Clinical trial NCT03296072
Conditions: Tooth Erosion
Sponsor: GlaxoSmithKline
Start date: 2017-11-13; Completion date: 2018-01-16
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This will be a randomized, controlled, single center, single- blind, 3 period, 3 treatment, cross-over, in situ design which consists of placing pre-eroded bovine enamel specimens intra orally using a palatal appliance and testing the remineralizing performance of the experimental (dentifrice containing 0.254 Percent weight by weight \[%, w/w\] sodium fluoride (1150 parts per million \[ppm\] fluoride) and 5% KNO3 \[potassium nitrate\]), comparator (dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride) and placebo (Fluoride free placebo containing 5% KNO3 \[0 ppm fluoride\] ) dentifrices 2 and 4 hours (hrs) post treatment application, based on surface micro hardness measurements. This study will be carried out in healthy adults with a maxillary dental arch suitable for the retention of the palatal appliance.

Detailed description:
The aim of this study is to investigate the performance of an experimental dentifrice formulation in promoting enamel remineralization and inhibiting post-treatment enamel demineralization in an in situ erosion model, in comparison with a fluoride-free placebo and with a marketed competitor dentifrice product. The study will have 4 visits, 1 screening visit to assess participants eligibility and 3 treatment visits to assess product efficacy, where the treatment product will be dispensed and used under the supervision of a suitably trained study site personnel. Prior to each treatment visit, there will be a washout period of a minimum of 3 days. During this period participants will use their own dentifrice for at least one day, and a fluoride free dentifrice (provided) for two days prior to the next scheduled visit (including in the morning of the scheduled visit) to minimize any carry-over effects of the fluoride toothpaste.

Arms: arm 1: Participants will apply a full ribbon of the test product (1.5 grams \[g\]) containing 0.254% w/w sodium fluoride and 5% KNO3. arm 2: Participants will apply a full ribbon of the comparator product (1.5 g orally) containing 0.454% w/w stannous fluoride. arm 3: Participants will apply a full ribbon of the placebo (1.5 g orally) containing 5% KNO3.
Interventions: intervention 1: 0.254% w/w sodium fluoride and 5% KNO3 intervention 2: 0.454% w/w stannous fluoride intervention 3: 5% KNO3
Intervention descriptions: intervention 1: Dentifrice containing 0.254% w/w sodium fluoride (1150 ppm fluoride) and 5% KNO3; plus 0.25% PVM/MA copolymer and 2.5% sodium lactate. Participants will brush it on the buccal surfaces of their natural teeth for 25 timed seconds and then swish the resulting toothpaste slurry around the mouth, without further brushing, for a timed period of 95 seconds. After expectorating the slurry, the participants will gently rinse their mouths with 15 millilitres \[mL\] of tap water for 10 seconds before expectorating again. intervention 2: Dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride). Participants will brush it on the buccal surfaces of their natural teeth for 25 timed seconds and then swish the resulting toothpaste slurry around the mouth, without further brushing, for a timed period of 95 seconds. After expectorating the slurry, the participants will gently rinse their mouths with 15 mL of tap water for 10 seconds before expectorating again. intervention 3: Fluoride free placebo dentifrice containing 5% KNO3 (0 ppm fluoride), 0.25% PVM/MA copolymer and 2.5% lactate. Participants will brush it on the buccal surfaces of their natural teeth for 25 timed seconds and then swish the resulting toothpaste slurry around the mouth, without further brushing, for a timed period of 95 seconds. After expectorating the slurry, the participants will gently rinse their mouths with 15 mL of tap water for 10 seconds before expectorating again.

Protocol documents:
Prot_000.pdf: 
Sodium fluoride and potassium nitrate
208166
Clinical Protocol 08 Aug 2017
Property of GSK Consumer Healthcare
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of GSK
Template Version Effective: 22-Jun-2017
CLINICAL PROTOCOL
A RANDOMIZED, EXAMINER BLIND, CROSSOVER, IN SITU EROSION STUDY TO 
INVESTIGATE THE EFFICACY OF AN EXPERIMENTAL DENTIFRICE IN 
REMINERALIZATION OF PREVIOUSLY SOFTENED ENAMEL COMPARED TO A 
PLACEBO DENTIFRICE
Compound Name:  
Sodium fluoride and potassium nitrate
United States (US) Investigational 
New Drug (IND) Number:
N/A
European Clinical Trials Database 
(EudraCT) Number:
N/A
Other Regulatory Agency Identified
Number:
N/A
Protocol Number:
208166
Phase:
III
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Sponsor information
Sponsor Legal Registered Address
GlaxoSmithKline Research & Development 
Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address
GlaxoSmithKline Consumer Healthcare (GSK CH)
GlaxoSmithKline Consumer Healthcare Holdings 
(US)
LLC
184 Liberty Corner Rd., Warren, NJ 07059 United 
States
Tel: 
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Document History
Document
Version Date
Summary of Changes 
Original protocol
08/08/2017
Not applicable (N/A)
Amendments incorporate all revisions to date, including amendments made at the request of 
country health authorities, institutional review boards/ethics committees (IRBs/ECs), etc.  
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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:
Dr. Anderson Hara 
Investigator Qualifications:
DDS, MS, PhD
Investigator Signature:
Date of Signature/ Agreement:
DD/MMM/YYYY
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Table of contents
Sponsor information........................................................................................................ 2
Document History........................................................................................................... 3
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE.............................. 4
Table of contents............................................................................................................. 5
List of tables ................................................................................................................... 9
SCHEDULE OF ACTIVITIES ..................................................................................... 10
1
INTRODUCTION ........................................................................................................ 12
1.1
Mechanism of Action/Indication........................................................................ 13
1.2
Background and Rationale ................................................................................. 13
2
STUDY OBJECTIVES AND ENDPOINTS ................................................................. 15
3
STUDY DESIGN AND SUBEJCT POPULATION...................................................... 16
4
SUBJECT SELECTION ............................................................................................... 18
4.1
Inclusion Criteria ............................................................................................... 18
4.2
Exclusion Criteria .............................................................................................. 19
4.3
Randomization Criteria...................................................................................... 19
4.4
Lifestyle Guidelines........................................................................................... 19
4.4.1
Meals and Dietary Restrictions .......................................................... 20
4.5
Screen Failures .................................................................................................. 20
4.6
Sponsor’s Qualified Medical Personnel.............................................................. 21
5
STUDY TREATMENTS .............................................................................................. 21
5.1
Blinding and Allocation to Treatment/Randomization........................................ 21
5.2
Breaking the Blind............................................................................................. 22
5.3
Subject Compliance ........................................................................................... 23
5.4
Investigational Product Supplies ........................................................................ 23
5.4.1
Dosage Form and Packaging.............................................................. 24
5.4.2
Preparation and Dispensing................................................................ 25
5.5
Administration................................................................................................... 25
5.5.1
Medication Errors.............................................................................. 25
5.6
Investigational Product Storage.......................................................................... 26
5.7
Investigational Product Accountability............................................................... 26
5.7.1
Destruction of Investigational Product Supplies ................................. 27
5.8
Concomitant Treatment(s) ................................................................................. 27
6
STUDY PROCEDURES............................................................................................... 27
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6.1
Visit 1 – Screening............................................................................................. 27
6.2
Study Period ...................................................................................................... 29
6.2.1
Visit 2 – Period 1............................................................................... 29
6.2.2
Visit 3 – Period 2............................................................................... 31
6.2.3
Visit 4 – Period 3............................................................................... 32
6.3
Subject Withdrawal............................................................................................ 34
7
ASSESSMENTS........................................................................................................... 36
7.1
Efficacy ............................................................................................................. 36
7.2
Safety ................................................................................................................ 36
7.3
Laboratory Procedures....................................................................................... 37
7.4
Salivary flow ..................................................................................................... 38
8
ADVERSE EVENT AND OTHER EVENTS OF SPECIAL INTEREST 
REPORTING................................................................................................................ 39
8.1
Definitions of Adverse Events and Serious Adverse Events ............................... 39
8.1.1
Adverse Event ................................................................................... 39
8.1.2
Serious Adverse Event....................................................................... 40
8.2
Reporting Period................................................................................................ 41
8.2.1
Adverse Event ................................................................................... 41
8.2.2
Serious Adverse Event....................................................................... 41
8.3
Reporting Procedures......................................................................................... 41
8.3.1
Adverse Event ................................................................................... 42
8.3.2
Serious Adverse Event....................................................................... 42
8.3.3
Sponsor’s Reporting Requirements to Regulatory Authorities and 
Ethics Committees ............................................................................. 43
8.4
Evaluating Adverse Events and Serious Adverse Events.................................... 44
8.4.1
Severity Assessment .......................................................................... 44
8.4.2
Causality Assessment......................................................................... 44
8.5
Withdrawal Due to an Adverse Event and Serious Adverse Events .................... 45
8.6
Pregnancy.......................................................................................................... 45
8.6.1
Time Period for Collecting Pregnancy Information ............................ 45
8.6.2
Action to be Taken if Pregnancy Occurs ............................................ 45
8.7
Follow-up of Adverse Events and Serious Adverse Events................................. 46
8.8
Definition of and Procedure for Reporting Medical Device Incidents................. 46
8.8.1
Definition of an Incident .................................................................... 46
8.8.2
Reporting of an Incidents and Malfunctions ....................................... 47
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8.8.3
Follow-up of Medical Device Incidents.............................................. 48
8.8.4
Regulatory and Ethics Reporting Requirements for Incidents............. 48
9
DATA MANAGEMENT.............................................................................................. 49
9.1
Source Documents/ Data.................................................................................... 49
9.2
Case Report Form.............................................................................................. 49
9.3
Data Handling.................................................................................................... 50
9.3.1
Queries .............................................................................................. 50
9.4
Processing Patient Reported Outcomes .............................................................. 50
9.5
External Data..................................................................................................... 51
10 STATISTICAL CONSIDERATIONS AND DATA ANALYSES................................. 51
10.1
Sample Size Determination................................................................................ 52
10.2
Statistical Methods and Analytical Plan ............................................................. 52
10.2.1
Demographic and Baseline Characteristics......................................... 52
10.2.2
Primary Analysis(es).......................................................................... 53
10.2.3
Secondary Analysis(es)...................................................................... 53
10.2.4
Safety Analysis(es) ............................................................................ 54
10.2.5
Other Analysis(es) ............................................................................. 55
10.2.6
Definition of Analysis Populations..................................................... 56
10.2.7
Exclusion of Data from Analysis........................................................ 56
10.2.8
Handling of Dropouts and Missing Data ............................................ 57
10.2.9
Interim Analysis ................................................................................ 57
11 STUDY GOVERNANCE CONSIDERATIONS........................................................... 57
11.1
Quality Control.................................................................................................. 57
11.2
Quality Assurance.............................................................................................. 58
11.3
Regulatory and Ethical Considerations............................................................... 58
11.3.1
Institutional Review Board/ Ethics Committee................................... 58
11.3.2
Ethical Conduct of the Study.............................................................. 58
11.3.3
Subject Information and Consent ....................................................... 59
11.3.4
Subject Recruitment........................................................................... 59
11.3.5
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP ........................................................................................... 59
11.4
Posting of Information on Publicly Available Clinical Trial Registers................ 60
11.5
Provision of Study Results to Investigators ........................................................ 60
11.6
Records Retention.............................................................................................. 60
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11.7
Conditions for Terminating the Study ................................................................ 61
11.8
Definition of Study End/ End of Study............................................................... 62
12 REFERENCES ............................................................................................................. 62
13 APPENDIX .................................................................................................................. 63
13.1
ABBREVIATION ............................................................................................. 64
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List of tables
Table 1-1
Schedule of Activities ........................................................................ 10
Table 2-1
Study Objectives and Endpoints......................................................... 15
Table 13-1
Abbreviation...................................................................................... 64
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the 
well-being of the subject.
Table 1-1
Schedule of Activities
Screening
Study period
Procedure/ Assessment
Period 1
Period 2 
Period 3
Visit 1 
Wash 
out
Visit 2
Wash 
out
Visit 3
Wash 
out
Visit 4
Informed consent
X
Minimum 3  days including a 2 days washout using a non fluoride toothpaste 
Minimum 3 days including a 2 days washout using a non fluoride toothpaste 
Minimum 3 days including a 2 days washout using a non fluoride toothpaste 
Demographics and ethnicity 
X
Medical history
X
Prior medications
X
Screening OHT assessment
X
Screening OST assessment 
X
Unstimulated saliva flow rate
X
Stimulated saliva flow rate
X
Inclusion / Exclusion Criteria
X
Subject Eligibility
X
Try-in palatal appliance
X
Dispense wash-out products
X
Concomitant medication
X
X
X
Continued eligibility  
X
X
X
Diary cards review 
X
X
X
Pre-treatment OST 
assessment
X
X
X
Randomize to treatment 
X
Place enamel specimens in 
X
X
X
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Abbreviations:  
OST: Oral soft tissue
OHT: Oral hard tissue 
Any serious adverse event assessed as related to study participation that occurs subsequent to the 
signing of informed consent and any adverse event that occurs subsequent to the screening visit will 
be recorded.
1. Laboratory analysis of enamel specimens performed prior to placing the specimens in intraoral appliance are specified in Section 7.3 
2. Four enamel specimens will be removed at 2 hours ± 10 min from palatal appliance for analysis. Laboratory analysis of enamel specimens 
described in Section 7.3.  
3. Four enamel specimens will be removed at 4 hours (2 hours ± 10 min from previous time point) from palatal appliance for analysis.
Laboratory analysis of enamel specimens described in Section 7.3.  
4. At the end of the intraoral phase, and after all enamel specimens are removed, the appliance will be disinfected and stored at site until the 
next treatment visit.  
palatal appliance 1
Place palatal appliance in 
subject’s mouth
X
X
X
Supervised Treatment 
X
X
X
Intra oral phase 2 hours 2
X
X
X
Intra oral phase 4 hours 3, 4
X
X
X
Post-treatment OST 
assessment 
X
X
X
Post-treatment OHT 
assessment
X
Collect wash-out products
X
Adverse Events
X
X
X
X
Incidents
X
X
X
X
Study Conclusion
X
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1
INTRODUCTION
Dental erosion is the irreversible loss of tooth substance by chemical processes not 
involving bacteria. It is a cyclical process, influenced by demineralization and 
remineralization. Demineralization of the enamel surface can occur by the exposure to acids 
either from internal origin, such as gastric acids from refluxes, and or external from dietary 
sources; if of sufficient frequency and severity. The erosive challenges in vivo are brief and 
it’s unlikely they are a major cause of surface loss when occurring on their own (Shellis et al 
2011), but this softening of the hard tissues surface makes it more susceptible to further 
physical wear from abrasion (tooth brushing) and attrition (grinding) resulting in tissue loss. 
The process of demineralization cycles with remineralization, which is the process of placing 
minerals back into the previously demineralized hard tissue, ideally to achieve mineral that is
more resistant to subsequent demineralization (Cochrane et al 2012). 
It is well accepted that fluoride containing dentifrices should be part of an appropriate 
clinical management strategy for the prevention of caries (Brunelle and Carlos 1990) (Stephen 
1993) (Bartizek et al 2001) and to promote tooth remineralization and reduce demineralization 
(Featherstone et al 1990) (Chow 1990). Fluoride can be administered in many different forms, 
most commonly sodium fluoride (NaF), sodium monofluorophosphate (NaMFP) and stannous 
fluoride (SnF2). However, besides the fluoride form and concentration, there are other aspects 
of a dentifrice that have a strong influence in the uptake of fluoride as has been shown in in 
vitro and in situ investigations (Barlow et al 2009, Fowler et al 2006, Fowler et al 2009). 
In vitro and in situ erosion models are the most commonly used methods to investigate 
the short term performance of new erosion formulations (Shellis et al 2011). Currently, there 
is no validated clinical methodology or clinical index to monitor the progression of erosive 
tooth wear and enamel tissue loss (Shellis et al 2011), and most of the devices used for 
detection of changes in mineral content can only be performed on specially prepared 
specimens (Attin 2006).  In situ erosion models involve the use of appliances or other devices 
in the human mouth that simulate the process (Zero 1995) and they allow the effect of an 
erosive challenge to be evaluated under intra oral conditions but with some controlled 
experimental variables. In situ models are placed in between the continuum of in vitro models 
and clinical studies and can provide evidence of the potential effect of new therapies in 
inhibiting demineralization and promoting remineralization (Zero 1995). However, the 
extrapolation of their result to clinically relevant evidence must be carefully considered.
An erosion in situ model will be used in this study to investigate the efficacy of an 
experimental dentifrice in promoting enamel remineralization of previously softened enamel. 
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1.1
Mechanism of Action/Indication
The test dentifrice formulation being investigated contains 0.254% w/w NaF, 
equivalent to 1150 ppm fluoride and 5% KNO3. The efficacy of the experimental dentifrice in 
enhancing enamel remineralization is being investigated in an in situ intraoral model with 
bovine enamel specimens in healthy subjects.
1.2
Background and Rationale
Justification and need to perform the study 
The experimental formulation tested in this study is based on the currently marketed
Sensodyne Pronamel dentifrice and tested in vitro for a superior performance. In order to 
support the experimental dentifrice market introduction in the US, an in situ investigation 
comparing the experimental dentifrice with a fluoride free placebo dentifrice (primary 
objective) and with a relevant marketed dentifrice is needed (secondary objective) to 
investigate the efficacy in enhancing remineralization and preventing demineralization. 
Therefore, the aim of this study is to investigate the performance of an experimental dentifrice 
formulation in promoting enamel remineralization and inhibiting post-treatment enamel 
demineralization in an in situ erosion model, in comparison with a fluoride-free placebo and 
with a marketed competitor dentifrice product.
The in situ model to be used in this study has been extensively used to investigate the 
performance of the currently marketed Sensodyne Pronamel in previously published studies 
(Barlow et al 2009) and other GSK CH studies (
, GSK-Z3480664 , 
, GSK-Z6961385). 
Study and dose rationale
This clinical investigation will use a previously published in situ remineralization 
model (Barlow et al 2009) which consists of placing pre-eroded sterilized bovine enamel 
specimens
intra orally using a palatal appliance and testing the enhancement of 
remineralization and prevention of demineralization performance of the experimental 
formulation after 2 and 4 hours post treatment application based on surface micro hardness 
measurements. Details of enamel and palatal appliance preparations are specified in protocol 
Section 7.3.  The palatal appliances (Figure 1) will be made for each eligible subject, and each 
will carry two plastic holders containing a total of eight bovine enamel specimens (four in 
each holder). 
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This will be a randomized, controlled, single center, single- blind (to the dental 
examiner and specimen analysts), 3 period, 3 treatment, cross-over, in situ study design. Each 
subject will brush their teeth once with each of the study products as described below. At each 
visit, and under supervision while the intraoral appliance is in place, the subjects will brush
the buccal surfaces of their natural teeth using 1.5 g dentifrice and a soft toothbrush for 25 
seconds to create a slurry. Subjects will be instructed not to expectorate the slurry. Subjects
will then swish the slurry around the mouth for 95 seconds to permit direct contact of the 
dentifrice slurry with the enamel specimens. The toothbrush however, will not come into 
contact with the enamel specimens or the appliance as this could cause abrasion on the enamel 
specimens. This will be followed by an intraoral remineralization period of up to 4 hrs.
Figure 1: Schematic diagram of a) intraoral appliance, b) enamel specimens’ holder, c) enamel 
specimens placed in the holder and d) palatal appliance with enamel specimens in the mouth. 
Oral tolerance
GSK CH has run numerous similar in situ clinical investigations with currently 
marketed and experimental Sensodyne Pronamel formulations. In all those studies, the 
products were generally well tolerated (
 
