Conditions: Gingivitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 130
Healthy volunteers: yes

Brief summary:
The aim of this study is to investigate the impact of a stannous fluoride containing toothpaste in reducing gingivitis when used twice daily for a maximum for 3 weeks, when compared to a standard sodium fluoride toothpaste (negative control).

Detailed description:
This will be a single center, controlled, single blind (examiner blind), randomized, two-treatment arm, parallel design, clinical study in participants (aged 18-65 years), with good general health (non-smokers) and generalized mild-moderate plaque-induced gingivitis and greater than equal to (\>=) 20 natural teeth. The study consists of 4 study visits. At Visit 1, Screening, after signing informed consent, participants will be assessed for eligibility based on the inclusion/exclusion criteria and will undergo oral soft tissue (OST) and oral hard tissue (OHT) assessments. Participants will return between 1 and 28 days following the screening visit for the Visit 2, baseline where they will undergo, a full OST examination followed by assessments of gingival inflammation (MGI), gingival bleeding (BI) and supra-gingival plaque (TPI). Eligible participants will be stratified based on gender and baseline mean whole mouth MGI score (low: less than equal to (\<=) 2.00/High greater than (\>) 2.00), to ensure a balance of gingivitis across both treatment groups and then randomized to study product. All randomized participants will receive full mouth dental prophylaxis (followed by flossing) to remove sub and supra-gingival calculus, stain, plaque and debris from the teeth. All participants will enter the treatment period with no visible plaque (TPI=0). After all clinical assessments, participants will be instructed to brush for 1 timed minute at site with their assigned study product, after which they will be instructed to continue using this twice daily (morning and evening) for 2 weeks. After 2 weeks the participants will return to site for their Week 2 (Visit 3) assessments. They will then continue using their test dentifrice for a further week and will continue to record all brushing events in the diary provided, after which they will return for their Week 3 (Visit 4) assessments. All assessments will be carried out on the facial and lingual/palatal surfaces of each incisor, canine, pre-molar and molar, excluding third molars. After the Week 3 visit, study closeout procedures will take place and the participant may undergo an additional prophylaxis if it is deemed necessary by the examiner. Adverse events and incidents will be recorded from informed consent and at the end of each study visit.

Arms:
arm 1: Participants with no visible plaque will be instructed to apply full ribbon of the test product (containing 0.454 percent \[%\] of stannous fluoride\] on head of toothbrush provided and brush their teeth for 1 timed minute twice a day (morning and evening), for 3 weeks. arm 2: Participants with no visible plaque will be instructed to apply full ribbon of the negative control dentifrice (containing sodium fluoride) on head of toothbrush provided and brush their teeth for 1 timed minute twice a day (morning and evening), for 3 weeks.

Interventions: intervention 1: Sensodyne Repair and Protect intervention 2: Colgate Cavity Protection
Intervention descriptions: intervention 1: Participants will brush their teeth with Sensodyne Repair and Protect (containing 0.454% stannous fluoride) for 1 timed minute twice a day (morning and evening), for 3 weeks. intervention 2: Participants will brush their teeth with Colgate Cavity Protection repair and protect (containing sodium fluoride) for 1 timed minute twice a day (morning and evening), for 3 weeks.

Protocol document:
Prot_000.pdf: 
Clinical Protocol 
212537 
A Randomized, Examiner Blind, Clinical Study Investigating the 
Efficacy of a Stannous Fluoride Dentifrice in Improving Gingival 
Health after 3 Weeks Use 
NCT04050722 
GlaxoSmithKline Consumer Healthcare 
(UK) Trading Limited  
980 Great West Road, Brentford, 
Middlesex, TW8 9GS 
United Kingdom (UK) 
Protocol approval date: 22-Jun-2019 
Copyright: GlaxoSmithKline. This document contains confidentiality statements 
that are not relevant for this publicly available version.  


Author(s) 
APPROVALS
Name
Reason for Approval
Approval Date CET*(MM/DD/YYYY)
6/18/2019 2:22:28 PM
6/20/2019 10:12:06 AM
6/22/2019 9:01:41 AM
Document Name 
Scope 
Document Type 
Document Subtype 
Document ID 
Version 
Approved Date in CET* 
Pages 
*CET: Central European Time
1.0
68
0900c3538148f970
Jun 22,2019  9:01:00 AM
212537-Clinical Protocol-
Clinical Protocol
Studies
003 Study protocol and Amendment
CCI
CCI
PPD
PPD
PPD
PPD


GSK Consumer Healthcare
Clinical Protocol
Protocol Number: 212537
This document contains confidentiality statements that are not relevant for this publicly 
available version.
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May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
SP1963/SOP-208661: Template Version: 14 Mar 2019
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CLINICAL PROTOCOL
A Randomized, Examiner Blind, Clinical Study Investigating the 
Efficacy of a Stannous Fluoride Dentifrice in Improving Gingival 
Health after 3 Weeks Use  
Protocol Number:
212537
Compound/Product Name:
Stannous Fluoride
United States (US) Investigational New Drug 
(IND) Number:
Not Applicable
European Clinical Trials Database (EudraCT) 
Number:
Not Applicable
Other Regulatory Agency Identified Number:
Not Applicable
Phase:
Phase IV


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Sponsor Information
Sponsor Name & Legal 
Registered Address
GlaxoSmithKline Consumer Healthcare (UK) 
Trading Limited
980 Great West Road,
Brentford,
Middlesex,
TW8 9GS,
United Kingdom (UK)
Sponsor Contact Details
GlaxoSmithKline Consumer Healthcare (GSK 
CH)
184 Liberty Corner, Warren, NJ, 07059, USA


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Document History
Document
Version
Summary of Changes 
Original protocol
1.0
Not applicable (N/A)
Amendment 1
Amendment 2
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 according to the current International Conference on Harmonisation Good 
Clinical Practice (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:
Investigator Qualifications:
Investigator Signature:
Date of Signature/Agreement:
DD-Mmm-YYYY
PPD
PPD


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Table of Contents
Sponsor Information ............................................................................................................2
Document History................................................................................................................3
Principal Investigator Protocol Agreement Page.................................................................4
Table of Contents.................................................................................................................5
1
PROTOCOL SUMMARY.................................................................................................10
1.1
Schedule of Activities............................................................................................12
2
INTRODUCTION .............................................................................................................15
2.1
Study Rationale......................................................................................................16
2.2
Background............................................................................................................16
2.3
Mechanism of Action/Indication ...........................................................................17
3
STUDY OBJECTIVES AND ENDPOINTS.....................................................................18
4
STUDY DESIGN ..............................................................................................................19
4.1
Overall Design .......................................................................................................19
4.2
Rationale for Study Design....................................................................................19
4.3
Justification for Dose .............................................................................................21
4.4
End of Study Definition.........................................................................................21
5
STUDY POPULATION....................................................................................................22
5.1
Type and Planned Number of Subjects..................................................................22
5.2
Inclusion Criteria....................................................................................................22
5.3
Exclusion Criteria ..................................................................................................23
5.4
Randomization Criteria..........................................................................................25
5.5
Lifestyle Considerations ........................................................................................25
5.5.1
Dental Product/Treatment and Oral Hygiene Restrictions....................25
5.5.2
Dietary Restrictions...............................................................................26
5.5.3
Medication and Treatment Restrictions.................................................26
5.6
Screen Failures.......................................................................................................26
5.7
Sponsor’s Qualified Medical Personnel.................................................................26
5.8
Rater/Clinical Assessor Qualifications ..................................................................27
6
INVESTIGATIONAL/STUDY PRODUCTS...................................................................27
6.1
Investigational/Study Product Supplies .................................................................27
6.1.1
Dosage Form and Packaging.................................................................29
6.1.2
Preparation and Dispensing...................................................................29
6.2
Administration .......................................................................................................29
6.2.1
Medication/Dosing Errors .....................................................................30
6.2.2
Overdose................................................................................................30
6.3
Investigational/Study Product Storage...................................................................31
6.4
Investigational/Study Product Accountability .......................................................31


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6.4.1
Destruction of Investigational/Study Product Supplies.........................32
6.5
Blinding and Allocation/Randomization ...............................................................32
6.6
Breaking the Blind .................................................................................................32
6.7
Compliance ............................................................................................................33
6.8
Concomitant Medication/Treatment(s)..................................................................33
7
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .........................................................................33
7.1
Subject Discontinuation/Withdrawal.....................................................................33
7.2
Lost to Follow up...................................................................................................34
8
STUDY PROCEDURES...................................................................................................34
8.1
Visit 1/Screening....................................................................................................34
8.1.1
Informed Consent..................................................................................35
8.1.2
Demographics........................................................................................35
8.1.3
Medical History and Prior Medication/Treatment ................................36
8.1.4
Oral Examination/Assessment...............................................................36
8.1.5
Inclusion/Exclusion Criteria..................................................................36
8.1.6
Subject Eligibility..................................................................................36
8.2
Study Period...........................................................................................................36
8.2.1
Visit 2/Day 1 (Baseline)........................................................................36
8.2.2
Visit 3/Day 14 (Week 2)........................................................................37
8.2.3
Visit 4 /Day 21 (Week 3).......................................................................37
8.2.4
Diary Review.........................................................................................38
8.2.5
Dental Prophylaxis ................................................................................38
8.3
Study Conclusion...................................................................................................38
8.4
End of Study Optional Prophylaxis .......................................................................39
8.5
Follow-up Visit ......................................................................................................39
9
STUDY ASSESSMENTS .................................................................................................39
9.1
Screening Assessments ..........................................................................................39
9.1.1
Oral Hard Tissue (OHT) Assessment....................................................39
9.1.2
Oral Soft (OST) Assessment .................................................................40
9.1.3
Gross Assessment of Gingival Health...................................................40
9.2
Efficacy Assessments.............................................................................................40
9.2.1
Modified Gingival Index (MGI)............................................................40
9.2.2
Bleeding Index (BI)...............................................................................41
9.2.3
Plaque Disclosure..................................................................................41
9.2.4
Turesky Plaque Index (TPI) ..................................................................42
9.2.5
Repeatability Assessments ....................................................................42
9.3
Safety and Other Assessments...............................................................................43


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9.3.1
Oral Hard Tissue Examination (OHT) ..................................................43
9.3.2
Oral Soft Tissue Examination (OST) ....................................................43
10 ADVERSE EVENT AND SERIOUS ADVERSE EVENTS............................................43
10.1
Definition of an Adverse Event (AE) ....................................................................43
10.2
Definition of a Serious Adverse Event (SAE) .......................................................44
10.3
Reporting of Adverse Events.................................................................................45
10.3.1
Reporting Period....................................................................................45
10.4
Reporting Procedures.............................................................................................45
10.4.1
Reporting of an Adverse Event .............................................................46
10.4.2
Reporting of a Serious Adverse Event ..................................................46
10.5
Evaluating Adverse Events....................................................................................47
10.5.1
Assessment of Intensity.........................................................................47
10.5.2
Assessment of Causality........................................................................48
10.6
Follow-up of Adverse Events ................................................................................48
10.7
Withdrawal Due to an Adverse Event....................................................................49
10.7.1
Sponsor’s Reporting Requirements to Regulatory Authorities and 
Ethics Committees.................................................................................49
10.8
Pregnancy...............................................................................................................49
10.8.1
Time Period for Collecting Pregnancy Information..............................49
10.8.2
Action to be Taken if Pregnancy Occurs...............................................50
10.9
Definition of and Procedure for Reporting Medical Device Incidents..................50
10.9.1
Definition of an Incident .......................................................................50
10.9.2
Reporting of Incidents and Malfunctions..............................................51
10.9.3
Follow-up of Medical Device Incidents................................................52
10.9.4
Regulatory and Ethics Reporting Requirements for Incidents..............52
11 DATA MANAGEMENT ..................................................................................................52
11.1
Case Report Form ..................................................................................................53
11.2
Data Handling ........................................................................................................53
11.2.1
Data Queries..........................................................................................53
11.3
Processing Patient Reported Outcomes .................................................................54
11.4
External Data..........................................................................................................54
12 STATISTICAL CONSIDERATIONS AND DATA ANALYSES...................................54
12.1
Sample Size Determination....................................................................................54
12.2
Statistical Methods and Analytical Plan ................................................................55
12.2.1
Definition of Analysis Populations .......................................................55
12.2.2
Exclusion of Data from Analysis ..........................................................55
12.2.3
Demographic and Baseline Characteristics...........................................56
12.2.4
Study Drug/Product Compliance and Use of Other Therapies .............56


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12.2.5
Primary Analysis(es) .............................................................................56
12.2.6
Secondary Analysis(es) .........................................................................56
12.2.7
Safety Analysis(es)................................................................................57
12.2.8
Other Analysis(es).................................................................................57
12.2.9
Handling of Dropouts and Missing Data...............................................58
12.2.10
Interim Analysis ....................................................................................58
13 STUDY GOVERNANCE CONSIDERATIONS..............................................................58
13.1
Quality Control ......................................................................................................58
13.2
Quality Assurance..................................................................................................58
13.3
Regulatory and Ethical Considerations..................................................................59
13.3.1
Institutional Review Board/ Ethics Committee (IRB/EC) ....................59
13.3.2
Ethical Conduct of the Study.................................................................59
13.3.3
Subject Information and Consent..........................................................59
13.3.4
Subject Recruitment ..............................................................................60
13.3.5
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP ...............................................................................................60
13.4
Posting of Information on Publicly Available Clinical Trial Registers.................60
13.5
Provision of Study Results to Investigators...........................................................61
13.6
Records Retention..................................................................................................61
13.7
Conditions for Terminating the Study ...................................................................62
14 REFERENCES ..................................................................................................................62
15 APPENDICIES..................................................................................................................66
15.1
Product Usage Instructions ....................................................................................66
15.2
ABBREVIATIONS ...............................................................................................67


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List of in text tables
Table 1-1
Schedule of Activities............................................................................13
Table 3-1
Study Objectives and Endpoints............................................................18
Table 6-1
Investigational/Study Product Supplies.................................................27
Table 6-2
Sundry Items..........................................................................................28
Table 9-1
The Modified Gingival Index................................................................41
Table 9-3
Turesky Plaque Index............................................................................42
Table 15-1
Abbreviations ........................................................................................67


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1
PROTOCOL SUMMARY 
Background and Rationale
This study is designed to evaluate the gingivitis efficacy of twice daily brushing with a 0.454% 
stannous fluoride (SnF2) dentifrice over 3 weeks in a population with mild-moderate plaque-
induced gingivitis. The study will compare a marketed dentifrice containing 0.454% SnF2 with 
a negative control dentifrice. The design of this study follows very closely that of previous GSK 
CH gingivitis studies (Parkinson et al, 2014; Parkinson et al, 2015; Parkinson et al, 2018a; 
Parkinson et al, 2018b) 
Objectives and Endpoints
Objective(s)
Endpoint(s)
Primary
To evaluate the clinical efficacy of a 0.454% 
SnF2  dentifrice in reducing gingivitis (following 
dental prophylaxis), as measured by the 
Bleeding Index (BI), compared to a negative 
control dentifrice, when used twice daily for 3 
weeks.
Mean BI at Week 3
Secondary
To evaluate the clinical efficacy of a 0.454% 
SnF2 dentifrice in reducing gingivitis (following 
dental prophylaxis), as measured by the BI 
compared to a negative control dentifrice, when 
used twice daily for 2 weeks.
Mean BI at Week 2
To evaluate the clinical efficacy of a 0.454% 
SnF2 dentifrice in reducing gingivitis (following 
dental prophylaxis), as measured by the number 
of bleeding sites (NBS), compared to a negative 
control dentifrice, when used twice daily for 2 
and 3 weeks.
Mean NBS  at Week 2 and Week 3
To evaluate the clinical efficacy of a 0.454% 
SnF2 dentifrice in reducing gingival inflammation 
(following dental prophylaxis), as measured by 
the Modified Gingival Index (MGI), compared to 
a negative control dentifrice, when used twice 
daily for 2 and 3 weeks.
Mean MGI at Week 2 and Week 3
To evaluate the clinical efficacy of a 0.454% 
SnF2 dentifrice in reducing supra – gingival 
plaque formation (following dental prophylaxis) 
as measured by the Turesky modification of the 
Quigley & Hein plaque index (TPI), compared to 
a negative control dentifrice, when used twice 
daily for 2 and 3 weeks.
Mean TPI (overall and interproximal) at Week 2 
and Week 3
Safety
To assess the safety and tolerability of a 0.454% 
SnF2 dentifrice when used twice daily over 3 
weeks.
Treatment emergent adverse events


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Study Design
This will be a single center, controlled, single blind (examiner blind), randomized, stratified 
(gender and baseline mean whole mouth MGI score) two-treatment arm, parallel design, clinical 
study. Study subjects will be aged 18-65 years, non-smokers, in good general health with 
generalized mild-moderate plaque-induced gingivitis and ≥ 20 natural teeth that meet all study 
criteria at both the Screening and Baseline visits (including ≥ 40 evaluable surfaces for MGI, 
BI, and TPI).
Approximately 130 (n=65/group) subjects will be randomized to one of the study products.
This study will consist of four study visits. At Visit 1, Screening, after signing informed consent, 
subjects will undergo an Oral Soft Tissue (OST) examination, an Oral Hard Tissue (OHT) 
examination and a gross assessment of gingival health, in addition to the standard (inclusion, 
exclusion, medical history, demographics, prior/current medications) procedures to assess 
eligibility for the study. Subjects will return to site 1-28 days after the Screening Visit, for Visit 
2, Baseline. 
At the Baseline Visit, subjects will undergo, in the following order, a full OST examination 
followed by assessments of gingival inflammation (MGI), gingival bleeding (BI) and supra-
gingival plaque using the Turesky Plaque Index (TPI). Eligible subjects will be stratified based 
on gender and baseline mean whole mouth MGI score (Low: ≤ 2.00/High >2.00), to ensure a 
balance of gingivitis across both treatment groups and then randomized to study product.
Subjects with mean MGI or TPI scores outside the study range will be discontinued from the 
study at this visit. To control inter-examiner variability, the same examiner will be used 
throughout the study for all clinical assessments (MGI, TPI, BI).
All randomized subjects will then receive a full mouth dental prophylaxis (followed by flossing) 
to remove sub and supra-gingival calculus, stain, plaque and debris from the teeth. All subjects 
will enter the treatment period with no visible plaque (TPI=0). 
After all clinical assessments, subjects will be instructed to brush for 1 timed minute, in their 
usual manner, with their assigned study product and then instructed to continue using their 
assigned product twice daily (morning and evening), after which they will return to site for their 
Week 2 (Visit 3) assessments. Subjects will then continue using their assigned dentifrice for a 
further week, after which they will return for their Week 3 (Visit 4) assessments. Subjects will 
continue to record all brushing events in the diary provided, and this will be reviewed by the 
site at each study visit.
After the Week 3 visit, study closeout procedures (return of study product etc.) will take place 
and the subject may undergo an additional prophylaxis if it is deemed necessary by the examiner. 
Safety and oral tolerability of the study products will be monitored over the 3-week treatment 
period by review of reported Adverse Events and Incidents.
Study Products
Test dentifrice: Sensodyne Repair and Protect containing 0.454% SnF2 (1100 parts per 
million(ppm) fluoride) 


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Negative control dentifrice: Colgate Cavity Protection (1100ppm fluoride as sodium 
monofluorophosphate (SMFP). 
Type and Planned Number of Subjects
Approximately 150 subjects will be screened to randomize 130 to ensure 60 evaluable subjects 
per treatment group complete the entire study. 
Statistical Analysis
The primary variable is the mean BI at week 3.
The mean BI score will be analyzed using ANCOVA with treatment group, gender, and baseline 
MGI stratification (low/high) as factors and baseline score as a covariate. Adjusted means of 
the two treatments and treatment difference will be provided together with 95% CIs and P-
values.
Secondary variables are: -
Mean BI at week 2
Mean NBS at week 2 and 3
Mean MGI at week 2 and 3
Mean TPI (Overall) at week 2 and 3
Mean TPI (Interproximal areas) at week 2 and 3
Each secondary variable will be analyzed separately as per the primary variable.  For the 
analysis of MGI the stratification factor of MGI will not be included as the baseline value of 
MGI is included as a covariate.
1.1
Schedule of Activities
The schedule of activities table provides an overview of the subject visits and study procedures.  


