In February 2013, Glaxosmithkline (GSK) Announced a Commitment To

In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.

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Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Synopsis Report Study Number 205051

Study Title A Study to Investigate the Ant imicrobial Activity of two Test toothpastes in a Plaque Glycolysis and Regrowth Model.

Test Product(s) Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w isopropylmethylpheno l (IPMP) and

1426ppm fluoride as sodium fluoride.

Indication Ant imicrobial activity

Phase Not Applicable

Authors:

Clinical Operations PPD , HND

BioStatistics PPD , BSc, MSc

Clinical Research PPD , BS

Approvers:

Clinical Operations PPD , PhD

BioStatistics PPD , BSc, CStat

Clinical Research PPD , BSc, MSc, CStat

Copyright: GlaxoSmithKline. An unpublished work subject to trade secret protection. This work contains confidential and proprietary information of GlaxoSmithKline and should not be copied, circulated, or distributed to persons not employed by GlaxoSmithKline unless specifically authorized. Unauthorized disclosure of this work is expressly prohibited.

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Table of Contents Page 205051 SYNOPSIS 4 TABLE 9.1.1.1 SUBJECT DISPOSITION BY TREATMENT GROUP ACROSS STUDY TREATMENT PERIODS ALL SCREENED SUBJECTS 20 TABLE 9.1.1.2 SUBJECT DISPOSITION BY TREATMENT GROUP AND STUDY TREATMENT PERIOD ALL SCREENED SUBJECTS 22 TABLE 9.1.2 PROTOCOL VIOLATIONS LEADING TO EXCLUSION FROM PER PROTOCOL ANALYSIS INTENT TO TREAT POPULATION 28 TABLE 9.2.1.1 DEMOGRAPHIC AND BASELINE CHARACTERISTICS SAFETY POPULATION 29 TABLE 9.2.1.2 DEMOGRAPHIC AND BASELINE CHARACTERISTICS PER PROTOCOL POPULATION 30 TABLE 9.3.1.1 SUMMARY AND ANALYSIS OF MEASUREMENTS OF GLYCOLYSIS BY TIMEPOINT PER PROTOCOL POPULATION 31 TABLE 9.3.1.2 TREATMENT COMPARISONS OF MEASUREMENTS OF GLYCOLYSIS BY TIMEPOINT PER PROTOCOL POPULATION 35 TABLE 9.3.1.3 SUMMARY AND ANALYSIS OF AUCGLY(0-90) PER PROTOCOL POPULATION 38 TABLE 9.3.2 SUMMARY AND ANALYSIS OF AUCGLY(0-90): SUBGROUP ANALYSIS BY PRE-STUDY BASELINE PH LEVEL PER PROTOCOL POPULATION 40 TABLE 9.3.3.1 SUMMARY AND ANALYSIS OF MEASUREMENTS OF REGROWTH RATIO BY TIMEPOINT PER PROTOCOL POPULATION 44 TABLE 9.3.3.2 TREATMENT COMPARISONS OF MEASUREMENTS OF REGROWTH RATIO BY TIMEPOINT PER PROTOCOL POPULATION 48 TABLE 9.3.3.3 SUMMARY AND ANALYSIS OF AUCREGROWTH(0-90) PER PROTOCOL POPULATION 51 TABLE 9.3.4.1 SUMMARY AND ANALYSIS OF MEASUREMENTS OF LIVE:DEAD STAIN RATIO BY TIMEPOINT PER PROTOCOL POPULATION 53 TABLE 9.3.4.2 TREATMENT COMPARISONS OF MEASUREMENTS OF LIVE:DEAD STAIN RATIO BY TIMEPOINT PER PROTOCOL POPULATION 57 TABLE 9.3.4.3 SUMMARY AND ANALYSIS OF AUCLIVE:DEAD(0-90) PER PROTOCOL 60 POPULATION TABLE 9.4.2 TREATMENT EMERGENT TREATMENT RELATED ADVERSE EVENTS 73 SAFETY POPULATION TABLE 9.4.3 TREATMENT EMERGENT ADVERSE EVENTS SAFETY POPULATION 75 TABLE 9.4.4 TREATMENT EMERGENT TREATMENT RELATED ADVERSE EVENTS SAFETY POPULATION 79 TABLE 9.4.5 TREATMENT EMERGENT ADVERSE EVENTS SAFETY POPULATION 81

FIGURE 9.1 MEAN PLAQUE INCUBATION PH OVER TIME PER PROTOCOL POPULATION 86

FIGURE 9.2 MEAN REGROWTH RATIO OVER TIME PER PROTOCOL POPULATION 87

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FIGURE 9.3 MEAN LIVE:DEAD STAIN RATIO OVER TIME PER PROTOCOL POPULATION 88 FIGURE 9.4 MEAN CHANGE IN PLAQUE INCUBATION PH FROM PRE-TREATMENT PER PROTOCOL POPULATION 89 FIGURE 9.5 MEAN CHANGE IN REGROWTH RATIO FROM PRE-TREATMENT PER PROTOCOL POPULATION 90 FIGURE 9.6 MEAN CHANGE IN LIVE:DEAD STAIN OVER TIME PER PROTOCOL POPULATION 91 FIGURE 9.7 SCATTER PLOT OF BASELINE PH VERSUS AUCGLY(0-90) PER PROTOCOL POPULATION 92

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Study: 205051 Synopsis Report

Name of Company: GlaxoSmithKline Consumer Healthcare Name of Finished Product: Toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium

Name of Active Ingredient: Zinc chlor ide, Isopropylmethylphenol, sodium fluoride

Title of Study: A Study to Investigate the Antimicrobial Activity of two Test Toothpastes in a Plaque Glycolysis and Regrowth Model. Investigator: Dr. David Payne, BDS Study centre: Intertek - Brindley Road, Manchester, UK

Publication (reference): Not Applicable

Study period: First Enrolment: 09 Nov 2015 Last Completed: 11 Dec 2015

Clinical Phase: Not Applicable

Objectives: Primary Objective To evaluate and compare the ability of a test toothpaste containing 0.6% zinc chloride and 0.1% isopropylmethylphenol (IPMP) to inhibit plaque glycolysis compared to a non-sodium lauryl sulphate (SLS) containing toothpaste.

Secondary Objectives To evaluate and compare the ability of a test toothpaste containing 0.6% zinc chloride and 0.1% IPMP to inhibit plaque viability by regrowth as compared to a non-SLS containing toothpaste.

To evaluate and compare the ability of a test toothpaste containing 0.6% zinc chloride and 0.1% IPMP to inhibit plaque viability by live:dead staining compared to a non- SLS containing toothpaste.

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To evaluate and compare the ability of a test toothpaste containing 0.6% zinc chloride (non-IPMP) to inhibit plaque glycolysis, and to inhibit plaque viability as assessed by

area under the curve regrowth (AUCregrowth) and by AUClive:dead(0-90), compared to a

non-SLS containing toothpaste and an SLS containing toothpaste.

To make all other comparisons between products in AUCgly(0-90), AUCregrowth(0-90) and

AUClive:dead(0-90).

Design / Methodology: This was a single-centre, analyst and examiner (plaque sample collector)-blind,

randomised, five-treatment, five-period cross -over study in healthy adult volunteers. At the screening visit, eligible subjects were provided with a standardised washout toothpaste to use at home, twice per day until the end of the study. Following screening, eligible subjects attended a plaque screening assessment visit where, having presented with overnight plaque (having not brushed their teeth since 11pm the evening before), a plaque sample was collected from the entire dentition using a swab. The acidgenicty of the plaque samples were determined and only subjects

demonstrating plaque acidogenicity in the pH range 5.0-5.7 progressed to the treatment phase of the study. At each treatment visit having presented with overnight plaque (having not brushed

their teeth since 11pm the evening before) subjects had an oral soft tissue (OST)

examination. Subjects then had their dental plaque from their maxilliary left quadrant (from both facial and lingual surfaces) collected using a swab. Subjects swilled around their mouth with a pre-prepared slurry of toothpaste, ensuring the slurry contacted their entire dentition for 60 s before expectorating. Further dental plaque samples were swabbed at 15 minutes post-treatm ent (maxilliary right quadrant), 45 minutes post-treatment (mandibular left quadrant) and 90 minutes post-treatment (mandibular right quadrant). Subjects subsequent ly underwent a further OST

examination and continued to attend further scheduled treatment visits until they had completed the study (allowing 2-10 between treatment visits). The ability for the plaque samples to generate acid (glycolysis) and to proliferate (regrowth) were assessed by standardising the plaque samples to an optical density of 0.2 cm-1, using tryptic soy broth (TSB) growth media supplemented with sucrose, and measuring the pH of the plaque suspension following 2 hours incubation at 37°C. The optical density was subsequently determined after a total of 4 hours of incubation at 37°C. The ratio of live to dead bacteria in the plaque samples were determined by

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addition of an aliquot of propidium iodide and Syto-9 dyes to the standardised plaque dispersion and the fluorescence of the result ing stained bacteria determined.

Number of subjects (planned and analysed):

It was planned that 45 subjects would be randomly assigned to a treatment sequence in order to yield 40 subjects that completed the entire study. A total of 150 subjects were screened of which 45 subjects were randomised and received study treatment. These 45 subjects constituted the Safety and Intent to Treat (ITT) Populations. One subject withdrew consent after the first treatment period and the remaining 44 subjects completed all five treatment periods . No subjects were entirely excluded

from the Per Protocol (PP) population, but several plaque samples were excluded

from the analysis. Subject disposition is presented in Table 9.1.1.1. Samples to be

excluded from analysis were identified prior to database lock and study unblinding.

As per the bioanalytical method, all plaque samples were to be diluted to an optical

density (OD) of 0.2 in order to standardise the bacterial load across all samples in the

regrowth and glycolysis assays. At the blinded data review, it was identified that a

large number of the samples had an OD <0.2. The reason for this low OD is believed

to be due to relatively and unexpectedly low amounts of plaque generated by some of

the subjects in this study. In order to ensure data from these assays were comparable

it was thus decided to relax this criterion, and to exclude all samples with OD <0.18

from statistical analysis. In addition, a further 20 samples were considered non-

evaluable for the live:dead stain analysis,. These samples, with a median %live <-

25% or >150%, were considered to be outside of the feasible range and so were

excluded from the live:dead stain analysis. It is unclear why values outside of the expected 0-100% range were attained in this study, although the calibration procedure employed may have been a contributory factor. Table 1 below depicts the number of excluded samples and shows that 292 samples (33% of the total number of samples) were considered non-evaluable for the analysis of all endpoints.

Table 1 Reason for Exclusion of Plaque Samples from Analysis – Safety Population Total Number of Plaque Samples Taken 884 No. of samples excluded from all analyses due to initial OD<0.18 292 (33.0%) Samples excluded from live:dead analysis 20 (2.3%) Source: Data Listing 2.2.

Main criteria for inclusion: Subjects with plaque sample acidogenicity in the pH range 5.0 to 5.7.

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Test products, dose and mode of administration:  Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride CCI ).

 Test toothpaste containing 0.6% w/w zinc chloride and 0% w/w IPMP and 1426ppm fluoride as sodium fluoride ()CCI . A slurry of approximately 1.5g of the toothpaste in 10mL of water swilled around the mouth for 60 seconds.

Reference therapies, dose and mode of administration:

 A marketed toothpaste containing 0.454% w/w stannous fluoride (Crest

ProHealth® – Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product). [Positive Control]  A marketed toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product) ()CCI . [Negative

Control]

 A marketed toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste) ()CCI . [Negative Control]

A slurry of approximately 1.5g of the toothpaste in 10mL of water swilled around the mouth for 60 seconds.

Duration of treatment:

Subjects used each study treatment once under supervision at the study site (one treatment at each of Visits 3-7). Criteria for evaluation:

Efficacy: The primary outcome measure of the study was considered valid if a statistically significant difference was observed between the positive control toothpaste and the non-SLS-negative control toothpaste with respect to mean glycolysis activity inhibition over the 90-minute sampling period (AUCgly(0-90)).

Following demonstration of the validity of the primary outcome measure, the success criterion for this study was to observe a statistically significant difference between the test Zinc-IPMP toothpaste and the non-SLS-negative control toothpaste, with respect to AUCgly(0-90).

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Safety:

Safety was assessed with respect to adverse events (AEs) and OST abnormalities (oral tolerability). Statistical methods:

With 40 completed subjects, the study had 80% power to detect a difference of 7.0 in

AUCgly(0-90) between treatment groups, at the 2-sided 5% level of significance, assuming a SD of the paired-subject differences of 15.4, based on GSK study RH01871. The observed SD of the paired-subject subject differences was 12.41, slightly less than predicted from the previous study.

Although both the intent-to-treat (ITT) and PP populations were defined, all efficacy analyses for this ex vivo plaque glycolysis regrowth model (PGRM) study design

were performed using the PP population only, as planned, with subjects analysed as

per randomised treatment.

For each endpoint, the comparison of positi ve control to non-SLS negative control was assessed first to test the validity of study results. After study validation (i.e. if a statistically significant difference was observed), the primary comparison of interest for each endpoint was to be the test Zinc-IPMP toothpaste versus the non-SLS- negative control.

All statistical analysis was performed in SAS version 9.2.

Primary Analysis:

The primary endpoint of interest in this study was AUC(0-90) for Glycolysis,

AUC ). This was calculated as the net incremental AUC using the trapezoidal gly(0-90) rule (i.e., areas above the baseline contribute a positive value and areas below the baseline contribute a negative value in the overall calculation of the AUCgly(0-90)). In the event of missing or unevaluable data, the AUC was not calculated; no imputation method was used. Due to the number of samples excluded from analysis, there was only 32% of subject visits with complete data at all time points (baseline, 15-mins,

45-mins and 90-mins) and thus included in the analysis of AUCgly(0-90). The impact of the data exclusions is assessed in the results section.

The primary endpoint was analysed using analysis of covariance (ANCOVA) including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period- minus subject-level pre-treatment

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values as covariates in the model. The pre-treatm ent values refer to the plaque samples collected prior to supervised treatment on each treatment day.

From the above model, treatment differences and associated 95% confidence intervals and p-values were presented. All tests were two-sided and were performed at the 5%

significance level under a null hypothesis of no difference between treatments.

Adjusted means and standard errors per treatment group were presented.

For the analysis of the primary endpoint and all other endpoints, the assumptions of normality and homogeneity of variance was investigated and found to be satisfied.

Secondary Analysis:

The secondary endpoints in this study were as follows:

 AUCregrowth(0-90).

 AUClive:dead(0-90).

The live:dead stain assay was performed in triplicate such that three %live readings were obtained for each plaque sample. It was originally planned to use the mean of the three readings as the value for statistical analysis, but due to the higher than expected variability across the three readings, the median value was used for analysis.

This decision was made prior to study unblinding.

Due to the number of samples excluded from analysis, there was only 32% (regrowth)

and 25% (live:dead stain) of subject visits wi th complete data at all time points (baseline, 15-mins, 45-mins and 90-mins) and thus this reduced number of subjects were included in the analysis of AUCregrowth(0 -90) and AUClive:dead(0-90).

The AUC variables were calculated and analysed using the same ANCOVA methodology used for the primary endpoint .

For both of the secondary endpoints, the same step-wise testing procedure was used as for the primary endpoint, whereby the validity of the endpoint was first assessed from the comparison of the positive control to the non-SLS-negative control.

Unadjusted means and standard errors (for observed values and change from pre- treatment values) were presented for the glycolysis, regrowth and live:dead stain values, per time-point, for each treatment.

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In addition, the change from pre-treatment in glycolysis, regrowth and live:dead stain values was subject to an ANCOVA at each time-point (i.e., 15, 45 and 90 minutes). The ANCOVA model included period and treatment as fixed effects, subject as a

random effect and subject-level pre-treatment values and period- minus subject-level

pre-treatment values as covariates in the model.

Exploratory Analysis:

An exploratory analysis was performed to invest igate the relationship between baseline plaque pH levels and the subsequent value of AUCgly(0-90). This was assessed using a scatter plot and Pearson’s correlatio n of the baseline pH versus AUCgly(0-90), for each treatment group.

In addition, subjects were split into two groups, according to the median baseline pH

value. A subgroup analysis for AUCgly(0-90) was performed to investigate whether there is a difference in the efficacy for subjects with baseline pH > median compared

to those with baseline pH ≤ median. This was accomplished from the same ANCOVA

model used for the primary endpoint, with the addition of terms for baseline pH group (low, high) and the interaction between treatment and baseline pH group.

Graphical presentations of the data include a line chart of the unadjusted (raw) means ± standard error (SE) for each of the glycolysis, regrowth and live:dead stain values as a function of time after product use, and also a bar chart of the mean ± SE for the change from baseline of the glycolysis, regrowth and live:dead stain values.

There were no unplanned analyses performed in this study.

Summary:

Demographic Results: Of the forty-five (45) subjects who were randomised and included in the Safety (and the PP) population, 30 (66.7%) were female and 15 (33.3%) male. Twenty-nine (64.4%) of these subjects were White, 7 (15.6%) were Black or African American, 7 (15.6%) were Multiple Race and 2 (4.4%)were Asian. The average age was 39.4 years (range 20 - 72 years) (Tables 9.2.1.1 and 9.2.1.2).

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Efficacy Results: Primary Efficacy Analyses:

Plaque Glycolysis: The adjusted treatment group means and pairwise comparisons

for AUCgly(0-90) are presented in Tables 2 and 3, respectively.

Table 2 Summary of AUCgly (0-90) [pH. min] - PP Population

Test Zinc- Test Zinc Positive Non-SLS SLS IPMP non-IPMP control negative negative control control (N=44) (N=44) (N=45) (N=44) (N=44)

n [1] 14 14 14 15 14

Adj Mean 42.64 34.20 28.88 2.46 31.78 (SE) [2] (3.437) (3.354) (3.384) (3.303) (3.512)

95% CI [2] 35.76, 49.52 27.48, 40.92 22.10, 35.65 -4.15, 9.08 24.75, 38.81

[1] n represents number of subjects with non-missing AUC value included in analysis. [2] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates. Source: Table 9.3.1.3.

Due to the number of samples that were considered non-evaluable and so unable to contribute to the calculation of AUC, the primary analysis is based on approximately one third of the plaque samples. Since the number of subjects excluded from the primary analysis (Table 2) is comparable across all treatment groups, it is considered that the study results are robust despite the number of excluded samples.

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Table 3 Treatment Comparisons of AUC gly (0-90) [pH. min] - PP Population Comparison Diff [1,2] 95% CI [1] p-value [1]

Pos control vs Non-SLS neg control 26.41 18.94, 33.88 <0.0001 Test Zinc-IPMP vs Non-SLS neg control 40.18 32.37, 47.99 <0.0001

Test Zinc-IPMP vs SLS neg control 10.86 3.13, 18.59 0.0072 Test Zinc non-IPMP vs Non-SLS neg control 31.74 24.18, 39.30 <0.0001

Test Zinc non-IPMP vs SLS neg control 2.42 -5.08, 9.92 0.5174

Test Zinc-IPMP vs Pos control 13.77 6.01, 21.53 0.0009 Test Zinc-IPMP vs Test Zinc non-IPMP 8.44 0.93, 15.95 0.0286

Test Zinc non-IPMP vs Pos control 5.32 -2.15, 12.79 0.1573 Pos control vs SLS neg control -2.91 -11.18, 5.37 0.4823 Non-SLS neg control vs SLS neg control -29.32 -37.20, -21.43 <0.0001

[1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates. [2] A positive difference indicates a greater inhibition of plaque glycolysis for first named treatment. Source: Table 9.3.1.3.

The difference in mean AUCgly(0-90) between the positive control and the non-SLS

negative control was statistically significant (mean difference 26.41, p<0.0001) in

favour of the positive control toothpaste (Table 3).

Given the statistically significant differences observed between the positive control and non-SLS negative control toothpastes for AUCgly(0-90) , study validity based on the glycolysis endpoint was established.

The difference in mean AUCgly(0-90) between the test Zinc-IPMP toothpaste and the non-SLS-negative control toothpaste was statist ically significant (mean difference 40.18, p<0.0001) in favour of the test toothpaste (Table 3). Furthermore, the test

Zinc-IPMP toothpaste had a statistically significantly higher AUCgly(0-90) compared to the positive control (mean differences of 13.77). The test Zinc non-IPMP toothpaste

had a numerically higher AUCgly(0-90) compared to the positive control, but it did not reach statistical significance (mean difference of 5.32).

Figure 1 presents the mean plaque incubation pH (glycolysis) (± SE) at baseline and at 15, 45 and 90 minutes post-treatment. A higher pH indicates greater inhibition of glycolysis.

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Figure 1 Mean Plaque Incubation pH Over Time - PP Population

6.3 6.2

6.1 6.0 5.9

5.8

Plaque Incubation pH IncubationPlaque 5.7 5.6

5.5 0 15 30 45 60 75 90 Time (minutes)

Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control

Values are raw means ± SE Source: Table 9.3.1.1, Figure 9.1.

Changes in plaque incubation pH over time are shown in Figure 9.4.

Treatment comparisons are presented at each time point in Table 9.3.1.2. Unlike

AUC, these do not rely on complete data bei ng available at all time points; hence fewer data points are excluded from the analysis. The results of the analysis by time point support the analysis based on the AUC variables, with statistically significant differences between the positive control and the non-SLS negative control, and also between the test Zinc-IPMP toothpaste and the non-SLS-negative control toothpaste, and the test Zinc non-IPMP toothpaste and the non-SLS-negative control toothpaste at all time points. The results from the analysis at each time point support the findings from the AUC analysis that were based on the reduced set of plaque samples.

Secondary Efficacy Analyses:

Plaque Regrowth: The adjusted treatment group means and pairwise comparisons

for AUCregrowth(0-90) are presented in Tables 4 and 5, respectively.

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Table 4 Summary of AUCregrowth (0-90) - PP Population Test Zinc- Test Zinc Positive Non-SLS SLS

IPMP non-IPMP control negative negative control control (N=44) (N=44) (N=45) (N=44) (N=44) n [1] 14 14 14 15 14

Adj Mean -239.81 -240.86 -179.55 53.66 -215.08 [2] (SE) (40.122) (39.118) (39.415) (38.443) (40.350) 95% CI [2] -320.06, -319.12, -258.40, -23.23, -295.79, -159.55 -162.61 -100.71 130.56 -134.37

Table 5 Treatment Comparisons of AUC regrowth (0-90) - PP Population Comparison Diff [1,2] 95% CI [1] p-value [1]

Pos control vs Non-SLS neg control -233.22 -332.88, -133.55 <0.0001 Test Zinc-IPMP vs Non-SLS neg control -293.47 -396.03, -190.91 <0.0001

Test Zinc-IPMP vs SLS neg control -24.73 -128.07, 78.61 0.6325

Test Zinc non-IPMP vs Non-SLS neg control -294.53 -395.43, -193.62 <0.0001 Test Zinc non-IPMP vs SLS neg control -25.78 -126.53, 74.96 0.6086

Test Zinc-IPMP vs Pos control -60.26 -162.72, 42.21 0.2427 Test Zinc-IPMP vs Test Zinc non-IPMP 1.05 -100.50, 102.61 0.9834

Test Zinc non-IPMP vs Pos control -61.31 -161.14, 38.52 0.2226

Pos control vs SLS neg control 35.53 -69.90, 140.96 0.5018 Non-SLS neg control vs SLS neg control 268.74 165.98, 371.51 <0.0001 [1] From ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates. [2] A negative difference indicates a greater inhibition of plaque regrowth for first named treatment. Source: Table 9.3.3.3.

The difference in mean AUCregrowth(0-90) between the positive control and the non-SLS negative control was statistically significant (-233.22, p<0.0001) in favour of the positive control toothpaste (Table 5).

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Given the statistically significant differences observed between the positive control

and non-SLS negative control toothpastes for AUCregrowth(0-90) , the study validity based on the regrowth endpoint was established .

The difference in mean AUCregrowth(0-90) between the test Zinc-IPMP toothpaste and

the non-SLS-negative control toothpaste was statistically significant (-293.47,

p<0.0001) in favour of the test toothpaste (Tabl e 5). Both the test Zinc-IPMP and test Zinc non-IPMP toothpastes had a numerically lower AUCregrowth(0-90) compared to the positive control (mean differences of -60.26 and -61.31, respectively), however these were not statistically significant.

Figure 2 presents the mean plaque regrowth ratio (± SE) at baseline and at 15, 45 and 90 minutes post-treatment. Inhibition in plaque regrowth is indicated by a reduction in the plaque regrowth ratio. A lower value, at each time point, indicates greater

plaque regrowth inhibition.

Figure 2 Mean Regrowth Ratio Over Time - PP Population

12 11

10 9

7 Regrowth Ratio Regrowth 6

5 4 0 15 30 45 60 75 90 Time (minutes) Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control

Values are raw means ± SE Source: Table 9.3.3.1, Figure 9.2.

Changes in regrowth ratio over time are shown in Figure 9.5.

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Treatment comparisons are presented at each time point in Table 9.3.3.2. Unlike AUC, these do not rely on complete data being available at all time points; hence fewer data points are excluded from the analysis. The results of the analysis by time

point support the analysis based on the AUC variables, with statistically significant

differences between the positive control and the non-SLS negative control, and also between the test Zinc-IPMP toothpaste and the non-SLS-negative control toothpaste, and the test Zinc non-IPMP toothpaste and the non-SLS-negative control toothpaste at all time points.

Live:Dead Stain: The adjusted treatment group means and pairwise comparisons for

AUClive:dead(0-90) are presented in Tables 6 and 7, respectively.

Table 6 Summary of AUClive:dead (0-90) [%live. min] - PP Population

Test Zinc- Test Zinc Positive Non-SLS SLS IPMP non-IPMP control negative negative control control (N=44) (N=44) (N=45) (N=44) (N=44) n [1] 9 10 11 14 12

Adj Mean 75.23 -691.41 72.19 346.11 -601.87 (SE) [2] (568.834) (508.108) (491.718) (431.974) (499.740) 95% CI [2] -1070.51, -1715.07, -918.20, -524.07, -1608.64,

1220.96 332.25 1062.58 1216.28 404.90

[1] n represents number of subjects with non-missing AUC value included in analysis. [2] From ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates. Source: Table 9.3.4.3.

Table 7 Treatment Comparisons of AUClive:dead (0-90) [%live. min] - PP Population [1,2] [1] [1] Comparison Diff 95% CI p-value Pos control vs Non-SLS neg control -273.92 -1550.45, 1002.61 0.6664 [1] From ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates. [2] A negative difference indicates a smaller live:dead stain ratio for first named treatment. Source: Table 9.3.4.3. Since there was no statistically significant difference between the positive control and

the non-SLS negative control for the AUClive:dead(0-90), the study validity based on the live:dead stain variable was not established. No further treatment comparisons are presented.

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Figure 3 presents the mean %live (± SE) at baseline and at 15, 45 and 90 minutes post-treatment. A lower value, at each time point, indicates a reduction in the number of live bacteria relative to dead bacteria.

Figure 3 Mean Live:Dead Stain Ratio (%live) Over Time - PP Population

100

50 Live:Dead Stain, %live Stain, Live:Dead 40 30 0 15 30 45 60 75 90 Time (minutes) Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control

Values are raw means ± SE

Source: Table 9.3.4.1, Figure 9.3.

Changes in %live over time are shown in Figure 9.6.

Treatment comparisons are presented at each time point in Table 9.3.4.2, and similar to the AUC parameter, study validity is not confirmed (no differences between the positive control and the non-SLS negative control at any time point).

Exploratory Efficacy Analyses:

The results of the subgroup analysis of AUCgly(0-90), for subjects with baseline pH > median compared to those with baseline pH ≤ median (where median pH was 5.55), are not presented here due to the small number of subjects in each subgroup. The results are presented in full in Table 9.3.2.

There was no relationship between baseline plaque pH levels and the subsequent

value of AUCgly(0-90) as demonstrated by low values of the Pearson correlation coefficient, as shown on the scatter plots in Figure 9.7.

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Safety results are presented in full in Tables 9.4.1 to 9.4.6. A total of 18 subjects reported 34 treatment-emergent AEs; 11 subjects reported a total of 20 oral AEs (all of mild intensity), and 11 subjects reported a total of 14 non oral AEs (all of mild

intensity with the exception of one case of nausea of moderate intensity in the test

Zinc-IPMP group). Two of the AEs were treatment related, ‘Paraesthesia Oral’ in the test Zinc-IPMP and SLS negative control groups . Both cases of ‘Paraesthesia Oral’ resolved prior to the end of the study. There were no serious AEs and no AEs lead to withdrawal from the study. Treatment emergent oral AEs are presented in Table 8.

Table 8 Overall Summary of Treatment Emergent Oral Adverse Events – Safety Population

Test Zinc- Test Zinc non- Positive control Non-SLS SLS negative IPMP(N=44) IPMP (N=44) (N=45) negative control control (N=44) (N=44) n (%) nAE n (%) nAE n (%) nAE n (%) nAE n (%) nAE

All AEs 8 (18.2) 10 6 (13.6) 6 6 (13.3) 9 3 (6.8) 3 2 (4.5) 6 Oral AEs 6 (13.6) 7 4 (9.1) 4 4 (8.9) 4 0 0 1 (2.3) 5 Lip Ulceration 2 (4.5) 3 0 0 0 0 0 0 0 0 Mouth Ulceration 1 (2.3) 1 0 0 0 0 0 0 0 0

Paraesthesia Oral 1 (2.3) 1 0 0 0 0 0 0 1 (2.3) 1

Toothache 1 (2.3) 1 0 0 0 0 0 0 0 0 Traumatic Ulcer 1 (2.3) 1 0 0 1 (2.2) 1 0 0 0 0 Coating in Mouth 0 0 1 (2.3) 1 0 0 0 0 0 0 Device Failure 0 0 0 0 0 0 0 0 1 (2.3) 3 Gingival 0 0 1 (2.3) 1 0 0 0 0 0 0

Ulceration

Oral Herpes 0 0 1 (2.3) 1 0 0 0 0 0 0 Oropharyngeal 0 0 0 0 2 (4.4) 2 0 0 0 0 Pain Pericoronitis 0 0 1 (2.3) 1 1 (2.2) 1 0 0 0 0 Tooth Fracture 0 0 0 0 0 0 0 0 1 (2.3) 1 Source: Table 9.4.3

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Conclusions:

In this exploratory study to evaluate the antimicrobial activity in the PGRM model of

two test toothpastes, one containing zinc chloride and IPMP and the other containing only zinc chloride, model validity was established for Glycolysis and Regrowth, but not for the Live:Dead Stain.

Compared to the non-SLS containing toothpa ste, a single treatment with the test toothpaste containing zinc chloride and IPMP significantly inhibited both plaque glycolysis and plaque regrowth in this model over the 90-minute evaluation period. Similarly, a single treatment with the test toothpaste containing zinc chloride but

without IPMP significantly inhibited both plaque glycolysis and plaque regrowth over

the 90-minute evaluation period. These results suggest that both test toothpastes demonstrate antimicrobial properties as assessed by this FDA-accepted model.

All study treatments were well-tolerated. No serious adverse events were observed in the study.

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.1.1.1 Subject Disposition by Treatment Group Across Study Treatment Periods All Screened Subjects

All Screened Subjects (N=150) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control Overall n (%) n (%) n (%) n (%) n (%) n (%) ______

TOTAL SUBJECTS SCREENED 150

SUBJECTS NOT RANDOMISED 105 DID NOT MEET STUDY CRITERIA 72 ADVERSE EVENT 0 LOST TO FOLLOW-UP 4 PROTOCOL DEVIATION 1 WITHDRAWAL OF CONSENT 5 OTHER 23

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______(Page 1 of 2) [1] For the treatment columns, number completed indicates number of subjects who completed the corresponding treatment period. For the Overall column, number completed indicates number of subjects who completed the study. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product). Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.1.1.1 Subject Disposition by Treatment Group Across Study Treatment Periods All Screened Subjects

All Screened Subjects (N=150) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control Overall n (%) n (%) n (%) n (%) n (%) n (%) ______

SUBJECTS RANDOMISED 45 RECEIVED TREATMENT 44 44 45 44 44 45 COMPLETED [1] 44 (100.0) 44 (100.0) 44 (97.8) 44 (100.0) 44 (100.0) 44 (97.8) DID NOT COMPLETE 0 0 1 (2.2) 0 0 1 (2.2) DID NOT MEET STUDY CRITERIA 0 0 0 0 0 0 ADVERSE EVENT 0 0 0 0 0 0 LOST TO FOLLOW-UP 0 0 0 0 0 0 PROTOCOL DEVIATION 0 0 0 0 0 0 WITHDRAWAL OF CONSENT 0 0 1 (2.2) 0 0 1 (2.2) OTHER 0 0 0 0 0 0

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SAFETY POPULATION 45 (100.0) ITT POPULATION 45 (100.0) PP POPULATION 45 (100.0)

______(Page 2 of 2) [1] For the treatment columns, number completed indicates number of subjects who completed the corresponding treatment period. For the Overall column, number completed indicates number of subjects who completed the study. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product). Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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SUBJECTS NOT RANDOMIZED 105 DID NOT MEET STUDY CRITERIA 72 ADVERSE EVENT 0 LOST TO FOLLOW-UP 4 PROTOCOL DEVIATION 1 WITHDRAWAL OF CONSENT 5 OTHER 23

SUBJECT RANDOMISED 45

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PERIOD 1 STARTED PERIOD 9 9 9 9 9 45 COMPLETED 9 (100.0) 9 (100.0) 9 (100.0) 9 (100.0) 9 (100.0) 45 (100.0) DID NOT COMPLETE 0 0 0 0 0 0 DID NOT MEET STUDY CRITERIA 0 0 0 0 0 0 ADVERSE EVENT 0 0 0 0 0 0 LOST TO FOLLOW-UP 0 0 0 0 0 0 PROTOCOL DEVIATION 0 0 0 0 0 0 WITHDRAWAL OF CONSENT 0 0 0 0 0 0 OTHER 0 0 0 0 0 0 ______(Page 1 of 6) Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.1.1.2 Subject Disposition By Treatment Group And Study Treatment Period All Screened Subjects Study Population: All Screened Subjects (N=150) ______non-SLS SLS negative Test Zinc-IPMP Test Zinc non-IPMP Positive control negative control control Overall n (%) n (%) n (%) n (%) n (%) n (%) ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ WASHOUT PERIOD 1 STARTED PERIOD 9 9 9 9 9 45 COMPLETED 9 (100.0) 9 (100.0) 8 (88.9) 9 (100.0) 9 (100.0) 44 (97.8) DID NOT COMPLETE 0 0 1 (11.1) 0 0 1 (2.2) DID NOT MEET STUDY CRITERIA 0 0 0 0 0 0 ADVERSE EVENT 0 0 0 0 0 0 LOST TO FOLLOW-UP 0 0 0 0 0 0 PROTOCOL DEVIATION 0 0 0 0 0 0 WITHDRAWAL OF CONSENT 0 0 1 (11.1) 0 0 1 (2.2) OTHER 0 0 0 0 0 0

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PERIOD 2 STARTED PERIOD 9 9 9 8 9 44 COMPLETED 9 (100.0) 9 (100.0) 9 (100.0) 8 (100.0) 9 (100.0) 44 (100.0) DID NOT COMPLETE 0 0 0 0 0 0 DID NOT MEET STUDY CRITERIA 0 0 0 0 0 0 ADVERSE EVENT 0 0 0 0 0 0 LOST TO FOLLOW-UP 0 0 0 0 0 0 PROTOCOL DEVIATION 0 0 0 0 0 0 WITHDRAWAL OF CONSENT 0 0 0 0 0 0 OTHER 0 0 0 0 0 0 ______(Page 2 of 6) Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.1.1.2 Subject Disposition By Treatment Group And Study Treatment Period All Screened Subjects Study Population: All Screened Subjects (N=150) ______non-SLS SLS negative Test Zinc-IPMP Test Zinc non-IPMP Positive control negative control control Overall n (%) n (%) n (%) n (%) n (%) n (%) ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ WASHOUT PERIOD 2 STARTED PERIOD 9 9 9 8 9 44 COMPLETED 9 (100.0) 9 (100.0) 9 (100.0) 8 (100.0) 9 (100.0) 44 (100.0) DID NOT COMPLETE 0 0 0 0 0 0 DID NOT MEET STUDY CRITERIA 0 0 0 0 0 0 ADVERSE EVENT 0 0 0 0 0 0 LOST TO FOLLOW-UP 0 0 0 0 0 0 PROTOCOL DEVIATION 0 0 0 0 0 0 WITHDRAWAL OF CONSENT 0 0 0 0 0 0 OTHER 0 0 0 0 0 0

