Clinical trial NCT02992691
Conditions: Dental Plaque
Sponsor: GlaxoSmithKline
Start date: 2016-12-19; Completion date: 2017-02-02
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The Dose response of three experimental toothpastes (test product 1, test product 2 and test product 3) to remove plaque after a single brushing, compared to a positive control and negative control dentifrice will be evaluated.

Detailed description:
This will be a single centre, controlled, examiner blind, five treatment, five period, crossover design study in healthy participants. This study will evaluate the dose response of three experimental toothpastes (test product 1, test product 2 and test product 3) to remove plaque after a single brushing, compared to a positive control and negative control dentifrice. Plaque removal efficacy will be measured by Turesky modification of Quigley Hein Plaque Index (TPI).

Arms: arm 1: Participants will be instructed to dose a toothbrush with full ribbon of dentifrice. Participants will brush their teeth once for one timed minute. arm 2: Participants will be instructed to dose a toothbrush with full ribbon of dentifrice. Participants will brush their teeth once for one timed minute. arm 3: Participants will be instructed to dose a toothbrush with full ribbon of dentifrice. Participants will brush their teeth once for one timed minute. arm 4: Participants will be instructed to dose a toothbrush with full ribbon of dentifrice. Participants will brush their teeth once for one timed minute. arm 5: Participants will be instructed to dose a toothbrush with full ribbon of dentifrice. Participants will brush their teeth once for one timed minute.
Interventions: intervention 1: 20% w/w sodium bicarbonate intervention 2: 35% w/w sodium bicarbonate intervention 3: 50% w/w sodium bicarbonate intervention 4: 67% w/w sodium bicarbonate intervention 5: 0% w/w sodium bicarbonate
Intervention descriptions: intervention 1: Dentifrice containing 20% w/w sodium bicarbonate. intervention 2: Dentifrice containing 35% w/w sodium bicarbonate. intervention 3: Dentifrice containing 20% w/w sodium bicarbonate. intervention 4: Dentifrice containing 67% w/w sodium bicarbonate. intervention 5: Dentifrice containing 0% sodium bicarbonate and 1450 parts per million (ppm) fluoride.

Protocol documents:
Prot_000.pdf: 
Copyright:  GlaxoSmithKline.  An unpublished work subject to trade secret 
protection.  This work containsconfidential and proprietary information of 
GlaxoSmithKline and should not be copied, circulated, or distributed to persons not 
employed by GlaxoSmithKline unless specifically authorised.  Un-authorised 
disclosure of this work is expressly prohibited.
Clinical Protocol
206886
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CONFIDENTIAL
SUMMARY INFORMATION
Title:
Dose Response of Three Experimental Dentifrices in 
Plaque Removal in a Single Brushing Model
Protocol Number:
206886
Sponsor:
GlaxoSmithKline Consumer Healthcare (GSKCH)
St Georges Avenue, Weybridge, Surrey, KT130DE,
United Kingdom (UK)
Tel: 
Product Name:
67% w/w sodium bicarbonate dentifrice 
(parodontax
®Classic)
1450 ppm sodium fluoride dentifrice (Macleans®
Fresh Mint Toothpaste)
20% w/w sodium bicarbonate dentifrice
35% w/w sodium bicarbonate dentifrice
50% w/w sodium bicarbonate dentifrice
Development Phase:
N/A
Expert Advice Outside of Normal 
Working Hours:
Tel: 
PRIMARY CONTACT
Clinical Study Manager:
, PhD
St Georges Avenue, Weybridge, Surrey, 
KT130DE,United Kingdom (UK)
Tel: 
Protocol Authors:
Clinical Research
, BDS, MSc, PhD
Biostatistician:
, BSc, PhD
Clinical Supplies:
                                               
®parodontax is a registered trademark of GlaxoSmithKline Consumer Healthcare, LP.
®Macleans is a registered trademark of GlaxoSmithKline Consumer Healthcare, LP.
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Principal Investigator:
Christina Krause (dentist)
Study Site Name & Address:
proDERM Institute,
Kiebitzweg 2,
22869 Schenefeld/Hamburg, Germany
Study Site Telephone Number:
Study Examiner:
 (dentist)
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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT 
PAGE
I confirm agreement to conduct the study in compliance with the protocol and 
any amendments and according to the current ICH GCP guidelines.
I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure site staff receives all appropriate information throughout the 
study.
I agree to conduct this study in full conformance with the laws and regulations 
of the country in which the research is conducted and the Declaration of 
Helsinki.
Investigator Name:
Investigator Qualifications:
Investigator Signature:
Date of Signature/ Agreement:
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Table of Content
SUMMARY INFORMATION...............................................2
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT 
PAGE..............................................................................4
Table of Content......................................................................5
PROCESS FOR AMENDING THE PROTOCOL...............9
PROTOCOL AMENDMENT PAGE....................................10
SCHEDULE OF EVENTS.....................................................11
PROTOCOL SYNOPSIS FOR STUDY 206886...................12
1. INTRODUCTION...............................................................17
2. OBJECTIVE(S) AND ENDPOINT(S)...............................18
3. STUDY PLAN.....................................................................18
3.1. Study Design.......................................................................18
3.2. Subject Restrictions...........................................................21
3.3. Type and Planned Number of Subjects............................22
3.4. Study Design and Dose Justification.................................22
4. SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA........................................24
4.1. Inclusion Criteria...............................................................24
4.2. Exclusion Criteria..............................................................25
4.3. Screening/ Baseline Failures..............................................27
4.4. Withdrawal/ Stopping Criteria.........................................27
4.5. Subject Replacement..........................................................27
4.6. Subject and Study Completion..........................................28
5. PRODUCT INFORMATION.............................................29
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5.1. Study Product.....................................................................29
5.2. Dose Schedule.....................................................................30
5.3. Dose Modification..............................................................30
5.4. Product Compliance..........................................................30
5.5. Precautions.........................................................................30
5.6. Overdose.............................................................................30
5.7. Rescue Therapy..................................................................31
5.8. Product Assignment...........................................................31
5.8.1 Randomization...................................................................31
5.8.2 Blinding...............................................................................31
5.8.3 Code Breaks........................................................................32
5.9. Packaging and Labelling...................................................32
5.9.1. Accountability of Product.................................................33
5.9.2. Storage of Product............................................................33
6. STUDY ASSESSMENTS AND PROCEDURES..............33
6.1. Visit 1 -Screening Visit......................................................34
6.1.1 Screening............................................................................34
6.1.2. Informed Consent.............................................................34
6.1.3. Demographics....................................................................34
6.1.4. Medical History and Concomitant Medication...............34
6.1.5. Oral Soft Tissue (OST) Examination...............................34
6.1.6. Oral Hard Tissue (OHT) Examination............................35
6.2. Visit 2, 3, 4 and 5 –Treatment 1, 2, 3 and 4.....................35
6.2.1. Oral Soft Tissue (OST) Examination...............................35
6.2.2. Oral Hard Tissue (OHT) Examination............................35
6.2.3. Dental Plaque Assessment (Turesky Modification of 
Quigley Hein Index [TPI])................................................36
6.2.4. Repeatability of Plaque Assessment.................................36
6.3. Visit 6 –Treatment Visit 5 –Last Subject Last Visit.......37
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6.3.1. Oral Soft Tissue (OST) Examination...............................37
6.3.2. Oral Hard Tissue (OHT) Examination............................37
6.3.3. Dental Plaque Assessment (Turesky Modification of 
Quigley Hein Index)..........................................................37
6.3.4. Repeatability of Plaque Assessment.................................37
6.3.6. Study Conclusion...............................................................37
7. SAFETY ASSESSMENTS..................................................37
7.1. Definitions of an Adverse Event and Serious Adverse 
Event.................................................................................37
7.1.1. Adverse Events..................................................................37
7.1.2. Serious Adverse Events.....................................................38
7.2. Recording Adverse Events and Serious Adverse Events.40
7.3. Evaluating Adverse Events and Serious Adverse Events40
7.4. Reporting Adverse Events and Serious Adverse Events..41
7.5. Follow-up of Adverse Events and Serious Adverse Events
..........................................................................................43
7.6. Collection of Pregnancy Information................................44
7.6.1. Time Period for Collecting of Pregnancy Information...44
7.6.2. Action to be Taken if Pregnancy Occurs.........................44
8. DATA MANAGEMENT....................................................45
8.1. Source Documents/ Data....................................................45
8.2. Electronic Case Report Form............................................45
8.3. Data Handling....................................................................46
8.3.1. Data Queries......................................................................46
8.4. Processing Patient Reported Outcomes............................46
8.5. External Data.....................................................................47
9. STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES....................................................................47
9.1 Sample Size Determination.................................................47
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9.2. General Considerations.....................................................48
9.2.1. Definition of Analysis Populations...................................48
9.2.2. Exclusion of Data from Analysis......................................48
9.2.3. Criteria for Evaluation.....................................................49
9.2.4. Criteria for Assessing Efficacy.........................................49
9.2.5. Criteria for Assessing Tolerability...................................49
9.2.6. Handling of Dropouts and Missing Data.........................49
9.3. Statistical Methods and Analytical Plan...........................49
9.3.1. Demographic and Baseline Characteristics.....................49
9.3.2. Primary Analysis...............................................................49
9.3.3.Secondary Analysis...........................................................50
9.3.4. Safety Analysis..................................................................51
9.3.5. Other Analysis...................................................................51
10. STUDY GOVERNANCE CONSIDERATIONS.............51
10.1. Posting of Information on Publicly Available Clinical 
Trials Registers................................................................51
10.2. Regulatory and Ethical Considerations, Including the 
Informed Consent............................................................51
10.3. Quality Control (Study Monitoring)...............................52
10.4. Quality Assurance............................................................53
10.5. Conditions for Terminating the Study............................53
10.6. Records Retention............................................................54
10.7. Provision of Study Results to Investigators, posting of 
Information on Publicly Available Clinical Trials 
Registers and Publication................................................55
11. REFERENCES..................................................................56
12. APPENDICES...................................................................57
12.1. Appendix 1 -Abbreviations and Trademarks................57
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PROCESS FOR AMENDING THE PROTOCOL
Protocol modifications to ongoing studies which could potentially adversely affect the 
safety of subjects or which alter the scope of the investigation, the scientific quality of 
the study, the experimental design, dosages, duration of therapy, assessment 
variables, the number of subjects treated, or subject selection criteria are considered 
major/substantial amendments and must be made only after appropriate consultation 
between an appropriate representative of GSKCH and the investigator.
Detailsof amendments to the protocols should be recorded on the following page. 
Protocol modifications must be prepared by a representative of GSKCH.  All changes 
must be justified in the Reason for Amendment section of the following Protocol 
Amendment Page. Approval of amendments will be made by the original protocol 
signatories or their appropriate designees.
All major/substantial protocol modifications must be reviewed and approved by the 
appropriate IECin accordance with local requirements, before the revised edition can 
be implemented. 
All non-substantial/ minor/ administrative amendments should be submitted to the 
IECas per country specific requirements. In some countries pre-approval of a minor 
amendment is not required and will just be held on file bythe sponsor and 
investigator.
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PROTOCOL AMENDMENT PAGE
Details of all amendments should be recorded in the table below. Affected sections should be listed in the table; the actual 
amendment/ change should be made in the relevant section of the main protocol. 
To highlight the change, the following features will be used: 
To addtext: Use of CAPITAL LETTERS, BOLD AND UNDERLINE
To delete text: Use of Strikethrough e.g. strikethrough
Amendment 
No. & New 
Protocol 
Version No.
Type of Amendment
Reason for Amendment
Other 
Documents 
Requiring 
Amendment
Section(s) Amended 
PI Amendment 
Agreement
Signature & 
Date
Amendment 
No.:
Non-Substantial/Minor    
Informed 
Consent   
Yes No
Safety 
Statement     
Yes No
CRF                       
Yes No
Signature:
Protocol 
Version 
No.:
Substantial/ Major           
Date:
Amendment 
No.:
Non-Substantial/Minor    
Informed 
Consent   
Yes No
Safety 
Statement     
Yes No
CRF                       
Yes No
Signature:
Protocol 
Version 
No.:
Substantial/ Major           
Date:
 
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SCHEDULE OF EVENTS
Activity
Visit 1
Screening 
Visit 2 
Treatment 
Period 1
Visit 3
Treatment 
Period2
Visit 4
Treatment 
Period3
Visit 5
Treatment 
Period4
Visit 6
Treatment 
Period 5
Informed Consent
X
7 to 28 days wash-in 
4 to 6 days washout
4 to 6 days washout
4 to 6 days washout
4 to 6 days washout
Demographics & Medical History
X
Current/concomitant medication
X
X
X
X
X
X
Oral soft tissue examination
X
X
X
X
X
X
Oral hard tissue examination
X
Plaque disclosure
X
Plaque assessment
X
Repeatability of plaque assessment in selection of 
subjects
X
X
X
X
X
X
Inclusion/Exclusion criteria
X1
X1
Dispense wash-out toothpaste, toothbrush, countdown 
timer and diary card with verbal instructions
X
Return wash-out toothpaste, toothbrush and diary card
X
X
X
X
X
Re-dispense wash-out toothpaste, toothbrush and diary 
card
X
X
X
X
Pre-brushing plaque disclosure
X
X
X
X
X
Pre-brushing plaque assessment
X
X
X
X
X
Randomisation
X
Supervised brushingwith assigned  toothpaste
X
X
X
X
X
Post brushing plaque disclosure
X
X
X
X
X
Post-brushing plaque assessment2
X
X
X
X
X
Brushing with washout toothpaste to remove stain 
from disclosing dye
X
X
X
X
X
X
Compliance check
X
X
X
X
X
Subject Adherence/Eligibility check
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Study Conclusion
X
1  Plaque (inclusion criteria 4 C) will be assessed at Visit 1 and Visit 2; use of antibiotics and Chlorhexidine mouthwashes(exclusion criteria 7 A and 8 K)at Visit 2 to determine eligibilityto 
continue.
 