, GSK-Z3480664 , GSK-Z6961385).  Oral soft tissue assessments will be 
carried out at all visits, pre and post intra oral phase and all adverse events will be recorded.
Complete information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Safety Statement (SS).
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2
STUDY OBJECTIVES AND ENDPOINTS
Table 2-1
Study Objectives and Endpoints
Objective(s)
Endpoint(s)
Primary
To investigate the efficacy of an experimental 
dentifrice containing 1150 ppm fluoride and 5% 
KNO3 to enhance remineralization of enamel 
relative to a fluoride free placebo dentifrice.
%SMHR after 4 hrs intraoral phase following a 
single exposure. 
Secondary
Efficacy
To investigate the efficacy of an experimental 
dentifrice containing 1150 ppm fluoride and 5% 
KNO3 to inhibit demineralization of enamel relative 
to a fluoride free placebo dentifrice.
%RER after 4 hrs intraoral phase following a 
single exposure.
To investigate the efficacy of an experimental 
dentifrice containing 1150 ppm fluoride and 5% 
KNO3 to promote fluoride uptake in enamel 
relative to a fluoride free placebo dentifrice.
EFU after 4 hrs intraoral phase following a single 
exposure.
To investigate the efficacy of an experimental 
dentifrice containing 1150 ppm fluoride and 5% 
KNO3 to enhance remineralization, to inhibit
demineralization and to promote fluoride uptake 
in enamel relative to a benchmark comparator 
containing 1100 ppm fluoride (Crest Pro Health).
%SMHR, %RER and EFU after 4 hrs intraoral 
phase following a single exposure.
Safety
To evaluate the oral tolerance of an experimental 
dentifrice containing 1150 ppm fluoride and 5% 
KNO3 following a single brushing event. 
Proportion of treatment emergent
oral adverse events post 4 hours intraoral 
exposure. 
Exploratory
To make all paired comparisons of the efficacy of 
an experimental dentifrice containing 1150 ppm 
fluoride and 5% KNO3 after 2 hours of intraoral 
exposure to enhance remineralization of enamel, 
to inhibit demineralization of enamel and to 
promote fluoride uptake in enamel.
%SMHR, %RER and EFU after 2 hrs intraoral 
phase following a single exposure.
To characterize the efficacy of the experimental 
dentifrice containing 1150 ppm fluoride and 5% 
KNO3; the fluoride free placebo; and the 
benchmark comparator containing 1100 ppm 
(Crest Pro Health) after 2 and 4 hours of intraoral 
exposure on resistance to acid challenge. 
Summary statistic table of ARR after 2 and 4 hrs 
intraoral phase. 
Abbreviations: SMHR: Surface micro hardness recovery, RER: Relative erosion resistance, EFU: Enamel 
fluoride uptake, ARR: Acid resistance ratio
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This study will be considered successful if the experimental dentifrice demonstrates a 
statistically significant enhancement of remineralization, as measured by %SMHR in 
comparison with the placebo dentifrice after 4 hours intraoral phase. 
3
STUDY DESIGN AND SUBJECT POPULATION
This will be a randomized, controlled, single center, single- blind (to the dental examiner and 
specimen analysts), 3 period, 3 treatment, cross-over, in situ design which consists of placing 
pre-eroded bovine enamel specimens intra orally using a palatal appliance and testing the 
remineralizing performance of the experimental, comparator and placebo dentifrices 2 and 4 
hours post treatment application, based on surface micro hardness measurements. This study 
will be carried out in healthy adults with a maxillary dental arch suitable for the retention of 
the palatal appliance. A sufficient number of healthy subjects will be screened so that up to 66 
subjects are randomized to participate in the study to ensure 60 evaluable subjects complete 
the entire study. Subjects will be recruited from an existing panel of subjects pre-fitted with a 
palatal appliance (IRB approved panel 
). For a subject whose appliance does not 
fit adequately and for whom adjustment of the appliance is not sufficient to obtain proper fit, 
the subject may have a new appliance made.
Surface microhardness (SMH) measures 
changes in the mineral content of enamel, and is used to calculate surface micro hardness 
recovery (%SMHR), relative erosion resistance (%RER) and acid resistance ratio (ARR). 
Fluoride uptake of the experimental dentifrice will be assessed by enamel fluoride uptake 
(EFU) measurements. For each treatment and subject these measurements will be performed 
on the same enamel specimen, in the four replicates for each time point. The erosive acid 
challenge, with a commercially available grapefruit juice, will be carried out ex vivo and 
therefore does not pose a risk to the subject’s teeth. The overall study design sequence of 
events is sketched in Figure 2. 
For the aim of this study, a fluoride-free placebo dentifrice will be used as comparator to 
establish if the fluoride present in the experimental dentifrice can provide and enhancement of 
remineralization and prevention of demineralization in this in situ model. Additionally, a
relevant commercially available dentifrice containing 1100 ppm fluoride (as stannous 
fluoride, SnF2) will be used as a comparator (secondary objectives) to investigate the superior 
performance of the experimental dentifrice in enhancing remineralization and preventing
demineralization. 
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Figure 2: Schematic diagram of the experimental phase for each subject and treatment showing the 
flow of events at each visit. 
In this study there will be 4 visits, 1 screening visit to assess subject eligibility and 3 treatment 
visits to assess product efficacy, where the treatment product will be dispensed and used 
under the supervision of a suitably trained study site personnel. Prior to each treatment visit, 
there will be a washout period of a minimum of 3 days. During this period subjects will use 
their own dentifrice for at least one day, and a fluoride free dentifrice (provided) for two days 
prior to the next scheduled visit (including in the morning of the scheduled visit) to minimize 
any carry-over effects of the fluoride toothpaste. Based on previous studies, two days are 
sufficient to minimize any carry-over effect. 
According to ICH guidelines, for a study to be classed as truly double blind, not only 
does the examiner (and any appropriate member of staff who may be involved in the 
dispensing of products, analysis of data etc.) need to be blinded to the treatment the subject 
receives, but the test products must be identical in every way (colour, flavour, appearance, 
packaging). Given that it is almost impossible to ensure identical appearance, taste and 
packaging for the dentifrices evaluated in this study, the level of blindness for this study is 
described as ‘examiner blind’ only.
The study statistician and other employees of the Sponsor who may influence study 
outcomes are blinded to the product allocation of subjects. The examiner and specimen 
analyst will be blinded to the treatment received. To ensure the examiner and specimen
analysts remain blinded throughout the study, the examiner and specimen analysts are not 
Baseline SMH      
(B)
Erosive challenge 1
Post erosion SMH
(E1)
Enamel specimens 
placed on 
appliance 
intraoral appliance placed 
in subject’s mouth
5 min equilibration 
25 sec toothbrushing
95 sec swirling 
2 hrs and 4 hrs intraoral 
Post erosion 
SMH (E2)
Erosive challenge 2
After remin SMH 
(R)
Measurement
Acid exposure
In situ
Enamel specimens 
removed from 
appliance at 2hrs 
and 4 hrs
L
specimens processed 
through sterilizer
EFU
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permitted in the room while product is dispensed. All study products will be overwrapped to 
conceal any labelling. In addition, subjects will receive treatment in a separate area from 
where clinical assessments are performed. The dispensing staff will not be involved in any 
clinical assessments or laboratory analysis during the study. Study site staff that perform study 
consent can only also dispense the study product but can not perform any other study activity. 
Laboratory personnel that carry out the specimen analysis will also be blinded to product 
allocation and not be involved in any clinical assessment.
4
SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.  
4.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subject must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent 
2. Male and female subjects who, at the time of screening, are between the ages of 18 and 65 
years, inclusive.
3. Subject who is willing and able to comply with scheduled visits, treatment plan, and other 
study procedures.
4. 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 oral examination. 
5. Male subject able to father children and female subject of childbearing potential and at 
risk for pregnancy must agree to use a highly effective method of contraception 
throughout the study and for 5 days after the last dose of assigned treatment.  
6. Good oral health without lesions of the oral cavity that could interfere with the study 
evaluations. 
7. Maxillary dental arch suitable for the retention of the palatal appliance
8. Unstimulated salivary flow rate of at least 0.2 mL/minute and a stimulated salivary flow 
rate of at least 0.8 mL/minute
9. Understands and is willing, able and likely to comply with all study procedures and 
restrictions.
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4.2
Exclusion Criteria  
Subjects with any of the following characteristics/conditions will not be included in the study:
1. Subjects who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are GSK employees directly involved in the conduct of the 
study.
2. Participation in other studies involving investigational drug(s) within 30 days prior to 
screening visit.
3. Participation in other studies involving investigational oral care or cosmetic products
within 30 days prior to screening visit.
4. Acute or chronic medical or psychiatric condition that may increase the risk associated 
with study participation or investigational product administration or may interfere with the 
interpretation of study results and, in the judgment of the investigator, would make the 
subject inappropriate for entry into this study.
5. Pregnant female subject (self – reported).
6. Breastfeeding female subject.
7. Known or suspected intolerance or hypersensitivity to the study materials (or closely 
related compounds) or any of their stated ingredients. 
8. Unwilling or unable to comply with the lifestyle guidelines described in this protocol. 
9. Medication that may interfere significantly with the saliva flow in the judgment of the 
investigator. Should new medications that may interfere with the saliva flow be added, a 
second salivary flow test will be performed.
10. Subject with any condition that would impact on their safety or wellbeing or affect their
ability to understand and follow study procedures and requirements.
11. Any sign of grossly carious lesions (active), moderate or severe periodontal conditions, or 
severe tooth wear. Subject presenting at screening with minor caries may continue in the 
study if their carious lesions are repaired prior to the first treatment visit of the study.
12. Wears oral appliance or orthodontia (besides subjects wearing permanent lower retainers, 
which are eligible).
13. Recent history (within the last year) of alcohol or other substance abuse.
14. Subject who has previously been enrolled in this study. 
4.3
Randomization Criteria
Subjects will be randomized into the study provided they have satisfied all subject selection 
criteria.
4.4
Lifestyle Guidelines
During the entire study:
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
Subjects will be asked to stop using their own dentifrice two days before Visit 2, 3 and 
4, when they will use the provided fluoride-free dentifrice and toothbrush to brush 
their teeth (including in the morning of the scheduled Visit).

Subjects will not be permitted to use any fluoride-containing products (including 
mouthwashes) for 2 days prior to Visit 2, 3 and 4. 

Subjects will be requested not to have any elective dental procedures including teeth 
professionally cleaned other than those performed within the study (excluding 
emergency dental treatment). 
During Visit 2, 3 and 4:

Subjects should refrain from talking for the first hour after brushing on each treatment 
visit.

Subjects should not leave the study site during the 4 hours treatment phase while 
wearing the intraoral appliances. 
4.4.1
Meals and Dietary Restrictions

Subjects must abstain from all food and drink (except water) at least 30 minutes prior 
to their scheduled Visit 2, 3 and 4. 
During Visit 2, 3 and 4:

Subjects will not be permitted to drink water for the first two hours of the intraoral test 
period (after treatment administration), but may drink water after the first two hours 
under the supervision of the study personnel. 

Subjects will not be permitted to eat during the four hours’ duration of the intraoral 
test period (after treatment administration). 
4.5
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomized. In order to ensure transparent reporting of screen failure 
subjects, a minimal set of screen failure information will include demography, screen failure 
details (e.g., withdrawal of consent), eligibility criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not
be re-screened.
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For a subject whose appliance does not fit adequately and for whom adjustment of the 
appliance is not sufficient to obtain proper fit, the subject may have a new appliance made. 
This will not be considered a screen failure. The subject may repeat the appliance try-in 
portion of the screening visit after fabrication of the new appliance. 
4.6
Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical/dental personnel for 
the study is documented in the study contact list in the Trial Master File.
The contact number can be used by investigational staff if they are seeking advice on 
medical/dental questions or problems; however, it should be used only in the event that the 
established communication pathways between the investigational site and the study team are 
not available. It is therefore intended to augment, but not replace, the established 
communication pathways between the investigational site and the study team for advice on 
medical/dental questions or problems that may arise during the study. The contact number is 
not intended for use by the subject directly, and if a subject calls that number, he or she will 
be directed back to the investigational site.
To facilitate access to appropriately qualified medical/dental personnel on study-related 
medical/dental questions or problems, subjects are provided with a contact card. The contact 
card contains, at a minimum, protocol identifiers, subject study numbers, contact information 
for the investigational site, and contact details in the event that the investigational site staff 
cannot be reached to provide advice on a medical question or problem identified from the 
subject’s healthcare professional other than the investigator.
5
STUDY TREATMENTS
5.1
Blinding and Allocation to Treatment/Randomization
Blinding
This is a single blind study, with the examiner being blind to the treatment each subject 
received. Subjects will not be blind to the treatment that they are receiving. 
The study statistician and other employees of the Sponsor who may influence study outcomes 
are blinded to the product allocation of subjects. The examiner will be blinded to the treatment 
received. To ensure the examiner and specimen analysts remain blinded throughout the study, 
the examiner and specimen analysts are not permitted in the room whilst product is dispensed. 
In addition, subjects should be treated in a separate area. The dispensing and laboratory staff 
will not be involved in any efficacy assessments during the study. Study site staff that perform 
study consent can only also dispense the study product but can not perform any other study 
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activity. Laboratory personnel that carry out the specimen analysis will also be blinded to 
product allocation and not be involved in any clinical assessment.
Allocation to treatment sequence
Subjects will be assigned to study product sequence in accordance with the randomization 
schedule generated by a Vendor under the supervision of the Biostatistics Department, GSK 
CH, prior to the start of the study, using a validated program. Subjects will be randomized in a 
Williams square design balanced for first period carryover.
Randomization
GSK CH will provide a randomization schedule to the investigator and, in accordance with 
the randomization numbers, subjects are planned to receive all treatments in a pre-determined 
order as specified by the randomisation schedule.  
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 randomisation schedule. Randomisation numbers will be assigned in 
ascending numerical order as each subject is determined to be fully eligible.
The study site will receive two versions of the randomisation schedule, each in a sealed 
envelope and clearly marked as either “For Dispensing” or “Emergency Use Only”. The “For 
Dispensing” schedule will contain the list of randomisation numbers only and will not include 
any coded description, just a letter A, B or C. The ‘Emergency Use Only’ randomisation 
schedule will only be removed from the sealed envelope in an emergency situation. This 
schedule will have a randomisation number followed by a sequence of letters A, B or C. The 
schedule will have a footnote with a key for A, B or C identifying the three treatment regimen 
sequences.
However, to maintain the blinding of the study as far as possible, all treatment allocations for 
all randomisation numbers on this randomisation schedule will be masked with scratch-off 
panels. Only the panels required for the unblinding the particular subject should be removed.
5.2
Breaking the Blind
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind.  The method will be manual.  Blinding codes should be broken only in emergency 
situations for reasons of subject safety.  Whenever possible, the investigator or sub-
investigator should consult with a member of the study team prior to breaking the blind unless 
the delay would endanger the subject’s health.  When the blinding code is broken, the reason 
must be fully documented and entered in the case report form (CRF). When documenting in 
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the CRF, the site should ensure that no text description has the potential to unblind any other 
subjects.
Any AE or serious AE (SAE) associated with breaking the blind must be recorded and 
reported as specified in this protocol. The study site is required to inform the IRB/EC if the 
blind is broken. 
5.3
Subject Compliance
Subjects will complete diary cards during the 2 days of washout period prior to the treatment 
visit. 
Study treatment will be administered under the supervision of investigator site personnel.  
5.4
Investigational Product Supplies
Test Product 
Comparator 
Product
Placebo Product
Product Name 
Experimental dentifrice 
containing 0.254% w/w 
sodium fluoride (1150 
ppm fluoride) and 5% 
KNO3; plus 0.25% 
PVM/MA copolymer 
and 2.5% sodium 
lactate
Crest ProHealth
Sensitivity & 
Enamel Shield
containing 0.454% 
w/w stannous 
fluoride (1100 ppm 
fluoride)
Fluoride free placebo 
containing 5% KNO3
(0 ppm fluoride); plus
0.25% PVM/MA 
copolymer and 2.5% 
lactate   
Product 
Formulation 
Code (MFC)
Commercially
available (US 
marketed)
Dose
1.5 g
1.5 g
1.5 g
Route of 
Administration
Oral
Oral
Oral
Dosing 
Instructions
Subjects will apply a full ribbon of the allocated product and brush the 
buccal surfaces of their natural teeth for 25 timed seconds and then 
swish the resulting toothpaste slurry around the mouth, without further 
brushing, for a timed period of 95 seconds. After expectorating the 
slurry, the subjects will gently rinse their mouths with 15 mL of tap 
water for 10 seconds before expectorating again
Sundry items: 
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
Oral-B Sensi Soft Manual Toothbrush 
o
Manual toothbrush to apply test and washout dentifrice 

Fluoride free toothpaste 
o
Fluoride free dentifrice to brush their teeth during the 2 days prior to treatment 
visit

Countdown timer
o
To ensure accurate brushing time 

Diary cards (to be supplied by GSK Warren)
o
Record washout product use.

Dosing cups
o
For rinsing after brushing.

