.0 20 0

Ceti 0.80 0.89 0.0 0.0 1.0 1.0 3.0 20 0

Lora 0.90 0.91 0.0 0.0 1.0 1.0 3.0 20 0

Ceti 0.75 0.91 0.0 0.0 0.5 1.0 3.0 20 0

Lora 0.80 0.95 0.0 0.0 0.5 1.5 3.0 20 0

Ceti 0.80 0.95 0.0 0.0 0.5 1.5 3.0 20 0

Lora 0.95 0.89 0.0 0.0 1.0 1.5 3.0 20 0

Cet i 0.75 0.91 0.0 0.0 0.5 1.0 3.0 20 0

Lora 0.75 0,97 0.0 0.0 0.5 1.0 3.0 20 0

Ceti 0.85 0.99 0.0 0.0 1.0 1.0 3.0 20 0

Lora 0.85 0.81 0.0 0.0 1.0 1.0 3.0 20 0

Ceti 0.80 0.89 0.0 0.0 1.0 1.0 3.0 20 0

Lora 0.89 0.74 0.0 0.0 1.0 1.0 2.0 19 1

Cet i 0.90 0.97 0.0 0.0 1.0 1.0 3.0 20 0

Lora 1.00 0.82 0.0 0.0 1.0 1.0 3.0 19 1

Ceti 0.85 1.04 0.0 0.0 0.5 1.5 3.0 20 0

Lora 1.05 0.71 0.0 1.0 1.0 2.0 2.0 19 1

Ceti 0.00 1.01 0.0 0.0 0.5 1.0 3.0 20 0

Lora 0.89 0.74 0.0 0.0 1.0 1.0 2.0 19 1

Ceti 0.65 0.99 0.0 0.0 0.0 1.0 3.0 20 0

Lora 1.05 0.78 0.0 0.0 1.0 2.0 2.0 19 1

Ceti 0.55 0.76 0.0 0.0 0.0 1.0 2.0 20 0

Lora 0.90 0.72 0.0 0.0 1.0 1.0 2.0 20 0

Ceti 0.50 0.76 0.0 0.0 0.0 1.0 2.0 20 0

Lora 1.00 1.03 0.0 0.0 1.0 2.0 3.D 20 0

Ceti 0.55 0.76 0.0 0.0 0.0 1.0 2.0 20 0

Lora 0.74 0.65 0.0 0.0 1.0 1.0 2.0 19 1

Ceti 0.55 0.69 0.0 0.0 0.0 1.0 2.0 20 0


,..--., ,,, ,., .,, .,,, .-, ,* . . .,


TABLE 14.2-26: DAILY RECORD CAROS - OCULAR PRURITUS


All patients

Mean

Day Treatment

1 Lora 0,74

Ceti 0.61

2 Lora 0.74

Ceti 0.55

3 Lora 0.65

Cet i 0.55

4 Lora 0.62

Cet i 0.39

5 Lora 0.65

Ceti 0.34

5 Lora 0.59

Ceti 0.32

7 Lora 0.76

Cet i 0.34

3 Lora 0.71

Ceti 0.39

3 Lora 0.71

Ceti 0.26

10 Lora 0.85

Cet i 0.32

11 Lora 0.85

Cet i 0.29

12 Lora 0.74

Ceti 0.29

13 Lora 0.56

Ceti 0.32

4 Lora 0.50

Ceti 0.42

St.dev Minimum P25 Median P75 Maximum Number Missing

1.05 0.0 0.0 0.0 1.0 3.0 34 3

0.89 0.0 0.0 0.0 1.0 3.0 38 1

0.93 0.0 0.0 0.0 1.0 3.0 34 3

0.80 0.0 0.0 0.0 1.0 3.0 38 1

0.88 0.0 0.0 0.0 1.0 3.0 34 3

0.80 0.0 0.0 0.0 1.0 3.0 38 1

0.85 0.0 0.0 0.0 1.0 3.0 34 3

0.68 0.0 0.0 0.0 1.0 2.0 38 1

0.77 0.0 0.0 0.5 1.0 3.0 34 3

0.58 0.0 0.0 0.0 1.0 2.0 38 1

0.74 0.0 0.0 0.0 1.0 2.0 ’34 3

0.57 0.0 0.0 0.0 1.0 2.0 38 1

0.89 0.0 0.0 1.0 1.0 3.0 34 3

0.63 0.0 0.0 0.0 1.0 2.0 38 1

0.87 0.0 0.0 0.5 1.0 3.0 34 3

0.64 0.0 0.0 0.0 1.0 2.0 3B 1

0.87 0.0 0.0 0.0 1.0 3.0 34 3

0.50 0.0 0.0 0.0 0.0 2.0 38 1

0.82 0.0 0.0 1.0 1.0 3.0 34 3

0.53 0.0 0.0 0.0 1.0 2.0 38 1

0.96 0.0 0.0 1.0 2.0 3.0 34 3

0.52 0.0 0.0 0.0 1.0 2.0 38 1

0.83 0.0 0.0 1.0 1.0 3.0 34 3

0.52 0.0 0.0 0.0 1.0 2.0 38 1,

0.82 0.0 0.0 0.0 1.0 3.0 34 3

0.53 0.0 0.0 0.0 1.0 2.0 38 1

0.71 0.0 0.0 0.0 1.0 3.0 34 3

0.64 0.0 0.0 0.0 1.0 2.0 38 1

( CONTINUED)


..=, ,,,., ,,, ,, .,,., ., .-! . . . . . w,, ,,


TABLE 14.2-26: DAILY RECORD CARDS - OCULAR PRURITUS


All patients

I

lCeti

16

1----

Lora

Ceti

-E17 Lora

Ceti

18 Lora

Cet iI

I

=

20 Lora

Ceti

21 Lora

Ceti

22 Lora

Ceti

+

23 Lora

Cet i

24 Lora

Ceti

+

25 Lora

Ceti

26 Lora

Ceti

27

F

Lora

Cet i

L--la


0.47 0.75 0.0 0.0 0.0 1.0 3.0 34 3

0.53 0.73 0.0 0.0 0.0 1.0 2.0 38 1

0.53 0.79 0.0 0.0 0.0 1.0 3.0 34 3

0.53 0.80 0.0 0.0 0.0 1.0 3.0 38 1

0.44 0.70 0.0 0.0 0.0 1.0 3.0 34 3

0.42 0.76 0.0 0.0 0.0 1.0 3.0 38 1

0.59 0.78 0.0 0.0 0.0 1.0 3.0 34 3

0.46 0.77 0.0 0.0 0.0 1.0 3.0 37 2

0.41 0.66 0.0 0.0 0.0 1.0 2.0 34 3

0.41 0.64 0.0 0.0 0.0 1.0 2.0 37 2

0.42 0.61 0.0 0,0 0.0 1.0 2.0 33 4

0.43 0.60 0.0 0.0 0.0 1.0 2.0 37 2

0.45 0.67 0.0 0.0 0.0 1.0 2.0 33 4

0.35 0.63 0.0 0.0 0.0 1.0 2.0 37 2

0.61 0.79 0.0 0.0 0.0 1.0 2.0 33 4

0.3B 0.59 0.0 0.0 0.0 1.0 2.0 37 2

0.48 0.71 0.0 0.0 0.0 1.0 2.0 33 4

0.27 0.56 0.0 0.0 0.0 0,0 2.0 37 2

0.58 0.83 0.0 0.0 0.0 1.0 3.0 33 4

0.32 0,71 0.0 0,0 0.0 0.0 3.0 37 2

0.65 0.75 0.0 0.0 0.0 1.0 3.0 33 4

0.22 0.48 0.0 0<0 0.0 0.0 2.0 37 2

0.47 0.75 0.0 0.0 0.0 1.0 3.0 34 3

0.24 0.43 0.0 0.0 0.0 0.0 1.0 37 2

0.44 0.79 0.0 0.0 0.0 1.0 3.0 34 3

0.22 0.42 0.0 0!0 0.0 0.0 1.0 37 2

0.47 0.72 0.0 0.0 0.0 1.0 2.0 32 5

0.17 0.3B 0.0 0.0 0.0 0.0 1.0 36 3


,. ... . .,, ,+,. ......


TABLE 14.2-26: DAILY RECORO CAROS - OCULAR PRURITUS


Centre 1

Day

1

2

3

4

5

6

7

8

9

10

11

12

13

14

( CONTINUED)

I Mean

+-

Treatment

Lora 0.50

Cet i 0.39

Lora 0.43

Cet i 0.39

Lora 0.29

Ceti 0.50

Lora 0.50

Ceti 0.28

Lora 0.43

Ceti 0.28

Lora 0.43

Ceti 0.33

Lora 0.43

Ceti 0.33

Lora 0.43

*

Ceti I 0.28

=---l-+=---+-=

.ora I 0.50

=--l--=:eti I 0.44

N. dev Minimum P25 Median P75 Maximum Number Missing

0.94 0.0 0.0 0.0 1.0 3.0 14 3

0.78 0.0 0.0 0.0 1.0 3.0 18 1

0.65 0.0 0.0 0.0 1.0 2.0 14 3

0.61 0.0 0.0 0.0 1.0 2.0 18 1

0.47 0.0 0.0 0.0 1.0 1.0 14 3

0.71 0.0 0.0 0.0 1.0 2.0 18 1

0.65 0.0 0.0 0.0 1.0 2.0 14 3

0.57 0.0 0.0 0.0 0.0 2.0 18 1

0.51 0.0 0.0 0.0 1.0 1.0 14 3

0.46 0.0 0.0 0.0 1.0 1.0 18 1

0.65 0.0 0.0 0.0 1.0 2.0 ‘14 3

0.49 0.0 0.0 0.0 1.0 1.0 18 1

0.65 0.0 0.0 0.0 1.0 2.0 14 3

0.59 0.0 0.0 0.0 1.0 2.0 18 1

0.85 0.0 0.0 0.0 1.0 3.0 14 3

0.62 0.0 0.0 0.0 1.0 2.0 18 1

0.76 0.0 0.0 0.0 1.0 2.0 14 3

0.46 0.0 0.0 0.0 1.0 1.0 18 1

0.51 0.0 0.0 0.0 1.0 1.0 14 3

0.61 0.0 0.0 0.0 1.0 2.0 18 1

0.74 0.0 0.0 0.0 0.0 2.0 14 3

0.59 0.0 0.0 0.0 1.0 2.0 18 1

0.65 0.0 0.0 0.0 1.0 2.0 14 3

0.57 0.0 0.0 0.0 0.0 2.0 18 1

0.47 0.0 0.0 0.0 1.0 1.0 14 3

0.59 0.0 0.0 0.0 1.0 2.0 18 1

0.50 0.0 0.0 0.0 1.0 1.0 14 3

0.70 0.0 0.0 0.0 1.0 2.0 18 1


---. .,,.. ,. . . . . . ,-, “.,.. ‘z...