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The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, to conduct evaluations or assessments required to protect the well-being 
of the subject.
Table 1-1
Schedule of Activities
Procedure/Assessment
Visit 1
Screening
Visit 2
Day 0
Baseline
Visit 3
Week 2 
(14± 2 days 
post V2)
Visit 4
Week 3 
(21± 2 days 
post V3)
Informed consent
X
Demographics 
X
Medical history 
X
Prior/current medications and treatments
X
OST assessment
X
X
X
X
OHT assessment
X
X
Gross assessment of gingival health1
X
Inclusion/Exclusion criteria
X
X
Subject Eligibility
X
X
Subject continuance
X
X
Concomitant medications and treatments
X
X
X
MGI assessment
X
X
X
Repeat MGI Assessment2
X
X
X
BI assessment
X
X
X
Disclose dental plaque 
X
X
X
TPI Assessment
X
X
X
Repeat TPI Assessment2
X
X
X
Stratification/Randomization
X
Dental Prophylaxis
X
Post-prophylaxis examination to confirm 
whole mouth TPI=0
X
Dispense study product, toothbrush and 
diary
X
Supervised brushing with study product
X
X
Subject brings study product, toothbrush 
and completed diary to site for compliance 
check3
X
X
Subject returns study product and diary to 
site
X
End of study dental prophylaxis (optional)
X
Adverse events/incidents4
X
X
X
X
Study conclusion
Lead-in Phase Minimum 1 day - Maximum 28 days
X
Abbreviations: 
OST
Oral soft tissue


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OHT
Oral hard tissue
MGI
Modified gingival index
BI
Bleeding index
TPI
Turesky plaque index
Footnotes: 
1. Subjects with generalized mild-moderate gingivitis, as determined by visual assessment of 
gingival health, will continue in the study.
2. At least 2 repeatability assessments should be performed each day (≥ 1 in the morning; ≥ 
1in the afternoon)
3. Visits 2-4: Adherence to Lifestyle Guidelines/Medication Requirements; 
Visits 3-4: Compliance with use of study product (visual check if returned study 
supplies/review of diary)
4. Adverse events (AEs)/incidents will be recorded from the signing of informed consent 
until 5 days after the last dose of study product.


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2
INTRODUCTION
Gingivitis is an inflammatory response to the presence of dental plaque (Kinane, 2001), which 
typically presents as redness, swelling (oedema) and/ or bleeding of the gums at the gingival 
margin surrounding the tooth. Gingivitis is a reversible condition but, if left untreated, can 
progress to the irreversible phase of periodontitis, where inflammation extends to the underlying 
tissues, periodontal ligament and alveolar bone. The resulting loss of these structures can 
eventually lead to tooth loss through destruction of the periodontal tissues supporting the tooth 
(Petersen and Ogawa, 2012). Periodontitis is reported to affect 5-20% of the world’s population 
(Petersen and Ogawa, 2012). The maintenance of good gingival health is therefore important in 
preventing gingivitis and the development of periodontal disease (Chapple et al, 2015).
Dental plaque is a soft, sticky, colourless deposit of bacteria which collects on teeth and along 
the gingival margin; it is the causative agent of gingivitis and periodontitis  (Chapple et al, 2015; 
Davies, 2008; Kinane, 2001; Silness and Löe, 1964; Theilade et al, 1966). Gingivitis develops 
when plaque elicits a local inflammatory response in the gingivae at the site of its accumulation 
(Davies, 2008; Marsh, 1992). Gingivitis is prevented and resolved through effective plaque 
control, primarily via mechanical plaque removal (i.e. toothbrushing) (Brook, 2003; Chapple et 
al, 2015; Davies, 2008; Marsh, 1992; Ower, 2003; Van der Weijden and Hioe, 2005).
Many people are unable to achieve adequate plaque control by toothbrushing alone. The effect 
of toothbrushing can be augmented by the use of dentifrice (Davies, 2008) and antimicrobial 
ingredients. Antimicrobial agents (such as metal salts, cetylpyridinium chloride and 
chlorhexidine) have been included in daily use dentifrice and mouth rinse formulations for 
many years, with a view to delivering improved plaque control and gum health benefits  
(Chapple et al, 2015). They complement mechanical plaque removal by inhibiting the growth 
of bacteria (via bacteriostatic and/or bactericidal activity)  in areas of the mouth less accessible 
to the toothbrush and by interfering with the re-colonisation of plaque bacteria (Teles and Teles, 
2009).
Stannous fluoride (SnF2) is a well-known chemotherapeutic agent which has been incorporated 
into dentifrices since the 1940s for its oral health benefits (Makin, 2013; Miller et al, 1994; Van 
Loveren, 1990a; Van Loveren, 2001). The stannous ion (Sn[II]) is a broad-spectrum 
antimicrobial agent which has been shown to reduce bacterial biomass/ virulence and inhibit 
bacterial metabolism (Archila et al, 2004; Bellamy et al, 2012; He et al, 2012; Tinanoff, 1990; 
Tinanoff, 1995). Sn [II] ions rapidly oxidize to “inactive” stannic ions (Sn [IV]) and hydrolyse 
to form insoluble tin compounds (for example, stannous hydroxide) in the presence of water 
(and saliva) and saliva-derived ions (Makin, 2013). To maximise the delivery of bioavailable 
Sn[II] ions to the oral cavity, SnF2 dentifrices are often “stabilized” by the addition of 
complexing agents or developed as low water content/anhydrous formulations.
Numerous clinical studies reported in the scientific literature demonstrate the anti-
gingivitis/anti-plaque efficacy of 0.4-0.454% SnF2 dentifrices for example, (Mallatt et al, 2007; 
Mankodi et al, 1997; Mankodi et al, 2005). GlaxoSmithKline Consumer Healthcare (GSKCH) 
has developed a ‘stabilized’ anhydrous 0.454% w/w SnF2 dentifrice and confirmed its gingivitis 
efficacy in four clinical studies (Parkinson et al, 2014; Parkinson et al, 2015; Parkinson et al, 
2018a; Parkinson et al, 2018b) in a population with mild-moderate plaque-induced gingivitis at 
timepoints ranging from 4 to 24 weeks.
The aim of the current clinical study is to evaluate the efficacy of a marketed 0.454% SnF2 
dentifrice (Sensodyne Repair and Protect, US market place product) in the treatment of 


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gingivitis (following dental prophylaxis) at earlier timepoints (over a 3-week treatment period) 
in a similar population. Efficacy will be compared to a negative control dentifrice.
2.1
Study Rationale
This study will compare a 0.454% SnF2 dentifrice (Sensodyne Repair and Protect) versus a 
negative control dentifrice. The aim of this study is to evaluate the gum health efficacy of twice 
daily brushing with a 0.454% SnF2 dentifrice over 3 weeks.
Several GSK CH studies (Parkinson et al, 2014; Parkinson et al, 2015; Parkinson et al, 2018a; 
Parkinson et al, 2018b) have previously investigated the gingival health benefits of SnF2 at 
timepoints ranging from 4 to 24 weeks, but to date there have been no GSK CH studies that 
have looked at timepoints earlier than 4 weeks for this stabilized anhydrous 0.454% SnF2 
dentifrice. There is a desire to show an improvement in gum health at earlier timepoints than 4 
weeks and it is believed that recordable gum health benefits may be feasible after 2 to 3 weeks 
of use (Löe et al, 1965). Therefore, this study is planned to investigate the efficacy of the 
dentifrice at reducing gingivitis and plaque at the earlier time points of 2 and 3 weeks.
As per the above-mentioned GSK CH studies, the main gingivitis indices that will be employed 
in this study will be the Bleeding Index (BI), number of bleeding sites (NBS), Modified 
Gingival Index (MGI) and the Turesky Plaque Index (TPI). This will be a parallel study design 
that will require subjects to use their assigned dentifrice twice daily for a maximum of 3 weeks, 
with measurements taken at 2 and 3 weeks.
This is a Phase IV study that is planned to be performed by a clinical site with experience in the 
above-mentioned gingivitis indices, and therefore a study site in the USA has been selected. 
Complete information for the Sensodyne Repair and Protect dentifrice may be found in the 
single reference safety document (SRSD), which for this study is the Investigator Brochure. 
2.2
Background
The effects of SnF2 containing dentifrices on gingivitis has been described in several clinical 
studies (Paraskevas and Van der Weijden, 2006). Perlich (Perlich et al, 1995) demonstrated 
that using an aqueous stabilized 0.454% w/w SnF2 dentifrice twice daily for 6 months resulted 
in 20.5% less gingivitis (p<0.05) and 33.4% less bleeding (p<0.05) when compared with a 
negative control dentifrice. Williams (Williams et al, 1997) reported that subjects who used a 
stabilized SnF2 dentifrice twice daily for 6 months resulted in a statistically significant 
reduction in plaque when compared to a negative control dentifrice. These results have also 
been duplicated in other similar 6-month studies (Mallatt et al, 2007; Mankodi et al, 1997; 
Mankodi et al, 2005).
However, it is well established that SnF2 reacts with water to form various stable stannous 
oxide and hydroxide species, and these stannous compounds may not be as therapeutic as the 
parent molecule. Literature evidence suggests that the largest reductions on gingivitis are 
observed following the use of “stabilized” SnF2 (Tinanoff, 1990). Stabilization of the stannous 
fluoride for the formulations was achieved by chemical methods using phosphates salts. An 
alternative approach to stabilize SnF2 is to use a non-aqueous based formulation. GSK CH has 
developed a non-aqueous SnF2 dentifrice and has confirmed its gingivitis efficacy in several 
clinical studies. GSKCH has conducted one exploratory 12 week gingivitis study (Parkinson 
et al, 2014), two 24 week gingivitis studies (Parkinson et al, 2015; Parkinson et al, 2018a), 
and one 12 week gingivitis study in a population with “blood in expectorate” as an inclusion 


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criteria (Parkinson et al, 2018b), on a stabilized 0.454% w/w SnF2 formulation. Most recently, 
a 12 week clinical trial in China showed the GSK formulation to provide reductions in BI and 
Plaque after 6 and 12 weeks (GSK Clinical Study 207014, 2017). All studies demonstrated 
statistically and clinically superior control of gingivitis (gingival bleeding and visual signs of 
gingival inflammation) and plaque compared to a fluoride only control toothpaste at 6 and 12 
weeks (Parkinson et al, 2014; Parkinson et al, 2018b) and 12 and 24 weeks (Parkinson et al, 
2015; Parkinson et al, 2018a). Study 205045 is the only study that has investigated a 4-week 
timepoint and this also showed a significant reduction in BI and MGI (TPI was not collected) 
versus a negative control.
This study is designed to investigate the efficacy of a 0.454% SnF2 dentifrice (Sensodyne 
Repair and Protect) at reducing gingivitis over a 3-week period when compared to a negative 
control dentifrice in a population with mild-moderate plaque-induced gingivitis. The design of 
this study will follow closely that of those summarized above and also recommendations from 
dental research communities and is consistent with the American Dental Association (ADA) 
guidelines for such studies (ADA, 2016).
2.3
Mechanism of Action/Indication
Stannous fluoride (SnF2) is a well-known chemotherapeutic agent, incorporated into 
dentifrices since the 1940s for its anti-caries, anti-dentin hypersensitivity and anti-plaque/anti-
gingivitis benefits (Makin, 2013; Miller et al, 1994; Van Loveren, 2001; Van Loveren, 
1990b) . 
The stannous ion (Sn [II]) is a broad-spectrum antimicrobial with bacteriostatic and 
bactericidal properties (Archila et al, 2004; Bellamy et al, 2012; He et al, 2012; Tinanoff, 
1995). It has been shown to interfere with the development and maturation of the plaque 
biofilm, inhibiting bacterial adherence and colonization of the oral surfaces, and penetrating 
the cell wall to interfere with bacterial metabolism (Tinanoff, 1990; Wilson and Pratten, 
1999) . These effects have been shown to carry through to in vivo effects on a range of 
microbial activities, resulting in anti-plaque benefits (Bacca et al, 1997; Kasturi et al, 1995; 
White et al, 1995).
The clinical anti-gingivitis efficacy of stannous fluoride in an anhydrous dentifrice format will 
be investigated in subjects with clinically diagnosed gingivitis.


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3
STUDY OBJECTIVES AND ENDPOINTS
Table 3-1
Study Objectives and Endpoints
Objective(s)
Endpoint(s)
Primary
Primary
To evaluate the clinical efficacy of a 0.454% 
SnF2  dentifrice in reducing gingivitis (following 
dental prophylaxis), as measured by the 
Bleeding Index (BI), compared to a negative 
control dentifrice, when used twice daily for 3 
weeks.
Mean BI at Week 3
Secondary
To evaluate the clinical efficacy of a 0.454% 
SnF2 dentifrice in reducing gingivitis (following 
dental prophylaxis), as measured by the BI 
compared to a negative control dentifrice, when 
used twice daily for 2 weeks.
Mean BI at Week 2 
To evaluate the clinical efficacy of a 0.454% 
SnF2 dentifrice in reducing gingivitis (following 
dental prophylaxis), as measured by the number 
of bleeding sites (NBS), compared to a negative 
control dentifrice, when used twice daily for 2 
and 3 weeks.
Mean NBS at Week 2 and Week 3
To evaluate the clinical efficacy of a 0.454% 
SnF2 dentifrice in reducing gingival inflammation 
(following dental prophylaxis), as measured by 
the Modified Gingival Index (MGI), compared to 
a negative control dentifrice, when used twice 
daily for 2 and 3 weeks.
Mean MGI at Week 2 and Week 3
To evaluate the clinical efficacy of a 0.454% 
SnF2 dentifrice in reducing supra-gingival plaque 
formation (following dental prophylaxis) as 
measured by the Turesky modification of the 
Quigley & Hein plaque index (TPI), compared to 
a negative control dentifrice, when used twice 
daily for 2 and 3 weeks.
Mean TPI (overall and interproximal) at Week 2 
and Week 3
Safety
To assess the safety and tolerability of a 0.454% 
SnF2 dentifrice when used twice daily over  3 
weeks.
Treatment emergent adverse events 
This study will be considered successful if there is a statistically significant difference in 
Bleeding index after 3 weeks of twice daily brushing with the SnF2 dentifrice compared to the 
control dentifrice and the difference is in favour of the SnF2 dentifrice.


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4
STUDY DESIGN 
4.1
Overall Design
This will be a single center, controlled, single blind (examiner blind), randomized, stratified 
(gender and baseline mean whole mouth MGI score) two-treatment arm, parallel design, clinical 
study. Study subjects will be aged 18-65 years, non-smokers in good general health with 
generalized mild-moderate plaque-induced gingivitis and ≥ 20 natural teeth that meet all study 
criteria at both the Screening and Baseline visits (including ≥ 40 evaluable surfaces for MGI, 
BI, and TPI).
Approximately 130 (n=65/group) subjects will be randomized to one of the study products.
This study consists of 4 study visits. At Visit 1, Screening, after signing informed consent, 
subjects will be assessed for eligibility based on the inclusion/exclusion criteria and will 
undergo Oral Soft and Hard Tissue (OST, OHT) assessments. 
Subjects will return between 1 and 28 days following the Screening Visit for the Visit 2, 
Baseline where they will undergo, in the following order, a full OST examination followed by 
assessments of gingival inflammation (MGI), gingival bleeding (BI) and supra-gingival plaque 
(TPI). Eligible subjects will be stratified based on gender and baseline mean whole mouth MGI 
score (Low: ≤2.00/High >2.00), to ensure a balance of gingivitis across both treatment groups 
and then randomized to study product.
All randomized subjects will receive full mouth dental prophylaxis (followed by flossing) to 
remove sub and supra-gingival calculus, stain, plaque and debris from the teeth. All subjects 
will enter the treatment period with no visible plaque (TPI=0). After all clinical assessments, 
subjects will be instructed to brush for 1 timed minute at site with their assigned study product, 
after which they will be instructed to continue using this twice daily (morning and evening) for 
2 weeks. After 2 weeks they will return to site for their Week 2 (Visit 3) assessments. They will 
then continue using their test dentifrice for a further week and will continue to record all 
brushing events in the diary provided, after which they will return for their Week 3 (Visit 4) 
assessments. All assessments will be carried out on the facial and lingual/palatal surfaces of 
each incisor, canine, pre-molar and molar, excluding third molars. To control inter-examiner 
variability, the same examiner will be used throughout the study for each clinical index. 
After the Week 3 visit, study closeout procedures (return of study product etc.) will take place 
and the subject may undergo an additional prophylaxis if it is deemed necessary by the examiner.
Adverse events and incidents will be recorded from informed consent and at the end of each 
study visit.
4.2
Rationale for Study Design
The main aim of this study is to investigate the efficacy of a 0.454% stannous fluoride 
toothpaste in reducing gingivitis compared to a negative control dentifrice, after 3 weeks of 
twice daily brushing as measured by the Bleeding Index.  The efficacy of SnF2 dentifrices has 
been demonstrated after 4, 6, 12 and 24 weeks twice daily use. Clinically relevant changes in 
gingival health are not expected earlier than 2 weeks use of a dentifrice.
This design is typical of many studies conducted to evaluate the clinical efficacy of dentifrices 
in the treatment of gingivitis. Study subjects with a pre-specified level of gingivitis are 
randomized to study product; efficacy is determined after professional dental cleaning and a 