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PROTOCOL SYNOPSIS FOR STUDY 206886
Brief Summary
Thiswill be a single centre, , controlled, examiner blind, five treatment, five period, 
crossover designstudy in healthy volunteers. This study will evaluate the dose 
response of three experimental toothpastes containing 20%, 35% and 50% w/w 
sodium bicarbonate to remove plaque after a single brushing, compared to a positive 
control(67% w/w sodium bicarbonate)and negative control (0% w/w sodium 
bicarbonate) dentifrice.  
This clinical study will be conducted at proDERM Institute, Germany and funded by 
GlaxoSmithKline Consumer Healthcare (GSKCH).
Objectives and Endpoints
Primary
Endpoint
To evaluate and compare the 
plaque removal efficacy, as 
measured byTuresky 
modification of Quigley Hein 
Plaque Index(TPI), of 67% w/w 
sodium bicarbonate, versus a 0% 
sodium bicarbonate toothpaste.
Change from Pre-brushing to 
Post-brushing TPI
Secondary
Endpoint
To evaluate and compare the 
plaque removal efficacy, as 
measured by TPI, of three 
toothpastes containing 20%, 35% 
and 50% w/w sodium 
bicarbonate, versus a 0% sodium 
bicarbonate toothpaste.
Change from Pre-brushing to 
Post-brushing TPI
To evaluate and compare the 
plaque removal efficacy, as 
measured by TPI, of three 
toothpastes containing 20%, 35% 
and 50% w/w sodium 
bicarbonate, versus a 67% sodium 
bicarbonate toothpaste.
Changefrom Pre-brushing to 
Post-brushing TPI
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Study Design
Overall Design
This will be a single centre, , controlled, examiner blind, five treatment, five period, 
crossover designstudy in healthy volunteers. At the screening visit, following 
provision ofwritten informed consent, all subjects will undergo an oral soft tissue 
(OST) examination and oral hard tissue (OHT) examination. Eligible subjects will be 
provided with a standard wash-out toothpaste and toothbrush to use at home during 
the study; and for at least 7 days (maximum 28 days) prior to the first treatment visit
(Visit 2).
For each treatment visit, subjects must abstain from oral hygiene for a period of 22 -
30 hours, immediately preceding the pre-brushing dental plaque evaluation. 
At Visit 2, all the subjects will undergo an OST examination followed by disclosing 
and a pre-brushing dental plaque assessment(TPI). Subjects meeting the entry criteria 
will be  to one of the five study treatments. Subjects will then perform a supervised 
brushing as per directions with the assigned test product. This will be followed by re-
disclosing and a post-brushing plaque assessment. Subjects will brush with the 
washout paste following the post brushing plaque assessmentsto remove stain from 
the disclosing dye.
A 4 –6 days washout period will follow each treatment period during which subjects 
will brush with the standard washout toothpaste. Subjects will complete five 
treatment visits and will brush once with each of the five test toothpastes throughout 
the course of the study.
At Visits 3, 4, 5 and 6, subjects will undergo the same assessments as performed at 
Visit 2.
At Visits 1, 2, 3, 4, 5 and 6, repeatability data will be generated for plaque assessment 
from replicate examinations on the same subject. If deemed necessary by the 
examiner, plaque may be re-disclosed if the dye has faded. Depending on subject visit 
scheduling, every effort will be made to complete repeatability examination for two 
subjects, that is, one in the morning and one in the afternoon on each assessment day. 
Repeatability examinations will be separated by a minimum of 10 minutes and, where 
possible, separated by another subject.
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Type and Planned Number of Subjects
Sufficient healthy subjects will be screened by the study site so that a maximumof 56 
subjects who fulfill all the entry criteria will be randomized, which should ensure that 
at least 50 evaluable subjects complete all study visits (thus allowing for atmosta
10% drop-out).
With 50 subjects completing all study visits, the study has 90% power to detect a 
treatment difference of 0.15in plaque index in a paired t-test of significance level 
0.05. The standard deviation of difference (between treatments) is 0.32 as reviewed 
from the results of RH01455. As this is an exploratory study, multiplicity adjustment 
willnot be applied.
Diagnosis and Main Criteria for Inclusion
Healthy subjects aged between 18 years and 65 years, having a minimum of 20 
permanent gradable teeth. Subjects must have a mean Turesky plaque score of ≥ 2.00 
at Visit 1 plaque assessment and Visit 2 pre-brushing plaque assessment.
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Product Information
Test Product 
1
Test Product 
2
Test Product 
3
Reference product
(Positive Control)
Reference Product
(Negative Control)
Product Name 
Experimental 
Dentifrice 
containing 
20% w/w 
sodium 
bicarbonate
Experimental
Dentifrice 
containing 
35% w/w 
sodium 
bicarbonate
Experimental
Dentifrice 
containing 
50% w/w 
sodium 
bicarbonate
Dentifrice containing 
67% w/w sodium 
bicarbonate (German 
marketed Parodontax 
Classic (non-fluoride) 
Toothpaste)
Dentifrice containing
0% w/w sodium 
bicarbonate (UK 
marketed  Macleans 
Fresh Mint Toothpaste
–1450 ppm Fluoride)
Product Formulation 
Code (MFC)
Commerciallyavailable Commercially available
Dose
Single supervised use of a full brush head of toothpaste
Route of 
Administration
Oral/ Topical Oral/ Topical 
Oral/ Topical 
Oral/ Topical
Oral/ Topical
Dosing Instructions
Supervised use:
Subjects will apply a full ribbon of dentifrice to the study toothbrush.
 
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CCI
CCI
CCI


Other items to be supplied by the Clinical Supplies Department, GSKCH:
Name of Item
Purpose
Macleans®Fresh Mint Toothpaste
(UK)
Wash-in and wash-out Toothpaste
Aquafresh®Clean Control 
Toothbrush (UK)
For toothpaste application
Countdown Timer
To time duration of brushing
Disclosing Solution
To disclose dental plaque for Plaque assessment
Dosing Cups
For dosing the disclosing solution
Statistical Methods
The change from pre-brushingTuresky modification of the Quigley Hein Index(post-
brushing -pre-brushing) will be analysedusing mixed effect Analysis of Covariance 
(ANCOVA). The ANCOVA model will include treatment group,study period as 
fixed effects, subject as a random effectand two baseline terms as covariates; (i) the 
subject-level baseline score calculated as the mean pre-brushing score across all 
periods within a subject, and (ii) the period level baseline minus the subject-level 
baseline. P-values for treatment comparisons, adjusted means of all treatments and 
treatment differences and their 95%CIs will be provided.
Only if the primary objective is met (comparison of 67% w/w sodium bicarbonate, 
versus a 0% sodium bicarbonate is significant), will the remaining secondary analyses 
be fully conducted. Otherwise no P-values will be provided for secondary 
comparisons. Only the estimations of treatment differences and confidence intervals 
will be provided.
To assess the dose-response relationship, linear and quadratic contrasts of treatment 
effects (in the above ANCOVA) will be tested for trends. When a trend is significant, 
a mixed effect regression (linear, quadratic etc) will be run to provide a dose-response 
curve.
                                               