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PERIOD 3 STARTED PERIOD 9 9 9 9 8 44 COMPLETED 9 (100.0) 9 (100.0) 9 (100.0) 9 (100.0) 8 (100.0) 44 (100.0) DID NOT COMPLETE 0 0 0 0 0 0 DID NOT MEET STUDY CRITERIA 0 0 0 0 0 0 ADVERSE EVENT 0 0 0 0 0 0 LOST TO FOLLOW-UP 0 0 0 0 0 0 PROTOCOL DEVIATION 0 0 0 0 0 0 WITHDRAWAL OF CONSENT 0 0 0 0 0 0 OTHER 0 0 0 0 0 0 ______(Page 3 of 6) Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.1.1.2 Subject Disposition By Treatment Group And Study Treatment Period All Screened Subjects Study Population: All Screened Subjects (N=150) ______non-SLS SLS negative Test Zinc-IPMP Test Zinc non-IPMP Positive control negative control control Overall n (%) n (%) n (%) n (%) n (%) n (%) ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ WASHOUT PERIOD 3 STARTED PERIOD 9 9 9 9 8 44 COMPLETED 9 (100.0) 9 (100.0) 9 (100.0) 9 (100.0) 8 (100.0) 44 (100.0) DID NOT COMPLETE 0 0 0 0 0 0 DID NOT MEET STUDY CRITERIA 0 0 0 0 0 0 ADVERSE EVENT 0 0 0 0 0 0 LOST TO FOLLOW-UP 0 0 0 0 0 0 PROTOCOL DEVIATION 0 0 0 0 0 0 WITHDRAWAL OF CONSENT 0 0 0 0 0 0 OTHER 0 0 0 0 0 0

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PERIOD 4 STARTED PERIOD 8 9 9 9 9 44 COMPLETED 8 (100.0) 9 (100.0) 9 (100.0) 9 (100.0) 9 (100.0) 44 (100.0) DID NOT COMPLETE 0 0 0 0 0 0 DID NOT MEET STUDY CRITERIA 0 0 0 0 0 0 ADVERSE EVENT 0 0 0 0 0 0 LOST TO FOLLOW-UP 0 0 0 0 0 0 PROTOCOL DEVIATION 0 0 0 0 0 0 WITHDRAWAL OF CONSENT 0 0 0 0 0 0 OTHER 0 0 0 0 0 0 ______(Page 4 of 6) Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.1.1.2 Subject Disposition By Treatment Group And Study Treatment Period All Screened Subjects Study Population: All Screened Subjects (N=150) ______non-SLS SLS negative Test Zinc-IPMP Test Zinc non-IPMP Positive control negative control control Overall n (%) n (%) n (%) n (%) n (%) n (%) ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ WASHOUT PERIOD 4 STARTED PERIOD 8 9 9 9 9 44 COMPLETED 8 (100.0) 9 (100.0) 9 (100.0) 9 (100.0) 9 (100.0) 44 (100.0) DID NOT COMPLETE 0 0 0 0 0 0 DID NOT MEET STUDY CRITERIA 0 0 0 0 0 0 ADVERSE EVENT 0 0 0 0 0 0 LOST TO FOLLOW-UP 0 0 0 0 0 0 PROTOCOL DEVIATION 0 0 0 0 0 0 WITHDRAWAL OF CONSENT 0 0 0 0 0 0 OTHER 0 0 0 0 0 0

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PERIOD 5 STARTED PERIOD 9 8 9 9 9 44 COMPLETED 9 (100.0) 8 (100.0) 9 (100.0) 9 (100.0) 9 (100.0) 44 (100.0) DID NOT COMPLETE 0 0 0 0 0 0 DID NOT MEET STUDY CRITERIA 0 0 0 0 0 0 ADVERSE EVENT 0 0 0 0 0 0 LOST TO FOLLOW-UP 0 0 0 0 0 0 PROTOCOL DEVIATION 0 0 0 0 0 0 WITHDRAWAL OF CONSENT 0 0 0 0 0 0 OTHER 0 0 0 0 0 0 ______(Page 5 of 6) Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.1.1.2 Subject Disposition By Treatment Group And Study Treatment Period All Screened Subjects Study Population: All Screened Subjects (N=150) ______non-SLS SLS negative Test Zinc-IPMP Test Zinc non-IPMP Positive control negative control control Overall n (%) n (%) n (%) n (%) n (%) n (%) ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ SAFETY POPULATION 45 (100.0) ITT POPULATION 45 (100.0) PP POPULATION 45 (100.0)

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______(Page 6 of 6) Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.1.2 Protocol Violations Leading To Exclusion From Per Protocol Analysis Intent to Treat Population Study Population: Intent to Treat (N=45) ______Test Zinc non-SLS SLS negative Test Zinc-IPMP non-IPMP Positive control negative control control Overall (N=44) (N=44) (N=45) (N=44) (N=44) (N=45) ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ PROTOCOL VIOLATIONS LEADING TO EXCLUSION N (%) %LIVE OUTSIDE THE RELIABLE RANGE 4 (9.1) 1 (2.3) 2 (4.4) 4 (9.1) 2 (4.5) 12 (26.7) CONSIDERED TO BE FROM -25 TO 150% BRUSHED TEETH ON MORNING OF VISIT. 0 1 (2.3) 0 0 0 1 (2.2) INITIAL TURBIDITY BELOW THE LOWER 30 (68.2) 30 (68.2) 31 (68.9) 29 (65.9) 30 (68.2) 43 (95.6) ACCEPTABLE LIMIT OF 0.18

NUMBER OF SUBJECTS WITH AT LEAST ONE PROTOCOL 33 (75.0) 31 (70.5) 32 (71.1) 29 (65.9) 30 (68.2) 45 (100.0) VIOLATION LEADING TO EXCLUSION N (%)

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 1 of 1) Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product). Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 28 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.2.1.1 Demographic and Baseline Characteristics Safety Population

Study Population: Safety (N=45) ______Overall (N=45) ______

SEX N (%) MALE 15 (33.3) FEMALE 30 (66.7)

RACE N (%) AMERICAN INDIAN OR ALASKA NATIVE 0 ASIAN 2 (4.4) BLACK OR AFRICAN AMERICAN 7 (15.6) NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER 0 WHITE 29 (64.4)

Document Version:1.0,CURRENT,Most-Recent,Effective MULTIPLE 7 (15.6)

OTHER 0

AGE (YEARS) N 45 MEAN 39.4 SD 12.60 MEDIAN 40.0 MINIMUM 20 MAXIMUM 72

______(Page 1 of 1)

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.2.1.2 Demographic and Baseline Characteristics Per Protocol Population

Study Population: PP (N=45) ______Overall (N=45) ______

SEX N (%) MALE 15 (33.3) FEMALE 30 (66.7)

RACE N (%) AMERICAN INDIAN OR ALASKA NATIVE 0 ASIAN 2 (4.4) BLACK OR AFRICAN AMERICAN 7 (15.6) NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER 0 WHITE 29 (64.4)

Document Version:1.0,CURRENT,Most-Recent,Effective MULTIPLE 7 (15.6)

OTHER 0

AGE (YEARS) N 45 MEAN 39.4 SD 12.60 MEDIAN 40.0 MINIMUM 20 MAXIMUM 72

______(Page 1 of 1)

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Page 30 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.1.1 Summary And Analysis Of Measurements Of Glycolysis By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ PRE-TREATMENT BASELINE N 25 20 20 27 23 MISSING 19 24 25 17 21 MEAN 5.59 5.62 5.59 5.67 5.61 SD 0.200 0.182 0.182 0.187 0.156 SE 0.040 0.041 0.041 0.036 0.033 MEDIAN 5.59 5.65 5.60 5.69 5.59 MINIMUM 5.3 5.3 5.2 5.3 5.3 MAXIMUM 6.1 5.9 5.9 6.1 6.0

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 1 of 4) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 31 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.1.1 Summary And Analysis Of Measurements Of Glycolysis By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 15 MINUTES N 22 14 23 14 25 16 21 17 18 16 MISSING 22 30 21 30 20 29 23 27 26 28 MEAN 6.16 0.56 6.17 0.51 6.03 0.39 5.66 0.07 6.11 0.48 SD 0.311 0.307 0.275 0.237 0.270 0.283 0.206 0.125 0.214 0.179 SE 0.066 0.082 0.057 0.063 0.054 0.071 0.045 0.030 0.051 0.045 MEDIAN 6.18 0.51 6.21 0.46 5.97 0.41 5.62 0.02 6.10 0.53 MINIMUM 5.5 -0.1 5.5 0.2 5.6 -0.1 5.3 -0.1 5.7 0.1 MAXIMUM 6.6 1.0 6.6 1.0 6.6 0.8 6.1 0.3 6.5 0.8

ADJUSTED MEAN (SE) [1] 0.54 (0.063) 0.50 (0.061) 0.40 (0.058) 0.05 (0.057) 0.48 (0.059)

Document Version:1.0,CURRENT,Most-Recent,Effective 95% CI [1] 0.42, 0.67 0.38, 0.63 0.28, 0.52 -0.06, 0.16 0.36, 0.59

______(Page 2 of 4) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 32 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.1.1 Summary And Analysis Of Measurements Of Glycolysis By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 45 MINUTES N 37 22 37 19 35 18 35 21 31 20 MISSING 7 22 7 25 10 27 9 23 13 24 MEAN 6.20 0.59 6.19 0.47 6.05 0.41 5.73 0.08 6.09 0.42 SD 0.189 0.209 0.270 0.274 0.224 0.265 0.209 0.138 0.227 0.262 SE 0.031 0.045 0.044 0.063 0.038 0.062 0.035 0.030 0.041 0.059 MEDIAN 6.18 0.59 6.28 0.55 6.04 0.38 5.73 0.10 6.12 0.38 MINIMUM 5.8 0.2 5.5 0.0 5.4 -0.1 5.3 -0.2 5.7 0.1 MAXIMUM 6.5 1.1 6.6 1.0 6.6 0.8 6.2 0.4 6.6 0.9

ADJUSTED MEAN (SE) [1] 0.60 (0.047) 0.50 (0.049) 0.40 (0.050) 0.06 (0.047) 0.44 (0.048)

Document Version:1.0,CURRENT,Most-Recent,Effective 95% CI [1] 0.50, 0.69 0.40, 0.59 0.30, 0.50 -0.03, 0.16 0.34, 0.53

______(Page 3 of 4) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 33 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.1.1 Summary And Analysis Of Measurements Of Glycolysis By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 90 MINUTES N 40 24 37 18 40 19 36 25 40 22 MISSING 4 20 7 26 5 26 8 19 4 22 MEAN 6.10 0.49 6.10 0.41 5.97 0.30 5.66 -0.05 6.03 0.34 SD 0.218 0.261 0.249 0.210 0.205 0.234 0.228 0.168 0.227 0.272 SE 0.034 0.053 0.041 0.049 0.032 0.054 0.038 0.034 0.036 0.058 MEDIAN 6.13 0.47 6.09 0.38 5.94 0.25 5.64 -0.09 6.05 0.40 MINIMUM 5.5 -0.2 5.5 0.1 5.6 -0.1 5.3 -0.5 5.5 -0.4 MAXIMUM 6.5 1.0 6.6 0.8 6.4 0.9 6.3 0.3 6.5 0.8

ADJUSTED MEAN (SE) [1] 0.46 (0.042) 0.42 (0.046) 0.29 (0.045) -0.02 (0.041) 0.35 (0.043)

Document Version:1.0,CURRENT,Most-Recent,Effective 95% CI [1] 0.38, 0.55 0.33, 0.51 0.20, 0.38 -0.11, 0.06 0.27, 0.44

______(Page 4 of 4) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 34 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.1.2 Treatment Comparisons Of Measurements Of Glycolysis By Timepoint Per Protocol Population Study Population: PP (N=45) ______DIFFERENCE (95% CI) [1,2] P-VALUE [1] ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 15 MINUTES TREATMENT COMPARISONS

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL 0.35 (0.20, 0.50) <.0001 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL 0.49 (0.33, 0.65) <.0001 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL 0.07 (-0.09, 0.23) 0.4007 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL 0.45 (0.30, 0.61) <.0001 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL 0.03 (-0.13, 0.19) 0.7021 TEST ZINC-IPMP VS. POSITIVE CONTROL 0.14 (-0.02, 0.31) 0.0853 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 0.04 (-0.13, 0.20) 0.6516 TEST ZINC NON-IPMP VS. POSITIVE CONTROL 0.11 (-0.05, 0.26) 0.1833 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL -0.08 (-0.23, 0.08) 0.3405 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL -0.42 (-0.58, -0.27) <.0001

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 1 of 3) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period-minus subject-level pre-treatment values as covariates in the model [2] Difference is first named treatment minus second named treatment such that a positive difference indicates a greater inhibition of plaque glycolysis for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 35 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL 0.33 (0.22, 0.45) <.0001 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL 0.53 (0.42, 0.65) <.0001 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL 0.16 (0.05, 0.27) 0.0053 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL 0.43 (0.32, 0.55) <.0001 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL 0.06 (-0.05, 0.17) 0.3006 TEST ZINC-IPMP VS. POSITIVE CONTROL 0.20 (0.08, 0.32) 0.0012 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 0.10 (-0.01, 0.21) 0.0816 TEST ZINC NON-IPMP VS. POSITIVE CONTROL 0.10 (-0.02, 0.21) 0.0901 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL -0.04 (-0.16, 0.08) 0.5069 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL -0.37 (-0.49, -0.26) <.0001

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 2 of 3) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period-minus subject-level pre-treatment values as covariates in the model [2] Difference is first named treatment minus second named treatment such that a positive difference indicates a greater inhibition of plaque glycolysis for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 36 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL 0.32 (0.21, 0.42) <.0001 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL 0.49 (0.39, 0.59) <.0001 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL 0.11 (0.01, 0.21) 0.0293 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL 0.45 (0.34, 0.55) <.0001 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL 0.07 (-0.03, 0.18) 0.1802 TEST ZINC-IPMP VS. POSITIVE CONTROL 0.17 (0.06, 0.28) 0.0022 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 0.04 (-0.07, 0.15) 0.4675 TEST ZINC NON-IPMP VS. POSITIVE CONTROL 0.13 (0.02, 0.24) 0.0204 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL -0.06 (-0.17, 0.05) 0.2774 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL -0.38 (-0.48, -0.27) <.0001

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 3 of 3) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period-minus subject-level pre-treatment values as covariates in the model [2] Difference is first named treatment minus second named treatment such that a positive difference indicates a greater inhibition of plaque glycolysis for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 37 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.1.3 Summary And Analysis Of AUCgly(0-90) Per Protocol Population Study Population: PP (N=45) ______non-SLS SLS negative Test Zinc-IPMP Test Zinc non-IPMP Positive control negative control control (N=44) (N=44) (N=45) (N=44) (N=44) ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ N 14 14 14 15 14 MISSING 30 30 31 29 30 MEAN 42.69 34.46 31.31 3.39 31.25 SD 13.449 13.590 18.530 7.883 17.693 SE 3.594 3.632 4.952 2.035 4.729 MEDIAN 44.06 37.65 27.41 3.23 29.29 MINIMUM 16.2 11.1 -6.3 -8.3 -1.0 MAXIMUM 60.2 54.0 61.3 17.5 66.8 ADJUSTED MEAN (SE) [1] 42.64 (3.437) 34.20 (3.354) 28.88 (3.384) 2.46 (3.303) 31.78 (3.512) 95% CI [1] 35.76, 49.52 27.48, 40.92 22.10, 35.65 -4.15, 9.08 24.75, 38.81

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 1 of 2) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. [2] Difference is first named treatment minus second named treatment such that a positive difference indicates a greater inhibition of plaque glycolysis for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 38 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.1.3 Summary And Analysis Of AUCgly(0-90) Per Protocol Population Study Population: PP (N=45) ______

ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ TREATMENT COMPARISONS DIFFERENCE (95% CI) [1,2] P-VALUE [1]

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL 26.41 (18.94, 33.88) <.0001 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL 40.18 (32.37, 47.99) <.0001 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL 10.86 (3.13, 18.59) 0.0072 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL 31.74 (24.18, 39.30) <.0001 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL 2.42 (-5.08, 9.92) 0.5174 TEST ZINC-IPMP VS. POSITIVE CONTROL 13.77 (6.01, 21.53) 0.0009 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 8.44 (0.93, 15.95) 0.0286 TEST ZINC NON-IPMP VS. POSITIVE CONTROL 5.32 (-2.15, 12.79) 0.1573 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL -2.91 (-11.18, 5.37) 0.4823 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL -29.32 (-37.20, -21.43) <.0001

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 2 of 2) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. [2] Difference is first named treatment minus second named treatment such that a positive difference indicates a greater inhibition of plaque glycolysis for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 39 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.2 Summary And Analysis Of AUCgly(0-90): Subgroup Analysis by Pre-Study Baseline pH Level Per Protocol Population Study Population: PP (N=45) ______non-SLS SLS negative Test Zinc-IPMP Test Zinc non-IPMP Positive control negative control control (N=44) (N=44) (N=45) (N=44) (N=44) ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ PRE-STUDY BASELINE PH <= MEDIAN

N 9 9 8 9 7 MISSING 14 14 15 14 16 MEAN 41.46 33.08 28.02 1.80 27.67 SD 15.444 15.144 18.529 7.517 20.699 SE 5.148 5.048 6.551 2.506 7.824 MEDIAN 41.25 36.97 27.41 -0.30 29.10 MINIMUM 16.2 11.1 -6.3 -5.4 -1.0 MAXIMUM 60.2 54.0 54.6 17.5 66.8 ADJUSTED MEAN (SE) [1] 36.15 (4.497) 29.58 (4.334) 22.54 (4.649) -2.70 (4.445) 27.08 (4.826)

Document Version:1.0,CURRENT,Most-Recent,Effective 95% CI [1] 27.12, 45.19 20.87, 38.29 13.21, 31.87 -11.63, 6.22 17.40, 36.75

______(Page 1 of 4) [1] Obtained from ANCOVA including period, treatment, baseline pH group (low, high) and interaction between treatment and baseline pH group as fixed effects,subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. [2] Difference is first named treatment minus second named treatment such that a positive difference indicates a greater inhibition of plaque glycolysis for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 40 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL 25.25 (15.69, 34.80) <.0001 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL 38.86 (28.67, 49.05) <.0001 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL 9.08 (-2.39, 20.54) 0.1173 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL 32.29 (22.62, 41.95) <.0001 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL 2.51 (-7.91, 12.92) 0.6280 TEST ZINC-IPMP VS. POSITIVE CONTROL 13.61 (3.70, 23.53) 0.0087 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 6.57 (-2.92, 16.07) 0.1677 TEST ZINC NON-IPMP VS. POSITIVE CONTROL 7.04 (-2.76, 16.84) 0.1529 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL -4.53 (-15.81, 6.74) 0.4200 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL -29.78 (-40.17, -19.39) <.0001

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 2 of 4) [1] Obtained from ANCOVA including period, treatment, baseline pH group (low, high) and interaction between treatment and baseline pH group as fixed effects,subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. [2] Difference is first named treatment minus second named treatment such that a positive difference indicates a greater inhibition of plaque glycolysis for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 41 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

N 5 5 6 6 7 MISSING 16 16 16 15 14 MEAN 44.90 36.94 35.70 5.78 34.83 SD 10.066 11.379 19.279 8.498 14.831 SE 4.502 5.089 7.871 3.469 5.606 MEDIAN 44.70 41.77 33.98 8.63 29.33 MINIMUM 31.1 17.3 12.8 -8.3 13.6 MAXIMUM 59.4 44.9 61.3 15.8 51.6 ADJUSTED MEAN (SE) [1] 51.23 (5.653) 38.89 (5.644) 35.24 (5.274) 8.49 (5.429) 37.74 (5.442)

Document Version:1.0,CURRENT,Most-Recent,Effective 95% CI [1] 39.90, 62.56 27.58, 50.21 24.67, 45.82 -2.40, 19.38 26.82, 48.65

______(Page 3 of 4) [1] Obtained from ANCOVA including period, treatment, baseline pH group (low, high) and interaction between treatment and baseline pH group as fixed effects,subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. [2] Difference is first named treatment minus second named treatment such that a positive difference indicates a greater inhibition of plaque glycolysis for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 42 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL 26.75 (13.77, 39.73) 0.0001 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL 42.74 (29.17, 56.31) <.0001 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL 13.50 (0.81, 26.18) 0.0377 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL 30.40 (16.38, 44.42) <.0001 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL 1.16 (-10.99, 13.31) 0.8478 TEST ZINC-IPMP VS. POSITIVE CONTROL 15.99 (2.01, 29.97) 0.0260 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 12.34 (-1.78, 26.46) 0.0849 TEST ZINC NON-IPMP VS. POSITIVE CONTROL 3.65 (-10.01, 17.30) 0.5923 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL -2.49 (-16.45, 11.46) 0.7210 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL -29.24 (-42.79, -15.69) <.0001

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 4 of 4) [1] Obtained from ANCOVA including period, treatment, baseline pH group (low, high) and interaction between treatment and baseline pH group as fixed effects,subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. [2] Difference is first named treatment minus second named treatment such that a positive difference indicates a greater inhibition of plaque glycolysis for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 43 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.3.1 Summary And Analysis Of Measurements Of Regrowth Ratio By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ PRE-TREATMENT BASELINE N 25 20 20 27 23 MISSING 19 24 25 17 21 MEAN 8.06 8.99 9.03 8.51 8.45 SD 3.252 3.854 2.859 2.496 3.032 SE 0.650 0.862 0.639 0.480 0.632 MEDIAN 7.34 8.11 8.32 8.63 7.99 MINIMUM 2.4 4.1 4.6 4.2 3.7 MAXIMUM 17.4 21.0 15.9 12.7 15.7

Document Version:1.0,CURRENT,Most-Recent,Effective

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Page 44 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.3.1 Summary And Analysis Of Measurements Of Regrowth Ratio By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 15 MINUTES N 22 14 23 14 25 16 21 17 18 16 MISSING 22 30 21 30 20 29 23 27 26 28 MEAN 4.97 -3.54 4.89 -3.35 5.47 -2.79 10.09 1.04 5.00 -3.50 SD 2.215 4.558 2.306 4.523 1.989 2.608 3.193 1.837 2.363 3.375 SE 0.472 1.218 0.481 1.209 0.398 0.652 0.697 0.446 0.557 0.844 MEDIAN 4.65 -2.13 4.35 -2.94 5.25 -2.72 9.64 1.14 4.47 -2.26 MINIMUM 1.8 -15.0 2.6 -14.4 2.1 -9.5 4.7 -1.7 2.5 -12.0 MAXIMUM 10.1 4.0 12.4 2.0 10.3 0.8 15.4 4.0 10.1 0.5

ADJUSTED MEAN (SE) [1] -3.08 (0.660) -3.56 (0.644) -3.18 (0.610) 1.25 (0.595) -3.95 (0.611)

Document Version:1.0,CURRENT,Most-Recent,Effective 95% CI [1] -4.39, -1.76 -4.85, -2.28 -4.40, -1.96 0.06, 2.44 -5.17, -2.72

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Page 45 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.3.1 Summary And Analysis Of Measurements Of Regrowth Ratio By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 45 MINUTES N 37 22 37 19 35 18 35 21 31 20 MISSING 7 22 7 25 10 27 9 23 13 24 MEAN 5.21 -3.03 4.92 -3.31 5.92 -2.14 8.12 -0.34 5.60 -2.58 SD 1.787 3.178 2.159 3.873 2.460 3.221 2.492 2.867 2.107 3.986 SE 0.294 0.678 0.355 0.888 0.416 0.759 0.421 0.626 0.379 0.891 MEDIAN 4.83 -2.45 4.39 -2.35 5.73 -1.99 8.32 -0.90 5.36 -2.72 MINIMUM 2.4 -12.7 1.7 -14.3 2.6 -10.2 3.4 -4.1 2.7 -13.0 MAXIMUM 9.4 1.8 10.4 2.9 14.4 4.4 12.8 5.5 11.5 5.2

ADJUSTED MEAN (SE) [1] -2.94 (0.491) -3.42 (0.512) -2.02 (0.529) 0.01 (0.492) -2.84 (0.501)

Document Version:1.0,CURRENT,Most-Recent,Effective 95% CI [1] -3.92, -1.96 -4.44, -2.40 -3.07, -0.97 -0.97, 0.99 -3.84, -1.85

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Page 46 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.3.1 Summary And Analysis Of Measurements Of Regrowth Ratio By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 90 MINUTES N 40 24 37 18 40 19 36 25 40 22 MISSING 4 20 7 26 5 26 8 19 4 22 MEAN 5.21 -2.76 5.72 -2.31 6.26 -2.12 9.35 1.20 5.85 -1.92 SD 1.798 3.744 2.789 4.657 2.110 3.286 2.921 2.846 2.439 3.547 SE 0.284 0.764 0.459 1.098 0.334 0.754 0.487 0.569 0.386 0.756 MEDIAN 4.95 -2.63 4.85 -1.36 5.73 -2.28 9.65 1.15 5.20 -2.78 MINIMUM 2.2 -15.2 2.0 -14.9 2.7 -8.2 4.0 -3.0 2.0 -11.7 MAXIMUM 10.2 1.9 16.4 5.0 12.2 2.3 16.6 7.4 13.0 5.0

ADJUSTED MEAN (SE) [1] -2.96 (0.524) -1.97 (0.581) -1.87 (0.574) 1.11 (0.507) -2.09 (0.533)

Document Version:1.0,CURRENT,Most-Recent,Effective 95% CI [1] -4.00, -1.92 -3.12, -0.81 -3.01, -0.73 0.10, 2.12 -3.15, -1.03

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Page 47 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.3.2 Treatment Comparisons Of Measurements of Regrowth Ratio By Timepoint Per Protocol Population Study Population: PP (N=45) ______DIFFERENCE (95% CI) [1,2] P-VALUE [1] ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 15 MINUTES TREATMENT COMPARISONS

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL -4.43 (-5.98, -2.89) <.0001 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL -4.33 (-5.96, -2.70) <.0001 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL 0.87 (-0.75, 2.49) 0.2863 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL -4.81 (-6.41, -3.22) <.0001 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL 0.38 (-1.19, 1.96) 0.6260 TEST ZINC-IPMP VS. POSITIVE CONTROL 0.11 (-1.54, 1.75) 0.8980 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 0.48 (-1.19, 2.16) 0.5632 TEST ZINC NON-IPMP VS. POSITIVE CONTROL -0.38 (-1.96, 1.21) 0.6336 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL 0.76 (-0.81, 2.34) 0.3363 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL 5.20 (3.64, 6.75) <.0001

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 1 of 3) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period-minus subject-level pre-treatment values as covariates in the model [2] Difference is first named treatment minus second named treatment such that a negative difference indicates a greater inhibition of plaque regrowth for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 48 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL -2.03 (-3.33, -0.73) 0.0027 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL -2.95 (-4.22, -1.68) <.0001 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL -0.10 (-1.35, 1.16) 0.8785 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL -3.43 (-4.73, -2.13) <.0001 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL -0.58 (-1.86, 0.70) 0.3710 TEST ZINC-IPMP VS. POSITIVE CONTROL -0.92 (-2.23, 0.40) 0.1685 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 0.48 (-0.80, 1.76) 0.4556 TEST ZINC NON-IPMP VS. POSITIVE CONTROL -1.40 (-2.71, -0.08) 0.0376 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL 0.82 (-0.52, 2.16) 0.2269 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL 2.85 (1.57, 4.13) <.0001

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 2 of 3) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period-minus subject-level pre-treatment values as covariates in the model [2] Difference is first named treatment minus second named treatment such that a negative difference indicates a greater inhibition of plaque regrowth for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 49 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL -2.98 (-4.34, -1.62) <.0001 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL -4.07 (-5.34, -2.81) <.0001 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL -0.87 (-2.16, 0.42) 0.1814 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL -3.08 (-4.44, -1.71) <.0001 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL 0.12 (-1.26, 1.50) 0.8604 TEST ZINC-IPMP VS. POSITIVE CONTROL -1.09 (-2.47, 0.28) 0.1175 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP -1.00 (-2.38, 0.39) 0.1553 TEST ZINC NON-IPMP VS. POSITIVE CONTROL -0.10 (-1.53, 1.33) 0.8917 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL 0.22 (-1.18, 1.62) 0.7546 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL 3.20 (1.93, 4.48) <.0001

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 3 of 3) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period-minus subject-level pre-treatment values as covariates in the model [2] Difference is first named treatment minus second named treatment such that a negative difference indicates a greater inhibition of plaque regrowth for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 50 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.3.3 Summary And Analysis Of AUCregrowth(0-90) Per Protocol Population Study Population: PP (N=45) ______non-SLS SLS negative Test Zinc-IPMP Test Zinc non-IPMP Positive control negative control control (N=44) (N=44) (N=45) (N=44) (N=44) ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ N 14 14 14 15 14 MISSING 30 30 31 29 30 MEAN -270.93 -232.81 -175.98 16.21 -202.25 SD 327.720 346.694 199.795 150.002 313.532 SE 87.587 92.658 53.397 38.730 83.795 MEDIAN -155.68 -145.69 -165.54 -15.71 -187.54 MINIMUM -1157.3 -1195.9 -485.7 -213.3 -1020.5 MAXIMUM 178.9 130.7 147.3 275.3 260.8 ADJUSTED MEAN (SE) [1] -239.81 (40.122) -240.86 (39.118) -179.55 (39.415) 53.66 (38.443) -215.08 (40.350) 95% CI [1] -320.06, -159.55 -319.12, -162.61 -258.40, -100.71 -23.23, 130.56 -295.79, -134.37

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 1 of 2) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. [2] Difference is first named treatment minus second named treatment such that a negative difference indicates a greater inhibition of plaque regrowth for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 51 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.3.3 Summary And Analysis Of AUCregrowth(0-90) Per Protocol Population Study Population: PP (N=45) ______

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL -233.22 (-332.88, -133.55) <.0001 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL -293.47 (-396.03, -190.91) <.0001 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL -24.73 (-128.07, 78.61) 0.6325 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL -294.53 (-395.43, -193.62) <.0001 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL -25.78 (-126.53, 74.96) 0.6086 TEST ZINC-IPMP VS. POSITIVE CONTROL -60.26 (-162.72, 42.21) 0.2427 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 1.05 (-100.50, 102.61) 0.9834 TEST ZINC NON-IPMP VS. POSITIVE CONTROL -61.31 (-161.14, 38.52) 0.2226 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL 35.53 (-69.90, 140.96) 0.5018 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL 268.74 (165.98, 371.51) <.0001

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 2 of 2) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. [2] Difference is first named treatment minus second named treatment such that a negative difference indicates a greater inhibition of plaque regrowth for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 52 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.4.1 Summary And Analysis Of Measurements of Live:Dead Stain Ratio By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ PRE-TREATMENT BASELINE N 19 16 17 26 21 MISSING 25 28 28 18 23 MEAN 58.01 76.58 70.83 67.69 67.10 SD 25.221 27.037 27.120 28.454 34.254 SE 5.786 6.759 6.578 5.580 7.475 MEDIAN 56.84 78.77 62.08 67.60 60.52 MINIMUM 15.2 25.2 21.4 19.2 -2.7 MAXIMUM 134.8 121.8 117.9 143.6 131.7

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Page 53 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.4.1 Summary And Analysis Of Measurements of Live:Dead Stain Ratio By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 15 MINUTES N 19 9 22 10 22 13 20 16 17 14 MISSING 25 35 22 34 23 32 24 28 27 30 MEAN 53.54 -9.80 44.13 -12.43 54.94 -9.02 73.21 -2.41 47.03 -23.73 SD 27.388 27.018 29.662 22.338 31.423 21.672 27.274 27.653 34.909 29.518 SE 6.283 9.006 6.324 7.064 6.699 6.011 6.099 6.913 8.467 7.889 MEDIAN 53.38 -12.90 36.09 -15.07 48.25 -12.97 71.05 2.59 43.01 -20.45 MINIMUM 1.6 -37.9 7.7 -36.9 10.8 -40.1 25.9 -47.7 1.2 -81.9 MAXIMUM 110.3 42.2 118.4 31.0 121.4 28.3 122.6 42.7 140.9 15.8

ADJUSTED MEAN (SE) [1] -7.87 (7.964) -11.45 (7.148) -9.18 (6.395) -0.48 (5.706) -23.69 (6.087)

Document Version:1.0,CURRENT,Most-Recent,Effective 95% CI [1] -23.86, 8.12 -25.80, 2.91 -22.02, 3.66 -11.93, 10.98 -35.91, -11.47

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Page 54 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.4.1 Summary And Analysis Of Measurements of Live:Dead Stain Ratio By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 45 MINUTES N 35 17 36 15 31 15 35 21 29 18 MISSING 9 27 8 29 14 30 9 23 15 26 MEAN 57.77 -0.77 48.48 -17.41 61.93 3.03 72.53 6.88 54.74 -7.32 SD 24.116 38.146 23.446 28.073 30.286 27.368 31.991 40.375 22.640 37.557 SE 4.076 9.252 3.908 7.248 5.439 7.066 5.407 8.810 4.204 8.852 MEDIAN 56.44 -2.77 46.94 -17.47 64.81 2.66 70.55 3.86 53.09 -2.45 MINIMUM 8.6 -95.1 8.3 -69.0 2.4 -50.3 7.2 -53.2 6.9 -100.0 MAXIMUM 118.7 67.7 116.0 21.7 115.5 62.4 146.3 110.5 98.2 70.8

ADJUSTED MEAN (SE) [1] -11.88 (6.383) -9.44 (6.607) 7.10 (6.649) 6.76 (5.616) -11.93 (5.999)

Document Version:1.0,CURRENT,Most-Recent,Effective 95% CI [1] -24.59, 0.84 -22.61, 3.72 -6.14, 20.35 -4.43, 17.95 -23.88, 0.02

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Page 55 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.4.1 Summary And Analysis Of Measurements of Live:Dead Stain Ratio By Timepoint Per Protocol Population Study Population: PP (N=45) ______Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) Observed Change Observed Change Observed Change Observed Change Observed Change ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 90 MINUTES N 37 18 36 14 36 16 33 23 37 20 MISSING 7 26 8 30 9 29 11 21 7 24 MEAN 60.63 5.91 52.48 -20.72 60.27 -1.47 74.37 4.77 61.00 -7.27 SD 30.962 29.004 21.315 15.908 26.897 29.661 30.536 36.434 30.581 26.915 SE 5.090 6.836 3.552 4.252 4.483 7.415 5.316 7.597 5.027 6.018 MEDIAN 58.47 1.51 54.21 -22.64 61.67 0.99 79.32 4.26 64.06 -5.13 MINIMUM 3.6 -36.2 7.2 -47.9 -0.3 -62.6 16.3 -77.5 5.1 -55.8 MAXIMUM 128.8 60.2 95.6 0.8 118.7 65.6 135.2 106.3 136.9 34.0

ADJUSTED MEAN (SE) [1] 1.60 (5.771) -13.33 (6.315) -1.94 (5.993) 8.67 (4.986) -8.16 (5.330)

Document Version:1.0,CURRENT,Most-Recent,Effective 95% CI [1] -9.89, 13.08 -25.90, -0.76 -13.87, 9.98 -1.26, 18.60 -18.77, 2.44

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Page 56 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.4.2 Treatment Comparisons Of Measurements of Live:Dead Stain Ratio By Timepoint Per Protocol Population Study Population: PP (N=45) ______DIFFERENCE (95% CI) [1,2] P-VALUE [1] ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 15 MINUTES TREATMENT COMPARISONS

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL -8.71 (-25.60, 8.19) 0.3042 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL -7.39 (-26.70, 11.92) 0.4439 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL 15.82 (-3.35, 35.00) 0.1032 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL -10.97 (-29.13, 7.19) 0.2295 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL 12.25 (-5.62, 30.12) 0.1731 TEST ZINC-IPMP VS. POSITIVE CONTROL 1.31 (-18.96, 21.58) 0.8970 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 3.57 (-17.08, 24.23) 0.7284 TEST ZINC NON-IPMP VS. POSITIVE CONTROL -2.26 (-20.88, 16.35) 0.8073 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL 14.51 (-2.72, 31.74) 0.0966 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL 23.22 (6.93, 39.51) 0.0064

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 1 of 3) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period-minus subject-level pre-treatment values as covariates in the model [2] Difference is first named treatment minus second named treatment such that a negative difference indicates a smaller live:dead stain ratio for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL 0.34 (-15.92, 16.60) 0.9668 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL -18.64 (-34.50, -2.78) 0.0220 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL 0.05 (-16.04, 16.15) 0.9947 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL -16.21 (-32.66, 0.25) 0.0534 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL 2.49 (-14.12, 19.10) 0.7654 TEST ZINC-IPMP VS. POSITIVE CONTROL -18.98 (-36.46, -1.50) 0.0338 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP -2.43 (-19.81, 14.94) 0.7804 TEST ZINC NON-IPMP VS. POSITIVE CONTROL -16.55 (-33.99, 0.90) 0.0626 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL 19.03 (2.22, 35.85) 0.0272 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL 18.69 (3.25, 34.13) 0.0185

