Clinical Evaluation of Oral Hygiene Products in an In Situ ... Parts per Million PRO Patient report...

CONFIDENTIAL

STATISTICAL ANALYSIS PLAN FOR PROTOCOL 203160

Clinical Evaluation of Oral Hygiene Products in an In SituCaries Model

BIOSTATISTICS DEPARTMENT

GLAXOSMITHKLINE CONSUMER HEALTHCARE

ST GEORGE’S AVENUE

WEYBRIDGE

SURREY KT13 0DE, UNITED KINGDOM

MSc

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Table of Contents

Glossary 4

1 Introduction 6

2 Objectives 6

2.1 Primary Objective 6

2.2 Secondary Objectives 6

3 Study Design 6

4 Sample Size Determination 8

5 Criteria for Evaluation 9

Criteria for assessing efficacy 9

Criteria for assessing tolerability 9

6 Data Considerations 9

6.1 Analysis Populations 9

6.2 Subgroups/Stratification 10

6.3 Time Windows 10

7 Demographics and Baseline Characteristics 11

7.1 Subject Disposition 11

7.2 Demographics 11

8 Treatment Compliance and Concomitant Medications11

8.1 Treatment Compliance 11

8.2 Concomitant Medications 11

9 Efficacy Analysis 11

10 Safety Analysis 14

11 Interim Analysis 15

12 Topline Summary 15

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13 Changes to Planned Analyses 16

14 References 16

APPENDIX 1 Study Schedule 17

Appendix 2 List of Tables, Figures & Listings 18

Appendix 3 Templates for Tables, Figures & Listings22

Table Templates 22

Listing Templates 27

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GlossaryADA American Dental Association

AE Adverse Event

ANCOVA Analysis of Covariance

ANOVA Analysis of Variance

ºC Degree Centigrade

CI Confidence Interval

cm centimeter

CRO Contract Research Organization

DW De-ionized Water

ECG Electrocardiogram

eCRF Electronic Case Report Form

EFU Enamel Fluoride Uptake

ºF Degree Fahrenheit

g gram

GCP Good Clinical Practice

GSKCH GlaxoSmithKline Consumer Healthcare

h hour

HMDS Hexamethyldisiloxane

ICH International Conference on Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for Human

Use

IRB Institutional Review Board

ITT Intention to Treat

MedDRA Medical Dictionary for Regulatory Activities

MFC Master Formulation Code

μl microliter

µm micrometer

mL milliliter

mL/min milliliter per minute

mm millimeter

NaOH Sodium hydroxide

OHRI Oral Health Research Institute

OHT Oral Hard Tissue

OST Oral Soft Tissue

PII Personally Identifiable Information

PP Per Protocol

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PPM Parts per Million

PRO Patient report outcome

SAE Serious Adverse Event

SAP Statistical Analysis Plan

SD Standard Deviation

SMH Surface Microhardness

SMHR Surface Microhardness Recovery

UK United Kingdom

US/USA United States/United States of America

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1 IntroductionThis document describes the statistical methods and data presentations to be used in

the summary and analysis of the final data from Protocol 203160.

This statistical analysis plan will be finalized and approved prior to study unblinding.

2 Objectives

2.1 Primary Objective

To evaluate and compare the potential anti-caries efficacy of a test regimen: placebo

(fluoride free) toothpaste (twice daily use) plus fluoride mouthwash (once daily use),

in comparison with a placebo toothpaste alone (twice daily use), to remineralize

previously demineralized enamel specimens, as measured by %SMHR.

2.2 Secondary Objectives

To evaluate and compare between treatments (other than the primary comparison) the

enamel remineralization potential of all treatment combinations with respect to

remineralization of previously demineralized enamel specimens, as measured by

%SMHR.

To evaluate and compare between treatments with respect to enamel fluoride uptake,

as measured by EFU.

To evaluate and compare between treatments with respect to fluoride content in

saliva.

To assess the relationship between EFU and fluoride content in saliva with the results

of enamel remineralization obtained based on %SMHR.