®Macleans is a registered trademark of GlaxoSmithKline Consumer Healthcare, LP.
®Aquafresh is a registered trademark of GlaxoSmithKline Consumer Healthcare, LP.
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1. INTRODUCTION
Dental plaque is a soft sticky biofilm that forms on the surface of teeth. It is a film of 
salivary mucoproteinswhich is colonisedby several different kinds of bacteria. 
Dental plaque begins forming on teeth just a fewminutes after brushing. If not 
removed, plaque can cause dental caries and periodontal disease, such asgingivitis 
and periodontitis. In its earliest stages, periodontal disease begins as an inflammation 
of the gums(gingivitis). If left untreated this can progress to periodontitis, a serious 
form of periodontal gum disease,which is one of the major causes of tooth loss
(Laudenbachand Simon., 2014; Petersen et al., 2004).
Good oral hygiene which includes regular tooth brushing with a toothpaste and 
cleaning between teeth (e.g.by flossing) can affect the formation and control the 
build-up of plaque and as a result prevent gum disease.
Various levels of sodium bicarbonate have been demonstrated to be effectiveat 
plaque removal including 67%, 62 % and 45% sodium bicarbonate toothpastes; 
however the relative performance of lower levelsof sodium bicarbonate in a 
toothpaste formulation compared to 67% sodium bicarbonate toothpaste has not been 
elucidated. Sodiumbicarbonate can negatively impact on the desired organoleptics of 
the toothpaste, and therefore tomaximiseconsumer acceptance, a lower level of 
sodium bicarbonate in the formulation is desired.
The mode of action of sodium bicarbonate on dental plaque and thus gingival health
and sodium bicarbonate has been shown not to have significant biocidal activity. It is
proposed that large crystals of sodium bicarbonate may facilitate physical disruption 
of plaque from thetooth surface, and that sodium bicarbonate may enhance plaque 
biofilm dispersion, contributing to moreeffective cleaning during tooth brushing 
(Prattenet al., 2015). The removal of plaque by sodium bicarbonatetoothpastes has 
been demonstrated clinically by GSKCHandothers (Mankodi et al.,  1998; Putt et 
al., 2008), and the effectiveness of 67%sodium bicarbonate toothpastes on gum 
health outcomes has been recently confirmed (RH02433,RH02434).
The aim of thisstudy is to explore the potential plaque removal efficacy of sodium 
bicarbonate toothpastes at levelsbelow 67%.
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2. OBJECTIVE(S) AND ENDPOINT(S)
Primary
Endpoint
To evaluate and compare the 
plaque removal efficacy, as 
measured byTuresky 
modificationof Quigley Hein 
Plaque Index(TPI), of 67% w/w 
sodium bicarbonate, versus a 0% 
sodium bicarbonate toothpaste.
Change from Pre-brushing to 
Post-brushing TPI
Secondary
Endpoint
To evaluate and compare the 
plaque removal efficacy, as 
measured by TPI, of three 
toothpastes containing 20%, 35% 
and 50% w/w sodium 
bicarbonate, versus a 0% sodium 
bicarbonate toothpaste.
Change from Pre-brushing to 
Post-brushing TPI
To evaluate and compare the 
plaque removal efficacy, as 
measured by TPI, of three 
toothpastes containing 20%, 35% 
and 50% w/w sodium 
bicarbonate, versus a 67% sodium 
bicarbonate toothpaste.
Change from Pre-brushing to 
Post-brushing TPI
3. STUDY PLAN
3.1. Study Design
Overall Design
This will be a single centre, , controlled, examiner blind, five treatment, five period, 
crossover designstudy in healthy volunteers. At the screening visit, following 
provision of written informed consent, all subjects will undergo an oral soft tissue 
(OST) examination and oral hard tissue (OHT) examination. Eligible subjects will be 
provided with a standard wash-out toothpaste and toothbrush to use at home during 
the study; and for at least 7 days (maximum 28 days) prior to the first treatment visit
(Visit 2).
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For each treatment visit, subjects must abstain from oral hygiene for a period of 22 -
30 hours, immediately preceding the pre-brushing dental plaque evaluation. 
At Visit 2, all the subjects will undergo an OST examination followed by disclosing 
and a pre-brushing dental plaque assessment(TPI). Subjects meetingthe entry criteria 
will be  to one of the five study treatments. Subjects will then perform a supervised 
brushing as per directions with the assigned test product. This will be followed by re-
disclosing and a post-brushing plaque assessment. Subjects willbrush with the 
washout paste following the post brushing plaque assessmentsto remove stain from 
the disclosing dye.
A 4 –6 days washout period will follow each treatment period during which subjects 
will brush with the standard washout toothpaste. Subjects will complete five 
treatment visits and will brush once with each of the five test toothpastes throughout 
the course of the study.
At Visits 3, 4, 5 and 6, subjects will undergo the same assessments as performed at 
Visit 2.
At Visits 1, 2, 3, 4, 5 and 6, repeatability data will be generated for plaque assessment 
from replicate examinations on the same subject. If deemed necessary by the 
examiner, plaque may be re-disclosed if the dye has faded. Depending on subject visit 
scheduling, every effort willbe made to complete repeatability examination for two 
subjects, that is, one in the morning and one in the afternoon on each assessment day. 
Repeatability examinations will be separated by a minimum of 10 minutes and, where 
possible, separated by another subject.
Visit 1 -Screening Visit
The following assessments will be conducted:
Written informed consent
Demographics
Medical history
Current and concomitant medications
Oral Soft Tissue Examination (OST)
Oral Hard Tissue Examination (OHT)
Plaque disclosure
Plaque assessment
Plaque assessment repeatability-randomly for selection of subjects
Inclusion/ Exclusion Criteria
Subject Eligibility
Dispense washout toothpaste, toothbrush, countdown timer and diary card 
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Brushing with washout toothpaste to remove stain from disclosing dye
Adverse events
Wash-in Period: 7 to 28 days
Visit 2 -Treatment 1
The following assessments will be conducted:
Current and concomitant medications
Return washout toothpaste, toothbrush and diary card 
Washout toothpaste compliance check (checking Diary and toothpaste tube)
OSTExamination
Adverse events 
Pre-brushing plaque disclosure
Pre-brushing plaque assessment
Plaque assessment repeatability-randomly for a selection of 2 subjectsin a 
day
Inclusion Criteria 4 C; and Exclusion criteria 7 Aand 8 K
Subject eligibility/ continuance
Randomisation
Supervised brushing with assigned treatment toothpaste
Post-brushing plaque disclosure
Post-brushing plaque assessment
Plaque assessment repeatability-randomly for a selection of 2 subjectsin a 
day
Brushing with washout toothpaste to remove stain from disclosing dye
Re-dispense washout toothpaste, toothbrush and diary card 
Wash-out Period: 4 to 6 days
Visit 3, 4 and 5–Treatment 2, 3 and 4
The following assessments will be conducted:
Current and concomitant medications
Return washout toothpaste, toothbrush and diary card 
Washout toothpaste compliance check (checking Diary and toothpaste tube)
OSTExamination
Adverse events 
Subject continuance 
Pre-brushing plaque disclosure
Pre-brushing plaque assessment
Plaque assessment repeatability-randomly for a selection of 2 subjectsin a 
day
Supervised brushing with assigned  toothpaste
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Post-brushing plaque disclosure
Post-brushing plaque assessment
Plaque assessment repeatability-randomly for a selection of 2 subjectsin a 
day
Brushing with washout toothpaste to remove stain from disclosing dye
Re-dispense washout toothpaste, toothbrush and diary card 
Wash-out Period: 4 to 6 days between treatments
Visit 6 –Treatment 5
The following assessments will be conducted:
Current and concomitant medications
Return washout toothpaste, toothbrush and diary card 
Washout toothpaste compliance check (checking Diary and toothpaste tube)
OSTExamination
Adverse events 
Subject continuance 
Pre-brushing plaque disclosure
Pre-brushing plaque assessment
Plaque assessment repeatability-randomly for a selection of 2 subjectsin a 
day
Supervised brushing with assigned treatment toothpaste
Post-brushing plaque disclosure
Post-brushing plaque assessment
Plaque assessment repeatability-randomly for a selection of 2 subjectsin a 
day
Brushing with washout toothpaste to remove stain from disclosing dye
Study Conclusion
3.2. Subject Restrictions
Lifestyle/ Dietary
During the entire study (Screening –LSLV):
Subjects will be requested not to have any elective dental procedures 
including teeth professionally cleaned other than those performed within the 
study (excluding emergency dental treatment).
Subjects should only use the dentifrice and toothbrushes provided and must 
abstain from use of all other oral hygiene products including mouthwash from 
Visit 1.
Subjects should abstain from chewing gum and consuming confectionery 
containing xylitol (e.g. mints). 
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Subjects should abstain from interproximal cleaning(use of dental floss, 
waterpick and toothpicks).  Use of toothpicks is permitted to remove impacted 
food.
At least 4 hours prior to Visits 1, 2, 3, 4, 5 and 6:
Subjects must abstain from eating for at least 4 hours and from drinking for at 
least 1 hour prior to all clinical assessments and until all assessments are 
complete.
At least 22 –30 hours preceding Visits 1, 2, 3, 4, 5 and 6:
Subjects must abstain from alloral hygiene procedures including use of dental 
floss, waterpick and toothpicks. Use of toothpicks is permitted to remove 
impacted food only.
Medications and Treatments
During the entire study (Screening –LSLV):
If current/ concomitant medications and/ or treatments are used during the 
study, theiridentity, as well as their dosage and frequency, start and stop dates 
must be reported to the Investigator/ Examiner and recorded in the CRF. 
Should a randomized subjectembark on a course of treatment during the study 
which included a prohibitedmedication(antibiotic treatment or any other 
treatment that [in the opinion of the investigator] would interfere with the 
study outcomes), the subject may be withdrawn.
Subjects who enter the study will be requested to delay having any non -
emergency, elective dental treatment until after study completion(including 
dental prophylaxis).
3.3. Type and Planned Number of Subjects
Sufficient healthy subjects will be screened by the study site so that a maximum
of 56 subjects who fulfill all the entry criteria will be randomized, which should 
ensure that at least 50 evaluable subjects complete all study visits (thus allowing for 
atmosta 10% drop-out).
3.4. Study Design and Dose Justification
Sodium bicarbonate based toothpastes have previously shown superior cleaning
efficacy against ‘everyday’ marketed toothpastes. Mankodi et al [1998] showed that a
toothpaste containing 65% sodium bicarbonateremoved significantly more plaque 
during aone minute single timed brushing than two conventional sodium bicarbonate
-free toothpastes.More recently, Putt et al [2008] has also shown that sodium 
bicarbonatetoothpastes rangingfrom 20 -65% exerted a superior and significant 
cleaning effect following a singletimed brushing compared to both sodium 
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fluoride/silica and triclosan/copolymerbased toothpastes. Both of theaforementioned 
papers identified a potential dose dependent relationship whereby there appears to be 
a positive relationship betweensodium bicarbonateconcentration and enhanced 
plaque removal. In the current study a dose response of sodium bicarbonate 
toothpastes ranging from 20% to 50% will be tested against two marketed 
toothpastes (Positive control: 67% sodium bicarbonate toothpaste and Negative 
control: 0% sodium bicarbonate toothpaste) using aone minute single timed brushing 
model.
The design of the current study is based on the model previously used by Putt et al 
[2008] andparallels used in otherGSK studies[E5931015, E5930966, RH01455] 
evaluating different commercially available formulations. 
The cross-over design will help minimiseinter-subject variability and allow greater 
sensitivity to analyze treatment differences. The current study will be performed at a 
single clinical site by a single dental examiner, thus eliminating the possibility of 
inter-examiner variability which will be confirmed by repeating assessments on the 
same subjects and formally tested. This allows for supervised control of brushing 
quantities and times, and clear identification of any differences in plaque removal by 
the different treatments.
Each subject will be randomly allocated to the orderin which they receive the five 
study treatments in order to avoid any potential bias that may occur across multiple 
treatments. Additionally, the dental examiner study will remain blinded to the 
treatment regime to ensure thereis no bias in the assessments.
The Turesky modification of the Quigley-Hein plaque index is recognised as industry 
standard for assessing plaque levels and will be performed by a trainedexaminer to 
accurately measure the levelof plaque removed by brushing, both across different 
areas of the tooth, and on teeth in different areas of the mouth.
A 7 to 28 day wash-inperiod will be utilisedbetween screening and the first of the 
five treatment visits. A wash-in is typically required in order to standardiseoral 
hygiene procedures and products prior to treatment and to allow sufficient time to 
have passed since the subject last used any oral hygiene products that could interfere 
with the outcome of the study (e.g. triclosancontaining toothpastes).The study will 
also employ a 4 to 7 day wash-out period between the treatments which is considered 
sufficient to avoid any carry over effects from the previous treatment.
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The study will be blinded with respect to the dental examiner to ensure there is no 
bias in the assessments. 
Subjects will brush their teeth under supervision with one full head of toothpaste (in 
line with the label instruction for the toothpaste). The full head of toothpaste would 
weigh approximately 1.5 grams which is the normal dose for a toothpaste. 
The age range of the subjects in the clinical study is 18 –65 as the target for this 
study is the adult population.
4. SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse 
events, and other pertinent information on the GSK investigational product or other 
study treatment that may impact subject eligibility is provided in the Safety 
Statement.
Deviations from inclusion and exclusion criteria are not allowed becausethey can 
potentially jeopardisethe scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is 
essential.
4.1. Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. CONSENT
Demonstrates understanding of the study procedures, restrictions and willingness to 
participate as evidenced by voluntary written informed consent and has received a 
signed and dated copy of the informed consent form. 
2. AGE
Aged between 18-65 years 
3. GENERAL HEALTH
Good general health with (in the opinion of the investigator) no clinically significant 
and relevant abnormalities of medical history or oral/dental examination. Absence of 
any condition that would impact on the subject’s safety or wellbeing or affect the 
individual’s ability to understand and follow study procedures and requirements.
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4. DENTAL HEALTH
A. Good dental health based on medical history and oral softtissue examination 
at screening.
B. A minimum of 20 permanent gradable teeth. (Gradable teeth are those where 
restorative materials cover less than 25% of the tooth surface to be graded).
C. Mean Turesky plaque score of ≥ 2.00 at Visit 1 and Visit 2 (pre-brushing 
plaque assessment).
5. COMPLIANCE
Understands and is willing, able and likely to comply with all study procedures and 
restrictions
4.2. Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. PREGNANCY
Women who are known to be pregnant or who are intending to become pregnant over 
the duration of the study. 
2. BREAST-FEEDING
Women who are breast-feeding
3. ALLERGY/ INTOLERANCE
Known or suspected intolerance or hypersensitivity to the study materials (or closely 
related compounds) or any of their stated ingredients.
4. CLINICAL STUDY/ EXPERMENTAL PRODUCT
A. Participation in another clinical study: cosmetic studies within 14 days of the 
screening visit or receipt of an investigational drug within 30 days of the 
screening visit.
B. Previous participation in this study.
5. SUBSTANCE ABUSE
Recent history (within the last year) of alcohol or other substance abuse.
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6. PERSONNEL
A. An employee of the sponsor or the study site or members of their immediate 
family.
B. An employee of any toothpaste manufacturer or their immediate family.
7. MEDICAL HISTORY/ CURRENT MEDICATIONS
A. Antibiotic treatment within 14 days prior to Visit 2 or throughout the study.
B. Any other treatment that would interfere with the study outcomes, at the 
discretion of the examiner or investigator.
8. DENTAL CONDITIONS
A. High levels of extrinsic stain or calculus deposits which might interfere with 
plaque assessmentsat the discretion of the investigator.
B. Dental conditions / disease requiring immediate treatment.
C. Pre-existing sensitivity to oral care products.
D. Severe gingivitis that may, in the opinion of the investigator, compromise the 
study or the oral health of the subjects if they participate in the study.
E. Presence of orthodontic bands or appliances, extensive crowns, partial 
dentures, or fixed retainers on the maxillary or mandibular teeth.
F. Active carious lesions needing immediate care.
G. Oral lesions/manifestations that would impact on the outcome of the study.
H. Presence of oral or peri-oral ulceration including herpetic lesions at the
       time of screening.
I.    Have current active caries or periodontitis that may, in the opinion of the 
investigator, compromise the study or the oral health of the subjects if they 
participate in the study.
J.    Restorations in a poor state of repair that may, in the opinion of the 
investigator, compromise the study or the oral health of the subjects if they 
participate in the study.
K.    Use of a chlorhexidine mouthwash within 14 days of Visit 2or through the 
study.
L.   Current use of Listerine, Corsodyl or any antimicrobial mouth rinseor 
        throughout the study.       
9. TOBACCO USERS AND E-CIGARETTE USERS
A. Subject unwilling to abstain from using chewing tobacco (with or without 
tobacco). 
B. Subject unwilling to abstain from smoking tobacco or E-cigarettes for 4 hours 
prior to all visits and until all dental assessments are completed at each visit.
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4.3. Screening/ Baseline Failures
Screen failures are defined as subjects who consent to participate in the study but are 
never subsequently .  In order to ensure transparent reporting of screen failure 
subjects, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and any Serious Adverse 
Events. Re-screening of subjects will notbe allowed in this study.
4.4. Withdrawal/ Stopping Criteria
A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. 
If the reason for removal of a subject from the study is an Adverse Event (AE) or an 
abnormal laboratory test result, the principal specific event or test will be recorded on
the electronic case report form (eCRF).  If a subject is withdrawn from the study 
because of a product limiting AE, thorough efforts should be clearly made to 
document the outcome. Any AEs ongoing at the final visit will be followed up until 
resolved, thecondition stabilises, is otherwise explained, or the subject is lost to 
follow-up.
The following actions must be taken in relation to a subject who fails to attend the 
clinic for a required study visit:
The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 
The site must counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to 
and/or should continue in the study. 
In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, at least 2 telephone calls). The contact attempt should be 
documented in the subject’s record. 
Should the subject continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost 
to Follow-up”.
4.5. Subject Replacement
Subjects who withdraw from the study post-randomisationwill not be replaced.
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4.6. Subject and Study Completion
A completed subject is one who has completed all phases of the study.
The end of the study is defined as the date of the last subject’s last visit.
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5. PRODUCT INFORMATION
5.1. Study Product
The following study products will be supplied by the Clinical Supplies Department, GSKCH:
Test Product 
1
Test Product 
2
Test Product 
3
Reference product
(Positive Control)
Reference Product
(Negative Control)
Product Name 
Experimental 
Dentifrice 
containing 
20% w/w 
sodium 
bicarbonate
Experimental
Dentifrice 
containing 
35% w/w 
sodium 
bicarbonate
Experimental
Dentifrice 
containing 
50% w/w 
sodium 
bicarbonate
Dentifrice containing 
67% w/w sodium 
bicarbonate (German 
marketed Parodontax 
Classic (non-fluoride) 
Toothpaste)
Dentifrice containing
0% w/w sodium 
bicarbonate (UK 
marketed  Macleans 
Fresh Mint Toothpaste
–1450 ppm Fluoride)
Product Formulation 
Code (MFC)
Commerciallyavailable Commercially available
Dose
Single supervised use of a full brush head of toothpaste
Route of 
Administration
Oral/ Topical Oral/ Topical 
Oral/ Topical 
Oral/ Topical
Oral/ Topical
Dosing Instructions
Supervised use:
Subjects will apply a full ribbon of dentifrice to the study toothbrush.
 