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 2 of 3) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period-minus subject-level pre-treatment values as covariates in the model [2] Difference is first named treatment minus second named treatment such that a negative difference indicates a smaller live:dead stain ratio for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 58 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL -10.62 (-24.93, 3.70) 0.1432 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL -7.07 (-21.04, 6.89) 0.3150 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL 9.76 (-4.33, 23.85) 0.1707 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL -22.00 (-36.78, -7.22) 0.0042 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL -5.17 (-20.09, 9.76) 0.4909 TEST ZINC-IPMP VS. POSITIVE CONTROL 3.54 (-11.91, 18.99) 0.6487 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 14.93 (-0.94, 30.80) 0.0648 TEST ZINC NON-IPMP VS. POSITIVE CONTROL -11.39 (-27.51, 4.74) 0.1629 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL 6.22 (-8.68, 21.12) 0.4075 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL 16.84 (3.69, 29.99) 0.0130

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 3 of 3) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period-minus subject-level pre-treatment values as covariates in the model [2] Difference is first named treatment minus second named treatment such that a negative difference indicates a smaller live:dead stain ratio for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.4.3 Summary And Analysis Of AUClive:dead(0-90) Per Protocol Population Study Population: PP (N=45) ______non-SLS SLS negative Test Zinc-IPMP Test Zinc non-IPMP Positive control negative control control (N=44) (N=44) (N=45) (N=44) (N=44) ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ N 9 10 11 14 12 MISSING 35 34 34 30 32 MEAN 96.35 -1172.55 -140.11 96.65 -788.88 SD 3104.242 1633.931 1616.516 2719.817 2502.121 SE 1034.747 516.694 487.398 726.902 722.300 MEDIAN -79.48 -1079.78 30.25 60.82 -453.62 MINIMUM -4714.4 -4370.6 -2080.5 -3581.6 -6412.4 MAXIMUM 4845.4 998.6 3840.5 7496.8 3021.5 ADJUSTED MEAN (SE) [1] 75.23 (568.834) -691.41 (508.108) 72.19 (491.718) 346.11 (431.974) -601.87 (499.740) 95% CI [1] -1070.51, 1220.96 -1715.07, 332.25 -918.20, 1062.58 -524.07, 1216.28 -1608.64, 404.90

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 1 of 2) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. [2] Difference is first named treatment minus second named treatment such that a negative difference indicates a smaller live:dead stain ratio for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 60 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.3.4.3 Summary And Analysis Of AUClive:dead(0-90) Per Protocol Population Study Population: PP (N=45) ______

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL -273.92 (-1550.45, 1002.61) 0.6664 TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL -270.88 (-1680.58, 1138.82) 0.6998 TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL 677.09 (-784.16, 2138.35) 0.3544 TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL -1037.52 (-2361.33, 286.29) 0.1210 TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL -89.54 (-1439.50, 1260.41) 0.8935 TEST ZINC-IPMP VS. POSITIVE CONTROL 3.04 (-1469.45, 1475.52) 0.9967 TEST ZINC-IPMP VS. TEST ZINC NON-IPMP 766.64 (-703.26, 2236.54) 0.2976 TEST ZINC NON-IPMP VS. POSITIVE CONTROL -763.60 (-2144.45, 617.25) 0.2702 POSITIVE CONTROL VS. SLS NEGATIVE CONTROL 674.06 (-692.21, 2040.33) 0.3249 NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL 947.97 (-361.95, 2257.90) 0.1511

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 2 of 2) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period minus subject-level pre-treatment values as covariates in the model. [2] Difference is first named treatment minus second named treatment such that a negative difference indicates a smaller live:dead stain ratio for the first named treatment. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® - Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product) Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

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Page 61 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.2 Treatment Emergent Treatment Related Adverse Events Safety Population

Study Population: Safety (N=45) ______non-SLS negative con Test Zinc-IPMP Test Zinc non-IPMP Positive control trol SLS negative control (N=44) (N=44) (N=45) (N=44) (N=44) ______n (%) nAE n (%) nAE n (%) nAE n (%) nAE n (%) nAE ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ

NUMBER OF SUBJECTS WITH AT LEAST ONE AE 1 ( 2.3) 1 0 0 0 0 0 0 1 ( 2.3) 1 NUMBER OF SUBJECTS WITH no AE 43 ( 97.7) 44 (100.0) 45 (100.0) 44 (100.0) 43 ( 97.7)

ORAL 1 ( 2.3) 1 0 0 0 0 0 0 1 ( 2.3) 1 PARAESTHESIA ORAL 1 ( 2.3) 1 0 0 0 0 0 0 1 ( 2.3) 1

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 1 of 2) n (%) = Number (percent) of subjects nAE = Number of adverse events. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

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Page 73 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.2 Treatment Emergent Treatment Related Adverse Events Safety Population

Study Population: Safety (N=45) ______Overall (N=45) ______n (%) nAE ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ

NUMBER OF SUBJECTS WITH AT LEAST ONE AE 2 ( 4.4) 2 NUMBER OF SUBJECTS WITH no AE 43 ( 95.6)

ORAL 2 ( 4.4) 2 PARAESTHESIA ORAL 2 ( 4.4) 2

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 2 of 2) n (%) = Number (percent) of subjects nAE = Number of adverse events. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

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Page 74 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.3 Treatment Emergent Adverse Events Safety Population

NUMBER OF SUBJECTS WITH AT LEAST ONE AE 8 ( 18.2) 10 6 ( 13.6) 6 6 ( 13.3) 9 3 ( 6.8) 3 2 ( 4.5) 6 NUMBER OF SUBJECTS WITH no AE 36 ( 81.8) 38 ( 86.4) 39 ( 86.7) 41 ( 93.2) 42 ( 95.5)

ORAL 6 ( 13.6) 7 4 ( 9.1) 4 4 ( 8.9) 4 0 0 1 ( 2.3) 5 LIP ULCERATION 2 ( 4.5) 3 0 0 0 0 0 0 0 0 MOUTH ULCERATION 1 ( 2.3) 1 0 0 0 0 0 0 0 0 PARAESTHESIA ORAL 1 ( 2.3) 1 0 0 0 0 0 0 1 ( 2.3) 1

Document Version:1.0,CURRENT,Most-Recent,Effective TOOTHACHE 1 ( 2.3) 1 0 0 0 0 0 0 0 0

TRAUMATIC ULCER 1 ( 2.3) 1 0 0 1 ( 2.2) 1 0 0 0 0 COATING IN MOUTH 0 0 1 ( 2.3) 1 0 0 0 0 0 0 DEVICE FAILURE 0 0 0 0 0 0 0 0 1 ( 2.3) 3 GINGIVAL ULCERATION 0 0 1 ( 2.3) 1 0 0 0 0 0 0 ORAL HERPES 0 0 1 ( 2.3) 1 0 0 0 0 0 0 OROPHARYNGEAL PAIN 0 0 0 0 2 ( 4.4) 2 0 0 0 0 PERICORONITIS 0 0 1 ( 2.3) 1 1 ( 2.2) 1 0 0 0 0 TOOTH FRACTURE 0 0 0 0 0 0 0 0 1 ( 2.3) 1

NON ORAL 2 ( 4.5) 3 2 ( 4.5) 2 4 ( 8.9) 5 3 ( 6.8) 3 1 ( 2.3) 1 HEADACHE 1 ( 2.3) 1 0 0 1 ( 2.2) 1 1 ( 2.3) 1 0 0 NAUSEA 1 ( 2.3) 1 0 0 0 0 0 0 0 0 RHINITIS 1 ( 2.3) 1 1 ( 2.3) 1 2 ( 4.4) 2 2 ( 4.5) 2 1 ( 2.3) 1 ______(Page 1 of 4) n (%) = Number (percent) of subjects nAE = Number of adverse events. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

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Page 75 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.3 Treatment Emergent Adverse Events Safety Population

LACERATION 0 0 1 ( 2.3) 1 0 0 0 0 0 0 LIGAMENT SPRAIN 0 0 0 0 1 ( 2.2) 1 0 0 0 0 SUPERFICIAL INJURY OF EYE 0 0 0 0 1 ( 2.2) 1 0 0 0 0

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 2 of 4) n (%) = Number (percent) of subjects nAE = Number of adverse events. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

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Page 76 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.3 Treatment Emergent Adverse Events Safety Population

NUMBER OF SUBJECTS WITH AT LEAST ONE AE 18 ( 40.0) 34 NUMBER OF SUBJECTS WITH no AE 27 ( 60.0)

ORAL 11 ( 24.4) 20 LIP ULCERATION 2 ( 4.4) 3 MOUTH ULCERATION 1 ( 2.2) 1 PARAESTHESIA ORAL 2 ( 4.4) 2 TOOTHACHE 1 ( 2.2) 1

Document Version:1.0,CURRENT,Most-Recent,Effective TRAUMATIC ULCER 2 ( 4.4) 2

COATING IN MOUTH 1 ( 2.2) 1 DEVICE FAILURE 1 ( 2.2) 3 GINGIVAL ULCERATION 1 ( 2.2) 1 ORAL HERPES 1 ( 2.2) 1 OROPHARYNGEAL PAIN 2 ( 4.4) 2 PERICORONITIS 2 ( 4.4) 2 TOOTH FRACTURE 1 ( 2.2) 1

NON ORAL 11 ( 24.4) 14 HEADACHE 3 ( 6.7) 3 NAUSEA 1 ( 2.2) 1 RHINITIS 6 ( 13.3) 7 LACERATION 1 ( 2.2) 1 ______(Page 3 of 4) n (%) = Number (percent) of subjects nAE = Number of adverse events. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

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Page 77 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.3 Treatment Emergent Adverse Events Safety Population

LIGAMENT SPRAIN 1 ( 2.2) 1 SUPERFICIAL INJURY OF EYE 1 ( 2.2) 1

Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 4 of 4) n (%) = Number (percent) of subjects nAE = Number of adverse events. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

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Page 78 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.4 Treatment Emergent Treatment Related Adverse Events Safety Population

NUMBER OF SUBJECTS WITH AT LEAST ONE AE 1 ( 2.3) 1 0 0 0 0 0 0 1 ( 2.3) 1 NUMBER OF SUBJECTS WITH NO AE 43 ( 97.7) 44 (100.0) 45 (100.0) 44 (100.0) 43 ( 97.7)

GASTROINTESTINAL DISORDERS 1 ( 2.3) 1 0 0 0 0 0 0 1 ( 2.3) 1 PARAESTHESIA ORAL 1 ( 2.3) 1 0 0 0 0 0 0 1 ( 2.3) 1

Document Version:1.0,CURRENT,Most-Recent,Effective

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Page 79 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.4 Treatment Emergent Treatment Related Adverse Events Safety Population

NUMBER OF SUBJECTS WITH AT LEAST ONE AE 2 ( 4.4) 2 NUMBER OF SUBJECTS WITH NO AE 43 ( 95.6)

GASTROINTESTINAL DISORDERS 2 ( 4.4) 2 PARAESTHESIA ORAL 2 ( 4.4) 2

Document Version:1.0,CURRENT,Most-Recent,Effective

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Page 80 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.5 Treatment Emergent Adverse Events by SOC and Preferred Term Safety Population

NUMBER OF SUBJECTS WITH AT LEAST ONE AE 8 ( 18.2) 10 6 ( 13.6) 6 6 ( 13.3) 9 3 ( 6.8) 3 2 ( 4.5) 6 NUMBER OF SUBJECTS WITH NO AE 36 ( 81.8) 38 ( 86.4) 39 ( 86.7) 41 ( 93.2) 42 ( 95.5)

GASTROINTESTINAL DISORDERS 6 ( 13.6) 7 2 ( 4.5) 2 0 0 0 0 1 ( 2.3) 1 LIP ULCERATION 2 ( 4.5) 3 0 0 0 0 0 0 0 0 MOUTH ULCERATION 1 ( 2.3) 1 0 0 0 0 0 0 0 0 NAUSEA 1 ( 2.3) 1 0 0 0 0 0 0 0 0

Document Version:1.0,CURRENT,Most-Recent,Effective PARAESTHESIA ORAL 1 ( 2.3) 1 0 0 0 0 0 0 1 ( 2.3) 1

TOOTHACHE 1 ( 2.3) 1 0 0 0 0 0 0 0 0 COATING IN MOUTH 0 0 1 ( 2.3) 1 0 0 0 0 0 0 GINGIVAL ULCERATION 0 0 1 ( 2.3) 1 0 0 0 0 0 0

INFECTIONS AND INFESTATIONS 1 ( 2.3) 1 3 ( 6.8) 3 3 ( 6.7) 3 2 ( 4.5) 2 1 ( 2.3) 1 RHINITIS 1 ( 2.3) 1 1 ( 2.3) 1 2 ( 4.4) 2 2 ( 4.5) 2 1 ( 2.3) 1 ORAL HERPES 0 0 1 ( 2.3) 1 0 0 0 0 0 0 PERICORONITIS 0 0 1 ( 2.3) 1 1 ( 2.2) 1 0 0 0 0

INJURY, POISONING AND PROCEDURAL 1 ( 2.3) 1 1 ( 2.3) 1 3 ( 6.7) 3 0 0 1 ( 2.3) 1 COMPLICATIONS TRAUMATIC ULCER 1 ( 2.3) 1 0 0 1 ( 2.2) 1 0 0 0 0 LACERATION 0 0 1 ( 2.3) 1 0 0 0 0 0 0 ______(Page 1 of 4) n (%) = Number (percent) of subjects nAE = Number of adverse events. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

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Page 81 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.5 Treatment Emergent Adverse Events by SOC and Preferred Term Safety Population

LIGAMENT SPRAIN 0 0 0 0 1 ( 2.2) 1 0 0 0 0 SUPERFICIAL INJURY OF EYE 0 0 0 0 1 ( 2.2) 1 0 0 0 0 TOOTH FRACTURE 0 0 0 0 0 0 0 0 1 ( 2.3) 1

NERVOUS SYSTEM DISORDERS 1 ( 2.3) 1 0 0 1 ( 2.2) 1 1 ( 2.3) 1 0 0 HEADACHE 1 ( 2.3) 1 0 0 1 ( 2.2) 1 1 ( 2.3) 1 0 0

Document Version:1.0,CURRENT,Most-Recent,Effective GENERAL DISORDERS AND ADMINISTRATION 0 0 0 0 0 0 0 0 1 ( 2.3) 3

SITE CONDITIONS DEVICE FAILURE 0 0 0 0 0 0 0 0 1 ( 2.3) 3

RESPIRATORY, THORACIC AND MEDIASTINAL 0 0 0 0 2 ( 4.4) 2 0 0 0 0 DISORDERS OROPHARYNGEAL PAIN 0 0 0 0 2 ( 4.4) 2 0 0 0 0

PPD

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.5 Treatment Emergent Adverse Events by SOC and Preferred Term Safety Population

NUMBER OF SUBJECTS WITH AT LEAST ONE AE 18 ( 40.0) 34 NUMBER OF SUBJECTS WITH NO AE 27 ( 60.0)

GASTROINTESTINAL DISORDERS 8 ( 17.8) 10 LIP ULCERATION 2 ( 4.4) 3 MOUTH ULCERATION 1 ( 2.2) 1 NAUSEA 1 ( 2.2) 1 PARAESTHESIA ORAL 2 ( 4.4) 2

Document Version:1.0,CURRENT,Most-Recent,Effective TOOTHACHE 1 ( 2.2) 1

COATING IN MOUTH 1 ( 2.2) 1 GINGIVAL ULCERATION 1 ( 2.2) 1

INFECTIONS AND INFESTATIONS 9 ( 20.0) 10 RHINITIS 6 ( 13.3) 7 ORAL HERPES 1 ( 2.2) 1 PERICORONITIS 2 ( 4.4) 2

INJURY, POISONING AND PROCEDURAL 6 ( 13.3) 6 COMPLICATIONS TRAUMATIC ULCER 2 ( 4.4) 2 LACERATION 1 ( 2.2) 1 LIGAMENT SPRAIN 1 ( 2.2) 1 ______(Page 3 of 4) n (%) = Number (percent) of subjects nAE = Number of adverse events. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

PPD

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Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.5 Treatment Emergent Adverse Events by SOC and Preferred Term Safety Population

SUPERFICIAL INJURY OF EYE 1 ( 2.2) 1 TOOTH FRACTURE 1 ( 2.2) 1

NERVOUS SYSTEM DISORDERS 3 ( 6.7) 3 HEADACHE 3 ( 6.7) 3

GENERAL DISORDERS AND ADMINISTRATION 1 ( 2.2) 3 SITE CONDITIONS

Document Version:1.0,CURRENT,Most-Recent,Effective DEVICE FAILURE 1 ( 2.2) 3

RESPIRATORY, THORACIC AND MEDIASTINAL 2 ( 4.4) 2 DISORDERS OROPHARYNGEAL PAIN 2 ( 4.4) 2

PPD

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PPD Protocol: 205051 SLS negativecontrol(AquafreshExtremeCleanWhitening). non-SLS negativecontrol(AquafreshBigTeeth). Positive control(CrestProHealth®). Test Zincnon-IPMP(0.6%w/wzincchloride,0% IPMP). Test Zinc-IPMP(0.6%w/wzincchlorideand0.1% w/w IPMP). Values areunadjusted(raw)means Study Population:PP(N=45) Plaque Incubation pH 5.4 5.5 5.6 5.7 5.8 5.9 6.0 6.1 6.2 6.3 6.4 6.5 0 Reason For Issue For Reason Type Name Document eldo_controlled

o-L eaiecnrlSLSnegativecontrol non-SLS negativecontrol Test Zinc-IPMP

standard errors(SE).

RH205051 Synopsis

Version

1.0; CURRENT;Most-Recent;Effective

Mean PlaqueIncubationpHOverTime

Per ProtocolPopulation

Figure 9.1

Time inMinutes

Test Zincnon-IPMP

090032d580d18c62 Identifier Document

ProgramRunDate:20MAY2016

Effective Date

Positive control

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PPD SLS negativecontrol(AquafreshExtremeCleanWhitening). non-SLS negativecontrol(AquafreshBigTeeth). Positive control(CrestProHealth®). Test Zincnon-IPMP(0.6%w/wzincchloride,0% IPMP). Test Zinc-IPMP(0.6%w/wzincchlorideand0.1% w/w IPMP). Values areunadjusted(raw)means Study Population:PP(N=45) Protocol: 205051 Regrowth Ratio 10 11 12 4 5 6 7 8 9 0 Reason For Issue For Reason Type Name Document eldo_controlled

o-L eaiecnrlSLSnegativecontrol non-SLS negativecontrol Test Zinc-IPMP

standard errors(SE).

RH205051 Synopsis

Version

1.0; CURRENT;Most-Recent;Effective

Mean RegrowthRatioOverTime

Per ProtocolPopulation

Figure 9.2

Time inMinutes

Test Zincnon-IPMP

090032d580d18c62 Identifier Document

ProgramRunDate:20MAY2016

Effective Date

Positive control

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PPD Protocol: 205051 SLS negativecontrol(AquafreshExtremeCleanWhitening). non-SLS negativecontrol(AquafreshBigTeeth). Positive control(CrestProHealth®). Test Zincnon-IPMP(0.6%w/wzincchloride,0% IPMP). Test Zinc-IPMP(0.6%w/wzincchlorideand0.1% w/w IPMP). Values areunadjusted(raw)means Study Population:PP(N=45) Live:Dead Stain Ratio 100 30 40 50 60 70 80 90 0 Reason For Issue For Reason Type Name Document eldo_controlled

o-L eaiecnrlSLSnegativecontrol non-SLS negativecontrol Test Zinc-IPMP

standard errors(SE).

RH205051 Synopsis

Version

1.0; CURRENT;Most-Recent;Effective Mean Live:DeadStainRatioOverTime

Per ProtocolPopulation

Figure 9.3

Time inMinutes

Test Zincnon-IPMP

090032d580d18c62 Identifier Document

ProgramRunDate:20MAY2016

Effective Date

Positive control

Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 20MAY2016 Figure 9.4 Mean Change in Plaque Incubation pH from Pre-Treatment Per Protocol Population

Study Population: PP (N=45)

1.0 0.9 Test Zinc-IPMP Test Zinc non-IPMP Positive control non-SLS negative control 0.8 SLS negative control 0.7 0.6 0.5 0.4 Document Version:1.0,CURRENT,Most-Recent,Effective 0.3

0.2 0.1 0.0 -0.1 Change in plaque Incubation pH from Pre-Treatment

15 45 90 Time in Minutes Values are unadjusted (raw) mean changes from (pre-treatment) baseline standard errors(SE) Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP) Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

PPD

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Protocol: 205051 Program Run Date: 20MAY2016 Figure 9.5 Mean Change in Regrowth Ratio from Pre-Treatment Per Protocol Population

Study Population: PP (N=45)

3 Test Zinc-IPMP Test Zinc non-IPMP Positive control 2 non-SLS negative control SLS negative control 1

-1

Document Version:1.0,CURRENT,Most-Recent,Effective -2

-3

-4 Change in Regrowth Ratio from Pre-Treatment -5

PPD

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Protocol: 205051 Program Run Date: 20MAY2016 Figure 9.6 Mean Change in Live:Dead Stain Over Time Per Protocol Population

Study Population: PP (N=45)

28 24 Test Zinc-IPMP Test Zinc non-IPMP Positive control 20 non-SLS negative control SLS negative control 16 12 8 4 0 -4 -8 Document Version:1.0,CURRENT,Most-Recent,Effective

-12 -16 -20 -24

Change in Live:Dead Stain Ratio -28 -32

PPD

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PPD SLS negativecontrol(Aquafresh ExtremeCleanWhitening). non-SLS negativecontrol(AquafreshBigTeeth). Positive control(CrestProHealth®). Test Zincnon-IPMP(0.6%w/wzincchloride,0% w/wIPMP). Test Zinc-IPMP(0.6%w/wzincchlorideand0.1% w/wIPMP). Study Population:PP(N=45) Protocol: 205051 AUCgly(0-90) -10 10 20 30 40 50 60 70 80 90 0 ...... 6.0 5.9 5.8 5.7 5.6 5.5 5.4 5.3 5.2 5.1 5.0 Pearson's correlationcoefficient=-0.0303 Reason For Issue For Reason Type Name Document eldo_controlled Test Zinc-IPMP

RH205051 Synopsis Version

Scatter PlotofBaselinepHversusAUCgly(0-90)

1.0; CURRENT;Most-Recent;Effective

Per ProtocolPopulation

Figure 9.7

pH Value

090032d580d18c62 Identifier Document

Effective Date

ProgramRunDate:20MAY2016

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PPD SLS negativecontrol(Aquafresh ExtremeCleanWhitening). non-SLS negativecontrol(AquafreshBigTeeth). Positive control(CrestProHealth®). Test Zincnon-IPMP(0.6%w/wzincchloride,0% w/wIPMP). Test Zinc-IPMP(0.6%w/wzincchlorideand0.1% w/wIPMP). Study Population:PP(N=45) Protocol: 205051 AUCgly(0-90) -10 10 20 30 40 50 60 70 80 90 0 ...... 6.0 5.9 5.8 5.7 5.6 5.5 5.4 5.3 5.2 5.1 5.0 Pearson's correlationcoefficient=-0.1768 Test Zincnon-IPMP Reason For Issue For Reason Type Name Document eldo_controlled

RH205051 Synopsis Version

Scatter PlotofBaselinepHversusAUCgly(0-90)

1.0; CURRENT;Most-Recent;Effective

Per ProtocolPopulation

Figure 9.7

pH Value

090032d580d18c62 Identifier Document

Effective Date

ProgramRunDate:20MAY2016

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PPD SLS negativecontrol(Aquafresh ExtremeCleanWhitening). non-SLS negativecontrol(AquafreshBigTeeth). Positive control(CrestProHealth®). Test Zincnon-IPMP(0.6%w/wzincchloride,0% w/wIPMP). Test Zinc-IPMP(0.6%w/wzincchlorideand0.1% w/wIPMP). Study Population:PP(N=45) Protocol: 205051 AUCgly(0-90) -10 10 20 30 40 50 60 70 80 90 0 ...... 6.0 5.9 5.8 5.7 5.6 5.5 5.4 5.3 5.2 5.1 5.0 Pearson's correlationcoefficient=0.0498 Reason For Issue For Reason Type Name Document eldo_controlled Positive control

RH205051 Synopsis Version

Scatter PlotofBaselinepHversusAUCgly(0-90)

1.0; CURRENT;Most-Recent;Effective

Per ProtocolPopulation

Figure 9.7

pH Value

090032d580d18c62 Identifier Document

Effective Date

ProgramRunDate:20MAY2016

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PPD SLS negativecontrol(Aquafresh ExtremeCleanWhitening). non-SLS negativecontrol(AquafreshBigTeeth). Positive control(CrestProHealth®). Test Zincnon-IPMP(0.6%w/wzincchloride,0% w/wIPMP). Test Zinc-IPMP(0.6%w/wzincchlorideand0.1% w/wIPMP). Study Population:PP(N=45) Protocol: 205051 AUCgly(0-90) -10 10 20 30 40 50 60 70 80 90 0 ...... 6.0 5.9 5.8 5.7 5.6 5.5 5.4 5.3 5.2 5.1 5.0 Pearson's correlationcoefficient=0.0806 non-SLS negativecontrol Reason For Issue For Reason Type Name Document eldo_controlled

RH205051 Synopsis Version

Scatter PlotofBaselinepHversusAUCgly(0-90)

1.0; CURRENT;Most-Recent;Effective

Per ProtocolPopulation

Figure 9.7

pH Value

090032d580d18c62 Identifier Document

Effective Date

ProgramRunDate:20MAY2016

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PPD SLS negativecontrol(Aquafresh ExtremeCleanWhitening). non-SLS negativecontrol(AquafreshBigTeeth). Positive control(CrestProHealth®). Test Zincnon-IPMP(0.6%w/wzincchloride,0% w/wIPMP). Test Zinc-IPMP(0.6%w/wzincchlorideand0.1% w/wIPMP). Study Population:PP(N=45) Protocol: 205051 AUCgly(0-90) -10 10 20 30 40 50 60 70 80 90 0 ...... 6.0 5.9 5.8 5.7 5.6 5.5 5.4 5.3 5.2 5.1 5.0 Pearson's correlationcoefficient=0.0568 SLS negativecontrol Reason For Issue For Reason Type Name Document eldo_controlled

RH205051 Synopsis Version

Scatter PlotofBaselinepHversusAUCgly(0-90)

1.0; CURRENT;Most-Recent;Effective

Per ProtocolPopulation

Figure 9.7

pH Value

090032d580d18c62 Identifier Document

Effective Date

ProgramRunDate:20MAY2016

Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Clinical Protocol

205051

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CONFIDENTIAL

SUMMARY INFORMATION

A Study to Investigate the Antimicrobial Activity of Title: two Test Toothpastes in a Plaque Glycolysis and

Regrowth Model.

Protocol Number: 205051 Sponsor: GlaxoSmithKline Consumer Healthcare (GSKCH)  GlaxoSmithKline Consumer Healthcare (UK) Trading Limited

Product Name: Development Phase: N/A

Expert Advice Outside of Normal Tel: PPD

Working Hours:

Key Protocol Authors: PRIMARY CONTACT PPD Clinical Study Manager: GSKCH, St George’s Avenue,

Weybridge, Surrey, KT13 0DE, UK. PPD Telephone: Biostatistician: PPD Clinical Research Lead: PPD Other Protocol Authors: Clinical Supplies: PPD Data Manager: PPD

Principal Investigator: Dr David Payne Study Site Name & Address: Intertek CRS, 6 Brindley Road, City Park  Business Village, Old Trafford, Manchester, M16 9HQ

 Document Version:3.0,Most-Recent,Effective,CURRENT Page 147 of 209 Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Study Site Telephone Number: Tel: PPD

Study Examiner: Dr PPD BDS

Clinical Laboratory: Intertek PSM P.O. Box 42, Hexagon Tower, Blackley, Manchester, M9 8ZS

Regulatory Agency Identifier Number N/A (if applicable):



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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE

 I confirm agreement to conduct the study in compliance with the protocol and any amendments and according to the current ICH GCP guidelines.

 I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described study.

 I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in

place to ensure site staff receives all appropriate information throughout the

study.

 I agree to conduct this study in full conformance with the laws and regulations of the country in which the research is conducted and the Declaration of Helsinki.

Investigator Name: David Payne

Investigator Qualifications: BDS

Investigator Signature: PPD

Date of Signature/ Agreement: PPD DD/MMM/YYYY

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Table of Contents

SUMMARY INFORMATION ...... 2

PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE ...... 4

Table of Contents ...... 5

PROCESS FOR AMENDING THE PROTOCOL...... 9

PROTOCOL AMENDMENT PAGE ...... 10 PROTOCOL SYNOPSIS FOR STUDY 205051 ...... 14

Success Criteria/Evaluation Criteria: ...... 19

1. INTRODUCTION...... 21

2. OBJECTIVES AND ENDPOINTS ...... 23 3. STUDY PLAN ...... 24

3.1. Study Design...... 24

3.2. Subject Restrictions ...... 25

3.3. Type and Planned Number of Subjects ...... 26 3.4. Study Design and Dose Justification ...... 26

4. SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA ...... 27

4.1. Inclusion Criteria...... 28

4.2. Exclusion Criteria ...... 28 4.3. Screening/ Baseline Failures...... 30 4.4. Withdrawal/ Stopping Criteria ...... 30 4.5. Subject Replacement...... 31 4.6. Subject and Study Completion...... 31 5. PRODUCT INFORMATION...... 31 5.1. Study Product...... 31

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5.2. Dose Schedule...... 33

5.3. Dose Modification ...... 34 5.4. Product Compliance ...... 34

5.5. Precautions ...... 34

5.6. Overdose...... 34

5.7. Rescue Therapy...... 34 5.8. Product Assignment...... 35

5.8.1 Randomization ...... 35 5.8.2 Blinding...... 35

5.8.3 Code Breaks...... 35 5.9. Packaging and Labelling ...... 36

5.9.1. Accountability of Product ...... 36 5.9.2. Storage of Product ...... 37

6. STUDY ASSESSMENTS AND PROCEDURES ...... 37 6.1. Visit 1 - Screening Visit (Day 0) ...... 38

6.1.1. Informed Consent ...... 38 6.1.2. Demographics...... 38

6.1.3. Medical History and Concomitant Medication ...... 39 6.1.4 Dispense Washout Product ...... 39

6.2. Visits 2 Baseline and Plaque Assessment...... 39 6.2.1. Full Oral Soft Tissue Examination ...... 39

6.2.2. Plaque Assessment ...... 39 6.3. Visits 3-7 (Treatment visits)...... 40 6.3.1. Full Oral Soft Tissue Examination...... 40 6.3.2. Pre-treatment Plaque Collection ...... 40 6.3.3. Randomisation...... 40 6.3.4 Treatment ...... 40 6.3.5. Full Oral Soft Tissue Examination...... 40 6.3.6 Exit the study (at final visit only) ...... 40

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7. SAFETY ASSESSMENTS...... 41

7.1. Definitions of an Adverse Event and Serious Adverse Event...... 41

7.1.1. Adverse Events ...... 41 7.1.2. Serious Adverse Events ...... 42

7.2. Recording Adverse Events and Serious Adverse Events .43 7.3. Evaluating Adverse Events and Serious Adverse Events 44

7.4. Reporting Adverse Events and Serious Adverse Events..45

7.5. Follow-up of Adverse Events and Serious Adverse Events ...... 46

7.6. Collection of Pregnancy Information ...... 48 7.6.1. Time Period for Collecting of Pregnancy Information ...48

7.6.2. Action to be Taken if Pregnancy Occurs ...... 48 8. DATA MANAGEMENT ...... 49

8.1. Source Documents/ Data...... 49

8.2. Electronic Case Report Form ...... 49 8.3. Data Handling ...... 50

8.3.1. Data Queries...... 50 8.4. External Data ...... 51

9. STATISTICAL CONSIDERATIONS AND DATA

ANALYSES ...... 51 9.1 Sample Size Determination ...... 51 9.2. General Considerations ...... 52 9.2.1. Definition of Analysis Populations ...... 52 9.2.2. Exclusion of Data from Analysis ...... 52 9.2.3. Criteria for Evaluation ...... 53 9.2.4. Criteria for Assessing Efficacy ...... 53 9.2.5. Criteria for Assessing Tolerability ...... 53

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9.2.6. Handling of Dropouts and Missing Data ...... 53 9.3. Statistical Methods and Analytical Plan...... 53

9.3.1. Demographic and Baseline Characteristics ...... 53 9.3.2. Statistical Analyses...... 53

10. STUDY GOVERNANCE CONSIDERATIONS ...... 56

10.1. Posting of Information on Publicly Available Clinical Trials Registers...... 56

10.2. Regulatory and Ethical Considerations, Including the Informed Consent...... 56

10.3. Quality Control (Study Monitoring) ...... 56 10.4. Quality Assurance...... 57

10.5. Conditions for Terminating the Study...... 57

10.6. Records Retention...... 58 10.7. Provision of Study Results to Investigators, posting of

Information on Publicly Available Clinical Trials Registers and Publication ...... 59

11. REFERENCES...... 60

12. APPENDICES ...... 62 12.1. Appendix 1 - Abbreviations and Trademarks...... 62

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PROCESS FOR AMENDING THE PROTOCOL

Protocol modifications to ongoing studies whic h could potentially adversely affect the safety of subjects or which alter the scope of the investigation, the scientific quality of the study, the experimental design, dosages, duration of therapy, assessment variables, the number of subjects treated, or subject selection criteria are considered

major/substantial amendments and must be made only after appropriate consultation

between an appropriate representative of GSKCH and the investigator. 

Details of amendments to the protocols should be recorded on the following page. Protocol modifications must be prepared by a representative of GSKCH. All changes must be justified in the Reason for Amendment section of the following Protocol Amendment Page. Approval of amendments will be made by the original protocol signatories or their appropriate designees.

All major/substantial protocol modifications must be reviewed and approved by the appropriate IEC in accordance with local requi rements, before the revised edition can

be implemented.

All non-substantial/ minor/ administrative amendments should be submitted to the

IEC as per country specific requirements. In some countries pre-approval of a minor amendment is not required and will just be held on file by the sponsor and investigator.

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PROTOCOL AMENDMENT PAGE

Details of all amendments should be recorded in the table below. Affected sections and pages should be listed in the table; the actual amendment/ change should be made in the relevant section of the main protocol.

To highlight the change, the following features will be used:

To add text: Use of CAPITAL LETTERS, BOLD AND UNDERLINE

To delete text: Use of Strikethrough e.g. strikethrough

Amendment Type of Amendment Reason for Amendment Other Section(s) Amended PI Amendment No. & New Documents Agreement

Document Version:3.0,Most-Recent,Effective,CURRENT Protocol Requiring Version No. Amendment Signature & Date

Amendment Non-Substantial/Minor Informed Signature: No.: Consent Yes No

Safety Protocol Substantial/ Major Date: Version Statement No.: Yes No

CRF Yes No

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Amendment Non-Substantial/Minor Informed Signature: No.: Consent Yes No

Safety Protocol Substantial/ Major Statement Date: Version Yes No No.: CRF Yes No Document Version:3.0,Most-Recent,Effective,CURRENT

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Schedule of Events The total duration of the study is approximately 8 weeks, comprising approximately 2 weeks to complete the screening procedures (Visits 1 and 2), and 1 week to complete each of the five treatment periods. A washout period of at least 48 hours will precede each treatment visit. Visit 1 Visit 2 Visit 3 Visit 4 PROCEDURE Screening Plaque Randomisation and Treatment 2 Screening Treatment 11 Assessment Informed consent X Demographics X Medical history X Concomitant medication X X X X Compliance check X X X

Document Version:3.0,Most-Recent,Effective,CURRENT OST examination X X X2 X2 Inclusion/exclusion criteria X X

Subject eligibility X X X visits X Visit 2 Plaque collection (screening) – whole mouth X Dispense washout toothpaste, toothbrush X treatment visits Randomisation X Plaque collection – quadrant 1 (Pre-treatment) X X Supervised treatment (rinse with test slurry) X X Plaque collection – quadrants 2,3 and 4 (15, 45 X X and 90 min Post-treatment respectively) Screenfail subjects at V2 OST and WO return X

Return washout toothpaste, toothbrush A minimum of 2 days a maximum of 10 days between and

Adverse events Maximum 14 days and a minimum of 48 hrs between Visit 1 X X Minimum of 2 days and a maximum 10 between treatment 1 Visits 3-7 should be performed where possible in the morning. 2 OST examination will be performed before treatment and after plaque sampling completed on each treatment visit 3 At final visit only. .