3 Study DesignThis is a single center, randomized, laboratory analyst blinded, four treatment, cross-

over study in healthy subjects. Subjects will be pre-screened through an IRB

approved protocol (OH study During each of the four two-week treatment

periods, subjects will apply a full brush head of the assigned study toothpaste on the

supplied toothbrush and brush for one timed minute. Subjects will then expectorate

toothpaste slurry, followed by a rinse with 10mL of tap water for five seconds and

then spit it out. This will be performed twice daily at home, and, for two of the four

test treatments; subjects will rinse with 10mL of the assigned mouthwash, for one

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minute, once daily post night time brushing except on the treatment visit day where

subjects will rinse at the study site. Subjects will not be allowed to rinse with water

after rinsing with the study mouthwash when randomized to one of the two treatment

regimens that contain both toothpaste and mouthwash.

At the start of each treatment period, subjects will receive two oral soft tissue (OST)

examinations; one at the beginning of the visit and one at the end of start treatment

visits. Two unstimulated saliva samples will also be collected during that visit; one

prior to supervised brushing/ rinsing of study product and one immediately after

supervised brushing/rinsing. Subjects will receive a subject kit containing test

toothpaste or a test toothpaste and mouthwash, a toothbrush, rinsing cups, a

countdown timer, home use instructions, and a diary card to record brushing times,

adverse events and concomitant medications.

During the treatment periods, subjects will be asked to wear their mandibular partial

denture housing two human tooth enamel specimens in the buccal flange area of the

denture for 24 hours a day. The enamel specimens will be prepared as described in

Section 7.3.1 – Intra-Oral Appliance.

The subject will then complete the initial brushing/rinsing at the site under the

supervision of a study technician on site. The toothpaste will be used twice daily by

subjects at home for two weeks. The mouthwash will be first used at the site, during

the first treatment day when subjects are allocated to the rinse containing treatment

regimen and then used at home once daily post night time brushing for the rest of the

two week treatment period.

At the end of each treatment period, subjects will be asked to return the study product

to the site. During end treatment visits, an OST examination will be performed and

an unstimulated saliva sample collected. The enamel specimens will be removed

from the mandibular partial denture and analyzed. Changes in the enamel surface

mineral content will be determined using the surface microhardness test (SMH)

[Zero, 1990; Zero, 1995]. Fluoride uptake in the enamel will be determined using the

microdrill enamel biopsy technique [Sakkab, 1984] and is detailed in Section 8.2-

Assessment of Enamel Fluoride Bioavailability. At the beginning and end of each

treatment period, saliva samples will be collected for evaluation of fluoride content,

as specified in section 8.3 – Fluoride Concentration in Saliva.

An oral hard tissue (OHT) examination will be performed at the screening visit and

after the first dental cleaning (prophylaxis) at Visit 2 to assure that there are no oral

problems which went undetected at the screening examination.

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Between each treatment period, subjects will use their usual toothpaste for at least

four days, and then switch to the wash-out fluoride free paste for two or three

days before starting the next study treatment period. This process will be repeated

until all subjects have used all four test treatments, as specified in the randomization

schedule. This process will be repeated until all subjects have used all four test

treatments. Order of test treatment use will follow a randomization schedule provided

by the study sponsor.

Study Products are

Fluoride dentifrice/Fluoride rinse: Treatment regimen with twice daily

brushing with a fluoride toothpaste containing 1150 ppm of fluoride as

sodium fluoride: Aquafresh® Extreme Clean Pure Breath Action Fluoride

Toothpaste ( immediately followed by once daily rinsing (post

night time brushing) with a fluoride mouthwash containing 220 ppm of

fluoride as sodium fluoride (

Placebo dentifrice/Fluoride rinse: Treatment regimen with twice daily

brushing with a non-fluoride (placebo) toothpaste ( immediately

followed by once daily rinsing (post night time brushing) with a fluoride

mouthwash containing 220 ppm of fluoride as sodium fluoride (

Fluoride dentifrice/No rinse: Treatment regimen with twice daily brushing

with a fluoride toothpaste containing 1150 ppm of fluoride as sodium fluoride:

Aquafresh® Extreme Clean Pure Breath Action Fluoride Toothpaste

(

Placebo dentifrice/No rinse: Treatment regimen with twice daily brushing

with a non-fluoride (placebo) toothpaste (

4 Sample Size DeterminationA sufficient number of subjects will be screened so that maximum of 62 subjects will

be randomized to participate in the study to ensure that approximately 50 subjects

will be evaluable for the efficacy analysis.