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CCI
CCI


Other items to be supplied by the Clinical Supplies Department, GSKCH:
Name of Item
Purpose
Macleans®Fresh Mint Toothpaste
(UK)
Wash-in and wash-out Toothpaste
Aquafresh®Clean Control 
Toothbrush (UK)
For toothpaste application
Countdown Timer
To time duration of brushing
Disclosing Solution
To disclose dental plaque for Plaque assessment
Dosing Cups
For dosing the disclosing solution
5.2. Dose Schedule
Subjects will use each  treatment once. Subjects will brush their teethoncefor one 
timed minutesupervised at site.
5.3. Dose Modification
No dose modification is permitted in this study.
5.4. Product Compliance
There is no treatment compliance measure as subjects will be required to use the
product on site under staff supervision.However, subjects will record each wash-in 
and wash-out toothpaste use in the diary providedfor compliance check for use at 
home.  Completed diaries and the toothpaste tubes will be reviewed at Visits2, 3, 4, 5 
and 6 at the study site, and any changes to medical/dental history andconcomitant 
medications will be confirmed. Any missed and additional brushings will be recorded 
in the CRF.
5.5. Precautions
No special precautions are necessary provided the study is carried out inaccordance 
with this protocol.
5.6.Overdose
An overdose is a deliberate or inadvertent administration of a product at a dose higher 
than specified in the protocol.
                                               
®Macleans is a registered trademark of GlaxoSmithKline Consumer Healthcare, LP.
®Aquafresh isa registered trademark of GlaxoSmithKline Consumer Healthcare, LP.
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Overdose is not likely to occur in this study.  Limited quantities of the product will be 
supplied, and closely monitored by the site for each subject.
Overdose per se is not an AE.  However, any clinical sequelae of an overdose should 
be reported as an AE (and serious adverse event (SAE), if appropriate).  For 
reporting, follow the AE and SAE reporting instructions.
5.7. Rescue Therapy
No rescue therapy is required in this study.
5.8. Product Assignment
Subjects will be assigned to study product in accordance with the randomization 
schedule generated by the Biostatistics Department, GSKCH, prior to the start of the 
study, using validated internal software.
5.8.1Randomization
A unique screening number will identify each subject screened for study 
participation.  Screening numbers will be assigned in ascending numerical order as 
each subject signs their consent form.  Subjects who meet all inclusion and exclusion 
criteria will be randomized according to the randomization schedule.  Randomization 
numbers will be assigned in ascending numerical order as each subject is determined 
to be fully eligible.
The randomisation schedule will be provided under the guidance of the Biostatistics 
Department,GSKCH.
5.8.2Blinding
The study statistician and other employees of the Sponsor who may influence study 
outcomes are blinded to the product allocation of subjects.
The examiner will be blinded to the treatment received. To ensurethe examiner 
remains blinded throughout the study, the examiner will not be permitted in the room 
where the test products are stored or dispensed. The product dispensing area will be 
separate from the subjects’ examination area. The dispensing staff will not be 
involved in any study efficacy assessments.
The study site will receive two versions of the randomisation schedule, each in a
sealed envelope and clearly marked as “For Dispensing” or “Emergency Use Only”.
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The dispensing schedule will be used by site for subject randomisation purposes and
will not identify the treatments by name (treatments will be identified as A, B etc.
corresponding to the labelled study supplies). The other randomisation schedule will
only be removed from the sealed envelope in an emergency situation. This schedule
however will be footnoted with a key identifying the content of treatments A, B etc.
However, to maintain the blinding of the study as far as possible, all treatment
allocations for all randomisation numbers on this randomisation schedule will be
masked with scratch off panels. Only the panels required for the subject unblinding
should be removed.
5.8.3Code Breaks
The blind must only be broken in an emergency where it is essential to know which 
product a subject received in order to give the appropriate medical care.  Wherever 
possible the Investigator (or designee) must contact the Sponsor prior to breaking the 
blind.  The investigator must document the reason for breaking the code and sign and 
date the appropriate document.
The study blind must be returned to GSKCH at the end of the study.
5.9. Packaging and Labelling
Packaging and labeling of all test products will be carried out according to ICH GCP 
guidelines and will be the responsibility of the Clinical SuppliesDepartment, 
GSKCH.
The wash-out dentifrice will be supplied in its commercial packaging with a study 
label affixed to each sample.  Sufficient product will be provided to last for the 
duration of all the washout periods.
All treatment products will be supplied in over-wrapped tubes with a study label 
affixed to each sample in order to mask their identity as much as possible.
The contents of the label will be in accordance with all applicable regulatory 
requirements and will be the responsibility of the Clinical Supplies Department, 
GSKCH.
All sundry items will be supplied in their commercial packaging for use as required 
throughout the course of the study.
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 
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for the duration of the study. Subjects should be instructed to not remove or deface 
any part of the study label.
Each study label will contain, but not be limited to, protocol number, product code 
letter (for treatment products only), directions for storage, emergency contact 
telephone number and “For Clinical Trial Use Only”.
5.9.1. Accountability of Product
All products supplied are for use only in this clinical study and should not be used for 
any other purpose.
The investigator or designee will maintain a full record of study product 
accountability. A Product Dispensing Log must be kept current and will contain the 
following information:
The identification of the subject to whom the study product was dispensed.
The date(s) and quantity of the study product dispensed to the subject.
The date(s) and quantity of the study product returned by the subject (if 
applicable).
The inventory must be available for inspection by the study monitorduring the study. 
At the end of the study, study product supplies will be verified by the monitor.  Study
 
product supplies will then be either collected by the study monitor or returned by the 
investigator or designee to the GSKCH Clinical Supplies Department or designated 
vendor.
5.9.2. Storageof Product
Study product supplies must be stored in compliance with the label requirements in a 
secure place with limited or controlled access.
6. STUDY ASSESSMENTS AND PROCEDURES
This section lists the procedures and parameters of each planned study assessment.  
Each assessment is listed in the Schedule of Events section.
Adherence to the study design requirements, including all assessments and 
procedures are essential and required for study conduct.
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6.1. Visit1 -Screening Visit
6.1.1 Screening
Prior to the screening visit, telephone screening of interested subjects will be 
conducted. This will be conducted by the site recruitment staff or designee.  
6.1.2. Informed Consent
The investigator, or designee, must obtain written (signed and dated by the subject) 
informed consent from each subject participating in this study after adequate 
explanation of the aims, methods, objectives, and potential hazards of the study.
The investigator, or designee, must also explain to the subjects that they are 
completely free to refuse to enter the study or to withdraw from it at any time.  
Appropriate forms for documenting a written consent will be provided by the 
investigator or by GSKCH.  The investigator, or designee, should sign and date the 
consent form to confirm that the consent process was completed correctly.  The 
subject, will be provided with a copy of their signed and dated consent form and any 
other written information which they should be instructed to retain.
If, during a subject’s participation in the study, any new information becomes 
available that may affect the subject’s willingness to participate in the study, each 
ongoing subject should receive a copy of this new information and be re-consented 
into the study. Subjects or be provided with a copy of the signed and dated amended 
consent form. The date of consent will be recorded on the CRF.
6.1.3. Demographics
The following demographic parameters will be captured by the Investigator or 
designee and recorded on the CRF: year of birth, gender and race. In accordance with 
FDA guidelines (Guidance for Industry: collection of Race and Ethnicity Data in 
Clinical Trials, 2005, FDA) the ethnicity of subjects will also be captured.
6.1.4. Medical History and Concomitant Medication
Medical history will be assessed as related to the inclusion/exclusion criteria by the 
Investigator or medically qualified designee.  Details of any relevant medical or 
surgical history (within the last year),including allergies or drug sensitivity, will be 
recorded on the CRF.  Any concomitant therapy taken in the 30 daysprior to the 
Screening Visit and throughout the study will also be recorded.
6.1.5. Oral Soft Tissue (OST) Examination 
Where possible, this procedure should be conducted by a single dental examiner or
clinically qualified designeefor all subjects for the duration of the study. The 
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examination will be accomplished by directobservation and palpation with retraction 
aids as appropriate. The examiner willinclude examination of the labial mucosa 
(including lips), buccal mucosa,mucogingival folds, gingival mucosa, hard palate, 
soft palate, tonsilar area,pharyngeal area, tongue, sublingual area, submandibular 
area and salivary glands.
The results of the examination will be recorded in the eCRFas either normal or
abnormal, with details of any abnormalities.Any post-treatment soft tissue
abnormality, or worsening of a pre-existing condition, observed by the examiner or
reported by the subject will be recorded on the CRF. Any abnormalities, or
worsening of pre-existing conditions, that occur from Visit 2 onwards will be
recorded as AEs.  
6.1.6. Oral Hard Tissue (OHT) Examination 
Where possible, this procedure should be conducted by a single dental examiner or
clinically qualified designee for all subjects. Subjects with evidence of gross intra-
oral neglect or the need for extensive dental therapy will be excluded.
The OHT examination will assess grossly carious lesionsor signs of erosive wear, 
enamel irregularities, tooth fracture, gross decay, decalcification and faulty 
restorations.
Observations will be listed as “Absent” or “Present” and conditions noted as present 
will be described.  Examination findings will be described and documented inthe 
eCRF.  Any observation thatchanges from “Absent” to “Present” from the screening 
assessment must be recorded as an AE. 
6.2. Visit 2, 3, 4 and 5 –Treatment 1, 2, 3 and 4
6.2.1. Oral Soft Tissue (OST) Examination
See Section 6.1.5.
6.2.2. Oral Hard Tissue (OHT) Examination
See Section 6.1.6.
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6.2.3. Dental Plaque Assessment (Turesky Modification of Quigley Hein 
Index [TPI])
The dental examiner will use the Turesky Modification of the Quigley Hein Index 
[1970] to assess plaque on all gradable teeth(TPI). Only natural teeth devoidof 
restorations which would prevent plaque grading can be assessed. This means no 
crowns, bridges, and teeth with fillings which, in the investigator
's judgment would 
prevent an accurate grading. Wisdom teeth are not to be assessed.
The lips of the subjects will first be applied with Vaseline (supplied by the site). Then
plaquewill be disclosed using 5 millilitre (ML)of the dye solution (Gum Red Cote
®) 
according to instructions. Subjectswill rinsefor 30 seconds with the dye and 
expectorate and then rinse with 10 ml of water for 10 seconds and expectorate again. 
Plaque will be assessed with each tooth being divided into 6 areas including the 
mesiofacial, facial, distofacial, mesiolingual, lingual and distolingual surfaces.
Disclosed plaque will be scored as follows for each tooth surface separately and 
recorded in the CRF:
Score Description
0
No plaque
1 
Slight flecks of plaque at the cervical margin of the tooth
2
A thin continuous band of plaque (1 mm or smaller) at the cervical margin
of the tooth
3 
A band of plaque wider than 1 mm but covering less than 1/3 of the crown
of the tooth
4 
Plaque covering at least 1/3 but less than 2/3 of the crown of the tooth
5
Plaque covering 2/3 or more of the crown of the tooth
Clinical assessments should be performed using a standard dental light to illuminate
the oral cavity. Compressed air, water and mirrors should be available to the dental
examiner.
6.2.4. Repeatability of Plaque Assessment
The repeatability of the examiner in conducting the plaque assessments either pre or 
post-brushing during the study will beperformed. Depending on subject visit 
scheduling,every effort will be made to complete repeatability examination for two
subjects, that is, one in the morning and one in theafternoon on each assessment day. 
Repeatability examinations will be separated by aminimum of 10 minutes and, where 
possible, separated by another subject.Every effort should be made to ensure the 
examiner does not refer to the results of the assessment completed prior to the repeat 
assessment. A weighted kappa coefficient will be calculated.
                                               