Unflavoured gum base
o
For stimulated saliva samples collection
All other items such as saliva sampling collection equipment will be supplied by the study 
site. Grapefruit juice (commercially available) for the ex vivo acid challenge will also be 
sourced by the study site. 
5.4.1
Dosage Form and Packaging
The contents of the label will be in accordance with all applicable regulatory requirements and 
will be the responsibility of the Clinical Supplies Department, GSK CH.
The fluoride-free washout toothpaste will be supplied in plain white tubes with a study label 
affixed. Each subject will receive a sufficient number of tubes to cover usage during the 
washout phase (for 2 days prior to Visit 2, 3 and 4). 
The experimental and placebo dentifrices will be supplied in plain white tubes. The 
comparator dentifrice will be sourced from the US market. All study products (experimental, 
comparator and placebo dentifrices) will be over-wrapped in white vinyl to maintain the study 
blind as much as possible.
Each tube will have a study label affixed. Each study label will contain, but not be limited to, 
protocol number, product code letter (for treatment products only), directions for storage, 
emergency contact telephone number and “For Clinical Trial Use Only”.
Toothbrushes and countdown timers will be supplied in their commercial packaging.
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Care should be taken with the supplied study 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 trial. Subjects should be instructed to not remove or deface any part of the 
study label.
5.4.2
Preparation and Dispensing 
Test, control and placebo dentifrices and manual toothbrush will be dispensed by qualified 
unblinded site personnel according to the dosing instructions (Section 5.4).
5.5
Administration
During Visit 2, 3 and 4 and following the pre treatment assessments, a suitably trained study 
site designee will place the palatal appliance holding eight bovine tooth enamel specimens in
the subjects’ mouth followed by an equilibration period of at least 5 minutes. Following the 
equilibration phase, and under the supervision of a trained unblinded study site designee, the 
subject will brush their own teeth following the dosing instructions (Section 5.4). 
5.5.1
Medication Errors
Medication errors may result, in this study, from the administration or consumption of: 

the wrong product,

by the wrong subject, 

at the wrong time, 

or at the wrong dosage strength 
Such medication errors occurring to a study participant are to be captured in the CRF. In the 
event of medication dosing error, the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the participating subject.
Whether or not a medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated adverse event(s) is 
captured on an adverse event (AE) CRF page.
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5.6
Investigational Product Storage
The investigator, or an approved representative, will ensure that all investigational products 
including any comparator, marketed products and washout products are stored in a secured 
area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements and product label.
Site systems must be capable of measuring and documenting (for example, via a log) 
minimum and maximum temperatures for all site storage locations.  This should be captured 
from the time of investigational product receipt throughout the study.  Even for continuous 
monitoring systems, a log or site procedure that ensures active evaluation for excursions 
should be available. The operation of the temperature-monitoring device and storage unit (for 
example, refrigerator), as applicable, should be regularly inspected to ensure it is maintained 
in working order. 
Any excursions from the product-label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the Sponsor.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until the Sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion. Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation.  Specific details regarding 
information the site should report for each excursion will be provided to the site. 
5.7
Investigational Product Accountability
All products supplied are for use only in this clinical study and should not be used for any 
other purpose.
Study treatments must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the staff have access. Upon 
receipt, all study treatments should be stored according to the instructions specified on the 
treatment labels. Clinical supplies are to be dispensed only in accordance with the protocol.
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All study drugs will be accounted 
for using a drug accountability form/record. 
The inventory must be available for inspection by the study monitor during the study. 
Monitoring of treatments accountability will be performed by the field monitor during site 
visits and at the completion of the study.
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5.7.1
Destruction of Investigational Product Supplies 
All investigational study treatments shipped for this clinical trial will be returned to the 
Sponsor at the termination of the study.  At the conclusion of the study, the Principal 
Investigator or an appropriate designee, and a representative of GSK CH will inventory all 
used and unused investigational study treatment.  The study treatment inventory record for 
returned study treatment will then be completed. All investigational product for this clinical 
study (empty containers), as well as all unused study product will be returned to the GSK CH 
Clinical Supplies Department designated vendor using the return instructions provided. 
5.8
Concomitant Treatment(s)
All concomitant treatments taken during the study must be recorded with indication, unit 
dose, daily dose, and start and stop dates of administration.  All subjects will be questioned 
about concomitant treatment at each clinic visit.
Treatments taken within 30 days before Screening visit will be documented as a prior 
treatment.  Treatments taken after the screening visit will be documented as concomitant 
treatments.
6
STUDY PROCEDURES
6.1
Visit 1 – Screening
Informed Consent
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed informed consent document.
The investigator, or designee, must explain to the subjects the aims, methods, objectives, and 
potential hazards of the study, and 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 GSK CH. 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 
their 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.
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Demographics and ethnicity
The following demographic parameters will be captured by the Investigator or designee and 
recorded on the CRF: year of birth, age, gender, race, and ethnicity. Ethnicity will be self-
reported and the choices offered will be Hispanic or Latino and Not Hispanic or Latino. 
Ethnicity will be captured by the Investigator or designee and recorded on the CRF.
Medical History and Prior medications 
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 prior treatment taken in the 30 days prior to the Screening Visit will be recorded as 
per Section 5.8 in CRF. 
Screening Oral Hard Tissue assessment 
OHT examination will be carried out at the Screening visit as described in Section 7.2 by 
dental examiner or clinically qualified designee. Assessment will be recorded in the CRF. 
Screening Oral Soft Tissue assessment 
OST examination will be carried out at the Screening visit as described in Section 7.2 by 
dental examiner or clinically qualified designee. Assessment will be recorded in the CRF. 
Unstimulated salivary flow rate
Unsitumulated salivary flow rate will be measured at the screening visit as described in 
Section 7.4 by dental examiner or clinically qualified designee.
Stimulated salivary flow rate
Stimulated salivary flow rate will be measured at the screening visit as described in Section 
7.4 by dental examiner or clinically qualified designee.
Inclusion and Exclusion criteria
The investigator, or a person designated by the investigator, will review the Inclusion and
Exclusion criteria as per Section 4.
Subject eligibility
Subject eligibility will be reviewed as per Section 4.
Try-In of Palatal Appliance
Palatal appliances (Figure 2) will be fitted and checked for comfort at the Screening visit. 
Subjects will be asked to wear their appliances for up to 15 minutes to determine comfort, fit 
and wearability. Appliances will be adjusted as needed. As indicated in section 7.3, intraoral 
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appliances will be fabricated as described in the work instructions document. For a subject 
whose appliance does not fit adequately and for whom adjustment of the appliance is not 
adequate to obtain proper fit, may have a new appliance made under IRB approved protocol 
.  The subject may repeat the appliance try-in portion of the screening visit after 
fabrication.
Dispense wash out products and diary cards
Subjects will be dispensed with the washout toothbrush and the fluoride free toothpaste to use 
during the washout period. Subjects will be instructed to brush their teeth with the fluoride 
free toothpaste during the 2 days prior to Visit 2, 3 and 4 (including the morning of the 
treatment visit). Subjects will receive a dairy card to record twice daily toothbrushing with the
washout assigned product during the 2 days washout period.
Adverse Events and Incidents 
Adverse Events and Incidents will be recorded in the CRF as described in Section 8. 
To prepare for study participation, subjects will be instructed on the use of the Lifestyle 
Guidelines and Concomitant Treatment(s) sections of the protocol.
Information will be recorded in the CRF. 
6.2
Study Period
There will be an interval of at least 3 days between study periods (i.e., administration of 
subsequent doses of investigational product will not occur until at least 3 days after the 
previous dose of investigational product).
6.2.1
Visit 2 – Period 1
Subjects will attend Visit 2 at least 3 days after Visit 1. Subjects will brush with their own
toothpaste for at least one day, and with the provided fluoride free toothpaste for two days 
prior to the visit. 
The following assessments will be conducted in the order written:
Concomitant Medication
Concomitant medications will be assessed as related to the inclusion/exclusion criteria by the 
Investigator or medically qualified designee. Any concomitant treatment taken throughout the 
study will be recorded in the CRF. 
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Continued eligibility
Subject continued eligibility will be reviewed as described in Section 4.
Diary cards review
Investigator or designee will review diary cards of wash out product usage during wash out 
period. 
Pre-Treatment Oral Soft Tissue assessment 
OST examination as described in section 7.2 by dental examiner or clinically qualified 
designee and recorded in the CRF. 
Randomize to treatment 
Subjects will be randomized to treatment order as described in section 5.1.
Place enamel specimens in palatal appliance 
Enamel specimens will be place in the palatal appliance after they are processed through 
sterilizer as described in Section 7.3.
Place palatal appliance in subject’s mouth. 
A suitably trained study site designee will place the palatal appliance in the subjects’ mouth 
followed by an equilibration period of at least 5 minutes. 
Supervised treatment
Study products will be used following the instructions and under the supervision of study site 
personnel as described in Section 5.4. 
Palatal appliances intra oral phase – 2 hours 
After completing the brushing procedures, subjects will wear their palatal appliance for 2 
hours ± 10 min. After this period, the study site designee will remove the appliance and four
pre-designated enamel specimens will be removed and sent for analysis (Section 7.3 for 
Laboratory Procedures). External Data will be recorded and transferred to GSK CH as 
detailed in Section 9.5.
Palatal appliances intra oral phase – 4 hours 
After removing 4 specimens at 2 hours, the study site designee will replace the palatal 
appliance in the subject’s mouth for a further 2 hours ± 10 min (4 hours total), after which the 
study site designee will again remove the palatal appliance. At this point, four pre-designated 
enamel specimens will be removed and sent for analysis (Section 7.3 for Laboratory 
Procedures). External Data will be recorded and transferred to GSK CH as detailed in Section 
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9.5. At the end of the intraoral phase, and after all enamel specimens are removed, the 
appliance will be disinfected and stored at site until the next treatment visit.  
Post-Treatment Oral Soft Tissue assessment 
OST examination as described in section 7.2 
Adverse Events and Incidents 
Adverse Events and Incidents will be recorded in the CRF as described in Section 8. 
Information will be recorded in the CRF. 
6.2.2
Visit 3 – Period 2 
Subjects will attend Visit 3 at least 3 days after Visit 2. Subjects will brush with their own 
toothpaste for at least one day, and with the provided fluoride free toothpaste for two days 
prior to the visit. 
The following assessments will be conducted in the order written:
Concomitant Medication
Concomitant medications will be assessed as related to the inclusion/exclusion criteria by the 
Investigator or medically qualified designee. Any concomitant treatment taken throughout the 
study will be recorded in the CRF. 
Continued eligibility
Subject continued eligibility will be reviewed as described in Section 4.
Diary cards review
Investigator or designee will review diary cards of wash out product usage during wash out 
period. 
Pre-Treatment Oral Soft Tissue assessment 
OST examination as described in section 7.2 by dental examiner or clinically qualified 
designee and recorded in the CRF.  
Place enamel specimens in palatal appliance 
Enamel specimens will be place in the palatal appliance after they are processed through 
sterilizer as described in Section 7.3
Place palatal appliance in subject’s mouth. 
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A suitably trained study site designee will place the palatal appliance in the subjects’ mouth 
followed by an equilibration period of at least 5 minutes. 
Supervised treatment
Study products will be used following the instructions and under the supervision of study site 
personnel as described in Section 5.4. 
Palatal appliances intra oral phase – 2 hours 
After completing the brushing procedures, subjects will wear their palatal appliance for 2 
hours ± 10 min. After this period, the study site designee will remove the appliance and four 
pre-designated enamel specimens will be removed and sent for analysis (Section 7.3 for 
Laboratory Procedures). External Data will be recorded and transferred to GSK CH as 
detailed in Section 9.5.
Palatal appliances intra oral phase – 4 hours 
After removing 4 specimens at 2 hours, the study site designee will replace the palatal 
appliance in the subject’s mouth for a further 2 hours ± 10 min (4 hours total), after which the 
study site designee will again remove the palatal appliance. At this point, four pre-designated 
enamel specimens will be removed and sent for analysis (Section 7.3 for Laboratory 
Procedures). External Data will be recorded and transferred to GSK CH as detailed in Section 
9.5. At the end of the intraoral phase, and after all enamel specimens are removed, the 
appliance will be disinfected and stored at site until the next treatment visit.  
Post-Treatment Oral Soft Tissue assessment 
OST examination as described in section 7.2 by dental examiner or clinically qualified 
designee and recorded in the CRF.  
Adverse Events and Incidents 
Adverse Events and Incidents will be recorded in the CRF as described in Section 8. 
Information will be recorded in the CRF. 
6.2.3
Visit 4 – Period 3
Subjects will attend Visit 4 at least 3 days after Visit 3. Subjects will brush with their own 
toothpaste for at least one day, and with the provided fluoride free toothpaste for two days 
prior to the visit. 
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The following assessments will be conducted in the order written:
Concomitant Medication
Concomitant medications will be assessed as related to the inclusion/exclusion criteria by the 
Investigator or medically qualified designee. Any concomitant treatment taken throughout the 
study will be recorded in the CRF. 
Continued eligibility
Subject continued eligibility will be reviewed as described in Section 4.
Diary cards review
Investigator or designee will review diary cards of wash out product usage during wash out 
period. 
Pre-Treatment Oral Soft Tissue assessment 
OST examination as described in section 7.2 by dental examiner or clinically qualified 
designee and recorded in the CRF.  
Place enamel specimens in palatal appliance 
Enamel specimens will be place in the palatal appliance after they are processed through 
sterilizer as described in Section 7.3
Place palatal appliance in subject’s mouth. 
A suitably trained study site designee will place the palatal appliance in the subjects’ mouth 
followed by an equilibration period of at least 5 minutes. 
Supervised treatment
Study products will be used following the instructions and under the supervision of study site 
personnel as described in Section 5.4. 
Palatal appliances intra oral phase – 2 hours
After completing the brushing procedures, subjects will wear their palatal appliance for 2 
hours ± 10 min. After this period, the study site designee will remove the appliance and four 
pre-designated enamel specimens will be removed and sent for analysis (Section 7.3 for 
Laboratory Procedures). External Data will be recorded and transferred to GSK CH as 
detailed in Section 9.5.
Palatal appliances intra oral phase – 4 hours
After removing 4 specimens at 2 hours, the study site designee will replace the palatal 
appliance in the subject’s mouth for a further 2 hours ± 10 min (4 hours total), after which the 
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study site designee will again remove the palatal appliance. At this point, four pre-designated 
enamel specimens will be removed and sent for analysis (Section 7.3 for Laboratory 
Procedures). External Data will be recorded and transferred to GSK CH as detailed in Section 
9.5. At the end of the intraoral phase, and after all enamel specimens are removed, the 
appliance will be disinfected and stored at site until the next treatment visit.  
Post-Treatment Oral Soft Tissue assessment 
OST examination as described in section 7.2 by dental examiner or clinically qualified 
designee and recorded in the CRF.  
Post-Treatment Oral Hard Tissue assessment 
OHT examination will be carried out by dental examiner or clinically qualified designee. 
Assessment will be recorded in the CRF. 
Collect wash-out products
A suitably trained study site designee will collect the wash-out products from the subject. 
Adverse Events and Incidents 
Adverse Events and Incidents will be recorded in the CRF as described in Section 8. 
Study conclusion
Subjects will be evaluated to determine if they completed all study procedures or if
they were discontinued from the study early. If the subject discontinued at any point
during the study, the primary reason for withdrawal should be recorded on the study
conclusion page of the CRF by selecting one of the options below.

Subject did not meet study criteria

Adverse event

Lost to follow up

Protocol violation

Withdrawal of consent

Other
Information will be recorded in the CRF. 
6.3
Subject Withdrawal
Should a subject attend Visit 2, 3 or 4 having used a fluoride oral care product within the 
previous 2 days, or having consumed food or drinks within 30 minutes prior to the scheduled
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visit, or should any other factor, in the opinion of the investigator, be thought to affect study 
outcomes (e.g. excessive alcohol consumption), every attempt will be made to reschedule the 
subject. If they cannot be reappointed they will be withdrawn from the study.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or, behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures.  
The following circumstances require discontinuation of study treatment and/or premature 
subject withdrawal:

Protocol violation that may impact the outcome of the subject’s safety

Withdrawal of informed consent

Subject lost to follow-up 

Unblinding of the subject 

Pregnancy

Death
If a subject is discontinued or prematurely withdraws from the study, reasons for 
discontinuation or withdrawal and associated date must be documented in the relevant 
section(s) of the CRF. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The Investigator or site staff should attempt to contact the subject twice.  After two 
attempts, clinical site staff must send a registered letter.  If no response is received from the 
subject, the subject will be considered lost to follow up.  All attempts to contact the subject 
and information received during contact attempts must be documented in the CRF.  In any 
circumstance, every effort should be made to document subject outcome, if possible.  The 
investigator should inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a final visit, if applicable, 
and follow-up with the subject regarding any unresolved adverse events (AEs).
It may be appropriate for the subject to return to the clinical site for final safety assessments. 
Subjects should be questioned regarding their reason for withdrawal.  Assessments, at the 
investigator’s discretion, will include the following:

Oral soft tissue examination

Oral hard tissue examination
Lack of completion of all or any of the early termination procedures will not be viewed as 
protocol deviations so long as the subject’s safety was preserved.
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
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collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7
ASSESSMENTS
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the subject.  When a protocol-required assessment cannot be performed, the 
investigator will document the reason for the missed assessment and any corrective and 
preventative actions that he or she has taken to ensure that required processes are adhered to 
as soon as possible.  The study team must be informed of these incidents in a timely manner.
7.1
Efficacy 
In this study there are no clinical efficacy assessments performed. All efficacy assessments 
will be performed ex vivo on the enamel specimens removed at the times defined in the Study 
Procedures section of this protocol. Enamel specimen preparation and analysis are described 
in Laboratory Procedures Section 7.3. 
7.2
Safety
The following safety assessments will be performed at times defined in the Study Procedures
section of this protocol.  
Oral Hard Tissue Examination (OHT)
Where possible, this procedure should be conducted by a single dental examiner or clinically 
qualified designee for all subjects. Subjects with evidence of gross intra-oral neglect or the 
need for extensive dental therapy will be excluded.
The OHT examination will assess grossly carious lesions or erosive wear, enamel 
irregularities, tooth fracture, gross decay, decalcification and faulty restorations.
Observations will be listed as “Absent” or “Present” and conditions noted as present will be 
described.  Examination findings will be described and documented in the CRF.  Any 
observation that changes from “Absent” to “Present” from the screening assessment must be 
recorded as an AE. 
Oral Soft Tissue Examination (OST)
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Where possible, this procedure should be conducted by a single dental examiner or clinically 
qualified designee for all subjects for the duration of the study. The examination will be 
accomplished by direct observation and palpation with retraction aids as appropriate. The 
examiner will include examination of the labial mucosa (including lips), buccal mucosa,
mucogingival folds, gingival mucosa, hard palate, soft palate, tonsilar area, pharyngeal area, 
tongue, sublingual area, submandibular area and salivary glands.
The results of the examination will be recorded in the CRF as either normal or abnormal, with 
details of any abnormalities. Any post-treatment soft tissue abnormality, or worsening of a 
pre-existing condition, observed by the examiner or reported by the subject will be recorded 
on the CRF. Any abnormalities, or worsening of pre-existing conditions, that occur from 
Visit 2 onwards will be recorded as AEs.  
7.3
Laboratory Procedures
All laboratory procedures will be provided in a separate work instruction document. The 
work instruction document will be prepared by PI or designee and reviewed by GSK CH 
(CRS or designee) in eDMS. The work instruction document will be approved by PI or 
designee and CRS or designee, and stored in eDMS prior to Screening Visit.
The work instruction document will cover, for example, the following elements: 
Preparation 

Preparation of enamel specimens

Preparation of test holders and palatal appliances

Assembly of the test holder

In vitro erosive challenge 
Efficacy measurements

Surface microhardness (SMH)

Enamel fluoride uptake (EFU)
Enamel Specimen Storage
All enamel specimen samples will be stored post completing the study and retained for up to 
six months after laboratory procedures detailed in the work instruction is finalized, as they 
may be subject to further analysis.
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Specimen Retention
Laboratory specimens will be retained by the study site for up to six months following 
database lock. Before destruction, clinical study site designee will contact the sponsor in 
writing requesting permission to destroy the specimens. Specimens will be destroyed by 
autoclaving. The sponsor will provide approval in writing or provide an alternate time period 
for destruction of specimens. Before destruction, GSK may have the option to require the 
transfer of a number of specimens after reporting and unblinding the study for further 
laboratory analysis with the aim to develop new analytical techniques or perform other 
analytical tests. 
7.4
Salivary flow 
At the screening visit, both stimulated and unstimulated saliva will be collected for evaluation 
of flow rates as part of the inclusion criteria. Saliva samples collected will be destroyed 
inmediatelly after they are measured. 
Unstimulated salivary flow
For the unstimulated saliva collection, subjects will sit quietly for five minutes before 
beginning the treatment period. During the five-minute test period, they will be instructed to 
allow their saliva to pool, emptying into a collection tube whenever they feel they need to 
swallow.  Samples will be weighed, pre/post collection and weights calculated (1g = 1ml).
Unstimulated saliva flow rate must be ≥ 0.2 ml/min. Saliva samples collected will be 
destroyed immediately after they are measured. 
Stimulated salivary flow
For the stimulated saliva collection, subjects will chew on a piece of unflavoured gum base 
for one timed minute. After one minute, subjects will be instructed to swallow any pooled 
saliva. They will then chew the gum base for two timed minutes during which time they will 
empty any pooled saliva into a collection tube. Samples will be weighed, pre/post collection 
and weights calculated (1g = 1ml). Stimulated saliva flow rate must be ≥ 0.8 ml/min. Saliva 
samples collected will be destroyed immediately after they are measured. 
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8
ADVERSE EVENT AND OTHER EVENTS OF SPECIAL 
INTEREST REPORTING
8.1
Definitions of Adverse Events and Serious Adverse Events
8.1.1
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of an investigational or washout product or medical device, whether or 
not considered related to the investigational or washout product or medical device.
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 a study treatment.
Events Meeting the AE Definition:  

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" per se will not be reported as an AE or SAE. Such instances will be 
captured in the efficacy assessments. However, the signs, symptoms, and/or clinical 
sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfill 
the definition of an AE or SAE. 
Events NOT meeting the AE definition: 

Any clinically significant abnormal laboratory findings (if applicable) or other 
abnormal safety assessments which are associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the subject’s condition. 