A sample size of 50 subjects will have 90% power to detect a difference of 7.91%

between treatment groups in terms of %SMH recovery with an estimated within-

subject standard deviation (SD) of the difference of 11.96%, based on results obtained

in study T3508565, and with a significance level of 0.05 using a two-sided paired t-

test.

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5 Criteria for Evaluation

Criteria for assessing efficacy

The primary endpoint will be Surface microhardness recovery (%SMHR) and the

primary treatment comparison will be of placebo toothpaste plus fluoride mouthwash

versus placebo toothpaste alone. The primary criterion will be to assess if %SMHR

for the placebo toothpaste plus fluoride mouthwash test treatment regimen is

statistically superior to the placebo toothpaste alone.

Fluoride Uptake Scores are available at the end of each treatment period. Fluoride

from saliva samples taken at the start of day 1 (D1) and Day 14 (D14) within each

treatment period will be available along with the level post D1 visit.

Criteria for assessing tolerability

Safety will be assessed with respect to AEs, incidents and OST abnormalities (oral

tolerability).

6 Data Considerations

6.1 Analysis Populations

The Safety population will consist of all subjects who were randomized and received

randomized study treatment.

Efficacy analysis will be conducted on the per-protocol (PP) population, defined as:

all subjects who are randomized into the study, received at least one dose of study

product, have at least one post-baseline efficacy assessment and have no protocol

violations deemed to affect efficacy during the study. Further details will be provided

in the statistical analysis plan (SAP).

Violations deemed to affect efficacy will be identified between the Biostatistician and

Medical Director or designee, before breaking the study blind. These will be excluded

from the PP analysis.

The intention to treat (ITT) population is defined as all subjects who are randomized

into the study, received at least one dose of study product and have at least one post-

baseline efficacy assessment.

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Efficacy analyses will be performed on ITT population also if there is more than a

10% difference in the number of subjects between the ITT and PP populations.

Any of the following may be considered as a major protocol violation which may

warrant exclusion from the PP analysis:

1. Violation of inclusion or exclusion criteria that may affect efficacy.

2. Significant non-compliance with treatment.

3. Significant non-compliance with the study schedule, e.g., with regards to

durations that appliances are worn.

4. Use of prohibited treatment or medication before or during the study, which is

deemed to affect the assessment of efficacy.

5. Any other reason identified which may affect the assessment of efficacy.

6. Listing of all SMH indent lengths and EFU values to identify extreme values

in the context of the planned range.

The primary population for analyses is PP. Additional analyses will be conducted on

the primary endpoint %SMHR endpoint using the ITT population if more than 5% of

subjects are additionally included in the ITT over the PP population. Further details

will be provided in the BDR specifications document.

All protocol violations considered to have the potential to affect efficacy assessments

and thus leading to exclusion from PP analyses will be documented in the Population

Definitions document. The content of this document will be agreed upon between the

Biostatistician and Medical Director or designee prior to database lock and breaking

of the study blind.

6.2 Subgroups/Stratification

No subgroup or stratified analyses are planned.

6.3 Time Windows

The appliance is in situ for 14 days. Deviations from this period may be considered

protocol deviations likely to affect the PP population. Further details will be given in

the BDR review document.

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7 Demographics and Baseline Characteristics

7.1 Subject Disposition

The following will be tabulated: the number of screened subjects, the number of

randomized subjects, the number and percentage of subjects included in the Safety

Population, ITT Population, and PP Population. The number and percentage of

subjects treated who discontinued will be provided for each specific reason for

termination by period. The number of subjects completing each sequence by period

will also be provided. The number of screen failures (not enrolled, i.e., not

randomized subjects) will also be given.

7.2 Demographics

Demographic characteristics (e.g. age, gender, ethnicity and race) will be summarized

using descriptive statistics (N, mean, standard deviation (STD), for age: counts and

proportions for categorical data) on the Safety, PP and (if appropriate) ITT

populations.

8 Treatment Compliance and Concomitant Medications

8.1 Treatment Compliance

Subject treatment compliance will be documented on the subject study compliance

records and recorded on the subject eCRF. All treatments will be first supervised by

qualified site staff then replicated by the subject at home over the remainder of the

two weeks treatment period. A treatment non-compliance listing will be produced for

blinded data review. Outcome measures considered to be impacted by such protocol

violations will be considered for exclusion from potential PP analyses.