®Gum Red Cote is a registered trademark of Sunstar Americas, Inc.
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6.3. Visit 6 –Treatment Visit 5 –Last Subject Last Visit
6.3.1. Oral Soft Tissue (OST) Examination
See Section 6.1.5.
6.3.2. Oral Hard Tissue (OHT) Examination
See Section 6.1.6.
6.3.3.Dental Plaque Assessment (Turesky Modification of Quigley Hein 
Index)
See Section 6.2.3.
6.3.4. Repeatability of Plaque Assessment
See Section 6.2.4.
6.3.6. Study Conclusion
Subjects will be evaluated to determine if they completed all study procedures or if 
they were discontinued from the study early.  If the subject discontinued at any point 
during the study, the primary reason for withdrawal should be recorded on the Study 
Conclusion page of the CRF by selecting one of the options below.
1.
Subject did not meet study criteria
2.
Adverse Event
3.
Lost to Follow Up
4.
Protocol Violation
5.
Withdrawal of Consent
6.
Other
7. SAFETY ASSESSMENTS
7.1. Definitions of an Adverse Event and Serious Adverse Event 
7.1.1. Adverse Events
The investigator or site staff will be responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
Adverse Event Definition:
An AE is any untoward medical occurrence in a patient or clinical 
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investigation subject, temporally associated with the use of an investigational 
or washout product, whether or not considered related to the investigational or 
washout product.
NOTE: An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of an investigational or 
washout product.
Events meeting AE definition include:
Any abnormal laboratory test results (if applicable) or other safety 
assessments, including those that worsen frombaseline, and felt to be 
clinically significant in the medical and scientific judgment of the 
investigator.
Exacerbation of a chronic or intermittent pre-existing condition including 
either an increase in frequency and/or intensity of the condition.
New condition(s) detected or diagnosed after study product administration 
even though it may have been present prior to the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study product or a concomitant medication (overdose per se will not be 
reported as an AE/SAE).
Events NOT meeting definition of an AE include:
Any clinically significant abnormal laboratory findings (if applicable) or other 
abnormal safety assessments which are associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the 
subject’s condition. 
The disease/disorder/ condition being studied or expected progression, signs, 
or symptoms of the disease/disorder being studied, unless more severe than 
expected for the subject’s condition.. 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is an AE.
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
7.1.2. Serious Adverse Events
Serious Adverse Event is defined as any untoward medical occurrence that, at 
any dose:
A. Results in death
B. Is life-threatening
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NOTE: The term 
'life-threatening
' in the definition of 
'serious
' refers to an 
event in which the subject was at risk of death at the time of the event.  It does 
not refer to an event, which hypothetically might have caused death, if it were 
more severe.
C. Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency 
ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or out-patient setting.  Complications that occur during
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious.
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
D. Results in disability/incapacity
NOTE: The term disability means a substantial disruption of a person’s ability 
to conduct normal life functions.
This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everydaylife functions but do not constitute a substantial 
disruption.
E. Is a congenital anomaly/birth defect
F. Other Situations
Medical or scientific judgment should be exercised in deciding 
whether reporting is appropriate in other situations, such as important 
medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardise the subject or may 
require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be 
considered serious.
Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization or 
development of drug dependency or drug abuse or reports of 
spontaneous abortion.
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7.2. RecordingAdverse Eventsand Serious Adverse Events
Recording of adverse events and serious adverse events:
The investigator or site staff will be responsible for detecting, documenting 
and reporting events that meet the definition of an AE or SAE. 
The investigator or site staff will then record all relevant information 
regarding an AE/SAE in the CRF.
There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception 
of the subject number, will be blinded on the copies of the medical records 
prior to submission of to GSK.
The investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information.  In such cases, the 
diagnosis will be documented as the AE/SAE and not the individual 
signs/symptoms. Clinical AEs will be described by diagnosis and not by 
symptoms when possible (e.g., upper respiratory tract infection, seasonal 
allergy, etc. instead of runny nose).
AEs will be collected from the start of the wash-in product at Visit 1 and until 
5days following last administration of the study product.
SAEs will be collected over the same time periodas stated above for AEs.  
However, any SAEs assessed as relatedto study participation (e.g., 
investigational product, protocol mandated procedures, invasive tests, or 
change in existing therapy) or related to a GSK concomitant medication will 
be recordedfrom the time a subject consents to participate in the study up to 
and including any follow-up contact.  
Medical conditions reported prior to the time period for reporting AEs/SAEs 
should be recorded as part of the subject’s medical history.
7.3. Evaluating Adverse Eventsand Serious Adverse Events
Assessment of Intensity:
The investigator or designee will make an assessment of intensity for each AE and 
SAE reported during the study and will assign it to one of the following categories:
Mild:  An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities
Severe:  An event that prevents normal everyday activities. -an AE that is 
assessed as severe will not be confused with an SAE. Severity is a category 
utilised for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.
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Note: An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality:
The investigator is obligated to assess the relationship between study product 
and the occurrence of each AE/SAE.
A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the 
event to the study product will be considered and investigated.
The investigator will also consult the Investigator Brochure (IB) and/or 
Product Information, for marketed products, in the determination of his/her 
assessment.
For each AE/SAE the investigator must document in the medical notes 
(source document) or CRF that he/she has reviewed the AE/SAE and has 
provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK.  However, it is 
very important that the investigator always make an assessment of 
causality for every event prior to the initial transmission of the SAE data 
to GSK.
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.
The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
7.4. Reporting Adverse Eventsand Serious Adverse Events
AE Reporting to GSKCH:
AEs will be recorded in the AE section of the CRF. 
Medical conditions recorded by the subject on a diary
 card or similar 
document that meet the definition of an AE must also be recorded in the AE 
section of the CRF, if not previously well-characterised by the investigator in 
the subject’s medical history. 
AEs elicited by the investigator in a standard manner at the study visits should 
also be recorded in the AE section of the CRF.  The investigator or designee 
must ask the subject the following question during each visit including any 
follow-up visits:  “Have you felt unwell, experienced any symptoms or taken 
any medication (since your last visit) (today) (since your last dose) (since the 
last session)?”
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The medically qualified investigator should review adverse events in a timely 
manner; this review should be documented in writing in the source document 
or in the CRF. 
After the study is completed at a given site, and the site has received their 
study data on Compact Discs (CDs), the electronic data collection tool will be 
removed from the internet to prevent the entry of new data or changes to 
existing data.
SAE Reporting to GSKCH:
A paper copy of the SAE form provided in the investigator study master file should 
be completed as fully as possible. 
It is essential to enter the following information: 
Protocol and subject identifiers
Subject’s demography
Description of events, with diagnosis if available
Investigator opinion of relationship to study product (see section 8.3)
Criterion for seriousness.
The following are desirable and are of particular relevance for investigator and 
GSKCH assessment of the SAE report:
Date of onset of AE 
Date AE stopped, if relevant
Study product start date
Study product end date if relevant
Action taken on study product
Outcome if known
The SAE form, completed as fully as possible, and SAE fax cover sheet must be 
faxed or e-mailed to the appropriate GSKCH Study Manager as soon as possible, but 
not later than 24 hoursafter study site personnel learn of the event. The GSKCH 
Study Manager should be notified of the situation by telephone or email.
Email Serious Adverse Events to:
Fax Serious Adverse Events to:UK: 
The GSKCH Study Manager will be responsible for forwarding the SAE form to the 
Case Management Group, Global Clinical Safety and Phamacovigilance, the Medical 
Director responsible for the study and other GSKCH personnel as appropriate via 
email.
The initial report will be followed up with more information as relevant, or as 
requested by the GSKCH study manager.
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7.5. Follow-up of Adverse Eventsand Serious Adverse Events
Follow-up of AEs and SAEs:
After the initial report, the investigator is required to proactively follow up 
with each subject and provide further information on the subject’s condition.
All AEs/SAEs will be followed until resolution, until the condition stabilises, 
until the event is otherwise explained, or until the subject is lost to follow-up.  
The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as may be indicated or as 
requested by GSK to elucidate as fully as possible the nature and/or causality 
of the AE or SAE.
Investigators are not obliged to actively seek AEs or SAEs in former subjects.  
However, if the investigator learns of any SAE, including the death, at any 
time after a subject has been discharged from the study,and considers the 
event reasonably related to the investigational product or study participation, 
the investigator will promptly notify GSKCH.
The investigator will submit any updated SAE data to GSK within the 
designated reporting time frames.
Regulatory and ethics reporting requirements for SAEs:
The investigator will promptly report all SAEs to GSKCH within the 
designated reporting timeframes (within 24 hours of learning of the event).  
GSKCH has a legal responsibility to notify, as appropriate, the local 
regulatory authority and other regulatory authorities about the safety of a 
product under clinical investigation.  Prompt notification of SAEs by the 
investigator to GSKCH is essential so that legal obligations and ethical 
responsibilities towards the safety of subjects are met.
GSKCH will comply with country specific regulatory requirements relating to 
safety reporting to the regulatory authority, IECand investigators.
Investigator safety reports are prepared according to GSKCH policy and are 
forwarded to investigators as necessary.  An investigator safety report is 
prepared for a SAE(s) that is both attributable to investigational product and 
unexpected.  The purpose of the report is to fulfill specific regulatory and 
GCP requirements, regarding theproduct under investigation.
An investigator who receives an investigator safety report describing a SAE(s) 
or other specific safety information (e.g., summary of listing of SAEs) from 
GSKCH will file it with the Investigator Brochure (or safety statement) and 
will notify the IEC, if appropriate according to local requirements.
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7.6. Collection of Pregnancy Information
7.6.1. Time Period for Collectingof Pregnancy Information
Collection of Pregnancy Information:
Pregnancy information will be collected on all pregnancies reported following 
administration of any investigational product (or washout product).
Information on pregnancy identified during the screening phase and prior to 
investigational product (or washout product)administration does not need to 
be collected.
7.6.2. Action to be Taken ifPregnancy Occurs
Action to be Taken:
The investigator will collect pregnancy information on any subject who 
becomes pregnant while participating in the study after administration of the 
investigational product (or washout product). Theinvestigator will record 
pregnancy information on the appropriate form and submit it to GSKCH 
within 2 weeks of learning of the subject becoming pregnant. The subject will 
be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and infant / neonate (including concomitant medications 
taken by the mother during the pregnancy) will be forwarded to GSKCH. 
Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE, any pregnancy 
complication or elective termination for medical reasons will be recorded as 
an AE or SAE.
A spontaneous abortion is always considered to be an SAE and will be 
reported as such. An SAE occurring in association with a pregnancy, brought 
to the investigator’s attention after the subject completed the study and 
considered by the investigator as possibly related to the investigational 
product, must be promptly forwarded to GSK.
While the investigator is not obliged to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting.
If the subject becomes pregnant during the study they should be withdrawn 
from the study and this should be recorded in the appropriate section of the 
CRF.”
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8. DATA MANAGEMENT
For this study subject data will be entered into an electronic case report form, using a 
GSKCH validated data system.
8.1. Source Documents/ Data
The source documents (e.g. hospital records, clinical and office charts, laboratory 
notes, memoranda, subjects’ diaries or 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 in the Source Document Designation Form.  In some cases the CRF can be 
used as a source document.
Each subject will be assigned and identified by a unique Screening Number. Any 
reference made to an individual subject within the study must be done using the 
unique Screening Number.
8.2. Electronic Case Report Form
A CRF is a printed, optical, or electronic document designed to record all of the 
protocol required information to be reported to the sponsor on each trial subject.
For each subject who has given informed consent/assent and has been screened, CRF 
must be completed and signed by the Principal Investigator (or authorized designee) 
to certify that the data are complete and correct.  
Management of clinical data will be performed in accordance with applicable 
GSKCH standards and data cleaning procedures to ensure the integrity of the data e.g. 
removing errors and inconsistencies in the data. 
In order to protect the privacy of subjects, no Personally Identifiable Information 
(PII) (including the subject
's name or initials or birth date) is to be recorded in the 
CRF or as part of the query text.
Adverse events and concomitant medications terms (if applicable) will be coded 
using MedDRA (Medical Dictionary for Regulatory Activities) and an internal 
validated medication dictionary, GSKDrug.  
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Subject data will be entered into GSKCH defined CRFs and transmitted electronically 
to GSKCH in a validated (21 CFR Part 11 compliant) web-based electronic data 
capture system (InForm
TM).
All CRF pages should be completed during a subject assessment when the CRF has 
been designated as the source.  Data that is sourced elsewhere should be entered into 
the CRF in an agreed upon timeframe between the Investigator and Sponsor.  
The CRFs (including queries,query responses and audit trails) will be retained by 
GSKCH. Site data archived compact discs (CD(s)) prepared by a third party will be 
sent to the investigator to maintain as the investigator copy following the 
decommissioning of the study.
8.3. Data Handling
Documentation of all data management 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.
8.3.1. Data Queries
Programmed edit checks will be generated automatically, as the data is being entered 
into the system. Data Management will also run reports and listings on the CRF data, 
in addition to the queries already programmed and generated by the system, to raise 
manual queries as needed for site clarification or correction. The Clinical Dictionary 
Development and Management Group will raise queries as needed on safety data to 
code the terms (Adverse Events and Drugs) are reported appropriately. 
The study monitor at the study site will review the CRFs in accordance with the 
monitoring plan, and any queries will be generated in the EDC System to the 
Investigator or designee, enabling the errors to be addressed in parallel with Data 
Management review. Monitor can also run reports and listings on the CRFs, to raise 
manual queries as neededfor site clarification or correction
8.4. Processing Patient Reported Outcomes
Patient reported outcome (PRO) data are collected directly from the subject PRO 
measures e.g. diary cards, questionnaires etc, and entered into the sponsor’s clinical 
data management system (DMS) by the study site representative. The site staff should 
ensure that any potential AEs recorded in the diary cards should be reported in the 
DMS. In instances where the PRO data is entered into the DMS by GSKCH, the 
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PROs will be anonymised, and forwarded to GSKCH for entry, as agreed and 
documented ahead of the study starting. PROs that are source will be retained by the 
investigator and certified copies will be sent to GSKCH. 
In order to protect the privacy of subjects, no Personally Identifiable Information 
(PII) (including the subject
's name or initials or birth date) is to be recorded on all 
PRO’s that will be forwarded to GSKCH.
8.5. External Data
External Data are subject data obtained externally to the CRF. These data are 
generated from laboratory instruments, computers or other sources and then 
transcribed into a file and format agreed upon by GSKCH to identify the subject and 
time point referenced in the CRF and/or protocol. 
An agreed upon quality control process is performedagainst the transcribed data to 
the source to ensure the accuracy of the transcription. The transcribed data is 
transmitted in an agreed upon format to GSKCH via secured web portal or CD/DVD 
via mail carrier with tracking capabilities. 
Proper reconciliation will be performed between the transcribed data and the clinical 
database to ensure subject and time point referenced in the Clinical Database match 
before Clinical Database Freeze (locking of the database) can occur.
9. STATISTICAL CONSIDERATIONS ANDDATA 
ANALYSES
9.1 Sample Size Determination
Sufficient healthy subjects will be screened by the study site so that a maximumof 56 
subjects who fulfill all the entry criteria will be randomized, which should ensure that 
at least 50 evaluable subjects complete all study visits (thus allowing for atmosta 
10% drop-out).
With 50 subjects completing all study visits, the study has 90% power to detect a 
treatment difference of 0.15in plaque index in a paired t-test of significance level 
0.05. The standard deviation of difference (between treatments) is 0.32 as reviewed 
from the results of RH01455. As this is an exploratory study, multiplicity adjustment 
(67%, 50%, 35%, 20% w/w sodium bicarbonate dentifrices vs. 0% w/w sodium 
bicarbonate dentifrice)willnot be applied.
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9.2.General Considerations
9.2.1.Definition of Analysis Populations
Safety population is defined as all subjects who are randomized and have received at 
least one dose of study products.
The intent to treat (ITT) population is defined asthose subjects who are randomized, 
receive at least one dose of study product and have at least one post-baseline efficacy 
measurement.
The Per Protocol (PP) population will be a subset of the ITT population. Subjects 
with a protocol violation that is deemed to affect efficacy for all efficacy assessments 
will be excluded from the PP population. 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, but their data will be excluded from the assessment at 
which the protocol violation occurred. Efficacy analysis will be based on ITT 
population. A PP analysis will be performed only if 10% or more ITT subjects are 
excluded from PP population.
The repeatability population is defined as all subjects who have a repeat clinical 
assessment (TPI) at any visit.
9.2.2.Exclusion of Data from Analysis
Any of the following will be considered a protocol violation which will warrant 
exclusion from efficacy analysis:
Violation of inclusion or exclusion criteria that are deemed to affect efficacy.
Medical history which is deemed to affect efficacy.
Use of prohibited treatment or medication before or during the study, which is 
felt to affect the assessment of efficacy.  The assessments affected will be 
determined prior to database lock.
Not receiving randomized treatment.
Noncompliance on treatment washout
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Further data listings will be included in the review of protocol violations but will be 
reviewed on a case-by-case basis to determine whether the data should be excluded 
from a PP. Full data listings will be provided in statistical analysis plan (SAP).
Protocol violations which warrant exclusion from efficacy analysis will be identified 
between the statistician and medical director or designee, ahead of database lock and 
breaking the study blind.
9.2.3.Criteria for Evaluation
Efficacy will be evaluated by ITT or PP population. Safety will be assessed by safety 
population.
9.2.4.Criteria for Assessing Efficacy
The success criterion of the study is to observe statistically significant reduction in 
TPI score in 67% w/w sodium bicarbonate dentifrice group compared to 0% sodium 
bicarbonate dentifrice group after a single brushing.
9.2.5.Criteria for Assessing Tolerability
No specific safety criteria are planned for this study. Adverse Events and OST 
abnormalities will be assessed for safety and tolerability.
9.2.6.Handling of Dropouts and Missing Data
Subjects who withdraw from the study early will be included in the statistical analysis 
up to the point of when they withdraw. Missing datawill not be replaced.
9.3. Statistical Methods and Analytical Plan
Additional details of the proposed statistical analysis will be documented in the 
statistical analysis plan (SAP), which will be written following finalization of the 
protocol and prior to study unblinding.
9.3.1.Demographic and Baseline Characteristics
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 data.
9.3.2.Primary Analysis
Primary efficacy endpoint will be the TPI score change from pre-brushing after a 
single brushing treatment. TPI score will be calculated as the average index over all 
tooth sites. Mixed effect ANCOVA model will be applied with treatment,study 
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period as fixed effects, subject as a random effectand two baseline terms as 
covariates; (i) the subject-level baseline score calculated as the mean pre-brushing 
score across all periods within a subject, and (ii) the period level baseline minus the 
subject-level baseline.P-values for treatment comparisons, adjusted means of all 
treatments and treatment differences and their 95%CIswill be provided. 
The primary analysis will be the comparison between the positive control and the 
negative control with null hypothesis H
0: there is no difference between two 
treatments, and alternative hypothesis H
a: there is a difference between two 
treatments. 
Only if the primary objective is met (comparison of 67% w/w sodium bicarbonate, 
versus a 0% sodium bicarbonate is significant), will the remaining secondary analyses
be fully conducted. Otherwise no P-values will beprovided for secondary 
comparisons. Only the estimations of treatment differences and confidence intervals 
will be provided. 
The assumption of residual normality and variance homogeneity in ANCOVA 
analysis will be investigated. If violated, data transformation or a non-parametric 
method (e.g., the Wilcoxon rank sum test) will be applied.
9.3.3. Secondary Analysis
Secondary analyses include the following treatment comparisons:
1. 50% sodium bicarbonate dentifrice versus a 0% sodium bicarbonate dentifrice;
2. 35% sodium bicarbonatedentifrice versus a 0% sodium bicarbonate dentifrice;
3. 20% sodium bicarbonate dentifrice versus a 0% sodium bicarbonate dentifrice;
4. 50% sodium bicarbonate dentifrice versus a 67% sodium bicarbonate dentifrice;
5. 35% sodium bicarbonate dentifrice versus a 67% sodium bicarbonate dentifrice;
6. 20% sodium bicarbonate dentifrice versus a 67% sodium bicarbonate dentifrice.
The analyses will be carried out by the same ANCOVA model in primary analysis. P-
values for treatment comparisons, adjusted means of all treatments and treatment 
differences and their 95%CIs will be provided.
IntheANCOVA analysis of the effects of the five treatments with different contents 
of sodium bicarbonate (0%, 20%, 35%, 50%, 67%), the linear and quadratic contracts 
will be tested for dose-response trend. When a trend is significant, a mixed effect 
regression (linear, quadratic etc) will be run to provide dose-response curve. The 
regression curve will be plotted together with the dose-response data. If neither linear 
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model nor quadratic model appears to fit the data well, other nonlinear models may 
also be considered.
9.3.4.Safety Analysis
No specific safety criteria are planned for this study. Adverse Events and OST 
abnormalities will be collected and listed. Treatment emergent AEs (i.e. those 
occurring after the first usage of the study treatments) will be tabulated.
9.3.5.Other Analysis
A number of subjects will have repeat plaque (TPI) andassessments conducted by the 
examiner.  The repeat assessments will be compared to the original assessments.  The 
repeat assessments will not be used in any efficacy analysis.  The first and second 
assessments on each tooth at a given visit will be cross-tabulated anda weighted 
Kappa coefficient (κ) will be calculated, along with the 95%confidence interval, to 
assess the intra-examiner repeatability.  Repeatability will be deemed [Fleiss]:
Excellent,
if κ> 0.75
Fair to good, if 0.4 ≤κ ≥ 0.75
Poor 
if κ< 0.4
All subjects who have repeatability data will be included in this analysis.
10. STUDY GOVERNANCE CONSIDERATIONS
10.1.Posting of Information on Publicly Available Clinical Trials 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.Regulatory and Ethical Considerations, Including the Informed 
Consent
The study will be conducted in accordance with all applicable regulatory 
requirements, and with GSK policy.
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The study will also be conducted in accordance with ICH Good ClinicalPractice 
(GCP), all applicable subject privacy requirements, and the guiding principles of the 
current version of the Declaration of Helsinki.  This includes, but is not limited to, the 
following:
Before initiating a trial, the investigator/institution should have written and 
dated approval/favorable opinion from the IECfor the trial protocol (including 
amendments), written informed consent form, consent form updates, subject 
recruitment procedures (e.g., advertisements), investigator brochure/ safety 
statement (including any updates) and any other written information to be 
provided to subjects. A letter or certificate of approval will be sent by the 
investigator to the sponsor prior to initiation of the study, and also when 
subsequent amendments to the protocol are made.
Signed informed consent  to be obtained for each subject before participation 
in the study (and for amendments as applicable)
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IEC)
GSK will provide full details of the above procedures, either verbally, in 
writing, or both.
10.3.Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and GSK procedures, GSK 
or designee (i.e. third party vendor) monitors will contact the site prior to the start of 
the study to review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements.
When reviewing data collection procedures, the discussion will include identification, 
agreement and documentation of data items for which the CRF will serve as the 
source document.
GSK or designee will monitor the study and site activity to verify that the:
Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol and 
any other study agreements, GCP, and all applicable regulatory requirements.
The extent and nature of monitoring will be described in a written monitoring plan on 
file at GSKCH. The investigator (or designee) agrees to allow the monitor direct 
access to all relevant documents and agrees to co-operate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
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10.4.Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 
In the event of an assessment, audit or 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 sponsor will be available to help investigators prepare for an inspection.
10.5.Conditions for Terminating the Study
Upon completion or premature discontinuation of the study, the GSKCH monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSKCH Standard 
Operating Procedures.
Both GSKCH and the Investigator reserve the right to temporarily suspend or 
prematurely discontinue this study at any time for reasons including, but not limited 
to, safetyor ethical issues or severe non-compliance. For multicenter studies (if 
applicable), this can occur at one or more or at all sites.  
If the trial is prematurely terminated or suspended for any reason, the investigator site 
should promptly inform the trial subjects and should assure appropriate therapy/ 
follow-up for the subjects. Where required by the applicable regulatory requirements, 
GSKCH should inform the regulatory authority(ies). 
In addition: 
If the investigator terminates or suspends a trial without prior agreement of 
GSKCH, the investigator site should promptly inform the sponsor and the 
IEC, and should provide the sponsor and the IECa detailed written 
explanation of the termination or suspension.
If the GSKCH terminates or suspends a trial,the investigator should promptly 
inform the IECand provide the IECa detailed written explanation of the 
termination or suspension. 
If the IECterminates or suspends its approval/favorable opinion of a trial, the 
investigator should promptly notify the GSKCH and provide GSKCH with a 
detailed written explanation of the termination or suspension.
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10.6.Records Retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere), in a safe 
and secure location.  
The records (study/ site master file) must be maintained to allow easy and timely 
retrieval, when needed (e.g., for a GSK audit or regulatory inspection) and must be 
available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken. 
The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.
The investigator must assure that the subject’s anonymity will be maintained.  On 
CRFs or other documents submitted to GSKCH, subjects should not be identified by 
their names or initials, but by an identification code. The investigator should keep a 
separate log of subjects’ codes, names and addresses.  Documents not for submission 
to GSKCH, e.g. subjects’ written consent forms, should be maintained by the 
investigator in strict confidence.
GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements (GSKCH recommends that 
documents be kept for 10 years). The investigator is also required to keep subject 
identification codes on file for at least 15 years after completion or discontinuation of 
the study. The minimumretention time will meet the strictest standard applicable to 
that site for the study, as dictated by any institutional requirements or local laws or 
regulations, GSK standards/procedures, and/or institutional requirements.  
No study document should be destroyed without a prior written agreement between 
GSKCH and the investigator. The investigator must notify GSK of any changes in the 
archival arrangements, including, but not limited to, archival at an off-site facility or 
transfer of ownership of the records in the event the investigator is no longer 
associated with the site.
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10.7.Provision of Study Results to Investigators, posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the clinical study report.  The investigator will be 
provided reasonable access to statistical tables, figures, and relevant reports and will 
have the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location.
GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects, 
as appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
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11. REFERENCES
Akwagyiram I, Lomax A, Targett D, Jean-Bapiste A, Milleman J, Milleman, KR, 
Bosma ML.2013. Plaque Removal Efficacy of Four Dentifrices in Single Brushing 
Model. IADR, Seattle,USA. Abstract No: 3328. GSK clinical study: RH01455
GSK clinical study: RH02433 -A Six Month Clinical Study Based in the US to 
Evaluate theEfficacy andTolerability of Sodium Bicarbonate Toothpaste
GSK clinical study: RH02434 -A Six Month Clinical Study Basedin the US to 
Evaluate theEfficacy and Tolerability of Sodium Bicarbonate Toothpaste and its 
Effect on Opportunistic orResistant Organisms
 