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Visit 5 Visit 6 Visit 7 PROCEDURE Treatment 3 Treatment 4 Treatment 5

Informed consent Demographics Medical history Concomitant medication X X X Compliance check X X X OST examination X2 X2 X2 Inclusion/exclusion criteria Subject eligibility X X X Plaque collection (screening) – whole mouth treatment visits treatment visits treatment visits

Document Version:3.0,Most-Recent,Effective,CURRENT Dispense washout toothpaste, toothbrush

Randomisation Plaque collection – quadrant 1 (Pre-treatment) X X X Supervised treatment (rinse with test slurry) X X X Plaque collection – quadrants 2,3 and 4 (15, 45 X X X and 90 min Post-treatment respectively) Return washout toothpaste, toothbrush X3 Adverse events Minimum of 2 days and a maximum 10 between X Minimum of 2 days and a maximum 10 between X Minimum of 2 days and a maximum 10 between X 1 Visits 3-7 should be performed where possible in the morning. 2 OST examination will be performed before treatment and after plaque sampling completed on each treatment visit 3 At final visit only.

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PROTOCOL SYNOPSIS FOR STUDY 20 5051

Brief Summary

Dental plaque contains bacteria that can cause several oral diseases, in particular gingivitis (gum inflammation, which can le ad to the more serious gum disease, periodontitis) and dental caries (tooth decay , by producing acids from sugars that slowly dissolve enamel). Bacteria-inhibiting agents in toothpastes can reduce the potential of dental plaque to cause disease by (i) reducing bacterial metabolism

(thereby reducing their ability to generate harmful acids from dietary carbohydrates,

and their ability to replicate), and/or (ii) by reducing viability (i.e. killing plaque bacteria outright).

The Plaque Glycolysis and Regrowth Model (PGRM) is a clinical method developed to measure the effect of an oral hygiene treatment on both of these end-points [White 1995]. The method measures plaque bacterial metabolism (i.e. bacteriostatic effects) and viability (i.e. bactericidal effects) ex vivo in samples of plaque swabbed from tooth surfaces, taken at various time-points before and after treatment. This approach

makes it a relatively precise clinical measurement, which helps understand the

potential plaque-inhibiting activity of the treatm ent, and its mode of action. It was originally developed to study the in vivo bacteria -inhibiting effects of dentifrices containing stannous fluoride, a known bacteria -inhibiting agent.

Two bacteria-inhibiting agents that have been incorporated into toothpastes are zinc and isopropylmethylphenol (IPMP). This study aims to determine, using an adaptation of the PGRM methodology, whether zinc+IPMP, or zinc alone, in a toothpaste can:

 reduce plaque bacterial metabolism

reduce plaque viability (by two different methods) 

The Test products will be compared with a positive control toothpaste containing stannous fluoride, and with two negative control toothpastes: one with the anionic detergent sodium lauryl sulphate (SLS) and one without (containing a non-ionic detergent instead).

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Objectives and Endpoints

Primary Endpoint

 To evaluate and compare the ability  Area under the curve for glycolysis

of a Test toothpaste containing 0.6% (AUCgly(0-90)) zinc chloride and 0.1% IPMP to

inhibit plaque glycolysis compared to

a non-SLS containing toothpaste. Secondary Endpoint

 To evaluate and compare the ability  Area under the curve for viability by of a Test toothpaste containing 0.6% regrowth (AUCregrowth(0-90)) zinc chloride and 0.1% IPMP to inhibit plaque viability by regrowth

as compared to a non-SLS containing

toothpaste.  To evaluate and compare the ability  Area under the curve for viability by of a Test toothpaste containing 0.6% live:dead stain. zinc chloride and 0.1% IPMP to inhibit plaque viability by live:dead staining compared to a non-SLS

containing toothpaste.

 To evaluate and compare the ability  Area under the curve for glycolysis of a Test toothpaste containing 0.6% (AUCgly(0-90)) zinc chloride (non-IPMP) to inhibit  Area under the curve for viability by

plaque glycolysis, and to inhibit regrowth AUCregrowth(0-90), plaque viability (assessed by  Area under the curve for viability by AUCregrowth and by live:dead stain by AUC live:dead(0-90) AUClive:dead(0-90), compared to a non- SLS containing toothpaste and an SLS containing toothpaste  To make all other comparisons  Area under the curve for glycolysis

between products in AUCgly(0-90), (AUCgly(0-90)) AUCregrowth(0-90) and AUClive:dead(0-90).  Area under the curve for viability by regrowth AUCregrowth(0-90)  Area under the curve for viability by

live:dead stain by AUClive:dead(0-90)

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Study Design

Overall Design This is a single-centre, analyst and examiner (plaque sample collector)-blind, randomised, five-treatment, five-period, cross -over study in healthy adult volunteers.

Visit 1 - Screening Visit (FSFV) Potential subjects will undergo the following assessments (in the order written):  Written informed consent.

 Demographics, medical history and concomitant medications will be taken.

 a full oral soft tissue (OST) examinat ion

 Inclusion and exclusion criteria review and completion.  Dispensation of a standard fluoride toothpaste (washout toothpaste), to use  twice-daily for the duration of the study (apart from on the morning of Visit 2

and morning of Visits 3-7)

Visit 2 – Baseline/Plaque assessment Visit The following assessments will be conducted in the order written.

 a full oral soft tissue (OST) examination,

 baseline plaque sample collection fro m the entire dentition at the plaque/gum interface (buccal and lingual surfaces), with a single sterile rayon fibre tipped swab

The swab will be placed in a labelled, capped, sterile tube and stored on ice until

processed for plaque acidogenicity (according to Intertek PGRM WI, 2013). Subjects with plaque sample acidogenicity within the range pH 5.0 – 5.7 will progress on to the treatment phase of the study. They will be informed via a telephone call.

Those with plaque sample acidogenicity outsi de this range will be discontinued at this point and will proceed to study conclusion. They will re-attend the clinic and receive an end-of-study OST examination.

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Visit 3-7 – Treatment visits The following assessments will be conducted in the order written. With at least 48 hours and no more than 10 days since the previous visit, and having not brushed since

the previous evening, subjects will:

 Undergo a full OST examination

 Undergo collection of Pre-treatment plaque samples from the subject’s maxillary dentition (left quadrant only) at the plaque/gum interface (buccal and lingual surfaces) with a single sterile rayon fibre tipped swab, being careful to avoid contact with the oral soft tissue.

 Be randomised to the order in which they will receive the five treatments (Visit 3 only)  Subjects will swill with a pre-prepared slurry of 1.5 g toothpaste in 10 mL

water (prepared according to Intertek WI-TPS, 2013) around their mouth for

60 seconds, making sure that the slurry contacts the entire dentition.  Expectorate the toothpaste slurry.

 Undergo collection of further plaque samples at 15 minutes (±2 minutes) post treatment from the subject’s right m axillary quadrant (buccal and lingual surfaces), 45 minutes (±2 minutes) post treatment from the subjects left mandibular quadrant (buccal and lingual surfaces) and 90 minutes (±5 minutes) post treatment from the subjects right mandibular quadrant (buccal

and lingual surfaces), each time wit h a new sterilised swab.  Undergo a full OST examination

 Exit the study (at final visit only) The swabs from all collections will be placed in labelled, capped, sterile tubes and

immediately stored on ice until processed for plaque acidogenicity, and viability by

both regrowth according to Intertek PGRM WI, 2013 and live:dead stain, according to Intertek Live-Dead Stain WI, 2015.

Type and Planned Number of Subjects

This study will recruit healthy adult volunteers with a plaque glycolysis value in the target range (see Study Design and Dose Justification).

For each endpoint separately (AUCgly(0-90), AUCregrowth(0-90) and AUClive:dead(0-90)), the comparison between the effects of the positive control and those of the non-SLS



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negative control will be used to validate the methodology. If no difference between these two treatments is observed, no further analysis will be performed for that endpoint. After validation of each endpoint (i.e. if a statistically significant difference is

observed), the primary comparison of interest for each endpoint will be the Test Zinc-

IPMP toothpaste versus the non-SLS negative control.

In the previous, closely related PGRM study [GSK Study RH01871], the standard deviation of the within-subject differences in AUCgly(0-90) was 15.4. Based on this same level of variability, a study with 40 com plete and evaluable subjects will have 80% power to show a difference of 7.0 in AUC gly(0-90) between any two treatment groups, at the 2-sided 5% level of significance (without adjustment for multiple

comparisons). A difference of 7.0 in AUCgly(0-90) represents approximately 1/3 of the

difference observed in the previous study between the test toothpaste (0.454%

Stannous Fluoride) and negative (non-SLS containing) control toothpaste, and is an effect that is considered large enough to be of interest and hence influence design of subsequent studies.

Allowing for subject dropouts and protocol violators, a maximum of 45 subjects will be randomised.

Diagnosis and Main Criteria for Inclusion

Healthy subjects with sound tooth enamel will be required for entry into this study. Inclusion criteria for this study include: aged at least 18 years, plaque acidogenicity value and in good general health, understands the study and is willing to participate.

Statistical Methods

Efficacy will be evaluated based on the primary endpoint which is AUCgly(0-90). This will be compared between treatments using an analysis of covariance (ANCOVA) including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and peri od- minus subject-level pre-treatment values as covariates in the model.Other endpoints of interest in this exploratory study

are AUCregrowth(0-90) and AUClive:dead(0-90). These will be analysed using the same ANCOVA methodology as for the primary endpoint.

For each endpoint separately, the comparison between the effects of the positive control and those of the non-SLS-negative control will be used to validate the methodology. If no difference between these two treatments is observed, no further analysis will be performed for that end-point. After validation (i.e. if a statistically

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significant difference is observed), the primary comparison of interest for each endpoint will be the Test Zinc-IPMP toothpaste versus the non-SLS-negative control.

Success Criteria/Evaluation Criteria:

Efficacy: The primary outcome measure of the study will be considered valid if a statistically significant difference is observed between the positive control toothpaste and the non-SLS-negative control toothpaste with respect to mean glycolysis activity inhibition over the sampling time period (AUCgly (0-90)).

Following demonstration of the validity of the primary outcome measure, the success

criterion for this study is to observe a statist ically significant difference between the Test Zinc-IPMP toothpaste and the non-SLS -negative control toothpaste, with respect to AUCgly (0-90).

Safety: Safety will be assessed with respect to adverse events (AEs) and OST abnormalities (oral tolerability).

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Product Information The following study products will be supplied by the Clinical Supplies Department, GSKCH:

Document Version:3.0,Most-Recent,Effective,CURRENT w/w IPMP and 1426ppm fluoride as sodium fluoride. IPMP toothpaste Rinse with pre - Positive control n/a Positive control toothpaste containing 0.454% w/w prepared slurry stannous fluoride (Crest ProHealth® – Clean Mint, Approx of toothpaste in oral Fluoride Toothpaste (1100ppm F as stannous fluoride) 1.5 g 10 mL water for USA Marketplace product). 60s SLS negative CCI Negative control toothpaste containing 2.0% SLS, 0.65% Then rinse with control Tegobetain and 1150 ppm fluoride as sodium fluoride 10mL water (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product). Negative control toothpaste containing 1426 ppm non-SLS CCI fluoride as sodium fluoride (Aquafresh Big Teeth negative control toothpaste).

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1. INTRODUCTION

Gingivitis is an inflammation of the soft tissue of the oral cavity that immediately surrounds the tooth. Gingivitis is reported to have a high prevalence worldwide [Albandar, 2002] and is one of the most common forms of periodontal disease [Oliver, 1998]. In its most common form, gingivitis is induced by a build-up of dental plaque resulting from inadequate control of

supragingival plaque [Kinane, 2001]. Plaque induced gingivitis is a reversible condition and

it can be prevented with good oral hygiene [Brook, 2003, Ower, 2003]. Approaches to the prevention and treatment of gingivitis are essentially twofold, being both mechanical and chemical in nature [Hancock, 1996]. The addition of bacteria-inhibiting ingredients to a toothpaste will complement mechanical removal by helping to inhibit the growth of plaque bacteria that remain after brushing, particularly from sites in the mouth that are less accessible to mechanical removal. Epidemiological and clinical studies have suggested that

the combined use of both mechanical and chemical therapy is the most efficient way to

control plaque [Ainamo 1977, Drisko 2001].

Dental caries is caused by the dissolution of tooth enamel by acids produced by bacterial metabolism of dietary sugars, and is widely prevalent in the population (Fejerskov 2003). The primary preventative routes recommended to control caries is reduction of sugars (fermentable carbohydrates) in the diet and twice -daily use of fluoride oral hygiene products. The use of agents that target the ability of bacteria to generate damagingly acidic conditions is less well developed but is a current focus for research and development of new products

[ten Cate 2013].

Bacteria-inhibiting agents have been incorporated into toothpastes for many years with a

view to delivering plaque control and gum benefits [Cummins, 1992]. Non-specific, broad- spectrum bacteria-inhibiting agents have been preferred for toothpastes intended for daily use, to avoid the risk of development of microbiological resistance. The metal ions stannous and zinc have been extensively used in marketed products to control oral bacteria, and are believed to have a similar mode of action [Scheie, 1989; Marsh, 1992]. Stannous fluoride was the first fluoride source to be used in toothpaste [van Loveren, 1990]. It has been shown to inhibit and reduce bacterial biomass, virulence and metabolism [Tinanoff, 1990]. Zinc ions, stabilised with citrate as counter ion, have similarly been shown to have bacteria- inhibiting effects, particularly via bacteriostatic action, and reduce plaque growth [Cummins, 1992].

Organic broad-spectrum bacteria-inhibiting agents have also been included extensively in marketed toothpaste formulations. Triclosan is a leading example of this class, where evidence supports antiplaque and antigingivitis effects [Riley, 2013]. It has been combined with zinc in toothpastes to create a dual-active plaque-inhibiting system, with evidence that it .

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is more effective than either alone against plaque and gingivitis [Svatun, 1993, Saxton 1988]. Isopropylmethylphenol (IPMP, formally o-cymen -5-ol) is an alternative, non-chlorinated, organic broad-spectrum agent to control bacteria. Toothpaste formulations incorporating this

agent at 0.1% w/w, together with zinc ions at 0.6% w/w, have also shown bacteria-inhibiting

and antiplaque activity in in vitro and in vivo studies [Kakar, 2011; Pizzey, 2011].

The plaque glycolysis regrowth model (PGRM) is a useful approach to understanding the potential of oral hygiene products to impact plaque and plaque-induced diseases such as gingivitis and caries. It employs in vitro methods to assess the potential of an agent to inhibit de novo plaque growth in vivo, by sampling and analysing plaque ex vivo from human subjects [White, 1995]. The model relies on the experimental observation that in vivo sampled de novo dental plaques, collected from different quadrants of the dentition, produce

equivalent rates of metabolic activity and viability when dispersed and normalised into

incubation media. The PGRM allows ex vivo evaluation of antimicrobial treatments by comparing both reduction of metabolism (glycolysis) – that is, bacteriostatic effects - and reduction in viability – that is, bactericidal effects - of in vivo-treated plaque with control plaque samples from non-treated sites in the same individual. Inhibition of glycolysis is assessed via a reduction in plaque sample acidogenicity (i.e. a reduction in pH drop on addition of sucrose). Inhibition of viability is evaluated through a reduction in regrowth rate

(i.e. a reduction in the rise in plaque suspension turbidity, a measure of cell concentration) on

incubation of the plaque sample in growth medium [White 1995]. There is no existing published data on the effects of the 0.6% zinc chloride system, with or without IPMP, using the PGRM method.

The aim of this exploratory study is, therefore, to assess the ability of two Test toothpastes containing 0.6% w/w zinc chloride stabilised with sodium citrate in a sodium lauryl sulfate (SLS)-containing base to reduce glycolytic metabolism and viability of de novo plaque bacteria using the PGRM. One of the test toothpastes will contain 0.1% w/w IPMP (‘Test

zinc-IPMP toothpaste’) and one will not (‘Test zinc-non-IPMP toothpaste’). Plaque-

inhibiting activity will be compared with three Reference toothpastes: (i) a marketed toothpaste containing 0.454% stannous fluoride in an SLS-containing base (positive control); (ii) a marketed toothpaste with SLS but no added plaque-inhibiting agent (SLS negative control); and (iii) a marketed toothpaste without SLS and with no added plaque-inhibiting agent (non-SLS negative control).

The study is powered to test for a difference of approximately 1/3 of that observed between a 0.454% Stannous Fluoride toothpaste and negative control toothpaste in a previous PGRM study [GSK Clinical Study RH01871], and is an effect that is considered large enough to be of scientific interest and hence influence design of subsequent studies.

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2. OBJECTIVES AND ENDPOINTS

Primary Endpoint

 To evaluate and compare the ability of  Area under the curve for a Test toothpaste containing 0.6% zinc glycolysis (AUCgly(0-90)) chloride and 0.1% IPMP to inhibit plaque glycolysis compared to a non- SLS containing toothpaste.

Secondary Endpoint

 To evaluate and compare the ability of  Area under the curve for viability a Test toothpaste containing 0.6% zinc by regrowth (AUCregrowth(0-90)) chloride and 0.1% IPMP to inhibit plaque viability by regrowth as compared to a non-SLS containing toothpaste.  To evaluate and compare the ability of  Area under the curve for viability a Test toothpaste containing 0.6% zinc by live:dead stain. chloride and 0.1% IPMP to inhibit plaque viability by live:dead staining compared to a non-SLS containing toothpaste.  To evaluate and compare the ability of  Area under the curve for glycolysis a Test toothpaste containing 0.6% zinc (AUCgly(0-90)) chloride (non-IPMP) to inhibit plaque  Area under the curve for viability by glycolysis, and to inhibit plaque regrowth AUCregrowth(0-90), viability (assessed by AUCregrowth(0-90)  Area under the curve for viability by and by AUClive:dead(0-90)), compared to live:dead stain by AUClive:dead(0-90) a non-SLS containing toothpaste and an SLS containing toothpaste  To make all other comparisons  Area under the curve for glycolysis

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3. STUDY PLAN

3.1. Study Design

Overall Design This is a single-centre, analyst and examiner (plaque sample collector)-blind, randomised, five-treatment, five-period, cross-over study in healthy adult volunteers.

Visit 1 - Screening Visit (FSFV)

Potential subjects will undergo the following assessments (in the order written):  Written informed consent.

 Demographics, medical history and concomitant medications.

 Oral soft tissue (OST) examination

 Inclusion and exclusion criteria review and completion.  Dispensation of a standard fluoride toothpaste (washout toothpaste), to use twice- daily for the duration of the study (apart from on the morning of Visit 2 and Visits 3-

Visit 2 – Baseline/Plaque assessment Visit The following assessments will be conducted in the order written.  a full oral soft tissue (OST) examination,

 baseline plaque sample collection from the entire dentition at the plaque/gum interface (buccal and lingual surfaces), with a single sterile rayon fibre tipped swab

The swab will be placed in a labelled, capped, sterile tube and stored on ice until processed for plaque acidogenicity (according to Intertek PGRM WI, 2013).

Subjects with plaque sample acidogenicity within the range pH 5.0 – 5.7 will progress on to

the treatment phase of the study. They will be informed via a telephone call. Those with plaque sample acidogenicity outside this range will be discontinued at this point and will proceed to study conclusion. They will re-attend the clinic and receive an end-of- study OST examination.

Visit 3-7 – Treatment visits The following assessments will be conducted in the order written. With at least 48 hours since the previous visit but a maximum of 10 days, and having not brushed since the previous evening, subjects will:  Undergo a full OST examination  Undergo collection of Pre-treatment plaque samples from the subject’s maxillary

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dentition (left quadrant only) at the plaque/gum interface (buccal and lingual surfaces) with a single sterile rayon fibre tipped swab, being careful to avoid contact with the oral soft tissue.

 Be randomised to the order in which they will receive the five treatments (Visit 3

only)  Swill with a pre-prepared slurry of 1.5 g toothpaste in 10 mL water (prepared according to Intertek WI-TPS, 2013) around their mouth for 60 seconds, making sure

that the slurry contacts the entire dentition.

 Expectorate the toothpaste slurry.

 Undergo collection of further plaque samples at 15 minutes (±2 minutes) post treatment from the subject’s right maxillary quadrant (buccal and lingual surfaces), 45 minutes (±2 minutes) post treatment from the subjects left mandibular quadrant (buccal and lingual surfaces) and 90 minutes (±5 minutes) post treatment from the subjects right mandibular quadrant (buccal and lingual surfaces), each time with a new sterilise swab.

 Undergo a full OST examination

 Exit the study (at final visit only)

The swabs from all collections will be placed in labelled, capped, sterile tubes and immediately stored on ice until processed for plaque acidogenicity, and viability by both regrowth according to Intertek PGRM WI, 2013 and live:dead stain, according to Intertek

live:dead stain WI, 2015.

3.2. Subject Restrictions

Lifestyle/ Dietary The following lifestyle restrictions apply for the duration of the study:

 Subjects should abstain from chewing gum, using mints or breath strips.  Subjects should only use the toothpaste and toothbrush provided and must abstain from use of all other oral hygiene products including mouthwashes

Prior to the Plaque Screening Assessment (Visit 2), and Randomisation (Visit 3) and Treatment (Visits 3-7) days:  Subjects must abstain from eating and drinking (with the exception of water) and oral hygiene procedures from 11:00 pm the evening before and on the

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morning of Visits 2, 3-7. Subjects are allowed to drink water up to 1 hour before the study visit.

 Subjects must abstain from drinking alcohol 24hrs prior to Visits 2, and 3-7.

Medications and Treatments

If concomitant medications are used during the study, their identity, as well as their dosage and frequency, start and stop dates m ust be reported to the investigator and recorded in the eCRF. Non-emergency dental treatment should not occur during the study (including prophylaxis).

3.3. Type and Planned Number of Subjects

This study will recruit healthy adult volunteers with a plaque glycolysis value in the

target range (see 3.4 Study Design and Dose Justification).

Approximately 120 subjects will be screened to allow a maximum of 45 subjects to

be randomised.

3.4. Study Design and Dose Justification

This is a single-centre, analyst and examiner (plaque sample collector)-blind, randomised, five-treatment, five-period, cross -over study in healthy adult volunteers.

tested in vitro and compared for plaque glycolysis and viability. The PGRM

evaluates biological factors important to antimicrobial effects in vivo, while benefiting from the improved precision and control provided by in vitro assessment. Fasted plaque is typically collected from subjects who demonstrate plaque acidogenicity (pH after incubation in sucrose solution) in the range 5.0 to 5.7. This pH window has been adopted to ensure that subjects are able to develop sufficient levels of viable acidogenic dental plaque suitable for measuring glycolysis in the PGRM assay conditions [White, 1995].

Products will be applied as aqueous slurries to ensure complete dispersion of the toothpaste in the oral environment, remove variability due to brushing, and preserve

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plaque for sampling. Samples will be taken up to 90 minutes post-treatment to ensure the majority of the window of effect of the agents is observed: a previous GSK PGRM study [GSK Study RH01871] indicated treatment effects are tailing off after

90 minutes. An estimate of the overall effect of the treatments on each measurement

will be made: this will be achieved via determining the Area Under the Curve (AUC) of the profile of treatment deviation from Pre -treatment value, across the 90-minute measurement window.

superior to a control toothpaste (which did not contain sodium lauryl sulphate (SLS)),

by both inhibition of glycolysis (as AUCgly(0 -90)) and inhibition of regrowth (as AUCregrowth(0-90)). It is therefore planned to include one of these test toothpastes (the aqueous marketed product) as a positive control, and a non-SLS toothpaste as a negative control in the proposed study.

sample, one which stains all bacteria green, and the other which stains non-viable

bacteria red. The ratio of green:red colour in the sample is a measure of relative bacterial cell viability of that sample. It is proposed to use this live:dead staining methodology in the present study, as an alternat ive method to assess plaque viability.

In view of the above evidence from previous studies, therefore, in this study product effects on metabolism will be measured by AUCgly(0-90), and product effects on viability will be measured in two ways: by AUCregrowth(0-90) and by AUClive:dead(0-90).

4. SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA

Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the Safety Statement.

Deviations from inclusion and exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or

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subject safety. Therefore, adherence to th e criteria as specified in the protocol is essential.

4.1. Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

1. CONSENT

Demonstrates understanding of the study procedures, restrictions and willingness to participate as evidenced by voluntary written informed consent and has received a signed and dated copy of the informed consent form. 

2. AGE

Aged at least 18 years.

3. GENERAL HEALTH

Good general and mental health with, in the opinion of the investigator or medically qualified designee no clinically significant and relevant abnormalities in medical history or upon oral examination.

4. ORAL HEALTH

Plaque sample acidogenicity in the pH range 5.0 to 5.7 at Visit 2.

4.2. Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. PREGNANCY

Women who are known to be pregnant or who are intending to become pregnant over the duration of the study.

2. BREAST-FEEDING

Women who are breast-feeding

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3. CONCURRENT MEDICATION/ MEDICAL HISTORY

Currently taking antibiotics or have taken ant ibiotics within 2 weeks of plaque assessment (Visit 2). A subject with any medical history that may prevent them from participating in the study until study conclusi on (such as diabetes).

4. ORAL DISEASE

Any sign of grossly carious lesions (active), moderate or severe periodontal

conditions, or severe tooth wear.

5. ALLERGY/ INTOLERANCE

Known or suspected intolerance or hypersensi tivity to the study materials (or closely related compounds) or any of their stated ingredients.

6. CLINICAL STUDY/ EXPERMENTAL PRODUCT

A. Participation in another clinical study (including cosmetic studies) or receipt of an investigational drug within 30 days of the screening visit.

B. Previous participation in this study.

7. SMOKERS

Current smokers, or smokers who have quit within 6 months of screening, or subjects currently using smokeless forms of tobacco, e.g. Gutkha, Pan containing tobacco, Pan Masala.

8. GENERAL DENTITION EXCLUSIONS

A. Current active caries or periodontitis that may compromise, in the opinion of

the investigator, study outcomes or the health of the subject. B. Restorations in a poor state of repair that may, in the opinion of the investigator, compromise study outcomes or the health of the subject. C. Partial dentures or orthodontic appliances that may, in the opinion of the investigator, compromise study outcomes or the health of the subject 9. SUBSTANCE ABUSE

Recent history (within the last year) of alcohol or other substance abuse.

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10. PERSONNEL

An employee of the sponsor or the study site or members of their immediate family.

4.3. Screening/ Baseline Failures

Screen failures are defined as subjects who consent to participate in the study but are

never subsequently randomized. In order to ensure transparent reporting of screen

failure subjects, a minimal set of screen failure information is required including Demography, Screen Failure details, Eligibilit y Criteria, and any Serious Adverse Events. Re-screening of subjects will not be allowed in this study.

4.4. Withdrawal/ Stopping Criteria

A subject may withdraw from the study at any time at his/her own request, or may be withdrawn at any time at the discretion of the investigator for safety, behavioural or administrative reasons. If a subject withdraws or is withdrawn from the study, all human biological samples collected before they left will be analyzed and reported

unless the subject requests otherwise. A subject may request for their human biological samples to be destroyed. In these cases, the investigator must document this in the site study records and the samples should not be used for any further research.

If the reason for removal of a subject from the study is an AE or an abnormal laboratory test result, the principal specific event or test will be recorded on the electronic case report form (CRF). If a subject is withdrawn from the study because

of a product-limiting AE, thorough efforts should be clearly made to document the

outcome. Any AEs ongoing at the final visit will be followed up until resolved, the condition stabilizes, is otherwise explained, or the subject is lost to follow-up.

The following actions must be taken in relation to a subject who fails to attend the clinic for a required study visit:

 The site must attempt to contact the subject and re-schedule the missed visit as soon as possible.  The site must counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether or not the subject wishes to and/or should continue in the study.

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 In cases where the subject is deemed ‘lost to follow up’, the investigator or designee must make every effort to regain contact with the subject (where possible, at least 2 telephone calls). The contact attempt should be

documented in the subject’s record.

 Should the subject continue to be unreachable, only then will he/she be considered to have withdrawn from the study with a primary reason of “Lost to Follow-up”.

4.5. Subject Replacement

Subjects who withdraw from the study post -randomization will not be replaced.

4.6. Subject and Study Completion

A completed subject is one who has completed all phases of the study.

The end of the study is defined as the date of the last subject’s last visit.

5. PRODUCT INFORMATION

5.1. Study Product

See over.

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The following study products will be supplied by the Clinical Supplies Department, GSKCH:

Product Name Abbreviated Product Dose Route of Dosing product name Formulation Adminis- Instructions Code (MFC) tration Test toothpaste containing 0.6% w/w zinc chloride and Test zinc-IPMP CCI 0.1% w/w IPMP and 1426ppm fluoride as sodium toothpaste fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% Test zinc non- CCI w/w IPMP and 1426ppm fluoride as sodium fluoride. IPMP toothpaste Rinse with pre- Positive control n/a Positive control toothpaste containing 0.454% w/w prepared slurry stannous fluoride (Crest ProHealth® – Clean Mint,

Document Version:3.0,Most-Recent,Effective,CURRENT Approx of toothpaste in oral Fluoride Toothpaste (1100ppm F as stannous fluoride) 1.5 g 10 mL water for USA Marketplace product). 60s SLS negative CCI Negative control toothpaste containing 2.0% SLS, 0.65% Then rinse with control Tegobetain and 1150 ppm fluoride as sodium fluoride 10mL water (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product). Negative control toothpaste containing 1426 ppm non-SLS CCI fluoride as sodium fluoride (Aquafresh Big Teeth negative control toothpaste).

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Other items to be supplied by the Clinical Supplies Department, GSKCH:

Name of Item Purpose

Aquafresh Extreme Clean Whitening, Washout product - for brushing teeth on USA Marketed toothpaste (CCI ; site and at home, between visits. washout product.)

Aquafresh® Clean Control Toothbrushes. For use with washout product

Countdown timers For recording swill times

Sterile rayon fibre tipped swabs and For sampling dental plaque

sterile capped tubes

Rinsing cups For rinsing with 10mL of water after brushing teeth

Whirlimixer (if required) For mixing test slurry

Injection quality water (sterile) For slurry preparation

Pots for slurry preparation and rinsing For slurry preparation and rinsing

Glycolysis, regrowth media and live:dead staining materials for in vivo determination of plaque glycolysis and viability will be source/manufactured by the Clinical Site/Analytical Contractor according to the specifications contained in the work

instruction, Intertek PGRM WI, 2013 and Intertek Live-Dead Stain WI, 2015.

5.2. Dose Schedule

Subjects will be provided with a standard fluoride toothpaste (washout toothpaste), to

use twice-daily (am & pm) for the duration of the study (apart from on the morning of Visit 2 and Visits 3-7)

Supervised Treatment (Visits 3-7): Subjects will swill with a pre-prepared slurry of approximately 1.5 g toothpaste in 10 mL water (prepared according to Intertek WI- TPS 2013) around their mouth for 60 seconds, making sure that the slurry contacts the entire dentition. They will then spit out the slurry then rinse with 10ml of water.

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At home (Washout): Subjects will apply a full ribbon of washout product dentifrice to the washout toothbrush and brush their teeth in their usual manner, once in the morning and once in the evening.

5.3. Dose Modification

No dose modification is permitted in this study .

5.4. Product Compliance

A record of the administration/dispensing of the study dentifrices will be kept using a

dispensing log and the eCRF.

Each supervised treatment occasion will be determined and recorded in the eCRF.

Subjects will be asked to bring their washout dentifrices and toothbrush back site.

5.5. Precautions

No special precautions are necessary provided the study is carried out in accordance with this protocol. Study products will be labelled “For Clinical Trial Use Only”.

5.6. Overdose

An overdose is a deliberate or inadvertent administration of a product at a dose higher than specified in the protocol.

Overdose is not likely to occur in this study . Limited quantities of the product will be supplied, and closely monitored by the site for each subject.

Overdose per se is not an AE. However, any clinical sequelae of an overdose should be reported as an AE (and serious adverse event (SAE), if appropriate). For reporting, follow the AE and SAE reporting instructions.

5.7. Rescue Therapy

No rescue therapy is required in this study.

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5.8. Product Assignment

Subjects will be assigned to study product in accordance with the randomization schedule generated by the Biostatistics Department, GSKCH, prior to the start of the study, using validated internal software.

5.8.1 Randomization

A unique screening number will identify each subject screened for study participation. Screening numbers will be assigned in ascending numerical order as each subject signs their consent form. Subjects who meet all inclusion and exclusion criteria will be randomized according to the randomization schedule. Randomization

numbers will be assigned in ascending numerical order as each subject is determined

to be fully eligible, and the randomization will follow a Williams’ square design for a 5x5 crossover study.

5.8.2 Blinding The examiner, personnel performing the plaque analysis, study statistician and other

employees of the Sponsor who may influence study outcomes are blinded to the

product allocation of subjects.

Treatments will be coded and blinded so that the analyst and examiner (plaque sample collector) will not have access to the study treatment decodes.

5.8.3 Code Breaks The blind must only be broken in an emergency where it is essential to know which

product a subject received in order to give the appropriate medical care. Wherever

possible the Investigator (or designee) must contact the Sponsor prior to breaking the blind. The investigator must document the reason for breaking the code and sign and date the appropriate document.

Two randomization schedules, one with and one without product decodes, will be sent to the site. The randomization schedule without product decodes will be used to manage the allocation of study treatments to subjects. The randomization schedule with product decodes will be contained in a tamper evident sealed envelope and will be masked with scratch off labels. The treatment decodes may only be revealed in case of emergency.

The study blind must be returned to GSKCH at the end of the study.

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5.9. Packaging and Labelling

The contents of the label will be in accordance with all applicable regulatory requirements and will be the responsibility of the Clinical Supplies Department, GSKCH.

The washout product (Aquafresh Extreme Clean Whitening Fluoride Toothpaste

(CCI )) will be sourced from the US market in commercial packaging. This

product will not be overwrapped but will have a study label affixed to the tube to indicate “Washout” Toothpaste.

The Negative non-SLS control toothpaste (Aquafresh Big Teeth Fluoride Toothpaste (CCI )), positive control toothpaste (Crest ProHealth Clean Mint Toothpaste, US marketplace product), Negative SLS-containing control toothpaste (Aquafresh Extreme Clean Whitening Fluoride Toothpaste (CCI )) and both the experimental treatment toothpastes will be overwrapped in opaque vinyl to maintain

as much study blind as possible. All treatment toothpaste tubes will be labelled

clearly to indicate the study product code.

Each study label will contain, but not limited to, protocol number, treatment product code letter, directions of storage, emergency contact telephone number and “For clinical trial use only”.

All treatment products will be supplied to the site in study product code specific shippers; each shipper will be clearly labeled with the relevant treatment product code as detailed on the randomization schedule.

All sundry items will be supplied in their commercial packaging for use by the site

staff as required.

Care should be taken with the supplied products and their labels so that they are

maintained in good condition. It is important that all labels remain intact and legible for the duration of the study. Subjects should be instructed to not remove or deface any part of the study label.

5.9.1. Accountability of Product All products supplied are for use only in this clinical study and should not be used for any other purpose.

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The investigator or designee will maintain a full record of study product accountability. A Product Dispensing Log must be kept current and will contain the following information:

 The identification of the subject to whom the study product was dispensed.  The date(s) and quantity of the study product dispensed to the subject.  The date(s) and quantity of the study product returned by the subject (if applicable).

The inventory must be available for inspect ion by the study monitor during the study. At the end of the study, study product supplies will be verified by the monitor. Study product supplies will then be either collected by the study monitor or returned by the

investigator or designee to the GSKCH Clinical Supplies Department or designated

vendor.

5.9.2. Storage of Product Study product supplies must be stored in compliance with the label requirements in a secure place with limited or controlled access.

6. STUDY ASSESSMENTS AND PROCEDURES

Plaque-containing swabs will be placed in labelled, capped, sterile tubes and stored on ice until processed for plaque acidogenicit y and viability by regrowth and by

live:dead stain. Analysis of the samples will commence within 3hrs of collection.

The plaque samples will be processed in accordance with the plaque glycolysis and

regrowth work instruction (Intertek PGRM WI, 2013) to assess the plaque for acidogenicity (glycolysis) and viability by regrowth. Samples for viability by live:dead stain will be processed according to Intertek Live-Dead Stain WI, 2015.

Plaque Glycolysis: The plaque acidogenicit y test gives a ‘terminal value’ for pH due to generation of acid from metabolism of sucrose on completion of the test. The terminal value for pH obtained for the sample at each time-point will be subtracted from the terminal value for pH obtained for the Pre-treatment sample (Pre-treatment pH – Post treatment pH) to give a value for the degree of inhibition of plaque glycolysis at that time-point.