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period of twice-daily brushing, compared to a control/comparator dentifrice. A standard 
fluoride dentifrice has been chosen as the negative control dentifrice in this study, as this is 
likely to reflect a subject’s typical oral care product use.
Healthy subjects with mild-moderate gingivitis will be included in the study population. The 
defined level of gingivitis at baseline, will help to minimize the risk of an atypical or potential 
lack of treatment response for subjects with high levels of gingivitis that may otherwise be 
managed professionally rather than solely via home use of a twice daily dentifrice. Healthy 
subjects with mild-moderate gingivitis will be stratified according to their gender and Baseline 
MGI score to ensure a balance in gingival health across all treatment groups. Gender is a known 
modifier of the initiation and outcome of conditions related to gingival health (Alam et al, 2012). 
Stratifying by MGI will facilitate evaluation of BI and MGI in low and high MGI subgroups.
The MGI and the BI are established clinical measures of gingival inflammation and gingival 
bleeding, respectively (i.e. gingival health); the TPI is an established clinical measure of 
supra-gingival plaque accumulation. To avoid inter-examiner variability, a single examiner 
will be responsible for the conduct of each of the clinical indices (MGI, BI, TPI).  To assess 
examiner reproducibility across the treatment period, repeat MGI and TPI assessments will be 
performed on selected subjects at Visits 2-4. Due to the invasive nature of the index, 
repeatability assessments are not feasible for the BI.
A parallel group design has been selected as more appropriate for this investigation. Anticipated 
differential changes in clinical variables among treatment groups could lead to carryover effects 
and an altered oral health state should a crossover design be employed. The dosage regimen of 
twice daily use (morning and evening) will be the same for each treatment group and is based 
on consumer habit and common practice within oral care clinical trials. The use of a Washout 
period prior to Baseline is not a requirement under the ADA guidelines (ADA, 2011), however 
it is recommended that subjects should not use antimicrobial mouth rinses or other dental 
products that might affect a subject’s plaque or gingivitis status. A minimum of 1 to maximum 
28 days lead-in Phase is appropriate to allow subjects to comply with study and lifestyle 
restrictions prior to Baseline Visit.
Within 1 to 28 days of Screening (Visit 1), eligible subjects will return to the site for the Baseline 
visit (Visit 2) with overnight plaque (subjects will abstain from oral hygiene for 12hours (+6 
hours; -2 hours) i.e. overnight immediately before the visit). At the Baseline visit (prior to 
randomisation), subjects will undergo, in the following order, a full OST and assessments of 
gingival inflammation (MGI), gingival bleeding (BI) and plaque disclosure followed by supra-
gingival plaque (TPI). The baseline levels of measures of gingivitis and plaque are consistent 
with previous GSKCH gingivitis studies including those investigating a sodium bicarbonate 
containing dentifrice with mean MGI 1.75-2.30 considered representative of generalised mild-
moderate gingivitis. Furthermore, a minimum of 20 permanent gradable teeth is similarly 
consistent with GSKCH gingivitis clinical studies and representative of a minimum of a 
“shortened dental arch” (Kayser, 1989) equating to anywhere between 20-28 gradable teeth 
(excluding 3rd molars) per subject. 
At Baseline Visit 2, following the clinical examinations (including initial MGI, BI & TPI 
assessments) dental prophylaxis will be performed for each subject using a standard polishing 
dental compound prophylaxis paste and periodontal instruments as required, followed by 
flossing by the clinician. Subjects teeth will then be re-disclosed using a disclosing solution to 
check for residual plaque. A second clinician will check to ensure all plaque has been removed. 
Any residual plaque remaining will be removed by the clinician as required and including dental 


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polishing with a standard polishing dental compound, sufficient to bring the subject to zero 
plaque (i.e. TPI=0). Dental prophylaxis removes all calculus and stain from the surface of the 
teeth (plaque retentive factors that could influence plaque accumulation) and ensures study 
subjects enter the treatment period with no visible plaque (TPI = 0). A dental prophylaxis is 
included as this is considered industry standard in agreement with Food and Drug 
Administration (FDA) guidelines (FDA., 2005), and  is consistent  with previous GSKCH 
gingivitis clinical studies, along with a lack of dental calculus/ staining that could otherwise act 
as plaque retentive factors for subjects participating in the clinical study.
Hormonal changes during pregnancy may affect the response of the gingival tissue to plaque 
bacteria and could impact the gingivitis efficacy measurements (Figuero et al, 2010). Therefore, 
women who are pregnant at screening will be excluded and woman who become pregnant 
during the course of the study will be discontinued. It should be noted however, that there are 
no safety concerns with pregnant women using any of the study products. 
The effects of smoking on periodontal health are well documented in the scientific literature. 
Smoking decreases blood flow within the gingival microvasculature and interferes with 
neutrophil function, suppressing the inflammatory response to dental plaque and masking the 
clinical signs of periodontal disease (Machuca et al, 2000; Obeid and Bercy, 2000). A 14-day 
experimental gingivitis model reported much less gingival bleeding in smokers compared to 
non-smokers, even though plaque levels and the composition of the oral microflora were similar 
between the two groups (Lie et al, 1998). Smokers will therefore be excluded from this 
investigation of product efficacy for the treatment of plaque-induced gingivitis.
According to International Conference on Harmonisation (ICH) guidelines [ICH, 1996], for a 
study to be classed as truly double blind, not only does the examiner (and any member of staff 
who may be involved in the dispensing of products and/or analysis of data) need to be blind to 
the treatment a subject receives, but the products under test must be identical in every way 
(color, flavour, appearance, packaging).  It can be difficult to achieve identical sensory profiles 
and visual appearance for products evaluated in oral care clinical studies. Where this is not 
possible, as in the current study, the level of blinding is described as ‘examiner-blind’.
4.3
Justification for Dose
Subjects will be instructed to dose a strip of dentifrice to cover the full brush head, and brush 
for 1 timed minute. The dosing regimen of twice daily use for 1 minute will be the same for 
each treatment and is based on consumer habit and common practice within other oral care 
clinical trials.
4.4
End of Study Definition
A subject is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities, 
Section 1.1.
The end of this study is defined as the date of last visit of the last subject in the study.


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5
STUDY POPULATION
5.1
Type and Planned Number of Subjects
Approximately 150 subjects will be screened to randomize 130 to ensure 60 evaluable subjects 
per treatment group complete the entire study. 
An enrolled subject is one who has agreed to participate in the clinical study following 
completion of the informed consent process directly, and has successfully met eligibility criteria 
to proceed beyond the screening visit and enter the Lead-In phase, as applicable for the protocol 
design. 
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 non-medical conditions should be taken into 
consideration when deciding whether a subject is suitable for this study.  
Subject eligibility to participate in the clinical study should be reviewed and documented by an 
appropriate member of the investigator’s study team before subjects are included in the study.
5.2
Inclusion Criteria
An individual must meet all the following inclusion criteria to be eligible for enrollment into 
the study:
1. Subject provision of a signed and dated informed consent document indicating that the 
subject has been informed of all pertinent aspects of the study before any assessment is 
performed.
2. Subject is male or female who, at the time of screening, is between the ages of 18-65years, 
inclusive.
3. A subject who is willing and able to comply with scheduled visits, treatment plan and 
other study procedures.
4. A subject in good general and mental health with, in the opinion of the investigator or 
medically qualified designee, no clinically significant or relevant abnormalities in medical 
history or upon oral examination, or condition, that would impact the subject’s safety, 
wellbeing or the outcome of the study, if they were to participate in the study, or affect the 
individual’s ability to understand and follow study procedures and requirements.
5. AT SCREENING (Visit 1):
a.
Subject with at least 20 natural, permanent teeth excluding 3rd molars.
b. Subjects with at least 40 evaluable surfaces.
An evaluable surface is defined as having 2/3rds of the natural tooth surface gradable 
for the selected clinical indices. The following should not be included in the evaluable 
surface count- third molars; fully crowned/extensively restored, grossly carious, 
orthodontically banded/bonded or abutment teeth; surfaces with calculus deposits 
which, in the opinion of the clinical examiner, would interfere with the baseline 
assessments of the selected clinical indices.
c.
Subject with generalized mild-moderate plaque-induced gingivitis, in the opinion of 
the clinical examiner, as confirmed by visual examinations.
6. AT BASELINE- Prior to Dental Prophylaxis (Visit 2):


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a.
Subject with ongoing hard tissue eligibility and, in the opinion of the clinical 
examiner, at least 40 evaluable surfaces.
b. Mean whole mouth MGI  ≥ 1.75 to ≤ 2.30
c.
Mean whole mouth supra-gingival TPI score ≥ 1.5
d. ≥ 20 bleeding sites 
5.3
Exclusion Criteria
An individual who meets any of the following exclusion criteria will not be eligible for 
enrollment into the study:
1. A subject who is an employee of the investigational site, either directly involved in the 
conduct of the study or a member of their immediate family; or an employee of the 
investigational site otherwise supervised by the investigator; or, a GSK CH employee 
directly involved in the conduct of the study or a member of their immediate family.
2. A subject who has participated in other studies (including non-medicinal studies) 
involving investigational product(s) within 30 days prior to study entry and/or during 
study participation.
3. A subject with, in the opinion of the investigator or medically qualified designee, an acute 
or chronic medical or psychiatric condition or laboratory abnormality 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 or medically qualified designee, would make the subject inappropriate for 
entry into this study.
4. Subjects with, in the opinion of the investigator or medically qualified designee, any 
clinically significant/relevant abnormalities in medical history or oral examination, or any 
other condition, that would affect the individual’s ability to understand and follow study 
procedures and requirements.
5. Subjects with any medical condition which, in the opinion of the investigator or medically 
qualified designee, is causing xerostomia.
6. Subjects with any medical condition which in the opinion of the investigator or medically 
qualified designee, could directly influence gingival bleeding.
7. A subject who is pregnant or intending to become pregnant over the duration of the study 
(self-reported).
8. A subject who is breastfeeding.
9. A subject with known or suspected intolerance or hypersensitivity to the study materials 
(or closely related compounds) or any of their stated ingredients. 
10. Known or suspected intolerance or hypersensitivity to the study materials (or closely 
related compounds) or any of their stated ingredients. 
11. Subjects with recent history (within the last year) of alcohol or other substance abuse.
12. Subject who is a current smoker or an ex- smoker who stopped within 6 months of 
Screening.
13. Subject who currently uses smokeless forms of tobacco (e.g. chewing tobacco, gutkha, 
pan containing tobacco, nicotine-based e-cigarettes).
14. Subjects with a severe oral condition (e.g. acute necrotizing ulcerative gingivitis or oral or 
peri-oral ulceration including herpetic lesions) that would, in the opinion of the 


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investigator, compromise study outcomes or the oral health of the subject/ examiner if 
they were to participate in the study. 
15. Presence of a tongue or lip piercing, or any other oral feature that could interfere with the 
usage of a toothbrush
16. A subject who, in the opinion of the investigator or medically qualified designee, should 
not participate in the study.
17. A subject unwilling or unable to comply with the Lifestyle Considerations described in 
this protocol. 
18. A subject that has used an anti-bacterial mouthwash (e.g. chlorhexidine) or use of any oral 
care product that in the view of the investigator could interfere with plaque formation or 
measures of gingivitis, within 14 days of the Baseline Visit.
19. Periodontal Exclusions: 
a) Subject with signs of active periodontitis.
b) Subject with gingivitis which, in the opinion of the investigator, is not expected to 
respond to treatment with an over-the-counter dentifrice.
c) A subject who is receiving or has received treatment for periodontal disease (including 
surgery) within 12 months of Screening
20. Dental Exclusions: 
a) Subject with active caries that could, in the opinion of the investigator, compromise 
study outcomes or the oral health of the subject if they were to participate in the study.
b) Subject with dentures (partial or full). 
c) Subject with an orthodontic appliance (bands, appliances or fixed/ removable 
retainers).
d) A subject who has received orthodontic therapy within 12 months of Screening
e) Subject with numerous restorations in a poor state of repair. 
f)
Subject with any dental condition (e.g. overcrowding) that could, in the opinion of the 
investigator, compromise study outcomes or the oral health of the subject if they were 
to participate in the study.
g) Subject who has had dental prophylaxis within 12 weeks of Screening
h) Subject who has had teeth bleaching within 12 weeks of Screening 
i)
A subject with high levels of extrinsic stain or calculus deposits that might interfere 
with plaque assessments.
21. Medication Exclusions
AT SCREENING (Visit 1):
a) Subject who requires antibiotics prior to dental prophylaxis or other dental procedures. 
b) Subject who is currently taking antibiotics 
c) Subject who is currently taking an anti-inflammatory medication which, in the opinion 
of the Investigator, could affect gingival condition (e.g. ibuprofen).


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c) Subject who is currently taking anti-coagulant medication which, in the opinion of the 
Investigator, could affect gingival condition (e.g. warfarin). 
d) Subject who is currently taking a systemic medication or traditional/herbal remedy 
which, in the opinion of the Investigator, could affect gingival condition (e.g. 
immunosuppressants such as cyclosporine, phenytoin, calcium channel blockers, 
aspirin therapy).
22. Medication Exclusions
AT BASELINE (Visit 2):
a) Subject who has taken antibiotics in the 14 days prior to Baseline
b) Subject who has taken an anti-inflammatory medication in the 14 days prior to 
Baseline which, in the opinion of the Investigator, could affect gingival condition (e.g. 
ibuprofen).
c) Subject who has taken anti-coagulant medication in the 14 days prior to Baseline 
which, in the opinion of the Investigator, could affect gingival condition (e.g. 
warfarin).
d) Subject who has taken a systemic medication or traditional/herbal remedy in the 14 
days prior to Baseline which, in the opinion of the Investigator, could affect gingival 
condition (e.g. immunosuppressants such as cyclosporine, phenytoin, calcium channel 
blockers, aspirin therapy).
e) Subject who has used an antibacterial dentifrice or mouth rinse in the period between 
Screening and Baseline.
23. Subject who is unwilling or unable to comply with the Lifestyle/Study Restrictions 
described in the study protocol.
24. Any subject who has previously been enrolled in this study.
25. Subjects who, in the judgement of the investigator, or medically qualified designee should 
not participate on the study.
5.4
Randomization Criteria
Subjects will be randomized into the study provided they have satisfied all subject selection 
criteria at the Baseline visit. 
5.5
Lifestyle Considerations
5.5.1
Dental Product/Treatment and Oral Hygiene Restrictions  
From Screening (Visit 1) to the Subject’s Last Study Visit

Subjects should not carry out any interproximal dental cleaning. Use of dental floss, 
toothpicks, waterpicks or inter-dental brushes is prohibited (except for the removal of 
impacted food with non-antimicrobial products only).

Subjects should not chew gum or consume any confectionery containing xylitol (e.g. 
sugar-free mints).

Subjects should delay any non-emergency dental treatment until after study 
completion (including dental prophylaxis).


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From Baseline (Visit 2) to the Subject’s Last Study Visit

Subjects should not use any other oral care products (e.g. dentifrices, toothbrushes, 
mouthrinses) than those provided during the study.
Before Clinical Efficacy Assessment Visits: Baseline (Visit 2), Week 2 (Visit 3) and Week 
3 (Visit 4)

Subjects should refrain from oral hygiene procedures for 12 hours (+6 hours, -2 hours) 
before their visit and attend the study site with overnight plaque growth.
5.5.2
Dietary Restrictions 
Before Clinical Efficacy Assessment Visits: Baseline (Visit 2), Week 2 (Visit 3) and Week 
3 (Visit 4)

Subjects must abstain from all food and drink (except water) for at least 4 hours prior 
to their scheduled assessment visits and until all assessments are complete during visit 
days. Water is permitted until 1 hour prior to their scheduled study visits. 
5.5.3
Medication and Treatment Restrictions
The following medication and treatment restrictions apply for the duration of the study:

If current/ concomitant medications/ treatments or traditional herbal ingredients/ 
treatments are used during the study, their identity, as well as their dosage and frequency, 
start and stop dates must be reported to the Investigator and recorded in the Case Report 
Form (CRF). 
For more information on concomitant medications, please refer to Section 6.8.
5.6
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomized. 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 adverse events or incidents as applicable. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be re-screened.
5.7
Sponsor’s Qualified Medical Personnel
Contact information for the sponsor's appropriately qualified medical/dental personnel for the 
study is documented in the Study Contact List located in the investigator study master file held 
at the study site.
The contact number is only to be used by investigational staff seeking advice on medical/ dental 
questions or problems in the event that the established communication pathways between the 
investigational site and the study team are not available.  
The contact number is not intended for direct use by study subjects.  To facilitate access to 
appropriately qualified medical/dental personnel on study-related medical/dental questions or 
problems, subjects will be provided with a contact card.  The contact card will provide, as a 


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minimum, protocol identifiers, the subject’s study identification number, contact information 
for the investigational site, and contact details in the event that the investigational site cannot 
be reached to provide advice on a medical question or problem identified by a healthcare 
professional other than the investigator.  
5.8
Rater/Clinical Assessor Qualifications
Clinical examiners involved in screening and efficacy assessments will be qualified dental 
professionals, registered to practice in the USA. Oral examinations to determine subject 
eligibility and all safety and efficacy assessments will be performed by appropriately trained 
clinical examiners. The clinical examiner(s) performing the MGI, BI and TPI assessments 
should have a demonstratable history of use of these indices in clinical trials.
6
INVESTIGATIONAL/STUDY PRODUCTS
For the purposes of this study, per International Conference on Harmonization (ICH) guidelines, 
and GSK policy, investigational product is defined as a pharmaceutical form of an active 
ingredient, a non-medicinal product (marketed or investigational), or a placebo, being tested or 
used as a reference (positive or negative control), in a clinical trial. This includes a product with 
a marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use. 
6.1
Investigational/Study Product Supplies
The following study products will be supplied by the Clinical Supplies Department, GSK CH:
Table 6-1
Investigational/Study Product Supplies
Investigational Products
Test Product
Negative Control Dentifrice
Product Name
Sensodyne Repair and Protect
Colgate Cavity Protection
Pack Design
Carton of 2 over-wrapped 
tubes
Carton of 2 over-wrapped 
tubes
Dispensing Details
1 carton of 2 tubes- Baseline 
visit
1 carton of 2 tubes- Baseline 
visit
Product Master 
Formulation Code 
(MFC)
Commercial Product (USA 
Market place product)
(
Commercial Product (USA 
Market place product)
Dose/Application
Full ribbon of toothpaste on 
head of toothbrush provided
Full ribbon of toothpaste on 
head of toothbrush provided
Route of 
Administration
Oral topical
Oral topical
CCI


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Usage Instructions
Subjects will brush their teeth 
for one timed minute twice a 
day (morning and evening) in 
their usual manner
Subjects will brush their teeth 
for one timed minute twice a 
day (morning and evening) in 
their usual manner
Return Requirements
All used/unused samples to be 
returned
All used/unused samples to 
be returned
Table 6-2
Sundry Items
Sundry Items to be supplied GSK CH 
Return/Disposal Details
Item
Supplied 
By
Pack Design
Dispensing 
Details
Used Samples
Unused 
Samples
Toothbrush 
(Aquafresh 
Clean 
Control)
GSK CH
Individual 
commercial 
pack – 2 per 
subject
2 at baseline for 
use with study 
product
Subject to keep or 
destroyed at site 
using site 
disposal 
procedures
Destroy at 
site using 
site disposal 
procedure
Countdown 
Timer
GSK CH
Individual 
commercial 
pack – 1 per 
subject
Baseline visit
Subject to keep or 
destroyed at site 
using site 
disposal 
procedures
Destroy at 
site using 
site disposal 
procedure
Prophylaxis 
paste
GSK CH
Baseline visit
Destroy at site 
using site 
disposal 
procedures
Destroy at 
site using 
site disposal 
procedure
Not dispensed 
to subjects; only 
used at study 
site
Non- 
antimicrobial 
dental floss  
GSK-CH
Not dispensed 
to subjects; only 
used at study 
site
Baseline visit
Destroy at site 
using site 
disposal 
procedures
Destroy at 
site using 
site disposal 
procedure
Trace Red 
Plaque 
disclosing 
solution
GSK-CH
Not dispensed 
to subjects; only 
used at study 
site
Baseline visit; Visit 
3 (wk 2); Visit 4 
(Wk 3)
Destroy at site 
using site 
disposal 
procedures
Destroy at 
site using 
site disposal 
procedure
Opaque 
recyclable 
bags
GSK-CH
Baseline visit; Visit 
3 (wk 2); Visit 4 
(Wk 3)
Destroy at site 
using site 
disposal 
procedures
Destroy at 
site using 
site disposal 
procedure
1 per subject


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Detailed instructions for the disposal of study product/study supplies for the accountability 
checks and subsequent destruction which will be provided by GSK CH during the study in time 
for study close out visit.
6.1.1
Dosage Form and Packaging
The investigational dentifrice and negative control dentifrice will be supplied to the clinical site 
by GSK CH. Both products will be supplied in commercial tubes and will be overwrapped in 
white opaque vinyl (to mask the identity and obscure any branding) with a study label affixed. 
Two tubes will be placed into a plain white carton and a study label will be applied to the carton. 
The content of the product labels will be in accordance with all applicable regulatory 
requirements and will be the responsibility of the GSK CH Global Clinical Supplies group. 
Each study label will contain, but not be limited to, protocol number, directions for use and 
storage requirements. 
Each eligible subject will receive sufficient tubes of their assigned study product to cover 
usage during the treatment period. Sundry items will be supplied in their commercial 
packaging for dispensing by study staff as required.
Care should be taken with the supplied products and their labels so that they are maintained in 
good condition.  It is important that all labels remain intact and legible for the duration of the 
study. Subjects should be instructed to not remove or deface any part of the study label.
All products supplied are for use only in this clinical study and should not be used for any other 
purpose.
6.1.2
Preparation and Dispensing 
All study products will be prepared and/or dispensed by qualified unblinded site personnel 
according to the dosage and administration instructions. 
Subjects will be assigned to products in accordance with the randomization schedule generated 
by an approved GSK CH vendor, prior to the start of the study, using validated software.
The product dispensing area will be separate from the clinical examination area. Study products 
will be dispensed in a blinded fashion and staff members involved in dispensing will not be 
involved in any safety, efficacy assessments or other aspects of the study that could be 
influenced by the knowledge of product a subject has been assigned to. An additional member 
of site staff should verify the dispensing procedures are completed accurately.
A record of product dispensing to each subject will be maintained in the dispensing log; 
completion of the dispensing procedure will be recorded in the eCRF.
6.2
Administration
Subjects will be instructed to self-administer their assigned product per the usage instructions 
provided to them along with their diaries. To help subjects understand the correct dose and 
usage instructions:

Site staff will demonstrate dispensing a full ribbon of dentifrice (along the length of 
the toothbrush head) to each eligible subject and supervise their first brushing with 
assigned test dentifrice/first diary entry at the end of Baseline, Visit 2 after all clinical 
assessments have been completed.