8.2 Concomitant Medications

Concomitant medication data will not be presented in the study report. A listing of

concomitant medications will be produced for evaluation of protocol violators only.

9 Efficacy Analysis

The primary population for all exploratory efficacy analyses will be the PP

population. The primary endpont will also be analyzed based on the ITT population

if more than 5% total subjects are excluded from the PP population. For all efficacy

analyses, subjects will be analyzed as per randomized treatment

All significance testing will be conducted at the two-sided 5% significance level.

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All outcome variables will be analyzed under a null hypothesis of no difference

between study treatments against an alternate hypothesis of a difference between

study treatments.

Calculation of %SMHR

Step 1: Calculate %SMHR at a specimen level

Let:

B = the mean of the 5 “baseline” measurements

E1 = the mean of the 5 “erosion challenge 1st” measurements

R = the mean of the 5 “in situ remin” measurements

Then:

% SMHR = [(E1-R) / (E1-B)] * 100

Step 2: Calculate %SMHR across specimens

The mean % SMHR will then be computed by averaging the two specimen level

results within a subject for each treatment.

Notes:

1. If any specific indentations are not evaluable, then B, E1 and R will be

calculated on the available indentation measurements. As a result, it is

possible that differing numbers of indentations contribute to each of these

calculations on which the specimen %SMHR is determined.

2. If a subject is missing an enamel specimen (e.g., due to loss of specimen,

damage to specimen, etc), the mean will be computed from the available

enamel specimen remaining.

3. No data imputation methods will be used in the event of missing data (e.g.,

due to withdrawals or unevaluable data).

Primary Efficacy Analysis

The %SMHR will be evaluated using an analysis of variance (ANOVA) model with

the %SMHR as the dependent variable, fixed effects of treatment and study period,

and a random effect of subject. The full ANOVA model will include the following

terms:

subject (random effect)

treatment (fixed effect)

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period (fixed effect)

Within treatment adjusted means, SE’s and 95% CI’s will be quoted and treatment

comparisons will be derived from the ANOVA model for %SMHR. Corresponding

95% CI and differences between least square means (LSM) will be presented together

with p-values for between treatment comparisons.

The primary criterion will be to assess if %SMHR for the placebo toothpaste plus

fluoride mouthwash test treatment regimen is statistically superior to the placebo

toothpaste alone. All other treatment comparisons will be made.

The assumptions underlying the ANOVA model will be examined and, if necessary,

appropriate transformations, sensitivity analysis (e.g. excluding outliers) or non-

parametric procedures will be used.

Secondary Efficacy Analysis

The %SMHR will be further evaluated (investigative analysis) using an analysis of

covariance (ANCOVA) model with the %SMHR as the dependent variable, fixed

effects of treatment and study period, and a random effect of subject and various

subject and period level baselines as covariates. The full ANCOVA model will

include the following terms:

subject (random effect)

treatment (fixed effect)

period (fixed effect)

subject-level baseline SMH/indentation length (covariate based on B values)

period-level baseline SMH/indentation length (covariate based on B values))

subject-level pre-treatment acid challenge enamel SMH/indentation length

(covariate based on E1 values))

period level acid challenge enamel SMH/indentation length (covariate based on

E1 values)..

For each subject, the subject-level covariates will be calculated as the mean SMH

across periods and the period-level covariates will be calculated as the period-level

mean SMH minus the subject-level covariate value.

Within treatment adjusted means, SE’s and 95% CI’s will be quoted and treatment

comparisons will be derived from the ANCOVA model for %SMHR. Corresponding

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95% CI and differences between least square means (LSM) will be presented together

with p-values for between treatment comparisons. The main emphasis will be to

assess if %SMHR for the placebo toothpaste plus fluoride mouthwash test treatment

regimen is statistically superior to the placebo toothpaste alone. All other treatment

comparisons will be made.

EFU will be evaluated by using 2 AN(C)OVA models identical to (i) the primary

efficacy analysis and (ii) the additional analysis including the same subject and period

baselines of SMH.

The assumptions underlying the ANOVA/ANCOVA models will be examined and, if

necessary, appropriate transformations, sensitivity analysis (e.g. excluding outliers) or

non-parametric procedures will be used.

Fluoride from Saliva is measured at Day1 pre treatment, Day1 immediately post

treatment and Day14 where there is no treatment on that day. The difference (a)

between Day 1 (pre treatment) minus Day14 will be calculated and analysed in an

identical fashion to the primary variable (this is the key measure of the effect of 14

days treatment).