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
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
Medical or surgical procedure (e.g., endoscopy, appendectomy) is not the AE. The 
condition that leads to the procedure is an AE (e.g., appendicitis).

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. 
8.1.2
Serious Adverse Event
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death

Is life-threatening

The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the participant 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;

Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant 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 outpatient setting. Complications that occur during 
hospitalization are AE. 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.

Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption

Results in congenital anomaly/birth defect

Other situations

Medical or scientific judgment should be exercised in deciding whether SAE 
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 
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may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
8.2
Reporting Period
8.2.1
Adverse Event
AEs will be collected from the end of the Screening Visit and until 5 days following last 
administration of the investigational product. 
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions section 
of the case report form (CRF) not the AE section.
8.2.2
Serious Adverse Event
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 provides informed consent, 
which is obtained prior to the subject’s participation in the study, i.e., prior to undergoing any 
study-related procedure and/or receiving investigational product and until 5 days days 
following last administration of the investigational product.
SAEs assessed as not related to study participation (e.g., investigational product, protocol 
mandated procedures, invasive tests, or change in existing therapy) or not related to a GSK 
concomitant medication will be recorded from the at least 1 dose of investigational product
and until 5 days following last administration of the investigational product. 
8.3
Reporting Procedures
The investigator and any designees are responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up on 
AEs that are serious, considered related to the study treatment or the study, or that caused the 
participant to discontinue the study. 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject. In addition, each study subject will be questioned about AEs. 
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
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When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to the 
event.
The investigator or site staff will then record all relevant information regarding an AE/SAE in 
the CRF.
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to GSK in lieu of completion of the GSK /AE/SAE CRF page.
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 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).
Medical conditions reported prior to the time period for reporting AEs/SAEs should be 
recorded as part of 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. Care will be taken not to introduce bias when 
detecting AE and/or SAE. Open-ended and non-leading verbal questioning of the participant 
is the preferred method to inquire about AE occurrence.
8.3.1
Adverse Event
All AEs will be reported on the AE page(s) of the CRF by the investigator or site staff.  It 
should be noted that the form for collection of SAE information is not the same as the AE
CRF.  Where the same data are collected, the forms must be completed in a consistent 
manner.  For example, the same AE term should be used on both forms.  AE should be 
reported using concise medical terminology on the CRF as well as on the form for collection 
of SAE information.
8.3.2
Serious Adverse Event
A paper copy of the SAE form provided in the investigator study master file should be 
completed as fully as possible. 
It is essential to enter the following information: 

Protocol and subject identifiers

Subject’s demography

Description of events, with diagnosis if available
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
Investigator opinion of relationship to study product 

Criterion for seriousness.
The following are desirable and are of particular relevance for investigator and GSK CH 
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, must be e-mailed to the GSK CH Clinical 
Operations Safety Reporting email box with the study number and subject number in the 
subject line of the email immediately and under no circumstance should this exceed 24 
hours after study site personnel learn of the event. The investigator will submit any updated 
SAE data to the sponsor, immediately and under no circumstance should this exceed 24 
hours of it being available. The GSK CH Study Manager should also be notified of the 
situation by telephone or email.
Email Serious Adverse Events to:
The GSK CH Study Manager or designee will be responsible for forwarding the SAE form to 
the Case Management Group, Global Clinical Safety and Pharmacovigilance mailbox 
The initial report will be followed up with more information as relevant, or as requested by 
the GSK CH study manager.
8.3.3
Sponsor’s Reporting Requirements to Regulatory Authorities and 
Ethics Committees
GSK has a legal responsibility to notify, as appropriate, the local regulatory authority and 
other regulatory authorities about the safety of a product under clinical investigation.  Prompt 
notification of SAEs by the investigator to GSK is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects are met.
GSK will comply with country specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/EC and investigators.
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Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information eg, summary or listing of SAE) from the sponsor will review and then file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according 
to local requirements.
8.4
Evaluating Adverse Events and Serious Adverse Events
8.4.1
Severity Assessment
The investigator or designee will make an assessment of severity 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 sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. 
Note: 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. For example, a headache may be severe (interferes significantly with the subject's 
usual function) but would not be classified as serious unless it met one of the criteria for 
SAEs, listed above. 
8.4.2
Causality Assessment
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. The 
investigator’s assessment of causality must be provided for all AEs (serious and non-serious); 
the investigator must record the causal relationship in the CRF, as appropriate, and report such 
an assessment in accordance with the SAE reporting requirements if applicable.
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
Generally, the facts (evidence) or arguments to suggest a causal relationship should be 
provided.
The investigator will use clinical judgment to determine the relationship and will also consult 
the Investigator Brochure (IB), Safety Statement and/or Product Information, for marketed 
products, in the determination of his/her assessment.  Alternative causes, such as underlying 
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disease(s), concomitant therapy, other risk factors, and the temporal relationship of the event 
to the study product will be considered and investigated.
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 and send an SAE follow-up report with the updated 
causality assessment. 
8.5
Withdrawal Due to an Adverse Event and Serious Adverse 
Events
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF
page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.6
Pregnancy
8.6.1
Time Period for Collecting Pregnancy Information
Pregnancy information will be collected on all pregnancies reported following administration 
of any investigational product or washout product and until 5 days after the last treatment. 
8.6.2
Action to be Taken if Pregnancy Occurs
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 e-
mail it to the GSK CH Clinical Operations Safety Reporting email box 
 within 24 hours of learning of the subject becoming pregnant. The GSK 
CH Study Manager or designee will be responsible for forwarding the SAE form to the Case 
Management Group, Global Clinical Safety and Pharmacovigilance mailbox 
.
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 by the investigator to the GSK CH Clinical 
Operations Safety Reporting email box and the GSK CH Study Manager or designee will 
forward this information to the Case Management Group, Global Clinical Safety and 
Pharmacovigilance group mailbox at GSK
 Generally, follow-up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported.
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While pregnancy itself is not considered to be an AE, abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered to be and should be recorded as an SAE.
Any female participant who becomes pregnant while participating will   discontinue study 
treatment or be withdrawn from the study. 
8.7
Follow-up of Adverse Events and Serious Adverse Events
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. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals.
New or updated information will be recorded in the originally completed CRF.
The investigator will submit any updated SAE data to GSK within 24 hours of receipt of the 
information.
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 investigational 
product or study participation, the investigator will promptly notify GSK by emailing the 
information to the GSK CH Clinical Operations Safety Reporting email box 
. The GSK CH Study Manager or designee will be responsible for 
forwarding the information to the Case Management Group, Global Clinical Safety and 
Pharmacovigilance group mailbox at GSK
.
The investigator will submit any updated SAE data to GSK within the designated reporting 
time frames.
8.8
Definition of and Procedure for Reporting Medical Device 
Incidents
Medical devices are being provided by GSK CH for use in this study; the medical device in 
this study is the washout manual toothbrush (Class I medical device).
8.8.1
Definition of an Incident
A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for use 
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which, directly or indirectly, might lead to or might have led to the death of a 
participant/user/other person or to a serious deterioration in his/her state of health.
Not all incidents lead to death or serious deterioration in health. The nonoccurrence of such a 
result might have been due to other fortunate circumstances or to the intervention of health 
care personnel.
It is sufficient that:

An incident associated with a device happened and

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the above 

Fetal distress, fetal death, or any congenital abnormality or birth defects
Examples of incidents:

A participant, user, caregiver, or healthcare professional is injured as a result of a 
medical device failure or its misuse.

A participant’s study treatment is interrupted or compromised by a medical device 
failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to medical device failure.
8.8.2
Reporting of an Incidents and Malfunctions

All incidents must be reported to GSK within 24 hours (or sooner if possible) of 
the investigator or designee becoming aware of the situation.

Any medical device incident occurring during the study will be documented in the 
subject's medical records, in accordance with the investigator's normal clinical 
practice, and on the appropriate Incident Report Form.  In addition, for incidents 
fulfilling the definition of an AE or an SAE, the appropriate AE CRF page or SAE 
form will be completed and reported as per the AE and SAE reporting sections.

The Incident Report Form will be completed as thoroughly as possible and signed by 
the investigator before transmittal to GSK CH.  It is very important that the 
investigator describes any corrective or remedial actions taken to prevent recurrence of 
the incident.
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
The completed Incident Report Form should be emailed to the GSK CH Clinical 
Operations Safety Reporting email box with the study number and subject number in 
the subject line of the email as soon as possible, but not later than 24 hours after 
study site personnel learn of the event. If there is an SAE, the completed SAE pages 
should be sent together with this report form.  However, if a copy of the SAE report is 
sent with this form, this does not replace the procedure to report an SAE.  The original 
Incident Report Form will remain with the subject’s records.

The GSK CH Study Manager should be notified of the situation by telephone or email.
Email the Incident Report Forms to:

The GSK CH Study Manager or designee will be responsible for forwarding the 
Incident Report Form to the Case Management Group, Global Clinical Safety and 
Pharmacovigilance group mailbox 
, responsible for the study 
and other GSK CH personnel as appropriate.

The initial report will be followed up with more information as relevant, or as 
requested by the GSK CH study manager.
The investigator will follow the following directions regarding the reporting of a device 
failure (malfunction):

Notify GSK CH immediately (by following the process described above).

Schedule the subject to return to the site promptly to return the failed device.

Record any incidents on the CRF and Incident Report Form following instructions 
given in the section above.

Return the failed device to the sponsor as soon as possible, including documentation of 
the details of the failure 
8.8.3
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in the 
same manner as other AEs. This applies to all participants, including those who 
discontinue study treatment or the study.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident.

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.
8.8.4
Regulatory and Ethics Reporting Requirements for Incidents

In order to fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of events meeting the definitions of 
incident or malfunction that occur during the study with such devices. Medical device 
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incidents or malfunctions of the device that result in an incident will be detected, 
documented, and reported during all periods of the study in which the medical device 
is used. 

The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (eg, the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
9
DATA MANAGEMENT
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
For this study subject data will be entered into an electronic CRF using a validated data 
system. 
9.1
Source Documents/ Data
The source documents, such as diary cards, which contain the source of data recorded in the 
CRF should be specified in Section 6. The CRF can be used as a source document at the 
discretion of data management.
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.
9.2
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. Refer to the 
appropriate CRO handbook and study-specific CRF specifications.
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 Third Party Biostatistics 
and Data Management vendor applicable standards and data cleaning procedures with 
oversight by GSK CH to ensure integrity of the data e.g., removing errors and inconsistencies 
in the data.
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In order to protect the privacy of subjects, no Personally Identifiable Information (PII) 
(including the subject's name or initials or full birth date) is to be recorded in the CRF or as 
part of the query text.
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.  
GSK CH will obtain and retain all CRFs and associated study data at the completion of the 
study. 
9.3
Data Handling
Documentation of all data management activities 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.
Adverse events will be coded using MedDRA (Medical Dictionary for Regulatory Activities) 
and concomitant medications terms (if applicable) using an internal validated medication 
dictionary, GSKDrug.  
9.3.1
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 clarification 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) 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. The study 
monitor can also run reports and listings on the CRFs, to raise manual queries as needed for 
site clarification or correction.
9.4
Processing Patient Reported Outcomes
Patient reported outcome (PRO) data may be collected from diary cards, questionnaires, etc, 
and entered into the sponsor’s clinical data management system (DMS).  In instances where 
the PRO data is entered into the DMS by GSK CH, the PROs will be anonymized as agreed 
and documented prior to study initiation. PROs that are source will be retained by the 
investigator and certified copies will be sent to GSK CH. 
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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 on all PRO’s that will 
be forwarded to GSK CH.
9.5
External Data 
External Data are subject data obtained externally to the CRF. These data are generated from 
laboratory instruments, computers or other sources and then transcribed into a file and format 
agreed upon by GSK CH 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 transcription. The transcribed data is transmitted in an agreed 
upon format to GSK CH. 
Reconciliation will be performed between the transcribed data and the clinical database to 
ensure subject and time point referenced in the Clinical Database.
10
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
The endpoints of this study are described below and in Section 10.2 
Primary end point: 
%SMHR 
The extent of remineralization will be calculated as the % recovery in SMH, which is 
calculated from the enamel indentation length at baseline, after the first erosive challenge and 
after the in situ remineralization phase after 4 hrs of intraoral phase. 
Secondary end point:
%RER 
This end point aims to test whether the formulations prevents enamel demineralization after 
the 4 hours intra oral remineralization phase as per a second erosion challenge. The %RER is 
calculated based on the indentation length at baseline, after the first and the second erosive 
challenge after 4 hrs. 
EFU
EFU is assessed by the microdrill enamel biopsy, and its determined after 4 hours in situ
remineralization period but before the second extra-oral erosive challenge. This measurement 
will provide with micrograms of fluoride per square centimeter (µg F/cm). 
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Exploratory end point: 
%SMHR, %RER and EFU after 2 hours of intraoral exposure will be evaluated as exploratory 
end point.  
The ARR measures acid resistance of the treated enamel after 2 and 4 hours intraoral phase. It 
is calculated based on the indentation length after the second erosive challenge and the in situ
remineralization phase, and after the first erosive challenge and baseline.
10.1
Sample Size Determination
A sufficient number of healthy subjects will be screened so that up to 66 subjects are
randomized to participate in the study to ensure 60 evaluable subjects complete the entire 
study. With a sample size of 60 subjects that complete the study, the study will have 90% 
power to detect a difference in means of 5.0 in %SMHR at 4 hours, assuming a standard 
deviation of differences of 11.92 (estimated from GSK study Z2560490, which was a study of 
similar design), using a paired t-test with a 0.05 two-sided significance level.
A sample size of 60 subjects will be large enough to also detect a difference of 7.4 in RER 
with 80% power. 
A sufficient number of healthy adult subjects will be selected from the Oral Health Research 
Institue’s IRB approved database of previous research studies or from persons expressing 
interest in participating in research, and screened for participation.
10.2
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.
Treatment differences in the study variables will be tested under the null hypothesis:
H0: there is no treatment difference versus the alternate hypothesis
H1: there is a treatment difference.
10.2.1
Demographic and Baseline Characteristics
Descriptive statistics (number of subjects, mean, standard deviation, median, minimum and 
maximum for continuous variables, and frequency and percentage for categorical variables) 
will be provided for demographic, ethnicity, baseline characteristics, concomitant 
medications, medical history and compliance.
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10.2.2
Primary Analysis(es) 
The primary efficacy variable is %SMHR after 4 hours of remineralization.
Definition of primary variable:
% SMH recovery = [(E1-R)/(E1-B)] * 100
B = indentation length (μm) of sound enamel at baseline
E1 = indentation length (μm) after first erosive challenge
R = indentation length (μm) after in situ remineralization
Per subject %SMHR will be determined from the %SMHR calculated for each specimen 
using five indentations measurements per specimen, averaged across the four specimens at 4 
hrs. Therefore, a single observation per treatment for each subject will be used in the 
statistical analyses. If a subject is missing an enamel specimen, the mean will be computed 
over the available enamel specimens.
The ANOVA model will include fixed factors for study period and treatment, and a random 
effect for subject. The baseline SMH and first demineralization level will not be included in 
the model as covariates as the samples will be preselected so that each sample has a 
measurement of 43 +/-3 μm (at baseline, B) and 120 ± 20 μm (after the first erosive challenge, 
E1).
The primary comparison of this study is the 1150 ppm fluoride experimental dentifrice versus
the fluoride free placebo (0 ppmF) and must be statistically significant to meet the success 
criteria. The treatment difference and 95% CI will be presented for the primary comparison 
and all other %SMHR paired comparisons (classed as secondary and exploratory objectives).  
P-Values for these secondary and exploratory comparisons will only be presented if the 
primary comparison is statistically significant.
The assumptions underlying the ANOVA will be examined, and if necessary, a suitable 
transformation or a non-parametric analysis will be performed (eg paired Wilcoxon Sign Rank 
test).
10.2.3
Secondary Analysis(es)
The secondary efficacy variables are:
i) % Relative Erosion Resistance (RER) after 4 hours intraoral phase.
ii) Enamel Fluoride Uptake (EFU) 4 hours intraoral phase.
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Definition of secondary variables
% Relative Erosion Resistance = [(E1-E2) / (E1-B)] * 100
B= Indentation length (μm) of sound enamel at baseline
E1= Indentation length (μm) after first erosive challenge
E2= Indentation length (μm) after second erosive challenge
Per subject % RER will be determined for each specimen using five indentations
measurements per specimen, averaged across the four specimens at 4 hours. Therefore, a 
single observation per treatment for each subject will be used in the statistical analyses. If a 
subject is missing an enamel specimen, the mean will be computed over the available enamel 
specimens.
Per subject EFU score will be calculated as follows: microdrill samples from each enamel 
specimen will be pooled and a value for fluoride content per enamel specimen determined. 
These values will be averaged across the four enamel specimens for each subject and time 
point to produce the subject-wise mean enamel fluoride uptake. 
Analysis of secondary variables
The same ANOVA model and testing procedure outlined for the primary variable will be 
conducted on the two secondary variables.
The treatment difference and 95% CI will be presented for all of the comparisons however the 
p-values for these secondary comparisons will only be presented if the primary comparison is 
statistically significant.
The assumptions underlying the ANOVA will be examined, and if necessary, a suitable 
transformation or a non-parametric analysis will be performed (eg paired Wilcoxon Sign Rank 
test).
10.2.4
Safety Analysis(es)
All assessments of safety will be based on the safety population, defined as all subjects who 
are randomised and receive at least one dose of study treatment during the study. Safety 
analyses will be performed according to the treatment that the subject received (using variable 
ATRT). All adverse events (AEs) will be reviewed by the Clinical Research Scientist or
Designee prior to database lock and unblinding and will be coded using the Medical
Dictionary for Regulatory Activities (MedDRA). During this review stage, AEs will be 
further categorized as oral or non-oral. AEs will be listed and summarized by treatment 
received. Serious AEs will also be listed. AEs will be regarded as treatment emergent if they 
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occur on or after the first treatment application at the baseline visit. The following AEs tables 
split by treatment will be produced:

Listing of all AEs (including Non-treatment emergent AEs from all subjects)

Listing of all AEs for screened subjects

Treatment emergent AEs by Oral/Non-Oral Preferred Term (PT)

Treatment emergent AEs by System Organ Class (SOC) and PT

Treatment emergent AEs by intensity and PT

Treatment emergent treatment related AEs by Oral/Non-Oral

Treatment emergent treatment related AEs by SOC

Listing of serious AEs (if there are none a null listing will be produced; if there are 
more than 5 treatment emergent serious AEs (SAEs) a table will be produced instead 
by SOC and PT)

Non-serious treatment emergent AEs by SOC and PT (only produced if there are more 
than 5 SAEs).