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
Supervised brushings with study product/diary entry will be carried out at the end of 
the Baseline (Visit 2) and Week 2 (Visit 3) visits - after all clinical assessments have 
been completed.
To facilitate compliance with dentifrice usage, subjects will use the diary provided to record 
the date/time of each brushing occasion throughout the treatment periods. They will also use 
the diary to note any additional brushings, the reasons for any missed or additional brushings, 
any issues with the dentifrice used, oral problems, adverse events and any additional 
medications taken. 
6.2.1
Medication/Dosing Errors
Study product/dosing 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. 
Such study product/dosing errors occurring to a study subject are to be captured in the eCRF.  
In the event of study product dosing error, the sponsor should be notified immediately and 
under no circumstance should this exceed 24 hours.
Study product /dosing errors are reportable irrespective of the presence of an associated AE, 
including:

study product /dosing errors involving subject exposure to any of the study products;

Potential study product/dosing errors or uses outside of what is foreseen in the 
protocol that do or do not involve the participating subject.
If a study product /dosing error is accompanied by an AE, as determined by the investigator, 
the study product /dosing error and, any associated adverse event(s) are to be captured in the 
eCRF AE form. 
6.2.2
Overdose
An overdose is a deliberate or inadvertent administration of a product at an amount higher than 
specified in the protocol.
Overdose is not likely to occur in this study.
Limited quantities of the study product(s) will be supplied, and closely monitored by the site 
for each subject.
Overdose per se is not an AE. However, any clinical sequelae of an overdose should be reported 
as an AE (and serious adverse event (SAE), if appropriate). For reporting, follow the AE and 
SAE reporting instructions.


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6.3
Investigational/Study Product Storage 
The investigator, or designee, will ensure that all study products at the site are stored in a secured 
area with controlled access under required storage conditions and in accordance with applicable 
regulatory requirements and the product label.  
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should be 
captured from the time of first product receipt throughout the study.  Even for continuous 
monitoring systems, a log or site procedure that ensures active daily 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 at site should be reported to the 
appropriate site staff upon discovery and communicated to the sponsor as soon as possible.  The 
site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Excursions from the storage requirements, 
including any actions taken, must be documented as a protocol deviation and reported to the 
Sponsor.  
Once an excursion at site is identified, the affected product (or products) must be quarantined 
and not used until the sponsor provides documentation of permission to use. Use of any of the 
affected product(s) prior to sponsor approval will be considered a protocol deviation.  
Site staff will instruct subjects on the proper storage requirements for all take-home products. 
6.4
Investigational/Study Product Accountability
All products supplied are for use only in this clinical study and should not be used for any other 
purpose.
All study products 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 products should be stored according to the instructions specified on the product 
labels. Study products are to be dispensed only to subjects enrolled in the study in accordance 
with the protocol, by authorized site staff.
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of all the product supplies. All study products will be accounted for using the 
investigational/study product accountability form/record. The investigator is responsible for 
study product accountability, reconciliation, and record maintenance. 
The accountability records must be available for inspection by the study monitor during the 
study. Monitoring of product accountability will be performed by the monitor during site visits 
and at the completion of the study. 
Study product (used and unused) will be returned to the clinical study site at Visit 4. Monitoring 
of product accountability will be performed by the study monitor during site visits and at 
completion of the study.


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6.4.1
Destruction of Investigational/Study Product Supplies 
At the end of the study, the Principal Investigator (PI) or an appropriate designee, and a 
representative of GSK CH (study monitor) will inventory all used and unused study products 
and sundry items.  The investigational/study product accountability record for returned study 
products will then be completed. All study product (used and unused) for this clinical study 
(including empty dentifrice tubes) will be returned for destruction to the GSK CH Clinical 
Supplies Department or designated vendor using the return instructions provided. Detailed 
instructions for the return of study product/study supplies for the accountability checks and 
subsequent destruction will be provided by GSK CH during the study in time for study close 
out visit.
6.5
Blinding and Allocation/Randomization
All subjects will be centrally randomized to one of the study arms using an Interactive Response 
Technology (IRT). Before the study is initiated, training, login information and directions for 
the IRT will be provided to the study site. Study products will be dispensed according to the 
instruction received through the IRT at the appropriate study visits.
Returned study products should not be re-dispensed to any subject.
The investigator’s knowledge of the product allocation should not influence the decision to 
enroll a subject or affect the order in which subjects are enrolled.
This study is described as examiner-blind (the clinical examiner will be blinded to the product 
received). The study statistician, other employees of the Sponsor (including CRS) and vendors 
acting on behalf of the sponsor, who may influence study outcomes will also be blinded to the 
product allocation. 
To ensure the examiner remains blinded throughout the study, staff involved in the preparation 
and dispensing of study products will work in a separate area. The examiner is not permitted in 
any area where study product is stored, dispensed, or in use. 
Subjects will be instructed not to remove study products from the opaque bags provided outside 
of the dispensing room, while at the study site. Dispensing staff will not be involved in any 
efficacy/safety assessment procedures during the study.  Subjects will be stratified by gender 
(male and female) and their baseline mean whole mouth MGI score (Low: ≤2.00/High >2.00).  
This will lead to 4 strata in total.
6.6
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 an electronic process.
The electronic system will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
subject’s product assignment is warranted. Subject safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a subject’s 
product assignment unless this could delay emergency treatment of the subject.
If a subject’s product assignment is unblinded, the sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and case report form, as applicable.


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Any AE associated with breaking the blind must be recorded and reported as specified in this 
protocol. The study site may also be required to inform the IRB/EC if the blind is broken. 
6.7
Compliance
Study products will be administered under the supervision of investigator site personnel.  
A diary will be supplied to promote compliance and to capture details of product use throughout 
the study period. Subjects may also record additional information such as AEs or medications 
used. Any additional details relevant to efficacy or safety should be reviewed by the investigator 
(or suitably qualified designee) with the subjects and transcribed to the eCRF as appropriate.
The number of any missed or additional applications or doses will be captured as protocol 
deviations and transcribed from the diary into the eCRF. Subjects will be re-instructed in the 
correct usage requirements and diary completion as needed.
6.8
Concomitant Medication/Treatment(s)
Any medications, treatments or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) taken during the study, from signing the informed consent, 
must be recorded in the eCRF with indication, reason for use, unit dose, daily dose, and start 
and stop dates of administration.  All subjects will be questioned about medication/treatments 
at each site visit.
Medication/treatments taken within 30 days of signing the informed consent form will be 
documented as a prior medication/treatment.  Medications/treatments taken after first dosing at 
Visit 2 will be documented as concomitant medication/treatments.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL
7.1
Subject Discontinuation/Withdrawal 
A subject may withdraw from the study at any time at his or her own request or may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, 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 product and/or premature subject 
withdrawal:

Protocol violation that may impact the subject’s safety

Withdrawal of informed consent

Subject lost to follow-up 

Unblinding of the subject 

Pregnancy
If a subject is discontinued or prematurely withdraws from the study, the reason(s) for 
discontinuation or withdrawal and the associated date must be documented in the relevant 
section(s) of the eCRF. 


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7.2
Lost to Follow up
If a subject fails to return to the site for a required study visit the site must attempt to contact 
the subject and reschedule the missed visit as soon as possible and counsel the subject on the 
importance of maintaining the assigned visit schedule and ascertain whether the subject wishes 
to and/or should continue in the study.
A subject will be considered lost to follow up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Before a subject is deemed lost to follow 
up, the investigator or designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented. If contact 
is made with the subject, the investigator should inquire about the reason for withdrawal, request 
that the subject return all products that they had been dispensed and if appropriate request that 
the subject return for a final visit and follow-up with the subject regarding any unresolved 
adverse events (AEs).
Final safety assessments may be carried out when the subject returns to the study site, at the 
investigator’s discretion, which could include an OST and OHT examination.
Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study and lost to follow up. 
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 withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
8
STUDY PROCEDURES
This section lists the procedures to be completed at each planned study visit.  The timing of 
each procedure is listed in the Schedule of Activities, Section 1.1.
Adherence to the study design requirements, including all procedures are essential and required 
for study conduct.
8.1
Visit 1/Screening
Screening procedures will be conducted by the Investigator, or suitably qualified designee.
The following procedures will be completed, and data recorded in the eCRF:

Informed consent.

Demographics, medical history, prior/current medication (including non-drug 
therapy), & smoking status. 

The oral care products the subject is currently using will be reviewed to confirm that 
they do not contain an anti-bacterial mouthwash (e.g. chlorhexidine) or use of any oral 
care product that in the view of the investigator could interfere with plaque formation 
or measures of gingivitis. Subjects will be required to bring the products to the study 


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site to enable study staff to check ingredient listings to ensure compliance with  
exclusion criteria 18. 

Oral soft tissue (OST) examination.

Oral hard tissue (OHT) examination.

Gross gingival assessment.

Inclusion/exclusion criteria.

Subject eligibility / continuance.

Adverse events & Incidents.
8.1.1
Informed Consent
The investigator, or designee, must obtain informed consent from each subject participating in 
this study after adequate explanation of the aims, methods, objectives, and potential hazards of 
the study. Two copies of the informed consent form (ICF) will be signed and dated by the 
subject, the subject will retain one copy and the other will be kept at site.
The investigator, or designee, must also explain to the subjects that they are completely free to 
refuse to enter the study or to withdraw from it at any time.  Appropriate forms for documenting 
a signed and dated consent will be provided by either the investigator or by GSK CH.
The investigator, or designee, should sign and date each copy of the ICF to confirm that the 
consent process was completed correctly after the subject has signed.  
The time the subject signed the informed consent form will also be captured on the Informed 
Consent Form as this is the point at which all Adverse Events will be captured from. The date 
and time of consent will be transcribed to the eCRF.
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. Each subject should 
be provided with a copy of the signed and dated amended consent form. The date of re-consent 
will be recorded on the eCRF.
After signing the ICF, subjects will undergo the screening assessments to confirm that they 
meet all the inclusion criteria and none of the exclusion criteria. If the subject is confirmed 
eligible by the investigator (or designee) to participate in the study the subject is considered 
enrolled in the study.
8.1.2
Demographics
The following demographic information will be recorded in the eCRF: year of birth, gender, 
ethnicity and race.
Ethnicity and race of subjects will be recorded in accordance with FDA guidance for Industry: 
Collection of Race and Ethnicity Data in Clinical Trials, 2005. This is required for this study as 
the product is marketed in the US and allows for summary of data across different clinical 
studies, and different launch markets. This aids in a better understanding of potential differences 
across ethnicities.


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8.1.3
Medical History and Prior Medication/Treatment
Details of relevant medical and surgical history (in the last 1 year), including allergies or drug 
sensitivity, will be documented in the eCRF.
Prior/current medications/treatments, including prescription and non-prescription drugs, dietary 
supplements and herbal remedies, taken in the last 30 days and prior to signing the informed 
consent form, will be documented in the eCRF.
8.1.4
Oral Examination/Assessment
Inclusion and exclusion criteria information will be documented in the eCRF. The following 
screening procedures should be carried out by a qualified dental professional:

Oral soft tissue (OHT) examination (as per Section 9.1.1).

Oral hard tissue (OST) examination (as per Section 9.1.2).

Gross assessment of gingival health (as per Section 9.1.3) The oral 
examinations/assessments should be carried out as described in Section 9. All findings 
will be recorded in the eCRF.
8.1.5
Inclusion/Exclusion Criteria
Inclusion and exclusion criteria information will be documented in the eCRF.
8.1.6
Subject Eligibility
The investigator and/or medically qualified designee will review inclusion/exclusion criteria, 
medical history, prior medications to confirm subject eligibility to participate in the clinical trial. 
This will be documented in the eCRF.
To prepare for study participation, subjects will be instructed in the Lifestyle Guidelines 
(Section 5.5) and any Concomitant Medication/Treatment(s) (Section 6.8) requirements of the 
protocol.
8.2
Study Period
8.2.1
Visit 2/Day 1 (Baseline)
Subjects will be admitted to the clinical study site 1 to 28 days after the Screening visit. The 
following procedures/ assessments will take place in the order listed below as much as possible 
and recorded in the eCRF:

Review of concomitant medications and non-drug treatments/ procedures and lifestyle 
restrictions.

Full oral soft tissue (OST) examination (Section 9.1.2).

MGI assessment (& repeatability assessment, where applicable) (Section (9.2.1).

BI assessment ( Section 9.2.2).

Plaque disclosure (Section 9.2.3).

TPI assessment (& repeatability assessment, where applicable) (Section 9.2.4).

Inclusion/exclusion criteria.

Subject eligibility / continuance.

Stratification/randomization.


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
Sub- & supra-gingival prophylaxis & flossing. 

Plaque disclosure followed by first examiner and second clinician check with residual 
plaque removal, if applicable following prophylaxis

Confirmed TPI= 0 following dental prophylaxis. 

Dispense study dentifrice, toothbrush, study instructions, diary & timer.

Supervised subject brushing at site.

Adverse events & Incidents (Section 10).
Changes in concomitant medication or non-drug treatments/procedures will be documented in 
the eCRF. 
Spontaneous reporting of adverse events and those elicited by asking subjects to respond to a 
non-leading question such as “How do you feel?” will be assessed and any AEs recorded in the 
eCRF.
8.2.2
Visit 3/Day 14 (Week 2) 
The following procedures/ assessments will take place in the order listed below as much as 
possible and recorded in the eCRF:

Collect study dentifrice, toothbrush & diary from subject.

Review of concomitant medications and non-drug treatments/ procedures, adverse 
events, incidents and lifestyle restrictions.

Compliance checks including diary review.

Subject eligibility / continuance.

Full OST examination (Section 9.1.2).

MGI assessment (& repeatability assessment, where applicable) (Section (9.2.1).

BI assessment (Section 9.2.2).

Plaque disclosure (Section 9.2.3).

TPI assessment (& repeatability assessment, where applicable) (Section 9.2.4)

Return study dentifrice, toothbrush, study instructions and diary to subject.

Supervised subject brushing at site.

Adverse events & Incidents (Section 10).
Changes in concomitant medication or non-drug treatments/procedures will be documented in 
the eCRF. 
Spontaneous reporting of adverse events and those elicited by asking subjects to respond to a 
non-leading question such as “How do you feel?” will be assessed and any AEs recorded in the 
eCRF.
8.2.3
Visit 4 /Day 21 (Week 3)
The following procedures/ assessments will take place in the order listed below as much as 
possible and recorded in the eCRF:

Collect study dentifrice, toothbrush, diary & timer (all study supplies) from subject.

Review of concomitant medications and non-drug treatments/ procedures, adverse 
events, incidents and lifestyle restrictions.

Compliance checks including diary review.


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
Subject eligibility / continuance.

Full OHT examination (Section 9.1.1).

Full OST examination (Section 9.1.2).

MGI assessment (& repeatability assessment, where applicable) (Section (9.2.1).

BI assessment ( Section 9.2.2).

Plaque disclosure (Section 9.2.3).

TPI assessment (& repeatability assessment, where applicable) (Section 9.2.4).

End of study dental prophylaxis (optional - if deemed necessary by examiner).

Adverse events & Incidents (Section 10).

Study conclusion
Changes in concomitant medication or non-drug treatments/procedures will be documented in 
the eCRF. 
Spontaneous reporting of adverse events and those elicited by asking subjects to respond to a 
non-leading question such as “How do you feel?” will be assessed and any AEs recorded in the 
eCRF.
8.2.4
Diary Review
The diary should be reviewed at every visit by the investigator, or suitably qualified designee, 
and the subject. Any subject comment captured in the diary which is considered an adverse 
event will be assessed and reported as per the defined procedure in this protocol. Adverse event 
reporting procedures are summarized in Section 10. 
Any additional comments relating to medications/treatments provided in the diary will be 
reviewed by the investigator or medically qualified designee with the subject and entered into 
the eCRF as appropriate. 
Additional and missed product applications will be considered deviations from the protocol and 
will be recorded on the Deviations Log and entered into the eCRF as appropriate.
8.2.5
Dental Prophylaxis
Randomized subjects will receive a full mouth dental prophylaxis (using conventional 
prophylaxis paste and periodontal instruments as required), followed by flossing, to remove 
sub- and supra-gingival calculus, stain, plaque and debris from the teeth. A second clinician 
will confirm all sub- and supra-gingival calculus, visible stain, plaque and debris has been 
removed (visually, and by tactile examination using a dental explorer). If necessary, 
additional dental cleaning will be carried out to achieve this. Prophylaxis may be carried out 
by different clinicians to facilitate subject flow. 
Following prophylaxis, it should be confirmed that the subject whole mouth post-prophylaxis 
TPI = 0. Completion of this procedure should be recorded in the eCRF.
8.3
Study Conclusion
The Study Conclusion page of the eCRF will be completed for all subjects whether they 
completed all study procedures or if they were discontinued from the study early.  If the subject 
discontinued early, at any point during the study, the primary reason for withdrawal should be 
recorded on the Study Conclusion page.