Plaque Viability by regrowth: The regrowth assay gives a value for the turbidity (assessed by optical absorbance at 600nm) of the sample at the start and end of a defined period of incubation in growth medium. Viable cell growth in the medium during the assay generates an increase in turbidity. The absorbance at the end of the

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incubation period is divided by the absorbance at the start, giving a ratio, ‘r’. The value for r for the sample at each time point will be subtracted from the value for the Pre-treatment sample (Pre-treatment ‘r’ – Pos t treatment ‘r’) to give a value for the

degree of inhibition of viability (by regrowth) due to treatment for that time-point.

Plaque Viability by live:dead stain: The live:dead stain assay gives a value for the

relative proportion of living and dead bacteri a in a test sample: i.e. a ratio of live:dead cells. The value for this ratio for the sample at each time point will be subtracted from the value for the Pre-treatment sample (Pre-treatment live:dead ratio – Post treatment live:dead ratio) to give a value for the degree of inhibition of viability (by live:dead stain) due to treatment for that time -point.

6.1. Visit 1 - Screening Visit (Day 0)

6.1.1. Informed Consent

The investigator, or designee, must obtain written (signed and dated by the subject) informed consent from each subject participating in this study after adequate explanation of the aims, methods, objectives, and potential hazards of the study.

The investigator, or designee, must also explain to the subjects that they are completely free to refuse to enter the study or to withdraw from it at any time. Appropriate forms for documenting a written consent will be provided by the

investigator or by GSKCH. The investigator, or designee, should sign and date the

consent form to confirm that the consent process was completed correctly. The subject will be provided with a copy of thei r signed and dated consent form and any other written information which they should be instructed to retain.

If, during a subject’s participation in the study , any new information becomes available that may affect the subject’s willingness to participate in the study, each ongoing subject should receive a copy of this new information and be re-consented into the study. Subjects should be provided with a copy of the signed and dated amended consent form. The date of consent will be recorded on the CRF.

6.1.2. Demographics The following demographic variables will be captured by the Investigator or designee and recorded on the CRF: age, year of birth and gender.

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6.1.3. Medical History and Concomitant Medication

Medical history will be assessed as related to the inclusion/exclusion criteria by the

Investigator or medically qualified designee. Details of any relevant medical or surgical history (within the last year), including allergies or drug sensitivity, will be recorded on the CRF. Any concomitant therapy taken in the 30 days prior to the Screening Visit and throughout the study will also be recorded.

6.1.4 Dispense Washout Product

Provision of a standard fluoride toothpaste (washout toothpaste), to use twice-daily for the duration of the study (apart from on the morning of Visit 2 and Visits 3-7).

6.2. Visits 2 Baseline and Plaque Assessment

6.2.1. Full Oral Soft Tissue Examination An oral soft tissue (OST) examination will be completed at the Screening and

Treatment visits as indicated in the schedule of events. The examination will be accomplished by direct observation and palpat ion with retraction aids as appropriate. This procedure will include examination of the mucosa (including lips), gingival mucosa, hard and soft palates, mucogingival folds, tongue, sublingual and submandibular areas, salivary glands and tonsilar and pharyngeal areas. The results of the examination will be recorded as either normal or abnormal with details of any abnormalities. Abnormalities, or worsening of pre-existing conditions, occurring from

first use of investigational product will be recorded as AEs.

6.2.2. Plaque Assessment

Baseline plaque sample collection from the entire dentition at the plaque/gum interface (buccal and lingual surfaces), with a single sterile rayon-tipped swab. The swab will be placed in a labelled, capped, sterile tube and stored on ice until

processed for plaque acidogenicity (according to Intertek PGRM WI, 2013).

Subjects with plaque sample acidogenicity within the range pH 5.0 – 5.7 will progress on to the treatment phase of the study. They will be informed via a telephone call.

Those with plaque sample acidity outside this range will be discontinued at this point and will proceed to study conclusion but will return to site for a final OST.

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6.3. Visits 3-7 (Treatment visits)

6.3.1. Full Oral Soft Tissue Examination

An oral soft tissue (OST) examination will be completed at the Screening and Treatment visits as indicated in the schedule of events (see Section 6.2.1).

6.3.2. Pre-treatment Plaque Collection Undergo collection of Pre-treatment plaque samples from the subject’s maxillary

dentition (right quadrant only) at the plaque/gum interface (buccal and lingual

surfaces) with a single sterile rayon-tipped swab, being careful to avoid contact with the oral soft tissue. 6.3.3. Randomisation

Subjects will be randomised to the order in which they will test the five treatments (Visit 3 only)

6.3.4 Treatment

Subjects will swill with a pre-prepared slurry of 1.5 g toothpaste in 10 mL water (prepared according to Intertek WI-TPS, 2013) around their mouth for 60 seconds, making sure that the slurry contacts the entire dentition.

They will then expectorate the toothpaste slurry then rinse with 10ml of water.

They will then undergo collection of further plaque samples at 15 minutes (±2

minutes) post treatment from the subject’s left maxillary quadrant (buccal and lingual surfaces), 45 minutes (±2 minutes) post treatment from the subjects left mandibular quadrant (buccal and lingual surfaces) and 90 minutes (±5 minutes) post treatment from the subjects right mandibular quadrant (buccal and lingual surfaces), each time with a new sterilised swab.

The swabs from all collections will be placed in a labelled, capped, sterile tubes and immediately stored on ice until processed fo r plaque acidogenicity, and viability by both regrowth according to Intertek PGRM WI, 2013and live:dead stain, according to Intertek Live-Dead Stain WI, 2015. 6.3.5. Full Oral Soft Tissue Examination Subjects will undergo a full OST examination post treatment. 6.3.6 Exit the study (at final visit only) Once subjects have completed all phases of the study they then exit the study.

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7. SAFETY ASSESSMENTS

7.1. Definitions of an Adverse Event and Serious Adverse Event

7.1.1. Adverse Events

The investigator or site staff will be responsible for detecting, documenting and

reporting events that meet the definition of an AE or SAE.

AEs will be collected from the first use of investigational product and until 5 days following last administration of the study product.

Adverse Event Definition:

 An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of an investigational product, whether or not considered related to the investigational product.  NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of an investigational product.

Events meeting AE definition include:

 Any abnormal laboratory test results (if applicable) or other safety assessments, including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgment of the investigator.  Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition.  New condition(s) detected or diagnosed after study product administration even though it may have been present prior to the start of the study.  Signs, symptoms, or the clinical sequelae of a suspected interaction.  Signs, symptoms, or the clinical sequelae of a suspected overdose of either study product or a concomitant medication (overdose per se will not be reported as an AE/SAE).

Events NOT meeting definition of an AE include:

 Any clinically significant abnormal laboratory findings (if applicable) or other abnormal safety assessments which are associated with the underlying disease,

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unless judged by the investigator to be more severe than expected for the subject’s condition.  The disease/disorder/ condition being studied or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition..  Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is an AE.  Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital).  Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

7.1.2. Serious Adverse Events

Serious Adverse Event is defined as any untoward medical occurrence that, at any dose:

A. Results in death

B. Is life-threatening

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an

event in which the subject was at risk of death at the time of the event. It does

not refer to an event, which hypothetically might have caused death, if it were

more severe.

C. Requires hospitalization or prolongation of existing hospitalization

NOTE: In general, hospitalization signifies that the subject has been detained

(usually involving at least an overnight stay) at the hospital or emergency

ward for observation and/or treatment that would not have been appropriate in

the physician’s office or out-patient setting. Complications that occur during

hospitalization are AEs. If a complication prolongs hospitalization or fulfills

any other serious criteria, the event is serious. When in doubt as to whether

“hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

D. Results in disability/incapacity NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions.

This definition is not intended to include experiences of relatively minor

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medical significance such as uncomp licated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life funct ions but do not constitute a substantial disruption.

E. Is a congenital anomaly/birth defect

F. Other Situations  Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervent ion to prevent one of the other outcomes listed in the above definition. These should also be considered serious.  Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsio ns that do not result in hospitalization or development of drug dependency or drug abuse or reports of spontaneous abortion.

7.2. Recording Adverse Events and Serious Adverse Events

Recording of adverse events and serious adverse events:

 The investigator or site staff will be responsible for detecting, documenting and reporting events that meet the definit ion of an AE or SAE.  The investigator or site staff will then record all relevant information regarding an AE/SAE in the CRF.  There may be instances when copies of medical records for certain cases are requested by GSK. In this instance, all subject identifiers, with the exception of the subject number, will be blinded on the copies of the medical records prior to submission of to GSK.  The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis will be documented as the AE/SAE and not the individual signs/symptoms. Clinical AEs will be described by diagnosis and not by symptoms when possible (e.g., upper respiratory tract infection, seasonal allergy, etc. instead of runny nose).  AEs will be collected from the start of the investigational product and until 5 days following last administration of the study product.  SAEs will be collected over the same time period as stated above for AEs.

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However, any SAEs assessed as related to study participation (e.g., investigational product, protocol mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact.  Medical conditions reported prior to the time period for reporting AEs/SAEs should be recorded as part of the subject’s medical history.

7.3. Evaluating Adverse Events and Serious Adverse Events

Assessment of Intensity:

The investigator or designee will make an assessment of intensity for each AE and SAE reported during the study and will assign it to one of the following categories:

 Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.  Moderate: An event that is sufficient ly discomforting to interfere with normal everyday activities  Severe: An event that prevents normal everyday activities. - an AE that is assessed as severe will not be confused with an SAE. Severity is a category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe.

Note: An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as described in the definition of an SAE.

Assessment of Causality:

 The investigator is obligated to assess the relationship between study product and the occurrence of each AE/SAE.  A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.  The investigator will use clinical judgment to determine the relationship.  Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the study product will be considered and investigated.  The investigator will also consult the Investigator Brochure (IB) and/or Product Information, for marketed products, in the determination of his/her

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assessment.  For each AE/SAE the investigator must document in the medical notes (source document) or CRF that he/she has reviewed the AE/SAE and has provided an assessment of causality.  There may be situations when an SAE has occurred and the investigator has minimal information to include in the initial report to GSK. However, it is very important that the investigator always make an assessment of causality for every event prior to the initial transmission of the SAE data to GSK.  The investigator may change his/her opinion of causality in light of follow-up information, amending the SAE data collection tool accordingly.  The causality assessment is one of the criteria used when determining regulatory reporting requirements.

7.4. Reporting Adverse Events and Serious Adverse Events

AE Reporting to GSKCH:

 AEs will be recorded in the AE sect ion of the CRF.  Medical conditions recorded by the subject on a diary card or similar document that meet the definition of an AE must also be recorded in the AE section of the CRF, if not previously well-characterized by the investigator in the subject’s medical history.  AEs elicited by the investigator in a standard manner at the study visits should also be recorded in the AE section of the CRF. The investigator or designee must ask the subject the following question during each visit including any follow-up visits: “Have you felt unwell, experienced any symptoms or taken any medication (since your last visit) (today) (since your last dose) (since the last session)?”

 The medically qualified investigator should review adverse events in a timely

manner; this review should be documented in writing in the source document

or in the CRF.  After the study is completed at a given site, and the site has received their study data on Compact Discs (CDs), the electronic data collection tool will be removed from the internet to prevent the entry of new data or changes to existing data.

SAE Reporting to GSKCH:

A paper copy of the SAE form provided in the investigator study master file should

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be completed as fully as possible.

It is essential to enter the following informat ion:

 Protocol and subject identifiers  Subject’s demography  Description of events, with diagnosis if available  Investigator opinion of relationship to study product (see section 8.3)  Criterion for seriousness.

The following are desirable and are of particular relevance for investigator and GSKCH assessment of the SAE report:

 Date of onset of AE  Date AE stopped, if relevant  Study product start date  Study product end date if relevant  Action taken on study product  Outcome if known

The SAE form, completed as fully as possible, and SAE fax cover sheet must be faxed or e-mailed to the appropriate GSKCH Study Manager as soon as possible, but

not later than 24 hours after study site personnel learn of the event. The GSKCH Study Manager should be notified of the situat ion by telephone or email.

Fax Serious Adverse Events to: UK: PPD

The GSKCH Study Manager will be responsible for forwarding the SAE form to the

Case Management Group, Global Clinical Safet y and Pharmacovigilance, the Medical Director responsible for the study and other GSKCH personnel as appropriate via email.

The initial report will be followed up with more information as relevant, or as requested by the GSKCH study manager.

7.5. Follow-up of Adverse Events and Serious Adverse Events

Follow-up of AEs and SAEs:

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 After the initial report, the investigator is required to proactively follow up with each subject and provide further information on the subject’s condition.  All AEs/SAEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up.  The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations as may be indicated or as requested by GSK to elucidate as fully as possible the nature and/or causality of the AE or SAE.  Investigators are not obliged to actively seek AEs or SAEs in former subjects. However, if the investigator learns of any SAE, including the death, at any time after a subject has been discharged from the study, and considers the event reasonably related to the invest igational product or study participation, the investigator will promptly notify GSKCH.  The investigator will submit any updated SAE data to GSK within the designated reporting time frames.

Regulatory and ethics reporting requirements for SAEs:

 The investigator will promptly report all SAEs to GSKCH within the designated reporting timeframes (within 24 hours of learning of the event). GSKCH has a legal responsibility to notify, as appropriate, the local regulatory authority and other regul atory authorities about the safety of a product under clinical investigation. Prompt notification of SAEs by the investigator to GSKCH is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.  GSKCH will comply with country specific regulatory requirements relating to safety reporting to the regulatory authori ty, IEC and investigators.  Investigator safety reports are prepared according to GSKCH policy and are forwarded to investigators as necessary. An investigator safety report is

prepared for a SAE(s) that is both attributable to investigational product and

unexpected. The purpose of the report is to fulfill specific regulatory and

GCP requirements, regarding the product under investigation.  An investigator who receives an investigator safety report describing a SAE(s) or other specific safety information (e.g., summary of listing of SAEs) from GSKCH will file it with the Investigator Brochure (or safety statement) and will notify the IEC, if appropriate according to local requirements.

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7.6. Collection of Pregnancy Information

7.6.1. Time Period for Collecting of Pregnancy Information

Collection of Pregnancy Information:

 Pregnancy information will be collected on all pregnancies reported following administration of any investigational product (or washout product). Information on pregnancy identified during the screening phase and prior to investigational product (or washout product) administration does not need to be collected.

7.6.2. Action to be Taken if Pregnancy Occurs

Action to be Taken:

 The investigator will collect pregnancy information on any subject who becomes pregnant while participating in the study after administration of the investigational product (or washout product). The investigator will record pregnancy information on the appropriate form and submit it to GSKCH within 2 weeks of learning of the subject becoming pregnant. The subject will be followed to determine the outcome of the pregnancy. Information on the

status of the mother and infant / neonate (including concomitant medications

taken by the mother during the pregnancy ) will be forwarded to GSKCH. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any terminat ion of the pregnancy will be reported.  While pregnancy itself is not considered to be an AE, any pregnancy complication or elective termination for medical reasons will be recorded as an AE or SAE.

 A spontaneous abortion is always considered to be an SAE and will be

reported as such. An SAE occurring in association with a pregnancy, brought to the investigator’s attention after the subject completed the study and considered by the investigator as possibly related to the investigational product, must be promptly forwarded to GSK.  While the investigator is not obliged to actively seek this information in former study participants, he or she may learn of an SAE through spontaneous reporting.  There is no requirement for the subject to be withdrawn from the study as a result of the pregnancy. However if they are withdrawn, this should be

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recorded in the appropriate section of the CRF.

8. DATA MANAGEMENT

For this study subject data will be entered into an electronic case report form, using a GSKCH validated data system.

8.1. Source Documents/ Data

The source documents (e.g. hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluat ion checklists, pharmacy dispensing records, recorded data from automated instruments, microfiches, photographic

negatives, microfilm or magnetic media, x-rays, subject files and records kept at the

pharmacy, at the laboratory and at the medico -technical departments involved in the clinical study) which contain the source of data recorded in the CRF should be specified in the Source Document Designat ion Form. In some cases the CRF can be used as a source document.

Each subject will be assigned and identified by a unique Screening Number. Any reference made to an individual subject within the study must be done using the unique Screening Number.

8.2. Electronic Case Report Form

A CRF is a printed, optical, or electronic document designed to record all of the

protocol required information to be reported to the sponsor on each trial subject.

For each subject who has given informed consent/assent and has been screened, CRF must be completed and signed by the Principal Investigator (or authorized designee) to certify that the data are complete and correct.

Management of clinical data will be performed in accordance with applicable GSKCH standards and data cleaning procedures to ensure the integrity of the data e.g. removing errors and inconsistencies in the data.

In order to protect the privacy of subjects, no Personally Identifiable Information (PII) (including the subject's name or initials or birth date) is to be recorded in the CRF or as part of the query text.

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Adverse events and concomitant medicatio ns terms (if applicable) will be coded using MedDRA (Medical Dictionary for Regul atory Activities) and an internal validated medication dictionary, GSKDrug.

Subject data will be entered into GSKCH defined CRFs and transmitted electronically

to GSKCH in a validated (21 CFR Part 11 compliant) web-based electronic data TM capture system (InForm ).

All CRF pages should be completed during a subject assessment when the CRF has been designated as the source. Data that is sourced elsewhere should be entered into the CRF in an agreed upon timeframe between the Investigator and Sponsor.

The CRFs (including queries, query responses and audit trails) will be retained by GSKCH. Site data archived compact discs (CD(s)) prepared by a third party will be sent to the investigator to maintain as the investigator copy following the decommissioning of the study.

8.3. Data Handling

Documentation of all data management activit ies should allow step-by-step

retrospective assessment of data quality and study performance. Any changes or corrections to data will be performed in the Electronic Data Capture (EDC) System, and it will include rationale for changes. The EDC system has an audit trail, which will provide a complete record of the changes and corrections endorsed by the Investigator.

8.3.1. Data Queries

Programmed edit checks will be generated automatically, as the data is being entered into the system. Data Management will also run reports and listings on the CRF data, in addition to the queries already programmed and generated by the system, to raise manual queries as needed for site clarificatio n or correction. The Clinical Dictionary Development and Management Group will raise queries as needed on safety data to code the terms (Adverse Events and Drugs) are reported appropriately.

The study monitor at the study site will review the CRFs in accordance with the monitoring plan, and any queries will be generated in the EDC System to the Investigator or designee, enabling the errors to be addressed in parallel with Data Management review. Monitor can also run reports and listings on the CRFs, to raise manual queries as needed for site clarification or correction.

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8.4. External Data

External Data are subject data obtained externally to the CRF. These data are generated from laboratory instruments, com puters or other sources and then transcribed into a file and format agreed upon by GSKCH to identify the subject and

time point referenced in the CRF and/or protocol.

An agreed upon quality control process is performed against the transcribed data to

the source to ensure the accuracy of the transcri ption. The transcribed data is transmitted in an agreed upon format to GSKCH via a secure web portal.

Proper reconciliation will be performed between the transcribed data and the clinical database to ensure subject and time point referenced in the Clinical Database match before Clinical Database Freeze (locking of the database) can occur.

9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES

9.1 Sample Size Determination

have 80% power to show a difference of 7.0 in AUCgly(0-90) between treatment groups,

at the 2-sided 5% level of significance. A difference of 7.0 in AUCgly(0-90) represents approximately 1/3 of the difference observed in the previous study between the test toothpaste (0.454% Stannous Fluoride) and negative (non-SLS containing) control toothpaste, and is an effect that is considered large enough to be of interest and hence influence the design of subsequent studies. In GSK Clinical Study RH01871, the difference between the positive and negative control toothpastes was 26.4 units. Since

the study is powered to show differences as small as 7.0 units, the impact of first

having to demonstrating study validity (posi tive control superior to negative control) will have only a negligible effect on the overall power of the primary objective (Test Zinc-IPMP toothpaste versus the non-SLS-negative control toothpaste).

Allowing for subject dropouts and protocol violators, a maximum of 45 subjects will be randomized.

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9.2. General Considerations

9.2.1. Definition of Analysis Populations

The intent to treat (ITT) population is defined as those subjects who are randomized, receive at least one dose of study product and have at least one post-baseline efficacy measurement.

The Per Protocol (PP) population is defined as those subjects in the ITT population who have at least one assessment of efficacy considered unaffected by protocol violation. Assessments of efficacy considered affected by protocol violation will be excluded from PP analyses.

Since this is an experimental study to establish the efficacy of test toothpastes in a

well controlled environment and in subjects who are fully compliant with the

protocol, only those subjects with no major protocol deviations will be included in the primary analysis population. Consequently, the primary population will be the PP population.

Subjects who are randomized and have received at least one dose of study product will be considered evaluable for the safety popul ation.

9.2.2. Exclusion of Data from Analysis

Data listings of protocol violations, but not necessarily limited to those listed below will be reviewed. Those protocol violations considered to have had affected efficacy will lead to exclusion of either subject or data from PP analyses:

1. Major violation of inclusion or excl usion criteria.

2. Significant non-compliance with the product administration procedure

3. Significant non-compliance with the visit schedule 4. Use of prohibited treatment or medication before or during the study

5. Medical history which is deemed to affect efficacy

6. Not receiving the assigned treatment as specified by the randomization schedule

All protocol violations reported and their impact on efficacy analyses will be determined between the Biostatistician and Medical Director or designee, ahead of database lock and unblinding.

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9.2.3. Criteria for Evaluation

Primary evaluation will be based on efficacy. Safety aspects will also be looked into.

9.2.4. Criteria for Assessing Efficacy

The primary outcome measure of the study will be considered valid if a statistically significant difference is observed between the positive control toothpaste and the non- SLS-negative control toothpaste with respect to mean glycolysis activity inhibition

over the sampling time period (AUCgly (0-90)). If no such difference is observed, no

further analysis will be performed for this en d-point.

Following demonstration of the validity of the primary outcome measure, the success criterion for this study is to observe a statist ically significant difference between the Test Zinc-IPMP toothpaste and the non-SLS -negative control toothpaste, with respect to AUCgly (0-90).

9.2.5. Criteria for Assessing Tolerability

Safety will be assessed with respect to adverse events (AEs) and OST abnormalities (oral tolerability).

9.2.6. Handling of Dropouts and Missing Data No data will be imputed.

9.3. Statistical Methods and Analytical Plan

Additional details of the proposed statistical analysis will be documented in the

statistical analysis plan (SAP), which will be written following finalization of the

protocol and prior to study unblinding.

9.3.1. Demographic and Baseline Characteristics Categorical measures (gender and race) will be tabulated by the number and percentage of subjects in each category. Descriptive statistics for continuous measures will include the number of subjects, mean, median, standard deviation and minimum/maximum.

9.3.2. Statistical Analyses All efficacy analyses will be performed using the PP population only, with subjects analysed as per randomized treatment.

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Primary Endpoint:

The primary endpoint of interest in this exploratory study is AUCgly(0-90).

This will be calculated as the net incremental AUC using the trapezoidal rule (i.e., areas above the baseline contribute a positive value and areas below the baseline

contribute a negative value in the overall calculation of the AUCgly(0-90)). In the event

of missing or unevaluable data, the AUC will not be calculated; no imputation

method will be used.

business decisions. Since the primary comparison of interest for the evaluation of the

efficacy of the test product is pre-specified, and all other comparisons are only of secondary interest, no adjustment for multiple comparisons is planned.

The primary hypotheses, relating to the study ’s success criteria, are as follows:

1. To test for study validity:

H10: The population means of AUC gly(0-90) for positive and non-SLS- negative control toothpastes are the same.

H1A: The population means of AUC gly(0-90) for positive and non-SLS- negative control toothpastes are different.

2. To test for efficacy of the test toothpaste:

H20: The population means of AUCgly(0-90) for test and non-SLS-negative control toothpastes are the same.

H2A: The population means of AUCgly(0-90) for test and non-SLS-negative control toothpastes are different.

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treatment values as covariates in the model. The pre-treatment values refer to the plaque samples collected prior to supervised treatment on each treatment day.

From the above model, treatment differences and associated 95% confidence intervals and p-values will be presented. All tests will be two-sided and performed at the 5%

significance level under a null hypothesis of no difference between treatments.

Adjusted means and standard errors per treatment group will also be presented.

The assumptions of normality and homogenei ty of variance will be investigated. If the assumptions are violated, a suitable transformation or a non-parametric test may be performed.

Secondary Endpoints:

One secondary endpoint of interest in this exploratory study is AUCregrowth(0-90). This will be calculated as net incremental AUC, and analysed using the same ANCOVA methodology as for the primary endpoint.

Another secondary endpoint of interest in this exploratory study is AUClive:dead(0-90) . This will be calculated as net incremental AUC, and analysed using the same

ANCOVA methodology as for the primary endpoint.

For both of the secondary endpoints, the same step-wise testing procedure will be used as for the primary endpoint, whereby the validity of the endpoint is first assessed from the comparison of the positive control to the non-SLS-negative control. If no such difference is observed in the end-point, no further analysis will be performed for that end-point.

Unadjusted means and standard errors (for observed values and change from pre- treatment values) will be presented for the glyco lysis, regrowth and live:dead stain values, per time-point, for each treatment.

Safety:

Safety will be assessed based on Safety population. All AEs will be coded using MedDRA. AEs will be categorized as oral and non-oral by the Medical Director or designee prior to database lock. Treatment-emergent AEs will be tabulated by treatment group.

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10. STUDY GOVERNANCE CONSIDERATIONS

10.1. Posting of Information on Publicly Available Clinical Trials Registers

Study information from this protocol will be posted on publicly available clinical trial registers before enrollment of subjects begins.

10.2. Regulatory and Ethical Considerations, Including the Informed Consent

The study will be conducted in accordance with all applicable regulatory

requirements, and with GSK policy.

The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all applicable subject privacy requirements, and the guiding principles of the current version of the Declaration of Helsinki. This includes, but is not limited to, the following:

 Before initiating a trial, the investigator/institution should have written and dated approval/favorable opinion from the IEC for the trial protocol (including amendments), written informed consent form, consent form updates, subject

recruitment procedures (e.g., advertisements), investigator brochure/ safety statement (including any updates) and any other written information to be provided to subjects. A letter or certificate of approval will be sent by the investigator to the sponsor prior to init iation of the study, and also when subsequent amendments to the protocol are made.  Signed informed consent to be obtained for each subject before participation in the study (and for amendments as applicable)

 Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IEC)  GSK will provide full details of the above procedures, either verbally, in writing, or both.

10.3. Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, GSK or designee (i.e. third party vendor) monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements.

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When reviewing data collection procedures, the discussion will include identification, agreement and documentation of data items for which the CRF will serve as the source document.

GSK or designee will monitor the study and site activity to verify that the:

 Data are authentic, accurate, and complete.  Safety and rights of subjects are being protected.  Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.

The extent and nature of monitoring will be described in a written monitoring plan on

file at GSKCH. The investigator (or designee) agrees to allow the monitor direct

access to all relevant documents and agrees to co-operate with the monitor to ensure that any problems detected in the course of these monitoring visits are resolved.

10.4. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study.

In the event of an assessment, audit or inspect ion, the investigator (and institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all

relevant documents and to allocate their time and the time of their staff to discuss the

conduct of the study, any findings/relevant issues and to implement any corrective and/or preventative actions to address any findings/issues identified.

The sponsor will be available to help investigators prepare for an inspection.

10.5. Conditions for Terminating the Study

Upon completion or premature discontinuation of the study, the GSKCH monitor will conduct site closure activities with the investigator or site staff, as appropriate, in accordance with applicable regulations including GCP, and GSKCH Standard Operating Procedures.

Both GSKCH and the Investigator reserve the right to temporarily suspend or prematurely discontinue this study at any time for reasons including, but not limited

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to, safety or ethical issues or severe non-co mpliance. For multicenter studies (if applicable), this can occur at one or more or at all sites.

If the trial is prematurely terminated or suspended for any reason, the investigator site should promptly inform the trial subjects and should assure appropriate therapy/

follow-up for the subjects. Where required by the applicable regulatory requirements,

GSKCH should inform the regulatory authori ty(ies).

In addition:

 If the investigator terminates or suspends a trial without prior agreement of

GSKCH, the investigator site should promptly inform the sponsor and the IEC, and should provide the sponsor and the IEC a detailed written explanation of the termination or suspe nsion.  If the GSKCH terminates or suspends a trial, the investigator should promptly inform the IEC and provide the IEC a detailed written explanation of the termination or suspension.

 If the IEC terminates or suspends its approval/favorable opinion of a trial, the

investigator should promptly notify the GSKCH and provide GSKCH with a detailed written explanation of the terminat ion or suspension.

10.6. Records Retention

Following closure of the study, the investigator must maintain all site study records (except for those required by local regulations to be maintained elsewhere), in a safe and secure location.

The records (study/ site master file) must be maintained to allow easy and timely retrieval, when needed (e.g., for a GSK audit or regulatory inspection) and must be

available for review in conjunction with assessment of the facility, supporting

systems, and relevant site staff. Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken.

The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.

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The investigator must assure that the subject’s anonymity will be maintained. On CRFs or other documents submitted to GSKCH, subjects should not be identified by their names or initials, but by an identificat ion code. The investigator should keep a

separate log of subjects’ codes, names and addresses. Documents not for submission

to GSKCH, e.g. subjects’ written consent forms, should be maintained by the investigator in strict confidence.

GSK will inform the investigator of the time period for retaining these records to comply with all applicable regulatory requi rements (GSKCH recommends that documents be kept for 10 years). The invest igator is also required to keep subject identification codes on file for at least 15 years after completion or discontinuation of the study. The minimum retention time will meet the strictest standard applicable to

that site for the study, as dictated by any institutional requirements or local laws or

regulations, GSK standards/procedures, and/or institutional requirements.

No study document should be destroyed wi thout a prior written agreement between GSKCH and the investigator. The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, archival at an off-site facility or transfer of ownership of the records in the event the investigator is no longer associated with the site.

10.7. Provision of Study Results to Investigators, posting of Information on Publicly Available Clinical Trials Registers and

Publication

Where required by applicable regulatory requi rements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.

The procedures and timing for public disclosure of the results summary and for development of a manuscript for publication will be in accordance with GSK Policy.

A manuscript will be progressed for publication in the scientific literature if the results provide important scientific or medical knowledge.

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11. REFERENCES

Ainamo, J. Control of plaque by chemical agents. Journal of Clinical Periodontology 1977:4; 23–35.

Albandar JM, Periodontal diseases in North America. Periodontology 2000. 2002;29: 31-69

Brook I, Microbiology and management of periodontal infections. General Dentistry 2003; 51:242-428.

Cummins D, Creeth J E. Delivery of antiplaque agents from toothpastes, gels and mouthwashes. J Dent Res. 1992; 71: 1439-1449.

Drisko, C. H. (2001) Nonsurgical periodontal therapy. Periodontology 2000, 2001:25;

77–88

Fejerskov O, Kidd EAM. Dental Caries: The Disease and its clinical management.

Blackwell Munksgaard 2003 p207-208.

Hancock EB. Periodontal diseases: prevent ion. Annals of periodontology 1996, 1, 223-249.

ICH Topic 6 Guideline for Good Clinical Pract ice CPMP/ICH/135/95 17th July 1996.

Intertek Live-Dead Stain WI, 2015

Intertek PGRM WI 2013

Intertek WI-TPS, 2013: Toothpaste Slurry Manufacture Work Instruction.

Kinane DF, Hodge PJ. Periodontal disease in children and adolescents: introduction and classification. Periodontology 2000, 2001; 26; 7-15.

Marsh, PD. Microbiological Aspects of the Chemical Control of Plaque and Gingivitis. Journal of Dental Research 1992;71:1431-1438.

Oliver RC, Brown LJ, Loe H. Periodontal diseases in the United States population. Journal of Periodontology, 1998; 69:269-278.

Ower P. The role of self-administered plaque control in the management of periodontal disease: I. A review of the evidence. Dental Update 2003; 30:60-68.

PGRM, 2012. Plaque Glycolysis and Regrowth Model Work Instruction.

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Quigley G, Hein J. Comparative cleansing efficacy of manual and power brushing. J Am Dent Assoc. 1962;65:26-29.

Riley P, Lamont T. Triclosan/copolymer containing toothpastes for oral health. Cochrane Database Syst Rev. 2013;12:CD010514. doi:

0.1002/14651858.CD010514.pub2.

Saxton CA, Svatun B, Lloyd AM. Antiplaque effects and mode of action of a

combination of zinc citrate and a nonionic antimicrobial agent. Scand J Dent Res.

1988;96(3):212-7.

Scheie AA. Modes of action of currently known chemical anti-plaque agents other than chlorhexidine. Journal of Dental Research 1989;68:1609-1616.

Study RH01871. An Exploratory Study to Investigate the Antimicrobial Activity of a Toothpaste in a Plaque Glycolysis and Regrowth Model.

Study RH02517. In-house study to determine the effect of two zinc-containing toothpaste formulations on viability of bacteria in saliva.

Svatun B, Saxton CA, Huntington E, Cummins D. The effects of three silica

dentifrices containing Triclosan on supragingival plaque and calculus formation and

on gingivitis. Int Dent J. 1993;43(4 Suppl 1):441-52.

ten Cate JM and Cummins D. Fluoride Toothpaste Containing 1.5% Arginine and

Insoluble Calcium as a New Standard of Care in Caries Prevention. Journal of Clinical Dentistry 2013;24:79-87.

Tinanoff, N. Review of the antimicrobial action of stannous fluoride. Journal of

Clinical Dentistry, 1990; 2:22–27.

Van Loveren, C. The antimicrobial action of fluoride and its role in caries inhibition. Journal of Dental Research, 1990; 9 (Spec No.): 676–683. White DJ. A new plaque glycoloysis and regrowth method (PGRM) for the in vivo determination of antimicrobial toothpaste/rinse efficacy towards the inhibition of plaque growth and metabolism – method development, validation and initial activity screens. J. Clin. Dent. 6, 29-36, 1995.

World Medical Association Declaration of Helsinki, 59th General Assembly, Seoul 2008

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12. APPENDICES

12.1. Appendix 1 - Abbreviations and Trademarks

Abbreviations

AE Adverse Event ANCOVA Analysis of Covariance

CD Compact Disc CRF Case Report Form

EDC Electronic Data Capture GCP Good Clinical Practice

GSKCH GlaxoSmithKline Consumer Healthcare ICH International Conference on Harmonizat ion of Technical Requirements for Registration of Pharmaceut icals for Human Use

IEC Independent Ethics Committee IRB Institutional Review Board

ITT Intention to Treat OST Oral Soft Tissue

PII Personally Identifiable Informat ion PP Per Protocol

SAE Serious Adverse Event SEM Scanning Electron Microscopy

WI Work Instruction

Trademark Information

Trademarks of the GlaxoSmithKline group of companies:

Aquafresh

Sensodyne

Pronamel

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SIGNATURE PAGE

RH205051 Synopsis

Date Signed By 29-Mar-2017 16:00:53 PPD Justification Approved

Date Signed By 30-Mar-2017 13:07:07 PPD Justification Clinical Operations Approval

Date Signed By 03-Apr-2017 06:34:24 PPD Justification Approved

Date Signed By 04-Apr-2017 05:38:48 PPD Justification Biostatistics Approval

Date Signed By

Justification

Date Signed By

Justification

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CONFIDENTIAL

STATISTICAL ANALYSIS PLAN FOR PROTOCOL 205051

A Study to Investigate the Antimicrobial Activity of two Test Toothpastes in a Plaque

Glycolysis and Regrowth Model

BIOSTATISTICS DEPARTMENT

GLAXOSMITHKLINE CONSUMER HEALTHCARE

ST GEORGE’S AVENUE

WEYBRIDGE

SURREY KT13 0DE

PPD , MSc (Statistician)

This SAP Template is associated with SP0674 V7

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Table of Contents Glossary...... 4 SAP Amendment Page...... 5 1 Introduction ...... 7

2 Objectives...... 7 Primary Objective...... 7

Secondary Objectives ...... 7 3 Study Design ...... 8 4 Sample Size Determination...... 9 5 Data Considerations ...... 9

5.1 Analysis Populations...... 9 5.2 Subgroups/Stratification ...... 10

5.3 Time Windows ...... 11 6 Demographics and Baseline Characteristics...... 11 6.1 Subject Disposition ...... 11 6.2 Demographics...... 11 6.3 Baseline Characteristics ...... 12 7 Treatment Compliance and Concomitant Medications ...... 12 7.1 Treatment Compliance ...... 12 7.2 Concomitant Medications...... 12 8 Efficacy Analysis...... 12 8.1 Primary Efficacy Analysis...... 12 8.2 Secondary Efficacy Analysis ...... 14 8.3 Other Efficacy Analysis ...... 15 9 Safety Analysis...... 16 10 Interim Analysis ...... 17 11 Topline Summary ...... 17

This SAP Template is associated with SP0674 V7

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12 Changes to Planned Analysis...... 18

13 References ...... 18

Appendix 1 Study Schedule...... 19

Appendix 2 List of Tables, Figures & Listings...... 21 Appendix 3 Templates for Tables, Figures & Listings ...... 26

This SAP Template is associated with SP0674 V7

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Glossary

AE Adverse Event

ANCOVA Analysis of Covariance AUC Area Under the Curve

GCP Good Clinical Practice

GSKCH GlaxoSmithKline Consumer Healthcare ITT Intention to Treat

MedDRA Medical Dictionary for Regulatory Activities OST Oral Soft Tissue

PGRM Plaque Glycolysis and Regrowth Model

PP Per Protocol SAP Statistical Analysis Plan

SD Standard Deviation SE Standard Error

SLS Sodium Lauryl Sulphate

This SAP Template is associated with SP0674 V7

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SAP Amendment Page

Timing of Amendment

Prior to database lock and study unblinding.