Centre 1

Day

15

16

19

20

21

22

23

?4


Treatment

Lora 0.21 0.43 0.0 0.0 0.0 0.0 1.0 14 3

Ceti 0.72 0.83 0.0 0.0 0.5 1.0 2.0 18 1

Lora 0.43 0.65 0.0 0.0 0.0 1.0 2.0 14 3

Ceti 0.67 0.97 0.0 0.0 0.0 1.0 3.0 18 1

Lora 0.29 0.47 0.0 0.0 0.0 1.0 1.0 14 3

Ceti 0.44 0.86 0.0 0.0 0.0 1.0 3.0 18 1

Lora 0.29 0.47 0.0 0.0 0.0 1.0 1.0 14 3

Ceti 0.47 0.B7 0.0 0.0 0.0 1.0 3.0 17 2

Lora 0.14 0.36 0.0 0.0 0.0 0.0 1.0 14 3

Ceti 0.35 0.61 0.0 0.0 0.0 1.0 2.0 17 2

Lora 0.21 0.43 0.0 0.0 0.0 0.0 1.0 ’14 3

Ceti 0.41 0.51 0.0 0.0 0.0 1.0 1.0 17 2

Lora 0.14 0.36 0.0 0.0 0.0 0.0 1.0 14 3

Ceti 0.29 0.59 0.0 0.0 0.0 0.0 2.0 17 2

Lora 0.43 0,65 0.0 0.0 0.0 1.0 2.0 14 3

Ceti 0.35 0.49 0.0 0.0 0.0 1.0 1.0 17 2

Lora 0.50 0.76 0.0 0.0 0.0 1.0 2.0 14 3

Ceti 0.18 0.39 0.0 0.0 0.0 0.0 1.0 17 2

.ora 0.29 0.61 0.0 0.0 0.0 0.0 2.0 14 3

:et i 0.24 0.56 0.0 0.0 0.0 0.0 2.0 17 2

.ora 0.29 0.47 0.0 0.0 0.0 1.0 1.0 14 3

>eti 0.12 0.33 0.0 0.0 0.0 0.0 1.0 17 2

.ora 0.14 0.36 0.0 0.0 0.0 0.0 1.0 14 3

:eti 0.29 0.47 0.0 0.0 0.0 1.0 1.0 17 2

.ora 0.14 0.36 0.0 0.0 0.0 0.0 1.0 14 3

:et i 0.29 0.47 0.0 0.0 0.0 1.0 1.0 17 2

.ora 0.15 0.55 0.0 0.0 0.0 0.0 2.0 13 4

;eti 0.13 0.34 0.0 0.0 0.0 0.0 1.0 16 3


--.., ,i”. , ,,. -1 .“,..--,,’


TABLE 14.2-26: DAILY RECORD CAHOS - OCULAR PRURITUS


Centre 2


lay Treatment

1 Lora 0.90 1.12 0.0 0.0 0.5 1.5 3.0 20 0

Ceti 0.80 0.95 0.0 0.0 0.5 1.5 3.0 20 0

~ Lora 0.95 1.05 0.0 0.0 1.0 2.0 3.0 20 0

Ceti 0.70 0.92 0.0 0.0 0.0 1.0 3.0 20 0

3 Lora 0.90 1.02 0.0 0.0 1.0 1.5 3.0 20 0

Cet i 0.60 0.88 0.0 0.0 0.0 1.0 3.0 20 0

$ Lora 0.70 0.98 0.0 0.0 0.0 1.5 3.0 20 0

Ceti 0.50 0.76 0.0 0.0 0.0 1.0 2.0 20 0

5 Lora 0.80 0.89 0.0 0.0 1.0 1.0 3.0 20 0

Ceti 0.40 0.68 0.0 0.0 0.0 1.0 2.0 20 0

5 Lora 0.70 0.80 0.0 0.0 0.5 1.0 2.0 “20 o

Ceti 0.30 0.66 0.0 0.0 0.0 0.0 2.0 20 0

7 Lora 1.00 0.97 0.0 0.0 1.0 1.5 3.0 20 0

Cet i 0.35 0.67 0.0 0.0 0.0 0.5 2.0 20 0

3 Lora 0.90 0.85 0.0 0.0 1.0 1.0 3.0 20 0

Ceti 0.35 0.67 0.0 0.0 0.0 0.5 2.0 20 0

I Lora 0.90 0.91 0.0 0.0 1.0 1.5 3.0 20 0

Cet i 0.25 0.55 0.0 0.0 0.0 0.0 2.0 20 0

0 Lora 1.15 0.68 0.0 0.5 1.0 2.0 3.0 20 0

Ceti 0.25 0.44 0.0 0.0 0.0 0.5 1.0 20 0

1 Lora 1.20 0.95 0.0 0.5 1.0 2.0 3.0 20 0

Ceti 0.25 0.44 0,0 0.0 0.0 0.5 1.0 20 0

2 Lora 0.90 0.91 0.0 0.0 1.0 1.5 3.0 20 0

Cet i 0.30 0.47 0.0 0.0 0.0 1.0 1.0 20 0

3 Lora 0.75 0.97 0.0 0.0 0.0 1.5 3.0 20 0

Ceti 0.30 0.47 0.0 0.0 0.0 1.0 1.0 20 0

4 Lora 0.60 0.82 0.0 0.0 0.0 1.0 3.0 20 0

Ceti 0.40 0.60 0.0 0.0 0.0 1.0 2.0 20 0

(CONTINUED)

REPORT ~0.: MRCE98G0201/1 V Study Report December 1, 1998

..”, ”,,, . . . ,, ., .- ......,,




Centre 2


Oay Treatment

15 Lora 0.65 0.88 0.0 0.0 0.0 1.0 3.0 20 0

Ceti 0.35 0.59 0.0 0.0 0.0 1.0 2.0 20 0

16 Lora 0.60 0.88 0.0 0.0 0.0 1.0 3.0 20 0

Cet i 0.40 0.60 0.0 0.0 0.0 1.0 2.0 20 0

17 Lora 0.55 0.83 0.0 0.0 0.0 1.0 3.0 20 0

Cet i 0.40 0.68 0.0 0.0 0.0 1.0 2.0 20 0

18 Lo ra 0.80 0.89 0.0 0,0 1.0 1.0 3.0 20 0

Ceti 0.45 0.69 0.0 0.0 0.0 1.0 2.0 20 0

19 Lora 0.60 0.75 0.0 0.0 0.0 1.0 2.0 20 0

Cet i 0.45 0.69 0.0 0.0 0.0 1.0 2.0 20 0

20 Lora 0.58 0.69 0.0 0.0 0.0 1.0 2.0 ‘19 1

Ceti 0.45 0.69 0.0 0.0 0.0 1.0 2.0 20 0

21 Lora 0.68 0.75 0.0 0.0 1.0 1.0 2.0 19 1

Cet i 0.40 0.68 0.0 0.0 0.0 1.0 2.0 20 0

22 Lora 0.74 0.87 0.0 0.0 0.0 2.0 2.0 19 1

Ceti 0.40 0.68 0.0 0.0 0.0 1.0 2.0 20 0

23 Lora 0.47 0.70 0.0 0.0 0.0 1.0 2.0 19 1

Cet i 0.35 0.67 0.0 0.0 0.0 0.5 2.0 20 0

24 Lora 0.79 0.92 0.0 0.0 1.0 1.0 3.0 19 1

Ceti 0.40 0.82 0.0 0.0 0.0 0.5 3.0 20 0

25 Lora 0.74 0.87 0.0 0.0 1.0 1.0 3.0 19 1

Ceti 0.30 0.57 0.0 0<0 0.0 0.5 2.0 20 0

26 Lora 0.70 0.86 0.0 0.0 0.5 1.0 3.0 20 0

Ceti 0.20 0.41 0.0 0.0 0.0 0.0 1.0 20 0

27 Lora 0.65 0.93 0.0 0.0 0.0 1.0 3.0 20 0

Cet i 0.15 0.37 0.0 0.0 0,0 0.0 1.0 20 0

28 Lora 0.68 0.75 0.0 0.0 1.0 1.0 2.0 19 1

Ceti 0.20 0.41 0.0 0.0 0.0 0.0 1.0 20 0


...M”,4. ,,,, ,, ,, ,,. ,. , . . ,-, ... ... ..