 
ICH Topic 6 Guideline for Good Clinical PracticeCPMP/ICH/135/95 17th July 1996.
Laudenbach JM, Simon Z. Common Dental and Periodontal Diseases: Evaluation and 
Management. Medical Clinics of North America. 2014: 98 (6); 1239-1260.
Mankodi S, Berkowitz H, Durbin K, Nelson B. Evaluation of the effects of brushing 
on the removal of dental plaque. JClin Dent: 1998; 9 (3): 57-60.
Petersen PE, Bourgeois D, Ogawa H, Estupinan-Day S, Ndiaye C. The global burden 
of oral diseases and risks to oral health. Bulletin of the World Helath Organization 
2005; 83: 661-669.
Pratten J Wiecek, N Mordan, A Lomax, NPatel, D Spratt, AM Middleton. Physical 
disruption of oral biofilms by sodium bicarbonate: an invitro study. Int J Dent
Hygiene: 2015;1-5.
Putt MS, Milleman KR, Ghassemi A, Vorwerk LM, Hooper WJ, Soparkar PM, 
Proskin HM. Enhancement of plaque removal efficacy by tooth brushing with baking
soda dentifrices: Results of five clinical studies. J Clin Dent: 2008 19: 111-119.
Turesky S, Gilmore N D, Glickman I. Reduced plaque formation by the chloromethyl 
analogue of Vitamin C. J Periodontol. 1970; 41: 41-44.
World Medical Association Declaration of Helsinki, 59th General Assembly, Seoul 
2008.
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12. APPENDICES
12.1. Appendix 1 -Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ANCOVA
Analysis of Covariance
CI
Confidence Intervals
CRF
Case Report Form
CRO
Contract Research Organization
EDC
Electronic Data Capture
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
GSKCH
GlaxoSmithKline Consumer Healthcare
ICH
International Conference on Harmonisation of Technical 
Requirements for Registrationof Pharmaceuticals for Human 
Use
IEC
Independent Ethics Committee
ITT
Intent to Treat
MedDRA
MedicalDictionary for Regulatory Activities
MFC
Master Formula Code
mL
Miliilitre
OHT
Oral HardTissue Examination
OST
Oral Soft Tissue Examination
PI
Plaque Index
PII
Personally Identifiable Information
PP
Per Protocol
PRO
Patient Reported Outcome
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
TPI
Turesky Modification of Quigley Hein Plaque Index
UK
United Kingdom
w/w
Weight/Weight
+
Plus or minus
>  / >
Greater than or equal to / greater than
</ <
Less than or equal to / less than
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Trademark Information
Trademarks of the GlaxoSmithKline group of companies:
Aquafresh
parodontax
Trademarks not owned by the GlaxoSmithKline group of companies:
Red Cote
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SIGNATURE PAGE 
 
  
 
Date 
Signed By
 
Justification 
 
 
 
Date 
Signed By
 
Justification 
 
 
 
Date 
Signed By
 
Justification 
 
 
 
Date 
Signed By
 
Justification 
 
 
 
Date 
Signed By
 
 
Justification 
 
 
 
Date 
Signed By
 
 
Justification 
 
 
25-Oct-2016 04:50:29
 
Biostatistics Approval
27-Oct-2016 12:48:27
Approved
24-Oct-2016 06:14:56
Clinical Operations Approval
Approved
206886 Protocol
21-Oct-2016 10:51:39
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SAP_001.pdf: 
CONFIDENTIAL
STATISTICAL ANALYSIS PLAN FOR PROTOCOL 206886
Dose Response of Three Experimental Dentifrices in Plaque Removal in a Single 
Brushing Model
BIOSTATISTICS DEPARTMENT
GLAXOSMITHKLINE CONSUMER HEALTHCARE
ST GEORGE’S AVENUE
WEYBRIDGE
SURREY  KT13 0DE
(PhD)
 