Idenitical more exploratory analyses will be performed for the 2 other paired

differences of the 3 fluoride in saliva values viz (b) Day1 (post) minus Day14 and (c)

Day1(pre) minus Day1(post). For each the three differences (a-c) the additional

analysis including SMH baselines will not be performed. These are exploratory

analyses.

The correlations between average %SMHR, EFU, and the three Fluoride in Saliva

differences will be examined over treatments. Pearson’s correlation coefficients will

be calculated between each pair of the 5 endpoints, no inference will be provided.

10 Safety AnalysisAll AEs and Incidents will be listed by treatment.

The safety profile of the study treatment regimens will be assessed with respect to

adverse events (AEs). Oral soft tissue (OST) abnormalities are included as AEs if

they appear or worsen after the initial assessment.

All safety data will be reported for the Safety population as per actual treatment

received. All subjects screened will be included in the list of AEs.

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All AEs will be reviewed by the Medical Director or Designee prior to database

freeze and will be coded using the Medical Dictionary for Regulatory Activities

(MedDRA). During this review stage, AEs will be further categorized as oral or non-

oral.

AEs that occur after the first supervised brushing with experimental product will be

termed as treatment-emergent AEs and will be tabulated. AEs occurring between

screening and randomization will be termed as pre-treatment AEs and will be

included in the AE listing. Any AEs occurring during the washout period between

treatments will be assigned to the last experimental treatment administered.

AE summaries will be produced for each of the following:

Listing of all AEs including pre-treatment

Table of Treatment emergent AEs by oral/non-oral and preferred term

(MedDRA coding terms)

Table of Treatment emergent AEs by SOC

Table of Treatment emergent, treatment related AEs, by oral/non-oral and

preferred term (MedDRA coding terms)

Listing of serious AEs, if more than 5 are observed these will be tabulated.

Table of Non Serious treatment emergent AEs by SOC and Preferred Term.

(only produced if there are > 5 SAEs)

Listing of incidents.

No inferential analyses will be performed to compare treatments with respect to

safety.

11 Interim Analysis

No interim analysis is planned.

12 Topline Summary

The following topline presentations will be made available. 9.1.1, 9.2.1.1, 9.3.1.1,

9.3.2.1, 9.4.1, 9.4.2

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13 Changes to Planned Analyses

OST abnormalities will not be listed. Any changes in OST abnormalities will be

included as AEs.

14 References

GSK Clinical Study T3508565: Clinical efficacy of fluoride toothpastes usingan in situ caries model

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APPENDIX 1 Study Schedule

1- At V3 only randomization is performed. 2- Subjects will undergo a wash-out period of at least four days during which they will use their usual toothpaste after 2 weeks of treatment use. 3- Dispense wash-out fluoride free toothpaste, toothbrush and countdown timer. Use wash out paste for two or three days prior to start of each treatment period. 4- Subject Kit to include toothbrush, dentifrice and oral rinse (where applicable), rinsing cup, home use diary card. Subject instructed to bring the kit back at next visit for compliance checks. 5- OST will also be performed at the beginning and at the end of all start treatment periods (V3, 6, 9, 12). 6- Saliva samples will be collected for fluoride concentration assessment at the beginning of each treatment period and immediately after supervised brushing/rinsing. After 14 days and at the end of each treatment period, a saliva sample will be collected at the beginning of the visit. 7- OHT will be performed as part of study termination/closure visit. * Subject eligibility only assessed at Visits 1 and 3. **AEs will be collected from the start of the 1st prophylaxis procedure. *** OHT will be performed after the first dental cleaning at the Visit 2 prophylaxis only to assure that there are no oral problems which went undetected at the screening examination. ┼ at V3, only check inclusion 5 and exclusion 5b.