TABLE 14.2-27: DAILY RECORD CARDS - TSS


All patients


Day Treatment

1 Lora 6.21 3.20 1.0 3.0 6.0 9.0 12.0 33 4

Ceti 6.37 3.70 0.0 4.0 6.0 9.0 15.0 3B 1

2 Lora 5.91 3.23 1.0 3.0 6.0 8.0 12.0 33 4

Cet i 5.74 3.72 0.0 3.0 5.5 10.0 13.0 38 1

3 Lora 6.09 3.08 2.0 4.0 6.0 8.0 12.0 34 3

Ceti 5.66 3.63 0.0 3.0 6.0 9.0 13.0 38 1

4 Lora 5.65 3.37 0.0 3.0 5.0 8.0 12.0 34 3

Ceti 5.39 3.30 0.0 3.0 5.0 7.0 12.0 38 1

5 Lora 5.50 3.22 0.0 3.0 6.0 8.0 11.0 34 3

Ceti 5.39 3.17 0.0 3.0 5.0 7.0 12.0 38 1

6 Lora 5.29 3.26 0.0 3.0 5.0 7.0 13.0 34 3

Cet i 5.29 3.24 0.0 3.0 5.0 8.0 13.0 38 1

7 Lora 5.32 3.25 0.0 2.0 5.0 8.0 12.0 34 3

Cet i 5.13 3.03 0.0 3.0 5.0 8.0 11.0 38 1

3 Lora 5.18 3.74 0.0 2.0 4.5 8.0 15.0 34 3

Cet i 4.84 2.93 0.0 2.0 5.0 7.0 11.0 38 1

3 Lora 5.38 3.23 0.0 3.0 5.0 8.0 12.0 34 3

Ceti 4.79 2.67 0.0 3.0 5.0 7.0 10.0 38 1

10 Lora 5.68 2.94 1.0 3.0 5.0 8.0 12.0 34 3

Cet i 4.97 3.17 0.0 3.0 5.0 8.0 13.0 38 1

11 Lora 5.44 3.21 1.0 3.0 5.0 8.0 12.0 34 3

Cet i 4.53 3.01 0.0 3.0 4.0 6.0 14.0 38 1

12 Lora 5.21 3.03 0.0 3.0 4.5 7.0 14.0 34 3

Ceti 4.53 3.24 0.0 2.0 4.0 7.0 14.0 38 1

13 Lora 4.97 2.82 0.0 3.0 5.0 7.0 12.0 34 3

Cet i 4.29 2.89 0.0 2.0 5.0 6.0 12.0 38 1

14 Lora 4.88 2.52 1.0 3.0 5.0 6.0 12.0 34 3

Ceti 4.53 2.92 0.0 2.0 5.0 6.0 12.0 38 1

(CONTINUEO)


., . , ....,, -, ..”., -,, ,




All patients

Day

15

16

17

18

19

20

21

25

26

27

28

Mean St. dev Minimum P25

Treatment

Lora 4.71 2.65 0.0 3.0

Ceti 4.71 3.03 0.0 2.0

Lora 4.68 3.05 0.0 2.0

Cet i 4.32 2.92 0.0 2.0

Lora 4.26 2.95 0.0 2.0

Ceti 4.49 3.01 0.0 2.0

Lora 4.85 3.13 0.0 3.0

Ceti 4.22 3.19 0.0 2.0

Lora 4.41 2.97 0.0 2.0

Ceti 4.14 2.95 0.0 2.0

Lora 4.33 2.87 0.0 3.0

Ceti 4.05 3.21 0.0 1.0

Lora 4.27 2.88 0.0 2.0

;et i 4.00 3.16 0.0 1.0

.ora 4.85 2.77 0.0 3.0

;et i 3.97 2.97 0.0 2.0

.ora 4.55 2.58 1.0 3.0

:eti 3.59 2.93 0.0 1.0

-era 4.45 2.87 0.0 3.0

;et i 3.68 3.18 0.0 1.0

-era 4.33 2.53 1.0 3.0

;eti 3.32 2.82 0.0 1.0

.ora 3.97 2.43 0.0 3.0

:et i 3.22 2.55 0.0 1.0

Lora 4.00 3.05 0.0 2.0

:eti 2.95 2.43 0.0 1.0

Lora 3.48 2.38 0.0 2.0

:eti 2.89 2.59 0.0 1.0

ledian P75 Maximum Number Missing

XLIz5.0 7.0 12.0 38 1

5.0 7.0 12.0 34 3

4.0 6.0 12.0 38 1

4.0 7.0 12.0 34 3

4.0 6.0 12.0 37 2

4.5 7.0 14.0 34 3

4.0 6.0 12.0 37 2

4.0 6.0 13.0 34 3

4.0 6.0 11.0 37 2

4.0 6.0 14.0 ’33 4

4.0 6.0 12.0 37 2

4.0 5.0 13.0 33 4

4.0 6.0 13.0 37 2

4.0 7.0 13.0 33 4

4.0 5.0 13.0 37 2

4.0 6.0 13.0 33 4

3.0 5.0 13.0 37 2

4.0 6.0 13.0 33 4

3.0 5.0 14.0 37 2

3.0 6.0 11.0 33 4

3.0 5.0 12.0 37 2

3.0 5.0 11.0 34 3

4.0 5.0 9.0 37 2

3.0 6.0 13.0 34 3

2.0 4.0 9.0 37 2

3.0 6.0 9.0 31 6

2.5 4.5 9.0 36 3


,,, ,, ,,. ,, ...,-.., m. ..,..,.

STUDY No.: 9153PROTOCOL No. : MPCE9 lL 1802/6D of 187



Centre 1

\Mean \St. dev\Minimum \ P25 lMedism I P75

m 562 362 10 30 50 ‘clCeti I 5.441 4.02/ o-o[ 2.o1 4.01 e.c

~ Lora 5.46 3.15 1.0 3.0 5.0 7.0

Cet i 4.89 3.77 0.0 1.0 4.0 10.0

3 Lora 5.14 2.51 2.0 3.0 5.0 7.0

Cet i 4.89 3.66 0.0 2.0 4.5 9.0

4 Lora 5.07 2.97 0.0 3.0 5.0 6.0

Ceti 4.83 3,37 0.0 3.0 4.0 7.0

5 Lora 5.07 3.20 0.0 3.0 6.0 6.0

Ceti 4.39 3.42 0.0 2.0 4.0 7.0

, Lora 5.29 4.01 0.0 2.0 5.0 7.0

Ceti 4.B3 3.02 0.0 1.0 4.0 B.O

Lora 4.64 3.23 0.0 2.0 4.5 7.0

Ceti 5.00 3.46 0.0 3.0 4.0 9.0

I Lora 4.71 3.87 0.0 2.0 4.0 7.0

Cet i 4.17 3.28 0.0 1.0 4.0 7.0

) Lora 5.07 3.22 0.0 3.0 4.5 7.0

Cet i 4.22 3.15 0.0 3.0 3.5 7.0

0 Lora 5.43 2.53 1.0 4.0 5.0 7.0

Ceti 4.72 3.77 0.0 2.0 3.0 8.0

1 Lora 5.21 2.94 2.0 2.0 4.5 7.0

lCeti I 4.oo1 3.241 0.01 2.01 4.01 5.o

2 I Lora \ 4.931 2.231 2.01 3.o\ 4.01 7.0

I I I I t I

Ceti 4.06 3.96 0,0 1.0 3.0 7.0

I I I I I I I

13 Lora 4.79 2.22 0.0 4.0 5.0 6.0,

Cet i 4.06 3.46 0.0 0.0 5.0 6.0

14 Lora 4.86 1.88 1.0 4.0 5.0 6.0

Cet i 4.2S 3.16 0.0 2.0 3.5 6.0

(CONTINUED)

Aaximum Number Missing

11.0 13 4

15.0 18 1

11.0 13 4

10.0 lB 1

10.0 14 3

12.0 18 1

11.0 14 3

12.0 18 1

10.0 14 3

12.0 18 1

13.0 ‘14 3

13.0 18 1

10.0 14 3

11.0 18 1

15.0 14 3

11.0 18 1

12.0 14 3

10.0 18 1

10.0 14 3

13.0 18 1

11.0 14 3

14.0 18 1

9.0 14 3

14.0 18 1

8.0 14 3

12.0 18 1

8.0 14 3

12.0 18 1

REPORT No.: MRCE98G020 1/1 V Study Report December 1, 1998

.-.4. . . . ,, “,, ., -......”-.!<.




Centre 1

I Mean lSt. dev

)ay Treatment

15 Lora 4.43 2.28

Ceti 4.67 3.22

16 Lora 4.64 2.59

Cet i 4.17 2.98

17 Lora 3.93 2.13

Ceti 4.06 2.92

18 Lora 4.00 1.71

Ceti 3.76 2.61

19 Lora 3.64 1.74

Ceti 3.53 2.29

!0 Lora 3.57 1.99

Ceti 3.41 2.76

“ E=I-+++‘2=ka=!3 Lora 4.00 1.92

Cet i I 2.76 2.14

?4 Lora 3.71 1.44

Ceti 2.71 2.17

?5 Lora 3.14 1.51

Ceti 2.35 1.80

?6 Lora 2.93 1.38

Ceti 2.82 2.16

Iceti I 2.131 2.03

Iinimur

O.c

O.c

O.c

O.c

1.0

0.0

1.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

2.0

0.0

2.0

0.0

1.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

P25 Median P75 Maximum Number Missing

3.0 4.0 7.0 8.0 14 3

2.0 5.0 8.0 10.0 18 1

2.0 5.0 6.0 10.0 14 3

2.0 4.0 6.0 11.0 18 1

2.0 4.0 5.0 8.0 14 3

2.0 3.0 6.0 10.0 18 1

3.0 3.5 5.0 7.0 14 3

2.0 3.0 5.0 10.0 17 2

3.0 4.0 4.0 7.0 14 3

1 , I I

2.0 4.0 5.0 9.0 17 2

3.0 3.0 5.0 8.0 ‘14 3

1.0 3.0 5.0 9.0 17 2

2.0 4.0 5.0 7.0 14 3

1.0 3.0 5.0 8.0 17 2

3.0 4.0 6.0 8.0 14 3

i I I I I

2.0 4.0 5.0 6.0 14 3

1.0 2.0 4.0 7.0 17 2

2.0 3.0 4.0 6.0 14 3

1.0 3.0 3.0 5.0 17 2

2.0 3.0 4.0 6.0 14 3

1.0 4.0 4.0 6.0 17 2

2.0 3.0 3.0 6.0 14 3

1.0 2.0 4.0 5.0 17 2

1.5 2.0 3.0 5.0 12 5

0.5 1.0 3.5 6.0 16 3

I I I I I I

REPORT No.: MRCE98G020 1/1 V Study Report December 1, 1998

,.”s -, ,..,.,, ,,,“ ~. , ,-. . .”-!.”.-.