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Table of Contents
Glossary................................................................................4
1
Introduction................................................................5
2
Objectives....................................................................5
3
Study Design...............................................................5
4
Sample Size Determination........................................6
5
Data Considerations...................................................7
5.1
Analysis Populations....................................................7
5.2
Subgroups/Stratification.............................................8
5.3
Time Windows.............................................................8
6
Demographics and Baseline Characteristics.............8
6.1
Subject Disposition......................................................8
6.2
Demographics...............................................................9
6.3
Baseline Characteristics..............................................9
7
Treatment Compliance and Concomitant Medications
.....................................................................................9
7.1
Treatment Compliance................................................9
7.2
Concomitant Medications............................................9
8
Efficacy Analysis.........................................................9
8.1
Primary Efficacy Analysis...........................................10
8.2
Secondary Efficacy Analysis.......................................10
8.3
Other Efficacy Analysis...............................................11
9
Safety Analysis............................................................11
10
Interim Analysis.........................................................12
11
Topline Summary.......................................................12
11.1 Variables for topline......................................................12
11.2 Outputs for topline.........................................................12
12
Changes to Planned Analysis.....................................13
 
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13
References...................................................................13
Appendix 1 Study Schedule.................................................14
Appendix 2 List of Tables, Figures & Listings...................15
Appendix 3 Templates for Tables, Figures & Listing........17
 
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Glossary
AE
Adverse Event
ANCOVA
Analysis of Covariance
CI
Confidence Interval
ITT
Intention to Treat
κ
Kappa
MedDRA
Medical Dictionary for Regulatory Activities
OHT
Oral hard Tissue
OST
Oral Soft Tissue
PP
Per protocol
SOC
System of Organ
TPI
Turesky modification of Quigley Hein Plaque Index
w/w
Weight by weight
 
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1
Introduction
This document describes the statistical methods and data presentations to be used in 
the summary and analysis of the final data from Protocol 206886.
2
Objectives
Primary
Endpoint
To evaluate and compare the 
plaque removal efficacy, as 
measured by Turesky
modification of Quigley Hein 
Plaque Index (TPI), of 67% w/w 
sodium bicarbonate, versus a 0% 
sodium bicarbonate toothpaste.
Change from Pre-brushing to 
Post-brushing TPI
Secondary
Endpoint
To evaluate and compare the 
plaque removal efficacy, as 
measuredby TPI, of three 
toothpastes containing 20%, 35% 
and 50% w/w sodium 
bicarbonate, versus a 0% sodium 
bicarbonate toothpaste.
Change from Pre-brushing to 
Post-brushing TPI
To evaluate and compare the 
plaque removal efficacy, as 
measured by TPI, of three 
toothpastes containing 20%, 35% 
and 50% w/w sodium 
bicarbonate, versus a 67% sodium 
bicarbonate toothpaste.
Change from Pre-brushing to 
Post-brushing TPI
3
Study Design
This will be a single centre, controlled, examiner blind, five treatment, five period, 
crossover design study in healthy volunteers. At the screening visit, following 
provision of written informed consent, all subjects will undergo an oral soft tissue 
(OST) examination and oral hard tissue (OHT) examination. Eligible subjects will be 
 
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provided with a standard wash-out toothpaste and toothbrush to use at home during 
the study; and for at least 7 days (maximum 28 days) prior to the first treatment visit 
(Visit 2).
For each treatment visit, subjects must abstain from oral hygiene for a period of 22 -
30 hours, immediately preceding the pre-brushing dental plaque evaluation. 
At Visit 2, all the subjects will undergo an OST examination followed by disclosing 
and a pre-brushing dental plaque assessment (TPI). Subjects meeting the entry criteria 
will be to one of the five study treatments. Subjects will then perform a supervised 
brushing as per directions with the assigned test product. This will be followed by re-
disclosing and a post-brushing plaque assessment. Subjects will brushwith the 
washout paste following the post brushing plaque assessments to remove stain from 
the disclosing dye.
A 4 –6 days washout period will follow each treatment period during which subjects 
will brush with the standard washout toothpaste. Subjects will complete five 
treatment visits and will brush once with each of the five test toothpastes throughout 
the course of the study.
At Visits 3, 4, 5 and 6, subjects will undergo the same assessments as performed at 
Visit 2.
At Visits 1, 2, 3, 4, 5 and 6, repeatability data will be generated for plaque assessment 
from replicate examinations on the same subject. If deemed necessary by the 
examiner, plaque may be re-disclosed if the dye has faded. Depending on subject visit 
scheduling, every effort will be made to complete repeatability examination for two 
subjects, that is, one in the morning and one in the afternoon on each assessment day. 
Repeatability examinations will be separated by a minimum of 10 minutes and, where 
possible, separated by another subject.
The five treatments of the study are as the following:
Test1:Experimental Dentifrice containing 20% w/w sodiumbicarbonate;
Test2:ExperimentalDentifrice containing 35% w/w sodium bicarbonate;
Test 3:ExperimentalDentifrice containing 50% w/w sodium bicarbonate;
Positive control:Dentifrice containing 67% w/w sodium bicarbonate;
Negative control:Dentifrice containing 0% w/w sodium bicarbonate.
4
Sample Size Determination
Sufficient healthy subjects will be screened by the study site so that a maximum of 56 
 
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subjects who fulfill all the entry criteria will be randomized, which should ensure that 
at least 50 evaluable subjects complete all study visits (thus allowing for at most a 
10% drop-out).
With 50 subjects completing all study visits, the study has 90% power to detect a 
treatment difference of 0.15 in plaque index in a paired t-test of significance level 
0.05. The standard deviation of difference (between treatments) is 0.32 as reviewed 
from the results of RH01455. As this is an exploratory study, multiplicity adjustment 
will not be applied.
5
DataConsiderations
5.1
Analysis Populations
Safety population is defined as all subjects who are randomized and have received at 
least one dose of study products.
The intent to treat (ITT) population is defined as those subjects who are randomized, 
receive at least one dose of study product and have at least one post-baseline efficacy 
measurement.
The Per Protocol(PP) population will be a subset of the ITT population. Subjects 
with a protocol violation that is deemed to affect efficacy for all efficacy assessments 
will be excluded from the PP population. 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, but their data will be excluded from the assessment at 
which the protocol violation occurred. Efficacy analysis will be based on ITT 
population. A PP analysis will be performed only if 10% or more ITT subjects are 
excluded from PP population.
The repeatability population is defined as all subjects who have a repeat clinical 
assessment (TPI) at any visit.
Any of the following will be considered a protocol violation which will warrant 
exclusion from efficacy analysis:
Violation of inclusion or exclusion criteria that are deemed to affect efficacy.
Medical history which is deemed to affect efficacy.
Use of prohibited treatment or medication before or during the study, which is 
felt to affect the assessment of efficacy.
 
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Not receiving randomized treatment.
Noncompliance on treatment washout
Further data listings will be included in the review of protocol violations but will be 
reviewed on a case-by-case basis to determine whether the data should be excluded 
from a PP. Full data listings will be provided inreview listing requirement document.
Protocol violations which warrant exclusion from efficacy analysis will be identified 
between the statistician and medical director or designee, ahead of database lock and 
breaking the study blind.
5.2
Subgroups/Stratification
There is no subgroup/Stratification in this study.
5.3
Time Windows
The study schedule should be followed as per protocol. Deviations from the study 
schedule with respect to visit timings will be reviewed on a case-by-case basis to 
determine whether the data should be excluded from PP analysis. Required time 
windows are presented below:
Visit 2 ─7-28daysfrom Visit 1
Visit 3─4-6days from Visit 2
Visit 4─4-6days from Visit 3
Visit 5─4-6days from Visit 4
Visit 6─4-6days from Visit 5.
6
Demographics and Baseline Characteristics
6.1
Subject Disposition
The subject disposition summary will include the number of screened subjects and 
screen failures overall andthe number of subjects randomised per treatment group 
and overall.
The number and percentage of subjects, in the Safety, ITT and PP populations will be 
presented per treatment group and overall. The percentages will be based upon the 
total number of subjects randomised.
 
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The number and percentage of subjects completing the study and not completing the 
study, including a breakdown of the reasons for not completing the study, will be 
presented per treatment group and overall. The percentages are based upon the total 
number of subjects randomised.
A separate summary table of protocol violations leading to exclusion from PP 
analyses will be produced indicating the number and percentage of subjects with each 
violation per treatment group and overall. Percentages will be based on the ITT 
population.
6.2
Demographics
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 data.These data include age, 
gender andethnicityand willbe presented for the Safety,ITT and PP populations.
6.3
Baseline Characteristics
Baseline efficacy measurements will be summarised in efficacy tables.
7
Treatment Compliance and Concomitant Medications
7.1
Treatment Compliance
Treatment compliance will be reviewed during blinded review and a listing will be 
produced for evaluation of protocol violations only. Non-compliance for extra/missed 
brushing will be assessed on a subject by subject basis. The data which are regarded 
as influenced by treatment non-compliance will be excluded from PP analysis. Any 
subject and/or timepointexcluded from PP analysis will be clearly documented in 
population definition document.
7.2
Concomitant Medications
Concomitant medication data will not be presented in the study report. A listing of
concomitant medications will be produced for evaluation of protocol violators only.
8
Efficacy Analysis
Turesky modification of Quigley Hein Plaque Index (TPI) is the efficacy measure of 
the study. Treatment comparisons are under the hypotheses:H0: ‘treatment difference 
 
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is null’ vs. Ha: ‘treatment difference is not null’. All statistical tests will be conducted 
at the two-sided 5% significance level. All analysis will be conducted in SAS 9.2.
The primary population for analysis will be ITT population.
8.1 Primary Efficacy Analysis
Primary efficacy endpoint will be the TPI score change from pre-brushing after a 
single brushing treatment. TPI score will be calculated as the average index over all 
tooth sites. Mixed effect ANCOVA model will be applied with treatment, study 
period as fixed effects, subject as a random effect and two baseline terms as 
covariates; (i) the subject-level baseline score calculated as the mean pre-brushing 
score across all periods within a subject, and (ii) the period level baseline minus the 
subject-level baseline.P-values for treatment comparisons, adjusted means of all 
treatments and treatment differences and their 95%CIs will be provided. 
The primary analysis will be the comparison between the positive control and the 
negative control. 
The assumption of residual normality and variance homogeneity in ANCOVA 
analysis will be investigated. If violated, data transformation or a non-parametric 
method (e.g., the Wilcoxon Signed-Ranktest) will be applied.If violation is caused 
by several extreme values, a sensitivity analysis maybe conducted by removing the 
extremevalues.
8.2 Secondary Efficacy Analysis
Only if the primary objective is met (comparison of 67% w/w sodium bicarbonate, 
versus a 0% sodium bicarbonate is significantat two-sided 5% level), will the 
remaining secondary analyses be fully conducted. Otherwise no P-values will be 
provided for secondary comparisons. Only the estimates of treatment differences and 
confidence intervals will be provided.
Secondary analyses include the following treatment comparisons:
1. 50% sodium bicarbonate dentifrice versus a 0% sodium bicarbonate dentifrice;
2. 35% sodium bicarbonate dentifrice versus a 0% sodium bicarbonate dentifrice;
3. 20% sodium bicarbonate dentifrice versus a 0% sodium bicarbonate dentifrice;
4. 50% sodium bicarbonate dentifrice versus a 67% sodium bicarbonate dentifrice;
5. 35% sodium bicarbonate dentifrice versus a 67% sodium bicarbonate dentifrice;
6. 20% sodium bicarbonate dentifrice versus a 67% sodium bicarbonate dentifrice.
 