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If a subject has any clinically significant, study-related abnormalities or AEs at the end of the 
study, the GSK CH medical monitor (or designated representative) should be notified and, the 
subject may be asked to remain at the clinical site or be asked to return for a follow-up visit to 
ensure any issue is resolved or deemed not clinically significant.
8.4
End of Study Optional Prophylaxis
Subjects who, in the opinion of the clinical examiner, would benefit from dental prophylaxis 
following their participation in the study will be offered full mouth dental prophylaxis (using 
conventional prophylaxis paste and periodontal instruments as required) on completion of all 
clinical assessments. Prophylaxis may be carried out by different, appropriately qualified 
clinicians to facilitate subject flow.
8.5
Follow-up Visit
The study site may contact a subject to follow up an AE post-study completion/withdrawal 
and, in some circumstances, request they return to the site for additional follow-up visits (final 
safety assessments). If needed, additional examinations may be carried out at such visits. Any 
follow-up details and updates/changes on AEs will be recorded in the eCRF.
9
STUDY 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 complete an assessment.  
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 (or 
designee) will document the reason for the missed assessment as a protocol deviation 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 Sponsor must be informed of any missed assessments in a 
timely manner.
9.1
Screening Assessments
Screening assessments will be performed by appropriately trained staff/clinical examiners at 
the times, and in the order, defined in the Study Procedures section of this protocol. A single 
examiner will be responsible for the conduct of the clinical measures of gingivitis/ plaque 
accumulation for the duration of the study. 
Eligible tooth assessments will be accomplished by oral examination and will evaluate 
dentition exclusions along with a gross gingival assessment in relation to the general dentition 
inclusion/ exclusion criteria. Assessments will be carried out by the investigator, or qualified 
designee, against the inclusion/ exclusion criteria. Ineligible subjects will not be re-screened. 
9.1.1
Oral Hard Tissue (OHT) Assessment
Examination of the oral hard tissues (all facial, lingual/ palatal, mesial/distal and occlusal 
surfaces) will be accomplished by direct observation, using retraction aids as appropriate. The 
presence of restorations (for example, amalgams, composites, veneers, crowns, bridges, 
implants), carious lesions, non-carious hard tissue loss (abrasion, attrition, abfraction and 
erosion) and any other hard tissue irregularity (for example, fractures, staining) will be recorded. 


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Observations will be listed as either absent or present, and conditions noted as present will be 
described in the eCRF.  Any abnormality or worsening of a pre-existing condition observed by 
the clinical examiner or reported by the subject from the OST examination carried out at 
Screening will be recorded as an AE. Findings from this Screening examination will be used to 
determine subject eligibility. 
In addition to the to the OHT, the presence of partial/full dentures, fixed or removable 
orthodontic braces/bands and fixed orthodontic retainers will also be recorded as part of the 
inclusion and exclusion criteria.
9.1.2
Oral Soft (OST) Assessment
Where possible, this procedure should be conducted by a single dental examiner or clinically 
qualified designee. The examination will be accomplished throughout the study 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, tonsillar area, pharyngeal area, tongue, sublingual area, 
submandibular area and salivary glands.
The results of the examination will be recorded in the eCRF as either normal or abnormal, 
with details of any abnormalities.  Any abnormality or worsening of a pre-existing condition 
observed by the clinical examiner or reported by the subject from the OST examination 
carried out at Screening will be recorded as an AE. 
Findings from this examination performed at the Screening Visit will be used to determine 
subject eligibility.
9.1.3
Gross Assessment of Gingival Health
Visual assessment of gingival health will be performed to record the presence/absence of 
generalized mild-moderate plaque-induced gingivitis as per the inclusion criteria.  (MGI/BI will 
not be recorded for this assessment).
Findings from this examination performed at the Screening Visit will be used to determine 
subject eligibility.
9.2
Efficacy Assessments
The following clinical efficacy assessments will be performed by a single, appropriately 
trained clinical examiner (at the times and in the order defined in the Study Procedures, 
Section 8), in the same room (with consistent light levels) for the duration of the study, to 
standardize assessment conditions.
An evaluable tooth surface is defined as having 2/3rd of the natural tooth surface gradable for 
the selected clinical indices. Gingivitis or plaque accumulation associated with third molars, 
fully crowned/extensively restored, grossly carious or abutment teeth will not be assessed. In 
addition, surfaces with calculus deposits which, in the opinion of the clinical examiner, would 
interfere with the baseline assessments of the selected clinical indices, will not be assessed.
9.2.1
Modified Gingival Index (MGI)
The MGI is a non-invasive modification of the original GI (Löe and Silness, 1963) which 
focuses on the visual symptoms of gingivitis (redness, texture, edema) (Lobene, 1986) . The 


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MGI will be assessed for the facial and lingual/palatal gingiva of all evaluable teeth, four sites 
per tooth (facial surface - papilla and margin; lingual/palatal surface - papilla and margin). 
The MGI scoring system will be as described in Table 9-1 and will be assessed by the same 
examiner on all evaluable teeth at Visit 2 (Baseline), Visit 3 (Wk 2) and Visit 4 (Wk 3). 
Table 9-1
The Modified Gingival Index
Score
Description 
0
Absence of inflammation
1
Mild inflammation: slight change in colour, little change in texture of any 
portion of the marginal or papillary gingival unit
2
Mild inflammation: criteria as [1] but involving the entire marginal or papillary 
gingival unit
3
Moderate inflammation: glazing, redness, edema, and/or hypertrophy of the 
marginal or papillary gingival unit 
4
Severe inflammation: marked redness, edema and/or hypertrophy of the 
marginal or papillary gingival unit, spontaneous bleeding, congestion, or 
ulceration
9.2.2
Bleeding Index (BI)
Gingival bleeding will be assessed as a measure of gingival health for facial and 
lingual/palatal gingiva of all evaluable teeth, six sites per tooth (mesiobuccal, buccal, 
distobuccal, mesiolingual/palatal, lingual/palatal and distolingual/palatal), using the Bleeding 
Index (BI) (Saxton and Van der Ouderaa, 1989).
To perform the assessment, a round-end probe (for example, a CPITN probe [CPITN = 
Community Periodontal Index of Treatment Needs]) is inserted approximately 1mm into the 
gingival sulcus (at approximately 60 degrees) and moved around the tooth, from the distal 
interproximal area to the mesial interproximal area, gently stretching the gingival epithelium. 
Contact with the tooth surface will be avoided. Gingival bleeding is assessed 30 secs after 
probing. Assessments will be performed one quadrant at a time; BI scores will be recorded 
before moving to the next quadrant. The scoring system is described in Table 9-2. Sites with a 
score of 1 or 2 will be classified as ‘bleeding’ sites.  The BI will be assessed by the same 
examiner on all evaluable teeth at Visit 2 (Baseline), Visit 3 (Wk 2) and Visit 4 (Wk 3). 
Table 9-2
The Bleeding Index (BI)
Score
Description 
0
Absence of bleeding on probing
1
Bleeding observed within 30 seconds of probing
2
Bleeding observed immediately on probing
9.2.3
Plaque Disclosure
Dental plaque is colorless and so is usually disclosed (‘stained’) prior to assessment. The 
disclosing solution will be used according to the manufacturer’s instructions. 


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
At the request of the subject, the clinician may apply a thin layer of petroleum jelly to 
the subject’s lips, as a barrier to help minimize staining by the disclosing solution. 
Care should be taken to ensure no petroleum jelly comes into contact with the labial 
surfaces of the anterior teeth as this could impact clinical assessments in this region.

The subject will rinse their mouth with 10 mL tap water for 10 seconds to remove any 
food debris and expectorate.

The clinician will then apply the Plaque disclosing solution as per the label 
instructions. Care will be taken not to dislodge the plaque during this process. The 
subject will then rinse with 10 mL tap water for 10 seconds and expectorate to remove 
excess solution.
Plaque may be redisclosed between the TPI and repeat assessments at the discretion of the 
clinical examiner. 
9.2.4
Turesky Plaque Index (TPI)
Supra-gingival plaque will be assessed on the facial and lingual surfaces of the teeth using the 
TPI (Lobene et al, 1982; Turesky et al, 1970). Third molars can be included in the assessment 
if, as a result tooth loss, they are functioning as second molars and gradable for TPI. 
Each tooth surface is divided into 3 areas; three scores are recorded facially (mesiofacial, 
facial, distofacial) and three scores lingually (mesiolingual, lingual and distolingual) 
generating a total of six scores per tooth. The plaque will be disclosed (as described in Section 
9.2.3) and scored for each site as follows.
Table 9-3
Turesky Plaque Index
Score
Description 
0
No plaque
1
Separate flecks of plaque at the cervical margin 
2
Thin continuous band of plaque (up to 1 mm) at the cervical margin 
3
Band of plaque wider than 1 mm but covering < 1/3 of the tooth surface
4
Plaque covering ≥ 1/3 but < 2/3 of the tooth surface
5
Plaque covering ≥ 2/3 of the tooth surface
9.2.5
Repeatability Assessments
The clinical examiner selected for this study will have demonstrated their ability to replicate 
their own scores (intra-examiner repeatability) on a tooth site-by-tooth site basis in previous 
studies and/or calibration exercises. Repeat MGI and TPI assessments will be performed by 
the clinical examiner at Visits 2 - 4. At least 2 repeat assessments should be performed for 
each index on each clinical assessment day (≥1 in the morning; ≥1 in the afternoon). ‘Repeat’ 
subjects will be selected at random from those in attendance. Different subjects can be used 
for repeat MGI and TPI assessments. 
There should be a delay of at least 10 minutes between original and repeat assessments for a 
given subject and ideally separated by another subject. No other procedure on the subject 


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should be carried out between the first and the repeat assessment. Where possible, the clinical 
examiner should assess a different subject in the intervening period.
Scores from the first assessment must not be visible to the examiner/scribe when the repeat 
assessment is carried out.
9.3
Safety and Other Assessments
The following safety assessments will be performed by appropriately trained staff/clinical 
examiners, at the times and in the order defined in the Study Procedures section of this protocol.  
9.3.1
Oral Hard Tissue Examination (OHT)
 Carried out as described in Section 9.1.1.
Any change observed by the clinical examiner or reported by the subject from Screening will 
be recorded as an AE.
9.3.2
Oral Soft Tissue Examination (OST)
Carried out as described in Section 9.1.2.
Any change observed by the clinical examiner or reported by the subject from Screening will 
be recorded as an AE.
10
ADVERSE EVENT AND SERIOUS ADVERSE EVENTS
10.1
Definition of an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study subject, temporally associated 
with the use of a study product including any washout or lead-in product (or medical device), 
whether or not considered related to the study product, including any washout or lead-in 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 product including any washout or lead-in product (or medical device).
Events Meeting the AE Definition:  

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g. ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., 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 product 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.


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
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
product or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE. 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 if they fulfill the definition of an AE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE if they fulfill the definition of an AE. Also, "lack of efficacy" or 
"failure of expected pharmacological action" constitutes an AE.
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. 

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. 
10.2
Definition of a Serious Adverse Event (SAE)
A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse 
outcome is serious. 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 subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe;

Requires inpatient hospitalization or prolongation of existing hospitalization 

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 


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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 (e.g. 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 
may jeopardize the subject 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.
Note: Classification of an AE as ‘serious’ is based on the outcome of the event and is a factor 
in determining reporting requirements.
10.3
Reporting of Adverse Events
10.3.1
Reporting Period 
All AEs, and therefore all SAEs will be collected immediately after a subject consents to 
participate in the study by the completion (signature) of the ICF and until 5 days following last 
administration of the study product (or last procedure). 
Medical occurrences that began before obtaining informed consent will be recorded in the 
Medical History/Current Medical Conditions section of the eCRF not the AE section.
Details recorded by the subject on a diary or similar document that meet the definition of an AE 
must also be discussed with the subjects and transcribed in the AE section of the eCRF. 
10.4
Reporting Procedures
The investigator and any designees are responsible for detecting, documenting and reporting 
events that meet the definition of an AE and remain responsible for following up on AEs that 
are serious, considered related to the study product(s), participation in the study, or a study 
procedure, or that caused the subject to discontinue the study product or study. 


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The investigator (or medically qualified designee) 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 a SAE.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
When an AE occurs, it is the responsibility of the investigator (or medically qualified designee) 
to review all documentation (e.g. 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 in the 
eCRF and all details relating to an SAE in the paper SAE Form provided.
It is not acceptable for the investigator (or medically qualified designee) to send photocopies 
of the subject’s medical records to GSK CH in lieu of completion of the AE eCRF page/SAE 
form.
There may be instances when copies of medical records for certain cases are requested by GSK 
CH.  In this instance, all subject identifiers, except for the subject number, will be redacted on 
the copies of the medical records prior to submission to GSK CH.
The investigator (or medically qualified designee) will attempt to establish a diagnosis of the 
event based on signs, symptoms, and/or other clinical information.  The diagnosis will be the 
documented as the AE/SAE where known and not the individual signs/symptoms. (e.g. upper 
respiratory tract infection, seasonal allergy, etc. instead of runny nose).
AEs elicited by the investigator (or medically qualified designee) in a standard manner at the 
study visits should also be recorded in the AE section of the eCRF and/or using the SAE form 
(subject to the classification of the AE). Care will be taken not to introduce bias when 
questioning a subject about any changes in their health. Open-ended and non-leading verbal 
questioning should be used.
10.4.1
Reporting of an Adverse Event
All AEs will be reported on the AE page of the eCRF 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 eCRF.  
Where the same data are collected, the AE eCRF page and the SAE form must be completed in 
a consistent manner.  For example, the same AE term should be used on both.  AEs should be 
reported using concise medical terminology on the eCRF as well as on the form for collection 
of SAE information.
10.4.2
Reporting of a Serious Adverse Event
In addition to recording the details of each AE on the AE eCRF page, an SAE form should be 
completed, as fully as possible. Hard copies of the ‘paper’ SAE form will be provided in the 
investigator study master file. Original SAE forms will be retained in the investigator study 
master file.
It is essential to enter the following information: 

Protocol and subject identifiers

Subject demography


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
Description of events, with diagnosis if available

Investigator opinion of relationship to study product (or study procedure, if appropriate)

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 in relation to the study product

Outcome if known
The SAE form, completed as fully as possible, must be scanned and 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.
10.5
Evaluating Adverse Events 
10.5.1
Assessment of Intensity
The investigator or medically qualified designee will make an assessment of intensity for each 
AE 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 should not be confused with an SAE. Severe is a 
category utilized for rating the intensity of an event; and both non-serious AEs and SAEs can 
be assessed as severe. For example, a headache may be severe (interferes significantly with the 
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subject's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above. An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe.
10.5.2
Assessment of Causality
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. For each AE (serious and non-serious), the investigator (or medically qualified 
designee) must provide an assessment of causality on the AE CRF page and the SAE form 
(subject to the classification of the AE). The investigator will also document in the medical 
notes that he/she has reviewed the AE and assessed causality, where 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 
disease(s), concomitant therapy, other risk factors, and the temporal relationship of the event to 
the study product will be considered and investigated.
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.
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 CH. 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. 
10.6
Follow-up of 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 (serious and non-serious) 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 CH to elucidate 
as fully as possible the nature and/or causality of the AE. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals.
New or updated information will be recorded on the AE CRF page and on the SAE form (subject 
to the classification of the AE).


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The investigator will submit any updated SAE data to GSK CH within 24 hours of receipt of 
the information.
Investigators are not obliged to actively seek AEs in former subjects.  However, if the 
investigator learns of a SAE, including death, at any time after a subject has been discharged 
from the study, and considers the event reasonably related to the study product or study 
participation, the investigator will promptly notify GSK CH 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 CH within the designated reporting 
time frames.
10.7
Withdrawal Due to an Adverse Event 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, according 
to the definition of an 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.
10.7.1
Sponsor’s Reporting Requirements to Regulatory Authorities and 
Ethics Committees
GSK CH 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 CH is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects are met.
GSK CH will comply with country specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/EC and investigators.
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 e.g. summary or listing of SAE from the sponsor will review and then file it 
along with the Investigator’s Brochure in the investigator study master file, and will notify the 
IRB/IEC, if appropriate according to local requirements.
10.8
Pregnancy
10.8.1
Time Period for Collecting Pregnancy Information
Pregnancy information will be collected on all pregnancies reported while a female subject is 
participating in the study from the signing of informed consent until 5 days after last 
administration of study product.
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10.8.2
Action to be Taken if Pregnancy Occurs
The investigator will record pregnancy information on the appropriate form scan 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 pregnancy form to the Case 
Management 
Group, 
Global 
Clinical 
Safety 
and 
Pharmacovigilance 
mailbox 
. Original pregnancy information forms will be retained in the 
investigator study master file. 
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.
While pregnancy itself is not considered to be an AE, abnormal pregnancy outcomes (e.g. 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are, and 
should be recorded as an SAE.
Any female subject who becomes pregnant while participating will discontinue study treatment 
and be withdrawn from the study.
10.9
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 toothbrush (Class 1 Medical Device) supplied to all subjects for use at site and 
throughout the treatment period.
10.9.1
 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 
which, directly or indirectly, might lead to or might have led to the death of a subject/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
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
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 subject, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse.

A subject’s study treatment is interrupted or compromised by a medical device failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A subject’s health deteriorates due to medical device failure.
10.9.2
Reporting of Incidents and Malfunctions
All incidents must be reported to GSK CH immediately and under no circumstance should 
this exceed 24 hours 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, if 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 
(serious and non-serious), the appropriate AE CRF page and 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.
The completed Incident Report Form should be scanned and 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 immediately and under no circumstance should this exceed 24 hours after 
study site personnel learn of the event. If there is an SAE, the completed SAE form 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 
be retained in the investigator study master file. 
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):
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
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 
10.9.3
Follow-up of Medical Device Incidents
Medical device incidents involving an AE will be followed and reported in the same manner as 
other AEs. This applies to all subjects, including those who discontinue study product or are 
withdrawn from 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 Incident Report form 
with all changes signed and dated by the investigator.
10.9.4
Regulatory and Ethics Reporting Requirements for Incidents
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 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 (e.g. the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of incidents to the IRB/IEC.
11
DATA MANAGEMENT
As used in this protocol, the term CRF is understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method. 
For this study, subject data will be entered into an electronic CRF (eCRF), using a validated 
system. Data relating to SAEs, pregnancy and incidents will also be collected on paper forms.
The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The source documents (e.g. hospital records, clinical and office charts, laboratory notes, 
memoranda, subject diaries, questionnaires, evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files and records kept at the pharmacy, at the laboratory and at 
the medico-technical departments involved in the clinical study) which contain the source of 
data recorded in the CRF should be specified.  The diary can be used as a source document at 
the discretion of data management.


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Each subject will be assigned and identified by a unique Screening Subject Number. Any 
reference made to an individual subject within the study must be done using their unique 
Screening Subject Number.
11.1
Case Report Form
A CRF is a printed, optical, or electronic document designed to record the protocol required 
information to be reported to the sponsor on each trial subject.
For each subject who has given informed consent/assent the CRF must be completed and signed 
by the Principal Investigator (or authorized designee) to certify that the data are complete and 
correct.  The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
Management of clinical data will be performed in accordance with Third Party BDM Vendor 
applicable standards and data cleaning procedures with oversight by GSK CH to ensure 
integrity of the data, for example, to remove errors and inconsistencies in the data. 
To protect the privacy of subjects, no Personal Information (PI) (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 as applicable at the 
completion of the study. 
11.2
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 Medical Dictionary for Regulatory Activities (MedDRA) 
and any concomitant medications terms (if applicable) using an internal validated medication 
dictionary, GSKDrug.  
11.2.1
Data Queries
Programmed edit checks will be generated automatically, as the data are being entered into the 
system. Reports and listings on the CRF data will also be run, 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 (AEs and Drugs or concomitant 
medication) appropriately. 
The study monitor will perform ongoing review the of the CRFs in accordance with the 
monitoring plan, to confirm that data entered into the CRF by authorized site personnel are 
accurate, complete, and verifiable from source documents; that the safety and rights of 


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participants are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.
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.
11.3
Processing Patient Reported Outcomes
Paper based patient reported outcome (PRO) data may be collected from a diary, questionnaire, 
or other specified document, etc. and entered into the data management system (DMS).  
Electronic Patient reported outcome (ePRO) data may be collected using electronic devices and 
transferred electronically to GSKCH or Third-party DM vendor.
All PRO source data should be reviewed by the study staff and the study monitor to ensure 
accurate transcription of data and that any potential AEs or concomitant medications reported 
on these documents are discussed with the subject and transcribed accurately to the CRF and/or 
DMS.  PROs that are classed as source data will be retained by the investigator and true/certified 
copies may be sent to a designated vendor or GSK CH as required.
To protect the privacy of subjects, no Personal Information (PI) (including the subject's name 
or initials or birth date) is to be recorded on any PRO/ePRO that will be forwarded to GSK CH 
or Third-Party Vendor.
11.4
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 quality control process will be 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 match before Clinical 
Database Freeze (locking of the database) can occur.
12
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
12.1
Sample Size Determination
A sufficient number of healthy subjects will be screened to randomize approximately 130 
subjects (65 per treatment group) to ensure 60 evaluable subjects per treatment complete the 
entire study. 