Listing of incidents (if there are none a null listing will be produced).
Further information related to safety also includes a table and listing of OST data.  The table 
will show changes in abnormality pre and post treatment.  A table of exposure not needed in 
this study as it is a single use study.
10.2.5
Other Analysis(es)
Exploratory efficacy variables are:
i) %SMHR after 2 hours intraoral phase
ii) % RER after 2 hours intraoral phase.
iii) EFU after 2 hours intraoral phase.
iv) ARR after 2 and 4 hours intraoral phase
Definition of exploratory variables
%SMHR as defined above per primary variable, and %RER and EFU as defined above per 
secondary variables.
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The ARR will be calculated as follows:
ARR = 1- [ (E2-R) / (E1-B )]
B= Indentation length (μm) of sound enamel at baseline
R= Indentation length (μm) after in situ remineralization
E1= Indentation length (μm) after first erosive challenge
E2= Indentation length (μm) after second erosive challenge
Analysis of exploratory variables
For %SMHR, %RER and EFU variables the same ANOVA model and testing procedure 
outlined for the primary and secondary variables will be conducted on these exploratory 
variables. All pair-wise treatment comparisons will be estimated form the respective models 
for the variables. The treatment difference and 95% CI will be presented for all of the 
comparisons made however the p-values for these exploratory comparisons will only be 
presented if the primary comparison is statistically significant.
For ARR, summary statistic table by treatment and time point will be provided.
10.2.6
Definition of Analysis Populations
All assessments of safety will be based on the safety population, defined as all subjects who 
are randomised and receive at least one dose of study treatment during the study. Safety 
population summaries will be presented by treatment received.
The primary population for efficacy assessment will be the intent-to-treat (ITT) population, 
defined as all subjects who are randomized, receive the study treatment at least once and 
provide at least one post-baseline (post treatment) assessment of efficacy. All ITT population 
summaries and analyses will be presented by treatment randomized.
10.2.7
Exclusion of Data from Analysis 
Exclusion of any data from the analyses will be determined during a Blind Data Review 
Meeting prior to database lock. Any reasons for exclusion from an analysis population will be 
listed, if applicable.
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The per protocol (PP) population is defined as all subjects in the ITT population who have at 
least one assessment of the primary endpoint efficacy considered unaffected by protocol 
violations.
PP analysis will be performed only on those data considered unaffected by protocol 
violations.
Efficacy analysis on the PP population will be performed only on the primary variable 
(%SMHR) only if there is more than 10% difference in the number of subjects per treatment
between PP and ITT populations. 
A decision on whether a PP analysis will be performed will be made prior to study unblinding
10.2.8
Handling of Dropouts and Missing Data 
Subjects who withdraw from the study early will be included in the study analysis up to the 
point of withdrawal. Subjects who withdraw will not be replaced. No data will be imputed in 
the case of dropouts or missing data.
10.2.9
Interim Analysis
No interim analysis is planned for this study
11
STUDY GOVERNANCE CONSIDERATIONS
11.1
Quality Control 
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.
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 
GSK CH. 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.
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11.2
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 inspection, 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 investigator(s) will notify GSK CH or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with GSK 
CH or its agents to prepare the study site for the inspection and will allow GSK CH or its 
agent, whenever feasible, to be present during the inspection. The investigator will promptly 
apply copies of the inspection finding to GSK CH or its agent. Before response submission to 
the regulatory authority, the investigator will provide GSK CH or its agents with an 
opportunity to review and comment on responses to any such findings. 
The sponsor will be available to help investigators prepare for an inspection.
11.3
Regulatory and Ethical Considerations
11.3.1
Institutional Review Board/ Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, investigator brochure/safety statement 
(including any updates) and other relevant documents, e.g., recruitment advertisements, if 
applicable, from the IRB/EC.  All correspondence with the IRB/EC should be retained in the 
investigator file.  Copies of IRB/EC approvals should be forwarded to GSK CH prior to the 
initiation of the study, and also when subsequent amendments to the protocol are made.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the investigator must notify the IRB/EC and GSK CH in writing immediately after the 
implementation.
11.3.2
Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), guidelines for GCP (ICH 1996 and revision 2), and the Declaration of 
Helsinki (World Medical Association 2013). 
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In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws.
11.3.3
Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by laws. 
When study data are compiled for transfer to GSK CH and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by GSK CH in order to de-identify study subjects.  
The study site will maintain a confidential list of subjects who participated in the study, 
linking each subject’s numerical code to his or her actual identity.  In case of data transfer, 
GSK CH will maintain high standards of confidentiality and protection of subjects’ personal 
data consistent with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be reviewed 
and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study subject, is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed informed consent document.
11.3.4
Subject Recruitment 
Advertisements approved by IRBs/ECs and investigator databases may be used as recruitment 
procedures.  Use of ethics committee approved, generic, prescreening questionnaire to assess 
basic subject characteristics to determine general eligibility for this study is allowed. This 
generic questionnaire may be used by sites as a phone script and/or to review internal 
databases to identify subjects.  
GSK CH will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used. 
11.3.5
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP 
Within a GSK CH a serious breach is defined as a breach likely to affect to a significant
degree the safety and rights of a subject or the reliability and robustness of the data generated 
in GSK CH- sponsored human subject research studies. 
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In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, GSK CH should be informed immediately. 
In addition, the investigator will inform GSK CH immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
11.4
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins in accordance with applicable GSK processes.
11.5
Provision of Study Results to Investigators
Where required by applicable regulatory requirements, 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.
11.6
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 
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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.
The investigator must assure that the subject’s anonymity will be maintained.  On CRFs or 
other documents submitted to GSK CH, subjects should not be identified by their names or 
initials, but by an identification code. The investigator should keep a separate log of subjects’ 
codes, names and addresses.  Documents not for submission to GSK CH, e.g. subjects’ 
written consent forms, should be maintained by the investigator in strict confidence.
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the investigator for 25 years from the issue of the final Clinical Study Report 
(CSR)/ equivalent summary unless local regulations or institutional policies require a longer 
retention period. 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 without a prior written agreement between GSK CH 
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.
11.7
Conditions for Terminating the Study 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of GSK CH.  In addition, GSK CH retains the right to discontinue development of 
the experimental dentifrice at any time. For multicenter studies (if applicable), this can occur 
at one or more or at all sites.  
If a study is prematurely terminated, GSK CH will promptly notify the investigator.  After 
notification, the investigator must promptly contact all participating subjects and should 
assure appropriate therapy/ follow-up for the subjects.  As directed by GSK CH, all study 
materials must be collected and all CRF completed to the greatest extent possible. Where 
required by the applicable regulatory requirements, GSK CH should inform the regulatory 
authority(ies) and the investigator should promptly inform the IRB/EC and provide the 
IRB/EC a detailed written explanation of the termination or suspension. 
If the IRB/EC terminates or suspends its approval/favorable opinion of a trial, the investigator 
should promptly notify the GSK CH and provide GSK CH with a detailed written explanation 
of the termination or suspension.
Upon completion or premature discontinuation of the study, the GSK CH monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in accordance 
with applicable regulations including GCP, and GSK CH Standard Operating Procedures.
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11.8
Definition of Study End/ End of Study 
The End of Study (EOS) is defined as the date of the last laboratory testing related to primary 
and secondary endpoints, to be achieved no later than 8 months after the date of the last 
subject last visit. 
12
REFERENCES
Attin T (2006). Methods for assessment of dental erosion, vol. 20. Karger Monographs in Oral 
Science.
Barlow AP, Sufi F, Mason SC (2009). Evaluation of different fluoridated dentifrice 
formulations using an in situ erosion remineralization model. J Clin Dent 20: 192-198.
Bartizek RD, Gerlach RW, Faller RV, Jacobs SA, Bollmer BW, Biesbrock AR (2001). 
Reduction in dental caries with four concentrations of sodium fluoride in a dentifrice: a meta-
analysis evaluation. J Clin Dent 12: 57-62.
Brunelle JA, Carlos JP (1990). Recent trends in dental caries in U.S. children and the effect of 
water fluoridation. J Dent Res 69 Spec No: 723-727; discussion 820-723.
Chow LC (1990). Tooth-bound fluoride and dental caries. J Dent Res 69 Spec No: 595-600; 
discussion 634-596.
Cochrane NJ, Zero DT, Reynolds EC (2012). Remineralization models. Adv Dent Res 24:
129-132.
Featherstone JD, Glena R, Shariati M, Shields CP (1990). Dependence of in vitro 
demineralization of apatite and remineralization of dental enamel on fluoride concentration. J 
Dent Res 69 Spec No: 620-625; discussion 634-626.
Fowler C, Willson R, Rees GD (2006). In vitro microhardness studies on a new anti-erosion 
desensitizing toothpaste. J Clin Dent 17: 100-105.
Fowler CE, Gracia L, Edwards MI, Willson R, Brown A, Rees GD (2009). Inhibition of 
enamel erosion and promotion of lesion rehardening by fluoride: a white light interferometry 
and microindentation study. J Clin Dent 20: 178-185.
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GSK-Z3480664 GSK Clinical Study (2013): Evaluation of a Test Mouthwash and Dentifrice 
Regimen in an In-Situ Model of Dental Erosion.
GSK-Z3480664 GSK Clinical Study (2013): Evaluation of a Test Mouthwash and Dentifrice 
Regimen in an In Situ Model of Dental Erosion.
GSK-Z6961385 GSK Clinical Study (2013): A Placebo Controlled Study to Evaluate the 
Effectiveness of Two Gel to Foam Toothpastes Using a Modified In situ Model of Dental 
Erosion and Remineralization.
Shellis RP, Ganss C, Ren Y, Zero DT, Lussi A (2011). Methodology and models in erosion 
research: discussion and conclusions. Caries Res 45 Suppl 1: 69-77.
Stephen KW (1993). Dentifrices: recent clinical findings and implications for use. Int Dent J
43: 549-553.
Zero DT (1995). In situ caries models. Adv Dent Res 9: 214-230; discussion 231-214.
13
APPENDIX
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13.1
ABBREVIATION
The following is a list of abbreviations that may be used in the protocol.
Table 13-1
Abbreviation
Abbreviation
Term
AE
adverse event
ANOVA
analysis of variance
ARR
Acid resistance ratio
CI
confidence interval
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CRS
clinical research scientist
DMS
data management system
EC
ethics committee
EDC
electronic data capture
EFU
Enamel fluoride uptake 
EudraCT
European Clinical Trials Database
GCP
Good Clinical Practice
gr
grams
GSK CH
GlaxoSmithKline Consumer Healthcare
hrs
hours
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ID
identification
IRB
institutional review board
ITT
intention to treat
MedDRA
medical Dictionary for Regulatory Activities
min
minutes
mL
milliliters
N/A
not applicable
OHT
oral hard tissue
OST
oral soft tissue 
PI
principal investigator
PII
personally identifiable information
PP
per protocol
PRO
patient reported outcome
RER
relative erosion resistance
PT
preferred term
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Abbreviation
Term
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
sec
seconds
SMH
surface micro hardness
SMHR
surface micro hardness recovery
SOC
system organ class
SRSD
single reference study document
US
United States
µg
micrograms 
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SIGNATURE PAGE 
 
  
 
Date 
Signed By
 
Justification 
 
 
 
Date 
Signed By
 
Justification 
 
 
 
Date 
Signed By
 
Justification 
 
 
 
Date 
Signed By
 
 
Justification 
 
 
 
Date 
Signed By
 
 
Justification 
 
 
 
Date 
Signed By
 
 
Justification 
 
 
 
07-Nov-2017 10:31:10
Approved
Biostatistics Approval
06-Nov-2017 11:39:27
Clinical Operations Approval
208166_Clinical Protocol.docx
06-Nov-2017 11:17:47
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PPD

SAP_001.pdf: 
Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
Property of GSK Consumer Healthcare 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of GSK 
Template Version Effective: 15-Jul-2017 
Page 1 of 55 
 
 
STATISTICAL REPORTING AND ANALYSIS PLAN  
 
 
 
 
A RANDOMIZED, EXAMINER BLIND, CROSSOVER, IN SITU EROSION STUDY TO 
INVESTIGATE THE EFFICACY OF AN EXPERIMENTAL DENTIFRICE IN 
REMINERALIZATION OF PREVIOUSLY SOFTENED ENAMEL COMPARED TO 
PLACEBO DENTIFRICE 
 
 
Protocol Number: 208166  
Phase: 
3 
 
 
 
 
 
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Document History 
 
Document 
Version Date 
Summary of Changes (New analysis or Change 
in planned analysis) 
Amendment 1 
27-Feb-2018 
Blinded data review of surface micro 
hardness data helped to identify a 
discrepancy between clinical protocol and 
analytical protocol. Following that 
identification, an administrative letter (#3- 
22FEB2018) was issued to correct that 
discrepancy. Therefore, 208166 Statistical 
Report and Analysis Plan is amended to 
reflect this administrative change. The 
following text from section 4.4.1.2 will be 
amended: 
Old text: 
The baseline surface micro hardness and 
first demineralization level (E1) will not 
be included in the model as covariates as 
the samples will be preselected so that 
each sample has a measurement of 43 +/-3 
μm (at baseline, B) and 120 ± 20 μm 
(after the first erosive challenge, E1). 
New text: 
The baseline surface micro hardness and 
first demineralization level will not be 
included in the model as covariates as the 
samples will be preselected so that each 
sample has a measurement of 43 +/-3 μm 
at baseline (B) and 10-20 μm greater 
than the baseline after the first erosive 
challenge (E1).  
Analysis Plan 
20-Dec-2017 
Not applicable (N/A) 
 
Amendments incorporate all revisions to date. 
 
 
 
 
 
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Table of contents 
Document History ............................................................................................................... 
2 
Table of contents ................................................................................................................. 
3 
Glossary 
............................................................................................................................... 
5 
1 Summary of Key Protocol Information 
............................................................................... 
6 
1.1 Study Design 
............................................................................................................ 
6 
1.2 Study Objectives 
...................................................................................................... 
7 
1.3 Treatments ............................................................................................................... 
8 
1.4 Sample Size Calculation 
.......................................................................................... 
9 
2 Planned Analyses 
................................................................................................................. 
9 
2.1 Interim Analysis 
....................................................................................................... 
9 
2.2 Final Analyses ....................................................................................................... 
10 
3 Considerations for data analyses and Data Handling Conventions 
................................... 
10 
3.1 Baseline Definition 
................................................................................................ 
10 
3.2 Subgroups/Stratifications 
....................................................................................... 
10 
3.3 Centers Pools 
......................................................................................................... 
10 
3.4 Timepoints and Visit Windows 
............................................................................. 
10 
4 Data Analysis 
..................................................................................................................... 
10 
4.1 Populations for Analysis 
........................................................................................ 
11 
4.1.1 
Subject Disposition 
............................................................................... 
11 
4.1.2 
Protocol Deviations 
............................................................................... 
11 
4.1.3 
Analysis Populations 
............................................................................. 
12 
4.2 Subject Demographics and Other Baseline Characteristics 
................................... 
13 
4.2.1 
Demographic Characteristics 
................................................................ 
13 
4.2.2 
General Medical History 
....................................................................... 
13 
4.3 Treatments (Study Drug, Rescue Medication, other Concomitant Therapies, 
Compliance) 
........................................................................................................... 
13 
4.3.1 
Study Product Compliance and Exposure 
............................................. 
13 
4.3.2 
Prior and Concomitant Medication 
....................................................... 
13 
4.4 Analysis of Efficacy .............................................................................................. 
14 
4.4.1 
Primary Efficacy Endpoint 
.................................................................... 
14 
4.4.2 
Secondary Efficacy Variables 
............................................................... 
15 
4.4.3 
Handling of Missing Values/Censoring/Discontinuations 
.................... 
15 
4.5 Analysis of Secondary Objectives 
......................................................................... 
15 
 
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4.5.2 
Exploratory Efficacy Variables 
............................................................. 
17 
4.6 Analysis of Safety 
.................................................................................................. 
18 
4.6.1 
Adverse Events and Serious Adverse Events 
........................................ 
18 
4.6.2 
Other Safety Variables 
.......................................................................... 
19 
4.7 Analysis of Other Variables 
................................................................................... 
20 
5 Changes to the Protocol Defined Statistical Analysis Plan 
............................................... 
20 
Appendix 1:  Subgroups 
.................................................................................................... 
21 
Appendix 2:  Center pools in multicenter studies ............................................................. 
21 
Appendix 3: Major Protocol Deviations 
............................................................................ 
21 
Attachment 1: List of Data Display 
.......................................................................................... 
22 
Appendix 4: Templates for Tables, Figures & Listings 
.................................................... 
23 
 