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The analyses will be carried out by the same ANCOVA model in primary analysis.
In the ANCOVA analysis of the effects of the five treatments with different levels of
sodiumbicarbonate (0%, 20%, 35%, 50%, 67%), the linear and quadratic contracts 
will be tested for dose-response trendif the difference between the highest dose 
(67%) and lowestdose (0%) is significant. When a trend is significant(significance 
level 5%),a mixed effect regression (linear, quadratic etc) will be run to provide 
dose-response regression curve. For example the quadratic regression will take dose 
and dose2as explanatory variables and subject as random effect.The regression 
curve will be plotted together with the dose-response data. If neither linear model nor 
quadratic model appears to fit the data well(through residual check), other nonlinear 
models may also be considered.
8.3 Other Efficacy Analysis
Allsubjects whohave repeat plaque (TPI)assessments (conducted by the examiner) 
form the repeatability population which will be used for repeatability analysis.The 
repeat assessments will be compared to the original assessments. The repeat 
assessments will not be used in any efficacy analysis. The first and second 
assessments on each tooth at a given visit will be cross-tabulated and a weighted 
Kappa coefficient (κ) will be calculated, along with the 95% confidence interval, to 
assess the intra-examiner repeatability.  Repeatability will be deemed:
Excellent,
if κ> 0.75
Fair to good, if 0.4 ≤κ ≥ 0.75
Poor 
if κ< 0.4
All subjects who have repeatability data will be included in this analysis.
9
Safety Analysis
The safety profile of the study treatments will be assessed with respect to adverse 
events (AEs). Oral soft tissue (OST) abnormalities are included as AEs if they appear 
or worsen after the initial assessment. All safety data will be reported for the Safety 
population as per treatment received (using variable ATRT). All AEs will be 
reviewed by the Clinical Research Director or Scientistprior to database lock and 
unblinding and will be coded using the Medical Dictionary for Regulatory Activities 
 
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(MedDRA). During this review stage, AEs will be further categorized as oral or non-
oral. AEs will be regarded as treatment emergent if they occur on or after the start 
time of the first treatment application (as determined by EXSTDT and EXSTTM 
from the EXPOSURE panel if this date is missing a suitable alternative will be used 
eg date and time of randomisation). All other AEs prior to this will be considered 
non-treatment emergent. The following summary tables and listings will be presented 
by treatment group.
Table of treatment emergent AEs by Oral/Non-Oral and Preferred Term
Table of treatment emergent AEsby SOC and Preferred Term
Treatment emergent treatment related AEs by Oral/Non-Oral and Preferred 
Term
Listing of all AEs (including Non-treatment emergent).
Listing of serious AEs. (if there are none,a null listing will be produced)
No inferential analyses will be performed to compare treatments with respect to 
safety.
10
Interim Analysis
There is no interim analysis planned for this study.
11
ToplineSummary
11.1 Variables for topline
Efficacy
TPI score change from pre-brushing after a single brushing treatment. Both primary 
comparison and secondary comparisons will be provided.
Safety
Adverse events
11.2 Outputs for topline
 
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Datasets/Tables
Description
Datasets
PONNFL, POPNEXCL, RANDOM
ADSL, ADAE, ADTPI, STAT1, STAT2
Tables –Efficacy
No efficacy tables required if information can be 
obtained directly from stats datasets otherwise define 
here
Tables Safety
9.4.1 –Listing Of Adverse Events     Safety 
Population
If there are <10 AEs the listing will be enough else:-
9.4.2 –Summary Of Treatment Emergent Adverse 
Events     Safety Population
Figures
Generated from data from stats datasets
Non priority outputs
Table 9.1.1 –Subject Disposition
12
Changes to Planned Analysis
There is no change to the planned analysis.
13
References
GSKCH clinical study RH01445     Plaque Removal Efficacy of Four Dentifrices in 
a Single Brushing Model.
 
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Appendix 1 Study Schedule
Activity
Visit 1
Screening 
Visit 2 
Treatment 
Period 1
Visit 3
Treatment 
Period 2
Visit 4
Treatment 
Period 3
Visit 5
Treatment 
Period 4
Visit 6
Treatment 
Period 5
Informed Consent
X
7 to 28 days wash-in 
4 to 6 days washout
4 to 6 days washout
4 to 6 days washout
4 to 6 days washout
Demographics & Medical History
X
Current/concomitant medication
X
X
X
X
X
X
Oral soft tissue examination
X
X
X
X
X
X
Oral hard tissue examination
X
Plaque disclosure
X
Plaque assessment
X
Repeatability of plaque assessment in selection of 
subjects
X
X
X
X
X
X
Inclusion/Exclusion criteria
X1
X1 
Dispense wash-out toothpaste, toothbrush, countdown 
timer and diary card with verbal instructions
X
Return wash-out toothpaste, toothbrush and diary card
X
X
X
X
X
Re-dispense wash-out toothpaste, toothbrush and diary 
card
X
X
X
X
Pre-brushing plaque disclosure
X
X
X
X
X
Pre-brushing plaque assessment
X
X
X
X
X
Randomisation
X
Supervised brushing with assigned  toothpaste
X
X
X
X
X
Post brushing plaque disclosure
X
X
X
X
X
Post-brushing plaque assessment2
X
X
X
X
X
Brushing with washout toothpaste to remove stain 
from disclosing dye
X
X
X
X
X
X
Compliance check
X
X
X
X
X
Subject Adherence/Eligibility check
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Study Conclusion
X
1  Plaque (inclusion criteria 4 C) will be assessed at Visit 1 and Visit 2; use of antibiotics and Chlorhexidine mouthwashes (exclusion criteria 7 A and 8 K) at Visit 2 to determine eligibility to continue.
 
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Appendix 2List of Tables, Figures & Listings
Table No.
Table Title (including population)
Standard Template
9.1.1.1
Subject DispositionBy Treatment Group –All 
Screened Subjects
X
9.1.1.2
Subject Disposition By Treatment Group and 
Study Period –All Screened Subjects
X
9.1.2
Protocol Violations Leading To Exclusion 
From Per Protocol Analysis –ITT Population
X
9.2.1.1
DemographicCharacteristics –Safety 
Population
X
9.2.1.2
Demographic Characteristics –ITTPopulation X
9.3.1.1
Analysis Of Turesky PlaqueScore Change 
from Pre-brushing –ITTPopulation
App 3
9.3.1.2*
Analysis Of Turesky PlaqueScoreChange 
from Pre-brushing–PPPopulation
9.3.1.1
9.3.2
Repeatability Analysis Of Turesky Plaque
Index –Repeatability Population
App 3
9.4.1.1**
Listing OfAdverse Events –Safety Population X
9.4.1.2**
Listing Of Serious Adverse Events –Safety 
Population
X
9.4.2
Treatment Emergent Adverse Events By 
Oral/Non Oral And PT –Safety Population
X
9.4.3
Treatment Emergent Treatment Related 
Adverse Events By Oral/Non Oral And PT –
Safety Population
X
9.4.4
Treatment Emergent Adverse Events By SOC 
And PT –Safety Population
X
9.4.5***
Treatment Emergent Non-Serious Adverse 
Events By SOC And PT –Safety Population
X
*provided only if PP analysis is done.                                                                          
** If there are non AEs a NULL listing will be provided. For 9.4.1.2, if there are 
more than 5 serious AEs a table will be done instead of listing.                                                     
 
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*** Provided only if there are more than 5 serious AEs.
FIGURES
Figure
No.
FigureTitle (including population)
Standard Template
9.1
Mean Turesky Plaque Score By Treatment –
ITTPopulation
App 3
9.2
Scatter Plot With Regression Curve Over Dose 
Range [0,67] (% sodium bicarbonate)–ITT 
Population
App 3
 
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Appendix 3Templates for Tables, Figures & Listing
Treatment headers will be: Test 1; Test 2; Test 3; Positive Control; Negative Control.
For all tables add footnotes
Test1:Experimental dentifrice containing 20% w/w sodium bicarbonate
Test 2: Experimental dentifrice containing 35% w/w sodium bicarbonate 
Test 3: Experimental dentifrice containing 50% w/w sodium bicarbonate 
Positive Control: Dentifrice containing 67% w/w sodium bicarbonate(German marketed Parodontax Classic (non-fluoride) Toothpaste)
Negative Control: Dentifrice containing 0% w/w sodium bicarbonate(UK marketed Macleans Fresh Mint Toothpaste –1450 ppm Fluoride)
 
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CCI


Protocol: 206886                                                                                                      Program Run Date: ddmonyyyy
Table 9.3.1.1
AnalysisOf Turesky PlaqueScore Change from Pre-brushing
ITT Population
Study Population: ITT (N=xxx)
Test 1
(N=xx)
Test 2
(N=xx)
... 
Positive Control
(N=xxx)
Negative Control
    (N=xx)
Raw       Change
Raw       Change 
... 
Raw       Change
   Raw       Change
Pre-brushing             
       
       
       
       
    N*
XX
XX
... 
XX
   XX
    MEAN
X.XX
X.XX
...
X.XX
  X.XX
    SD
X.XXX
X.XXX
...
X.XXX
  X.XXX
    SE
X.XXX
X.XXX
...
X.XXX
  X.XXX
    MEDIAN
X.XX
X.XX
...
X.XX
  X.XX
    MINIMUM
X.X
X.X
...
X.X
  X.X
    MAXIMUM
X.X
X.X
...
X.X
  X.X
Post-brushing             
    N*
XX         XX 
XX         XX
... 
XX         XX
   XX         XX
    MEAN
X.XX       X.XX
X.XX      X.XX
...
X.XX      X.XX
  X.XX      X.XX
    SD
X.XXX      X.XXX
X.XXX     X.XXX 
...
X.XXX     X.XXX
  X.XXX     X.XXX
    SE   
X.XXX      X.XXX
X.XXX     X.XXX 
...
X.XXX     X.XXX
  X.XXX     X.XXX
    MEDIAN
X.XX       X.XX
X.XX      X.XX
...
X.XX      X.XX
  X.XX      X.XX
    MINIMUM
X.X        X.X
X.X       X.X
...
X.X       X.X
  X.X       X.X
    MAXIMUM
X.X        X.X
X.X       X.X
...
X.X       X.X
  X.X       X.X
    ADJUSTED MEAN [1]
           X.XX
X.XX      X.XXX 
...
X.XX      X.XX
  X.XX      X.XX
SE[1]
           X.XXX
          X.XXX               
...
X.XXX     X.XXX
  X.XXX     X.XXX
TREATMENT COMPARISONS [1]
DIFFERENCE(CI)[1][2]
          P-VALUE[1]           
   Pos.Control vs. Neg.Control
  Test 1 vs. Neg.Control
   Test 2 vs. Neg.Control
   Test.3 vs. Neg.Control
   Test 1 vs. Pos.Control
   Test.2 vs. Pos.Control
   Test 3 vs. Pos.Control
   Linear Contrast
   Quadratic Contrast
    X.XX (X.XX, X.XX)
X.XX (X.XX, X.XX)
X.XX (X.XX, X.XX)
X.XX (X.XX, X.XX)
X.XX (X.XX, X.XX)
X.XX (X.XX, X.XX)
X.XX (X.XX, X.XX)
          0.XXXX
          0.XXXX**
          0.XXXX**
          0.XXXX**
          0.XXXX**
          0.XXXX**
          0.XXXX**
          0.XXXX**
          0.XXXX**
*Number of subjects with non-missing values
**P-value for test products against two controls will be provided only if Pos.Control vs neg.Control is significant.
[1] From ANCOVA analysis for change from pre-brushing with treatment and period as fixed effect, subject as random effect, subject-level baseline and period-
levelminus subject-level baseline as covariates.
[2] Difference is first named treatment minus second named treatment such that a negative difference favors the first namedtreatment
                                                                                                                                  (Page X of Y)
                                                                 
 
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Protocol: 206886                                                                                                    Program Run Date: ddmonyyyy
Table 9.3.2
Repeatability Analysis of Turesky PlaqueIndex 
Repeatability Population
Study Population: Repeatability (N=xx)
_________________________________________________________________________________________________________________________________________________
                                                                        Second Assessment
                             -------------------------------------------------------------------------------------------------------------
First Assessment [1]          Missing             0                1                2                3                4                
_________________________________________________________________________________________________________________________________________________
MISSING                        xx              xx                xx               xx               xx               xx               
    0                           xx              xx (xx.x%)        xx (xx.x%)       xx (xx.x%)       xx (xx.x%)       xx (xx.x%)       
    1                           xx              xx (xx.x%)        xx (xx.x%)       xx (xx.x%)       xx (xx.x%)       xx (xx.x%)       
    2                           xx              xx (xx.x%)        xx (xx.x%)       xx (xx.x%)       xx (xx.x%)       xx (xx.x%)       
    3                           xx              xx (xx.x%)        xx (xx.x%)       xx (xx.x%)       xx (xx.x%)       xx (xx.x%)       
    4                           xx              xx (xx.x%)        xx (xx.x%)       xx (xx.x%)       xx (xx.x%)       xx (xx.x%)       
    
WEIGHTED KAPPA = 0.xxx
95% C.I. = 0.xxx, 0.xxx
________________________________________________________________________________________________________________________________________________
                                                                                                                                
Note: Percentages are based on total of all non-missing combinations
[1] The first assessment is the one used in the efficacy analysis.
0: No plaque                                                                                                                                             
1: Slight flecks of plaque at the cervical margin of the tooth                                                                                           
2: A thin continuous band of plaque (1 mm or smaller) at the cervical margin of the tooth                                                                
3: A band of plaque wider than 1 mm but covering less than 1/3 of the crown of the tooth                                                                 
4: Plaque covering at least 1/3 but less than 2/3 of the crown of the tooth                                                                              
5: Plaque covering 2/3 or more of the crown of the tooth                                                                          
                                                                                                                                   (Page X of Y)
                                                                    
 
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eldo_clinical_doc
1.0; CURRENT; Most-Recent; Effective
206886 SAP
Auto Issue
090032d580cd9b2d
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Protocol: 206886                                                                                          Program Run Date: DDMMMYYYY
Figure 9.1
Mean TPI change from pre-brushing (±SE) by treatment
ITT Population
Study Population: ITT (N=xxx)
                                            
.
                                                             
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
Negative 
Control
Test 1 
Test 2 
Test 3
Postive 
Control 
TPI change from pre-brushing 
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
04-Jan-2017 09:07:54
eldo_clinical_doc
1.0; CURRENT; Most-Recent; Effective
206886 SAP
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090032d580cd9b2d
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Protocol: 206886                                                                                          Program Run Date: DDMMMYYYY
Figure 9.2
Scatter plot with regression curve over dose range [0,67] (% sodium bicarbonate) 
ITT Population
Study Population: ITT (N=xxx)
                                    
Regressioncurve: TPI change=a +b*dose+c*dose2 from mixed effect model with dose, dose2 as regressors and subject as random effect.
                                                            
Dose (Sodium Bicarbonate %)
TPI change from pre-brushing
0
20
35
50
67
0.2
0.0
-0.2
-0.4
-0.6
-0.8
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
04-Jan-2017 09:07:54
eldo_clinical_doc
1.0; CURRENT; Most-Recent; Effective
206886 SAP
Auto Issue
090032d580cd9b2d
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Approved
 
Biostatistics Approval
04-Jan-2017 09:07:47
206886 SAP
03-Jan-2017 10:59:49
 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
04-Jan-2017 09:07:54
 
eldo_clinical_doc
1.0; CURRENT; Most-Recent; Effective
206886 SAP
Auto Issue
090032d580cd9b2d
Page 23 of 23
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