Steps V1

Wash out2 andProphylaxis

START END2

V2, V5, V8, V11 – prophy Trt 1, 2, 3, 4

V3, V6, V9, V112–Treatment, Trt

1, 2, 3, 4

V4, V7, V10, V13 -Trt 1, 2, 3, 4

Sign-in X X X X

Subject Eligibility* X X

Informed consent X

Demographics X

Medical history X

Concomitant medications X X X X

Full OST examination X X X5 X

Full OHT examination X X*** X7

Salivary flow rates (screening) X

Inclusion / Exclusion criteria X X┼

Subject Adherence X X X

Prophylaxis procedure** X

Dispensing wash-out products3 X

Collect wash-out products X

Randomization X1

Saliva samples for fluoride X6 X6

Dispense Study Subject kits4X

Supervised Brushing /Rinsing

X

Collecting subject kits and

Home use Diary cardX

Adverse events X X X

Study close out X

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Appendix 2 List of Tables, Figures & Listings

In all outputs, the treatment labels and order for presentation in tables and listings is as follows:

’Treatment 1’ to be displayed as ‘Fluoride Dentifrice/Fluoride Rinse’’Treatment 2’ to be displayed as ‘Fluoride Dentifrice/No Rinse’’Treatment 3’ to be displayed as ‘Placebo Dentifrice/Fluoride Rinse’’Treatment 4’ to be displayed as ‘Placebo Dentifrice/No Rinse’

All tables and listings which make use of the above treatment labels will, in addition, include the following footnotes:

Fluoride dentifrice/Fluoride rinse: 1150ppmF NaF ( + 220ppm NaF mouthwash (

Placebo dentifrice/Fluoride rinse: Placebo non Fluoride ( + 220ppm NaF mouthwash (

Fluoride dentifrice/No rinse: 1150ppmF NaF ( + No Rinse

Placebo dentifrice/No rinse: Placebo non Fluoride ( + No Rinse All the details of dosing / administration will be in the study report

Table No. Title Standard / Template

Comments / Changes to Footnotes

Table 9.1.1 Subject DispositionAll Screened Subjects

Appendix 4

Table 9.1.2 Protocol Violations Leading to Exclusion from Per Protocol AnalysesIntent to Treat Population

Appendix 4

Table 9.2.1.1 Demographic CharacteristicsSafety Population

Standard

Table 9.2.1.2 Demographic CharacteristicsPer Protocol Population

Standard

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Table 9.2.1.3 Demographic CharacteristicsIntent to Treat Population

Standard

Table 9.3.1.1 % Surface Microhardness Recovery(%SMHR)

Per Protocol Population

Appendix 4


Intent to Treat Population

Table 9.3.1.1 As required.


ANCOVA Including Pre-Treatment SMH Values as CovariatesPer Protocol Population

Appendix 4

Table 9.3.2.1 Enamel Fluoride Uptake (EFU)Per Protocol Population

Table 9.3.1.1

Table 9.3.2.2 Enamel Fluoride Uptake (EFU)ANCOVA Including Pre-Treatment SMH Values as CovariatesPer Protocol Population

Table 9.3.1.3

Table 9.3.3.1 Change From Day 1 pre Treatment Saliva Fluoride to Day 14 Saliva FluoridePer Protocol Population

Table 9.3.1.1 Include another row below 95% CI as

P-Value 0.XXXX … 0.XXXX

Table 9.3.3.2 Change From Day 1 pre Treatment Saliva Fluoride to Day 1 post Treatment Saliva FluoridePer Protocol Population

Table 9.3.1.1

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Table 9.3.3.3 Change From Day 1 post Treatment Saliva Fluoride to Day 14 Saliva FluoridePer Protocol Population

Table 9.3.1.1

Table 9.3.4 Correlation of % Surface Microhardness Recovery (%SMHR), Enamel Fluoride Uptake (EFU) and Saliva Fluoride ChangesPer Protocol Population

Appendix 4

Table 9.4.1 Listing of All Adverse Events All Subjects Screened

OHC standard Include pre-treatment

Table 9.4.2 Treatment Emergent Adverse Events by Oral/Non-Oral and Preferred TermSafety Population

OHC standard

Table 9.4.3 Treatment Emergent Adverse Events by SOC and Preferred TermSafety Population

OHC standard

Table 9.4.4 Treatment Emergent Treatment Related Adverse Events by Oral/Non-Oral and Preferred TermSafety Population

OHC standard No related TEAEs then null table please.