Centre 2

Mean St. dev

Oay Treatment

1 Lora 6.60 2.93

Ceti 7.20 3.27

2 Lora 6.20 3.33

Ceti 6.50 3.59

‘=--+-a+5 I I 4 329Lora

Ceti 6.30 2.70

6 Lora 5.30 2.74

Ceti 5.70 2.64

7 Lora 5.80 3.27

Cet i 5.25 2.67

B Lora 5.50 3.71

Ceti 5.45 2.50

9 Lora 5.60 3.30

Ceti 5.30 2.11

10 Lora 5.85 3.25

Ceti 5.20 2.61

11 Lora 5.60 3.45

Ceti 5.00 2.79

12 Lora 5.40 3.53

Cet i 4.95 2.46

13 Lora 5.10 3.23

Ceti 4.50 2.35

14 Lora 4.90 2.94

Ceti 4.75 2.75

(CONTINUED)

!inimum P25 Median P75 Maximum Number

2.0 4.0 7.0 9.0 12.0 20

2.0 4.5 6.5 10.5 13.0 20

1.0 3.0 6.0 8.5 12.0 20

1.0 3.5 6.5 9.0 13.0 20

2.0 4.0 7.0 9.5 12.0 20

1.0 3.0 6.0 9.0 13.0 20

1.0 3.5 5.0 8.5 12.0 20

1.0 3.5 6.0 7.5 12.0 20

0.0 3.0 6.0 8.5 11.0 20

0.0 4.5 6.5 8.0 10.0 20

1.0 3.5 5.0 6.5 11.0 ’20

1<0 4.0 5.5 7.5 10.0 20

I I

0.0 2.0 5.5 9.0 11.0 20

! I I I

2.0 3.5 5.0 7.0 11.0 20

I I I I !

0.0/ 3.01 5.01 8.51 11.01 20

1.01 4.51 5.01 7.01 9.01 201 I I I i

1.01 3.01 5.51 9.01 12.01 20I I I I I

0.0 3.0 5.5 7.0 10.0 20

1.0 3.0 5.0 8.5 12.0 20

0.0 3.5 5.5 7.0 9.0 20

0.01 3.01 5.01 7.51 14. o\ 20

0.01 3.51 5.01 7.01 8.01 20

1.0 2.01 5.01 7.51 12.0 20

0.01 3.01 5.0/ 6.51 8.01 20

1 I [ I I

1.01 2.51 5.51 6.51 12.01 20

I I [ I I

0.0 2.5 5.0 6.5 12.0 20

issing

o

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0


,,, ... - , ..-’.,’..”..


TABLE 14.2-27: DAILY RECORO CARDS - TSS


Centre 2

I [ I 1 1

+

Mean St. dev

Day Treatment

Lora15

$4.90 2.92

4.75 2.94

4.70 3.40

4.45 2.95

4.50 3.44

4.B9 3.11

5.45 3.76

0.0 2.0 5.0 7.0 12.0 20 c

0.0 2.0 5.0 7.0 12.0 20 c

Ceti

16 Lora1 I , I

0.0 2.0 4.5 6.5 12.0 20 cCeti

0.0 1.0 4.5 7.0 12.0 20 c

0.0 2.0 5.0 7.0 12.0 19 1

17 Lora

Ceti1 1 , I

0.0 2.5 5.0 8.0 14.0 20 c18 LoraI

1 1 I I0.0 1.0 4.5 7.0 12.0 20 c

2=4.60 3.63

4.95 3,53

4.65 3.3e

4.89 3.31

Ceti1 ! 1 ! , I

0.0 2.0 5.0 7.0 13.0 20 c19 LoraI I 1 I I I

0.0 1.5 4.0 7.0 11.0 20 cCetiI I 1 I I

0.0 2.0 5.0 7,0 14.0 ’19 120 LoraI I I I I I

0.0 1.5 4,0 6.0 12.0 20 (

+

4.60 3.53

4.89 3.31

4.75 3.45

5.26 3.11

4.60 3.52

4.95 2.95

4.30 3.36

Ceti

0.0 2.0 5.0 7.0 13.0 19 1

0.0 2.0 4.5 6.0 13.0 20 0

0.0 3.0 5.0 7.0 13.0 19 1

0.0 2.0 4.0 6.5 13.0 20 0

1.0 3.0 4.0 7.0 13.0 19 1

21 Lora

Ceti

Lora

Ceti

Lora

Cet i

Lora

Ceti

Lora

Cet i

I I I I I0.0 1.5 4.0 5.5 13.0 20 0

I

0.0 3.0 4.0 7.0 13.0 19 1

0.0 1.5 4.5 6.5 14.0 20 0

1.0 3.0 5.0 7.0 11.0 19 1

5.00 3.53

4.50 3.69

5.21 2.80

4.15 3.28

4.70 2.75

3.55 2.86

4,65 3.63

3.45 2.82

4.26 2.60

3.50 2.87

1 , I0.0 1.5 4.5 6.5 12.0 20 0

1 1 I1.0 3.0 4.0 6.5 11.0 20 0Lora

Ceti

Lora

Ceti

Lora

Ceti

1 , I

0.0 1.0 4.0 5.0 9.0 20 0

0.0 2.0 4.0 7.0 13.0 20 0

0.0 1.0 3.0 5.0 9.0 20 c

0.0 2.0 5.0 6.0 9.0 19 1

0.0 1.0 3.5 6.0 9.0 20 c

27


,..-.,,,< ,, ,,, ,, .,., ,-,...... . .


14.3SAFETY DATA

“ABLE 14.3-1: LABORATORY DATA - ERYTHROCYTES

ntention to Treat Population


(N= 37) (N= 39)

lisit 1- All patientsBelow 2 ( 5.4?ko) 6 (16.2’XO)

Within 34 (91.9%) 31 (83.8%)

Above 1 ( 2.7’Yo) o ( O.OYO)

Missing o 2

(isit 1- Centre 1Below 1 ( 5.9!40) 1 ( 5.9?40)

Within 16 (94.1%) 16 (94.1%)

Above o ( O.OYO) o ( 0.0?40)

Missing o 2

v’isit 1- Centre 2Below 1 ( 5.OYO) 5 (25.OYO)

Within 18 (90.0%) 15 (75.0%)

Above 1(Missing o

Visit 2- All patientsBelow 6(’

Within 26(!

Above 0(

Missing 5

(isit 2- Centre 1

5 .070) o ( 0.0%)o

8.8?40) 8 (23.5’XO)

1.3YO) 25 (73.5Yo)

0.0%) 1 ( 2.9%)5

Below 3 (25.0%) 2 (14.3YO)

Within 9 (75.0’%0) 11 (78.6’XO)

Above o ( 0.0?40) 1 ( 7.lYO)

Missing 5 5

Visit 2- Centre 2

Below 3 (15.0%) 6 (30.0%)

Within 17 (85.0%) 14 (70. O’XO)

Above o ( 0.0%) o ( 0.0?40)

Missing o 0


-“. -.. ..” .,,, ,,.. ,,”. . m,.., . . ,,


I’ABLE 14.3-1- Continued: LABORATORY DATA - ERYTHROCYTES[ntention to Treat Population


(N= 37) (N= 39)

Shift between visit 1 and visit 2

Ml patientsBelow-belowBelow-withinBelow-aboveWithin-belowWithin-withinWithin-aboveAbove-belowAbove-withinAbove-aboveMissing

Centre 1Below-belowBelow-withinBelow-aboveWithin-belowWithin-withinWithin-aboveAbove-belowAbove-withinAbove-aboveMissing


1 ( 3.lYO)1 ( 3.1’?40)o ( 0.0?40)5 (15.6%)

24 (75.0’%0)o ( 0.0%)o ( 0.0?40)1 ( 3.1%)o ( O.OYO)5

1 ( 8.3’?40)o ( O.OYO)o ( O.OYO)2 (16.7%)9 (75.0%)o ( 0.0’?40)o ( 0.0%)o ( O.O’YO)o ( O.OYO)5

0 ( 0.0?40)1 ( 5.0%)o ( O.OYO)3 (15.0’?40)

15 (75.0%)o ( 0.0%)o ( 0.0%)1 ( 5.0?40)o ( 0.0%)o

4 (12.5Yo)2 ( 6.3’XO)o ( O.OYO)4 (12.5%)

22 (68.8’YO)o ( 0.0%)o ( 0.0%)o ( O.OYO)o ( O.OYO)7

‘ 1 ( 8.3Yo)o ( O.O’YO)o ( 0.0%)1 ( 8.3%)

10 (83.3%)o ( 0.0?40)o ( 0.0?40)o ( O.OYO)o ( 0.0%)7

3 (15. O’XO)2 (10.0%)o ( 0.0%)3 (15.0940)