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The primary objective for this study is to evaluate the clinical efficacy of a 0.454% SnF2  
dentifrice in reducing gingivitis (following dental prophylaxis), as measured by the Bleeding 
Index (BI), compared to a negative control dentifrice, when used twice daily for 3 weeks. 
With 60 evaluable subjects per treatment group, it should be possible to detect a 0.1 difference 
in BI sd=0.17 (Parkinson et al, 2018b) with 90% power and a two sided 5% significance level.  
This difference would approximately represent a 23% difference between treatment groups.
This estimate will allow detection of a 5% difference in a key secondary variable MGI with 
90% power.
12.2
Statistical Methods and Analytical Plan
Additional details of the proposed statistical analysis will be documented in the Statistical 
Report and Analysis Plan (RAP), which will be written following finalization of the protocol 
and prior to study unblinding (release of randomization codes). 
Treatment comparisons will be tested under the null hypothesis:
H0: there is no treatment difference, versus the following alternate hypothesis.
H1: there is a treatment difference.
12.2.1
Definition of Analysis Populations
All assessments of safety will be based on the Safety population. The Safety population will 
comprise all randomized subjects who receive at least one dose of the study product. This 
population will be based on the product the subject actually received.
The primary population for efficacy assessment will be the modified intent-to-treat (m-ITT) 
population, defined as all subjects who are randomized, received at least one dose of the study 
treatments and provided at least one post-baseline assessment of efficacy. All m-ITT population 
summaries and analyses will be presented according to the treatment randomized.
The per protocol (PP) population is defined as all subjects in the m-ITT population who have 
at least one assessment of efficacy considered unaffected by protocol violations.
The Repeatability population is defined as all subjects who have a repeat clinical assessment of 
efficacy (R) at any visit.  There will be a separate population for repeat Plaque assessment and 
repeat MGI assessment.
12.2.2
Exclusion of Data from Analysis 
Exclusion of any data from the analyses will be determined during a Blinded Data Review 
(BDR) Meeting prior to database lock. Any reasons for exclusion from an analysis population 
will be listed, if applicable.
A PP analysis will be performed only on the primary variable (BI score) if there is more than 
10% difference in the number of subjects between the PP and m-ITT populations.  A decision 
on whether a PP analysis will be performed will be made prior to study unblinding (release of 
the randomization codes).


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Any repeat clinical data collected for the repeatability assessment will only be used to assess 
repeatability.  The main assessment of efficacy will be based on the initial assessment.
12.2.3
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 and baseline characteristics. Demographic and baseline 
characteristics will be summarized by treatment group for the Safety and mITT populations and 
the PP population if a PP analysis is performed.
12.2.4
Study Drug/Product Compliance and Use of Other Therapies
12.2.4.1 Study Drug/Product Compliance
The number of brushings and compliance rate will be summarized by treatment group between 
treatment visits and across the whole duration.
Compliance will be defined as :-
100 x (number of brushings)/(2x(visitn  - visitn-1);
12.2.4.2 Prior and Concomitant Medications
Prior medications, concomitant medications and significant non-drug therapies taken during the 
study will be listed for the Safety population.
12.2.5
Primary Analysis(es) 
The Primary efficacy variable is the mean BI at week 3.
The whole mouth means BI score for each subject will be derived from the total BI score divided 
by the number of tooth sites scored.  
The BI score will be analyzed using analysis of covariance (ANCOVA) with treatment group, 
gender, and baseline MGI stratification as factors and baseline score as a covariate. Adjusted 
means of the two treatments and the treatment difference will be provided together with 95%CI 
and P-values and percent difference between treatment groups.
The assumption of normality and homogeneity of variance in the ANCOVA model will be 
investigated. Violation of this assumption will be overcome using a suitable data transformation 
or a non-parametric technique (e.g. Van Elteren test).
12.2.6
Secondary Analysis(es)
Secondary variables are: -
Mean BI at week 2
Mean NBS at week 2 and 3
Mean MGI at week 2 and 3
Mean TPI (Overall) at week 2 and 3
Mean TPI (Interproximal areas) at week 2 and 3


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Each variable will be calculated separately in a similar manner to the primary variable in that 
the whole mouth average will be calculated based on the total mouth score divided by the 
number of tooth sites assessed.  The number of bleeding sites is derived from the BI Index 
where a bleeding site is a site scored as a 1 or 2.  For interproximal plaque only the relevant 
sites will be used.
Each secondary variable will be analyzed separately as per the primary variable.  For the 
analysis of MGI the stratification factor of MGI will not be included as the baseline value of 
MGI is included as a covariate.
The assumption of normality and homogeneity of variance in the ANCOVA model will be 
investigated. Violation of this assumption will be overcome using a suitable data transformation 
or a non-parametric technique (e.g. Van Elteren test).
12.2.7
Safety Analysis(es)
Safety variables will focus on: -
Exposure
AEs 
OST 
Incidents 
All AEs will be coded using MedDRA. AEs will be categorised as oral and non-oral by the 
primary investigator. Treatment-emergent adverse events (Oral AEs as well as all AEs) will be 
associated with the most recent treatment received. The number of AEs and number of subjects 
with AEs will be listed and tabulated by treatment. The results of OST exams will be tabulated. 
Incidents will be listed. 
Exposure to treatment is covered under treatment compliance and the number of brushings.
12.2.8
Other Analysis(es)
12.2.8.1 Repeatability assessment
The repeat dental assessments (MGI and TPI) will be compared to the original assessments and 
the repeat assessments will not be used in any efficacy analyses. The first and repeat 
assessments on each tooth site will be cross tabulated. A weighted Kappa coefficient (κ), along 
with the 95% CI will be calculated to assess the intra-examiner reliability. Fleiss-Cohen 
weighted kappa will be calculated for the repeatability analysis. Reliability will be deemed 

Excellent if κ > 0.75

Fair to good if 0.4 ≤ κ ≤ 0.75

Poor if κ <0.4
This analysis will be conducted using the Repeatability population.


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12.2.9
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.
12.2.10
Interim Analysis 
No interim analysis is planned for this study
13
STUDY GOVERNANCE CONSIDERATIONS
13.1
Quality Control 
In accordance with applicable regulations including GCP, and GSK CH procedures, GSK CH 
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 CH 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 CH 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.
13.2
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK CH 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 


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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.
13.3
Regulatory and Ethical Considerations
13.3.1
Institutional Review Board/ Ethics Committee (IRB/EC)
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.
13.3.2
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), 
International Ethical Guidelines for Health-Related Research Involving Humans (Council for 
International Organizations of Medical Sciences, 2016), guidelines for GCP (ICH 1996 and 
revision 2), and the Declaration of Helsinki (World Medical Association 2013). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws.
13.3.3
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.


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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. 
Whenever consent is obtained from a subject’s legally acceptable representative, the subject’s 
assent (affirmative agreement) must subsequently be obtained when the subject has the capacity 
to provide assent, as determined by the IRB/EC.  If the investigator determines that a subject’s 
decisional capacity is so limited that he or she cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
subject’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study subject does not provide his or her own consent, the source documents 
must record why the subject did not provide consent (e.g. minor, decisional impaired adult), 
how the investigator determined that the person signing the consent was the subject’s legally 
acceptable representative, the consent signer’s relationship to the study subject (e.g. parent, 
spouse), and that the subject’s assent was obtained or waived.  If assent is obtained verbally, it 
must be documented in the source documents.
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.
13.3.4
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. 
13.3.5
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP 
Within 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. 
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.
13.4
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 CH processes.


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GSK intends to make anonymized subject-level data from this trial available to external 
researchers for scientific analyses or to conduct further research that can help advance medical 
science or improve patient care. This helps ensure the data provided by trial participants are 
used to maximum effect in the creation of knowledge and understanding
13.5
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 CH site or other mutually-agreeable location.
GSK CH 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 CH Policy.
A manuscript will be progressed for publication in the scientific literature if the results provide 
important scientific or medical knowledge.
13.6
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 CH audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of these records 
can be maintained in a format other than hard copy (e.g. microfiche, scanned, electronic); 
however, caution needs to be exercised before such action is taken. 
The investigator must ensure that all reproductions are legible and are a true and accurate copy 
of the original and meet accessibility and retrieval standards, including re-generating a hard 
copy, if required.  Furthermore, the investigator must ensure there is an acceptable back-up of 
these reproductions and that an acceptable quality control process exists for making these 
reproductions.
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) 
or 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 
CH standards/procedures, and/or institutional requirements.  


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No study document should be destroyed without a prior written agreement between GSK CH 
and the investigator. The investigator must notify GSK CH 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.
13.7
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 study product safety problems, or at the discretion of GSK 
CH.  In addition, GSK CH retains the right to discontinue development of stannous fluoride 
dentifrices at any time. 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 eCRFs 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.
14
REFERENCES
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. Contraceptive 
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ICH Topic E6 (R2) Guideline for Good Clinical Practice, Nov 2016.
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ADA. Adjunctive dental therapies for the reduction of plaque nad gingivitis. 2011.
ADA. Chemotherapeutic products for control of gingivitis. 2016.
Alam MN, Mishra P, Chandrasekaran SJIJBAMR. Gender basis of periodontal diseases. 
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Archila L, Bartizek RD, Winston JL, et al. The comparative efficacy of stabilized stannous 
fluoride/sodium hexametaphosphate dentifrice and sodium fluoride/triclosan/copolymer 
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periodontology. 2004;75(12):1592-9.
Bacca L, Leusch M, Lanzalaco A, et al. A comparison of intraoral antimicrobial effects of 
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Bellamy P, Boulding A, Farmer S, et al. Randomized digital plaque imaging trial evaluating 
plaque inhibition efficacy of a novel stabilized stannous fluoride dentifrice compared with an 
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Brook I. Microbiology and management of periodontal infections. General dentistry. 
2003;51(5):424-8.
Chapple IL, Van der Weijden F, Doerfer C, et al. Primary prevention of periodontitis: Managing 
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Davies RM. Toothpaste in the control of plaque/gingivitis and periodontitis. Periodontology 
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Figuero E, Carrillo‐de‐Albornoz A, Herrera D, et al. Gingival changes during pregnancy: I. 
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GSK Clinical Study 207014. A clinical study investigating the gingivitis efficacy of a stannous 
fluoride dentifrice in a chinese population. 2017.
He T, Barker ML, Goyal CR, et al. Anti-gingivitis effects of a novel 0.454% stabilized stannous 
fluoride dentifrice relative to a positive control. American journal of dentistry. 2012;25(3):136.
Kasturi R, White D, Lanzalaco A, et al. Effects of nine weeks' use of a new stabilized stannous 
fluoride dentifrice on intrinsic plaque virulence expressed as acidogenicity and regrowth: A 
modified pgrm study. 1995;6:71-9.
Kayser AF. Shortened dental arch: A therapeutic concept in reduced dentitions and certain high-
risk groups. The International journal of periodontics & restorative dentistry. 1989;9(6):426-
49. Epub 1989/01/01. PubMed PMID: 2640215.
Kinane DF. Periodontal disease in children and adolescents: Introduction and classification. 
Periodontology 2000. 2001;26(1):7-15.
Lie MA, van der Weijden GA, Timmerman MF, et al. Oral microbiota in smokers and non-
smokers in natural and experimentally-induced gingivitis. Journal of clinical periodontology. 
1998;25(8):677-86. Epub 1998/08/29. PubMed PMID: 9722273.
Lobene R, Soparkar P, Newman M. Use of dental floss. Effect on plaque and gingivitis. Clinical 
preventive dentistry. 1982;4(1):5-8.
Lobene RJCpD. A modified gingival index for use in clinical trials. 1986;8:3-6.
Löe H, Silness JJAos. Periodontal disease in pregnancy i. Prevalence and severity. 
1963;21(6):533-51.
Löe H, Theilade E, Jensen SBJTJop. Experimental gingivitis in man. 1965;36(3):177-87.
Machuca G, Rosales I, Lacalle JR, et al. Effect of cigarette smoking on periodontal status of 
healthy young adults. The Journal of periodontology. 2000;71(1):73-8. Epub 2000/03/01. doi: 
10.1902/jop.2000.71.1.73. PubMed PMID: 10695941.
Makin SA. Stannous fluoride dentifrices. American journal of dentistry. 2013;26:3A-9A.
Mallatt M, Mankodi S, Bauroth K, et al. A controlled 6‐month clinical trial to study the effects 
of a stannous fluoride dentifrice on gingivitis. Journal of clinical periodontology. 
2007;34(9):762-7.
Mankodi S, Petrone D, Battista G, et al. Clinical efficacy of an optimized stannous fluoride 
dentifrice, part 2: A 6-month plaque/gingivitis clinical study, northeast USA. Compendium of 
continuing education in dentistry (Jamesburg, NJ: 1995). 1997;18:10-5.
Mankodi S, Bartizek RD, Leslie Winston J, et al. Anti‐gingivitis efficacy of a stabilized 0.454% 
stannous fluoride/sodium hexametaphosphate dentifrice: A controlled 6‐month clinical trial. 
Journal of clinical periodontology. 2005;32(1):75-80.


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Marsh P. Microbiological aspects of the chemical control of plaque and gingivitis. Journal of 
Dental Research. 1992;71(7):1431-8.
Miller S, Truong T, Heu R, et al. Recent advances in stannous fluoride technology: 
Antibacterial efficacy and mechanism of action towards hypersensitivity. International dental 
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Obeid P, Bercy P. Effects of smoking on periodontal health: A review. Advances in therapy. 
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Ower P. The role of self-administered plaque control in the management of periodontal diseases: 
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Paraskevas S, Van der Weijden GJJocp. A review of the effects of stannous fluoride on 
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Parkinson C, Shaw D, Milleman J, et al. Gingivitis efficacy of an experimental stannous 
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anti-gingivitis efficacy of a 0.454% w/w stannous fluoride dentifrice. 2018b;31(2):81-5.
Perlich M, Bacca L, Bollmer B, et al. The clinical effect of a stabilized stannous fluoride 
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Petersen PE, Ogawa H. The global burden of periodontal disease: Towards integration with 
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Saxton C, Van der Ouderaa FJJoPR. The effect of a dentifrice containing zinc citrate and 
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Teles RP, Teles FRF. Antimicrobial agents used in the control of periodontal biofilms: Effective 
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Theilade E, Wright W, Jensen SB, et al. Experimental gingivitis in man: Ii. A longitudinal 
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Tinanoff N. Review of the antimicrobial action of stannous fluoride. The Journal of clinical 
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Tinanoff N. Progress regarding the use of stannous fluoride in clinical dentistry. The Journal of 
clinical dentistry. 1995;6:37-40.
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Van der Weijden G, Hioe K. A systematic review of the effectiveness of self‐performed 
mechanical plaque removal in adults with gingivitis using a manual toothbrush. Journal of 
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Van Loveren C. The antimicrobial action of fluoride and its role in caries inhibition. Journal of 
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Van Loveren C. Antimicrobial activity of fluoride and its in vivo importance: Identification of 
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May not be used, divulged, published or otherwise disclosed without the consent of GSKCH
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Van Loveren CJJodr. The antimicrobial action of fluoride and its role in caries inhibition. 
1990b;69(2_suppl):676-81.
White D, Cox E, Liang N, et al. A new plaque glycolysis and regrowth method (pgrm) for the 
in vivo determination of antimicrobial dentifrice/rinse efficacy towards the inhibition of plaque 
growth and metabolism--method development, validation and initial activity screens. 
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Williams C, McBride S, Bolden T, et al. Clinical efficacy of an optimized stannous fluoride 
dentifrice, part 3: A 6-month plaque/gingivitis clinical study, southeast USA. 1997;18:16-20.
Wilson M, Pratten J, editors. Laboratory assessment of antimicrobials for plaque-related 
diseases1999: Bioline.


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15
APPENDICIES
15.1
Product Usage Instructions
INSTRUCTIONS
Brush twice a day (morning and evening) for 1 timed minute.
Each time you brush:

Dispense a ribbon of toothpaste covering the entire length of the toothbrush head (see 
picture below).

Set your timer for 1 minute, and then brush all the teeth in your mouth in your usual 
manner for 1 timed minute.

Please record each brushing in the diary. Note any changes to these brushing 
procedures and reasons for changes (e.g. missed brushings, extra brushings).

On the day before your next visit, please record the actual time of your last 
brushing before attending site. Please remember to not brush your teeth within 12 
hours (+6 hours, -2 hours) before your scheduled study assessment visits.

Please record any changes to your health, medications (prescription and over the 
counter medications) or treatments in the diary.

Please bring your diary (completed and not completed), toothpaste and toothbrush to 
the next study visit.

Please do not remove or deface any part of the study label
Please do not share your study toothpaste with anybody and do not discuss with the 
examiner your experience with your assigned toothpaste (e.g. taste, color or smell).


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15.2
ABBREVIATIONS
The following is a list of abbreviations that may be used in the protocol.
Table 15-1
Abbreviations
Abbreviation
Term
AE
adverse event
ANCOVA
analysis of Covariance
BI
Bleeding Index
ADA
American Dental Association
BDR
blinded data review
CI
confidence interval
CPITN
Community Periodontal Index of Treatment Needs
eCRF
Electronic case report form
DMS
Data Management System
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
GCP
Good Clinical Practice
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IND
Investigational New Drug
IRB
institutional review board
IRT
Interactive Response Technology
ITT
Intention to Treat
MedRA
Medical Dictionary for Regulatory Activities
MGI
Modified Gingival Index
MFC
Master Formulation Code
NBS
Number of Bleeding Sites
OHT
Oral Hard Tissue
OST
Oral Soft Tissue
PI
principal investigator
PI
Personal information
PP
Per Protocol
ePRO
Electronic Patient Reported Outcome
PRO
Patient Reported Outcome
RAP
Statistical Report and Analysis Plan
SAE
serious adverse event
SMFP
Sodium monofluorophosphate
SnF2
Stannous fluoride
SRSD
Single Reference Safety Document
TPI
Turesky Plaque Index
USA
United States of America
US
United States

SAP_001.pdf: 
Statistical Analysis Plan for Protocol 
212537 
A Randomized, Examiner Blind, Clinical Study Investigating the Efficacy of a 
Stannous Fluoride Dentifrice in Improving Gingival Health after 3 Weeks Use 
NCT04050722
GlaxoSmithKline Consumer Healthcare 
980 Great West Road, Brentford, 
Middlesex, TW8 9GS 
United Kingdom (UK) 
Amendment to Statistical Analysis Plan approval date: 4-Oct-2019 
Copyright: GlaxoSmithKline. This document contains confidentiality statements 
that are not relevant for this publicly available version. 