 
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Glossary  
AE 
adverse event 
ARR 
acid resistance ratio 
ANOVA 
analysis of variance 
BDRM 
blind data review meeting 
CI 
confidence interval 
EFU 
Enamel fluoride uptake 
GSKCH 
GlaxoSmithKline Consumer Healthcare 
IRB 
institutional review board 
ITT 
intent-to-treat 
MedDRA 
medical dictionary for regulatory activities 
OHT 
oral hard tissue 
OST 
oral soft tissue 
PDMP 
Protocol Deviation Management Plan 
PP 
per protocol 
RER 
relative erosion resistance 
RLR 
review listing requirement 
SD 
standard deviation 
SE 
standard error 
SMHR 
surface micro hardness recovery 
SOC 
System Organ Class 
TEAE 
treatment emergent adverse event 
TLF 
tables, listings and figures 
 
 
 
 
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The purpose of this Statistical Reporting and Analysis Plan is to describe the planned analyses 
and outputs to be included in the Clinical Study Report for Protocol 208166. 
1 
Summary of Key Protocol Information 
 
The aim of this study is to investigate the performance of an experimental dentifrice 
formulation in promoting enamel remineralization and inhibiting post-treatment enamel 
demineralization in an in situ erosion model, in comparison with a fluoride-free placebo and 
with a marketed competitor dentifrice product. 
1.1 
Study Design 
 
This will be a randomized, controlled, single center, single- blind (to the dental examiner and 
specimen analysts), 3 period, 3 treatment, cross-over, in situ design which consists of placing 
pre-eroded bovine enamel specimens intra orally using a palatal appliance and testing the 
remineralizing performance of the experimental, comparator and placebo dentifrices 2 and 4 
hours post treatment application, based on surface micro hardness measurements. This study 
will be carried out in healthy adults with a maxillary dental arch suitable for the retention of 
the palatal appliance. 
There will be 4 visits, 1 screening visit to assess subject eligibility and 3 treatment visits to 
assess product efficacy, where the treatment product will be dispensed and used under the 
supervision of a suitably trained study site personnel. Prior to each treatment visit, there will 
be a washout period of a minimum of 3 days. During this period subjects will use their own 
dentifrice for at least one day, and a fluoride free dentifrice (provided) for two days prior to 
the next scheduled visit (including in the morning of the scheduled visit) to minimize any 
carry-over effects of the fluoride toothpaste. 
The overall study design sequence of events is sketched in the figure below: 
 
Baseline SMH      
(B) 
Erosive challenge 1 
Post erosion SMH 
(E1) 
Enamel 
specimens placed 
on appliance  
intraoral appliance 
placed in subject’s 
mouth  
5 min equilibration  
25 sec toothbrushing 
95 sec swirling  
2 hrs and 4 hrs intraoral 
phase 
 Post erosion 
SMH  (E2) 
Erosive challenge 2 
After remin SMH  
(R) 
Measurement 
Acid exposure 
In situ 
Enamel 
specimens 
removed from 
appliance at 2hrs 
and 4 hrs 
Lege
specimens 
processed through 
sterilizer 
EFU 
 
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1.2 
Study Objectives 
 
Objectives 
Endpoints 
Primary Objective 
 
To investigate the efficacy of an 
experimental dentifrice containing 1150 
ppm fluoride and5% KNO3 to enhance 
remineralization of enamel relative to a 
fluoride free placebo dentifrice. 
%SMHR after 4 hours intraoral phase 
following a single exposure. 
Secondary Objectives 
 
Efficacy 
 
To investigate the efficacy of an 
experimental dentifrice containing 1150 
ppm fluoride and 5% KNO3 to inhibit 
demineralization of enamel relative to a 
fluoride free placebo dentifrice. 
%RER after 4 hours intraoral phase 
following a single exposure. 
To investigate the efficacy of an 
experimental dentifrice containing 1150 
ppm fluoride and 5% KNO3 to promote 
fluoride uptake in ename relative to a 
fluoride free placebo dentifrice. 
EFU after 4 hours intraoral phase following a 
a single exposure. 
To investigate the efficacy of an 
experimental dentifrice containing 1150 
ppm fluoride and 5% KNO3 to enhance 
remineralization, to inhibit 
demineralization and to promote fluoride 
uptake in enamel relative to a benchmark 
comparator containing 1100 ppm fluoride 
(Crest Pro Health). 
%SMHR, %RER and EFU after 4 hours 
intraoral phase following a single exposure. 
Safety 
 
To evaluate the oral tolerance of an 
experimental dentifrice containing 1150 
ppm fluoride and 5% KNO3 following a 
single brushing event. 
Proportion of treatment emergent oral 
adverse events post 4 hours intraoral 
exposure. 
Exploratory Objectives 
Exploratory Endpoints 
To make all paired comparisons of the 
efficacy of an experimental dentifrice 
containing 1150 ppm fluoride and 5% 
KNO3 after 2 hours of intraoral exposure 
to enhance remineralization of enamel, to 
inhibit demineralization of enamel and to 
%SMHR, %RER and EFU after 2 hours 
intraoral phase following a single exposure. 
 
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Objectives 
Endpoints 
promote fluoride uptake in enamel. 
To characterize the efficacy of the 
experimental dentifrice containing 1150 
ppm fluoride and 5% KNO3; the fluoride 
free placebo; and the benchmark 
comparator containing 1100 ppm (Crest 
Pro Health) after 2 and 4 hours of 
intraoral exposure on resistance to acid 
challenge. 
Summary statistic table of ARR after 2 and 4 
hours intraoral phase. 
Abbreviations: SMHR: Surface micro hardness recovery, RER: Relative erosion resistance, EFU: Enamel 
fluoride uptake, ARR: Acid resistance ratio 
1.3 
Treatments 
 
This is a single blind study, with the examiner and specimen analyst being blind to the 
treatment each subject received.  Given that it is almost impossible to ensure identical 
appearance, taste and packaging for the dentifrices evaluated in this study, the level of 
blindness for this study is described as ‘examiner blind’ only. All study products 
(experimental, comparator and placebo dentifrices) will be over-wrapped in white vinyl to 
maintain the study blind as much as possible. 
Subjects will be assigned to study product sequence in accordance with the randomization 
schedule generated by Inventiv Health under the supervision of the Biostatistics Department, 
GlaxoSmithKline Consumer Health (GSK CH), prior to the start of the study, using a 
validated program. Subjects will be randomized in a Williams square design balanced for first 
period carryover. 
 
The details of the study treatments is outlined in below table 
 
 
Test Product 
Comparator 
Product 
Placebo Product 
Product Name Experimental 
dentifrice containing 
0.254% w/w sodium 
fluoride (1150 ppm 
fluoride) and 5% 
KNO3; plus 0.25% 
PVM/MA 
copolymer and 2.5% 
sodium lactate 
Crest ProHealth 
Sensitivity & 
Enamel Shield 
containing 0.454% 
w/w stannous 
fluoride (1100 ppm 
fluoride) 
Fluoride free placebo 
containing 5% KNO
3 
(0 ppm fluoride); plus 
0.25% PVM/MA 
copolymer and 2.5% 
lactate 
 
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1.4 
Sample Size Calculation 
 
A sufficient number of healthy subjects will be screened so that up to 66 subjects are 
randomized to participate in the study to ensure 60 evaluable subjects complete the entire 
study. 
 
 
 
 
 
A sample size of 60 subjects will be large enough to also detect a difference of 7.4 in RER 
with 80% power. 
 
A sufficient number of healthy adult subjects will be selected from the Oral Health Research 
Institue’s IRB approved database of previous research studies or from persons expressing 
interest in participating in research, and screened for participation. 
2 
Planned Analyses 
2.1 
Interim Analysis 
No interim analysis is planned. 
Product 
Formulation 
Code (MFC) 
 
 
Commercially 
available (US 
marketed) 
 
Dose 
1.5 g 
1.5 g 
1.5 g 
Route of 
Administration 
Oral 
Oral 
Oral 
Dosing 
Instructions 
Subjects will apply a full ribbon of the allocated product and brush 
the buccal surfaces of their natural teeth for 25 timed seconds and 
then swish the resulting toothpaste slurry around the mouth, without 
further brushing, for a timed period of 95 seconds. After 
expectorating the slurry, the subjects will gently rinse their mouths 
with 15 mL of tap water for 10 seconds before expectorating again 
 
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2.2 
Final Analyses 
The final planned primary analyses will be performed after the completion of the following 
sequential steps: 
1. All subjects have completed the study as defined in the protocol. 
2. All required database cleaning activities have been completed and database has been 
locked. 
3. All criteria for unblinding the randomization codes have been met and the randomization 
codes have been distributed. 
3 
Considerations for data analyses and Data Handling 
Conventions 
3.1 
Baseline Definition 
For Efficacy analyses: 
Subject level baseline is defined as the latest assessment with a non-missing value before the 
first erosive challenge. 
Period level baseline is defined as the latest assessment with a non-missing value the first 
erosive challenge for a given period. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and will 
be set to missing. 
3.2 
Subgroups/Stratifications 
No stratification or subgrouping is planned for this study. 
3.3 
Centers Pools 
This is single centre study, therefore pooling of centers is not applicable. 
3.4 
Timepoints and Visit Windows 
The study schedule should be followed as per protocol. Deviations from the study schedule 
with respect to visit timings and the amount of time the appliance was worn at each visit will 
be reviewed and significant deviations in timings classified as protocol deviations potentially 
affecting efficacy assessment. A time window non-compliance listing will be produced for 
blinded data review. 
4 Data Analysis 
Data analysis will be performed by inVentiv Health Clinical. The statistical analysis software 
used will be SAS version 9.4 (Studio) or higher. 
 
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Prior to database closure a blind data review meeting (BDRM) will be conducted in which 
various aspects of the trial will be discussed and agreed. 
Unless otherwise described, all listings will be produced for all randomized subjects. 
4.1 
Populations for Analysis 
4.1.1 Subject Disposition 
Screen failures are defined as subjects who consent to participate in the study but are never 
subsequently randomized. A summary of the number of subjects screened and the number of 
screen failures will be provided. Percentage calculation for screen failures will based on all 
screened subjects. 
Subject disposition will be summarized as the number and percentage of subjects who 
complete the study, with the number who discontinue, broken down by reason for 
discontinuation.  The percentages are based on the total number of subjects randomized. The 
table will also summarise the number and percent of subjects assigned to each analysis 
population (defined in Section 4.1.3). The summary will be presented by treatment group and 
overall (Table 14.1.1). In addition summary will be presented by sequence group, period and 
overall (Table 14.1.2). 
Subject disposition including the subject status (completer, Yes/No), critical demographic 
data (age, sex and race) will be listed for randomized subjects (Listing 16.2.1.1) and non-
randomized subjects (Listing 16.2.1.2) separately. 
4.1.2 Protocol Deviations 
Protocol deviations will be tracked by the study team throughout the conduct of the study. All 
deviations will be reviewed prior to unblinding and closure of the database to ensure all 
important deviations are captured and categorised. 
The following will be taken into consideration when determing the protocol deviations with 
the potential to affect primay efficacy assessment. 
• Deviation from the inclusion/exclusion criteria 
• Use of prohibited medication before or during the study which is deemed to affect the 
assessment of efficacy. 
• Significant non-compliance of product use. 
• Significant non-compliance with the study schedule e.g., with regards to durations that 
appliances are worn. 
• Significant deviation from planned time of an evaluation. 
• Treatment not received in defined order. 
•  Any other reason identified which may affect the assessment of efficacy. 
 
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Major deviations deemed to affect primary efficacy will be identified between the 
Biostatistician and Clinical Research Director or designee, before breaking the study blind 
and will be documented in the Population Definition Document. These will be excluded from 
the Per-Protocol (PP) analysis. 
Minor deviations will be identified as those not classified as major deviations. 
More details on protocol deviations can be found in the Protocol Deviation Management Plan 
(PDMP) of this study. 
The number and percentage of subjects with any major protocol deviations and with each type 
of major protocol deviations will be presented by treatment (Table 14.1.3) and listed (Listing 
16.2.2.1). Any minor protocol deviations will be listed similarly (Listing 16.2.2.2). 
4.1.3 Analysis Populations 
Following analysis populations are defined. 
Population 
Definition / Criteria 
Analyses Evaluated 
All Screened 
Subjects 
All subjects who are screened 
Disposition 
Randomized 
All subjects who are randomized and may or 
may not receive the study treatment. 
Protocol deviations 
Safety 
Safety population includes all subjects who 
are randomized and receive at least one dose 
of study treatment during the study. Safety 
population summaries will be presented by 
treatment received. 
Safety analysis 
Intent-to-Treat 
(ITT) 
The primary population for efficacy 
assessment will be the (ITT) population, 
defined as all subjects who are randomized, 
receive the study treatment at least once and 
provide at least one post-baseline (post 
treatment) assessment of primary efficacy.  
All ITT population summaries and analyses 
will be presented by treatment randomized. 
Efficacy analysis 
PP 
The PP population is defined as all subjects 
in the ITT population who have at least one 
assessment of the primary endpoint efficacy 
considered unaffected by protocol violations. 
Primary efficacy 
analysis 
(%SMHR) only 
Efficacy analysis on PP population will be performed only if there is more than 10% 
difference in the overall number of subjects between PP and ITT populations.  
A decision on whether a PP analysis will be performed will be made prior to study 
unblinding. Subjects excluded from any of the analysis populations will be listed (Listing 
16.2.3.1). 
 
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4.2 
Subject Demographics and Other Baseline Characteristics 
4.2.1 Demographic Characteristics 
Demographic and baseline characteristics summaries will be produced for the Safety 
Population (Table 14.1.4.1). ITT Population (Table 14.1.4.2), and PP Population (Table 
14.1.4.3) (if PP analysis is performed).  
Categorical demographic variables include sex, ethnicity and race, will be summarized by the 
number and percentage of subjects in each treatment group. The continuous demographic 
variable age (in years) and will be summarized by the mean, standard deviation (SD), median, 
minimum and maximum values. All summaries will be presented by overall. 
All demographic information will be listed for randomized subjects (Listing 16.2.4.1). 
4.2.2 General Medical History 
Medical history and current medical conditions for all randomized subjects will be listed 
(Listing 16.2.4.2) with start date and end date or ongoing at the first application of study drug.  
4.3 Treatments (Study Drug, Rescue Medication, other Concomitant 
Therapies, Compliance) 
Treatment compliance will also be listed for the blinded data review and specified in the 
review listing requirement (RLR) document. 
4.3.1 Study Product Compliance and Exposure 
Subjects will complete diary cards during the 2 days of washout period prior to the treatment 
visit. Study product compliance will be listed (Listing 16.2.5.3).  
4.3.2 Prior and Concomitant Medication 
Prior medications are defined as those stopped before the first administration of study drug.  
Any medication that has started prior to first dose of study drug and is still continuing is 
termed as concomitant medication. 
Concomitant medication is also defined as any medication taken between the date of first dose 
of study drug and the date of last dose of study drug. 
In this crossover trial, medications will be assigned to the treatment group based on the 
treatment being received at that date. Medications with a date time between treatments periods 
will be assigned to the treatment received in the previous period. Medications with a date after 
last treatment or the end of the study will be assigned to the treatment taken in the last period. 
There will be no imputation of unknown dates. However if the start date is unknown, then it 
will be assumed to concomitant (all treatment periods) unless the partial start date or stop date 
indicates differently. 
 
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Prior and concomitant medications and siginificant non-drug therapies will be listed by 
subject, with preferred term, indication, dose, dose form, frequency, route, start date, end date 
or ongoing and start day relative to first dose of study drug (Listing 16.2.5.1 and Listing 
16.2.5.2). 
4.4 
Analysis of Efficacy  
4.4.1 Primary Efficacy Endpoint 
4.4.1.1 Primary Efficacy Endpoint Definition 
 
The primary efficacy endpoint is %SMHR after 4 hours of remineralization. 
 
Definition of primary variable:  % SMH recovery = [(E1-R)/(E1-B)] * 100 
 
B = indentation length (μm) of sound enamel at baseline 
E1 = indentation length (μm) after first erosive challenge 
R = indentation length (μm) after in situ remineralization 
 
Per subject %SMHR will be determined from the %SMHR calculated for each specimen 
using five indentations measurements per specimen, averaged across the four specimens at 4 
hours. Therefore, a single observation per treatment for each subject will be used in the 
statistical analyses. If a subject is missing an enamel specimen, the mean will be computed 
over the available enamel specimens. 
4.4.1.2 Statistical Hypothesis, Model, and Method of Analysis 
 
The primary comparison of this study is the 1150 ppm fluoride experimental dentifrice versus 
the fluoride free placebo (0 ppmF) in %SMHR at 4 hours and must be statistically significant 
to meet the success criteria.  
 
The extent of remineralization will be calculated as the % recovery in SMH (%SMHR), which 
is calculated from the enamel indentation length at baseline, after the first erosive challenge 
and after the in situ remineralization phase after 4 hrs of intraoral phase. 
 
Statistical testing of all endpoints in this study will be conducted at a two-sided significance 
level of 0.05. As a primary objective has been defined prior to analysis, there will be no 
adjustment for multiple comparisons. The null and alternative hypotheses are 
 
• H0: there is no difference between treatment groups;  
• H1: there is a difference between treatment groups. 
 
 
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The analysis of variance (ANOVA) will be used to analyze the treatment difference. The 
ANOVA model will include fixed factors for study period and treatment, and a random effect 
for subject. The baseline SMH and first demineralization level will not be included in the 
model as covariates as the samples will be preselected so that each sample has a measurement 
of 43 +/-3 μm at baseline (B) and 10-20 μm greater than the baseline after the first erosive 
challenge (E1). 
Summary statistics including mean, standard deviation (SD), standard error (SE), median, 
min, max will be provided on the analysis population used for statistical analysis (Table 
14.2.1.1) by treatment group.  
Adjusted means of two treatments and treatment difference will be provided together with 
95% confidence interval (CI) and p-values (Table 14.2.1.1) by treatment group. 
The assumption of residual normality and variance homogeneity in ANOVA analysis will be 
investigated through residual plots. If violated, a nonparametric method (paired Wilcoxon 
Sign Rank test) will be performed. If the violation is caused by extreme values, a sensitivity 
analysis will be conducted by removing the extreme values and same analysis will be repeated 
without those extreme values. If nonparametric test is performed and the inferences on 
treatment comparisons are similar to that of ANOVA, both sets of results will be reported and 
the emphasis will be made on the ANOVA results. Otherwise, nonparametric results will be 
used to draw conclusions. 
A Bar Chart (Figure 14.2.1.5) with Error Bars (±SD) will be created. 
4.4.1.3 Supportive Analyses 
If there are more than 10% differences in the overall number of subjects between PP and ITT 
populations, a PP analysis will be performed for primary efficacy variable. This analysis 
would be considered as supportive analysis (Table 14.2.1.3). 
A summary table (Table 14.2.1.4) for derived specimens by timepoint and treatment groups 
will be provided. 
4.4.2 Secondary Efficacy Variables 
Secondary efficacy variables of the study are defined in section 4.5. 
4.4.3 
Handling of Missing Values/Censoring/Discontinuations 
Missing data will not be replaced or imputed. Dropouts will be included in analyses up to the 
point of discontinuation. 
4.5 Analysis of Secondary Objectives 
 
 
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The treatment difference, SE and 95% CI will be presented for all of the comparisons 
however the p-values for these secondary comparisons will only be presented if the primary 
comparison is statistically significant. 
 