12 (60. O’XO)o ( 0.0%)o ( O.ovo)o ( O.OYO)o ( 0.0%)o


STUDY No.: 9153PROTOCOL No.: MPCE91 L1802/6D

of 187

‘ABLE 14.3-2: LABORATORY DATA - HEMATOCRITntention to Treat Population


(N= 37) (N= 39)

Tisit 1 - All patients

Below 5 (13.5YO) 7 (17.9’%0)

Within 25 (67.6%) 22 (56.4Yo)

Above 7 (18.9?ZO) 10 (25.6’XO)

Missing o 0

~isit 1- Centre 1Below o ( 0.0?40) o ( 0.070)

Within 10 (58.8’?40) 9 (47.470)

Above 7 (41 .270) 10 (52.6%)

Missing o 0

(isit 1- Centre 2Below 5 (25.OYO) 7 (35. O’YO)

Within 15 (75.OYO) 13 (65. O’%0)

Above o ( O.OYO) ‘o ( 0.0%)

Missing o 0

Visit 2- All patientsBelow 7 (20.6Yo) 5 (13.5’XO)

Within 24 (70.6%) 25 (67.6%)

Above 3 ( 8.8YO) 7 (18.9VO)

Missing 3 2

Visit 2- Centre 1Below o ( O.OYO) o ( 0.0940)

Within 11 (78.6’XO) 10 (58.8%)

Above 3 (21 .4YO) 7 (41 .2%)

Missing 3 2

Visit 2- Centre 2Below 7 (35.0%) 5 (25.OYO)

Within 13 (65.OYO) 15 (75.OYO)

Above o ( O.OYO) o ( O.ovo)

Missing o 0


.,,=-,,,, ,, ., .,” “.....q.>,.w. ,,

STUDY No.: 9153PROTOCOL No.: MPCE91L1802/6D of187

TABLE 14.3-2- Continued: LABORATORY DATA - HEMATOCRITIntention to Treat Population



All patientsBelow-below 2 ( 5.9%) 2 ( 5.4’?ZO)

Below-within 3 ( 8.8YO) 5 (13.5YO)

Below-above o ( O.o’xo) o ( 0.0’?40)

Within-below 5 (14.7%) 3 ( 8.lYo)

Within-within 18 (52.9Yo) 14 (37.8Yo)

Within-above 1 ( 2.9Yo) 4 (10.870)

Above-below o ( 0.0’%0) o ( 0.0?40)

Above-within 3 ( 8.8%) 6 (16.2?40)

Above-above 2 ( 5.9?40) 3 ( 8.1%)’

Missing 3 2

Centre 1Below-below o ( O.OYO) ‘o ( O.ovo)

Below-within o ( 0.0%) o ( 0.0%)

Below-above o ( 0.0%) o ( 0.0%)

Within-below o ( 0.0%) o ( O.OYO)

Within-within 8 (57.lYo) 4 (23.5%)

Within-above 1 ( 7.1%) 4 (23.5%)

Above-below o ( 0.0%) o ( 0.070)

Above-within 3 (21 .4YO) 6 (35.3%)

Above-above 2 (14.3YO) 3 (17.6?40)

Missing 3 2

Centre 2Below-below 2 (10.0%) 2 (10.0?40)

Below-within 3 (15.0’?40) 5 (25.0%)

Below-above o ( 0.0%) o ( O.ofxo)

Within-below 5 (25.0%) 3 (15.0%)

Within-within 10 (50.0%) 10 (50.OYO)

Within-above o ( 0.0?40) o ( 0.0’%0)

Above-below o ( O.OYO) o ( 0.0?40)

Above-within o ( O.OYO) o ( 0.0?40)

Above-above o ( 0.0%) o ( 0.0%)

Missing o 0



r

1

7

,

.

1

rABLE 14.3-3: LABORATORY DATA - HEMOGLOBINhtention to Treat Population


(N= 37) (N= 39)

Visit 1- All patientsBelow 6 (16.2?40) 8 (20.5%)

Within 23 (62.2Yo) 20 (51 .3VO)

Above 8 (21 .6’?40) 11 (28.2%)

Missing o 0

Visit 1- Centre 1Below o ( 0.0’?40) o ( 0.0’%0)

Within 9 (52.9?40) 8 (42. lYo)

Above 8 (47.1%) 11 (57.9%)

Missing o 0

Visit 1- Centre 2Below 6 (30.OYO) 8 (40.OYO)

Within 14 (70.0%) 12 (60.OYO)

Above o ( O.ovo) ‘o ( 0.0%)

Missing o 0

Visit 2- All patientsBelow 5 (14.7YO) 7 (18.9Yo)

Within 26 (76.5?40) 24 (64.9%)

Above 3 ( 8.870) 6 (16.2Yo)

Missing 3 2

Visit 2- Centre 1Below o ( 0.0%) o ( 0.0%)

Within 11 (78.6%) 11 (64.7%)

Above 3 (21 .4!40) 6 (35,3Yo)

Missing 3 2

Visit 2- Centre 2Below 5 (25.OVO) 7 (35.0%)

Within 15 (75.070) 13 (65.0%)

Above o ( 0.0%) o ( 0.0%)

Missing o 0


,., .,. .. .. ... . . ,- ,.W.....,.


rABLE 14.3-3- Continued: LABORATORY DATA - HEMOGLOBINntention to Treat Population


(N= 37) (N= 39)

;hift between visit 1 and visit 2

*11patientsBelow-belowBelow-withinBelow-aboveWithin-belowWithin-withinWithin-aboveAbove-belowAbove-withinAbove-aboveMissing

2entre 1Below-belowBelow-withinBelow-aboveWithin-belowWithin-withinWithin-aboveAbove-belowAbove-withinAbove-aboveMissing


1 ( 2.9%)5 (14.7?40)o ( O.OYO)4(11.8%)

17 (50.0%)1 ( 2.9%)o ( 0.070)4(1 1.8Yo)2 ( 5.9%)3

0 ( 0.0’?40)o ( 0.0’%0)o ( 0.0’%0)o ( 0.0%)7 (50.OYO)1 ( 7.1’%0)o ( O.OYO)4 (28.6Yo)2 (14.370)3

1 ( 5.0?40)5 (25.0%)o ( O.OYO)4 (20.0%)

10 (50.OVO)o ( 0.0?40)o ( 0.0?40)o ( 0.0%)o ( 0.0?40)o

3 ( 8.lYo)5 (13.5?ko)o ( 0.0%)4 (10.8%)

15 (40.5%)o ( O.OYO)o ( O.OYO)4 (10.8%),6 (16.2Yo)2

‘o ( 0.0%)o ( 0.0%)o ( 0.070)o ( O.OYO)7 (41 .2%)o ( 0.0?40)o ( 0.070)4 (23.5Yo)6 (35.3Yo)2

3 (15.0%)5 (25.0?40)o ( 0.0%)4 (20.0?40)8 (40.0%)o ( 0.0’%0)o ( 0.0’%0)o ( 0.0!40)o ( 0.0%)o



~ABLE 14.3-4: LABORATORY DATA - WHITE BLOOD COUNTntention to Treat Population


(N= 37) (N= 39)

/isit 1- All patientsBelow 1 ( 2.7%) o ( O.ovo)

Within 36 (97.3%) 38 (97.4%)

Above o ( 0.0?40) 1 ( 2.6%)

Missing o 0

Visit 1- Centre 1Below o ( o%) o ( o%)

Within 17 (loo%) 19 (loo%)

Above o ( o%) o ( OYO)

Missing o 0

(isit 1- Centre 2Below 1 ( 5.070) o ( O.ovo)

Within 19 (95.0%) 19 (95.0%)

Above o ( O.OYO) ‘ 1 ( 5.OVO)

Missing o 0

Visit 2- All patientsBelow 1 ( 2.9Yo) 2 ( 5.4YO)

Within 33 (97.1%) 34 (91 .9%)

Above o ( O.OYO) 1 ( 2.7?40)

Missing 3 2

Visit 2- Centre 1Below o ( o%) o ( o%)

Within 14 (100?40) 17 (loo%)

Above o ( o%) o ( o%)

Missing 3 2

Visit 2- Centre 2Below 1 ( 5.0?40) 2 (10.0?40)

Within 19 (95.0%) 17 (85.OYO)

Above o ( O.OYO) 1 ( 5.0%)

Missing o 0


ST[JDY No.: 9153——PROTOCOL No.: MPCE91 L 1802/6D of 187

rABLE 14.3-4- Continued: LABORATORY DATA - WHITE BLOOD COUNTntention to Treat Population


(N=37) (N= 39)

ihift between visit 1 and visit 2

%11patientsBelow-below o ( O.OYO) o ( O.ovo)

Below-within 1 ( 2.9%) o ( O.OYO)

Below-above o ( O.OYO) o ( 0.0%)

Within-below 1 ( 2.9Yo) 2 ( 5.4%)

Within-within 32 (94. 1%) 33 (89.2%)

Within-above o ( 0.0%) 1 ( 2.7?ZO)

Above-below o ( O.OYO) o ( 0.070)

Above-within o ( O.OYO) 1 ( 2.7%)

Above-above o ( 0.0%) o ( O.ovo)

Missing 3 2

Centre 1Below-below o ( o%) ‘0( 0’%0)

Below-within o ( o%) o ( 0?40)

Below-above o ( o%) o ( 070)

Within-below o ( o%) o ( 0?40)

Within-within 14 (loo%) 17 (1OO’YO)

Within-above o ( 0?40) o ( 0?40)

Above-below o ( o%) o ( 0’%0)

Above-within o ( OYO) o ( o%)