Reason for Amendment

Whilst conducting the blinded data review, it was decided that a large number of the data points are considered non-evaluable, which means that it will not be possible to calculate an AUC for several subjects. In order to extract as much information as possible from this study, additional analyses have been added, whereby the glycolysis, regrowth and live:dead stain values will be analysed and treatment comparisons performed at each time-point (15, 45 and 90 minutes). This is considered an exploratory analysis.

In addition, there is no longer a business need for a topline summary and so this has been removed.

The safety section has been revised to include standard set of AE tables.

Other typographical errors in the original SAP have been corrected.

Sections Amended

Section 8.2 Secondary Efficacy Analysis

Analysis of glycolysis, regrowth and live:dead stain values at each time-point has been added.

Section 9 Safety Analysis

Included AE tables by Oral/Non-oral categorisation.

Section 11 Topline Summary

There is no longer a business need for a topline summary and so this has been removed.

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Section 12 Changes to Planned Analysis

Analysis of glycolysis, regrowth and live:dead stain values at each time-point has been added.

Appendix 2 List of Tables, Figures & Listings

Additional tables added to include the analysis and treatment comparisons of glycolysis, regrowth and live:dead stain values at each time-point.

Added standard AE tables.

Typographical errors corrected.

Appendix 3 Templates for Tables, Figures & Listings

Additional tables added to include the analysis and treatment comparisons of glycolysis, regrowth and live:dead stain values at each time-point.

Added standard AE tables.

Typographical errors corrected.

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1 Introduction

This document describes the statistical methods and data presentations to be used in the summary and analysis of the final data from Protocol 205051.

The aim of the study is to determine, using an adaptation of the Plaque Glycolysis and Regrowth Model (PGRM) methodology, whether zinc+IPMP, or zinc alone, in a toothpaste can:

 reduce plaque bacterial metabolism.

 reduce plaque viability (by two different methods).

The statistical analysis plan (SAP) will be finalised and approved prior to database lock and study unblinding. 2 Objectives

Primary Objective To evaluate and compare the ability of a Test toothpaste containing 0.6% zinc chloride and 0.1% IPMP to inhibit plaque glycolysis compared to a non-SLS containing toothpaste.

Secondary Objectives To evaluate and compare the ability of a Test toothpaste containing 0.6% zinc chloride and 0.1% IPMP to inhibit plaque viability by regrowth as compared to a non- SLS containing toothpaste.

To evaluate and compare the ability of a Test toothpaste containing 0.6% zinc chloride and 0.1% IPMP to inhibit plaque viability by live:dead staining compared to a non-SLS containing toothpaste.

To evaluate and compare the ability of a Test toothpaste containing 0.6% zinc chloride (non-IPMP) to inhibit plaque glycolysis, and to inhibit plaque viability

(assessed by AUCregrowth and by AUClive:dead(0-90), compared to a non-SLS This SAP Template is associated with SP0674 V7

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containing toothpaste and an SLS containing toothpaste

To make all other comparisons between products in AUCgly(0-90), AUCregrowth(0-90) and AUC . live:dead(0-90)

3 Study Design

This is a single-centre, analyst and examiner (plaque sample collector)-blind, randomised, five-treatment, five-period, cross-over study in healthy adult volunteers.

In the PGRM methodology, overnight fasted dental plaque, representing natural outgrowth of biofilm, is collected from an area (typically a single quadrant) of the dentition. Topical formulations are administered in vivo, and dental plaque samples are collected from other (un-sampled) dentition areas at intervals post treatment (typically 15, 45 and 90 minutes). In vivo-treated and non-treated samples are then tested in vitro and compared for plaque glycolysis and viability. The PGRM evaluates biological factors important to antimicrobial effects in vivo, while benefiting from the improved precision and control provided by in vitro assessment. Fasted plaque is typically collected from subjects who demonstrate plaque acidogenicity (pH after incubation in sucrose solution) in the range 5.0 to 5.7. This pH window has been adopted to ensure that subjects are able to develop sufficient levels of viable acidogenic dental plaque suitable for measuring glycolysis in the PGRM assay conditions [White, 1995].

Products will be applied as aqueous slurries to ensure complete dispersion of the toothpaste in the oral environment, remove variability due to brushing, and preserve plaque for sampling. Samples will be taken up to 90 minutes post-treatment to ensure the majority of the window of effect of the agents is observed: a previous GSK PGRM study [GSK Study RH01871] indicated treatment effects are tailing off after 90 minutes. An estimate of the overall effect of the treatments on each measurement will be made: this will be achieved via determining the Area Under the Curve (AUC) of the profile of treatment deviation from Pre-treatment value, across the 90-minute measurement window.

This previous study [GSK Study RH01871] determined the bacteria-inhibiting effects of an aqueous marketed toothpaste and a non-aqueous experimental toothpaste, both containing 0.454% weight/weight (w/w) stannous fluoride. In that study, the potential plaque inhibiting activity of both toothpastes was shown to be clearly superior to a control toothpaste (which did not contain sodium lauryl sulphate (SLS)), by both inhibition of glycolysis (as AUCgly(0-90)) and inhibition of regrowth (as This SAP Template is associated with SP0674 V7

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AUCregrowth(0-90)). It is therefore planned to include one of these test toothpastes (the aqueous marketed product) as a positive control, and a non-SLS toothpaste as a negative control in the proposed study.

GSKCH has also conducted a recent study in which viability of saliva bacteria was measured effectively ex vivo using a live:dead bacterial staining assay [Study RH02517]. In this method, two DNA-staining dyes are incubated with the bacterial sample, one which stains all bacteria green, and the other which stains non-viable bacteria red. The ratio of green:red colour in the sample is a measure of relative bacterial cell viability of that sample. It is proposed to use this live:dead staining methodology in the present study, as an alternative method to assess plaque viability. In view of the above evidence from previous studies, therefore, in this study product effects on metabolism will be measured by AUCgly(0-90), and product effects on viability will be measured in two ways: by AUCregrowth(0-90) and by AUClive:dead(0-90).

4 Sample Size Determination

In a previous study with a closely related design [GSK Clinical Study RH01871], the standard deviation of the within-subject differences in AUCgly(0-90) was 15.4. Based on this same level of variability, a study with 40 complete and evaluable subjects will have 80% power to show a difference of 7.0 in AUCgly(0-90) between treatment groups, at the 2-sided 5% level of significance. A difference of 7.0 in AUCgly(0-90) represents approximately 1/3 of the difference observed in the previous study between the test toothpaste (0.454% Stannous Fluoride) and negative (non-SLS containing) control toothpaste, and is an effect that is considered large enough to be of interest and hence influence the design of subsequent studies. In GSK Clinical Study RH01871, the difference between the positive and negative control toothpastes was 26.4 units. Since the study is powered to show differences as small as 7.0 units, the impact of first having to demonstrating study validity (positive control superior to negative control) will have only a negligible effect on the overall power of the primary objective (Test Zinc-IPMP toothpaste versus the non-SLS-negative control toothpaste).

Allowing for subject dropouts and protocol violators, a maximum of 45 subjects will be randomised. 5 Data Considerations

5.1 Analysis Populations

All assessments of safety will be based on the Safety Population, defined as subjects This SAP Template is associated with SP0674 V7

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who are randomised and have received at least one dose of study product.

The intent to treat (ITT) population is defined as those subjects who are randomised, receive at least one dose of study product and have at least one post-baseline efficacy measurement.

Since this is an experimental study to establish the efficacy of test toothpastes in a well controlled environment and in subjects who are fully compliant with the protocol, only those subjects with no major protocol deviations will be included in the primary analysis population. Consequently, the primary population will be the PP population. A separate analysis will not be performed on the ITT population.

A blinded data review will be performed prior to database lock, in order to identify data to be excluded from the Per Protocol analysis. Data listings of protocol violations, but not necessarily limited to those listed below will be reviewed. Those protocol violations considered to have had affected efficacy will lead to exclusion of either subject or data from PP analyses:

1. Major violation of inclusion or exclusion criteria. 2. Significant non-compliance with the product administration procedure. 3. Significant non-compliance with the visit schedule. 4. Significant non-compliance with the plaque sampling schedule. 5. Use of prohibited treatment or medication before or during the study. 6. Medical history which is deemed to affect efficacy. 7. Not receiving the assigned treatment as specified by the randomization schedule.

Details of blinded review listings will be given in the Review Listings Requirements document. All protocol violations reported and their impact on efficacy analyses will be determined between the Biostatistician and Medical Director or designee, ahead of database lock and unblinding.

5.2 Subgroups/Stratification

There are no subgroups or stratification in this study. This SAP Template is associated with SP0674 V7

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5.3 Time Windows

The study schedule should be followed as per protocol. This includes:

 Between 2 and 10 days between treatment visits.

 Plaque sampling to be 15 minutes (±2 minutes) post treatment for the first plaque sample, 45 minutes (±2 minutes) post treatment for the second plaque sample, and 90 minutes (±5 minutes) post treatment for the final plaque sample.

Deviations from the above will be evaluated on a case by case basis to decide on exclusion from the PP population.

6 Demographics and Baseline Characteristics

6.1 Subject Disposition

The subject disposition summary will include the number of screened subjects and screen failures overall and the number of subjects randomised per treatment group and overall.

The number and percentage of subjects, in the Safety, ITT and PP populations will be presented per treatment group and overall. The percentages will be based upon the total number of subjects randomised.

The number and percentage of subjects completing the study and not completing the study, including a breakdown of the reasons for not completing the study, will be presented per treatment group and overall. The percentages are based upon the total number of subjects randomised.

A separate summary table of protocol violations leading to exclusion from PP analyses will be produced indicating the number and percentage of subjects with each violation per treatment group and overall. Percentages will be based on the ITT population.

6.2 Demographics

Summary of demographic information will include age, gender and race. Categorical measures (gender and race) will be summarised by the number and percentage of subjects in each category. Descriptive statistics for age will include the mean, This SAP Template is associated with SP0674 V7

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median, standard deviation and minimum/maximum.

6.3 Baseline Characteristics

No additional baseline characteristics are being collected in this study. 7 Treatment Compliance and Concomitant Medications

7.1 Treatment Compliance

A subject will be considered to be compliant with the treatment regimen in a particular study period if they are administered the product according to the protocol. Subjects not compliant with the treatment regimen will be reviewed prior to study unblinding for determination of major protocol violators.

7.2 Concomitant Medications

Concomitant medication data will not presented in the study report. A listing of concomitant medications will be produced for evaluation of protocol violators only.

8 Efficacy Analysis

8.1 Primary Efficacy Analysis

The primary endpoint of interest in this exploratory study is AUCgly(0-90).

This will be calculated as the net incremental AUC using the trapezoidal rule (i.e., areas above the baseline contribute a positive value and areas below the baseline contribute a negative value in the overall calculation of the AUCgly(0-90)). The basic formula for calculation of the AUC is:

where t represents time-point of assessment, and y represents response of interest. Nominal assessment times will be used for AUC calculation (i.e. 15, 45 and 90 minutes).

The AUC should be adapted to ensure that areas below the baseline value (t=0) This SAP Template is associated with SP0674 V7

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contribute a negative value to the AUC calculation. Figure 1 shows which areas should contribute a negative and positive value to the AUC calculation. In the event of missing or unevaluable data, the AUC will not be calculated; no imputation method will be used.

Figure 1 Calculation of AUC

5.9

5.8

H p

n o

t 5.7 a b u

c +A2 +A3 n I

e 5.6 u

a -A1 l P 5.5

5.4 0 15 30 45 60 75 90 Time (mins)

The AUC for the profile in Figure 1 will be calculated as A2 + A3 – A1.

For the primary endpoint, the comparison of the positive control to the non-SLS- negative control will be assessed first to test the validity of study results. If statistical significance at the 5% significance level is observed between these two treatments, hypothesis testing for the Test Zinc-IPMP toothpaste versus the non-SLS-negative control will also be assessed. P-values, point estimates and associated 95% confidence intervals will be presented for all pair-wise treatment comparisons to aid business decisions. For each endpoint, since (a) the primary treatment comparison is pre-specified, (b) a 2-stage procedure is to be implemented (the primary comparison will only be considered valid if the study validity is first confirmed), and (c) all other comparisons are only of secondary interest, no adjustment for multiple comparisons is planned.

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The primary hypotheses, relating to the study’s success criteria, are as follows:

1. To test for study validity:

H10: The population means of AUCgly(0-90) for positive and non-SLS- negative control toothpastes are the same.

H1A: The population means of AUCgly(0-90) for positive and non-SLS- negative control toothpastes are different.

2. To test for efficacy of the test toothpaste:

H20: The population means of AUCgly(0-90) for the Test zinc-IPMP

toothpaste and non-SLS-negative control toothpaste are the same.

H2A: The population means of AUCgly(0-90) for the Test zinc-IPMP toothpaste and non-SLS-negative control toothpaste are different.

The primary analysis of these endpoints will be via analysis of covariance (ANCOVA) including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period- minus subject-level pre- treatment values as covariates in the model. The pre-treatment values refer to the plaque samples collected prior to supervised treatment on each treatment day.

From the above model, treatment differences and associated 95% confidence intervals and p-values will be presented. All tests will be two-sided and performed at the 5% significance level under a null hypothesis of no difference between treatments. Adjusted means and standard errors per treatment group will also be presented.

For the analysis of the primary endpoint and all other endpoints, the assumptions of normality and homogeneity of variance will be investigated. If the assumptions are violated, a suitable transformation or a non-parametric test may be performed.

8.2 Secondary Efficacy Analysis

The secondary endpoints in this exploratory study are:

 AUCregrowth(0-90).

 AUClive:dead(0-90).

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These AUC parameters will be calculated as net incremental AUC using the formula given in Section 8.1, and analysed using the same ANCOVA methodology as for the primary endpoint.

Unadjusted means and standard errors (for observed values and change from pre- treatment values) will be presented for the glycolysis, regrowth and live:dead stain values, per time-point, for each treatment.

In addition, the change from pre-treatment in glycolysis, regrowth and live:dead stain values will be subject to an ANCOVA at each time-point (15, 45 and 90 minutes). The ANCOVA model will include period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period- minus subject-level pre-treatment values as covariates in the model. The pre-treatment values refer to the plaque samples collected prior to supervised treatment on each treatment day.

Graphical presentations of the data will include a line chart of the unadjusted (raw) means ± standard error (SE) for each of the glycolysis, regrowth and live:dead stain values as a function of time after product use, and also a bar chart of the mean ± SE for the change from baseline of the glycolysis, regrowth and live:dead stain values.

8.3 Other Efficacy Analysis

An exploratory analysis will be performed to investigate the relationship between baseline plaque pH levels and the subsequent value of AUCgly(0-90). This will include a scatter plot and Pearson’s correlation of the baseline pH versus AUCgly(0-90), for each treatment group.

Pearson’s correlation statistic between 2 variables (X and Y) will be calculated using the following SAS procedure:

PROC CORR; VAR X Y; RUN;

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In addition, subjects will be split into two groups, according to the median baseline pH value. A subgroup analysis for AUCgly(0-90) will be performed to investigate whether there is a difference in the efficacy for subjects with baseline pH > median compared to those with baseline pH ≤ median. This will be accomplished by including terms for baseline pH group (low, high) and the interaction between treatment and baseline pH group. The results of this analysis may inform the inclusion criteria with respect to pH values for future studies.

9 Safety Analysis

Safety variables include:-

 Treatment Emergent Oral AEs

 Treatment Emergent Non-oral AEs

 Oral Soft Tissue (OST) data

Only AEs occurring after the time the first randomised product is administered to the subject will be considered treatment emergent. All AEs with an onset date during the washout period between study periods will be assigned to the treatment received in the previous period. All AEs taking place at the end of the study will be assigned to period 5 or the last treatment period preceding the end of the study. AEs with an onset date/time prior to the date/time of first supervised product use in period 1 will be considered as non-treatment emergent.

If the intensity of a continuous AE from one treatment period / baseline period to the following treatment period worsens, then the AE will be considered as emergent in the subsequent treatment period.

All AEs will be coded using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). Only treatment emergent AEs will be tabulated by System Organ Class (or Oral/Non-oral) and Preferred Term. All AEs will be listed under Pre Study Treatment (for non treatment emergent AEs), or by treatment group (for treatment emergent AEs).

No statistical comparisons will be made between treatment groups.

OST abnormalities will be captured as AEs and will not be listed separately.

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10 Interim Analysis

No interim analysis is planned. 11 Topline Summary

No topline summary is planned for this study.

The following outputs will be produced for the topline summary:

Table No. Table Title (including population)

9.1.1.1 Subject Disposition by Treatment Group Across Study Treatment Periods – All Screened Subjects 9.1.1.2 Subject Disposition By Treatment Group And Study

Treatment Period – All Screened Subjects

9.3.1.1 Summary Of Plaque Incubation pH By Timepoint – Per Protocol Population

9.3.1.2 Summary And Analysis Of AUCgly(0-90) – Per Protocol Population

9.3.2 Summary And Analysis Of AUCgly(0-90): Subgroup Analysis by Baseline pH Level – Per Protocol Population

9.3.3.1 Summary Of Regrowth Ratio By Timepoint – Per Protocol Population

9.3.3.2 Summary And Analysis Of AUCregrowth(0-90) – Per Protocol Population

9.3.4.1 Summary Of Measurements of Live:Dead Stain Ratio By Timepoint – Per Protocol Population

9.3.4.2 Summary And Analysis Of AUClive:dead(0-90) – Per Protocol Population

9.4.1 Listing Of Adverse Events – All Screened Subjects

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9.4.2 Summary Of Treatment Emergent Adverse Events – Safety Population

9.4.3 Summary Of Treatment Emergent Treatment Related

Adverse Events – Safety Population

12 Changes to Planned Analysis

There are no changes to the analyses planned in the protocol.

An exploratory subgroup analysis based on baseline pH levels has been added.

Due to non-evaluable data at one or more of the time-points for several subjects, it will not be possible to calculate an AUC in these cases. In order to extract as much information as possible from this study, additional analyses have been added, whereby the glycolysis, regrowth and live:dead stain values will be analysed and treatment comparisons performed at each time-point (15, 45 and 90 minutes). This is considered an exploratory analysis. 13 References

Study RH01871. An Exploratory Study to Investigate the Antimicrobial Activity of a Toothpaste in a Plaque Glycolysis and Regrowth Model.

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Appendix 1 Study Schedule

The total duration of the study is approximately 8 weeks, comprising approximately 2 weeks to complete the screening

procedures (Visits 1 and 2), and 1 week to complete each of the five treatment periods. A washout period of at least 48 hours will precede each treatment visit.

Visit 1 1 Visit 2 Visit 3 Visit 4

t e i PROCEDURE Screening Plaque Randomisation and n Treatment 2 s e e i

1 e w t V Screening Treatment 1

w e t n b e

e Assessment b s e

y s

Informed consent w

X a t y d e a

b Demographics X d 0

s 1 0

r f Medical history 1 h X

o f

8 o

4 m

Concomitant medication X X X X s s u f m t t i i o u m

Compliance check X s X s X 2 i i i

m t m

x 3 3 v i v i

a OST examination X u X X X s x t t i a n n m m

i V Inclusion/exclusion criteria X X e X e m a n

i d m m a d t t

Subject eligibility X n X X X a a m a d

m e e n a r r a

Plaque collection (screening) – whole mouth X t t a

s d s y n

Dispense washout toothpaste, toothbrush X y a a

d 2 s

d Randomisation X y 2

2 a f d f o

Plaque collection – quadrant 1 (Pre-treatment) X X

o 4

Supervised treatment (rinse with test slurry) 1 m X X

m u u m

Plaque collection – quadrants 2,3 and 4 (15, 45 m u i m

X i X n m i and 90 min Post-treatment respectively) n i i x m

a Return washout toothpaste, toothbrush M A Adverse events X M X X X

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Visit 5 Visit 6 Visit 7 n n n

PROCEDURE e Treatment 3 e Treatment 4 e Treatment 5

e e e w w w t t t e e e b b b Informed consent s s s y y y

Demographics a a a d d d

Medical history 0 0 0 1 1 1

f f f

Concomitant medication o X o X o X

s s s m m m t t t

Compliance check i X i X i X u u u s s s

i 3 i 3 i 3 m m m i i i OST examination v X v X v X

x x x t t t a a a Inclusion/exclusion criteria n n n e e e m m m

m m m

Subject eligibility a X a X a X t t t

a a a d d d

Plaque collection (screening) – whole mouth e e e n n n r r r t t t a a a

Dispense washout toothpaste, toothbrush s s s y y y

Randomisation a a a d d d

2 2 2

Plaque collection – quadrant 1 (Pre-treatment) X X X f f f o o o

Supervised treatment (rinse with test slurry) X X X m m m

Plaque collection – quadrants 2,3 and 4 (15, 45 u u u X X X m m m

and 90 min Post-treatment respectively) i i i n n n Return washout toothpaste, toothbrush i i i X4 Adverse events M X M X M X 1 Visits 3-7 should be performed where possible in the morning. 2 At Visit 3 only. 3 OST examination will be performed before treatment and after plaque sampling completed on each treatment visit 4 At final visit only.

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Appendix 2 List of Tables, Figures & Listings

Table No. Table Title (including population) Standard Template 9.1.1.1 Subject Disposition by Treatment Group App 3 Across Study Treatment Periods – All

Screened Subjects 9.1.1.2 Subject Disposition By Treatment Group App 3 And Study Treatment Period – All Screened Subjects

9.1.2 Protocol Violations Deemed to Affect App 3 Efficacy - Intent to Treat Population

9.2.1.1 Demographic and Baseline Characteristics X - Safety Population

9.2.1.2 Demographic and Baseline Characteristics X

– Per Protocol Population

9.3.1.1 Summary And Analysis Of Plaque App 3 Incubation pH Measurements of Glycolysis By Timepoint – Per Protocol Population

9.3.1.2 Treatment Comparisons Of App 3 Measurements of Glycolysis By Timepoint – Per Protocol Population

9.3.1.2 Summary And Analysis Of AUCgly(0-90) – App 3 9.3.1.3 Per Protocol Population

9.3.2 Summary And Analysis Of AUCgly(0-90): App 3 Subgroup Analysis by Pre-Study Baseline pH Level – Per Protocol Population

9.3.3.1 Summary And Analysis Of 9.3.1.1 Measurements of Regrowth Ratio By Timepoint – Per Protocol Population

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9.3.3.2 Treatment Comparisons Of 9.3.1.2 Measurements of Regrowth Ratio By

Timepoint – Per Protocol Population

9.3.3.2 Summary And Analysis Of AUCregrowth(0-90) 9.3.1.2 9.3.3.3 – Per Protocol Population 9.3.1.3

9.3.4.1 Summary And Analysis Of Measurements 9.3.1.1 of Live:Dead Stain Ratio By Timepoint –

Per Protocol Population

9.3.4.2 Treatment Comparisons Of 9.3.1.2 Measurements of Live:Dead Stain Ratio By Timepoint – Per Protocol Population

9.3.4.2 Summary And Analysis Of AUC 9.3.1.2 live:dead(0- 9.3.4.3 90) – Per Protocol Population 9.3.1.3

9.4.1 Listing Of Adverse Events – All Screened X Subjects

9.4.3 9.4.2 Summary Of Treatment Emergent X Treatment Related Adverse Events by Oral/Non-Oral and Preferred Term – Safety Population

9.4.2 9.4.3 Summary Of Treatment Emergent Adverse X Events by Oral/Non-Oral and Preferred Term – Safety Population

9.4.4 Summary of Treatment Emergent X Treatment Related AEs by SOC and Preferred Term

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9.4.5 Listing Of Serious Adverse Events – All X

Screened Subjects

(if no SAEs then print a blank table with “THERE WERE NO SERIOUS ADVERSE EVENTS REPORTED”)

Figure Figure Title (including population) Standard Template

No.

9.1 Mean Plaque Incubation pH Over Time – App 3 Per Protocol Population

9.2 Mean Regrowth Ratio Over Time – Per 9.1 Protocol Population

9.3 Mean Live:Dead Stain Ratio Over Time – 9.1 Per Protocol Population

9.4 Mean Change in Plaque Incubation pH App 3 from Pre-Treatment – Per Protocol Population

9.5 Mean Change in Regrowth Ratio From 9.4 Pre-Treatment – Per Protocol Population

9.6 Mean Change in Live:Dead Stain Over 9.4 Time – Per Protocol Population

9.7 Scatter Plot of Baseline pH versus App 3

AUCgly(0-90) – Per Protocol Population

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Listing Listing Title (including population) Standard Template No.

2.1 Randomisation Information – All App 3

Randomised Subjects

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Treatment labels to be used on tables are:

Treatment 1: Test Zinc-IPMP Treatment 2: Test Zinc non-IPMP

Treatment 3: Positive control Treatment 4: non-SLS negative control Treatment 5: SLS negative control

This SAP Template is associated with SP0674 V7

Page 25 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Appendix 3 Templates for Tables, Figures & Listings

Protocol: 205051 Program Run Date: DDMMMYYYY Table 9.1.1.1 Subject Disposition by Treatment Group Across Study Treatment Periods All Screened Subjects Study Population: All Screened Subjects (N=xx)

Treatment 1 Treatment 2 .... Overall n (%) n (%) n (%)

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) PPD Programming Notes: Table to include columns for all 5 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.

This SAP Template is associated with SP0674 V7

Page 26 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: DDMMMYYYY Table 9.1.1.2 Subject Disposition By Treatment Group And Study Treatment Period All Screened Subjects Study Population: All Screened Subjects (N=xx)

Treatment 1 Treatment 2 .... Overall n (%) n (%) n (%)

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

PERIOD 1 STARTED PERIOD XX XX . XX 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)

(Page X of Y) PPD Programming Notes: Table to include columns for all 5 treatments and overall. Percentages to be computed using number of subjects starting each period as the denominator. Washout period is defined per subject as the interval starting the date after the last dose of each treatment through the day before the date of the first dose of the next treatment in the sequence.

This SAP Template is associated with SP0674 V7

Page 27 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: DDMMMYYYY Table 9.1.1.2 Subject Disposition By Treatment Group And Study Treatment Period All Screened Subjects Study Population: All Screened Subjects (N=xx)

Treatment 1 Treatment 2 .... Overall n (%) n (%) n (%)

WASHOUT PERIOD 1 STARTED PERIOD XX XX . XX 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) PERIOD 2 STARTED PERIOD XX XX . XX 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) ETC ...

CONTINUE FOR PERIODS 3, 4 AND 5 AND CORRESPONDING WASHOUT PERIODS SAFETY POPULATION XX (XX.X) ITT POPULATION XX (XX.X) PP POPULATION XX (XX.X)

(Page X of Y)

PPD

Programming Notes: Table to include columns for all 5 treatments and overall. Percentages to be computed using number of subjects starting each period as the denominator. Washout period is defined per subject as the interval starting the date after the last dose of each treatment through the day before the date of the first dose of the next treatment in the sequence.

This SAP Template is associated with SP0674 V7

Page 28 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: ddmonyyyy Table 9.1.2 Protocol Violations Leading To Exclusion From Per Protocol Analysis Intent to Treat Population Study Population: ITT (N=xx) Treatment 1 Treatment 2 Overall (N=xx) (N=xx) ... (N=xxx) PROTOCOL VIOLATIONS LEADING TO EXCLUSION N (%) VIOLATION 1 XX (X.X) XX (X.X) . XX (X.X) VIOLATION 2 XX (X.X) XX (X.X) . XX (X.X) VIOLATION 3 XX (X.X) XX (X.X) . XX (X.X) VIOLATION 4 XX (X.X) XX (X.X) . XX (X.X)

NUMBER OF SUBJECTS WITH AT LEAST ONE PROTOCOL XX (X.X) XX (X.X) . XX (X.X) VIOLATION LEADING TO EXCLUSION N (%)

(Page X of Y) PPD Programming Note: Table to include columns for all 5 treatments and overall.

This SAP Template is associated with SP0674 V7

Page 29 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: ddmonyyyy Table 9.3.1.1 Summary And Analysis Of Measurements Of Glycolysis By Timepoint Per Protocol Population

Study Population: PP (N=xx) Treatment 1 Treatment 2 (N=xx) (N=xx)

Observed Change Observed Change PRE-TREATMENT BASELINE N XX XX MISSING X X MEAN XX.X XX.X SD XX.XX XX.XX SE XX.XX XX.XX MEDIAN XX.X XX.X MINIMUM XX XX MAXIMUM XX XX

(Page X of Y) Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® – Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product). Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

PPD Programming Notes: Table to include columns for all 5 treatments. If able to fit more than 2 treatment groups on a page, please do so.

Continue table for 45 minute and 90 minute timepoints.

Repeat for Tables 9.3.3.1 and 9.3.4.1.

This SAP Template is associated with SP0674 V7

Page 30 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: ddmonyyyy Table 9.3.1.1 Summary And Analysis Of Measurements Of Glycolysis By Timepoint Per Protocol Population

Study Population: PP (N=xx) Treatment 1 Treatment 2 (N=xx) (N=xx)

Observed Change Observed Change

15 MINUTES N XX XX XX XX MISSING X X X X MEAN XX.X XX.X XX.X XX.X SD XX.XX XX.XX XX.XX XX.XX SE XX.XX XX.XX XX.XX XX.XX MEDIAN XX.X XX.X XX.X XX.X MINIMUM XX XX XX XX MAXIMUM XX XX XX XX

ADJUSTED MEAN (SE) [1] XX.X (XX.XX) XX.X (XX.XX) 95% CI [1] XX.X, XX.X XX.X, XX.X (Page X of Y) Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® – Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product). Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product). PPD Programming Notes: Table to include columns for all 5 treatments. If able to fit more than 2 treatment groups on a page, please do so.

Continue table for 45 minute and 90 minute timepoints.

Repeat for Tables 9.3.3.1 and 9.3.4.1.

This SAP Template is associated with SP0674 V7

Page 31 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: ddmonyyyy Table 9.3.1.2 Treatment Comparisons Of Measurements Of Glycolysis By Timepoint Per Protocol Population Study Population: PP (N=xxx)

15 MINUTES

TREATMENT COMPARISONS DIFFERENCE (95% CI) [1,2] P-VALUE [1] POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC-IPMP VS. POSITIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC-IPMP VS. TEST ZINC NON-IPMP X.XX (X.XX, X.XX) X.XXXX TEST ZINC NON-IPMP VS. POSITIVE CONTROL X.XX (X.XX, X.XX) X.XXXX POSITIVE CONTROL VS. SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX

(Page X of Y) [1] Obtained from ANCOVA including period and treatment as fixed effects, subject as a random effect and subject-level pre-treatment values and period-minus subject-level pre-treatment values as covariates in the model. [2] Difference is first named treatment minus second named treatment such that a negative difference indicates the first treatment has smaller AUC. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® – Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product). Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product). PPD Programming Notes: Repeat Tables 9.3.3.2 and 9.3.4.2.

Continue table for 45 minute and 90 minute timepoints.

This SAP Template is associated with SP0674 V7

Page 32 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: ddmonyyyy Table 9.3.1.2 Table 9.3.1.3 Summary And Analysis Of AUCgly(0-90) Per Protocol Population Study Population: PP (N=xxx)

Treatment 1 Treatment 2 Treatment 5 (N=xx) (N=xx) ... (N=xxx)

N XX XX . XX MISSING XX XX . XX MEAN X.XX X.XX . X.XX SD X.XXX X.XXX . X.XXX SE X.XXX X.XXX . X.XXX MEDIAN X.XX X.XX . X.XX MINIMUM X.X X.X . X.X MAXIMUMUM X.X X.X . X.X ADJUSTED MEAN (SE) [1] X.XX (X.XXX) X.XX (X.XXX) X.XX (X.XXX) 95% CI [1] X.XX, X.XX X.XX, X.XX X.XX, X.XX

This SAP Template is associated with SP0674 V7

Page 33 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Repeat for Tables 9.3.3.2 9.3.3.3 and 9.3.4.2 9.3.4.3.

This SAP Template is associated with SP0674 V7

Page 34 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: ddmonyyyy Table 9.3.1.2 Table 9.3.2 Summary And Analysis Of AUCgly(0-90): Subgroup Analysis by Pre-Study Baseline pH Level Per Protocol Population Study Population: PP (N=xxx)

Treatment 1 Treatment 2 Treatment 5 (N=xx) (N=xx) ... (N=xxx) PRE-STUDY BASELINE PH ≤ MEDIAN

N XX XX . XX MISSING XX XX . XX MEAN X.XX X.XX . X.XX SD X.XXX X.XXX . X.XXX MINIMUM X.X X.X . X.X MAXIMUMUM X.X X.X . X.X ADJUSTED MEAN (SE) [1] X.XX (X.XXX) X.XX (X.XXX) X.XX (X.XXX) 95% CI [1] X.XX, X.XX X.XX, X.XX X.XX, X.XX

TREATMENT COMPARISONS DIFFERENCE (95% CI) [1,2] P-VALUE [1]

POSITIVE CONTROL VS. NON-SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC-IPMP VS. NON-SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC-IPMP VS. SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC NON-IPMP VS. NON-SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC NON-IPMP VS. SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC-IPMP VS. POSITIVE CONTROL X.XX (X.XX, X.XX) X.XXXX TEST ZINC-IPMP VS. TEST ZINC NON-IPMP X.XX (X.XX, X.XX) X.XXXX TEST ZINC NON-IPMP VS. POSITIVE CONTROL X.XX (X.XX, X.XX) X.XXXX POSITIVE CONTROL VS. SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX NON-SLS NEGATIVE CONTROL VS. SLS NEGATIVE CONTROL X.XX (X.XX, X.XX) X.XXXX

Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product). PPD Programming Note: Table to include columns for all 5 treatments. Repeat on page 2 for PRE-STUDY BASELINE PH > MEDIAN.

This SAP Template is associated with SP0674 V7

Page 35 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: ddmonyyyy Figure 9.1 Mean Plaque Incubation pH Over Time Per Protocol Population Study Population: PP (N=xxx)

(Page X of Y)

PPD

Programming Note: Please use the treatment labels for the products that appear in Appendix 2 versus the wording in the key that appears on the figure above. Also in the footnotes, please use treatment names as per those used in the table mock-ups. For Figure 9.2, Y-axis will be labeled Regrowth Ratio. For Figure 9.3, Y-axis will be labeled Live:Dead Stain Ratio.

This SAP Template is associated with SP0674 V7

Page 36 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: ddmonyyyy Figure 9.4 Mean Change in Plaque Incubation pH from Pre-Treatment Per Protocol Population Study Population: PP (N=xxx)

(Page X of Y)

PPD

Programming Note: Please use the treatment labels for the products that appear in Appendix 2 versus the wording in the key that appears on the figure above. Also in the footnotes, please use treatment names as per those used in the table mock-ups. For Figure 9.5, Y-axis will be labeled Change in Regrowth Ratio. For Figure 9.6, Y-axis will be labeled Change in Live:Dead Stain Ratio.

This SAP Template is associated with SP0674 V7

Page 37 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: ddmonyyyy Figure 9.7 Scatter Plot of Baseline pH versus AUCgly(0-90) Per Protocol Population Study Population: PP (N=xxx) Treatment 1

(Page X of Y) PPD

Do one plot for each treatment group (Treatment 1 on page 1, Treatment 2 on page 2, etc).

Plot baseline pH value on X-axis and AUCgly(0-90) on Y-axis.

In the top section of each plot write: Pearson’s correlation coefficient = 0.xx.

This SAP Template is associated with SP0674 V7

Page 38 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

Protocol: 205051 Program Run Date: ddmonyyyy Data Listing 2.1 Randomisation Information All Randomised Subjects

______Subject Treatment Randomisation Randomisation Number Sequence [1] Number Date ______xxSXXXX A/B/C/D/E xxxx DDMONYYYY xxSXXXX E/D/C/B/A xxxx DDMONYYYY

xxSXXXX C/A/E/D/B xxxx DDMONYYYY

______(Page x of y)

[1] A = Test Zinc-IPMP. B = Test Zinc non-IPMP. C = Positive control. D = non-SLS negative control. E = SLS negative control. Test toothpaste containing 0.6% w/w zinc chloride and 0.1% w/w IPMP and 1426ppm fluoride as sodium fluoride. Test toothpaste containing 0.6% w/w zinc chloride, 0% w/w IPMP and 1426ppm fluoride as sodium fluoride. Positive control toothpaste containing 0.454% w/w stannous fluoride (Crest ProHealth® – Clean Mint, Fluoride Toothpaste (1100ppm F as stannous fluoride) USA Marketplace product). Negative control toothpaste containing 1426 ppm fluoride as sodium fluoride (Aquafresh Big Teeth toothpaste). Negative control toothpaste containing 2.0% SLS, 0.65% Tegobetain and 1150 ppm fluoride as sodium fluoride (Aquafresh Extreme Clean Whitening Fluoride Toothpaste USA Market place product).