Table 9.4.5 Treatment Emergent Adverse Events by SOC and Preferred TermSafety Population

OHC standard

Table 9.4.6 Listing of All Serious Adverse Events All Subjects Screened

OHC standard Note if >5 SAEs please produce table as 9.4.1, NO SAEs produce null table

Table 9.4.7 Listing of All Non-Serious Adverse Events All Subjects Screened

OHC standard Only produce if f >5 SAEs please

Table 9.4.8 Listing of All IncidentsSafety Population

OHC standard

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Listing No. Title Standard / Template


Listing 2.1 Randomization Details Standard

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Appendix 3 Templates for Tables, Figures & ListingsTable TemplatesProtocol: 203160 Program Run Date: DDMMMYYYY

Table 9.1.1Subject Disposition

Treatment 1 n (%)

Treatment 2n (%)

…….. Overalln (%)

TOTAL SUBJECTS SCREENED XX

SUBJECTS NOT RANDOMISED XX DID NOT MEET STUDY CRITERIA XX ADVERSE EVENT XX PROTOCOL DEVIATION XX WITHDRAWAL OF CONSENT XX OTHER XX

SUBJECTS RANDOMISED XX RECEIVED TREATMENT XX (XX.X) XX (XX.X) . XX (XX.X) COMPLETED XX (XX.X) XX (XX.X) . XX (XX.X) DID NOT COMPLETE XX (XX.X) XX (XX.X) . XX (XX.X) ADVERSE EVENT XX (XX.X) XX (XX.X) . XX (XX.X) LOST TO FOLLOW - UP XX (XX.X) XX (XX.X) . XX (XX.X) PROTOCOL DEVIATION XX (XX.X) XX (XX.X) . XX (XX.X) WITHDRAWAL OF CONSENT XX (XX.X) XX (XX.X) . XX (XX.X) OTHER XX (XX.X) XX (XX.X) . XX (XX.X)

SAFETY POPULATION XX (XX.X)ITT POPULATION XX (XX.X)PP POPULATION XX (XX.X)

(Page X of Y)

Programming Note: Table to include columns for all 4 treatments and overall.

Percentages should be calculated using the Number who Received Treatment as the denominator. If a subject withdraws during the washout period between treatments, they should be counted as withdrawing during the

treatment taken immediately prior to withdrawing.

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Protocol: 203160 Program Run Date: DDMMMYYYYTable 9.1.2

Protocol Violations Leading to Exclusion from Per Protocol AnalysesIntent to Treat Population

Study Population: ITT (N=XX)Overall(N=XX)

n (%)

NUMBER OF SUBJECTS WITH AT LEAST ONE PROTOCOL VIOLATION AFFECTING EFFICACY XX (XX.X)

NUMBER OF SUBJECTS EXCLUDED FROM PER PROTOCOL POPULATION XX (XX.X)

PROTOCOL VIOLATIONS AFFECTING EFFICACY FOR SUBJECTS EXCLUDED FROM THE PER PROTOCOL POPULATION: PROTOCOL VIOLATION 1 XX (XX.X) PROTOCOL VIOLATION 2 XX (XX.X) ETC

PROTOCOL VIOLATIONS LEADING TO DATA EXCLUSION ONLY: PROTOCOL VIOLATION 1 XX (XX.X) PROTOCOL VIOLATION 2 XX (XX.X) ETC

(Page X of Y)Subjects may have more than one associated violation

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Protocol: 203160 Program Run Date: DDMMMYYYYTable 9.3.1.1

% Surface Micro Hardness Recovery (%SMHR) ANOVA Per Protocol Population

Study Population: ITT (N=XX) Treatment 1 ... (N=XX)

Treatment 4(N=XX)

N XX XX MISSING X X MEAN XX.XX XX.XX SD XX.XXX XX.XXX SE XX.XXX XX.XXX MEDIAN XX.XX XX.XX MINIMUM X.XX X.XX MAXIMUM X.XX X.XX

ADJUSTED MEAN [1] XX.XX XX.XXSTANDARD ERROR [1,2] 95% CI

X.XXXXX.XXX-XX.XXX

X.XXXXX.XXX-XX.XXX

COMPARISON BETWEEN TREATMENTS DIFFERENCE [1,3] 95% CI [1] P VALUE [1]

Treatment 3 vs Treatment 4Treatment 1 vs Treatment 2Treatment 1 vs Treatment 4Treatment 2 vs Treatment 4Treatment 1 vs Treatment 3Treatment 2 vs Treatment 3

X.XXX.XXX.XXX.XXX.XXX.XX

(XX.XXX, XX.XXX)

(XX.XXX, XX.XXX)

X.XXXX

X.XXXX

See treatments at start of section for decode.(Page X of Y)

[1] From ANOVA: subject (random), treatment (fixed), period (fixed) [2] Within-subject standard error for Adjusted Mean.[3] Difference is first named treatment minus second named treatment such that a positive difference implies a larger response value for the first named treatment.