Above-above o ( OYO) o ( o%)

Missing 3 2

Centre 2Below-below o ( O.OYO) o ( O.OYO)

Below-within 1 ( 5.OYO) o ( 0.0%)

Below-above o ( 0.0%) o ( 0.0%)

Within-below 1 ( 5.0?40) 2 (10.OYO)

Within-within 18 (90.OYO) 16 (80. O’YO)

Within-above o ( 0.070) 1 ( 5.070)

Above-below o ( O.OYO) o ( 0.0%)

Above-within o ( 0.0%) 1 ( 5.OYO)

Above-above o ( 0.0?40) o ( O.OYO)

Missing o 0


STUDY No.: 9153PROTOCOL No.: MPCE91LI 802/6D

paue 166 of 187

“ABLE 14.3-5: LABORATORY DATA - NEUTROPHILSntention to Treat Population


(N= 37) (N= 39)

Jisit 1- All patientsBelowWithinAboveMissing

Visit 1- Centre 1BelowWithinAboveMissing

Qisit 1- Centre 2BelowWithinAboveMissing

Visit 2- All patientsBelowWithinAboveMissing



5 (13.5%)31 (83.8Yo)

1 ( 2.7Yo)o

4 (23.5Yo)13 (76.5Yo)o ( 0.00/0)o

1 ( 5.070)18 (90.0%)

1 ( 5.0%)o

0 ( O.o’xo)32 (94.1%)

2 ( 5.9?40)3

0 ( 0’%0)14 (1OOYO)o ( o%)3

0 ( 0.0?40)18 (90.0%)2 (10.OYO)o

7 (17.9%)28 (71.8Yo)

4 (10.3940)o

5 (26.3%)14 (73.7%)o ( 0.0%)o

2 (10.0%)14 (70.0%)4 (20.0%)o

3 ( 8.170)28 (75.7!XO)

6 (16.2%)2

2 (11.8’%0)15 (88.2’XO)o ( 0.0%)2

1 ( 5.0%)13 (65.0%)6 (30.0%)o



ABLE 14.3-5- Continued: LABORATORY DATA - NEUTROPHILSltention to Treat Population


(N=37) (N= 39)

hift between visit 1 and visit 2

.11patientsBelow-belowBelow-withinBelow-aboveWithin-belowWithin-withinWithin-aboveAbove-belowAbove-withinAbove-aboveMissing

;entre 1Below-belowBelow-withinBelow-aboveWithin-belowWithin-withinWithin-aboveAbove-belowAbove-withinAbove-aboveMissing

2entre 2Below-belowBelow-withinBelow-aboveWithin-belowWithin-withinWithin-aboveAbove-belowAbove-withinAbove-aboveMissing

o ( 0.0%)4(11.8?40)o ( 0.0%)o ( 0.0?40)

28 (82.4?40)1 ( 2.9%)o ( 0.070)o ( 0.0%)1 ( 2.9%)3

0 ( 0.0’%0)3 (21 .4’XO)o ( 0.0?40)o ( 0.0%)

11 (78.6%)o ( 0.0’70)o ( O.O’YO)o ( 0.0’?40)o ( 0.0%)3

0 ( O.OYO)1 ( 5.O’YO)o ( 0.0?40)o ( 0.0!40)

17 (85.0?40)1 ( 5.0’?40)o ( O.OYO)

o ( 0.0%)1 ( 5.0%)o

3 ( 8.1 Yo)4 (10.8%)o ( 0.0%)o ( O.OYO)

22 (59.55VO)4 (10.8?40)o ( 0.0%)2 ( 5.4VO)2 ( 5.4%)2

‘2(11.8%)3 (17.6Yo)o ( O.OYO)o ( O.OYO)

12 (70.6%)o ( O.O’YO)o ( 0.0%)o ( 0.0%)o ( 0.0%)

2

1 ( 5.OVO)1 ( 5.0%)o ( 0.070)o ( 0.0?40)

10 (50.0%)4 (20.OYO)o ( 0.070)2 (10.OYO)2 (10.0%)o


,..-. ,., . ,., ., .,,, ,-, ... .... ..


rABLE 14.3-6: LABORATORY DATA - EOSINOPHILSntention to Treat Population


(N= 37) (N= 39)

Visit 1- All patientsBelow o ( 0.0%) o ( 0.0%)

Within 22 (59.570) 29 (74.4Yo)

Above 15 (40.5%) 10 (25.6!40)

Missing




Visit 2- Centre 1BelowWithinAbove

o

0 ( O.OYO)10 (58.8Yo)7 (41.2%)o

0 ( O.O’YO)12 (60.OYO)8 (40. O’YO)o

0 ( 0.0%)22 (64.7Yo)12 (35.370)3

0 ( 0.0’%0)11 (78.6%)

3 (21 .4?40)

o

0 ( 0.0?40)18 (94.7Yo)

1 ( 5.3%)o

0 ( 0.0’?40)11 (55.070)‘9 (45.0%)o

0 ( 0.0%)30(81 .lYo)

7 (18.9Yo)2

0 ( O.ovo)15 (88.2’%0)2(11.8%)

Missing 3 2

Visit 2- Centre 2Below o ( 0.0?40) o ( O.ovo)

Within 11 (55.0?40) 15 (75.070)

Above 9 (45.0%) 5 (25.OYO)

Missing o 0


..-. <..- . ,,, , ,!, .,, ,.


TABLE 14.3-6- Continued: LABORATORY DATA - EOSINOPHILSIntention to Treat Population



All patientsBelow-belowBelow-withinBelow-aboveWithin-belowWithin-withinWithin-aboveAbove-belowAbove-withinAbove-aboveMissing



o ( 0.0’%0)o ( 0.0?40)o ( O.o’xo)o ( 0.0?40)

16 (47. 1%)4(11.8%)o ( 0.0%)6 (17.6Yo)8 (23.5%)3

0 ( 0.0?40)o ( O.OYO)o ( O.OYO)o ( 0.0%)7 (50.070)1 ( 7.1%)o ( O.OYO)4 (28.6Yo)2 (14.3%)3

0 ( O.OYO)o ( 0.070)o ( 0.0%)o ( 0.0?40)9 (45.0%)3 (15.0940)o ( O.OYO)2 (10.0%)6 (30.0%)o

0 ( 0.0’%0)o ( O.ovo)o ( O.ovo)o ( O.OYO)

22 (59.5%)5 (13.5%)o ( O.OYO)8 (21 .6!40)2 ( 5.4%)’2

‘o ( O.OYO)o ( 0.070)o ( 0.0%)o ( 0.0%)

14 (82.4%)2 (11.8Yo)o ( O.OYO)1 ( 5.9%)o ( 0.0%)2

0 ( O.ovo)o ( 0.0?’40)o ( 0.0!40)o ( 0.0%)8 (40.0%)3 (15.OVO)o ( O.OYO)7 (35.0%)2 (10.0%)o



rABLE 14.3-7: LABORATORY DATA - BASOPHILSntention to Treat Population


(N= 37) (N= 39)

(isit 1- All patientsBelow o ( 0.070) o ( O.OYO)

Within 33 (89.2%) 36 (92.3Yo)

Above 4 (10.8%) 3 ( 7.7%)

Missing o 0

Visit 1- Centre 1Below o ( 0.070) o ( 0.0?40)

Within 14 (82.4%) 16 (84.2Yo)

Above 3 (17.6Yo) 3 (15.8%)

Missing o 0

Visit 1- Centre 2Below o ( O.ovo) o ( o%)

Within 19 (95.0%) 20 (1OOYO)

Above 1 ( 5.0%) ‘0( o%)

Missing o 0

Visit 2- All patientsBelow o ( 0.0%) o ( 0.0%)

Within 30 (88.2%) 35 (94.6Yo)

Above 4(11.8%) 2 ( 5.4YO)

Missing 3 2



o ( 0.0’%0) o ( 0.0%)10 (71 .4’%0) 15 (88.2Yo)

4 (28.6%) 2(11.8VO)

3 2

0 ( o%) o ( o%)20 (1OOYO) 20 (loo%)

o ( o%) o ( 070)

o 0



rABLE 14.3-7- Continued: LABORATORY DATA - BASOPHILS[ntention to Treat Population


(N= 37) (N= 39)


411patientsBelow-belowBelow-withinBelow-aboveWithin-belowWithin-withinWithin-aboveAbove-belowAbove-withinAbove-aboveMissing

~entre 1Below-belowBelow-withinBelow-aboveWithin-belowWithin-withinWithin-aboveAbove-belowAbove-withinAbove-aboveMissing


o ( 0.0?40)o ( 0.0’%0)o ( O.OYO)o ( 0.0?40)

28 (82.4’?40)2 ( 5.9YO)o ( 0.0’?40)2 ( 5.9%)2 ( 5.9%)3

0 ( 0.0%)o ( O.ovo)o ( 0.0%)o ( 0.0%)9 (64.3%)2 (14.3YO)o ( O.OYO)1 ( 7.1’%0)2 (14.3?40)3

0 ( O.OYO)o ( O.OYO)o ( O.o’xo)o ( O.O’YO)

19 (95.OYO)

o ( O.OYO)o ( O.ovo)1 ( 5.OYO)o ( 0.0%)o

0 ( O.OYO)o ( 0.0’70)o ( 0.0%)o ( 0.0940)

33 (89.2?40)1 ( 2.7’Yo)o ( 0.0!’+0)2 ( 5.470)1 ( 2.7%j2

‘o ( 0.0%)o ( 0.0%)o ( 0.0%)o ( O.OYO)

13 (76.5Yo)1 ( 5.9%)o ( O.OYO)2(11.8?40)1 ( 5.9YO)2

0 ( 0.0’?40)o ( 0.0%)o ( 0.0%)o ( 0.0%)

20 (1OOYO)

o ( 0.0’?40)o ( 0.0%)o ( 0.070)o ( 0.0%)o


--.,,,.,, ,, ,, ,., ,, ,,, , .,. ..’” ..-+.