Stannous Fluoride  
Protocol Number: 212537 
Statistical Reporting and Analysis Plan Text, Amendment 1, Final V1.0, 04 Oct 2019 
This document contains confidentiality statements that are not relevant for this publicly available 
version.
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Confidential 
May not be used, divulged, published or otherwise disclosed without the consent of GSK 
Template Version Effective: 15-Jul-2017 
Page 1 of 24 
STATISTICAL REPORTING AND ANALYSIS PLAN 
A Randomized, Examiner Blind, Clinical Study Investigating the 
Efficacy of a Stannous Fluoride Dentifrice in Improving Gingival 
Health after 3 Weeks Use  
Protocol Number: 212537 
Phase: 
4 


Stannous Fluoride  
Protocol Number: 212537 
Statistical Reporting and Analysis Plan Text, Amendment 1, Final V1.0, 04 Oct 2019 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
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Document History 
 
Document 
Version Date 
Summary of Changes (New analysis or 
Change in planned analysis) 
Original Analysis Plan 
28-Aug-2019 
Not applicable  
Amendment 1 
04-Oct-2019 
• Table 1-1 
Schedule of Activities: 
Visit 4 Week 3 (21± 2 days post V3) 
updated to Visit 4 Week 3 (21± 2 days post 
V2) in accordance with Clinical Protocol 
Administrative Change Letter v1.0, dated 
11-Sep-2019. 
• Figure 14.2.1 Mean Bleeding Index Score 
over Time, updated to topline in list of TLFs 
 


Stannous Fluoride  
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Table of contents 
Document History ............................................................................................................... 2 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 4 
Abbreviations ...................................................................................................................... 5 
1 
Summary of Key Protocol Information ............................................................................... 6 
1.1 
Study Design ............................................................................................................ 6 
1.2 
Study Objectives ...................................................................................................... 8 
1.3 
Treatments ............................................................................................................... 9 
1.4 
Sample Size Calculation ........................................................................................ 10 
2 
Planned Analyses ............................................................................................................... 10 
2.1 
Interim Analysis ..................................................................................................... 10 
2.2 
Final Analyses ....................................................................................................... 10 
3 
Considerations for data analyses and Data Handling Conventions ................................... 10 
3.1 
Baseline Definition ................................................................................................ 10 
3.2 
Subgroups/Stratifications ....................................................................................... 11 
3.3 
Centers Pools ......................................................................................................... 11 
3.4 
Timepoints and Visit Windows ............................................................................. 11 
4 
Data Analysis ..................................................................................................................... 11 
4.1 
Populations for Analysis ........................................................................................ 12 
4.1.1 
Subject Disposition ............................................................................... 12 
4.1.2 
Protocol Deviations ............................................................................... 12 
4.1.3 
Analysis Populations ............................................................................. 13 
4.2 
Subject Demographics and Other Baseline Characteristics ................................... 14 
4.2.1 
Demographic Characteristics ................................................................ 14 
4.2.2 
Baseline Characteristics ........................................................................ 14 
4.2.3 
General Medical History ....................................................................... 14 
4.3 
Treatments (Study Product, Rescue Medication, other Concomitant 
Therapies, Compliance) ......................................................................................... 14 
4.3.1 
Study Product Compliance and Exposure ............................................. 15 
4.3.2 
Prior and Concomitant Medication ....................................................... 15 
4.4 
Analysis of Efficacy .............................................................................................. 16 
4.4.1 
Primary Efficacy Endpoint .................................................................... 16 
4.4.2 
Secondary Efficacy Variables ............................................................... 18 


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4.4.3 
Handling of Missing Values/Censoring/Discontinuations .................... 19 
4.5 
Analysis of Secondary Objectives ......................................................................... 19 
4.5.1 
Efficacy (Secondary) ............................................................................. 19 
4.6 
Analysis of Safety .................................................................................................. 21 
4.6.1 
Adverse Events and Serious Adverse Events ........................................ 21 
4.6.2 
Other Safety Variables .......................................................................... 22 
4.7 
Analysis of Other Variables ................................................................................... 22 
5 
Changes to the Protocol Defined Statistical Analysis Plan ............................................... 23 
Attachment 1: List of Data Displays ........................................................................................ 24 
 
List of tables 
Table 1-1 
Schedule of Activities ............................................................................. 7 
Table 1-2 
Investigational/Study Product Supplies .................................................. 9 
Table 4-1 
Analysis Populations ............................................................................. 13 
Table 4-2 
The Bleeding Index (BI) ....................................................................... 16 
Table 4-3 
The Modified Gingival Index ................................................................ 18 
Table 4-4 
Turesky Plaque Index ............................................................................ 19 
 


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Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BDRM 
Blind Data Review Meeting 
BI 
Bleeding Index 
CI 
Confidence Interval 
eCRF 
electronic case report form 
GSK CH 
GlaxoSmithKline Consumer Healthcare 
ICF 
Informed Consent Form 
κ 
Kappa coefficient 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFC 
Master Formulation Code 
MGI 
Modified Gingival Index 
m-ITT 
Modified Intent-To-Treat 
NA 
Not Applicable 
NBS 
number of bleeding sites 
OHT 
Oral Hard Tissue 
OST 
Oral Soft Tissue 
PP 
Per Protocol 
ppm 
parts per million 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SD 
Standard Deviation  
SE 
Standard Error 
SMFP 
sodium monofluorophosphate 
SnF2 
stannous fluoride 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TPI 
Turesky Plaque Index 
 


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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 212537 version 1.0 dated 
22-Jun-2019 and Protocol Administrative Change Letter version 1.0 dated 11-Sep-2019. 
1 
Summary of Key Protocol Information 
This study is designed to evaluate the gingivitis efficacy of twice daily brushing with a 0.454% 
stannous fluoride (SnF2) dentifrice over 3 weeks in a population with mild to moderate plaque-
induced gingivitis.  
The study will compare a marketed dentifrice (Sensodyne Repair and Protect) containing 
0.454% SnF2 with a negative control dentifrice. 
This study will be considered successful if there is a statistically significant difference in 
Bleeding Index (BI) after 3 weeks of twice daily brushing with the SnF2 dentifrice compared to 
the negative control dentifrice and the difference is in favour of the SnF2 dentifrice. 
1.1 
Study Design 
This will be a single center, controlled, single blind (examiner blind), randomized, stratified 
(gender and baseline mean whole mouth Modified Gingival Index [MGI] score), two-treatment 
arm, parallel design, clinical study.  Study subjects will be aged 18-65 years, non-smokers, in 
good general health with generalized mild to moderate plaque-induced gingivitis and ≥ 20 
natural teeth that meet all study criteria at both the Screening and Baseline visits, including ≥ 40 
evaluable surfaces for MGI, BI, and Turesky Plaque Index (TPI). 
Approximately 130 (n=65/group) subjects will be randomized to one of the study products. 
The schedule of activities in Table 1-1 provides an overview of the subject visits and study 
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. 


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Table 1-1 
Schedule of Activities 
Procedure/Assessment 
Visit 1 
Screening 
Lead in Phase Minimum 1 day - Maximum 28 days 
Visit 2 
Day 0 
Baseline 
 
Visit 3 
Week 2  
(14± 2 days 
post V2) 
Visit 4 
Week 3  
(21± 2 days 
post V2) 
Informed consent 
X 
 
 
 
Demographics  
X 
 
 
 
Medical history  
X 
 
 
 
Prior/current medications and treatments 
X 
 
 
 
OST assessment 
X 
X 
X 
X 
OHT assessment 
X 
 
 
X 
Gross assessment of gingival health1 
X 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
Subject Eligibility 
X 
X 
 
 
Subject continuance 
 
 
X 
X 
Concomitant medications and treatments 
 
X 
X 
X 
MGI assessment 
 
X 
X 
X 
Repeat MGI Assessment2 
 
X 
X 
X 
BI assessment 
 
X 
X 
X 
Disclose dental plaque  
 
X 
X 
X 
TPI Assessment 
 
X 
X 
X 
Repeat TPI Assessment2 
 
X 
X 
X 
Stratification/Randomization 
 
X 
 
 
Dental Prophylaxis 
 
X 
 
 
Post-prophylaxis examination to confirm 
whole mouth TPI=0 
 
X 
 
 
Dispense study product, toothbrush and 
diary 
 
X 
 
 
Supervised brushing with study product 
 
X 
X 
 
Subject brings study product, toothbrush 
and completed diary to site for compliance 
check3 
 
 
X 
X 
Subject returns study product and diary to 
site 
 
 
 
X 
End of study dental prophylaxis (optional) 
 
 
 
X 
Adverse events/incidents4 
X 
X 
X 
X 
Study conclusion 
 
 
 
X 
Abbreviations: OST = Oral soft tissue, OHT = Oral hard tissue, MGI = Modified gingival index, BI = 
Bleeding index, TPI = Turesky plaque index 
Footnotes:  
1. Subjects with generalized mild-moderate gingivitis, as determined by visual assessment of gingival 
health, will continue in the study. 


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2. At least 2 repeatability assessments should be performed each day (≥ 1 in the morning; ≥ 1in the 
afternoon) 
3. Visits 2-4: Adherence to Lifestyle Guidelines/Medication Requirements;  
Visits 3-4: Compliance with use of study product (visual check if returned study supplies/review of 
diary) 
4. Adverse events (AEs)/incidents will be recorded from the signing of informed consent until 5 days 
after the last dose of study product. 
1.2 
Study Objectives 
The study objectives are as follows: 
Objective(s) 
Endpoint(s) 
Primary 
To evaluate the clinical efficacy of a 0.454% SnF2 
dentifrice in reducing gingivitis (following dental 
prophylaxis), as measured by the Bleeding Index 
(BI), compared to a negative control dentifrice, 
when used twice daily for 3 weeks. 
Mean BI at Week 3 
 
Secondary 
To evaluate the clinical efficacy of a 0.454% SnF2 
dentifrice in reducing gingivitis (following dental 
prophylaxis), as measured by the BI compared to a 
negative control dentifrice, when used twice daily 
for 2 weeks. 
Mean BI at Week 2  
 
To evaluate the clinical efficacy of a 0.454% SnF2 
dentifrice in reducing gingivitis (following dental 
prophylaxis), as measured by the number of 
bleeding sites (NBS), compared to a negative 
control dentifrice, when used twice daily for 2 and 3 
weeks. 
Mean NBS at Week 2 and Week 3 
To evaluate the clinical efficacy of a 0.454% SnF2 
dentifrice in reducing gingival inflammation 
(following dental prophylaxis), as measured by the 
Modified Gingival Index (MGI), compared to a 
negative control dentifrice, when used twice daily 
for 2 and 3 weeks. 
Mean MGI at Week 2 and Week 3 
To evaluate the clinical efficacy of a 0.454% SnF2 
dentifrice in reducing supra-gingival plaque 
formation (following dental prophylaxis) as 
measured by the Turesky modification of the 
Quigley & Hein plaque index (TPI), compared to a 
negative control dentifrice, when used twice daily 
for 2 and 3 weeks. 
Mean TPI (overall and interproximal) at 
Week 2 and Week 3 
Safety 
To assess the safety and tolerability of a 0.454% 
SnF2 dentifrice when used twice daily over 3 
weeks. 
Treatment emergent adverse events  
 


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1.3 
Treatments 
There are two study product groups in this study: 
• Test dentifrice: Sensodyne Repair and Protect containing 0.454% SnF2 (1100 parts per 
million (ppm) fluoride)  
• Negative control dentifrice: Colgate Cavity Protection (1100ppm fluoride as sodium 
monofluorophosphate [SMFP]).  
The following study products will be supplied by the Clinical Supplies Department, 
GlaxoSmithKline Consumer Healthcare (GSK CH): 
Table 1-2 
Investigational/Study Product Supplies 
 
Investigational Products 
Test Product 
Negative Control Dentifrice 
Product Name 
Sensodyne Repair and Protect 
Colgate Cavity Protection 
Pack Design 
Carton of 2 over-wrapped 
tubes 
Carton of 2 over-wrapped 
tubes 
Dispensing Details 
1 carton of 2 tubes- Baseline 
visit 
1 carton of 2 tubes- Baseline 
visit 
Product Master 
Formulation Code 
(MFC) 
Commercial Product (USA 
Market place product) 
(
) 
Commercial Product (USA 
Market place product) 
Dose/Application 
Full ribbon of toothpaste on 
head of toothbrush provided 
Full ribbon of toothpaste on 
head of toothbrush provided 
Route of 
Administration 
Oral topical 
Oral topical 
Usage Instructions 
Subjects will brush their teeth 
for one timed minute twice a 
day (morning and evening) in 
their usual manner 
Subjects will brush their teeth 
for one timed minute twice a 
day (morning and evening) in 
their usual manner 
Return Requirements 
All used/unused samples to be 
returned 
All used/unused samples to 
be returned 
 
CCI


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1.4 
Sample Size Calculation 
A sufficient number of healthy subjects will be screened to randomize approximately 130 
subjects (65 per study product group) to ensure 60 evaluable subjects per treatment complete 
the entire study.  
The primary objective for this study is to evaluate the clinical efficacy of a 0.454% SnF2  
dentifrice in reducing gingivitis (following dental prophylaxis), as measured by the BI, 
compared to a negative control dentifrice, when used twice daily for 3 weeks.  
With 60 evaluable subjects per study product group, it should be possible to detect a 0.1 
difference in BI (sd=0.17) [Parkinson et al, 2018b] with 90% power and a two sided 5% 
significance level.  This difference would approximately represent a 23% difference between 
study product groups. 
This estimate will allow detection of a 5% difference in a key secondary variable MGI with 
90% power. 
2 
Planned Analyses 
2.1 
Interim Analysis 
No interim analysis is planned for this study. 
2.2 
Final Analyses 
The final planned analyses will be performed after the completion of the following sequential 
steps: 
• All subjects have completed the study as defined in the protocol. 
• All required database cleaning activities have been completed and database has been 
locked. 
• 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 all endpoints the baseline value will be  the latest non-missing assessment prior to first study 
product use (Visit 2, Day 0).  
Unless otherwise stated, if baseline data are missing, no derivation will be performed and will 
be set to missing. 


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3.2 
Subgroups/Stratifications 
Subjects will be stratified by gender (Male/Female) and baseline mean whole mouth MGI 
score (Low: ≤2.0/High: >2.0). 
Based on above stratification factors, there will 4 strata as follows: 
• Stratum 1: Male, Low MGI Score (Baseline MGI ≤ 2.00) 
• Stratum 2: Male, High MGI Score (Baseline MGI > 2.00) 
• Stratum 3: Female, Low MGI Score (Baseline MGI ≤ 2.00) 
• Stratum 4: Female, High MGI Score (Baseline MGI > 2.00) 
All eligible subjects will be stratified based on above 4 strata, to ensure a balance of gender and 
gingivitis across both study product groups and then randomized to study product. 
The primary and secondary analysis will include gender, and baseline MGI stratification as 
factors, with the exception of the analysis of MGI, for which the stratification factor of MGI 
will not be included as the baseline value of MGI will be included as a covariate. 
No subgroup analyses are planned for this study. 
3.3 
Centers Pools 
Since this is single center study, pooling of centres is not applicable. 
3.4 
Timepoints and Visit Windows 
The timepoints and visits for this study are defined in Table 1-1, “Schedule of Activities”.  Any 
deviation from the study schedule may be reviewed on case-by-case basis at the Blinded Data 
Review Meeting (BDRM) to determine whether the data should be excluded from the Per 
Protocol (PP) population. 
4 
Data Analysis 
Data analysis will be performed by Syneos Health. The statistical analysis software used will 
be SAS version 9.4 or higher.  
Prior to database closure a 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.  


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4.1 
Populations for Analysis 
4.1.1 
Subject Disposition 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomized.  An enrolled subject is a subject who has signed informed consent 
and is eligible to proceed beyond the screening visit. 
The number of subjects screened, enrolled and randomized will be presented in Table 14.1.1.  
The number and percentage of screen failure subjects (subjects not randomized) with reasons 
why subjects are not randomized will also be displayed.  Percentages for screen failure subjects 
will be based on the total number of subjects screened.   
The number and percentage of subjects who complete and discontinue the study, broken down 
by reason for discontinuation, will be presented by study product group and overall in 
Table 14.1.1.  The percentages will be based on the number of subjects randomized. 
Table 14.1.1 will also present the number and percentage of subjects in each of the defined 
analysis populations by study product group and overall.  Percentages will be based on the 
number of subjects randomized in the relevant study product group or overall. 
Subject disposition including demographic data (age, sex and race), screening date, study 
product 
start 
date 
and 
time, 
the 
subject 
status 
(completer, 
Yes/No), 
study 
completion/withdrawal date, duration (in days) in the study (defined as [(date of completion or 
withdrawal – study product start date) + 1], the primary reason for withdrawal and further details 
for withdrawal will be listed (Listing 16.2.1.1). 
Subject disposition information will be listed for non-randomized subjects (Listing 16.2.1.2), 
including demographic information (age, sex and race), screening date, reason for screen failure 
and any further details of reason for screen failure. 
4.1.2 Protocol Deviations 
Protocol deviations will be tracked by the study team throughout the conduct of the study.  Data 
will be reviewed prior to unblinding and closure of the database to ensure all important 
deviations are captured and categorized.  Subjects with important protocol deviations liable to 
influence the efficacy outcomes will be excluded from the PP population.  Subjects may also 
be identified as having important protocol devitions not leading to exclusion from the PP 
population.  
Important deviations of the protocol procedures may include, but will not be necessarily be 
limited to the following:  
• Violation of inclusion or exclusion criteria 
• Non-compliance with study product use 
• Use of prohibited treatment or medication before or during the study  
• Violation of visit windows 


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The specific details of the important protocol deviations and how these will be assesed will be 
specified in the Blind Data Review Plan and subjects with important protocol devitions will be 
identified at the BDRM. 
The number and percentage of subjects with at least one important protocol deviation, important 
protocol deviations not leading to exclusion from PP population with reasons for deviations and 
subjects with important protocol deviations leading to exclusion from the PP population with 
reasons for deviations will be presented by study product group and overall (Table 14.1.2) and 
listed in Listing 16.2.2.1.  
All protocol deviations collected on the protocol deviation case report form will be listed in 
Listing 16.2.2.2.  The listing will present date of deviation, type of deviation and deviation 
description.   
4.1.3 Analysis Populations 
The analysis populations defined for this study are as follows:  
Table 4-1 
Analysis Populations  
Population 
Definition/Criteria 
Analyses 
Evaluated 
Safety 
• 
All randomized subjects who receive at least one 
dose of the study product. 
This population will be based on the study product the subject 
actually received. 
Safety 
Modified 
Intent-To-Treat 
(m-ITT) 
• 
All randomized subjects who received at least one 
dose of the study product and provided at least one 
post-baseline assessment of efficacy (BI, MGI or 
TPI). 
All m-ITT population summaries and analyses will be 
presented according to the study product randomized. 
Efficacy 
Per Protocol (PP) 
• 
All subjects included in the m-ITT population who 
have at least one assessment of efficacy (BI, MGI or 
TPI) considered unaffected by protocol violations. 
Subjects with a protocol violation that is deemed to affect 
efficacy for only some (but not all) of the efficacy assessments 
will be part of the PP population. 
Protocol deviations that would exclude subjects from the PP 
population are defined in Section 4.1.2 (Protocol Deviations). 
Efficacy 
analyses for 
BI score 
Repeatability 
• 
Comprise of all subjects who have a repeat clinical 
assessment of efficacy (R) at any visit.  There will be 
a separate population for repeat MGI assessment 
and repeat TPI assessment: 
• 
MGI Repeatability population: Subjects with at 
least one initial and repeat assessment of MGI 
at any visit. 
Repeatability 
analyses 


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Population 
Definition/Criteria 
Analyses 
Evaluated 
• 
TPI Repeatability population: Subjects with at 
least one initial and repeat assessment of TPI at 
any visit. 
The primary population for assessment of efficacy will be the m-ITT Population.  A PP analysis 
will be performed only on the primary variable (BI score) if more than 10% of subjects in the 
m-ITT population are excluded from the PP Population.  
Any repeat clinical data collected for the repeatability assessment will only be used to assess 
repeatability.  The main assessment of efficacy will be based on the initial assessment. 
Subjects excluded from any of the analysis populations will be listed in Listing 16.2.3.1.  
4.2 
Subject Demographics and Other Baseline Characteristics 
4.2.1 Demographic Characteristics 
Descriptive statistics [number of subjects (n), mean, standard deviation (SD), median, minimum 
and maximum for continuous variables, frequency count (n) and percentage (%) of subjects for 
categorical variables] will be presented for demographic characteristics by study product group 
and overall.  These variables include gender, race, ethnicity and age (years), and will be 
presented for the Safety population (Table 14.1.3.1), the m-ITT population (Table 14.1.3.2) and 
if applicable, for the PP population (Table 14.1.3.3).   
Demographic information will be listed for all randomized subjects in Listing 16.2.4.1.1. 
4.2.2 Baseline Characteristics 
Baseline characteristics presented for the Safety population (Table 14.1.4.1) include baseline 
mean MGI score, category (≤2.00/>2.00) and the the number and percentage of subjects 
included in each stratum as described in Section 3.2 (Subgroups/Stratifications).  Baseline 
characteristics will also be presented for the m-ITT population (Table 14.1.4.2) and the PP 
Population (Table 14.1.4.3). 
Baseline characteristics will be listed for all randomized subjects in Listing 16.2.4.1.2. 
4.2.3 General Medical History 
Medical history data will be listed (Listing 16.2.4.2) with start date and end date or ongoing at 
the start of the study.  
4.3 
Treatments (Study Product, Rescue Medication, other 
Concomitant Therapies, Compliance) 
Randomization details will be listed, including the planned study product, the actual study 
product the subject was randomized to and the randomization date (Listing 16.1.7).  