Same model and analysis methods of primary efficacy endpoint will be conducted for all 
secondary efficacy endpoints. 
4.5.1.1 Percent Relative Erosion Resistance (RER) after 4 Hours 
The %RER is calculated based on the indentation length at baseline, after the first and the 
second erosive challenge after 4 hours. 
 
% Relative Erosion Resistance = [(E1-E2) / (E1-B)] * 100 
B= Indentation length (μm) of sound enamel at baseline 
E1= Indentation length (μm) after first erosive challenge 
E2= Indentation length (μm) after second erosive challenge 
 
Per subject % RER  will be determined from the % RER calculated for each specimen 
using five indentations measurements per specimen, averaged across the four specimens at 4 
hours. Therefore, a single observation per treatment for each subject will be used in the 
statistical analyses. If a subject is missing an enamel specimen, the mean will be computed 
over the available enamel specimens. 
Summary statistics including mean, SD, SE, median, min, max will be provided on the 
analysis population used for statistical analysis (Table 14.2.2.1) by treatment group. Adjusted 
means of two treatments and treatment difference will be provided together with 95% 
confidence interval (CI) and p-values (Table 14.2.2.1) by treatment group. As a primary 
objective has been defined prior to analysis, there will be no adjustment for multiple 
comparisons. 
A Bar Chart (Figure 14.2.2.3) with Error Bars (±SD) will be created. 
4.5.1.2 Enamuel Fluoride Uptake (EFU) after 4 Hours 
EFU is assessed by the microdrill enamel biopsy, and is determined after 4 hours in situ 
remineralization period but before the second extra-oral erosive challenge. This measurement 
will provide with micrograms of fluoride per square centimeter (μg F/cm2). 
 
Per subject EFU score will be calculated as follows: microdrill samples from each enamel 
specimen will be pooled and a value for fluoride content per enamel specimen determined. 
These values will be averaged across the four enamel specimens for each subject and time 
point to produce the subject-wise mean enamel fluoride uptake. 
Summary statistics including mean, standard deviation (SD), standard error (SE), median, 
min, max will be provided on the analysis population used for statistical analysis (Table 
14.2.3.1) by treatment group. Adjusted means of two treatments and treatment difference will 
 
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be provided together with 95% CI and p-values (Table 14.2.3.1) by treatment group. As a 
primary objective has been defined prior to analysis, there will be no adjustment for multiple 
comparisons. 
A Bar Chart (Figure 14.2.3.3) with Error Bars (±SD) will be created. 
4.5.2 Exploratory Efficacy Variables 
Exploratory variables of the study are listed below. Unless not stated otherwise same model 
and analysis methods will be conducted as for the secondary endpoints. 
4.5.2.1 Percent  Surface Microhardness Recovery after 2 Hours 
The extent of remineralization will be calculated as the % recovery in SMH, which is 
calculated from the enamel indentation length at baseline, after the first erosive challenge and 
after the in situ remineralization phase after 2 hours of intraoral phase. 
Summary statistics including mean, SD, SE, median, min, max will be provided on the 
analysis population used for statistical analysis (Table 14.2.1.2) by treatment group. Adjusted 
means of two treatments and treatment difference will be provided together with 95% CI and 
p-values (Table 14.2.1.2) by treatment group. As a primary objective has been defined prior to 
analysis, there will be no adjustment for multiple comparisons. 
A Bar Chart (Figure 14.2.1.5) with Error Bars (±SD) will be created. 
4.5.2.2 Percent Relative Erosion Resistance after 2 Hours 
This end point aims to test whether the formulations prevents enamel demineralization after 
the 2 hours intra oral remineralization phase as per a second erosion challenge. The %RER is 
calculated based on the indentation length at baseline, after the first and the second erosive 
challenge after 2 hours. 
Summary statistics including mean, SD, SE, median, min, max will be provided on the 
analysis population used for statistical analysis (Table 14.2.2.2) by treatment group. Adjusted 
means of two treatments and treatment difference will be provided together with 95% CI and 
p-values (Table 14.2.2.2) by treatment group. As a primary objective has been defined prior to 
analysis, there will be no adjustment for multiple comparisons. 
A Bar Chart (Figure 14.2.2.3) with Error Bars (±SD) will be created. 
4.5.2.3 Enamuel Fluoride Uptake (EFU) after 2 Hours 
EFU is assessed by the microdrill enamel biopsy, and is determined after 2 hours in situ 
remineralization period but before the second extra-oral erosive challenge. This measurement 
will provide with micrograms of fluoride per square centimeter (μg F/cm2). 
Summary statistics including mean, SD, SE, median, min, max will be provided on the 
analysis population used for statistical analysis (Table 14.2.3.2) by treatment group. Adjusted 
means of two treatments and treatment difference will be provided together with 95% CI and 
 
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p-values (Table 14.2.3.2) by treatment group. As a primary objective has been defined prior to 
analysis, there will be no adjustment for multiple comparisons. 
A Bar Chart (Figure 14.2.3.3) with Error Bars (±SD) will be created. 
4.5.2.4 Acid Resistance Ratio (ARR) 
The ARR measures acid resistance of the treated enamel after 2 and 4 hours intraoral phase. It 
is calculated based on the indentation length after the second erosive challenge and the in situ 
remineralization phase, and after the first erosive challenge and baseline. 
 
The ARR will be calculated as follows: ARR = 1- [ (E2-R) / (E1-B) ] 
 
B= Indentation length (μm) of sound enamel at baseline 
E1= Indentation length (μm) after first erosive challenge 
E2= Indentation length (μm) after second erosive challenge 
R = indentation length (μm) after in situ remineralization 
 
Only summary statistics including mean, SD, SE, median, min, max will be provided by 
randomized treatment group (Table 14.2.4.1, Table 14.2.4.2) for 4 hours and 2 hours 
respectively. 
A Bar Chart (Figure 14.2.4.3) with Error Bars (±SD) will be created. 
4.6 
Analysis of Safety 
4.6.1 
Adverse Events and Serious Adverse Events 
All summaries of safety will be performed using the safety population and will be analyzed 
based on treatment actually received. No formal statistical testing will be performed on 
summary comparisons related to safety related measurements. 
All AEs will be coded using the medical dictionary for regulatory activities (MedDRA). AEs 
will be classified by system organ class (SOC) and by preferred term (PT). In addition, prior 
to database lock all AEs will be reviewed by the Clinical Research Director (or designee) and 
categorized as either oral or non-oral. Safety will be assessed based on any oral AEs (this 
includes those that are identified as treatment emergent oral soft tissue (OST) abnormalities 
and spontaneously reported oral AEs). Any new or worsening OST condition that occurs after 
the OST examinations at Screening will be recorded as an AE. 
 
In this crossover trial, events will be assigned to the treatment group based on the treatment 
being received at the onset of the event. TEAEs with an onset date time between treatments 
perods will be assigned the treatment received in the previous period. TEAEs with an onset 
after last treatment or the end of the study will be assigned to the treatment taken in the last 
period. If an emergent AE continues to another treatment period and worsens, the AE will be 
 
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considered emergent in both the period in which it started and also the period in which it 
worsened. 
AEs will be summarized using descriptive statistics (frequency tables) by treatment group. 
Summary tables will indicate both the number of events and the number (percent) of subjects 
involved. Summaries of AEs will also include TEAEs unless otherwise noted. TEAEs are 
defined as new AEs that occur on or after the date/time of the first supervised use of the 
randomized treatment (or events aggravated in severity following treatment). Events with an 
onset date/time prior to first use of a treatment will be considered as non-treatment emergent. 
The following summary tables and listings will be presented by treatment group. 
 
• Table of Treatment emergent AEs by SOC and PT (Table 14.3.1.1) 
• Table of Treatment emergent AEs by Oral/Non-Oral and PT (Table 14.3.1.2) 
• Table of treatment emergent treatment related AEs by SOC and Preferred Term  
(Table 14.3.1.3). 
• Table of treatment emergent treatment related AEs by Oral/Non-Oral and Preferred 
Term (Table 14.3.1.4). 
• Table of treatment emergent AEs by intensity and Preferred Term. 
(Table 14.3.1.5). 
• Listing of all AEs (including all subjects: Listing 16.2.7.1 for all randomized subjects; 
Listing 16.2.7.2 for non-randomized subjects). 
• Listing of death (Listing 14.3.2.1). 
• Listing of serious AEs (Listing 14.3.2.2) (if there are more than 5 treatment emergent 
serious AEs (SAEs) a table (Table 14.3.1.6) will be produced instead by SOC and PT). 
• Listing of treatment emergent AEs leading to withdrawal (Listing 14.3.2.3). 
• Listing of treatment emergent AEs classified as oral (Listing 14.3.2.4). 
• Listing of non-fatal serious treatment emergent AEs (Listing 14.3.2.5) (only produced 
if there are more than 5 SAEs). 
In the event that there is nothing to report a null listing will be produced. 
4.6.2 
Other Safety Variables 
A listing (Listing 16.2.7.3) for incidents will be produced. A table (Table 14.4.1.1) for OST 
will be produced for changes in abnormality pre- and post treatment. In addition a listing 
(Listing 16.2.9.2) for oral hard tissue (OHT) and OST (Listing 16.2.9.1) will be displayed. 
 
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4.7 
Analysis of Other Variables 
Not applicable. 
5 
Changes to the Protocol Defined Statistical Analysis Plan 
There are no changes to the protocol-planned statistical analyses.  
Top-line Summary: 
For the top-line report selected outputs will be produced as documented in the attached 
worksheet excel file. 
 
 
 
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Appendix 1:  Subgroups 
Not Applicable 
Appendix 2:  Center pools in multicenter studies 
Not Applicable 
Appendix 3: Major Protocol Deviations 
Protocol deviations will be tracked by the study team throughout the conduct of the study. 
More details on protocol deviations can be found in the Protocol Deviation Management Plan 
(PDMP) of this study. 
All deviations will be reviewed prior to study unblinding and closure of the database. Details 
will be given in the populations’ definitions document.  
 
 
 
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Attachment 1: List of Data Display 
Worksheet 
in 
208166_RAP Final v1.0_20Dec2017.xlsx
 
 
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Appendix 4: Templates for Tables, Figures & Listings 
The following provides detail of the  treatment labels to be used on the table, figure and listings and and general footnotes. 
The treatment labels will be specified as follows: 
 
Test Product 
Comparator Product 
Placebo Product 
 
If there are no data to display generate a null table or listing. 
 
Add following footnote to all TFLs: 
 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA 
copolymer and 2.5% sodium lactate; Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w 
stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% 
PVM/MA copolymer and 2.5% lactate. 
 
 
 
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Page 24 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Table 14.1.1 
Subject Disposition by Treatment Group Across Study Treatment Periods 
All Screened Subjects 
All Screened Subjects (N=xxx) 
 
Test Product 
  n (%) 
Comparator Product 
   n (%) 
Placebo Product 
   n (%) 
Overall 
   n    (%) 
TOTAL SUBJECTS SCREENED 
 
 
 
  xxx 
 
 
 
 
 
SUBJECTS NOT RANDOMIZED 
 
 
 
  xxx 
       DID NOT MEET STUDY CRITERIA 
 
 
 
  xxx  (xx.x) 
       ADVERSE EVENT 
 
 
 
  xxx  (xx.x) 
       LOST TO FOLLOW UP 
 
 
 
  xxx  (xx.x) 
       PROTOCOL VIOLATION 
 
 
 
  xxx  (xx.x) 
       WITHDRAWAL OF CONSENT 
 
 
 
  xxx  (xx.x) 
       OTHER 
 
 
 
  xxx  (xx.x) 
 
 
 
 
 
SUBJECTS RANDOMIZED 
  xxx 
  xxx 
  xxx 
  xxx 
   COMPLETED STUDY 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
   DID NOT COMPLETE STUDY 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
       DID NOT MEET STUDY CRITERIA 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
       ADVERSE EVENT 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
       LOST TO FOLLOW-UP 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
       PROTOCOL VIOLATION 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
       WITHDRAWAL OF CONSENT 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
       OTHER 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
 
 
 
 
 
SAFETY POPULATION 
 
 
 
  xxx  (xx.x) 
ITT POPULATION 
 
 
 
  xxx  (xx.x) 
PP POPULATION 
 
 
 
  xxx  (xx.x) 
For categories under ‘Subjects Not Randomized’ percentages will be calculated using the number of ‘All Screened Subjects’ as the denominator. Percentages under 
the ‘Subjects Randomized’ categories will be computed using number of subjects randomized as the denominator. 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
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Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
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Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Table 14.1.2 
Subject Disposition by Sequence Group and Period 
All Screened Subjects 
All Screened Subjects (N=xxx) 
 
Treatment Sequence 
 
 
A/B/C 
A/C/B 
B/A/C 
B/C/A 
C/A/B 
C/B/A 
OVERALL 
 
n  (%) 
n  (%) 
n  (%) 
n  (%) 
n  (%) 
n  (%) 
n  (%) 
TOTAL SUBJECTS SCREENED 
  
  
  
  
  
  
XX 
 
 
 
 
 
 
 
 
SUBJECTS NOT RANDOMIZED: 
  
  
  
  
  
  
XX 
    DID NOT MEET STUDY CRITERIA 
  
  
  
  
  
  
XX  
    ETC. 
 
 
 
 
 
 
.. 
 
 
 
 
 
 
 
 
SUBJECTS RANDOMIZED 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
  PERIOD X: 
 
 
 
 
 
 
 
  STARTED PERIOD: 
XX  
XX  
XX  
XX  
XX  
XX  
XX  
  COMPLETED  
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
  DID NOT COMPLETE:  
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    DID NOT MEET STUDY CRITERIA 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    ETC. 
.. 
.. 
.. 
.. 
.. 
.. 
.. 
 
 
 
 
 
 
 
 
SAFETY POPULATION 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
ITT POPULATION 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
PP POPULATION 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
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Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
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Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Table 14.1.3 
Incidence of Major Protocol Deviations 
All Randomized Subjects 
Randomized Population (N=xxx) 
 
   A/B/C 
 
   n     (%) 
 
  A/C/B 
 
   n (   %) 
B/A/C 
  
   n      (%) 
 
B/C/A 
  
   n      (%) 
 
C/A/B 
  
   n      (%) 
 
C/B/A 
  
   n      (%) 
Overall 
  
   n      (%) 
 
 
 
 
 
 
 
 
SUBJECTS WITH AT LEAST ONE 
MAJOR PROTOCOL VIOLATION 
 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
MAJOR PROTOCOL VIOLATIONS NOT 
LEADING TO EXCLUSION FROM PP 
 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
    VIOLATION REASON 1 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
 
 
 
 
 
 
 
 
MAJOR PROTOCOL VIOLATIONS 
LEADING TO EXCLUSION FROM PP 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
   All VISITS 
   
   
 
 
 
 
 
     VIOLATION REASON 1 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
   WEEK Y 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
     VIOLATION REASON 1 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
  xxx  (xx.x) 
 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
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Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
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Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Table 14.1.4.1 
Demographics Characteristics 
Safety Population 
Safety Population (N=xxx) 
 
Overall 
   N   (%) 
SEX n (%) 
 
       Male 
  xx (xx.x) 
       Female 
  xx (xx.x) 
 
 
RACE n (%) 
 
       African American/African Heritage 
  xx (xx.x) 
       American Indian or Alaskan Native 
  xx (xx.x) 
       Asian - Central/South Asian Heritage 
  xx (xx.x) 
       Asian - East Asian Heritage 
  xx (xx.x) 
       Asian - Japanese Heritage 
  xx (xx.x) 
       Asian - South East Asian Heritage 
  xx (xx.x) 
       Native Hawaiian or Other Pacific Islander 
  xx (xx.x) 
       White - Arabic/North African Heritage 
  xx (xx.x) 
       White - White/Caucasian/European Heritage 
  xx (xx.x) 
 
 
ETHNICITY n (%) 
 
       Hispanic or Latino 
  xx (xx.x) 
       Not Hispanic or Latino 
  xx (xx.x) 
 
 
AGE (YEARS) 
 
       N 
  xx 
       MEAN 
  xx.x 
       SD 
  xx.xx 
       MEDIAN 
  xx.x 
       MINIMUM 
  xx 
       MAXIMUM 
  xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
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Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
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Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Table 14.2.1.1 
Statistical Analysis of Percent Surface Microhardness Recovery at 4 Hours by Treatment Group 
ITT Population  
Intent-to-Treat Population (N=XX) 
 
 
Test Product         
 (N=XX) 
Comparator Product 
(N=XX) 
 
Placebo Product 
          (N=XX) 
n  
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.xx    ... 
x.xx 
x.xx 
MAXIMUM 
X.xx    ... 
x.xx 
x.xx 
 
 
 
 
ADJUSTED MEAN [1] 
      xx.xx 
      xx.xx 
      xx.xx 
STANDAR ERROR 
       x.xxx 
       x.xxx 
       x.xxx 
 
 
 
 
COMPARISON BETWEEN TREATMENTS 
DIFFERENCE [1,2] 
95% CI [1] 
P-VALUE [1] 
 
 
 
 
TEST PRODUCT VS PLACEBO PRODUCT 
x.xx 
(xx.xx, xx.xx) 
x.xxxx 
TEST PRODUCT VS COMPARATOR PRODUCT 
x.xx 
xx.xx, xx.xx) 
x.xxxx 
 
 
 
 
[1] From ANOVA with fixed factors for study period and treatment, and a random effect for subject. 
[2] Difference is first-named treatment minus second-named treatment such that a positive difference favors the first named treatment. 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
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Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
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Page 29 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Table 14.2.1.4 
Summary Table of Indents Measures by Timepoint and Treatment Group 
ITT Population  
Intent-to-Treat Population (N=XX) 
Timepoint 
  Treatment 
 
 
   N 
Indentation length of 
sound enamel at baseline 
(B)(μm) 
Mean      SE 
Indentation length 
after first Erosive 
Challenge (E1) (μm) 
Mean      SE 
Indentation length 
after second Erosive 
Challenge (E2) (μm) 
Mean      SE 
Indentation length after in situ 
Remineralization (R) (μm) 
Mean      SE 
 
 
 
 
 
 
 
4 Hours 
  Test Product 
  XX 
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
 
  Comparator Product   XX 
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
 
  Placebo Product 
 
  XX   
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
 
 
 
 
 
 
 
2 Hours 
  Test Product 
  XX 
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
 
  Comparator Product   XX 
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
 
  Placebo Product 
 
  XX 
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
xx.xx     x.xxx 
 
 
 
 
 
 
 
 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 30 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Figure 14.2.1.5 
Bar Chart with Error Bars (+/- SD)for % Surface Microhardness Recovery 
ITT Population 
 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
Programming Note: Please adapt this figure with study specfic informations and title specifications. Please include 2 hour and 4 hour in same figure. 
 