TABLE 14.3-8: LABORATORY DATA - MONOCYTESIntention to Treat Population


(N= 37) (N= 39)

Visit 1- All patientsBelow 3 ( 8.1%) 5 (12.8%)

Within 34 (91 .9%) 32 (82.lVO)

Above o ( 0.0%) 2( 5.1%)

Missing o 0

Visit 1- Centre 1Below 3 (17.6’XO) 5 (26.3%)

Within 14 (82.4%) 13 (68.4?40)

Above o ( O.OYO) 1 ( 5.3%)

Missing o 0

Visit 1- Centre 2Below o ( 0.0%) o ( 0.0%)

Within 20(1 Oovo) 19 (95.0%)

Above o ( o%) ‘ 1 ( 5.0?40)

Missing o 0

Visit 2- All patientsBelow 4(1 1.8’?40) 5 (13.5?40)

Within 30 (88.2%) 27 (73.0%)

Above o ( 0.0?40) 5 (13.5YO)

Missing 3 2



4 (28.6%) 5 (29.4%)

1o(71 .4%) 11 (64.7Yo)

o ( 0.0?40) 1 ( 5.9%)

3 2

0 ( o%) o ( 0.0%)

20 (1OOYO) 16 (80.OYO)

o ( OYO) 4 (20.0’?40)

o 0


,.,.-,, ,“, . ., ,. ,,. ,.. -., c ,- . .“....”,


TABLE 14.3-8- Continued: LABORATORY DATA - MONOCYTESIntention to Treat Population


(N= 37) (N= 39)





3 ( 8.8%)o ( O.OYO)o ( O.OYO)1 ( 2.9Yo)

30 (88.2?40)o ( O.O’YO)o ( 0.0%)o ( 0.0?40)o ( 0.0?40)3

3 (21 .4YO)o ( 0.0?40)o ( 0.0%)1 ( 7.1%)

10 (71.4YO)o ( 0.0%)o ( O.OYO)o ( O.OYO)o ( 0.0%)3

0 ( 0?40)o ( O’xo)o ( 0?40)o ( OYO)

20 (10070)o ( OYO)o ( OYO)o ( o%)o ( OYO)o

5 (13.5%)o ( 0.0%)o ( O.OYO)o ( O.OYO)

26 (70.3Yo)4 (10.8%)o ( 0.0%)1 ( 2.7Yo)1 ( 2.7%)’2

‘5 (29.4Yo)o ( O.OYO)o ( 0.0?40)o ( O.OYO)

10 (58.8%)1 ( 5.9YO)o ( 0.070)1 ( 5.9’?40)o ( 0.0%)2

0 ( 0.0?40)o ( 0.0’%0)o ( 0.0’?40)o ( 0.0!40)

16 (80.0’%0)3 (15.0?40)o ( 0.070)o ( 0.0%)1 ( 5.0’?40)o


,.—.,,,.” ., . ., .,. ., ,,, ., , ,,*.. ,-..—,, ,!


TABLE 14.3-9: LABORATORY DATA - LYMPHOCYTESIntention to Treat Population








2 ( 5.4%)25 (67.6%)10 (27.0%)o

0 ( 0.070)12 (70.6Yo)5 (29.4%)o

2 (10.OYO)13 (65.0?40)5 (25. O’?40)o

2 ( 5.9YO)25 (73.5Yo)

7 (20.6Yo)3

0 ( 0.0%)11 (78.6%)3 (21 .4%)3

2 (10.0%)14 (70.0?40)4 (20.0%)o

4 (10.3YO)25 (64. l~o)10 (25.6%)o

0 ( O.OYO)13 (68.4Yo)6 (31.6%)o

4 (20.OYO)12 (60.0%)‘4 (20.0%)o

6 (16.2!40)27 (73.0%)

4 (10.8Yo)2

0 ( 0.0%)14 (82.4Yo)3 (17.6Yo)2

6 (30.0%)13 (65.0%)

1 ( 5.0%)o



rABLE 14.3-9- Continued: LABORATORY DATA - LYMPHOCYTES[ntention to Treat Population


(N= 37) (N= 39)





1 ( 2.9Yo)1 ( 2.9%)o ( 0.0%)1 ( 2.9%)

20 (58.8?40)3 ( 8.8’%0)o ( O.OYO)4(11.8%)4(11.8Yo)3

0 ( 0.070)o ( 0.0%)o ( O.OYO)o ( 0.0%)

10 (71 .4%)1 ( 7.1!40)o ( O.OYO)1 ( 7.1?/0)2 (14.3YO)3

1 ( 5.OYO)1 ( 5.0%)o ( 0.0%)1 ( 5.O’YO)

10 (50. O’XO)2 (10.OYO)o ( 0.0%)3 (15. O’XO)2 (10.0%)o

1 ( 2.7Yo)2 ( 5.4?40)1 ( 2.7%)4 (10.8Yo)

18 (48.6Yo)1 ( 2.7Yo)1 ( 2.7%)7 (18.9%)2 ( 5.4?40)”2

‘o ( O.OYO)o ( O.OYO)o ( 0.0%)o ( 0.0%)

10 (58.8’?40)1 ( 5.9YO)o ( 0.0%)4 (23 .5%)2(11.8%)2

1 ( 5.OVO)2 (10.0%)1 ( 5.0%)4 (20.0%)8 (40.OYO)o ( 0.070)1 ( 5.0%)3 (15.OYO)o ( O.ovo)o


STUDY No.: 9153PROTOCOL No. : MPCE91L1802/6D of 187

TABLE 14.3-10: LABORATORY DATA - PLATELETS[ntention to Treat Population


(N= 37) (N= 39)

Visit 1- All patientsBelow 2 ( 5.4%) 2( 5.1%)

Within 32 (86.5%) 34 (87.25ZO)

Above 3 ( 8.1%) 3 ( 7.7%)

Missing o 0

Visit 1- Centre 1Below o ( 0.0’%0) o ( 0.0?40)

Within 14 (82.4%) 16 (84.2%)

Above 3 (17.6?40) 3 (15.8Yo)

Missing o 0

Visit 1- Centre 2Below 2 (10.OYO) 2 (10.0?40)

Within 18 (90.0%) 18 (90.OYO)

Above o ( 0.0%) ‘o ( 0.0%)

Missing o 0



Visit 2- Centre 2Below

WithinAboveMissing

1 ( 2.9Yo)32 (94.1%)

1 ( 2.9%)3

0 ( O.ovo)13 (92.9Yo)

1 ( 7.lYO)3

1 ( 5.0%)

19 (95.0%)o ( 0.0?40)o

3 ( 8.3%)27 (75.0%)

6 (16.7%)3

0 ( O.OYO)10 (62.5%)6 (37.5Yo)3

3 (15.0%)

17 (85.OYO)o ( 0.0%)o


.“-. . . . . .,,, ,., ~,.. ... ,.,,W. .--m,. ,,


TABLE 14.3-10- Continued: LABORATORY DATA - PLATELETSIntention to Treat Population



All patientsBelow-below 1 ( 2.9Yo) 1 ( 2.8Yo)Below-within 1 ( 2.9%) 1 ( 2.8%)Below-above o ( O.OYO) o ( O.OYO)Within-below o ( 0.0%) 2 ( 5.6?40)Within-within 29 (85.3?40) 25 (69.4%)Within-above o ( 0.0%) 4(11.1%)Above-below o ( O.OYO) o ( 0.0%)Above-within 2 ( 5.9%) 1 ( 2.8%)Above-above 1 ( 2.9Yo) 2 ( 5.6?40)”Missing 3 3

Centre 1Below-below o ( 0.070) ‘o ( 0.070)Below-within o ( 0.070) o ( 0.0%)Below-above o ( O.OYO) o ( O.OYO)Within-below o ( 0.0%) o ( 0.0%)Within-within 11 (78.6Yo) 9 (56.3VO)Within-above o ( 0.0’%0) 4 (25.OYO)Above-below o ( O.OYO) o ( O.OYO)Above-within 2 (14.3YO) 1 ( 6.3Yo)Above-above 1 ( 7.1’%0) 2 (12.5Yo)Missing 3 3

Centre 2Below-below 1 ( 5.0?40) 1 ( 5.0?40)Below-within 1 ( 5.0?40) 1 ( 5.0?40)Below-above o ( 0.0?40) o ( 0.0?40)Within-below o ( 0.0%) 2 (10.0%)Within-within 18 (90.0%) 16 (80.0%)

Within-above o ( 0.0%) o ( O.ovo)Above-below o ( O.OYO) o ( O.OYO)Above-within o ( 0.0%) o ( O.ovo)Above-above o ( 0.0%) o ( O.OYO)Missing o 0


STUDY No.:9153PROTOCOL No.: MPCE91 L 1802/6D of 187

TABLE 14.3-11: LABORATORY DATA - UREAIntention to Treat Population


(N=37) (N= 39)







2 ( 7.1%)23 (82. l~o)

3 (10.7%)9

2 (25.OYO)3 (37.5%)3 (37.5%)9

0 ( 0?40)20 (loo%)

o ( o%)o

0 ( O.OYO)23 (92.0%)

2 ( 8.0%)12

0 ( 0.0%)3 (60.0’?40)2 (40.OYO)

12

0 ( o%)

20(1 00Y0)o ( 070)o

3 (10.7?40)21 (75.OYO)

4 (14.3YO)11

3 (37.50!0)1 (12.5Yo)4 (50.0%)