PPD Programmers Note: The treatment assignments for A, B, C, D, E are only used here for example. The true assignments will not be known until after unblinding.

This SAP Template is associated with SP0674 V7

Page 39 of 40 Document Name Statistical Analysis Plan 205051 Type Version Document Identifier Effective Date eldo_clinical_doc 2.0; Most-Recent; Effective; CURRENT 090032d580b871eb 12-Apr-2016 06:23:22 Reason For Issue Auto Issue

SIGNATURE PAGE

Statistical Analysis Plan 205051

Date Signed By

01-Mar-2016 07:55:41 PPD Justification Biostatistics Approval

Date Signed By 12-Apr-2016 06:23:09 PPD Justification Clinical Research

Date Signed By

Justification

Date Signed By

Justification

Date Signed By

Justification

Date Signed By

Justification

Page 40 of 40

Annotated Study Book - 205051 Page 1 of 49

Annotated Study Book for Study Design: 205051

Study Design Version: 0.0

Protocol: 205051

GSKCH 205051 Study

Generated by Central Designer TM

September 24, 2015 3:47PM

PPD 9/24/2015

Annotated Study Book - 205051 Page 2 of 49

Time and Events Schedule For Study Design: 205051 Element System CORE_LIB_ELEMENTS Assessment CRF SCREEN ENROLL VISIT VISIT VISIT VISIT VISIT VISIT VISIT AE/CONMED/NONDRUG STUDYCONC (SCR) (ENR) 1/SCR 2/BASE 3/TREATMENT 4/TREATMENT 5/TREATMENT 6/TREATMENT 7/TREATMENT (AE/CONMED/NONDRUG) (STUDYCONC) [S] [S] (V1/SCR) (V2/BASE) 1 2 3 4 5 [S] [S] [S] [S/D] (V3/TRT1) (V4/TRT2) (V5/TRT3) (V6/TRT4) (V7/TRT5) [S/D] [S/D] [S/D] [S/D] [S/D] Visit Start Hours 0 0 0 24 48 72 96 120 144 168 192 1 INFORM SCREENING SCREEN 1 2 SUBJECT ENROLLMENT ENROL 1 3 DATE OF VISIT/ASSESSMENT DOV 1 1 1 1 1 1 1 4 SUBJECT IDENTIFICATION SUBID 2 5 CONSENT CONSENT 3 6 DEMOGRAPHY DEMO 4 7 ANY MEDICAL HISTORY ANY MEDHIST 5 8 MEDICAL HISTORY MEDHIST 6-DF 9 ORAL SOFT TISSUE EXAMINATION OSTEXAM 7 4 5-DF 10 INCLUSION CRITERIA INCLUS 8 11 EXCLUSION CRITERIA EXCLUS 9 12 SUBJECT ELIGIBILITY (Screening) ELIG 10 13 PRODUCT DISPENSING INFORMATION - WASHOUT PRODUCT PRODDISP 11 14 SUBJECT ADHERENCE TO SUBJECT RESTRICTIONS RESADHERE 2 2 2 2 2 2 15 EVALUATION OF CONCOMITANT MEDICATIONS CMEVAL 3 3 16 PLAQUE COLLECTION WHOLE MOUTH PLQCOL 5 17 INCLUSION CRITERIA INCLUS 6 18 EXCLUSION CRITERIA EXCLUS 7 19 SUBJECT ELIGIBILITY (Post-Screening) ELIG 8 5 20 PRE TREATMENT ORAL SOFT TISSUE EXAMINATIONOSTEXAM(PRE) 44444 21 SUBJECT RANDOMISATION RAND 6 22 PLAQUE COLLECTION QUADRANT 1 PLQCOLQ1 7 5 5 5 5 23 SUPERVISED TREATMENT SUPTREATMENT 8 6 6 6 6 PLQCOL(Q2- 24 PLAQUE COLLECTION QUADRANT 2,3 & 4 97777 Q4) OSTEXAM 25 POST TREATMENT ORAL SOFT TISSUE EXAMINATION 108888 (POST) 26 EVALUATION OF ADVERSE EVENTS AEEVAL 11 27 EVALUATION OF ADVERSE EVENTS AND CONCOMITANT MEDICATIONS AECMEVAL 3333 AE-CONMED- 28 ANY ADVERSE EVENTS AND PAST/CONCOMITANT MEDICATIONS 1 NONDRUG 29 CONCOMITANT MEDICATIONS CONMED 2-DF-C-RF 30 CONCOMITANT NON-DRUG TREATMENT/PROCEDURES NONDRUG 3-DF-C-RF 31 ADVERSE EVENTS AE 4-DF-C-RF ANY 32 ANY PROTOCOL DEVIATIONS 1 DEVIATION 33 PROTOCOL DEVIATIONS DEVIATION 2-DF 34 PRODUCT RETURN INFORMATION PRODRET 3 35 OPTIONAL ORAL SOFT TISSUE EXAM OPTOST 4 36 STUDY CONCLUSION STUDYCONC 6

Key: [S] = Scheduled Visit [D] = Dynamic Visit [U] = Unscheduled Visit [R] = Repeating Visit C = Common Form DF = Dynamic Form RF = Repeating Form

PPD 9/24/2015

Annotated Study Book - 205051 Page 3 of 49

205051: INFORM SCREENING (SCREEN) [SCREEN_CH] INFORM SCREENING [sctSCREEN] 1. Subject Initials [hidden] [txtScrSINIT] [Subject Initials] A3

2.* Year of Birth [DOBDT_1] [Year of Birth] Req (1900-2015)

Key: [*] = Item is required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

PPD 9/24/2015

Annotated Study Book - 205051 Page 4 of 49

205051: SUBJECT ENROLLMENT (ENROL) [ENROL_CH] SUBJECT SCREENING NUMBER [sctENROL]

1.* Subject Screening Number [txtSubjectNumber] [Subject Screening Number] A6

Key: [*] = Item is required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

PPD 9/24/2015

Annotated Study Book - 205051 Page 5 of 49

205051: DATE OF VISIT/ASSESSMENT (DOV) [DOV_CH] DATE OF VISIT/ASSESSMENT [sctDOV]

1.* Date of Visit [DOV] [Date of Visit] Req / Req / Req (2015-2018)

Key: [*] = Item is required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

PPD 9/24/2015

Annotated Study Book - 205051 Page 6 of 49

205051: SUBJECT IDENTIFICATION (SUBID) [SUBID_CH] SUBJECT IDENTIFICATION [sctSUBID]

1.* Subject Screening Number [txtSubjectNumber] [Subject Screening Number] A6

Key: [*] = Item is required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

PPD 9/24/2015

Annotated Study Book - 205051 Page 7 of 49

205051: CONSENT (CONSENT) [CONSENT_CH] CONSENT [sctCONSENT]

1.* Date of Consent [CONSDT] [Date of Consent] Req / Req / Req (2015-2018)

Key: [*] = Item is required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

PPD 9/24/2015

Annotated Study Book - 205051 Page 8 of 49

205051: DEMOGRAPHY (DEMO) [DEMO_CH] DEMOGRAPHY [sctDEMO]

1.* Year of Birth [DOBDT] [Year of Birth] Req (1900-2015)

2.* Age [AGE] [Age] N2

3.* Sex [SEX] [Sex] [A:M] Male [A:F] Female

4.* Race [cmpRACECD] [Race] (Check all that apply) [RACECD11] [N:11] African American/African Heritage [RACECD12] [N:12] American Indian or Alaskan Native [RACECD13] [N:13] Asian - Central/South Asian Heritage [RACECD14] [N:14] Asian - East Asian Heritage [RACECD15] [N:15] Asian - Japanese Heritage [RACECD16] [N:16] Asian - South East Asian Heritage [RACECD17] [N:17] Native Hawaiian or Other Pacific Islander [RACECD18] [N:18] White - Arabic/North African Heritage [RACECD19] [N:19] White - White/Caucasian/European Heritage

Key: [*] = Item is required [D] = Source verification required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

PPD 9/24/2015

Annotated Study Book - 205051 Page 9 of 49

205051: ANY MEDICAL HISTORY (ANY MEDHIST) [ANYMHX_CH] ANY MEDICAL HISTORY [sctANYMHX] List relevant previous and current medical conditions (including allergies or drug sensitivity) and surgery that the subject has experienced. NOTE: If treatment is currently taken for any medical conditions, complete the Concomitant Medications page.

1.* Are there any medical conditions to report? [MHANY] [Any Medical History] [A:Y] Yes [A:N] No If Yes, complete Medical History page

Key: [*] = Item is required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

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205051: MEDICAL HISTORY (MEDHIST) [MEDHIST_CH] Medical Condition Start Date Ongoing Medical Condition 1.

MEDICAL HISTORY Entry [sctMEDHIST] List any relevant previous and current medical conditions (including allergies or drug sensitivity) and surgery that the subject has experienced. NOTE: If treatment is currently taken for any medical conditions, complete the Concomitant Medications page. 1.1 Sequence Number [hidden] [MHSEQ] [Sequence Number] N8

1.2* Medical Condition [MHTERM] [Medical Condition] A100

1.3* Start Date [MHSTDT] [Start Date] Req/Unk / Req/Unk / Req/Unk (1900-2018)

1.4* Ongoing Medical Condition? [MHONGO] [Ongoing Medical Condition] [A:Y] Yes [A:N] [MHENDT] No, provide End Date: Req/Unk / Req/Unk / Req/Unk (1900-2018)

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205051: ORAL SOFT TISSUE EXAMINATION (OSTEXAM) [OSTEXAM_CH] DATE/TIME OF ASSESSMENT [sctOSTDATE]

1.* Date and Time of Assessment [OSDTTM] [Date and Time of Assessment] Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock

ORAL SOFT TISSUE EXAMINATION [sctOSTEXAM] Note: Any new or worsened Oral Soft Tissue conditions after Screening should be recorded as an Adverse Event.

2.* Labial Mucosa (including lips) [OSRESCD1] [Labial Mucosa (including lips)] [A:1] Normal [A:2] [OSABDESC1] Abnormal, describe abnormality: A200

[A:3] [OSREASND1] Not Examined, provide details: A200

3.* Buccal Mucosa [OSRESCD2] [Buccal Mucosa] [A:1] Normal [A:2] [OSABDESC2] Abnormal, describe abnormality: A200

[A:3] [OSREASND2] Not Examined, provide details: A200

4.* Mucogingival Folds [OSRESCD3] [Mucogingival Folds] [A:1] Normal [A:2] [OSABDESC3] Abnormal, describe abnormality: A200

[A:3] [OSREASND3] Not Examined, provide details: A200

5.* Gingival Mucosa [OSRESCD4] [Gingival Mucosa] [A:1] Normal [A:2] [OSABDESC4] Abnormal, describe abnormality: A200

[A:3] [OSREASND4] Not Examined, provide details: A200

6.* Hard Palate [OSRESCD5] [Hard Palate] [A:1] Normal [A:2] [OSABDESC5] Abnormal, describe abnormality: A200

[A:3] [OSREASND5] Not Examined, provide details: A200

7.* Soft Palate [OSRESCD6] [Soft Palate] [A:1] Normal

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[A:2] [OSABDESC6] Abnormal, describe abnormality: A200

[A:3] [OSREASND6] Not Examined, provide details: A200

8.* Tonsilar Area [OSRESCD7] [Tonsilar Area] [A:1] Normal [A:2] [OSABDESC7] Abnormal, describe abnormality: A200

[A:3] [OSREASND7] Not Examined, provide details: A200

9.* Pharyngeal Area [OSRESCD8] [Pharyngeal Area] [A:1] Normal [A:2] [OSABDESC8] Abnormal, describe abnormality: A200

[A:3] [OSREASND8] Not Examined, provide details: A200

10.* Tongue [OSRESCD9] [Tongue] [A:1] Normal [A:2] [OSABDESC9] Abnormal, describe abnormality: A200

[A:3] [OSREASND9] Not Examined, provide details: A200

11.* Sublingual Area [OSRESCD10] [Sublingual Area] [A:1] Normal [A:2] [OSABDESC10] Abnormal, describe abnormality: A200

[A:3] [OSREASND10] Not Examined, provide details: A200

12.* Submandibular Area [OSRESCD11] [Submandibular Area] [A:1] Normal [A:2] [OSABDESC11] Abnormal, describe abnormality: A200

[A:3] [OSREASND11] Not Examined, provide details: A200

13.* Salivary Glands [OSRESCD12] [Salivary Glands] [A:1] Normal [A:2] [OSABDESC12]

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Abnormal, describe abnormality: A200

[A:3] [OSREASND12] Not Examined, provide details: A200

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205051: INCLUSION CRITERIA (INCLUS) [INCLUSION_CH] INCLUSION CRITERIA [sctINCLUSION] Mark the correct answers to the following Inclusion Criteria questions.

1.* Inclusion #1) Consent - Demonstrates understanding of the study procedures, restrictions and willingness to participate as evidenced [IECRTNUMI01] by voluntary written informed consent and has received a signed and dated copy of the informed consent form. [A:Y] Yes [A:N] No [Inclusion #1) Consent]

2.* Inclusion #2) Age - Aged at least 18 years. [IECRTNUMI02] [Inclusion #2) Age] [A:Y] Yes [A:N] No

3.* Inclusion #3) General health - Good general and mental health with, in the opinion of the investigator or medically qualified designee [IECRTNUMI03] no clinically significant and relevant abnormalities in medical history or upon oral examination. [A:Y] Yes [A:N] No [Inclusion #3) General health]

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205051: EXCLUSION CRITERIA (EXCLUS) [EXCLUSION_CH] EXCLUSION CRITERIA [sctEXCLUSION] Mark the correct answers to the following Exclusion Criteria questions.

1.* Exclusion #1) Pregnancy - Women who are known to be pregnant or who are intending to become pregnant over the duration of the [IECRTNUME01] study. [A:Y] Yes [A:N] No [A:X] NA [Exclusion #1) Pregnancy]

2.* Exclusion #2) Breast-feeding - Women who are breast-feeding [IECRTNUME02] [Exclusion #2) Breast-feeding] [A:Y] Yes [A:N] No [A:X] NA

3.* Exclusion #3) Concurrent Medication/ Medical History - Currently taking antibiotics or have taken antibiotics within 2 weeks of plaque [IECRTNUME03] assessment (Visit 2). A subject with any medical history that may prevent them from participating in the study until study conclusion [A:Y] Yes [A:N] No (such as diabetes). [Exclusion #3) Concurrent Medication/ Medical History]

4.* Exclusion #4) Oral Disease - Any sign of grossly carious lesions (active), moderate or severe periodontal conditions, or severe tooth [IECRTNUME04] wear. [A:Y] Yes [A:N] No [Exclusion #4) Oral Disease]

5.* Exclusion #5) Allergy/Tolerance - Known or suspected intolerance or hypersensitivity to the study materials (or closely related [IECRTNUME05] compounds) or any of their stated ingredients. [A:Y] Yes [A:N] No [Exclusion #5) Allergy/Intolerance]

6.* Exclusion # 6A) Clinical Study/Experimental Product - Participation in another clinical study (including cosmetic studies) or receipt of [IECRTNUME06A] an investigational drug within 30 days of the screening visit. [A:Y] Yes [A:N] No [Exclusion # 6A) Clinical Study/Experimental Product]

7.* Exclusion # 6B) Clinical Study/Experimental Product - Previous participation in this study. [IECRTNUME06B] [Exclusion # 6B) Clinical Study/Experimental Product] [A:Y] Yes [A:N] No

8.* Exclusion #7) Smokers - Current smokers, or smokers who have quit within 6 months of screening, or subjects currently using [IECRTNUME07] smokeless forms of tobacco, e.g. Gutkha, Pan containing tobacco, Pan Masala. [A:Y] Yes [A:N] No [Exclusion #7) Smokers]

9.* Exclusion #8A) General Dentition Exclusions - Current active caries or periodontitis that may compromise, in the opinion of the [IECRTNUME08A] investigator, study outcomes or the health of the subject. [A:Y] Yes [A:N] No [Exclusion #8A) General Dentition Exclusions]

10.* Exclusion #8B) General Dentition Exclusions - Restorations in a poor state of repair that may, in the opinion of the investigator, [IECRTNUME08B] compromise study outcomes or the health of the subject. [A:Y] Yes [A:N] No [Exclusion #8B) General Dentition Exclusions]

11.* Exclusion #8C) General Dentition Exclusions - Partial dentures or orthodontic appliances that may, in the opinion of the investigator, [IECRTNUME08C] compromise study outcomes or the health of the subject [A:Y] Yes [A:N] No [Exclusion #8C) General Dentition Exclusions]

12.* Exclusion #9) Substance Abuse - Recent history (within the last year) of alcohol or other substance abuse. [IECRTNUME09] [Exclusion #9) Substance Abuse] [A:Y] Yes [A:N] No

13.* Exclusion #10) Personnel - An employee of the sponsor or the study site or members of their immediate family. [IECRTNUME10] [Exclusion #10) Personnel] [A:Y] Yes [A:N] No

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205051: SUBJECT ELIGIBILITY (ELIG) [ELIG_CH] SUBJECT ELIGIBILITY [sctELIG] NOTE: If the subject is not eligible to continue in the study, complete the Study Conclusion visit.

1.* On the basis of Visit assessment(s), is the subject eligible and fit to participate in the next part of the study? [ELIG] [Subject eligible to continue in the study] [A:Y] Yes [A:N] No

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205051: WASHOUT PRODUCT DISPENSATION (PRODDISP) [DADISP_CH] WASHOUT PRODUCT DISPENSATION [sctDADISP]

1.* Date and Time Product Dispensed [DADDTTM] [Date and Time Product Dispensed] Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock

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205051: SUBJECT ADHERENCE TO SUBJECT RESTRICTIONS (RESADHERE) [RESADHERE_CH] SUBJECT ADHERENCE TO SUBJECT RESTRICTIONS [sctRESADHERE]

1.* Did the subject adhere to the subject restrictions since the previous visit? [RESADH] [Subject Adherence to Subject Restrictions] [A:Y] Yes [A:N] No If No, complete the Protocol Deviations page

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205051: EVALUATION OF CONCOMITANT MEDICATIONS (CMEVAL) [CMEVAL_CH] EVALUATION OF CONCOMITANT MEDICATIONS [sctCMEVAL] Record subject's response to the below question.

1.* Have there been any changes to your concomitant medication use (existing or new) since your last visit? [CMCHANGE1] [CONMED Changes at Visit] [A:Y] Yes [A:N] No If Yes, complete Concomitant Medications page

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205051: PLAQUE COLLECTION WHOLE MOUTH (PLQCOL) [PLQCOL] PLAQUE COLLECTION WHOLE MOUTH [sctPLQCOL]

1.* Was the plaque collection performed? [PLQPERF] [Was the plaque collection performed] [A:Y] [PLQDTTM] Yes, provide: Date/Time of Plaque Collection Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock [PLQSMP] Sample Number A10 [A:N] No If No, complete the Study Conclusion page.

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205051: INCLUSION CRITERIA (INCLUS) [INCLUSION_CH_1] INCLUSION CRITERIA [sctINCLUSION_1] Mark the correct answers to the following Inclusion Criteria questions.

1.* Inclusion #4) Oral Health - Plaque sample acidogenicity in the pH range 5.0 to 5.7 at Visit 2. [IECRTNUMI04] [Inclusion #4) Oral Health] [A:Y] Yes [A:N] No

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205051: EXCLUSION CRITERIA (EXCLUS) [EXCLUSION_CH_1] EXCLUSION CRITERIA [sctEXCLUSION_1] Mark the correct answers to the following Exclusion Criteria questions.

1.* Exclusion #3) Concurrent Medication/ Medical History - Currently taking antibiotics or have taken antibiotics within 2 weeks of plaque [IECRTNUME03] assessment (Visit 2). A subject with any medical history that may prevent them from participating in the study until study conclusion [A:Y] Yes [A:N] No (such as diabetes). [Exclusion #3) Concurrent Medication/ Medical History]

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205051: SUBJECT ELIGIBILITY (ELIG) [ELIG_1_CH] SUBJECT ELIGIBILITY [sctELIG_1] NOTE: If the subject is not eligible to continue in the study, complete the Study Conclusion visit.

1.* On the basis of Visit assessment(s), is the subject eligible and fit to participate in the next part of the study? [ELIG] [Subject eligible to continue in the study] [A:Y] Yes [A:N] No

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205051: PRE TREATMENT ORAL SOFT TISSUE EXAMINATION (OSTEXAM(PRE)) [OSTEXAM_CH_1] DATE/TIME OF ASSESSMENT [sctOSTDATE]

1.* Date and Time of Assessment [OSDTTM] [Date and Time of Assessment] Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock

ORAL SOFT TISSUE EXAMINATION [sctOSTEXAM] Note: Any new or worsened Oral Soft Tissue conditions after Screening should be recorded as an Adverse Event.

2.* Labial Mucosa (including lips) [OSRESCD1] [Labial Mucosa (including lips)] [A:1] Normal [A:2] [OSABDESC1] Abnormal, describe abnormality: A200

[A:3] [OSREASND1] Not Examined, provide details: A200

3.* Buccal Mucosa [OSRESCD2] [Buccal Mucosa] [A:1] Normal [A:2] [OSABDESC2] Abnormal, describe abnormality: A200

[A:3] [OSREASND2] Not Examined, provide details: A200

4.* Mucogingival Folds [OSRESCD3] [Mucogingival Folds] [A:1] Normal [A:2] [OSABDESC3] Abnormal, describe abnormality: A200

[A:3] [OSREASND3] Not Examined, provide details: A200

5.* Gingival Mucosa [OSRESCD4] [Gingival Mucosa] [A:1] Normal [A:2] [OSABDESC4] Abnormal, describe abnormality: A200

[A:3] [OSREASND4] Not Examined, provide details: A200

6.* Hard Palate [OSRESCD5] [Hard Palate] [A:1] Normal [A:2] [OSABDESC5] Abnormal, describe abnormality: A200

[A:3] [OSREASND5] Not Examined, provide details: A200

7.* Soft Palate [OSRESCD6] [Soft Palate] [A:1] Normal

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[A:2] [OSABDESC6] Abnormal, describe abnormality: A200

[A:3] [OSREASND6] Not Examined, provide details: A200

8.* Tonsilar Area [OSRESCD7] [Tonsilar Area] [A:1] Normal [A:2] [OSABDESC7] Abnormal, describe abnormality: A200

[A:3] [OSREASND7] Not Examined, provide details: A200

9.* Pharyngeal Area [OSRESCD8] [Pharyngeal Area] [A:1] Normal [A:2] [OSABDESC8] Abnormal, describe abnormality: A200

[A:3] [OSREASND8] Not Examined, provide details: A200

10.* Tongue [OSRESCD9] [Tongue] [A:1] Normal [A:2] [OSABDESC9] Abnormal, describe abnormality: A200

[A:3] [OSREASND9] Not Examined, provide details: A200

11.* Sublingual Area [OSRESCD10] [Sublingual Area] [A:1] Normal [A:2] [OSABDESC10] Abnormal, describe abnormality: A200

[A:3] [OSREASND10] Not Examined, provide details: A200

12.* Submandibular Area [OSRESCD11] [Submandibular Area] [A:1] Normal [A:2] [OSABDESC11] Abnormal, describe abnormality: A200

[A:3] [OSREASND11] Not Examined, provide details: A200

13.* Salivary Glands [OSRESCD12] [Salivary Glands] [A:1] Normal [A:2] [OSABDESC12]

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Abnormal, describe abnormality: A200

[A:3] [OSREASND12] Not Examined, provide details: A200

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205051: SUBJECT RANDOMISATION (RAND) [RAND_CH] SUBJECT RANDOMISATION [sctRAND]

1.* Was subject randomised? [RANDYN] [Subject randomised] [A:Y] [cmpRAND_Yes] [RANDNUM] Yes, provide: Randomisation Number N6

[RANDDTTM] Randomisation Date Req / Req / Req (2015-2018) [A:N] No

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205051: PLAQUE COLLECTION QUADRANT 1 (PLQCOLQ1) [PLQCOL_1] PLAQUE COLLECTION QUADRANT 1 [sctPLQCOL_1]

1.* Date/Time of Plaque Collection [PLQDTTMQ1] [Date/Time of Plaque Collection] Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock

2.* Sample Number [PLQSMPQ1] [Sample Number] A10

3.* Was Plaque Collection Performed per Protocol? [PLQCOLQ1] [Was Plaque Collection Performed per Protocol] [A:Y] Yes [A:N] No If No, complete the Protocol Deviations page

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205051: SUPERVISED TREATMENT (SUPTREATMENT) [EXPOSURE_3] SUPERVISED TREATMENT [sctEXPOSURE_3]

1.* Date and Time Product Started [EXSTDTTM] [Date and Time Product Started] Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock

2.* Was supervised treatment performed per protocol? [EXTREAT] [Supervised treatment performed] [A:Y] Yes [A:N] No If No, complete the Protocol Deviations page

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205051: PLAQUE COLLECTION QUADRANT 2,3 & 4 (PLQCOL(Q2-Q4)) [PLQCOL_2] DATE OF PLAQUE COLLECTION [sctPLQCOLDTTM]

1.* Date of Plaque Collection [PLQDT] [Date of Plaque Collection] Req / Req / Req (2015-2018)

15 MINUTES POST TREATMENT (QUADRANT 2) [sctPLQCOL15M]

2.* Was Plaque Collection Performed? [PLQPERFQ2] [Was Plaque Collection Performed] [A:Y] [PLQTMQ2] Yes Time of Plaque Collection Req/Unk : Req/Unk 24-hour clock [PLQSMPQ2] Sample Number A10 [A:N] No If No, complete the Protocol Deviations page

3.* Was Plaque Collection Performed per Protocol? [PLQCOLQ2] [Was Plaque Collection Performed per Protocol] [A:Y] Yes [A:N] No If No, complete the Protocol Deviations page 45 MINUTES POST TREATMENT (QUADRANT 3) [sctPLQCOL45M]

4.* Was Plaque Collection Performed? [PLQPERFQ3] [Was Plaque Collection Performed] [A:Y] [PLQTMQ3] Yes Time of Plaque Collection Req/Unk : Req/Unk 24-hour clock [PLCOSMPQ3] Sample Number A10 [A:N] No If No, complete the Protocol Deviations page

5.* Was Plaque Collection Performed per Protocol? [PLQCOLQ3] [Was Plaque Collection Performed per Protocol] [A:Y] Yes [A:N] No If No, complete the Protocol Deviations page 90 MINUTES POST TREATMENT (QUADRANT 4) [sctPLQCOL90M]

6.* Was Plaque Collection Performed? [PLQPERFQ4] [Was Plaque Collection Performed] [A:Y] [PLQTMQ4] Yes Time of Plaque Collection Req/Unk : Req/Unk 24-hour clock [PLQSMPQ4] Sample Number A10 [A:N] No If No, complete the Protocol Deviations page

7.* Was Plaque Collection Performed per Protocol? [PLQCOLQ4] [Was Plaque Collection Performed per Protocol] [A:Y] Yes [A:N] No If No, complete the Protocol Deviations page

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205051: POST TREATMENT ORAL SOFT TISSUE EXAMINATION (OSTEXAM(POST)) [OSTEXAM_CH_2] DATE/TIME OF ASSESSMENT [sctOSTDATE]

1.* Date and Time of Assessment [OSDTTM] [Date and Time of Assessment] Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock

ORAL SOFT TISSUE EXAMINATION [sctOSTEXAM] Note: Any new or worsened Oral Soft Tissue conditions after Screening should be recorded as an Adverse Event.

2.* Labial Mucosa (including lips) [OSRESCD1] [Labial Mucosa (including lips)] [A:1] Normal [A:2] [OSABDESC1] Abnormal, describe abnormality: A200

[A:3] [OSREASND1] Not Examined, provide details: A200

3.* Buccal Mucosa [OSRESCD2] [Buccal Mucosa] [A:1] Normal [A:2] [OSABDESC2] Abnormal, describe abnormality: A200

[A:3] [OSREASND2] Not Examined, provide details: A200

4.* Mucogingival Folds [OSRESCD3] [Mucogingival Folds] [A:1] Normal [A:2] [OSABDESC3] Abnormal, describe abnormality: A200

[A:3] [OSREASND3] Not Examined, provide details: A200

5.* Gingival Mucosa [OSRESCD4] [Gingival Mucosa] [A:1] Normal [A:2] [OSABDESC4] Abnormal, describe abnormality: A200

[A:3] [OSREASND4] Not Examined, provide details: A200

6.* Hard Palate [OSRESCD5] [Hard Palate] [A:1] Normal [A:2] [OSABDESC5] Abnormal, describe abnormality: A200

[A:3] [OSREASND5] Not Examined, provide details: A200

7.* Soft Palate [OSRESCD6] [Soft Palate] [A:1] Normal

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[A:2] [OSABDESC6] Abnormal, describe abnormality: A200

[A:3] [OSREASND6] Not Examined, provide details: A200

8.* Tonsilar Area [OSRESCD7] [Tonsilar Area] [A:1] Normal [A:2] [OSABDESC7] Abnormal, describe abnormality: A200

[A:3] [OSREASND7] Not Examined, provide details: A200

9.* Pharyngeal Area [OSRESCD8] [Pharyngeal Area] [A:1] Normal [A:2] [OSABDESC8] Abnormal, describe abnormality: A200

[A:3] [OSREASND8] Not Examined, provide details: A200

10.* Tongue [OSRESCD9] [Tongue] [A:1] Normal [A:2] [OSABDESC9] Abnormal, describe abnormality: A200

[A:3] [OSREASND9] Not Examined, provide details: A200

11.* Sublingual Area [OSRESCD10] [Sublingual Area] [A:1] Normal [A:2] [OSABDESC10] Abnormal, describe abnormality: A200

[A:3] [OSREASND10] Not Examined, provide details: A200

12.* Submandibular Area [OSRESCD11] [Submandibular Area] [A:1] Normal [A:2] [OSABDESC11] Abnormal, describe abnormality: A200

[A:3] [OSREASND11] Not Examined, provide details: A200

13.* Salivary Glands [OSRESCD12] [Salivary Glands] [A:1] Normal [A:2] [OSABDESC12]

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Abnormal, describe abnormality: A200

[A:3] [OSREASND12] Not Examined, provide details: A200

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205051: EVALUATION OF ADVERSE EVENTS (AEEVAL) [AEEVAL_CH] EVALUATION OF ADVERSE EVENTS [sctAEEVAL] Record subject's response to the below question.

1.* Have you felt unwell or experienced any symptoms (since your last visit) (today) (since your last dose) (since the last session)? [AESYMANY1] [AE Evaluation at Visit] [A:Y] Yes [A:N] No If Yes, complete Adverse Events page

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205051: EVALUATION OF ADVERSE EVENTS AND CONCOMITANT MEDICATIONS (AECMEVAL) [AECMEVAL_CH] EVALUATION OF ADVERSE EVENTS AND CONCOMITANT MEDICATIONS [sctAECMEVAL] Record subject's response to the below questions.