 
 
 
 
 
Document Name 
 
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Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 31 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Table 14.2.4.1 
Summary Statistics of  Acid Resistance Ratio (ARR) at 4 Hours by Treatment Group 
ITT Population  
Intent-to-Treat Population (N=XX) 
 
 
Test Product         
 (N=XX) 
Comparator Product 
(N=XX) 
 
Placebo Product 
          (N=XX) 
n  
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.xx    ... 
x.xx 
x.xx 
MAXIMUM 
x.xx    ... 
x.xx 
x.xx 
 
 
 
 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
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Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 32 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Table 14.3.1.1 
Treatment Emergent Adverse Event by System Organ Class and Preferred Term 
Safety Population 
Safety Population (N=xx) 
 
 
SOC  
   Preferred Term 
 
Test 
 Product  
(N=XX) 
Comparator Product  
(N=XX) 
Placebo 
 Product  
(N=XX) 
 
Overall 
(N=XXX) 
 
n (%) 
nAE 
n (%)     nAE 
n (%)     nAE 
n (%) 
nAE 
NUMBER OF SUBJECTS WITH AT 
LEAST ONE AE 
xx (xx.x) 
xx 
xx (xx.x)    xx 
xx (xx.x)    xx 
xx (xx.x) 
xx 
NUMBER OF SUBJECTS WITH NO AE 
xx (xx.x) 
xx 
xx (xx.x)    xx 
xx (xx.x)    xx 
xx (xx.x) 
xx 
 
 
 
 
 
 
 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
xx (xx.x) 
xx 
xx (xx.x)    xx 
xx (xx.x)    xx 
xx (xx.x) 
xx 
  ERYTHEMA 
xx (xx.x) 
xx 
xx (xx.x)    xx 
xx (xx.x)    xx 
xx (xx.x) 
xx 
  DERMATITIS 
xx (xx.x) 
xx 
xx (xx.x)    xx 
xx (xx.x)    xx 
xx (xx.x) 
xx 
 
 
 
 
 
GASTROINTESTINAL SYSTEM 
xx (xx.x) 
xx 
xx (xx.x)    xx 
xx (xx.x)    xx 
xx (xx.x) 
xx 
  ABDOMINAL PAIN 
xx (xx.x) 
xx 
xx (xx.x)    xx 
xx (xx.x)    xx 
xx (xx.x) 
xx 
  DRY MOUTH 
xx (xx.x) 
xx 
xx (xx.x)    xx 
xx (xx.x)    xx 
xx (xx.x) 
xx 
  VOMITTING 
 
Etc. 
xx (xx.x) 
xx 
xx (xx.x)    xx 
xx (xx.x)    xx 
xx (xx.x) 
xx 
n (%) = Number (percent) of subjects nAE = Number of adverse events. SOC=System organ class 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 33 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Table 14.3.1.2 
Treatment Emergent Adverse Event by Oral/Non-Oral and Preferred Term 
Safety Population  
Safety Population (N=xx) 
 
       Preferred Term 
Test Product 
(N=XX) 
__________________ 
n    (%)    nAE 
 
Comparator Product 
(N=XX) 
__________________ 
n    (%)    nAE 
 
Placebo Product 
(N=XX) 
__________________ 
n    (%)    nAE 
Overall 
(N=XXX) 
__________________ 
n    (%)    nAE 
NUMBER OF SUBJECTS WITH AT LEAST ONE TEAE     xx  ( xx.x)   xx 
    xx  ( xx.x)    xx 
    xx  ( xx.x)    xx 
      xx  ( xx.x)    xx 
 
 
 
 
 
NUMBER OF SUBJECTS WITH NO TEAE 
    xx  ( xx.x) 
    xx  ( xx.x) 
    xx  ( xx.x) 
      xx  ( xx.x) 
 
 
 
 
 
ORAL 
    xx  ( xx.x)   xx 
    xx  ( xx.x)    xx 
    xx  ( xx.x)    xx 
      xx  ( xx.x)    xx 
   SENSITIVITY OF TEETH 
    xx  ( xx.x)   xx 
    xx  ( xx.x)    xx 
    xx  ( xx.x)    xx 
      xx  ( xx.x)    xx 
   ORAL MUCOSAL EXOLIATION 
    xx  ( xx.x)   xx 
    xx  ( xx.x)    xx 
    xx  ( xx.x)    xx 
      xx  ( xx.x)    xx 
 
 
 
 
 
NON ORAL 
    xx  ( xx.x)   xx 
    xx  ( xx.x)    xx 
    xx  ( xx.x)    xx 
      xx  ( xx.x)    xx 
   BRONCHITIS 
    xx  ( xx.x)   xx 
    xx  ( xx.x)    xx 
    xx  ( xx.x)    xx 
      xx  ( xx.x)    xx 
   COUGH 
    xx  ( xx.x)   xx 
    xx  ( xx.x)    xx 
    xx  ( xx.x)    xx 
      xx  ( xx.x)    xx 
 
 
 
 
 
n (%) = Number (percent) of subjects nAE = Number of adverse events. 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 34 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Table 14.3.1.5 
Treatment Emergent Adverse Events by Intensity and Preferred Term 
Safety Population 
Study Population: Safety Population 
 
                                            Test              Comparator             Placebo          Overall      
                                          Product              Product              Product                        
Preferred Term                             N=XXX                 N=XXX               N=XXX            (N=XXX)      
                         Intensity    n    (%)   [AEs]    n    (%)   [AEs]     n   (%)   [AEs]     n   (%)   [AEs] 
 
 
Preferred Term #1        MILD        XXX  (XX.X) [XXX]    XXX  (XX.X) [XXX]    XXX (XX.X) [XXX]    XXX (XX.X) [XXX] 
                         MODERATE    XXX  (XX.X) [XXX]    XXX  (XX.X) [XXX]    XXX (XX.X) [XXX]    XXX (XX.X) [XXX] 
                         SEVERE      XXX  (XX.X) [XXX]    XXX  (XX.X) [XXX]    XXX (XX.X) [XXX]    XXX (XX.X) [XXX] 
 
Preferred Term #2        MILD        XXX  (XX.X) [XXX]    XXX  (XX.X) [XXX]    XXX (XX.X) [XXX]    XXX (XX.X) [XXX] 
                         MODERATE    XXX  (XX.X) [XXX]    XXX  (XX.X) [XXX]    XXX (XX.X) [XXX]    XXX (XX.X) [XXX] 
                         SEVERE      XXX  (XX.X) [XXX]    XXX  (XX.X) [XXX]    XXX (XX.X) [XXX]    XXX (XX.X) [XXX] 
 
Preferred Term #3        MILD        XXX  (XX.X) [XXX]    XXX  (XX.X) [XXX]    XXX (XX.X) [XXX]    XXX (XX.X) [XXX] 
                         MODERATE    XXX  (XX.X) [XXX]    XXX  (XX.X) [XXX]    XXX (XX.X) [XXX]    XXX (XX.X) [XXX] 
                         SEVERE      XXX  (XX.X) [XXX]    XXX  (XX.X) [XXX]    XXX (XX.X) [XXX]    XXX (XX.X) [XXX] 
 
 
n (%) = Number (percent) of subjects nAE = Number of adverse events. 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 35 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Table 14.4.1.1 
Summary of Oral Soft Tissue - Changes from Pre-treatment to Post-treatment 
Safety Population 
Safety Population (N=xx) 
                                                                       Post-Treatment (4 hours) 
                                                             Normal      Abnormal     Not Examined  
Treatment            AREA            Pre-Treatment             n   (%)      n   (%)      n   (%)      
  
Test Product 
                    Labial Mucosa    Normal                 XX (XX.X)    XX (XX.X)    XX (XX.X)    
                                     Abnormal               XX (XX.X)    XX (XX.X)    XX (XX.X)    
                                     Not Examined           XX (XX.X)    XX (XX.X)    XX (XX.X)    
 
                    Buccal Mucosa    Normal                 XX (XX.X)    XX (XX.X)    XX (XX.X)    
                                     Abnormal               XX (XX.X)    XX (XX.X)    XX (XX.X)    
                                     Not Examined           XX (XX.X)    XX (XX.X)    XX (XX.X)    
 
                    [other]          Normal                 XX (XX.X)    XX (XX.X)    XX (XX.X)    
                                     Abnormal               XX (XX.X)    XX (XX.X)    XX (XX.X)    
                                     Not Examined           XX (XX.X)    XX (XX.X)    XX (XX.X)    
 
Comparator Product 
 
Placebo Product 
 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Programmer Note: please add all different areas for all treatments. 
 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 36 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.1.7.1 
Randomization Details 
All Randomized Subjects 
 
Subject Number 
Age/Sex/ Race [1] 
Randomization Number 
Treatment Sequence [2] 
Randomization Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
[2] A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Programmer Note: correct seed number an block size to be added after unblinding in a footnote 
 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 37 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.1.1 
Subject Disposition 
All Randomized Subjects 
 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
 
Age/Sex/ 
Race [1] 
Screening 
Date 
 
Period 
Treatment 
Start Date 
and Time 
Date of 
Completion or 
Withdrawal 
Period of 
Withdrawal 
Completed 
(Yes/No) 
Primary Reason for 
Withdrawal 
 
 
Further Details [2] 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
[2] Further details of reasons for withdrawal. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 38 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.1.2 
Subject Disposition 
Non-Randomized Subjects 
 
Subject 
Number 
 
Age/Sex/ Race [1] 
Screening Date Reason for Screen Failure 
 
Further Details [2] 
 
 
 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
[2] Further details of reasons for screen failure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 39 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.2.1 
Important and Major Protocol Deviations 
All Randomized Subjects 
 
Treatment Sequence: XXXXXXXXXX 
Subject Number 
Age/Sex/Race [1] 
Period 
Deviation Sequence 
Date of Deviation 
Deviation Type 
Deviation Description 
 
 
 
 
 
 
 
XXXXXX 
XX/F/A1 
 
1 
28JUN201 
XXXXXX 
XXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 [1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian 
Heritage, A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-
Arabic/North African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
Programming Note: Listing 16.2.2.1 lists only those identified in population definition document to be excluded from PP population. 
 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 40 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.2.2 
Minor Protocol Deviations 
Randomized Population 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
 
Age/Sex/ Race [1] 
 
Period 
 
Deviation Sequence 
 
Protocol Deviation 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 41 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.3.1 
Exclusions from Analysis Populations 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject Number 
Age/Sex/ Race [1] 
Randomized 
Safety 
ITT 
Per Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 42 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.4.1 
Demographic Characteristics 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
Sex 
Race 
Age (years) 
Ethnicity 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 43 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.4.2 
Medical History and Current Medical Conditions 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
Age/Sex/ 
Race [1] 
Any Medical 
History? 
Medical Condition 
Start Date 
Ongoing? 
End Date 
 
 
 
 
 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 44 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.5.1 
Prior Medications and Significant Non-Drug Therapies Prior to Treatment 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
Age/Sex/ Race [1] Treatment
(GSK Drug 
Synonym) 
Reason for 
Medication 
Route of 
Administration 
Dose per 
Administration 
Frequency 
Start Date 
(Study Day 
[2]) 
End Date/ 
Ongoing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
[2] Study day relative to the date of first dose of treatment. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 45 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.5.2 
Concomitant Medications and Significant Non-Drug Therapies During Treatment 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
Age/Sex/ Race [1] Treatment
(GSK Drug 
Synonym) 
Medication 
assigned 
Period 
Reason for 
Medication 
Route of 
Administration 
Dose per 
Administration 
Frequency 
Start Date 
(Study Day 
[2]) 
End Date/ 
Ongoing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
A=Test Product; B=Comparator Product; C=Placebo Product 
[2] Study day relative to the date of first dose of treatment. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Programmer Note: Subject will be listed by treatment groups. Same subjects could be listed on different treatment groups 
 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 46 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.5.3 
Study Product Compliance 
All Randomized Subjects 
 
Subject Number 
Age/Sex/ Race [1] 
Treatment 
Sequence 
Period 
Subject Compliance to use 
of washout period (Yes/No) 
Number of missed 
product uses since the 
last visit 
Number of additional 
product uses since 
the last visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 47 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.6.1 
Surface Microhardness Recovery 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
Age/Sex/ Race 
[1] 
Timepoint 
Specimen 
Information 
Period 
Treatment 
Measurement 
Indentation 
length of 
sound enamel 
at baseline 
(B) 
(μm) 
Indentation 
length after 
first Erosive 
Challenge 
(E1) 
(μm) 
Indentation 
length after in 
situ 
Remineralization 
(R) 
(μm) 
% SMHR 
 
 
 
 
 
 
 
 
 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
Each value is calculated as the average of five indentations measurements per specimen, averaged across the four specimens for 2hours or 4hours. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
Programmer Note: Please add all “other” information and timepoints for each subject in chronological order. For each subject we will have four specimen 
informations (XXX1 to XXX4) per subject and period. Overall endpoint value to be calculated as mean of averages per period. 
 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 48 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.6.2 
Relative Erosion Resistance 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
Age/Sex/ Race 
[1] 
Timepoint 
Specimen 
Information 
Period 
Treatment 
Measurement 
Sound 
Enamel at 
Baseline 
(μm) 
First Erosive 
Challenge 
(μm) 
Indentation 
length after 
second Erosive 
Challenge (E2) 
(μm) 
% RER  
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
Each value is calculated as the average of five indentations measurements per specimen, averaged across the four specimens for 2hours or 4hours. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
Programmer Note: Please add all “other” information and timepoints for each subject in chronological order. For each subject we will have four specimen 
informations (XXX1 to XXX4) per subject and period. Overall endpoint value to be calculated as mean of averages per period. 
 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 49 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.6.3 
Enamel Fluoride Uptake 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
Age/Sex/ Race 
[1] 
Timepoint 
Period 
Treatment 
Specimen 
Information 
1  
Specimen 
Information 
2 
Specimen 
Information  
3 
Specimen 
Information 
4 
Enamel Fluoride 
Uptake 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 50 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.6.4 
Acid Resistance Ratio 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
Age/Sex/ 
Race [1] 
Timepoint 
Specimen 
Information 
Period 
Treatment 
Measurement 
Sound 
Enamel at 
Baseline 
(μm) 
First 
Erosive 
Challenge 
(μm) 
Second 
Erosive 
Challenge 
(μm) 
In situ 
Remineralization 
(μm) 
Acid 
Resistance 
Ratio 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
Each value is calculated as the average of five indentations measurements per specimen, averaged across the four specimens for 2hours or 4hours. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
Programmer Note: Please add all “other” information and timepoints for each subject in chronological order. For each subject we will have four specimen 
informations (XXX1 to XXX4) per subject and period. Overall endpoint value to be calculated as mean of averages per period. 
 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 51 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.7.1 
Adverse Events 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
Age/Sex/ 
Race [1] 
Adverse Event 
(Preferred 
Term) 
[System of 
Organ Class] 
Start Date 
(Study 
Day)[2] 
Start 
Time 
End Date 
End 
Time 
AE 
assigned 
Period 
Frequency/ 
Intensity[3] 
Related 
to Study 
Product? 
Action 
Taken re 
Study 
Product 
Outcome 
Seri
ous? 
With-
drew?
[4] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
@@ Adverse events with verbatim text ending in this are classified as Oral AEs. 
 [1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian 
Heritage, A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-
Arabic/North African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
[2] Study day is the day relative to start of treatment, Day 1 being the day of first treatment. Period day is the day relative to the start of treatment being 
received in that period 
[3] INT = Intermittent and SGLE = Single. [4] Did subject withdraw from study as a result of this adverse event? 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 52 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.7.2 
Adverse Events 
Non-Randomized Subjects 
 
Subject 
Number 
Age/Sex/ 
Race [1] 
Adverse Event 
(Preferred 
Term) 
[System of 
Organ Class] 
Start Date 
 
Start 
Time 
End Date 
End 
Time 
Frequency/ 
Intensity[2] 
Related 
to Study 
Product? 
Action 
Taken re 
Study 
Product 
Outcome 
Seri
ous? 
With-
drew?
[3] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
@@ Adverse events with verbatim text ending in this are classified as Oral AEs. 
 [1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian 
Heritage, A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-
Arabic/North African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
[2] INT = Intermittent and SGLE = Single. 
[3] Did subject withdraw from study as a result of this adverse event? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 53 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.7.3 
Listing of Incidents 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject Number 
Age/Sex/Race[1] 
Treatment 
Period 
Date of the 
Incident 
Incident 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 54 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.9.1 
Oral Soft Tissue Examination 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
Age/Sex/ Race [1] 
Visit 
Timepoint 
Date of  
Assessment 
Time of 
Assessment 
Area 
Abnormality 
Details for not 
examined  
 
 
 
 
 
 
 
 
 
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD


Sodium fluoride and potassium nitrate 
208166 
Statistical Reporting and Analysis Plan Amendment 1, 27 Feb 2018 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 55 of 55 
Protocol No. 208166 
 
 
 
 
 
 
 
 
 
 
 
       Program Run Date:xxxx 
Listing 16.2.9.2 
Oral Hard Tissue Examination 
All Randomized Subjects 
Treatment Sequence: XXXXXXXXXX 
Subject 
Number 
Age/Sex/ Race 
[1] 
Timepoint 
Date of  
Assessment 
Time of 
Assessment 
Area 
Abnormality 
Details for not 
examined  
 
[1] Age in years; Sex: F=Female, M=Male; Race: A1=African American/African Heritage, A2=American Indian Or Alaskan Native, A3=Asian-Central/South Asian Heritage, 
A4=Asian-East Asian Heritage, A5=Asian-Japanese Heritage, A6=Asian-South East Asian Heritage, N=Native Hawaiian Or Other Pacific Islander, W1=White-Arabic/North 
African Heritage, W2=White-White/Caucasian/European Heritage, MT=Multiple. 
A=Test Product; B=Comparator Product; C=Placebo Product 
Test Product: Experimental dentifrice containing 0.254% w/w sodium fluoride (1 150 ppm fluoride) and 5% KNO3 plus 0.25% PVM/MA copolymer and 2.5% sodium lactate; 
Comparator Product: Crest ProHealth Sensitivity & Enamel Shield dentifrice containing 0.454% w/w stannous fluoride (1100 ppm fluoride); Placebo Product: Fluoride 
free placebo dentifrice containing 5% KNO3 (0 ppm fluoride); plus 0.25% PVM/MA copolymer and 2.5% lactate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Page x of y 
 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
gsk-208166-reporting-and-analysis-plan-redact.pdf
eldo_controlled
0.1; CURRENT; Most-Recent; In Review
090032d58126e110
PPD
PPD