11

0 ( O’xo)20 (100’?40)‘0( o%)o

0 ( 0.0’%0)27 (90.OYO)

3 (10.0%)9

0 ( O.OYO)7 (70.OVO)3 (30.0%)9

0 ( o%)

20 (loo%)o ( o%)o


,.,s... ,,“, “... ,-. . .+ ..”. ,,


TABLE 14.3-11- Continued: LABORATORY DATA - UREAIntention to Treat Population



All patientsBelow-below o ( 0.070) o ( O.OYO)

Below-within o ( 0.0?40) 2 ( 7.4%)

Below-above o ( 0.0%) o ( O.ovo)

Within-below o ( 0.0%) o ( O.ovo)

Within-within 21 (84.0%) 21 (77.8%)

Within-above 1 ( 4.0%) o ( 0.070)

Above-below o ( 0.0%) o ( O.OYO)

Above-within 2 ( 8.0’?40) 1 ( 3.7VO)

Above-above 1 ( 4.0%) 3 (ll.lYoj

Missing 12 12

Centre 1Below-below o ( O.OYO) ‘o ( O.OYO)

Below-within o ( 0.0%) 2 (28.6%)

Below-above o ( 0.070) o ( 0.0%)

Within-below o ( 0.0%) o ( O.OYO)

Within-within 1 (20.0?40) 1 (14.3?40)

Within-above 1 (20.OYO) o ( 0.0%)

Above-below o ( 0.0?40) o ( O.OYO)

Above-within 2 (40.OYO) 1 (14.370)

Above-above 1 (20.0%) 3 (42.9VO)

Missing 12 12

Centre 2Below-below o ( o%) o ( o%)

Below-within o ( 070) o ( o%)

Below-above o ( 0?40) o ( O$xo)

Within-below o ( o%) o ( o%)

Within-within 20(1 00%) 20 (loo%)

Within-above o ( o%) o ( OYO)

Above-below o ( o%) o ( o%)

Above-within o ( Ovo) o ( o%)

Above-above o ( o%) o ( o%)

Missing o 0


--. .. . ,,, . ,., ,, ...,. . . . . ”..””...-. !O. .


TABLE 14.3-12: LABORATORY DATA - BUNIntention to Treat Population








o ( O.o’xo)8 (88.9?40)1 (11.1?40)

28

0 ( 0.0’%0)8 (88.9Yo)1 (11.1%)8

0 ( 0.0?+0)10 (90.9YO)

1 ( 9.lYO)28

0 ( O.O’YO)10 (90.90/40)

1 ( 9.170)8

20

0 ( O’YO)9 (loo%)o ( OYO)

28

0 ( O’MO)9 (1OOYO)o ( O’YO)8

20

20

0 ( 0?40)7 (loo%)o ( 0’?40)

32

0 ( o%)7 (100?40)o ( OYO)

12

20



TABLE 14.3-12- Continued: LABORATORY DATA - BUNIntention to Treat Population






o ( 0.070)o ( O.o’xo)o ( 0.0%)o ( 0.0’?40)6 (85.7%)o ( 0.0?40)o ( 0.0?40)1 (14.3%)o ( 0.0’?40)

30

0 ( 0.0%)o ( O.OYO)o ( O.OYO)o ( 0.0%)6 (85.7Yo)o ( 0.0%)o ( O.o!xo)1 (14.370)o ( 0.0?40)

10

20

0 ( O.o’zo)o ( 0.0%)o ( 0.070)o ( 0.0?40)5 (83.3%)o ( 0.0%)o ( 0.0?40)1 (16.7Yo)o ( 0.0%)’

33

‘o ( 0.0%)o ( O.ovo)o ( 0.0’%0)o ( 0.0%)5 (83.3%)o ( O.OYO)o ( 0.070)1 (16.7%)o ( 0.0’%0)

13

20


.,s.,! ).. ,, ,., ,., ,.. . .,.,-. ..u $,


TABLE 14.3-13: LABORATORY DATA - CREATININEIntention to Treat Population








2 ( 5.4%)35 (94.6Yo)

o ( 0.0%)o

0 ( 0!40)17 (loo%)o ( o%)o

2 (10.0?40)18 (90.0%)o ( 0.0?40)o

2 ( 5.9YO)32 (94. lYo)

o ( 0.0?40)3

0 ( 0’%0)14 (100?40)o ( 0?40)3

2 (10.0%)18 (90.0?40)o ( 0.0?40)o

3 ( 7.7YO)36 (92.3Yo)

o ( 0.0%)o

0 ( O’YO)19 (100?40)o ( o%)o

3 (15.0%)17 (85.OVO)‘o ( O.ovo)o

0 ( 070)37 (1OOYO)

o ( 070)2

0 ( OYO)17 (1OOYO)o ( 070)2

0 ( o%)20 (1OOYO)

o ( OYO)o



TABLE 14.3-13- Continued: LABORATORY DATA - CREATININEIntention to Treat Population






o ( 0.0%)2 ( 5.9%)o ( 0.0?40)2 ( 5.9?40)

30 (88.2?40)o ( 0.0%)o ( 0.0?40)o ( 0.0%)o ( 0.0%)3

0 ( o%)o ( .OYO)o ( o%)o ( Ovo)

14 (1OOYO)o ( o%)o ( OYO)o ( OYO)o ( o%)3

0 ( 0.0’%0)2 (10.0%)o ( 0.0%)2 (10.OYO)

16 (80.OVO)o ( 0.0%)o ( O.OYO)o ( 0.0%)o ( 0.0%)o

0 ( 0.0%)3 ( 8.lYo)o ( 0.0?40)o ( 0.0%)

34 (91.9YO)o ( 0.0?40)o ( 0.0%)o ( 0.0%)o ( 0.0%)’2

‘o ( o%)o ( o%)o ( o%)o ( OYO)

17 (1OOYO)o ( o%)o ( o%)o ( o%)o ( o%)2

0 ( 0.0%)3 (15.070)o ( O.OYO)o ( O.O’YO)

17 (85.0?40)o ( O.OYO)o ( O.O’YO)o ( 0.0%)o ( O.OYO)o


,.q,. ,.,., . ,., 1’ . . ,,. ,. . “.,. .”....-. !, .,..,


~ABLE 14.3-14: LABORATORY DATA – TGPntention to Treat Population


(N= 37) (N= 39)

/isit 1- All patientsBelowWithinAboveMissing


Jisit 1- Centre 2BelowWithinAboveMissing

o ( 0.0%)

36 (97.3Yo)1 ( 2.7Yo)o

0 ( 0’%0)17 (loo%)o ( 070)o

0 ( O.OYO)19 (95.0%)

1 ( 5.0?40)o

0 ( o%)

39 (1OOYO)o ( 0’%0)o

0 ( o%)19 (loo%)o ( 070)o

0 ( 0’%0)20 (loo%)‘0( o%)o

Visit 2- All Datients1

Below o ( Ovo) o ( OYO)

Within 34 (loo%) 37 (loo%)

Above o ( o%)

Missing 3

Visit 2- Centre 1Below o ( 0?40)

Within 14 (loo%)

Above o ( 070)

Missing 3

Visit 2- Centre 2Below o ( 0?40)

o ( o%)2

0 ( o%)7 (loo%)o ( o%)2

0 ( Ovo)

Within 20 ~loo%j 20 (loo%)

Above o ( o%) o ( o%)

Missing o 0


,a—,,.., . ,, 1-’,., ,. ,,.,..,,. .w . ! .- .+..”.. ,,


TABLE 14.3-14- Continued: LABORATORY DATA - TGPIntention to Treat Population





Centre 2Below-belowBelow-withinBelow-aboveWithin-belowWithin-withinWithin-aboveAbove-belowAbove-within

Above-aboveMissing

o ( 0.0’?40)o ( 0.0’?40)o ( 0.0%)o ( O.ovo)

33 (97.1%)o ( O.OYO)o ( O.OYO)1 ( 2.9Yo)o ( O.OYO)3

0 ( 070)o ( o%)o ( o%)o ( o%)

14 (loo%)o ( o%)o ( Ovo)o ( o%)o ( o%)3

0 ( O.OYO)o ( O.OYO)o ( 0.0?40)o ( O.O’YO)

19 (95.0%)o ( O.OYO)o ( 0.0%)1 ( 5.0%)o ( 0.0%)o

0 ( 09’0)o ( o%)o ( OYO)o ( o%)

37 (loo%)o ( o%)o ( o%)o ( 0?40)o ( OYO)2

~o ( OYO)o ( o%)o ( o%)o ( o%)

17 (loo%)o ( o%)o ( o%)o ( 0?40)o ( o%)2

0 ( O’YO)o ( OYO)o ( O’YO)o ( o%)

20 (1OOYO)o ( Ovo)o ( OYO)o ( Ovo)

o ( o%)o


—. ! .. ,, ,,, , ,., ,, ,. .,, “. ..-, ..—., ,, .

STUDY No.: 9153PROTOCOL No.: MPCE91 LI 802/6D of 187

14.3.1 Display of Adverse Events

A display of the adverse events is provided in Section 12.2.

14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events

No serious adverse events were reported during the study.

14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant AdverseEvents

No deaths or other serious adverse events were reported during the study.


,,. ,,, ,!. . . . ,,”... ... .—.,!, . .


15. REFERENCE LIST

There are no additional references as compared to those provided in the protocol.

16. APPENDICES

16.1 STUDY INFORMATION

16.2 PATIENT DATA LISTING

16.3 CASE REPORT FORMS

16.4 INDIVIDUAL SUBJECTS DATA LISTINGS


.-,..,,.. , ,,, ,, ,., ,,. ,. ... . ‘ -.. !,....-. !, .

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