Post on 27-Jun-2018
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 No. Title Standard / Template
Comments / Changes to Footnotes
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
Table 9.3.1.2 % Surface Microhardness Recovery(%SMHR)
Intent to Treat Population
Table 9.3.1.1 As required.
Table 9.3.1.3 % Surface Microhardness Recovery(%SMHR)
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 No. Title Standard / Template
Comments / Changes to Footnotes
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
Comments / Changes to Footnotes
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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Medical Affairs Approval
Biostatistics Approval
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Medical Affairs Approval
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