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Protocol: 203160 Program Run Date: DDMMMYYYYTable 9.3.1.3

% Surface Micro Hardness Recovery (%SMHR) ANCOVA Including Pre-Treatment SMH Values as Covariates

Per Protocol PopulationStudy Population: ITT (N=XX)

Treatment 1 ... (N=XX)

Treatment 4(N=XX)

N XX XX MISSING X X MEAN XX.XX XX.XX SD XX.XXX XX.XXX SE XX.XXX XX.XXX MEDIAN XX.XX XX.XX MINIMUM X.XX X.XX MAXIMUM X.XX X.XX

ADJUSTED MEAN [1] XX.XX XX.XXSTANDARD ERROR [1,2] 95% CI

X.XXXXX.XXX-XX.XXX

X.XXXXX.XXX-XX.XXX

COMPARISON BETWEEN TREATMENTS DIFFERENCE [1,3] 95% CI [1] P VALUE [1]

Treatment 3 vs Treatment 4Treatment 1 vs Treatment 2Treatment 1 vs Treatment 4Treatment 2 vs Treatment 4Treatment 1 vs Treatment 3Treatment 2 vs Treatment 3

X.XXX.XXX.XXX.XXX.XXX.XX

(XX.XXX, XX.XXX)

(XX.XXX, XX.XXX)

X.XXXX

X.XXXX

(Page X of Y)[1] From ANCOVA: subject (random), treatment (fixed), period (fixed) and subject-level baseline SMH/indentation length, period-level baseline SMH/indentation length - subject-level baseline SMH/indentation length, subject-level pre-treatment acid challenge SMH/indentation length and period-level pre-treatment acid challenge SMH/indentation length - subject-level pre-treatment acid challenge SMH/indentation length as covariates.[2] Within-subject standard error for Adjusted Mean.[3] Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment.

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Protocol: 203160 Program Run Date: DDMMMYYYYTable 9.3.4

Correlation of % Surface Microhardness Recovery (%SMHR), Enamel Fluoride Uptake (EFU) and Saliva Fluoride ChangesPer Protocol Population

Treatment

Pearson Correlation Coefficient

EFU Saliva Fluoride (D1pre-D14)

Saliva Fluoride (D1post-D14)

Saliva Fluoride (D1pre-D1post)

Treatment 1 %SMHR XX.XXX XX.XXX XX.XXX XX.XXX EFU XX.XXX XX.XXX XX.XXX

%SMHR XX.XXX XX.XXX XX.XXX XX.XXX Treatment 2 EFU XX.XXX XX.XXX XX.XXX

%SMHR XX.XXX XX.XXX XX.XXX XX.XXX

EFU XX.XXX XX.XXX XX.XXX Treatment 3

%SMHR XX.XXX XX.XXX XX.XXX XX.XXX EFU XX.XXX XX.XXX XX.XXX

Treatment 4 %SMHR XX.XXX XX.XXX XX.XXX XX.XXX EFU XX.XXX XX.XXX XX.XXX

All Treatments %SMHR XX.XXX XX.XXX XX.XXX XX.XXX

EFU XX.XXX XX.XXX XX.XXX

Note to programmers Proc Corr data=all;by trt_t; for blocks 1-4 above and without by trt; for final block. Corelations to be done at subject level (ie average values rather than individual ones).

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Listing Templates

Protocol: 203160 Program Run Date: DDMMMYYYYData Listing 2.1

Randomization Details

Subject Number

Randomization Number

Randomized Treatment

Period 1 Period 2 Period 3 Period 4

01Sxxxx 10XX TREATMENT 1 TREATMENT 2 TREATMENT 3 TREATMENT 4

etc.

(Page X of Y)

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SIGNATURE PAGE

Date Signed By Justification






06-Jul-2015 10:50:54

Medical Affairs Approval

Biostatistics Approval

03-Jul-2015 04:44:24

Medical Affairs Approval

SAP_203160.doc

29-Jun-2015 10:14:37

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