1.* Have you felt unwell or experienced any symptoms (since your last visit) (today) (since your last dose) (since the last session)? [AESYMANY] [AE Evaluation at Visit] [A:Y] Yes [A:N] No If Yes, complete Adverse Events page

2.* Have there been any changes to your concomitant medication use (existing or new) since your last visit? [CMCHANGE] [CONMED Changes at Visit] [A:Y] Yes [A:N] No If Yes, complete Concomitant Medications page

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205051: ANY ADVERSE EVENTS, PAST/CONCOMITANT MEDICATIONS AND NON-DRUG TREATMENTS (AE-CONMED-NONDRUG) [ANYAECM_CH] ANY ADVERSE EVENTS, PAST/CONCOMITANT MEDICATIONS AND NON-DRUG TREATMENTS [sctANYAECM]

1.* Is the subject taking past / concomitant medications? [CMANY] [Any Medications] [A:Y] Yes [A:N] No If Yes, complete Concomitant Medications page

2.* Did the subject have any Non-Drug Treatment / Procedures during the study? [NDANY] [Any Non-Drug Treatment / Procedures] [A:Y] Yes [A:N] No If Yes, complete Concomitant Non-Drug Treatment / Procedures page

3.* Did the subject experience any adverse events? [AEANY] [Any AE] [A:Y] Yes [A:N] No If Yes, complete Adverse Events page

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205051: PAST/CONCOMITANT MEDICATIONS (CONMED) - Repeating Form [CONMEDS_CH] # Drug Name Reason for Medication Route of Administration Dose per Administration Dose Frequency Start Date Ongoing Medication 1

PAST/CONCOMITANT MEDICATIONS [sctCM] 1. Sequence Number [hidden] [CMSEQ] [Sequence Number] N8

2.* Drug Name [CMTERM] (trade name preferred) A100 [Drug Name] 3. GSK Drug Synonym [hidden] [CMDRGSYN] [GSK Drug Synonym] A100

4. Modified Reported Term [hidden] [CMMODIFY] [Modified Reported Term] A100

5. GSK Drug Collection Code [hidden] [CMDRGCOL] [GSK Drug Collection Code] A10

6. Failed Coding [hidden] [calCM_FAILED] [Failed Coding] A10

7.* Reason for Medication [CMREAS] [Reason for Medication] A70

8.* Route of Administration [CMROUTCD] [Route of Administration] [clROUTE]

9.* Dose per Administration [cmpCMDOSE] [Dose per Administration] [CMUDOS] [CMDOSU] Dose A10 Unit [clDOSUNIT]

10.* Frequency [CMFREQ] [Dose Frequency] [clDOSEFREQ]

11.* Start Date [CMSTDT] [Start Date] Req/Unk / Req/Unk / Req/Unk (1900-2018)

12.* Ongoing Medication? [CMONGO] [Ongoing Medication] [A:Y] Yes [A:N] [CMENDT] No, provide End Date: Req/Unk / Req/Unk / Req/Unk (1900-2018)

13. Event Diagnosis Only (if known) Otherwise Sign/Symptom [hidden] [CMCOMPARE] [Event] A100

14. Modified reported term [hidden] [CMMODCOMPARE] [Modified reported term] A100

Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

Codelist Values Tables: PAST/CONCOMITANT MEDICATIONS Codelist RefName Codelist Data Type Label Code Codelist Item RefName Data Variable RefName clROUTE String Epidural EP Epidural CMROUTCD Gastrostomy tube GTT Gastrostomytube Intra-arterial IA Intraarterial Intra-articular IART Intraarticular Intra-bursa IB Intrabursa Intradermal ID Intradermal Inhalation IH Inhalation Intralesional ILES Intralesional

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Intramuscular IM Intramuscular Intranasal IN Intranasal Injection INJ Injection Intraocular IO Intraocular Intraosteal IOS Intraosteal Intraperitoneal IP Intraperitoneal Intrathecal IT Intrathecal Intrauterine IU Intrauterine Intravenous IV Intravenous Jejunostomy feeding tube (JEJ or PEJ) JEJ Jejunostomyfeedingtube Nasogastric NG Nasogastric Nasal NS Nasal Right eye OD Righteye Opthalmic OP Opthalmic Left eye OS Lefteye Otic OT Otic Other OTH Other Both eyes OU Botheyes Oral PO Oral Rectal PR Recal Subcutaneous SC Subcutaneous Sublingual SL Sublingual Transdermal TD Transdermal Transmucosal TM Transmucosal Topical TP Topical Unknown UNK Unkown Vaginal VG Vaginal clDOSUNIT String Actuation ACTU DOSUNIT_ACTU CMDOSU Ampoule AMP DOSUNIT_AMP Application APP DOSUNIT_APP Area under curve AUC DOSUNIT_AUC Bottle BOT DOSUNIT_BOT Capsule CAP DOSUNIT_CAP Caplet CAPT DOSUNIT_CAPT Cubic centimeter CC DOSUNIT_CC Cup CUP DOSUNIT_CUP Finger tip unit FTU DOSUNIT_FTU Gamma per kilogram per minute GA/KG/MIN DOSUNIT_GAPKGPMIN Gram G DOSUNIT_G Grams per kilogram G/KG DOSUNIT_GPKG Grams per litre G/L DOSUNIT_GPL Grams per metre squared G/M2 DOSUNIT_GPM2 Grams per metre squared per 12 hours G/M2/12HR DOSUNIT_GPM2P12HR Grams per metre squared per day G/M2/DAY DOSUNIT_GPM2PDAY Grams per millitre G/ML DOSUNIT_GPML Drops GTT DOSUNIT_GTT Gum GUM DOSUNIT_GUM

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Inhalation INH DOSUNIT_INH 100 International units/ml 100IU/ML DOSUNIT_100IUPML International units IU DOSUNIT_IU International units per kilogram IU/KG DOSUNIT_IUPKG International units per kilogram per hour IU/KG/HR DOSUNIT_IUPKGPHR International units per millitre IU/ML DOSUNIT_IUPML Litre L DOSUNIT_L Litres per minute L/MIN DOSUNIT_LPMIN Lozenge LOZ DOSUNIT_LOZ Mega becquerels (MBq) MBQ DOSUNIT_MBQ Megaunits (million units) MU DOSUNIT_MU Microgram (MCG) MCG DOSUNIT_MCG Microgram (UG) UG DOSUNIT_UG Micrograms per gram MCG/G DOSUNIT_MCGPG Micrograms per hour MCG/HR DOSUNIT_MCGPHR Microgram per kilogram MCG/KG DOSUNIT_MCGPKG Microgram per kilogram per minute MCG/KG/MIN DOSUNIT_MCGPKGPMIN Microgram per minute MCG/MIN DOSUNIT_MCGPMIN Microgram per millitre MCG/ML DOSUNIT_MCGPML Microlitre MCL DOSUNIT_MCL Micromoles UMOL DOSUNIT_UMOL Micromoles per 24 hours UMOL/24HR DOSUNIT_UMOLP24H Millicurie MCI DOSUNIT_MCI Milliequivalent MEQ DOSUNIT_MEQ Milliequivalents per 24 hours MEQ/24HR DOSUNIT_MEQP24HR Milligram MG DOSUNIT_MG Milligram per day MG/DAY DOSUNIT_MGPDAY Milligram per hour MG/HR DOSUNIT_MGPHR Milligram per kilogram MG/KG DOSUNIT_MGPKG Milligram per kilogram per hour MG/KG/HR DOSUNIT_MGPKGPHR Milligram per kilogram per minute MG/KG/MIN DOSUNIT_MGPKGPMIN Milligrams per metre squared MG/M2 DOSUNIT_MGPM2 Milligrams per metre squared per day MG/M2/DAY DOSUNIT_MGPM2PDAY Milligrams per millilitre MG/ML DOSUNIT_MGPML Milligram per week MG/WK DOSUNIT_MGPWK Milligrams percent MG% DOSUNIT_MGPER Millilitre ML DOSUNIT_ML Millilitres per hour ML/HR DOSUNIT_MLPHR Millilitres per kilogram ML/KG DOSUNIT_MLPKG Millilitres per minute ML/MIN DOSUNIT_MLPMIN Millimole MMOL DOSUNIT_MMOL Millimoles per kilogram MMOL/KG DOSUNIT_MMOLPKG Millimoles per millilitre MMOL/ML DOSUNIT_MMOLPML Million international units MIU DOSUNIT_MIU Minimum alveolar concentration MAC DOSUNIT_MAC Nanogram per kilogram per minute NG/KG/MIN DOSUNIT_NGPKGPMIN Nebule NEB DOSUNIT_NEB Nanogram

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NG DOSUNIT_NG Ounce OZ DOSUNIT_OZ Pack PACK DOSUNIT_PACK Patch PATCH DOSUNIT_PATCH Pill PILL DOSUNIT_PILL Powder POW DOSUNIT_POW Pulveris PUL DOSUNIT_PUL Percent % DOSUNIT_Per Puff PUFF DOSUNIT_PUFF Ring RING DOSUNIT_RING Sachet SACH DOSUNIT_SACH Spray SPR DOSUNIT_SPR Suppository SUPP DOSUNIT_SUPP Tablet TAB DOSUNIT_TAB Tablespoon TBLSP DOSUNIT_TBLSP Trouche TRO DOSUNIT_TRO Teaspoon TSP DOSUNIT_TSP Units U DOSUNIT_U Units per gram U/G DOSUNIT_UPG Units per hour U/HR DOSUNIT_UPHR Units per kilogram U/KG DOSUNIT_UPKG Units per kilogram per minute U/KG/MIN DOSUNIT_UPKGPMIN Units per minute U/MIN DOSUNIT_UPMIN Unknown UNK DOSUNIT_UNK Vial VIAL DOSUNIT_VIAL clDOSEFREQ String 1 x Daily OD DOSEFREQ_OD CMFREQ 2 x Daily BID DOSEFREQ_BID 3 x Daily TID DOSEFREQ_TID 4 x Daily QID DOSEFREQ_QID At bedtime HS DOSEFREQ_HS As required PRN DOSEFREQ_PRN Daily dosing every other week QDQOW DOSEFREQ_QDQOW Once in the morning 1XAM DOSEFREQ_1XAM Once in the evening 1XPM DOSEFREQ_1XPM Twice in the morning 2XAM DOSEFREQ_2XAM Twice weekly 2XW DOSEFREQ_2XW 2 x per cycle 2XCYC DOSEFREQ_2XCYC 3 x per cycle 3XCYC DOSEFREQ_3XCYC 3 TIMES A WEEK 3XW DOSEFREQ_3XW 4 TIMES A WEEK 4XW DOSEFREQ_4XW 5 TIMES A WEEK 5XW DOSEFREQ_5XW 6 TIMES A WEEK 6XW DOSEFREQ_6XW Every 3 days Q3D DOSEFREQ_Q3D Every 4 days Q4D DOSEFREQ_Q4D Every 5 days Q5D DOSEFREQ_Q5D Every 6 days Q6D DOSEFREQ_Q6D Every morning QAM DOSEFREQ_QAM

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Every day QD DOSEFREQ_QD Every other day QOD DOSEFREQ_QOD Every week QWK DOSEFREQ_QWK Every 2 weeks Q2WK DOSEFREQ_Q2WK Every 3 weeks Q3WK DOSEFREQ_Q3WK Every 4 weeks Q4S DOSEFREQ_Q4S Every 3 months Q3MTH DOSEFREQ_Q3M

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205051: CONCOMITANT NON-DRUG TREATMENT/PROCEDURES (NONDRUG) - Repeating Form [NDRUGTX_CH] # Non-Drug Treatment / Procedure Name Reason for Non-Drug Treatment / Procedure Frequency Start Date Ongoing Non-Drug Treatment / Procedure 1

CONCOMITANT NON-DRUG TREATMENT/PROCEDURES [sctNDRUGTX] 1. Sequence Number [hidden] [NDSEQ] [Sequence Number] N8

2.* Name of Non-Drug Treatment / Procedure [NDTERM] [Non-Drug Treatment / Procedure Name] A100

3.* Reason for Non-Drug Treatment / Procedure [NDREAS] [Reason for Non-Drug Treatment / Procedure] A200

4.* Frequency [NDFREQ] [Frequency] A200

5.* Start Date [NDSTDT] [Start Date] Req/Unk / Req/Unk / Req/Unk (1900-2018)

6.* Ongoing Non-Drug Treatment / Procedure? [NDONGO] [Ongoing Non-Drug Treatment / Procedure] [A:Y] Yes [A:N] [NDENDT] No, provide End Date: Req/Unk / Req/Unk / Req/Unk (1900-2018)

Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

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205051: ADVERSE EVENTS (AE) - Repeating Form [AE_CH] # Adverse Event Start Date and Time Outcome Frequency Intensity Relationship to Investigational Product Action Taken with the Investigational Product Serious Subject Withdrawn 1

ADVERSE EVENTS [sctAE] 1. Sequence Number [hidden] [AESEQ] [Sequence Number] N8

2.* Adverse Event [AETERM] [Adverse Event] A100

3. Modified Term [hidden] [AEMODIFY] [Modified Term] A100

4. MedDRA Synonym [hidden] [AEMEDSYN] [MedDRA Synonym] A100

5. MedDRA Lower Level Term Code [hidden] [AELLTCD] [MedDRA Lower Level Term Code] A10

6. Failed Coding [hidden] [calAE_FAILED] [Failed Coding] A10

7.* Start Date and Time [AESTDTTM1] [Start Date and Time ] Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock

8.* Outcome / End Date and Time [AEOUTCD] [Outcome] [A:1] [AEENDTTM1] Recovered/Resolved, provide End Date and Time: Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock [A:2] Recovering/Resolving [A:3] Not recovered/Not resolved [A:4] [AEENDTTM2] Recovered/Resolved with sequelae, provide End Date and Time: Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock [A:5] [AEENDTTM3] Fatal, provide Death Date and Time: Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock

9.* Frequency [AEFREQCD] [Frequency] [A:1] Single Episode [A:2] Intermittent

10.* Intensity [AESEVCD] [Intensity] [A:1] Mild [A:2] Moderate [A:3] Severe

11.* Is there a reasonable possibility that the AE may have been caused by the investigational product? [read-only] [AEREL] [Relationship to Investigational Product] [A:Y] Yes [A:N] No

12.* Action taken with the investigational product as a result of the AE [AEACTRCD] [Action Taken with the Investigational Product] [A:1] Investigational product(s) withdrawn [A:2] Dose reduced [A:3] Dose increased [A:4] Dose not changed [A:5] Dose interrupted [A:X] Not applicable

13.* Serious [AESER] [Serious] [A:Y] Yes

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[A:N] No NOTE: All serious adverse events must be reported to the study manager within 24 hours and require additional reporting on an SAE form

14.* Did the subject withdraw from study as a result of this AE? [AEWD] [Subject Withdrawn] [A:Y] Yes [A:N] No If Yes, complete the Study Conclusion page with primary reason for withdrawal as Adverse Event 15. Event Diagnosis Only (if known) Otherwise Sign/Symptom [hidden] [AECOMPARE] [Event] A100

16. Event Diagnosis Only (if known) Otherwise Sign/Symptom [hidden] [AEMODCOMPARE] [Event] A100

Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

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205051: ANY PROTOCOL DEVIATIONS (ANY DEVIATION) [ANYDEV_CH] ANY PROTOCOL DEVIATIONS [sctANYDEV]

1.* Have there been any protocol deviations? [DVANY] [Any Deviations] [A:Y] Yes [A:N] No If Yes, complete Deviations page

Key: [*] = Item is required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

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205051: PROTOCOL DEVIATIONS (DEVIATION) [DEVIATION_CH] Protocol Deviation Start Date/Time of Deviation End Date/Time of Deviation 1.

PROTOCOL DEVIATIONS Entry [sctPROTDEV] 1.1 Sequence Number [hidden] [DVSEQ] [Sequence Number] N8

1.2* Protocol Deviation [DVTERM] [Protocol Deviation] A200

1.3* Start Date/Time of Deviation [DVSTDTTM] [Start Date/Time of Deviation] Req/Unk / Req/Unk / Req/Unk (2015-2018)

Req/Unk : Req/Unk 24-hour clock

1.4* End Date/Time of Deviation [DVENDTTM] [End Date/Time of Deviation] Req/Unk / Req/Unk / Req/Unk (2015-2018)

Req/Unk : Req/Unk 24-hour clock

Key: [*] = Item is required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

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205051: PRODUCT RETURN INFORMATION (PRODRET) [DARET_CH] PRODUCT RETURN INFORMATION [sctDARET]

1.* Date and Time Product Returned [DARDTTM] [Date and Time Product Returned] Req / Req / Req (2015-2018)

Req/Unk : Req/Unk 24-hour clock

Key: [*] = Item is required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

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205051: OPTIONAL ORAL SOFT TISSUE EXAM (OPTOST) [OPTOST] Optional Oral Soft Tissue Exam [sctOPTOST]

1.* Was an end of study OST performed? [OPOST] D [Was an end of study OST performed?] [A:Y] Yes [A:N] No

Key: [*] = Item is required [D] = Source verification required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

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205051: STUDY CONCLUSION (STUDYCONC) [DS_CONCLUSION_CH] STUDY CONCLUSION [sctDS_CONCLUSION]

1.* Date of subject completion or withdrawal [DSSTDT] [Date of subject completion or withdrawal] Req / Req / Req (2015-2018)

2.* Was the subject withdrawn from study? [DSFAIL] D [Subject withdrawn from study] [A:Y] [DSRSCD] Yes, provide primary reason for withdrawal: [A:1] [DSRSSP1] Subject did not meet study criteria; specify the criterion or assessment not met NOTE: If the subject failed Inclusion/Exclusion criteria, specify the criteria numbers failed with a prefix of I(Inclusion criteria) or E(Exclusion criteria) A200

[A:2] Adverse Event, complete Adverse Events page [A:3] Lost to Follow-up [A:4] [DSRSSP4] Protocol Violation, specify details A200

[A:5] [DSRSSP5] Withdrawal of consent, specify details A200

[A:99] [DSRSSP99] Other, specify details A200

[A:N] No

Key: [D] = Source verification required Note: Source verification critical settings made in InForm will override any settings made in Central Designer.

PPD 9/24/2015 PPD - This section contained Curriculum Vitae(s) and has been excluded to protect personal privacy. Volunteer Information and Informed Consent Final Version 1.0 DATE: 02 October 2015 PRINCIPAL INVESTIGATOR: David Payne Study Number: 205051 Page 1 of 6

Volunteer Information and Informed Consent Form Study 205051 A Study to Investigate the Antimicrobial Activity of two Test Toothpastes in a Plaque Glycolysis and Regrowth Model. Introduction You are being invited to take part in a research study. The sponsoring company for this study is GlaxoSmithKline Consumer Healthcare. Before you decide whether or not you wish to take part, it is important that you read this document carefully and fully understand why the research is being done and what it will involve. The study procedures will be fully explained to you by the Principal Investigator or Study Staff. This document may include a few technical terms that you may not be familiar with. Please feel free to ask the Principal Investigator or the Study Staff any questions you may have about the study, so you fully understand what your participation will involve. What is the Purpose of the Study? The purpose of this study is to investigate the antimicrobial effect of two toothpastes on plaque (Dental plaque is a sticky, colourless film of bacteria and sugars, that constantly forms on our teeth). What is Being Tested? The products being tested are two toothpastes (both containing zinc chloride and sodium fluoride). These will be compared against marketed toothpastes, one which contains stannous fluoride, the second tegobetain and sodium fluoride and the third contains sodium fluoride.

If you are accepted onto the study, at visits 3 to 7 you will be asked to 'swill' a slurry (toothpaste and water mixture) of one of the toothpastes around your mouth for 1 minute.

You will use each product once, in a random order. Randomisation is like rolling dice. You will not be able to choose the product you use during the visit. Plaque samples will be collected before and after use of the toothpaste slurry and analysed to determine the effect of the toothpaste on the plaque.

Is my participation Voluntary? You are free to decide whether or not you wish to take part in the study. If you decide to volunteer, you will be given this information sheet to keep and you will be asked to sign the consent form. If you decide to volunteer, you will be free to withdraw at any time and without giving a reason and without a penalty or loss of benefits to which you are otherwise entitled. The Investigator or Sponsoring Company may discontinue your participation in the study at any time without your consent. What will happen to me if I decide to take part? In total, your involvement in this study will be approximately 7 weeks from screening visit to final assessment. This study requires you to make up to 7 visits to the study site. Between visits 2 and 3 we will phone you and let you know if you have suitable plaque in order to qualify for the remainder of the study. If you do not have suitable plaque, you will attend one further visit to have a health check and receive your payment for the visits you have completed. By deciding to take part, you are agreeing to provide accurate information and to follow all study instructions as given to you. You will be required to provide proof of your identification (photographic identification is preferred, otherwise an official document such as a utility bill will be accepted) and we will take a photocopy. This will be kept confidential as will any other documentation pertaining to your identification. To take part, you should be aged at least 18 years old, in good general health and have good oral health (as assessed by the dentist).

You will not be able to take part:  If you have taken antibiotics in the two weeks prior to Visit 2.  If you have taken part in another study in the last 30 days.  If you are allergic or hypersensitive to any of the ingredients in the study toothpastes. Please check the list of ingredients provided by the study staff.

YOU WILL NOT BE ABLE TO PARTICIPATE IF YOU ARE PREGNANT, OR PLANNING TO BECOME PREGNANT, OR BREASTFEEDING.

PROHIBITIONS AND RESTRICTIONS WHILST TAKING PART IN THE STUDY There are a few restrictions we will ask you to comply with while taking part in the study. PI Contact Address: Intertek CRS, Elm House, Unit A4, Oaklands Office Park, Hooton road, Hooton, CH66 7NZ Study Site Addresses: Intertek CRS, 6 Brindley Road, City Park Business Village, Old Trafford, M16 9HQ Volunteer Information and Informed Consent Final Version 1.0 DATE: 02 October 2015 PRINCIPAL INVESTIGATOR: David Payne Study Number: 205051 Page 2 of 6

 Please do not let anyone else use the washout toothpaste and toothbrush allocated to you.  Please do not have any elective dental procedures other than those performed within the study (excluding emergency dental treatment).  Please abstain from chewing gum, using mints or breath strips for the duration of the study.  Please only use the toothpaste and toothbrushes provided and abstain from use of all other oral hygiene products including mouthwash and floss for the duration of the study.  Prior to Visits 2 to 7: Please abstain from eating and drinking (with the exception of water) and oral hygiene procedures from 11:00 pm the evening before and the morning of the study dates. You will be allowed to drink water up to 1 hour before the study visit.  Prior to Visits 2 to 7: Please abstain from drinking alcohol 24 hours prior to the study visit. IF YOU FEEL UNWELL, PLEASE TAKE THE MEDICATION YOU NEED AND ALWAYS FOLLOW YOUR DOCTOR’S ADVICE. PLEASE INFORM US OF ANY CHANGES IN YOUR MEDICATION AT YOUR NEXT SCHEDULED VISIT STUDY PROCEDURES Visit 1 – Screening Appointment (Approximately 40 minutes)  Once you have read the information sheet and consent form, study staff will tell you about the study and what taking part will involve.  If you wish to take part in the study you will be asked to sign the information sheet and consent form. One copy will be retained by us and a copy will be given to you to keep. You must keep this information for the duration of the study as it contains instructions and important telephone numbers. By signing the consent, you are agreeing to provide accurate information and to follow the study procedures.  If you would rather not take part, please just hand the forms back to the staff member and tell them you no longer wish to be considered for the study. If you would prefer not to answer any questions that you are asked, or to undergo any of the procedures outlined in this consent form, please inform a staff member as soon as you can.  Once you have consented to take part in the study, study staff will go through some questions with you which will involve recording information on your general health and any medication you are taking. You will be asked a series of questions that will help us to decide if you are suitable to take part in the study or not. NOTE: If any new medical conditions become evident during the study, if you start using a new medication or if you become pregnant, please notify a member of the study staff or contact PPD , Study Coordinator at Intertek CRS on PPD as soon as possible to report this information. In case of a medical or dental emergency call PPD (available 24 hours)  When the questions are complete, a Dentist will look inside your mouth to assess your general oral health and condition of individual teeth to confirm your suitability to take part in the study.  If you are not suitable to continue in the study you will be given a payment of £10 for your time and inconvenience.  If you are suitable to continue in the study you will be given an appointment and asked to return on that day having refrained from oral hygiene and eating and drinking (excluding water) from 11:00pm the evening before. You will also be given a toothbrush and toothpaste to use at home in place of your normal toothbrush and paste throughout the duration of the study. This is a marketed toothpaste. You should brush twice daily according to your usual habit. At each brushing, you should dispense one ribbon of paste covering the length of the head of the toothbrush. These products are for your own use only. You must return this toothpaste and toothbrush at the end of your study participation. Visit 2 Plaque Screening Assessment (approximately 45 minutes) YOU MUST FOLLOW THE RESTRICTIONS DETAILED ON PAGE 2 OF THIS INFORMATION SHEET  You will be asked about any changes to your medical health or medication taken since your last visit. We will check your eligibility to continue by asking you a few compliance questions.

PI Contact Address: Intertek CRS, Elm House, Unit A4, Oaklands Office Park, Hooton road, Hooton, CH66 7NZ Study Site Addresses: Intertek CRS, 6 Brindley Road, City Park Business Village, Old Trafford, M16 9HQ Volunteer Information and Informed Consent Final Version 1.0 DATE: 02 October 2015 PRINCIPAL INVESTIGATOR: David Payne Study Number: 205051 Page 3 of 6

 A clinician will look in your mouth to assess your general oral health and to confirm your suitability to continue in the study.  They will then use a soft swab to collect plaque from your teeth.  The plaque will be sent off for analysis of acidity levels to determine if it is suitable for this study. Once we receive the results we will phone you and let you know if your plaque acidity levels are within the range we are looking for. Please look out for our call  If you are not suitable, your participation in the study will end and you will be asked to return to site for Visit 3 (in the afternoon) for a final dental check up and to return the washout brush and paste. You will not need to attend any further visits and will be compensated for your time and inconvenience. Please note that even if you do have the right levels of plaque acidity, we may not be able to take you if the study is already full. You will be paid for the visits that you have made up to and including visit 3.  If you are suitable, you will be given an appointment for visits 3, 4, 5, 6 and 7. You will be asked to continue using the washout toothbrush and paste. Visit 3 Randomisation and Treatment (approximately 2 hours) YOU MUST FOLLOW THE RESTRICTIONS DETAILED OF PAGE 2 OF THIS INFORMATION SHEET  You will be asked about any changes to your medical health or medication taken since your last visit. We will check your eligibility to continue by asking a few compliance questions.  A clinician will look in your mouth to assess your general oral health and to confirm your suitability to continue in the study.  A clinician will then use a soft swab to collect baseline plaque from some of your teeth  You will then be randomised to one of the test toothpastes. You will ‘swish’ a test toothpaste slurry (mixture of toothpaste and water) around your mouth for 60 seconds on site under supervision.  The Clinician will then take 3 more plaque collections approximately 15 minutes, 45 minutes and 90 minutes after you used the product and a last general oral health check will be carried out by the clinican at the end.  You will then be free to leave the study site. You must continue using the washout toothpaste and brush until the next visit. Visit 4, 5, 6 Treatment use (approximately 2 hours) YOU MUST FOLLOW THE RESTRICTIONS DETAILED OF PAGE 2 OF THIS INFORMATION SHEET  The procedures will be the same as visit 3 (except for randomisation) Visit 7 Treatment use (approximately 2 hours) YOU MUST FOLLOW THE RESTRICTIONS DETAILED OF PAGE 2 OF THIS INFORMATION SHEET Please bring the washout toothpaste and toothbrush back with you to this visit  This will be the same as visit 4  You will return the washout toothpaste and toothbrush.  Once all study procedures are complete, you will then be compensated for your time and inconvenience. You will then be free to leave the study site and return to your usual oral hygiene routine. If you experience any new medical conditions or feel unwell up to 5 days following the product use at Visit 7 please report this to the study site staff on PPD . A representative from the sponsor company may observe the study procedures at one or more study visits.

Plaque Sample If you are accepted onto the study, one plaque sample will be collected at visit 2. If you are suitable for the rest of the study, twenty further plaque samples will be taken (four times at visits 3, 4, 5, 6 and 7). These samples will be used to determine the acidity of your plaque, and also to determine the concentration and health of the bacteria in your plaque. This data will be used to to assess the antimicrobial activity of the toothpastes being evaluated in the study. The samples will not be used for genetic testing or to test for any unknown diseases.

The plaque samples will be transferred to a laboratory (Intertek PSM, Hexagon Tower, Blackley, Manchester, M9 8GQ, UK) for analysis. The plaque samples collected in the clinic will be destroyed during the analysis process or once each sample has been analysed. No samples will be transferred to and used by GSK or any other commercial institution. The samples will be taken and handled following the relevant laws or guidelines covering the collection, use, storage, transportation and disposal of human tissue and protection of data privacy (UK Human Tissue Act). The samples will be identified in a way that preserves your anonymity to ensure that you are not identified by name, using only sample codes. Anyone who works with your samples will hold the information and results in confidence. The location of your samples will be traceable using this unique code at any time from sample collection through to sample destruction. The sponsoring company (GlaxoSmithKline Consumer Healthcare) will own the information resulting from the analyses, similar to information collected in the study, the results from your samples may also be shared by GSK with other companies or universities to better understand plaque acidity and plaque bacteria formation or to further develop the study product or other products. None of this information will identify you, but you will not benefit financially aside from the compensation you receive for taking part in the study. If you decide you no longer wish to take part in this study, all the previously collected samples submitted for analysis before you withdrew from the study will still be analysed and reported. If after withdrawal from the study you wish any of your samples not analysed to be destroyed prior to the analysis, please inform us to this effect in writing. Are there any possible side effects of the test products? There are no side effects expected with the use of the study products. Medicines or products and their possible side effects can affect individual people in different ways. Since there is always the possibility that a rare or previously unknown side effect may occur in somebody using this or any other product trained medical staff will be available at Intertek CRS. If you experience a medical problem after leaving the site please contact us on PPD . How many subjects will be taking part in the study? Approximately 45 subjects will be taking part in the test visits (3, 4, 5, 6 and 7).

What are the possible benefits in taking part? There are no direct benefits to you in taking part in this study. However, your involvement in the study may contribute to the development of a new or improved product.

Are there any alternative procedures/treatments? There are alternative toothpaste products available on the market within the European Union (EU). What if new information becomes available? If new information about the study products becomes available during the course of the study, the Investigator or study staff will tell you about it and discuss with you whether you want to continue with the study.

Are there any reasons why my participation in this study could be ended? You are free to withdraw from participating in this study at any time and for whatever reason, specified or unspecified, and without prejudice. The following are reasons why you may be asked to withdraw from the study.  The Investigator's request.  Your safety (such as an adverse reaction).  At your request.  If you don’t comply with the study procedures.  Your use of or need for other medications or therapy that could interfere with the study results.  If you do not have the required levels of plaque acidity following the visit 2 plaque sample  If you do have the require levels of plaque acidity following visit 2 analysis but the study is full

What if something goes wrong? Compensation for any injury caused by taking part in this study will be in accordance with the guidelines of the Association of the British Pharmaceutical Industry (ABPI). Broadly speaking the ABPI guidelines recommend that ‘the sponsor’, without legal commitment, should compensate you without you having to prove that it is at fault. This applies in cases where it is likely that such injury results from giving any new drug or any procedure carried out in accordance PI Contact Address: Intertek CRS, Elm House, Unit A4, Oaklands Office Park, Hooton road, Hooton, CH66 7NZ Study Site Addresses: Intertek CRS, 6 Brindley Road, City Park Business Village, Old Trafford, M16 9HQ Volunteer Information and Informed Consent Final Version 1.0 DATE: 02 October 2015 PRINCIPAL INVESTIGATOR: David Payne Study Number: 205051 Page 5 of 6

with the protocol for the study. ‘The sponsor’ will not compensate you where such injury results from any procedure carried out which is not in accordance with the protocol for the study. Your right at law to claim compensation for injury where you can prove negligence is not affected. Copies of the ABPI guidelines are available upon request.

Will my taking part in this study be confidential? If you consent to take part in this study, Intertek CRS and the sponsoring company, in accordance with international regulatory guidelines, will store the information collected during the study. All data collected will be protected under the Data Protection Act. The information may also be made available within and outside the EEA to monitors, auditors (both from the research organisation and Sponsor Company), members of the Ethics Committee and staff from regulatory authorities, for the purposes of data verification. Only Intertek CRS staff and the monitors will know that the information is related to you and this information is kept separate and confidential.

The data from this study will be stored on a password protected electronic database called ‘Inform’. Only data needed to meet the study objectives will be collected. Throughout the study, all data will be identified only by a unique identification number. Your name is never entered into the electronic database.

Data will be transferred outside of the EEA (to the USA and India) for data processing and analysis. Procedures will be put in place to protect your information even in countries whose data privacy laws are less strict than those of this country. If you consent to take part in this study Intertek CRS will notify your dentist of your participation and may contact your family doctor in the case of an emergency. A representative from the sponsor company may observe the study in progress.

A description of this clinical study will be available on the GSK Clinical Study Register: http://www.gsk- clinicalstudyregister.com and may also appear in clinical trial/study registries in countries in which the clinical study is conducted. GSK may publish study results for medical journals, meetings and on the internet for other researchers to use; your name will not appear in any publication.

If you consent to take part in this study Intertek CRS will notify your dentist of your participation. We may contact your doctor if deemed necessary.

GSK Intellectual Property

The information and any materials or items that you are given about or during the study – such as information regarding the toothpaste or the type of study being performed – should be considered the confidential business information of the study sponsor. You are of course, free to discuss with your friends and family while considering whether to participate in this study or at any time when discussing your present or future healthcare.

Will I be compensated for taking part in this study? If you are not suitable to take part in the study after Visit 1, you will receive a payment of £10. If you are not suitable at visit 3 you will receive a payment of £55. All subjects that complete the study will receive a cheque for £180 for your time, inconvenience and travel expenses. Visits Completed Payment Received Visit 1 10 Visit 2 10 Visit 3 - 7 20 Completion bonus (all visits completed) 60 Total upon completion of whole study 180 Please note that it is your responsibility to inform the HM Revenue & Customs of the financial expenses received for participating in this study. Intertek CRS is legally obliged to disclose the amount. Is there a contact for further information? For any further information on this study, including questions about your rights as a volunteer and about any study procedures please contact Intertek CRS on PPD during normal office hours quoting the study number 205051. In Case of Medical or Dental Emergency call PPD . Thank you very much for your assistance. PI Contact Address: Intertek CRS, Elm House, Unit A4, Oaklands Office Park, Hooton road, Hooton, CH66 7NZ Study Site Addresses: Intertek CRS, 6 Brindley Road, City Park Business Village, Old Trafford, M16 9HQ Volunteer Information and Informed Consent Final Version 1.0 DATE: 02 October 2015 PRINCIPAL INVESTIGATOR: David Payne Study Number: 205051 Page 6 of 6

Study Number: 205051 Subject Screening Number:

CONSENT FORM

A Study to Investigate the Antimicrobial Activity of two Test Toothpastes in a Plaque Glycolysis and Regrowth Model. Please initial box

1. I confirm that I have read and understand the information sheet for the above study and have had the opportunity to ask questions.

2. I understand that my participation is voluntary and that I am free to withdraw at any time, without giving any reason, without my medical care or legal rights being affected.

3. I understand that sections of my medical history screening questionnaire may be looked at by responsible individuals from GlaxoSmithKline Consumer Healthcare or from regulatory authorities where it is relevant to my taking part in research. I give permission for these individuals to have access to my records.

4. I agree to take part in the above study and understand/agree to provide accurate information. I give permission for a copy of my ID to be held securely on site during the study and I understand it will then be securely archived with the other study documents.

5. I agree to provide the contact details of my General Practitioner and my Dentist, as appropriate and I agree to my dentist being informed of my participation in this study. I agree to my GP being contacted in the case of an emergency.

6. I confirm that I have been shown the list of ingredients of the products to be used in this study and am not aware of having had a previous adverse or allergic reaction to any of the ingredients listed.

7. I agree to give plaque samples that will be analysed as explained in the information sheet. I understand the sponsoring company will have ownership of the research results from these analyses.

8. I agree to waive ownership of all data collected including the right to withdraw data from the study, and I give permission for the data to be transferred to countries outside the EU.

______Name of Subject Date Signature (Please include any middle names)

______Name of Person taking consent Date Signature

One copy of this information sheet will be retained by Intertek CRS. Another signed copy will be retained by the subject.

PI Contact Address: Intertek CRS, Elm House, Unit A4, Oaklands Office Park, Hooton road, Hooton, CH66 7NZ Study Site Addresses: Intertek CRS, 6 Brindley Road, City Park Business Village, Old Trafford, M16 9HQ Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Table of Contents Page

TABLE 9.4.1 LISTING OF ADVERSE EVENTS SAFETY POPULATION 86 TABLE 9.4.6 LISTING OF SERIOUS ADVERSE EVENTS SAFETY POPULATION 87 DATA LISTING 2.1 RANDOMISATION INFORMATION DATA LISTING 2.2 LISTING OF EXTERNAL PLAQUE SAMPLE DATA SAFETY 97 POPULATION 101

Page 2 of 209 PPD- This section has been excluded to protect patient privacy Document Name RH205051 Synopsis Type Version Document Identifier Effective Date eldo_controlled 1.0; CURRENT; Most-Recent; Effective 090032d580d18c62 Reason For Issue

Protocol: 205051 Program Run Date: 19MAY2016 Table 9.4.6 Listing of Serious Adverse Events Safety Population ______

Document Version:1.0,CURRENT,Most-Recent,Effective THERE WERE NO SERIOUS ADVERSE EVENTS REPORTED

______(Page 1 of 1)

PPD

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Protocol: 205051 Program Run Date: 24MAY2016 Data Listing 2.1 Randomisation Information

Study Population: Randomised (N=45) ______Subject Treatment Randomisation Randomisation Number Sequence[1] Number Date ______

PPD B/E/C/D/A PPD 09NOV2015

A/C/D/B/E 13NOV2015

C/E/B/A/D 11NOV2015

A/C/D/B/E 10NOV2015

D/A/E/C/B 10NOV2015

B/C/E/A/D 10NOV2015 Document Version:1.0,CURRENT,Most-Recent,Effective

D/A/E/C/B 09NOV2015

E/A/C/D/B 11NOV2015

D/A/B/E/C 12NOV2015

D/E/A/B/C 12NOV2015

C/A/B/D/E 09NOV2015

A/D/E/C/B 13NOV2015

E/D/B/A/C 10NOV2015 ______(Page 1 of 4) [1] A = Test Zinc-IPMP. B = Test Zinc non-IPMP. C = Positive control. D = non-SLS negative control. E = SLS negative control. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

PPD

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Protocol: 205051 Program Run Date: 24MAY2016 Data Listing 2.1 Randomisation Information

Study Population: Randomised (N=45) ______Subject Treatment Randomisation Randomisation Number Sequence[1] Number Date ______PPD PPD B/E/C/D/A 10NOV2015

B/E/C/D/A 12NOV2015

B/D/C/A/E 12NOV2015

C/B/A/E/D 10NOV2015

C/B/D/E/A 13NOV2015

E/A/B/D/C 13NOV2015 Document Version:1.0,CURRENT,Most-Recent,Effective

E/B/D/C/A 09NOV2015

A/E/D/C/B 11NOV2015

D/B/A/C/E 11NOV2015

A/C/D/B/E 09NOV2015

B/C/E/A/D 09NOV2015

B/C/D/E/A 11NOV2015

E/D/B/A/C 09NOV2015 ______(Page 2 of 4) [1] A = Test Zinc-IPMP. B = Test Zinc non-IPMP. C = Positive control. D = non-SLS negative control. E = SLS negative control. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

PPD

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Protocol: 205051 Program Run Date: 24MAY2016 Data Listing 2.1 Randomisation Information

Study Population: Randomised (N=45) ______Subject Treatment Randomisation Randomisation Number Sequence[1] Number Date ______PPD D/E/A/B/C PPD 10NOV2015

E/B/D/C/A 10NOV2015

A/D/E/B/C 11NOV2015

C/A/B/D/E 11NOV2015

C/B/A/E/D 09NOV2015

C/A/B/D/E 12NOV2015 Document Version:1.0,CURRENT,Most-Recent,Effective

C/B/E/D/A 12NOV2015

B/C/E/A/D 12NOV2015

A/D/C/E/B 12NOV2015

E/C/A/B/D 11NOV2015

B/E/C/A/D 13NOV2015

E/B/D/C/A 12NOV2015

C/B/A/E/D 13NOV2015 ______(Page 3 of 4) [1] A = Test Zinc-IPMP. B = Test Zinc non-IPMP. C = Positive control. D = non-SLS negative control. E = SLS negative control. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

PPD

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Protocol: 205051 Program Run Date: 24MAY2016 Data Listing 2.1 Randomisation Information

Study Population: Randomised (N=45) ______Subject Treatment Randomisation Randomisation Number Sequence[1] Number Date ______PPD PPD A/D/C/E/B 09NOV2015

D/C/A/B/E 13NOV2015

A/D/C/E/B 11NOV2015

E/D/B/A/C 13NOV2015

D/A/E/C/B 13NOV2015

D/E/A/B/C 10NOV2015 Document Version:1.0,CURRENT,Most-Recent,Effective

______(Page 4 of 4) [1] A = Test Zinc-IPMP. B = Test Zinc non-IPMP. C = Positive control. D = non-SLS negative control. E = SLS negative control. Test Zinc-IPMP (0.6% w/w zinc chloride and 0.1% w/w IPMP). Test Zinc non-IPMP (0.6% w/w zinc chloride, 0% w/w IPMP). Positive control (Crest ProHealth®). non-SLS negative control (Aquafresh Big Teeth). SLS negative control (Aquafresh Extreme Clean Whitening).

PPD

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