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4.3.1 Study Product Compliance and Exposure 
Product compliance will be recorded as number of missed brushings since last visit and number 
of additional brushings since last visit.  
Exposure to study product will be calculated for each visit interval and overall study product 
duration as follows: 
• Exposure (Days) = Date of Visitn – Date of Visitn-1. 
Compliance will be calculated for each visit interval and overall as: 
• Compliance (%) = (Actual number of brushings / Expected number of brushings) x 100. 
Where: 
• Expected number of brushings = (Date of Visitn – Date of Visitn-1) x 2. 
• Actual number of brushings = Expected number – missed brushings + additional 
brushings. 
Overall exposure and compliance will be calculated from Visit 2 (Day 0) to Visit 4 (Week 3) 
[or the last available visit for subjects who discontinue prior to Visit 4 (Week 3)]. 
The number of missed brushings, additional brushings and percentage compliance will be 
summarized by study product group using descriptive statistics (n, mean, SD, median, minimum 
and maximum) for each visit interval and overall study product duration, in Table 14.2.1.1.1 
for the Safety population and Table 14.2.1.1.2 for the m-ITT population.  In addition, the 
number and percentage of subjects <80%, between 80% - 120% and >120% compliant will also 
be presented.   
Product exposure (days) will be summarized by study product group using descriptive statistics 
(n, mean, SD, median, minimum and maximum), for each visit interval and overall study 
product duration, in Table 14.2.1.2.1 for the Safety population and Table 14.2.1.2.2 for the m-
ITT population. 
Compliance and exposure data will be listed for all randomized subjects (Listing 16.2.5.1) 
4.3.2 Prior and Concomitant Medication 
Prior or concomitant medication taken by or administered to a subject will be recorded in the 
case report form. The prior and concomitant medications will be coded using an internal 
validated medication dictionary, GSK Drug.  
Prior medication will be listed by subject, with drug name, GSK drug synonym, dose, 
frequency, route, start date, study day relative to first use of study product and end date 
(Listing 16.2.4.3).  Prior medications are defined as those which stopped before the date of first 
use of the study product.  If the stop date is unknown or incomplete and the medication cannot 
be considered as stopped prior to the first use of study product then the medication will be 
considered as a concomitant medication.  


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Concomitant medications and significant non-drug therapy will be listed similarly 
(Listing 16.2.4.4) with either ongoing or end date displayed.  Concomitant medications are 
defined as medications that started or stopped on or after the date of first use of the study 
product, or are ongoing.  
Unknown dates will not be imputed, however if the start or stop date is unknown, then it will 
be assumed to be concomitant medication unless the partial start date or stop date indicates 
differently. 
4.4 
Analysis of Efficacy  
The analysis of primary and secondary efficacy variables will be based on the initial assessment. 
4.4.1 Primary Efficacy Endpoint 
4.4.1.1 
Primary Efficacy Endpoint Definition 
The primary efficacy endpoint is the mean whole mouth BI score at Week 3. 
The BI will be assessed for the facial and lingual/palatal gingival surfaces of all evaluable teeth, 
six sites per tooth (mesiobuccal, buccal, distobuccal, mesiolingual/palatal, lingual/palatal and 
distolingual/palatal).  Gingival bleeding is assessed 30 seconds after probing.  Assessments will 
be performed one quadrant at a time; BI scores will be recorded before moving to the next 
quadrant.  The BI will be assessed by the same examiner on all evaluable teeth at 
Baseline (Visit 2), Week 2 (Visit 3) and Week 3 (Visit 4).  The BI scoring system will be as 
follows: 
Table 4-2 
The Bleeding Index (BI) 
 
Score 
Description  
0 
Absence of bleeding on probing 
1 
Bleeding observed within 30 seconds of probing 
2 
Bleeding observed immediately on probing 
The mean whole mouth BI score for each subject will be derived from the total BI score divided 
by the number of tooth sites scored.  
4.4.1.2 
Statistical Hypothesis, Model, and Method of Analysis 
Descriptive statistics (n, mean, SD, SE, median, minimum, maximum) of the primary variable 
will be provided at Baseline, Week 2 and Week 3 visits by study product group for the m-ITT 
population (Table 14.2.2.1).  
The primary analysis is a comparison of the mean whole mouth BI score between the test 
dentifrice and negative control dentifrice at Week 3 for subjects eligible for the m-ITT 
population. 


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The null hypothesis for the primary endpoint is that there is no difference in the mean BI score 
between the 2 study product groups. 
H0: µ1 = µ2 
The alternative hypothesis is that there is a difference in the mean BI score between the 2 study 
product groups. 
H1: µ1 ≠ µ2 
The mean BI score will be analyzed using analysis of covariance (ANCOVA) with study 
product group, gender, and baseline MGI stratification as factors and baseline mean BI score as 
a covariate.  Adjusted means and their SEs, for each study product group will be displayed with 
the study product group difference, SE, 95% confidence interval (CI) of the difference, 
between-product p-value and percent difference between study product groups in Table 14.2.2.2 
for m-ITT population.   
Percent difference will be calculated as: 
• Percent Difference = (Adjusted Mean Difference/Adjusted Mean of Negative Control 
Dentifrice)*100.   
All statistical tests of hypotheses will be two-sided and will employ a level of significance of α 
= 0.05. 
This study will be considered successful if a statistically significant difference between the 
adjusted mean BI scores of the two study product groups at Week 3 is observed to be in favor 
of the test dentifrice (SnF2 dentifrice). 
The assumption of normality and homogeneity of variance in the ANCOVA model will be 
investigated.  Violation of this assumption will be overcome using a suitable data 
transformation or a non-parametric technique (e.g. Van Elteren test). 
The raw mean and SE of the BI score for each study product group will be presented graphically 
over time for the m-ITT population in Figure 14.2.1. 
The BI obtained for each tooth, surface and site will be listed by subject and visit in 
Listing 16.2.6.1 for all randomized subjects.  The mean whole mouth BI score will be listed by 
subject and visit in Listing 16.2.6.4 for all randomized subjects. 
4.4.1.3 Supportive Analyses 
If there is more than 10% difference in the overall number of subjects between PP and m-ITT 
populations, a summary of the primary efficacy variable will be presented for all subjects in the 
PP population (Table 14.2.2.3) and the same ANCOVA model applied to the primary analysis 
will be performed on the PP population (Table 14.2.2.4). 


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4.4.2 Secondary Efficacy Variables 
4.4.2.1 
Mean BI at Week 2 
The mean BI score at Week 2 will be calculated in the same way as stated in Section 4.4.1.1. 
4.4.2.2 
Number of Bleeding Sites at Week 2 and Week 3 
The number of bleeding sites (NBS) will be derived from BI , where a bleeding site is a site 
scored as 1 or 2.  The BI scoring system is described in Section 4.4.1.1. 
4.4.2.3 
Modified Gingival Index at Week 2 and Week 3 
The MGI will be assessed for the facial and lingual/palatal gingiva of all evaluable teeth, four 
sites per tooth (facial surface - papilla and margin; lingual/palatal surface - papilla and margin). 
The MGI scoring system will be as decribed in Table 4-3 and will be assessed by the same 
examiner on all evaluable teeth at Baseline (Visit 2), Week 2 (Visit 3) and Week 3 (Visit 4). 
Table 4-3 
The Modified Gingival Index 
Score 
Description  
0 
Absence of inflammation 
1 
Mild inflammation: slight change in colour, little change in texture of any portion of 
the marginal or papillary gingival unit 
2 
Mild inflammation: criteria as [1] but involving the entire marginal or papillary 
gingival unit 
3 
Moderate inflammation: glazing, redness, edema, and/or hypertrophy of the 
marginal or papillary gingival unit  
4 
Severe inflammation: marked redness, edema and/or hypertrophy of the marginal 
or papillary gingival unit, spontaneous bleeding, congestion, or ulceration 
The mean whole mouth MGI score for each subject will be derived from the total MGI score 
divided by the number of tooth sites scored.  
4.4.2.4 
Turesky Plaque Index (Overall and Interproximal) at Week 2 and 
Week 3 
Supra-gingival plaque will be assessed on the facial and lingual surfaces of the teeth using the 
TPI.  Each tooth surface will be divided into three areas; three scores will be recorded facially 
(mesiofacial, facial, distofacial) and three scores lingually (mesiolingual, lingual and 
distolingual) generating a total of six scores per tooth.  The plaque will be disclosed and scored 
for each site as follows. 


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Table 4-4 
Turesky Plaque Index 
Score 
Description  
0 
No plaque 
1 
Separate flecks of plaque at the cervical margin  
2 
Thin continuous band of plaque (up to 1 mm) at the cervical margin  
3 
Band of plaque wider than 1 mm but covering < 1/3 of the tooth surface 
4 
Plaque covering ≥ 1/3 but < 2/3 of the tooth surface 
5 
Plaque covering ≥ 2/3 of the tooth surface 
The mean Overall TPI score for each subject will be derived from the total TPI score over all 
tooth sites divided by the number of tooth sites scored.  
The mean Interproximal TPI score for each subject will be derived from the total TPI score over 
all interproximal tooth sites divided by the number of interproximal tooth sites scored.  
4.4.3 
Handling of Missing Values/Censoring/Discontinuations 
Missing data will not be replaced or imputed.  Subjects who withdraw from the study early will 
be included in the statistical analysis up to the point of withdrawal.  Subjects who withdraw will 
not be replaced. 
4.5 
Analysis of Secondary Objectives 
Each secondary variable will be analyzed separately as per the primary variable 
(Section 4.4.1.2).  All analyses will be conducted on the m-ITT population only.  For the 
analysis of MGI the stratification factor of MGI will not be included as the baseline value of 
MGI is included as a covariate. 
4.5.1 
Efficacy (Secondary) 
4.5.1.1 
Mean BI at Week 2 
The mean BI score at Week 2 will be analyzed in the same way as stated in Section 4.4.1.2. 
4.5.1.2 
Number of Bleeding Sites at Week 2 and Week 3 
Descriptive statistics (n, mean, SD, SE, median, minimum, maximum) of the NBS will be 
provided by visit and randomized study product group for the m-ITT population 
(Table 14.2.3.1). 
The NBS will be analyzed using ANCOVA with study product group, gender, and baseline 
MGI stratification as factors and baseline NBS as a covariate.  Adjusted means and their SEs 
for each study product group will be displayed along with the study product group difference, 
SE, 95% CI of the difference, between-product p-value and percent difference between study 
product groups in Table 14.2.3.2 for m-ITT population.   


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The assumption of normality and homogeneity of variance in the ANCOVA model will be 
investigated.  Violation of this assumption will be overcome using a suitable data 
transformation or a non-parametric technique (e.g. Van Elteren test). 
The raw mean and SE of the NBS for each study product group will be presented graphically 
over time for the m-ITT population in Figure 14.2.2. 
Bleeding sites will be listed in Listing 16.2.6.1 for all randomized subjects. The NBS will be 
listed by subject and visit in Listing 16.2.6.4 for all randomized subjects. 
4.5.1.3 
Mean MGI at Week 2 and Week 3 
Descriptive statistics (n, mean, SD, SE, median, minimum, maximum) of the mean MGI score 
will be provided by visit and randomized study product group for the m-ITT population 
(Table 14.2.4.1).  
The mean MGI score will be analyzed using ANCOVA with study product group and gender 
as factors and baseline mean MGI score as a covariate.  Adjusted means and their SEs for each 
study product group will be displayed with the study product group difference, SE, 95% CI of 
the difference, between-product p-value and percent difference between study product groups 
in Table 14.2.4.2 for m-ITT population.   
The assumption of normality and homogeneity of variance in the ANCOVA model will be 
investigated.  Violation of this assumption will be overcome using a suitable data 
transformation or a non-parametric technique (e.g. Van Elteren test). 
The raw mean and SE of the MGI score will be presented graphically over time by study product 
group for the m-ITT population in Figure 14.2.3. 
The MGI obtained for each tooth, surface and site will be listed by subject and visit in 
Listing 16.2.6.2 for all randomized subjects.  The mean whole mouth MGI score will be listed 
by subject and visit in Listing 16.2.6.4 for all randomized subjects. 
4.5.1.4 
Mean TPI (Overall) at Week 2 and Week 3 
Descriptive statistics (n, mean, SD, SE, median, minimum, maximum) of the mean Overall TPI 
score will be provided by visit and randomized study product group for the m-ITT population 
(Table 14.2.5.1).  
The mean Overall TPI will be analyzed using ANCOVA with study product group, gender, and 
baseline MGI stratification as factors and baseline mean Overall TPI score as a covariate.  
Adjusted means and their SEs for each study product group will be displayed with the study 
product group difference, SE, 95% CI of the difference, between-product p-value and percent 
difference between study product groups in Table 14.2.5.2 for m-ITT population.   
The assumption of normality and homogeneity of variance in the ANCOVA model will be 
investigated.  Violation of this assumption will be overcome using a suitable data 
transformation or a non-parametric technique (e.g. Van Elteren test). 


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The raw mean and SE of the Overall TPI score for each study product group will be presented 
graphically over time for the m-ITT population in Figure 14.2.4. 
The TPI obtained for each tooth, surface and site will be listed by subject and visit in 
Listing 16.2.6.3 for all randomized subjects.  The mean Overall TPI score will be listed by 
subject and visit in Listing 16.2.6.4 for all randomized subjects. 
4.5.1.5 
Mean TPI (Interproximal) at Week 2 and Week 3 
Descriptive statistics (n, mean, SD, SE, median, minimum, maximum) of the mean 
Interproximal TPI score will be provided by visit and randomized study product group for the 
m-ITT population (Table 14.2.6.1).  
The mean Interproximal TPI will be analyzed using ANCOVA with study product group, 
gender, and baseline MGI stratification as factors and baseline mean Interproximal TPI score 
as a covariate.  Adjusted means and their SEs for each study product group will be displayed 
with the study product group difference, SE, 95% CI of the difference, between-product p-value 
and percent difference between study product groups in Table 14.2.6.2 for m-ITT population.   
The assumption of normality and homogeneity of variance in the ANCOVA model will be 
investigated.  Violation of this assumption will be overcome using a suitable data 
transformation or a non-parametric technique (e.g. Van Elteren test). 
The mean Interproximal TPI score will be listed by subject and visit in Listing 16.2.6.4 for all 
randomized subjects. 
4.6 
Analysis of Safety 
All safety data will be reported for the Safety population as per actual study product received.  
The safety profile of the study products will be assessed with respect to Exposure, AEs, 
incidents and OST.  
Exposure is described in Section 4.3.1 (Study Product Compliance and Exposure). 
4.6.1 
Adverse Events and Serious Adverse Events 
All AEs will be reviewed by the Clinical Research Scientist or Designee prior to database lock 
and will be coded to a system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA).  
AEs will be classified as oral and non-oral on the AE page of the electronic case report form 
(eCRF). 
Treatment emergent adverse events (TEAEs) are defined as AEs with an onset date/time on or 
after the date/time of first study product use.  Adverse events with an onset date/time prior to 
the first study product use will be considered as non-treatment emergent. 
The following summary tables and listings will be presented by study product group:  


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• Table of treatment-emergent AEs by system organ class (SOC) and Preferred Term (PT) 
(Table 14.3.1.1.1). Summary of the number and percentage of subjects with at least one 
AE, total number of AEs, number and percentage of AEs within each SOC and PT will be 
displayed. 
• Table of treatment-emergent AEs by Oral/Non-Oral and PT (Table 14.3.1.1.2) 
• Table of related treatment-emergent AEs by Oral/Non-Oral and PT (Table 14.3.1.1.3) 
• Listing of all AEs (Listing 16.2.7.1 for all randomized subjects; Listing 16.2.7.2 for non-
randomized subjects) 
• Listing of incidents (Listing 16.2.7.3) 
• Listing of deaths (Listing 14.3.2.1) 
• Listing of non-fatal SAEs (Listing 14.3.2.2) 
• Listing of treatment-emergent AEs leading to study or drug discontinuation 
(Listing 14.3.2.3) 
• Listing of treatment-emergent AEs classified as oral (Listing 14.3.2.4) 
In the event that there is nothing to report, a null table or listing will be produced.   
4.6.2 
Other Safety Variables 
A shift table of OST by examination will be provided, for each of the study products 
(Table 14.3.4.1) comparing baseline results to post-baseline results at Week 2 and Week 3, for 
the Safety population. 
Oral soft tissue (OST) and oral hard tissue examination (OHT) data will be listed 
(Listing 16.2.9.1 and Listing 16.2.9.2 respectively) for all randomized subjects. 
4.7 
Analysis of Other Variables 
Repeat MGI and TPI assessments will be performed by the clinical examiner at 
Baseline (Visit 2), Week 2 (Visit 3) and Week 3 (Visit 4).  At least 2 repeat assessments should 
be performed for each index on each clinical assessment day (≥1 in the morning; ≥1 in the 
afternoon).  ‘Repeat’ subjects will be selected at random from those in attendance.  Different 
subjects can be used for repeat MGI and TPI assessments.  
The repeat dental assessments (MGI and TPI) will be compared to the original assessments and 
will be used to investigate intra-examiner variability.  The repeat assessments will not be used 
in any efficacy analyses..   
The first and repeat assessments for each tooth site will be cross tabulated for MGI 
(Table 14.2.7.1) and for TPI (Table 14.2.7.2). 
A weighted Kappa coefficient (κ), along with the 95% CI will be calculated to assess the intra-
examiner reliability.  Fleiss-Cohen weighted kappa will be calculated for the repeatability 
analysis.  Reliability will be deemed: 


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• Excellent if κ > 0.75 
• Fair to good if 0.4 ≤ κ ≤ 0.75 
• Poor if κ <0.4 
This analysis will be conducted for MGI using the MGI Repeatability population and for TPI 
using the TPI Repeatability population. 
5 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis specified in 
the protocol, dated 22-Jun-2019 and protocol administrative change letter, dated 11-Sep-2019. 
 


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Attachment 1: List of Data Displays 
212537 (
 
Gingivitis) List of TFLs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI