Clinical trial NCT06150573
Conditions: Dentin Sensitivity Oral Hygiene
Sponsor: HALEON
Start date: 2023-11-27; Completion date: 2024-07-18
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main aim of this study is to investigate the ability of an experimental dentifrice containing 5 percent (%) potassium nitrate (KNO3), 1% alumina and 5% sodium tripolyphosphate (STP), to maintain tooth color and reduce extrinsic dental stain accumulation following peroxide tooth bleaching compared to a regular fluoride dentifrice.

Detailed description:
This will be a randomized, single-blind, single-center, controlled, two arm, stratified (clinically diagnosed dentine hypersensitivity \[DH\] \[Yes/No\]), parallel group study to evaluate the efficacy of an experimental dentifrice containing 5% KNO3, 1% alumina and 5% STP, to maintain tooth color and reduce the accumulation of extrinsic tooth stain following peroxide tooth bleaching compared to a regular fluoride-containing dentifrice. The study will recruit generally healthy participants who wish to undergo peroxide tooth bleaching. Sufficient participants will be screened to randomize approximately 160 participants to study treatment to ensure approximately 128 evaluable participants complete the study.

Arms: arm 1: Participants will dose the toothbrush provided with a strip of test dentifrice (5% KNO3, 1% alumina, 5% STP and 1150 parts per million \[ppm\] fluoride as sodium fluoride) and will brush for two timed minutes twice daily (morning and evening) for up to 27 weeks (dentifrice will be used for 2 weeks pre peroxide, 1 week during peroxide and 24 weeks post peroxide application). At Week 3, participants will perform the first application of peroxide tooth bleaching as per the instructions provided and continue the application daily for up to 7 days. arm 2: Participants will dose the toothbrush provided with a strip of reference dentifrice (dentifrice containing 1150 ppm fluoride as sodium fluoride) and will brush for two timed minutes twice daily (morning and evening) for up to 27 weeks (dentifrice will be used for 2 weeks pre peroxide, 1 week during peroxide and 24 weeks post peroxide application). At Week 3, participants will perform the first application of peroxide tooth bleaching as per the instructions provided and continue the application daily for up to 7 days.
Interventions: intervention 1: Test Dentifrice intervention 2: Reference Dentifrice (Aquafresh Cavity Protection)
Intervention descriptions: intervention 1: Dentifrice containing 5% weight by weight (w/w) KNO3, 1% alumina, 5% STP and 1150 ppm fluoride as sodium fluoride. intervention 2: Dentifrice containing 1150 ppm fluoride as sodium fluoride.

Protocol documents:
Prot_000.pdf: 
Haleon
Clinical Protocol
Protocol Number: 300109
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CLINICAL PROTOCOL
A Randomized, Controlled, Single-Blind Clinical Study Assessing 
the Effects of an Experimental Dentifrice in Maintaining Tooth Color 
Following Tooth Bleaching
Protocol Number:
300109
Compound/Product Name:
Potassium Nitrate Dentifrice
United States (US) Investigational 
New Drug (IND) Number:
N/A
European Clinical Trials Database 
(EudraCT) Number:
N/A
Other Regulatory Agency Identified 
Number:
N/A
Phase:
N/A
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Sponsor Information
Sponsor Name & Legal 
Registered Address
Haleon (UK) 
St Georges Avenue,
Weybridge,
Surrey,
KT13 0DE,
United Kingdom (UK)
Sponsor Contact Details
Haleon
184 Liberty Corner Road, Warren, NJ, USA
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Document History
Document
Version
Summary of Changes 
Original protocol
1.0
Not applicable (N/A)
Amendment 1
2.0
Change of the peroxide bleaching treatment from 
Captivate to Opalescence and update of associated 
application instructions.
Removal of custom fitting of tray (no longer required 
with Opalescence peroxide trays).
Addition of return of peroxide kit at Visit 3
Alignment of name of “Whitening history” and “Post-
whitening” questionnaires throughout.
Deletion of statement that questionnaire and diaries 
will be sourced by the study site.
Amendments incorporate all revisions to date, including amendments made at the request of 
country health authorities, institutional review boards/ethics committees (IRBs/ECs), etc.  
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Principal Investigator Protocol Agreement Page
•
I confirm agreement to conduct the study in compliance with the protocol and any 
amendments according to the current International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) guidelines.
•
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
•
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure site staff 
receives all appropriate information throughout the study.
•
I agree to conduct this study in full conformance with the laws and regulations of the 
country in which the research is conducted and the Declaration of Helsinki.
Investigator Name:
Investigator Qualifications:
Investigator Signature:
Date of Signature/Agreement:
DD-Mmm-YYYY
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Table of Contents
Sponsor Information............................................................................................................2
Document History ...............................................................................................................3
Principal Investigator Protocol Agreement Page ................................................................4
Table of Contents ................................................................................................................5
PROTOCOL SUMMARY .........................................................................................................9
1.1
Synopsis...................................................................................................................9
1.2
Schedule of Activities............................................................................................12
2
INTRODUCTION.............................................................................................................14
2.1
Study Rationale......................................................................................................14
2.2
Background............................................................................................................15
2.3
Benefit/Risk Assessment .......................................................................................15
2.4
Mechanism of Action/Indication ...........................................................................16
3
STUDY OBJECTIVES AND ENDPOINTS ....................................................................16
4
STUDY DESIGN ..............................................................................................................17
4.1
Overall Design.......................................................................................................17
4.2
Scientific Rationale for Study Design ...................................................................20
4.3
Justification for Dose.............................................................................................21
4.4
End of Study Definition.........................................................................................21
5
STUDY POPULATION....................................................................................................22
5.1
Type and Planned Number of Subjects .................................................................22
5.2
Inclusion Criteria ...................................................................................................22
5.3
Exclusion Criteria..................................................................................................23
5.4
Randomization Criteria..........................................................................................24
5.5
Lifestyle Considerations........................................................................................24
5.5.1
Oral Hygiene Restrictions.....................................................................24
5.5.2
Dietary Restrictions...............................................................................24
5.5.3
Use of Cosmetics ..................................................................................24
5.5.4
Medication and Treatment Restrictions ................................................24
5.5.5
Contraception........................................................................................25
5.6
Screen Failures.......................................................................................................25
5.7
Sponsor’s Qualified Medical Personnel ................................................................25
5.8
Clinical Examiner Qualifications ..........................................................................25
6
INVESTIGATIONAL/STUDY PRODUCTS...................................................................25
6.1
Investigational/Study Product Supplies.................................................................26
6.1.2
Medical Devices....................................................................................28
6.1.3
Dosage Form and Packaging.................................................................28
6.1.4
Preparation and Dispensing...................................................................28
6.2
Administration.......................................................................................................29
6.2.1
Product Usage Errors ............................................................................29
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6.2.2
Overdose ...............................................................................................30
6.3
Investigational/Study Product Storage ..................................................................30
6.4
Investigational/Study Product Accountability.......................................................30
6.4.1
Destruction of Investigational/Study Product Supplies ........................31
6.5
Blinding and Allocation/Randomization...............................................................31
6.6
Breaking the Blind.................................................................................................31
6.7
Compliance............................................................................................................32
6.8
Concomitant Medication/Treatment(s)..................................................................32
7
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .........................................................................33
7.1
Subject Discontinuation/Withdrawal.....................................................................33
7.2
Lost to Follow up...................................................................................................33
8
STUDY PROCEDURES...................................................................................................34
8.1
Visit 1/Screening ...................................................................................................34
8.1.1
Screening Procedures............................................................................34
8.2
Study Period ..........................................................................................................36
8.2.1
Visit 2/ start of peroxide tooth bleaching..............................................36
8.2.2
Visit 3/ End of tooth bleaching .............................................................37
8.2.3
Visit 4 /12 weeks post tooth bleaching .................................................37
8.2.4
Visit 5 /24 weeks post tooth bleaching .................................................37
8.2.5
Study Procedures...................................................................................38
9
STUDY ASSESSMENTS.................................................................................................38
9.1
Screening Assessments..........................................................................................39
9.1.1
OST Examination..................................................................................39
9.1.2
OHT Examination.................................................................................39
9.1.3
Dentine Hypersensitivity Assessments .................................................39
9.1.4
Assessment of Tooth Color and Extrinsic Tooth Stain.........................41
9.2
Efficacy Assessments ............................................................................................41
9.2.1
Tooth Color Assessment .......................................................................41
9.2.2
Macpherson Modification of the Lobene Stain Index (MLSI) .............42
9.2.3
Tooth Sensitivity Questionnaire............................................................43
9.2.4
Whitening History and Post-Whitening Questionnaires.......................44
9.3
Safety and Other Assessments...............................................................................44
9.3.1
Oral Soft Tissue (OST) Examination....................................................44
9.3.2
Oral Hard Tissue (OHT) Examination..................................................44
9.3.3
Pregnancy Testing.................................................................................45
10 ADVERSE EVENT AND SERIOUS ADVERSE EVENTS ...........................................45
10.1
Definition of an Adverse Event (AE) ....................................................................45
10.2
Definition of a Serious Adverse Event (SAE).......................................................46
10.3
Time Period and Frequency for Collecting AE and SAE Information..................47
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10.4
Reporting Procedures.............................................................................................47
10.4.1
Reporting of an Adverse Event.............................................................48
10.4.2
Reporting of a Serious Adverse Event..................................................48
10.5
Evaluating Adverse Events....................................................................................49
10.5.1
Assessment of Intensity ........................................................................49
10.5.2
Assessment of Causality .......................................................................49
10.6
Follow-up of AEs and SAEs..................................................................................50
10.7
Withdrawal Due to an Adverse Event ...................................................................50
10.8
Regulatory Reporting Requirements for SAEs......................................................51
10.9
Pregnancy ..............................................................................................................51
10.9.1
Time Period for Collecting Pregnancy Information..............................51
10.9.2
Action to be Taken if Pregnancy Occurs ..............................................51
10.10 Medical Device Incidents ......................................................................................51
10.10.1
Definition of an Incident.......................................................................52
10.11 Reporting of Incidents and Malfunctions ..............................................................52
10.12 Follow-up of Medical Device Incidents ................................................................53
10.13 Regulatory Reporting Requirements for Medical Device Incidents......................53
11 DATA MANAGEMENT..................................................................................................53
11.1
Case Report Form..................................................................................................54
11.2
Data Handling........................................................................................................54
11.2.1
Data Queries..........................................................................................55
11.3
Processing Patient Reported Outcomes.................................................................55
12 STATISTICAL CONSIDERATIONS AND DATA ANALYSES ..................................55
12.1
Sample Size Determination ...................................................................................55
12.2
Populations for Analysis........................................................................................56
12.3
Statistical Analyses................................................................................................56
12.3.1
Primary Analysis...................................................................................56
12.3.2
Secondary Analyses ..............................................................................57
12.3.3
Exploratory Analysis.............................................................................57
12.3.4
Safety Analyses.....................................................................................58
12.3.5
Other Analyses......................................................................................58
12.3.6
Exclusion of Data from Analysis ..........................................................59
12.3.7
Demographic and Baseline Characteristics...........................................59
12.3.8
Study Product Compliance....................................................................59
12.3.9
Handling of Dropouts and Missing Data ..............................................59
12.3.10
Interim Analysis....................................................................................59
13 STUDY GOVERNANCE CONSIDERATIONS..............................................................60
13.1
Quality Control......................................................................................................60
13.2
Quality Assurance..................................................................................................60
13.3
Regulatory and Ethical Considerations .................................................................60
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13.3.1
Institutional Review Board/ Ethics Committee.....................................60
13.3.2
Ethical Conduct of the Study ................................................................61
13.3.3
Subject Information and Consent..........................................................61
13.3.4
Subject Recruitment..............................................................................61
13.3.5
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP...............................................................................................62
13.4
Posting of Information on Publicly Available Clinical Trial Registers.................62
13.5
Provision of Study Results to Investigators...........................................................62
13.6
Records Retention..................................................................................................62
13.7
Conditions for Terminating the Study...................................................................63
14 REFERENCES..................................................................................................................64
15 APPENDICIES..................................................................................................................66
15.1
ABBREVIATIONS...............................................................................................66
15.2
Study Product Usage Instructions Sheet................................................................68
15.3
Tooth Sensitivity Questionnaire (EXAMPLE)......................................................69
15.4
Whitening History Questionnaire..........................................................................71
15.5
Post-Whitening Questionnaire...............................................................................72
List of in text tables
Table 1-1
Schedule of Activities ...........................................................................12
Table 3-1
Study Objectives and Endpoints ...........................................................16
Table 6-1
Investigational/Study Product Supplies ................................................26
Table 6-2
Sundry Items .........................................................................................27
List of figures
Figure 4-1
Schematic of Flow of Key Study Assessments/Procedures..................19
Figure 9-1
MLSI Assessment Sites: Body (B), Gingival (G), Mesial (M), 
Distal (D)...............................................................................................42
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PROTOCOL SUMMARY 
1.1
Synopsis
Short Title:
Randomised, Controlled Clinical Study Assessing the Effects of an Experimental Dentifrice in 
Maintaining Tooth Color Following Tooth Bleaching
Background and Rationale:
The main aim of this study is to investigate the ability of an experimental dentifrice containing 
5% potassium nitrate (KNO3), 1% alumina and 5% sodium tripolyphosphate (STP), to maintain 
tooth color and reduce extrinsic dental stain accumulation following peroxide tooth bleaching 
compared to a regular fluoride dentifrice.  Additionally, the ability of the test dentifrice to 
reduce tooth sensitivity concurrent with peroxide tooth bleaching will be explored.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To compare tooth color after 24 weeks twice daily use of a ‘5% 
KNO3/1% alumina/5% STP’ dentifrice compared to a regular 
fluoride dentifrice following peroxide tooth bleaching as measured 
by VITA Bleachedguide 3D-Master.
Mean VITA shade score at 24 
weeks after tooth bleaching.
Secondary
To compare tooth color after 12 weeks twice daily use of a ‘5% 
KNO3/1% alumina/5% STP’ dentifrice compared to a regular 
fluoride dentifrice following peroxide tooth bleaching as measured 
by VITA Bleachedguide 3D-Master.
Mean VITA shade score at 12 
weeks after tooth bleaching.
To compare extrinsic dental stain after 12 and 24 weeks, twice 
daily use of a ‘5% KNO3/1% alumina/5% STP’ dentifrice compared 
to a regular fluoride dentifrice following peroxide tooth bleaching
as measured by Modified Lobene Stain Index.
Mean MLSI at 12 and 24 
weeks after tooth bleaching in:
•
Total MLSI (Area (A) x
Intensity (I))
•
Gingival sites (AxI)
•
Interproximal sites (AxI)
•
Body sites (AxI)
•
MLSI (A)
•
MLSI (I)
Exploratory
To compare subject-perceived tooth sensitivity during peroxide 
tooth bleaching with twice daily use of a ‘5% KNO3/1% 
alumina/5% STP’ dentifrice compared to a regular fluoride 
dentifrice, as measured by subject-completed sensitivity 
questionnaire overall and within strata (clinically-diagnosed DH 
[Y/N]).
Mean sensitivity questionnaire 
scores pre and post peroxide 
tooth bleaching in:
•
Visual analogue scale
(VAS)
•
Labelled Magnitude scales
(Intensity, Duration. 
Tolerability, Description) - LMS
•
Bothersomeness score -
NRS
To explore subject’s experience of peroxide tooth bleaching when 
simultaneously using either a ‘5% KNO3/1% alumina/5% STP’ 
dentifrice or a regular fluoride dentifrice.
Post-whitening questionnaire
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To confirm the tooth whitening efficacy of peroxide tooth bleaching 
with concurrent, twice daily use of ‘5% KNO3/1% alumina/5% 
STP’ dentifrice and a regular fluoride dentifrice as measured by 
VITA Bleachedguide 3D Master.
Change in mean VITA shade 
score from pre to post tooth 
bleaching
Safety
To assess the safety and tolerability of a ‘5% KNO3/1% 
alumina/5% STP’ dentifrice.
Treatment emergent adverse 
events
Abbreviations: MLSI: Modified Lobene Stain Index, VAS: Visual Analogue Scale, LMS: Labelled Magnitude 
Scales, NRS: Numerical Rating Scale.
Study Design:
This will be a randomized, single-blind, single-center, controlled, two arm, stratified (clinically 
diagnosed DH (Y/N)), parallel group study to evaluate the efficacy of an experimental dentifrice 
containing 5% potassium nitrate (KNO3), 1% alumina and 5% sodium tripolyphosphate (STP), 
to maintain tooth color and reduce the accumulation of extrinsic tooth stain following peroxide 
tooth bleaching compared to a regular fluoride-containing dentifrice.  The study will recruit 
generally healthy subjects who wish to undergo peroxide tooth bleaching.
Potential subjects will attend a screening visit (Visit 1) to determine their suitability to 
participate.  Having obtained their written informed consent, relevant details of their 
demography, medical history and current medications will be recorded, followed by oral soft 
tissue (OST) and oral hard tissue (OHT) examinations.  Subjects will undergo an assessment of 
the tooth color (shade) of the facial surfaces of the six maxillary anterior teeth (tooth numbers 
6-11) [Universal tooth numbering system] using the VITA Bleachedguide 3D-MASTER 
(Gomez-Polo et al., 2015) and extrinsic tooth stain on the facial surfaces of the same teeth using 
the MacPherson modification (Macpherson et al., 2000) of the Lobene Stain Index(Lobene, 
1968) (MLSI).  Those subjects with a self-reported history of dentine hypersensitivity (DH) 
will be clinically-evaluated to confirm their DH status (including Erosion/Abrasion/Recession
(EAR) assessment, gingival assessment, tooth mobility assessment and evaporative (air) 
sensitivity assessment (Schiff Sensitivity score)). 
Subjects meeting all study criteria, will be considered as eligible to proceed, stratified (based 
upon their clinically-diagnosed DH status [Y/N]) and randomized to treatment group.  
Randomized subjects will then complete the tooth sensitivity questionnaire.  Subjects will be 
dispensed their study products (including diary and sundry items) and undertake a supervised 
brushing with their allocated dentifrice at the clinical site and be scheduled to attend Visit 2 (2 
weeks ± 2 days after Screening/Randomization).  Subjects will continue to use their allocated 
study products (twice-daily) throughout the study and will record this usage in their study diary.
At Visit 2 (2 weeks after Screening/randomization) subjects will undergo a review of their diary 
and current medications and will then undergo an OST examination.  Tooth color and extrinsic 
tooth stain will be assessed for the same teeth in the same way as at Visit 1.  Subjects who fulfil 
all inclusion/exclusion criteria will continue in the study and will complete the tooth sensitivity 
questionnaire and the whitening history questionnaire.  Subjects will have their tooth bleaching 
tray custom made per manufacturer’s instructions (at the examiner’s discretion this can be 
performed at Visit 1 instead).  Subjects will then be dispensed a commercially available 15% 
peroxide tooth bleaching kit for use at home for 7 days, once per day, as per pack instructions 
Subjects will undergo a supervised tooth brushing (with their study dentifrice) and will floss
their teeth and have their first application of the peroxide bleaching at the study site under 
supervision in accordance with the manufacturer’s instructions.  Subjects will be instructed in 
the correct use of the peroxide product for at home use in accordance with the manufacturer’s 
instructions. Subjects will continue to use their assigned dentifrice twice daily and perform 
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their peroxide bleaching daily per instructions, and to record this usage in their supplied diary.  
Subjects will be scheduled to return to the study site for Visit 3 (after the completion of their 7 
-days tooth bleaching period).
After the completion of the tooth bleaching period at Visit 3 [7 days after the commencement 
of tooth bleaching, with an acceptable range of 7-9 days] subjects will return to the clinical site 
and undergo a review of their diary and current medications and undergo an OST examination.  
Tooth color and extrinsic tooth stain will be assessed for the same teeth in the same way as at 
Visit 1.  Subjects will then complete the tooth sensitivity questionnaire and the post-whitening 
questionnaire and scheduled to return for Visit 4 (12 weeks [±1 week] after completion of the
peroxide tooth bleaching).
At Visit 4 subjects will return to the clinical site and undergo a review of their diary and current 
medications and an OST examination.  Tooth color and extrinsic tooth stain will be assessed 
for the same teeth in the same way as at Visit 1.  Subjects will then be scheduled to return for 
Visit 5 (24 weeks [±1 week] after completion of the peroxide tooth bleaching).
At Visit 5 subjects will return to the clinical site and return their study products and undergo a 
review of their diary and current medications and an OST and OHT examination.  Tooth color 
and extrinsic tooth stain will be assessed for the same teeth in the same way as at Visit 1.  
Subjects will then exit the study.
Safety and oral tolerability of the study products will be monitored over the duration of the 
study by review of reported AEs and through Oral Soft Tissue examinations.  Medical device 
incidents will also be monitored for the device in this study which is the study toothbrushes.
Study Products:
Experimental Dentifrice
Reference Dentifrice
5% KNO3 dentifrice with 1% alumina and 
5% STP 
Regular Fluoride Dentifrice 
(Aquafresh Cavity Protection, US market)
Each study dentifrice will contain 0.2542% sodium fluoride
(1100 parts per million (ppm) fluoride)
Type and Planned Number of Subjects:
Study subjects will be of either sex and any gender, aged 18-65 years, in good general and oral 
health, with the required level of tooth color and who are willing and able to undergo peroxide 
tooth bleaching.
Sufficient subjects will be screened to randomize approximately 160 subjects to study 
treatment (approximately 80 per treatment group) to ensure approximately 128 evaluable 
subjects complete the study with an assumed dropout rate of 20%.  Subjects will be stratified 
according to their clinically-diagnosed DH status [Clinically diagnosed DH (Y/N)].
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1.2
Schedule of Activities
The schedule of activities table provides an overview of the subject visits and study procedures.  
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, to conduct evaluations or assessments 
required to protect the well-being of the subject.
Table 0-1
Schedule of Activities
Procedure/Assessment
Screening
/Randomization
Study Period
Visit 1
Visit 2
(Start of tooth 
bleaching)
Visit 3
(End of tooth 
bleaching)
Visit 4
(12 weeks post 
tooth bleaching)
Visit 5
(24 weeks post 
tooth bleaching)
Informed consent
X
2 Weeks ±2days
7 days (acceptable range 7-9 days)
12 weeks ±1week
12 weeks ±1week
Demographics
X
Medical history
X
Current/prior/concomitant medication review
X
X
X
X
X
OST Examination
X
X
X
X
X
OHT Examination
X
X
Assessment of tooth color and extrinsic tooth stain1
X
X
X
X
X
DH assessments (EAR, MGI, tooth mobility and evaporative air 
sensitivity)2
X
Review of inclusion/exclusion criteria
X
Subject eligibility
X
Stratification followed by randomization to treatments3
X
Subject completes tooth sensitivity questionnaire at site4
X
X
X
Dispense study products, sundry items and diary
X
Supervised toothbrushing at site
X
X
Diary review
X
X
X
X
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Procedure/Assessment
Screening
/Randomization
Study Period
Visit 1
Visit 2
(Start of tooth 
bleaching)
Visit 3
(End of tooth 
bleaching)
Visit 4
(12 weeks post 
tooth bleaching)
Visit 5
(24 weeks post 
tooth bleaching)
Subject continuance
X
Whitening History Questionnaire
X
Subject returns used peroxide kit
X
Subject dispensed bleaching treatment, petroleum jelly and 
floss for at home use with first application at study site under 
supervision5
X
Post-Whitening Questionnaire
X
Adverse events review6
X
X
X
X
X
Medical device incidents review6
X
X
X
X
X
Return study products, diary and sundry items
X
Study conclusion
X
Abbreviations: OST: Oral Soft Tissue, OHT: Oral Hard Tissue, MLSI: Modified Lobene Stain Index, LMS: Labelled Magnitude Scales, VAS: Visual analogue Scale, NRS: Numerical Rating Scale.
Footnotes:
1.
Tooth color (Vita Bleachedguide 3D Master) and tooth stain (MLSI) assessed on facial surfaces of the maxillary anterior 6 teeth (tooth numbers 6-11).
2.
Only subjects with a self-reported history of DH will be clinically assessed for DH.
3.
Stratification will be based on clinically-diagnosed DH (Y/N) at screening.
4.
The tooth sensitivity questionnaire will include Labelled Magnitude Scales (LMS) and a Visual Analogue Scale (VAS) to assess tooth sensitivity and a Numerical Rating Scale
(NRS).
5.
The supplied tooth bleaching treatment will be used once under supervision at the study site (for first application) and then daily, at home (for a total of 7 days) in accordance with 
the manufacturer’s instructions.
6.
Adverse Events (AEs), Serious Adverse Events (SAEs) and medical device incidents collected immediately after subject provides consent to participate in the study by the 
completion of the Informed Consent Form (ICF).  Medical device in this study is the supplied toothbrush.
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2
INTRODUCTION
Tooth bleaching is a widely performed treatment that aims to improve the color (increase 
whiteness) of teeth to provide a cosmetic benefit.  The most commonly used bleaching 
ingredient is hydrogen peroxide (or hydrogen peroxide-releasing ingredients such as carbamide 
peroxide), which functions by diffusing through the tooth enamel and oxidizing chromophores 
within the porous matrix of enamel and the underlying dentine.  This has the effect of reducing 
the color within the tooth making the teeth appear whiter.  The whitening benefit though is not 
permanent, with exposure to dietary chromogens eventually causing tooth color to return.  The 
duration of the whitening benefit is therefore patient-specific with estimates ranging from a few 
months to 3 years (UK National Health Service, 2023).  One study, however, found a reduction 
in the whitening benefit in as little as 7 days (Lunardi and Correr, 2014), and another after 10 
months (Corcodel et al., 2017).  It is therefore of interest to investigate whether a topical, daily-
use dentifrice can help maintain tooth color following peroxide tooth bleaching.
Additionally, a common side effect of tooth bleaching is tooth sensitivity, the prevalence of 
which ranges from 10%-90% (West, 2023a), depending on the type, concentration and 
application method of the bleaching agent.  Tooth sensitivity is most often reported for 
peroxide-based bleaching agents and usually occurs at the time of treatment and can last from 
several days up to 2 weeks.  Peroxide has been shown to have the ability to diffuse through the 
enamel into the enamel-dentin junction and the dentin and induce localized reversible pulpitis. 
Tooth sensitivity management works on the principle of either employing potassium-based 
agents aiming to stabilize pulpal nerve depolarization, or dentinal tubule occlusion agents 
aiming to occlude patent dentinal tubules (Pollard et al., 2023).  However, the number of 
published studies in support of potassium-based dentifrices to reduce tooth sensitivity 
experienced during tooth bleaching are few (and the results have not been confirmed with 
follow-up studies) and the studies employed low numbers of subjects (Haywood et al., 2005, 
Pierote et al., 2019, 
). Therefore, conclusions from these 
published studies are difficult to interpret with any certainty and further studies are needed to 
explore the efficacy of potassium-containing dentifrice to reduce tooth sensitivity experienced 
during tooth bleaching.
The primary aim of this study is to evaluate whether an experimental dentifrice containing 5% 
potassium nitrate (KNO3), 1% alumina and 5% sodium tripolyphosphate (STP) is able to better 
maintain tooth color after peroxide tooth bleaching.
2.1
Study Rationale
This 24-week, randomized, controlled, 2 arm, parallel-design, stratified (clinically diagnosed 
DH (Y/N)) clinical study has been designed to evaluate the ability of an experimental dentifrice 
containing 1% alumina, 5% STP and 5% KNO3 to maintain tooth color and reduce extrinsic 
dental stain accumulation following peroxide tooth bleaching compared to a regular fluoride 
dentifrice.  Additionally, the ability of the test dentifrice to reduce tooth sensitivity concurrent 
with peroxide tooth bleaching will be explored.
Whilst the dental stain removal and tooth whitening properties of dentifrices containing 1% 
alumina with 5% STP has been demonstrated (see Section 2.2); additional data are required to 
support new claims and benefits of the experimental dentifrice specifically when used 
concomitantly with and post peroxide tooth bleaching.
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2.2
Background
Dentifrices containing 1% alumina and 5% STP have been evaluated previously in five 
unpublished clinical studies (Haleon Clinical Study 300024, 2023, 
, 
).  These studies, taken as a whole, demonstrate 
the ability of dentifrice containing 1% alumina and 5% STP to whiten teeth, reduce dental stain 
and help reduce further dental stain.  None of these studies, however, evaluated the use of 
dentifrice containing 1% alumina and 5% STP concurrently with peroxide tooth bleaching.
The tooth sensitivity benefits of KNO3 containing dentifrices are well established (Sharma et 
al., 2012, Hu et al., 2018).  However, the evidence supporting the use of potassium ions to 
reduce tooth sensitivity associated with tooth bleaching is less clear.  One study evaluated the 
twice-daily use of a 5% KNO3 dentifrice for 2 weeks before, and during a 14 day treatment with 
a 9.5% hydrogen peroxide gel (Haywood et al., 2005) compared to a standard dentifrice.  The 
study concluded that use of the potassium-containing dentifrice resulted in statistically 
significantly more sensitive-free days than the control dentifrice.  Similar findings were found
in another study (Pierote et al., 2020) where a variety of dentifrices were used during and after 
peroxide bleaching with a 26% hydrogen peroxide gel, concluding that dentifrices containing 
potassium nitrate were able to reduce tooth sensitivity during peroxide bleaching.  The same 
study also evaluated tooth color finding that all of the tested dentifrices (including controls) led 
to the same tooth color at 4 and 24 weeks after bleaching, with teeth becoming darker with time.  
A separate study by the same authors concluded that a potassium-containing dentifrice was 
effective at helping to reduce tooth sensitivity when applied via a tray for 4 hours per night 
during the bleaching period (Pierote et al., 2019).  In a further study (Adil et al., 2021), use of 
a potassium nitrate / sodium monofluophosphate gel post bleaching was found to be effective 
at reduction of tooth sensitivity when a 35% hydrogen peroxide bleaching treatment was used.  
Tooth sensitivity relief while using a KNO3 dentifrice was also observed in a population with 
mild-to-moderate fluorosis following 35% hydrogen peroxide treatment (Nanjundasetty and 
Ashrafulla, 2016).  Contrastingly, application of a KNO3 gel immediately prior to bleaching 
with hydrogen peroxide was not found to reduce tooth sensitivity but also did not adversely 
affect the whitening efficacy of the bleaching treatment (de Lima et al., 2022).  Further, an 
unpublished study found that use of a 5% KNO3 dentifrice before, during and after a bleaching 
treatment led to a non-statistically significant reduction in tooth sensitivity during the 7 days 
post treatment, although statistically significant fewer subjects reported tooth sensitivity 
compared to the control dentifrice (
).  A systematic 
review of tooth sensitivity associated with tooth bleaching, drawing on 13 publications, has 
concluded that 5% KNO3 is effective at reducing tooth sensitivity at least up to 24 hours post 
conclusion of the bleaching treatment (Krishnakumar et al., 2022).
Therefore the aims of this study are to investigate the ability of an experimental dentifrice 
containing 5% potassium nitrate (KNO3), 1% alumina and 5% sodium tripolyphosphate (STP), 
to maintain tooth color and reduce extrinsic dental stain accumulation following peroxide tooth 
bleaching compared to a regular fluoride-containing dentifrice.  Additionally, the ability of the 
test dentifrice to reduce tooth sensitivity concurrent with peroxide tooth bleaching will be 
explored.
2.3
Benefit/Risk Assessment 
Complete information for the dentifrices under evaluation in this study may be found in the 
single reference safety document (SRSD), which for this study is the Safety Statement (SS). 
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Formulations containing 5% KNO3, 1% alumina and 5% STP have been evaluated in clinical 
studies to evaluate their cleaning efficacy (see Background Section 2.2).  These studies 
demonstrated the efficacy and safety of these formulations.  The active ingredients and 
formulation excipients contained in the study dentifrices have a history of safe use in oral care 
products and are currently used in marketed daily-use dentifrices.
The experimental dentifrice under evaluation is therefore considered generally safe for topical 
oral use, with twice daily brushing, under the controlled conditions of a clinical trial.
2.4
Mechanism of Action/Indication
The test dentifrice being investigated contains 1% alumina and 5% sodium tripolyphosphate 
(STP) which provide tooth whitening/stain removal benefits (
, 
Haleon Clinical Study 300024, 2023).  Additionally, the test 
dentifrice contains 5% w/w KNO3, which provides relief from tooth sensitivity through pulpal 
nerve depolarization (Sharma et al., 2012, Hu et al., 2018).
Both the test and the reference dentifrice contain 0.254% w/w NaF, equivalent to 1150ppm 
fluoride.  Sodium fluoride in both dentifrices provides an anti-caries benefit (Griffin et al., 2007, 
Marinho et al., 1996).
3
STUDY OBJECTIVES AND ENDPOINTS
Table 3-1
Study Objectives and Endpoints
Objectives
Endpoints
Primary
To compare tooth color after 24 weeks twice daily use of a ‘5% 
KNO3/1% alumina/5% STP’ dentifrice compared to a regular 
fluoride dentifrice following peroxide tooth bleaching as measured 
by VITA Bleachedguide 3D-Master.
Mean VITA shade score at 24 
weeks after tooth bleaching.
Secondary
To compare tooth color after 12 weeks twice daily use of a ‘5% 
KNO3/1% alumina/5% STP’ dentifrice compared to a regular 
fluoride dentifrice following peroxide tooth bleaching as measured 
by VITA Bleachedguide 3D-Master.
Mean VITA shade score at 12 
weeks after tooth bleaching.
To compare extrinsic dental stain after 12 and 24 weeks, twice 
daily use of a ‘5% KNO3/1% alumina/5% STP’ dentifrice compared 
to a regular fluoride dentifrice following peroxide tooth bleaching
as measured by Modified Lobene Stain Index.
Mean MLSI at 12 and 24 
weeks after tooth bleaching in:
•
Total MLSI (Area (A) x 
Intensity (I))
•
Gingival sites (AxI)
•
Interproximal sites (AxI)
•
Body sites (AxI)
•
MLSI (A)
•
MLSI (I)
Exploratory
To compare subject-perceived tooth sensitivity during peroxide 
tooth bleaching with twice daily use of a ‘5% KNO3/1% 
alumina/5% STP’ dentifrice compared to a regular fluoride 
dentifrice, as measured by subject-completed sensitivity 
questionnaire overall and within strata (clinically-diagnosed DH 
Mean sensitivity questionnaire 
scores pre and post peroxide 
tooth bleaching in:
•
Visual analogue scale
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[Y/N]).
(VAS)
•
Labelled Magnitude scales 
(Intensity, Duration. 
Tolerability, Description) - LMS
•
Bothersomeness score -
NRS
To explore subject’s experience of peroxide tooth bleaching when 
simultaneously using either a ‘5% KNO3/1% alumina/5% STP’ 
dentifrice or a regular fluoride dentifrice.
Post-whitening questionnaire
To confirm the tooth whitening efficacy of peroxide tooth bleaching 
with concurrent, twice daily use of ‘5% KNO3/1% alumina/5% 
STP’ dentifrice and a regular fluoride dentifrice as measured by 
VITA Bleachedguide 3D Master.
Change in mean VITA shade 
score from pre to post tooth 
bleaching
Safety
To assess the safety and tolerability of a ‘5% KNO3/1% 
alumina/5% STP’ dentifrice.
Treatment emergent adverse 
events
Abbreviations: MLSI: Modified Lobene Stain Index, VAS: Visual Analogue Scale, LMS: Labelled Magnitude 
Scales, NRS: Numerical Rating Scale.
This study will be considered successful if the Test dentifrice containing 5% KNO3, 1% alumina 
and 5% STP demonstrates statistically significant whither teeth as measured by Vita 
Bleachedguide Shade in comparison with the reference dentifrice 24 weeks after peroxide tooth 
bleaching.
4
STUDY DESIGN 
4.1
Overall Design
This will be a randomized, single-blind, single-center, controlled, two arm, stratified (clinically 
diagnosed DH (Y/N)), parallel group study to evaluate the efficacy of an experimental dentifrice 
containing 5% potassium nitrate (KNO3), 1% alumina and 5% sodium tripolyphosphate (STP), 
to maintain tooth color and reduce the accumulation of extrinsic tooth stain following peroxide 
tooth bleaching compared to a regular fluoride-containing dentifrice.  The study will recruit 
generally healthy subjects who wish to undergo peroxide tooth bleaching.  A schematic of the 
principal study assessments and procedures is provided in Fig 4-1.
Potential subjects will attend a screening visit (Visit 1) to determine their suitability to 
participate.  Having obtained their written informed consent, relevant details of their 
demography, medical history and current medications will be recorded, followed by oral soft 
tissue (OST) and oral hard tissue (OHT) examinations.  Subjects will undergo an assessment of 
the tooth color (shade) of the facial surfaces of the six maxillary anterior teeth (tooth numbers 
6-11) [Universal tooth numbering system] using the VITA Bleachedguide 3D-MASTER 
(Gomez-Polo et al., 2015) and extrinsic tooth stain on the facial surfaces of the same teeth using 
the MacPherson modification (Macpherson et al., 2000) of the Lobene Stain Index(Lobene, 
1968) (MLSI).  Those subjects with a self-reported history of dentine hypersensitivity (DH) 
will be clinically-evaluated to confirm their DH status (including Erosion/Abrasion/Recession 
(EAR) assessment, gingival assessment, tooth mobility assessment and evaporative (air) 
sensitivity assessment (Schiff Sensitivity score)). 
Subjects meeting all study criteria, will be considered as eligible to proceed, stratified (based 
upon their clinically-diagnosed DH status [Y/N]) and randomized to treatment group.  
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Randomized subjects will then complete the tooth sensitivity questionnaire.  Subjects will be 
dispensed their study products (including diary and sundry items) and undertake a supervised 
brushing with their allocated dentifrice at the clinical site and be scheduled to attend Visit 2 (2 
weeks ± 2 days after Screening/Randomization).  Subjects will continue to use their allocated 
study products (twice-daily) throughout the study and will record this usage in their study diary.
At Visit 2 (2 weeks after Screening/randomization) subjects will undergo a review of their diary 
and current medications and will then undergo an OST examination.  Tooth color and extrinsic 
tooth stain will be assessed for the same teeth in the same way as at Visit 1.  Subjects who fulfil 
all inclusion/exclusion criteria will continue in the study and will complete the tooth sensitivity 
questionnaire and the whitening history questionnaire.    Subjects will then be dispensed a 
commercially available 15% peroxide tooth bleaching kit for use at home for 7 days, once per 
day, as per pack instructions and as detailed in Section 6.1.1.1. Subjects will undergo a 
supervised tooth brushing (with their study dentifrice) and will floss their teeth and have their 
first application of the peroxide bleaching at the study site under supervision in accordance with 
the manufacturer’s instructions.  Subjects will be instructed in the correct use of the peroxide 
product for at home use in accordance with the manufacturer’s instructions.  Subjects will 
continue to use their assigned dentifrice twice daily and perform their peroxide bleaching daily 
per instructions, and to record this usage in their supplied diary.  Subjects will be scheduled to 
return to the study site for Visit 3 (after the completion of their 7 -days tooth bleaching period).
After the completion of the tooth bleaching period at Visit 3 [7 days after the commencement 
of tooth bleaching, with an acceptable range of 7-9 days] subjects will return to the clinical site 
and return their used bleaching kit and undergo a review of their diary and current medications 
and undergo an OST examination.  Tooth color and extrinsic tooth stain will be assessed for the 
same teeth in the same way as at Visit 1.  Subjects will then complete the tooth sensitivity 
questionnaire and the post-whitening questionnaire and scheduled to return for Visit 4 (12 
weeks [±1 week] after completion of the peroxide tooth bleaching).
At Visit 4 subjects will return to the clinical site and undergo a review of their diary and current 
medications and an OST examination.  Tooth color and extrinsic tooth stain will be assessed 
for the same teeth in the same way as at Visit 1.  Subjects will then be scheduled to return for 
Visit 5 (24 weeks [±1 week] after completion of the peroxide tooth bleaching).
At Visit 5 subjects will return to the clinical site and return their study products and undergo a 
review of their diary and current medications and an OST and OHT examination.  Tooth color 
and extrinsic tooth stain will be assessed for the same teeth in the same way as at Visit 1.  
Subjects will then exit the study.
Safety and oral tolerability of the study products will be monitored over the duration of the 
study by review of reported AEs and through Oral Soft Tissue examinations.  Medical device 
incidents will also be monitored for the device in this study which is the study toothbrushes.
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Figure 4-1
Schematic of Flow of Key Study Assessments/Procedures
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4.2
Scientific Rationale for Study Design
This is a randomized, controlled, single-blind (to the dental examiner(s) and outcome assessors), 
single-center, 2 treatment group, stratified (clinically diagnosed DH (Y/N)), parallel study in 
subjects who wish to undergo tooth bleaching treatment.  This study has specifically been 
designed to investigate the efficacy of an experimental dentifrice containing KNO3), STP and 
alumina to maintain tooth color and reduce extrinsic dental stain accumulation following 
peroxide tooth bleaching compared to a regular fluoride dentifrice.  Additionally, the ability of 
the test dentifrice to reduce tooth sensitivity concurrent with peroxide tooth bleaching will be 
explored.
A parallel group experimental design was selected as subjects would not be expected to repeat 
peroxide tooth bleaching more than once per year, precluding the use of a cross-over design.
This is a single-center study.  The same examiner(s) will perform the clinical assessments 
throughout the study to reduce inter-examiner variability.
A 24 week treatment period is deemed sufficient to observe the anticipated effects in tooth color;
a 12 week assessment is included should more rapid clinical effects occur. A regular fluoride 
dentifrice has been selected as the reference dentifrice.  For the purposes of this study, it was 
deemed more relevant to compare the efficacy of the experimental dentifrice against a typical 
daily use, fluoride-containing dentifrice (which contains dental abrasive) rather than a placebo 
with no abrasive cleaning component.  This reference dentifrice is representative of a standard 
family dentifrice commonly available in the country where the study will be performed (USA).
The subjects in this study who have self-reported DH will be clinically evaluated to confirm 
their DH status.  Whilst there are no protocol requirements associated with this assessment, DH 
is prevalent at 30-50% of the population (West, 2023b) and the enrollment to this study is 
expected to mirror this.  It is anticipated that the test dentifrice, will be marketed for consumers 
with DH.  However, it is anticipated that it will be purchased both by consumers with DH and 
those without, but who are recommended to use an anti-sensitivity dentifrice prior to, during 
and post peroxide tooth bleaching.  A mixed population of those with clinically-diagnosed DH 
and those without is therefore appropriate.  Subjects will be stratified according to their 
clinically-diagnosed DH status [DH positive or negative] to ensure a balanced population across 
treatment groups.
Demography information will be recorded as part of this study, including age, race and gender. 
In accordance with the United States Food and Drug Administration (US FDA) guidelines 
(FDA, 2005) the ethnicity of subjects will also be captured.
According to the International Conference on Harmonisation (ICH) guidelines (ICH, Nov 2016), 
for a study to be classified as truly double-blind, not only does the examiner (and any 
appropriate member of staff who may be involved in the dispensing of products, analysis of 
data etc.) need to be blind to the treatment a subject receives, but the products under test must 
be identical in every way (color, flavor, appearance, packaging).  Given the experimental 
dentifrices and the reference dentifrice will differ in appearance and flavor, the level of 
blindness for this study is described as ‘examiner blind’.  The study will be blinded with respect 
to the dental examiner(s) and other outcome assessors to ensure there is no bias in the 
assessments.  Study dentifrices will be supplied in overwrapped tubes.  The blind will be 
maintained by staff involved in dispensing, brushing instruction and supervised brushings who 
will not be involved in any clinical examinations.
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Whilst the study products are not contra-indicated for pregnancy (their use would not be 
expected to cause harm either to the mother or foetus), pregnant females will be excluded from 
this study due to the increased prevalence and severity of gingivitis and periodontal disease 
along with increased amounts of calculus and oral debris observed with pregnancy, both of 
which could impact dental stain and tooth color (Samant et al., 1976).  The severity of these 
conditions is known to vary during the course of pregnancy (Samant et al., 1977), thus 
pregnancy would be a confounding factor for the objectives of this study.  Pregnant females and 
those intending to become pregnant will be excluded.  Pregnancy will be monitored throughout 
the study by subject-reported pregnancy status.
Whilst evaluation of tooth color is the primary endpoint in this study, it is believed that surface 
tooth stain can lead to longer-term increase in tooth color.  Measurement of extrinsic dental 
stain will therefore also be performed using the MacPherson modification (Macpherson et al., 
2000) of the Lobene Stain Index (Lobene, 1968)(MLSI).
The clinical measures of tooth color and extrinsic tooth stain used in this study, VITA shade 
guide and MLSI respectively, are well established in the scientific literature for the evaluation 
of dental stain and tooth color respectively (Joiner and Luo, 2017).  VITA shade guides are 
routinely used by dentists in practice to assess the color of natural teeth to enable accurate 
matching of prosthetic devices (e.g. crowns, partial dentures) to the natural dentition.  The VITA 
shade guide selected for use in this study (VITA Bleachedguide 3D-MASTER) has the 
advantage over the classic VITA shade guide in providing a linear presentation of tooth shade 
which will enable more accurate assessment of shade changes (Paravina, 2008).  Furthermore, 
it is accepted by the American Dental Association for use in determining the efficacy of tooth 
whitening products (ADA, 2020). LMS and VAS (which in this study are components of the 
tooth sensitivity questionnaire) have been previously used and validated for measurement of
tooth sensitivity in clinical studies evaluating the efficacy of dentifrices (Mason et al., 2019, 
Heaton et al., 2015, Holland et al., 1997, Gillam et al., 1997, Rocha et al., 2020).
4.3
Justification for Dose
Subjects will brush with their assigned dentifrices twice daily for 2 timed minutes as per the 
American Dental Association recommendations for effective toothbrushing (ADA, 2022) and 
the UK National Health Service teeth cleaning guide (NHS, 2019).  Additionally this brushing 
time is consistent with that used in a recently completed study evaluating the test dentifrice 
(Haleon Clinical Study 300024, 2023).
On each brushing occasion, the toothbrush will be dosed with a ribbon of dentifrice (covering 
the entire length of the toothbrush), in line with the proposed product labelling for the 
experimental dentifrice and the current product labelling for the marketed reference dentifrice.
No dose modification is permitted in this study.  Any variation from the product usage 
instructions should be communicated to study site personnel and recorded as a deviation.
4.4
End of Study Definition
A subject is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities.
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5
STUDY POPULATION
5.1
Type and Planned Number of Subjects
Healthy volunteers of either sex and any gender, aged 18 – 65 years who wish to have their 
teeth whitened and meet all the inclusion/exclusion criteria will be recruited.
Sufficient subjects will be screened to randomize approximately 160 to ensure approximately 
128 evaluable subjects complete the study. 
An enrolled subject is one who has agreed to participate in the clinical study following 
completion of the informed consent process directly or via their legally authorized 
representative and successfully met eligibility criteria and has been randomized to treatment 
group.
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether a subject is suitable for this protocol.  
Subject eligibility to participate in the clinical study should be reviewed and documented by an 
appropriate member of the investigator’s study team before subjects are included in the study.
5.2
Inclusion Criteria
An individual must meet all the following inclusion criteria to be eligible for enrolment into, 
and continuance in the study:
1. Subject provision of a signed and dated informed consent document indicating that the 
subject has been informed of all pertinent aspects of the study before any assessment is 
performed.
2. Subject is of either sex and any gender who, at the time of screening, is between the ages 
of 18-65 years, inclusive.
3. Subject is willing and able to comply with scheduled visits, and other study procedures 
and restrictions.
4. Subject in good general and mental health with, in the opinion of the investigator or 
medically qualified designee, no clinically significant or relevant abnormalities in medical 
history (for example, a medical condition confirmed to be causing xerostomia),or upon 
oral examination, that would impact the subject’s safety, wellbeing or the outcomes of the 
study, if they were to participate in the study, or affect the subject’s ability to understand 
and follow study procedures and requirements.
5. Subject who is willing and able to undergo at-home tooth bleaching with peroxide-
containing treatment unsupervised.
6. Subject with generally good oral health that fulfil all of the following:
a.
Teeth suitable for peroxide bleaching and gradable for tooth color and suitable for 
MLSI evaluation with no significant defects, calculus, restorations, crowns or veneers 
that could impact peroxide tooth bleaching performance or study evaluations as 
judged by the clinical examiner.
b. Facial surfaces of maxillary anterior 6 teeth (tooth numbers 6-11) [Universal tooth 
number system] with mean Vita Bleachedguide shade ≥13 at Visits 1 and 2
c.
Having no lesions of the teeth or oral cavity that could interfere with the study 
evaluations.
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d. Having a minimum of 16 natural teeth.
5.3
Exclusion Criteria
An individual who meets any of the following exclusion criteria will not be eligible for 
enrolment into the study:
1. Subject who is an employee of the investigational site, either directly involved in the 
conduct of the study or a member of their immediate family; or an employee of the 
investigational site otherwise supervised by the investigator; or, a Haleon employee 
directly involved in the conduct of the study or a member of their immediate family.
2. Subject who has participated in other studies (including non-medicinal studies) involving 
investigational product(s) within 60 days prior to study entry and/or during study 
participation.
3. Subject with, in the opinion of the investigator or medically qualified designee, an acute or 
chronic medical or psychiatric condition or laboratory abnormality that may increase the 
risk associated with study participation or investigational product administration or may 
interfere with the interpretation of study results and, in the judgment of the investigator or 
medically qualified designee, would make the subject inappropriate for entry into this 
study.
4. Subject who is pregnant (self-reported) or intending to become pregnant over the duration 
of the study or who is breastfeeding.
5. Subject with known or suspected intolerance or hypersensitivity to the study materials 
[including the peroxide bleaching treatment] (or closely related compounds) or any of 
their stated ingredients. 
6. Subject who, in the opinion of the investigator or medically qualified designee, has a 
condition that would impact on their safety or wellbeing or affect their ability to 
understand and follow study procedures and requirements or who should not participate in 
the study for other reasons.
7. Subject unwilling or unable to comply with the Lifestyle Considerations described in this 
protocol. 
8. Subject with a recent history (within the last year) of alcohol or other substance abuse.
9. Subject with gross periodontal disease or who has had treatment for periodontal disease 
(including surgery) within 12 months of Screening or who has had scaling or root 
planning within 3 months of Screening.
10. Subject who has had a peroxide tooth bleaching procedure (either professionally-
dispensed or at-home [including peroxide-containing dentifrices]) within 12 months of 
Screening.
11. Subject who has had a dental prophylaxis within 8 weeks of screening.
12. Subject who has used tooth desensitizing treatment (eg dentifrice, mouthwash etc) within 
2 weeks of screening.
13. Subject with a fixed or removable partial prosthesis, multiple dental implants or 
orthodontic braces/bands or fixed retainer or togue/lip piercing which, in the opinion of 
the investigator, could impact study outcomes.
14. During the study period, subject taking daily doses of medication/treatments which, in the 
opinion of the investigator or medically qualified designee, could interfere with their 
perception of tooth sensitivity (examples of such medications include analgesics, 
anticonvulsants, antihistamines that cause marked or moderate sedation, sedatives, 
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tranquillizers, antidepressants, mood-altering and anti-inflammatory drugs).  Subjects will 
be allowed to use analgesics ad hoc to manage pain.
15. Subject who has tooth abnormalities such as cracking or gross caries lesions that may, in 
the opinion of the investigator, impact the ability to evaluate tooth sensitivity.
16. Subject who has previously been enrolled in this study.
5.4
Randomization Criteria
Subjects who have satisfied all subject selection criteria will be stratified according to their 
Clinical diagnosis of DH [Clinicall diagnosed DH (Y/N) (as defined in section 9.1.3)] and 
randomized to study treatment.  Whilst there are no protocol requirements associated with this 
assessment, DH is prevalent at 30-50% of the population (West, 2023b) and the enrollment to 
this study is expected to mirror this.
5.5
Lifestyle Considerations
5.5.1
Oral Hygiene Restrictions
•
On Study Days, Visits 1-5: Subjects will abstain from all oral hygiene procedures 
(including tooth brushing) for at least 6 hours prior to and during their clinical 
assessment visits.
•
From Visit 1 to end of study: Subjects should not use any other oral care products (for 
example, toothpastes, toothbrushes, oral rinses, tongue cleaners, whitening/bleaching 
products, interdental cleaning products) other than those provided during the study. 
•
From Visit 1 to end of study: Subjects should not use any product intended for treating 
or caring for sensitive teeth (including herbal remedies) other than those provided during 
the study.
5.5.2
Dietary Restrictions
On study days, for the Duration of the Study: Visit 1-5
Subjects will abstain from eating and drinking (with the exception of small amounts of water 
required for taking medication) for at least 2 hours prior to and during their clinical assessment 
visits.
5.5.3
Use of Cosmetics
On study days, Visit 1-5
Subjects will refrain from applying lipstick or colored lip coverings prior to and during their 
clinical assessment visits.
5.5.4
Medication and Treatment Restrictions
•
From Visit 1 to end of study: Subjects will be asked to delay elective dental 
treatment (for example, dental prophylaxis) for the duration of the study. They will be 
required to inform site staff of any emergency treatment they receive during the study.
•
From Visit 3 to end of study: Subjects must inform site staff of changes to their 
medications/treatments for the duration of the study. Should a subject commence a 
course of medication which, in the opinion of the investigator or medically qualified 
designee, could impact study outcomes, the subject may be withdrawn.
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•
From Visit 2 to end of study: Subjects who use ad hoc medication to relieve tooth 
sensitivity should note this in their tooth sensitivity questionnaire.
5.5.5
Contraception
There are no contraception requirements for subjects participating in this study.  At each visit, 
female subjects of child-bearing potential should verbally confirm they are not currently 
pregnant or planning to become pregnant.
5.6
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomized. To ensure transparent reporting of screen failure subjects, a 
minimal set of screen failure information will include demography, screen failure details (e.g. 
withdrawal of consent), eligibility criteria, any protocol deviations and any adverse events or 
incidents as applicable. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be re-screened.
5.7
Sponsor’s Qualified Medical Personnel
Contact information for the sponsor's appropriately qualified medical/dental personnel for the 
study is documented in the Study Contact List located in the investigator study master file held 
at the study site.
The contact number is only to be used by investigational staff seeking advice on medical/ dental 
questions or problems in the event that the established communication pathways between the 
investigational site and the study team are not available. 
The contact number is not intended for direct use by study subjects.  To facilitate access to 
appropriately qualified medical/dental personnel on study-related medical/dental questions or 
problems, subjects will be provided with a contact card. The contact card will provide, as a 
minimum, protocol identifiers, the subject’s study identification number, contact information 
for the investigational site, and contact details in the event that the investigational site cannot 
be reached to provide advice on a medical question or problem identified by a healthcare 
professional other than the investigator.
5.8
Clinical Examiner Qualifications
Clinical examiner(s) involved in the screening, safety and efficacy assessments will be 
appropriately qualified dental professionals, registered to practice in the USA. 
Oral examinations to determine subject eligibility and to monitor the safety/performance of 
study products will be performed by appropriately trained clinical examiner(s), with prior 
relevant clinical experience.  Clinical examiner(s) will also be experienced in use of the VITA 
Bleachedguide (or equivalent) for measurement of tooth color, the MLSI (or similar) for 
measurement of dental stain and the evaporative (air) stimulus measured by Schiff sensitivity 
score for determination of DH status.
6
INVESTIGATIONAL/STUDY PRODUCTS
For the purposes of this study, per International Conference on Harmonization (ICH) guidelines, 
and Haleon policy, study intervention is defined as any investigational intervention(s), marketed 
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product(s), placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol.
This includes a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use. 
6.1
Investigational/Study Product Supplies
The following study products will be supplied by the Clinical Supplies Department, Haleon:
Table 6-1
Investigational/Study Product Supplies
Test Dentifrice
Reference Dentifrice
Product Description
Dentifrice containing 5% w/w 
KNO3, 1% alumina, 5% STP and 
1150ppm fluoride as sodium 
fluoride
Dentifrice containing 1150ppm 
fluoride as sodium fluoride
Product Name
Experimental Dentifrice
Aquafresh Cavity Protection
Product Master 
Formulation Code
Commercial product – US 
marketplace (
)
Pack Design
Carton of overwrapped tubes
Carton of overwrapped tubes
Dispensing Details
Dentifrice kit dispensed at 
Screening Visit
Dentifrice kit dispensed at 
Screening Visit
Return 
Requirements
All used/unused samples to be 
returned
All used/unused samples to be 
returned
Dose/Application
Subjects will dose the toothbrush provided with a strip of dentifrice (a 
full brush head) on each brushing occasion.  Subjects will brush for 
two timed minutes twice daily (morning and evening); subjects will 
be permitted to rinse with water post-brushing.
Route of 
Administration
Oral topical
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The following sundry items will be supplied by the sponsor’s Global Clinical Supplies Group.
Table 6-2
Sundry Items
Sundry Items to be supplied:
Item
Supplied By Pack Design
Dispensing 
Details
Return/Disposal Details
Used 
Samples
Unused 
Samples
parodontax Complete 
Protection Soft-Bristled 
Toothbrush (US market)
Haleon
Twin Pack
Two packs at 
Screening 
(visit 1)
Subjects will 
be instructed 
by site staff to 
start using a 
new brush at 
V3 and at V4.
Destroy at 
site using 
site disposal 
procedures
Return
Countdown Timer
Haleon
Individual 
commercial 
pack
At Screening 
(visit 1)
To be kept 
by subject or 
disposed of.
Return
Opalescence Go 15%
Peroxide Kit [USA 
Marketplace]
Study Site
Commercial 
pack
First use at 
site, dispensed 
for at-home 
use at visit 2
Return
Return
Petroleum Jelly
Haleon
Commercial 
pack
First use at 
site, dispensed 
for at-home 
use at visit 2
Destroy at 
site using 
site disposal 
procedures
Return
Dental Floss
Haleon
Commercial 
pack
First use at 
site, dispensed 
for at-home 
use at Visit 2
Destroy at 
site using 
site disposal 
procedures
Return
Detailed instructions for the return of study product/study supplies for the accountability checks 
and subsequent destruction which will be provided by Haleon during the study in time for study 
close out visit.
The toothbrushes are marketed medical devices and will be used in accordance with the label 
instructions.
6.1.1.1
Application of the Peroxide Bleaching
The peroxide tooth bleaching procedure should be performed at-home (except for the first 
application which will be performed under supervision at the study site) following manufacturer 
instructions.  Subjects should brush their teeth with the study dentifrice and floss their teeth 
prior to applying the peroxide gel.  Subjects will apply the supplied gel-containing tray to their 
maxillary teeth per the product instructions.  Subjects should apply their peroxide-containing 
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tray to their maxillary teeth once per day for 15 timed minutes immediately after either their 
morning or evening tooth brushing with their assigned study dentifrice.  Subjects should attempt 
to perform the tooth bleaching at approximately the same time of day wherever possible.  
Subjects should perform peroxide bleaching for 7 consecutive days.  Should subjects experience 
gum sensitivity/irritation due to the peroxide, they should apply a thin layer of the supplied 
petroleum jelly to the affected gum tissue prior to applying the peroxide, taking care not to 
contact the teeth with the petroleum jelly.
Subjects should note every bleaching event in their diaries to help monitor compliance.
6.1.2
Medical Devices
The definitions and procedures detailed are in accordance with ISO 14155.
•
The Haleon manufactured medical devices (provided for use in this study) are the study 
toothbrushes.
•
All device deficiencies (including malfunction, use error and inadequate labelling) shall be 
documented and reported by the investigator throughout the clinical investigation (see 
Section 10.10) and appropriately managed by the sponsor.
6.1.3
Dosage Form and Packaging
The study products are dentifrices, intended for topical oral use, and will be applied by 
toothbrushing using a manual toothbrush.
The experimental dentifrice will be manufactured and filled into plain white tubes by the 
sponsor; the reference dentifrice will be supplied in its commercial pack and sourced from the 
market the study is performed in (USA).  All study dentifrices will be overwrapped in white 
vinyl (to mask their identity and obscure the branding of the marketed product) with a study 
label affixed. The content of the product labels will be in accordance with all applicable 
regulatory requirements and will be the responsibility of the sponsor’s Global Clinical Supplies 
Group. Each study label will contain, but not be limited to, protocol number, directions for use 
and storage requirements. 
Each subject will receive sufficient tubes of their assigned study dentifrice for usage during the 
24-week treatment period. Sundry items (including the peroxide bleaching treatment) will be 
supplied in their commercial packaging for dispensing by study staff as specified in Table 6.2. 
Care should be taken with the supplied products and their labels so that they are maintained in 
good condition.  It is important that all labels remain intact and legible for the duration of the 
study. Subjects should be instructed to not remove or deface any part of the study label.
All products supplied are for use only in this clinical study and should not be used for any other 
purpose.
6.1.4
Preparation and Dispensing 
Subjects will be assigned to study treatment in accordance with the randomization schedule 
generated by an approved sponsor vendor, prior to the start of the study, using validated 
software.
The product dispensing area will be separate from the clinical examination area. Study 
dentifrices and peroxide bleaching treatment will be dispensed to the subject, by trained site 
personnel.  These staff members will not be involved in any safety/product performance 
assessments or any other aspect of the study that could be influenced by the knowledge of 
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product a subject has been assigned to.  An additional member of the site staff will verify the 
dispensing procedure has been completed accurately for each subject.
6.2
Administration
Only subjects enrolled in the study may receive study products and only authorized site staff 
may supply or administer study products. All study interventions must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the authorized site staff only.
Subjects will be instructed to self-administer their assigned study dentifrice and tooth bleaching
treatment according to the usage instructions provided to the subject.  Additionally, subjects 
will undergo supervised brushing with dentifrice at Visit 1 and 2 and application of the tooth 
bleaching treatment at Visit 2 to ensure compliance with application instructions.  The reference 
dentifrice and the tooth bleaching treatment are commercially available, and the application 
instructions described in this protocol are consistent with their label instructions.  The 
experimental dentifrice is intended for commercialization and the application instructions here 
are consistent with the intended label instructions.
To help ensure subjects understand the amount of dentifrice they should use each time they 
brush, brushing instructions and diary completion requirements:
•
Staff will demonstrate dispensing a full ribbon of dentifrice along the length of the 
toothbrush head to each randomized subject and supervise their first brushing with study 
dentifrice (Visit 1&2) and diary completion at the screening visit (Visit 1).
•
Staff will demonstrate and aid subjects for their first application of the peroxide tooth 
bleaching procedure at Visit 2.
•
staff will review diary completion and subject’s study products at Visits 2-5.
On-site administration of study products will also be recorded in the CRF.
Instructions on usage of the study products are detailed in the Appendices.
6.2.1
Product Usage Errors
In this study, product usage errors may result, in this study, from the administration or 
consumption of: 
•
the wrong product,
•
by the wrong subject, 
•
at the wrong time, 
•
or at the wrong dosage. 
Such errors occurring to a study subject are to be captured in the CRF.  In the event of a product 
usage error, the sponsor should be notified immediately and under no circumstance should 
this exceed 24 hours.
Product usage errors are reportable irrespective of the presence of an associated AE, including:
•
Usage errors involving subject exposure to any of the study products;
•
Potential product errors or uses outside of what is foreseen in the protocol that do or do 
not involve the participating subject.
If a study product usage error is accompanied by an AE, as determined by the investigator, the 
usage error and, any associated adverse event(s) are to be captured in the CRF AE form. 
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6.2.2
Overdose
An overdose is a deliberate or inadvertent administration of a product at an amount higher than 
specified in the protocol.
Overdose is not likely to occur in this study.
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.
6.3
Investigational/Study Product Storage
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study products received and any discrepancies are reported and 
resolved before use according to the supplied shipping documentation.
The investigator, or designee, will ensure that all study products are stored in a secured area 
with controlled access under required storage conditions and in accordance with applicable 
regulatory requirements and the product label.  
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should be 
captured from the time of first product receipt throughout the study.  Even for continuous 
monitoring systems, a log or site procedure that ensures active daily evaluation for excursions 
should be available.  The operation of the temperature-monitoring device and storage unit (for 
example, refrigerator), as applicable, should be regularly inspected to ensure it is maintained in 
working order. 
Any excursions from the product-label storage conditions should be reported to appropriate site 
staff upon discovery and communicated to sponsor as soon as possible.  The site should actively 
pursue options for returning the product to the storage conditions as described in the labeling, 
as soon as possible.  Excursions from the storage requirements, including any actions taken, 
must be documented as a protocol deviation and reported to the Sponsor.  
Once an excursion is identified, the affected product (or products) must be quarantined and not 
used until the sponsor provides documentation of permission to use. Use of any of the affected 
product(s) prior to sponsor approval will be considered a protocol deviation.  
Site staff will instruct subjects on the proper storage requirements for all take-home products. 
6.4
Investigational/Study Product Accountability
All products supplied are for use only in this clinical study and should not be used for any other 
purpose.
All study products must be received by a designated person at the study sites, handled and stored 
safely and properly, and kept in a secured location to which only the staff have access. Upon 
receipt, all study products should be stored according to the instructions specified on the product 
labels. Study products are to be dispensed only to subjects enrolled in the study in accordance 
with the protocol, by authorized site staff.
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of all the product supplies. All study products will be accounted for using the 
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investigational/study product accountability form/record. The investigator is responsible for 
study product accountability, reconciliation, and record maintenance. 
The accountability records must be available for inspection by the study monitor during the
study. Monitoring of product accountability will be performed by the monitor during site visits 
and at the completion of the study. 
Subjects should return their used and unused study products to the clinical site at Visit 5 in 
accordance with the study schedule.  Study product return will be documented.  Subjects will 
complete diaries to detail their usage of study products which will be used to monitor usage 
compliance.
6.4.1
Destruction of Investigational/Study Product Supplies 
At the end of the study, the Principal Investigator or an appropriate designee, and a 
representative of Haleon (study monitor) will inventory all used and unused study products and 
sundry items.  The investigational/study product accountability record for returned study 
products will then be completed. All study product (used and unused) for this clinical study 
(including empty containers), will be returned for destruction to the Haleon Clinical Supplies 
Department or designated vendor using the return instructions provided. Detailed instructions 
for the return of study product/study supplies for the accountability checks and subsequent 
destruction will be provided by Haleon during the study in time for study close out visit.
6.5
Blinding and Allocation/Randomization
All subjects will be centrally randomized to one of the two study products using an Interactive 
Response Technology (IRT). Before the study is initiated, training, login information and 
directions for the IRT will be provided. Study products will be dispensed according to the 
instruction received through the IRT at the appropriate study visits.
Returned study products should not be re-dispensed to any subject.
The investigator’s knowledge of the product allocation should not influence the decision to 
enroll a subject or affect the order in which subjects are enrolled.
This study is described as single-blind (the clinical examiner(s) performing the efficacy 
assessments will be blinded to the product received).  To ensure the examiner(s) remains 
blinded throughout the study, the examiner(s) will not be permitted in any area where study 
product is stored, dispensed, or in use staff involved in the preparation and dispensing of study 
products will work in a separate area, and subjects will be instructed not to remove study 
products from the opaque bags provided/cartons outside of the dispensing room, while at the 
study site. Dispensing staff will not be involved in any efficacy/safety assessment procedures 
during the study.
Site staff, study statistician(s), data management staff and other employees of the sponsor and 
vendors acting on behalf of the sponsor, who may influence study outcomes will be blinded to 
the product allocation.
Prior to randomization, subjects will be stratified on their DH status as detailed in Section 5.4.
6.6
Breaking the Blind
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind.  The method will be an electronic process.
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The electronic system will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
subject’s product assignment is warranted. Subject safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a subject’s 
product assignment unless this could delay emergency treatment of the subject.
If a subject’s product assignment is unblinded, the sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and case report form, as applicable.
Any AE associated with breaking the blind must be recorded and reported as specified in this 
protocol. The study site may also be required be required to inform the Institutional Review 
Board (IRB) if the blind is broken. 
6.7
Compliance
To facilitate subject compliance with product usage requirements: 
•
First use of their assigned study dentifrice will be carried out under supervision at the 
study site at the end of the screening visit (Visit 1) and additionally at Visit 2; study staff 
will demonstrate the correct amount of dentifrice to dispense and how to use the timer to 
ensure a 2-minute brushing time. Subjects will be provided with a diary at Screening 
(Visit 1) to record each completed brushing.
•
First use of the peroxide tooth bleaching procedure will be carried out under supervision at 
the study site at Visit 2; study staff will demonstrate the application of the bleaching gel 
according to manufacturer’s instructions. Subjects will be provided with a diary to record 
each completed tooth bleaching treatment.
•
Subjects will attend each study visit with all tubes of dentifrice provided (used and 
unused) for a visual check of product usage, and with their completed diary for review by 
study staff. Any suspected over or under use, the number of any missed or additional 
brushings will be documented as deviations in the CRF; subjects will be re-instructed in 
the correct use of product and diary completion, as required.
•
Subjects will also use the diary to note any issues with their study product, any oral 
problems, illnesses and new medications/ treatments. Details relevant to safety or efficacy 
should be reviewed by the investigator (or suitably qualified designee) and transcribed to 
the CRF, as appropriate; AEs must be documented in the CRF.
The number of any missed or additional applications or doses will be captured as protocol 
deviations. Subjects will be re-instructed in the correct usage requirements and diary completion 
as needed.
A record of the number of dentifrice tubes dispensed to and taken by each subject must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the CRF.
6.8
Concomitant Medication/Treatment(s)
Any medications, treatments or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) taken during the study, from signing the informed consent, 
must be recorded in the CRF with indication, reason for use, unit dose, daily dose, and start and 
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stop dates of administration.  All subjects will be questioned about medications/treatments at 
each site visit.
Medication/treatments taken 28 days prior to signing the informed consent form and until first 
study product application will be documented as a prior medication/treatment.  
Medications/treatments taken after first study product application will be documented as 
concomitant medication/treatments.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL
7.1
Subject Discontinuation/Withdrawal 
A subject may withdraw from the study at any time at his or her own request or may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures.  
The following circumstances require discontinuation of study product and/or premature subject 
withdrawal:
•
Protocol violation that may impact the subject’s safety
•
Withdrawal of informed consent
•
Subject lost to follow-up
•
Unblinding of the subject
•
Pregnancy
If a subject is discontinued or prematurely withdraws from the study, the reason(s) for 
discontinuation or withdrawal and the associated date must be documented in the relevant 
section(s) of the CRF. 
7.2
Lost to Follow up
If a subject fails to return to the site for a required study visit the site must attempt to contact 
the subject and reschedule the missed visit as soon as possible and counsel the subject on the 
importance of maintaining the assigned visit schedule and ascertain whether the subject wishes 
to and/or should continue in the study.
A subject will be considered lost to follow up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Before a subject is deemed lost to follow 
up, the investigator or designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented. If contact 
is made with the subject, the investigator should inquire about the reason for withdrawal, request 
that the subject return all products that they had been dispensed and if appropriate request that 
the subject return for a final visit and follow-up with the subject regarding any unresolved 
adverse events (AEs).
Final safety assessments may be carried out when the subject returns to the study site, at the 
investigator’s discretion, which could include OST and OHT examinations.
Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study and lost to follow up. 
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Lack of completion of all or any of the early termination procedures will not be viewed as 
protocol deviations so long as the subject’s safety was preserved.
If the subject withdraws from the study and withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
8
STUDY PROCEDURES
This section lists the procedures to be completed at each planned study visit.  The timing of 
each procedure is listed in the Schedule of Activities section.
Adherence to the study design requirements, including all procedures are essential and required 
for study conduct.
8.1
Visit 1/Screening
Screening procedures will be conducted by the Investigator, or suitably qualified designee.
The following screening procedures will be completed, in the following order (wherever 
possible), and the findings recorded in the CRF.  To facilitate subject flow, clinical assessments 
may be recorded on a paper source document and later transcribed into the CRF.
1. Informed Consent.
2. Demographics.
3. Review of medical history (including smoking/tobacco use status) and prior/concomitant 
medication/treatment.
4. OST and OHT examinations.
5. Assessment of tooth color and extrinsic tooth stain.
6. For subjects with a self-reported history of DH, assessment of DH, including EAR, MGI
and tooth mobility assessments and Evaporative (Air) Sensitivity Assessment (Schiff 
sensitivity score).
7. Review of the inclusion/exclusion criteria.
8. Subject eligibility assessed.  Subjects who do not meet the criteria for participation will be 
discontinued.
9. Qualifying subjects will be stratified and randomized to treatment groups.
10. Subject completes the tooth sensitivity questionnaire at site.
11. Study products will be dispensed, including sundry items, and diary.  
12. Instruct subject in product usage requirements/diary completion and demonstrate 
dispensing ribbon of dentifrice on to toothbrush head; supervise first brushing and first 
diary entry.
13. AEs and incidents recorded.
8.1.1
Screening Procedures
8.1.1.1
Informed Consent
The investigator, or designee, must obtain informed consent from each subject participating in 
this study after adequate explanation of the aims, methods, objectives, and potential hazards of 
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the study. An ingredients listing for the study dentifrices and peroxide tooth beaching kit will 
be provided to each subject during the consent process to enable them to confirm they are not 
aware of any allergy or hypersensitivity to any of the ingredients listed.  Two copies of the 
informed consent form (ICF) will be signed and dated by the subject, the subject will retain one 
copy and the other will be kept at site.
The investigator, or designee, must also explain to the subjects that they are completely free to 
refuse to enter the study or to withdraw from it at any time.  Appropriate forms for documenting 
a signed and dated consent will be provided by either the investigator or by the sponsor.
The investigator, or designee, should sign and date each copy of the ICF to confirm that the 
consent process was completed correctly after the subject has signed.  
The time the subject signed the ICF will be captured as this is the point from which all AEs will 
be captured. The date and time of consent will be recorded in the CRF.
If, during a subject’s participation in the study, any new information becomes available that 
may affect the subject’s willingness to participate in the study, each ongoing subject should 
receive a copy of this new information and be re-consented into the study. Each subject should 
be provided with a copy of the signed and dated amended consent form. The date of re-consent 
will be recorded on the CRF.
After signing the ICF, subjects will undergo the screening assessments to confirm that they 
meet all the inclusion criteria and none of the exclusion criteria. If the subject is confirmed 
eligible by the investigator (or designee) to participate in the study the subject is considered 
enrolled in the study.
8.1.1.2
Demographics
The following demographic information will be recorded in the CRF: year of birth, gender, 
ethnicity and race.  Ethnicity and race of subjects will be recorded in accordance with FDA 
Guidance (US FDA, 2005).
Inclusion and exclusion criteria information will be documented in the CRF.
8.1.1.3
Medical History and Prior Medication/Treatment
Details of relevant medical and surgical history (in the last year), including allergies or drug 
sensitivity, will be documented in the CRF.
Prior medications/treatments, including prescription and non-prescription drugs, dietary 
supplements and herbal remedies, taken in the last 28 days and prior to signing the informed 
consent form, will be documented in the CRF.
8.1.1.4
Oral Examinations
The clinical examiner(s) will perform the following examinations/assessments.
•
OST examination.
•
OHT examination.
•
Assessment of tooth color and extrinsic tooth stain.
•
Clinical assessment of incisors, canines and pre-molars for dentition exclusions, erosion 
abrasion and attrition (EAR), Modified Gingival Index (MGI) adjacent to the test area 
only, and clinical mobility to clinically diagnose DH for those subjects with a self-
reported history of DH.
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Oral examinations/assessments should only be performed by suitably qualified examiner(s) as 
described in Section 5.8.
To facilitate subject flow, clinical assessments may be recorded on a paper source document 
and later transcribed into the CRF. 
8.1.1.5
Inclusion/Exclusion Criteria
Inclusion and exclusion criteria information will be documented in the CRF.
8.1.1.6
Subject Eligibility
The investigator and/or medically qualified designee will review the inclusion/exclusion criteria, 
medical history, prior and current medications/treatments and the findings of the oral 
examinations to confirm subject eligibility to participate in the clinical trial. This will be 
documented in the CRF.
To prepare for study participation, subjects will be instructed in the Lifestyle Guidelines and 
any Concomitant Medication/Treatment(s) requirements of the protocol.
8.2
Study Period
Changes in concomitant medication or non-drug treatments/procedures will be documented in 
the CRF. 
Spontaneous reporting of adverse events and those elicited by asking subjects to respond to a 
non-leading question such as “How do you feel?” will be assessed and any AEs recorded in the 
CRF.
To facilitate subject flow, clinical assessments may be recorded on a paper source document 
and later transcribed into the CRF.
8.2.1
Visit 2/ start of peroxide tooth bleaching
Procedures will be conducted by the Investigator, or suitably qualified designee.
Subjects will undergo, in the following order (wherever possible).
1. Changes in concomitant medication or non-drug treatments/procedures will be 
documented. 
2. Spontaneous reporting of AEs and those elicited by asking subjects to respond to a 
non-leading question such as “How do you feel?” will be assessed.
3. Subject will return study products and diary for visual inspection to evaluate product 
compliance and adherence to protocol.
4. Subject undergoes an OST examination.
5. Subject undergoes assessment of tooth color (Vita Shade) and extrinsic tooth stain
(MLSI).
6. Subject continuance in the study is assessed.  Subjects who do not meet the criteria for 
participation will be discontinued.
7. Subject completes the tooth sensitivity questionnaire.
8. Subject completes the whitening history questionnaire.
9. Subject undergoes supervised tooth brushing using their study dentifrice.  Subject flosses 
their teeth.
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10. Subject is dispensed the peroxide tooth bleaching kit (including petroleum jelly and dental 
floss) and instructions for at home use.
11. Subject undergoes the first application of the peroxide tooth bleaching under supervision 
at the study site.
12. AEs and incidents recorded.
8.2.2
Visit 3/ End of tooth bleaching
Procedures will be conducted by the Investigator, or suitably qualified designee.
Subjects will undergo, in the following order (wherever possible).
1. Changes in concomitant medication or non-drug treatments/procedures will be 
documented. 
2. Spontaneous reporting of adverse events and those elicited by asking subjects to respond 
to a non-leading question such as “How do you feel?” will be assessed.
3. Subject will return study products and diary for visual inspection to evaluate product 
compliance and adherence to protocol.
4. Subject undergoes an OST examination.
5. Subject undergoes assessment of tooth color (Vita Shade) and extrinsic tooth stain 
(MLSI).
6. Subject completes the tooth sensitivity questionnaire.
7. Subject completes post-whitening questionnaire.
8. AEs and incidents recorded.
8.2.3
Visit 4 /12 weeks post tooth bleaching
Procedures will be conducted by the Investigator, or suitably qualified designee.
Subjects will undergo, in the following order (wherever possible).
1. Changes in concomitant medication or non-drug treatments/procedures will be 
documented. 
2. Spontaneous reporting of AEs and those elicited by asking subjects to respond to a 
non-leading question such as “How do you feel?” will be assessed.
3. Subject will return study products and diary for visual inspection to evaluate product 
compliance and adherence to protocol.
4. Subject undergoes an OST examination.
5. Subject undergoes assessment of tooth color (Vita Shade) and extrinsic tooth stain 
(MLSI).
6. AEs and incidents recorded.
8.2.4
Visit 5 /24 weeks post tooth bleaching
Procedures will be conducted by the Investigator, or suitably qualified designee.
Subjects will undergo, in the following order (wherever possible).
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1. Changes in concomitant medication or non-drug treatments/procedures will be 
documented. 
2. Spontaneous reporting of adverse events and those elicited by asking subjects to respond 
to a non-leading question such as “How do you feel?” will be assessed.
3. Subject will return study products and diary for visual inspection to evaluate product 
compliance and adherence to protocol.
4. Subject undergoes OST and OHT examinations.
5. Subject undergoes assessment of tooth color (Vita Shade) and extrinsic tooth stain 
(MLSI).
6. AEs and incidents recorded.
7. Study conclusion.
8.2.5
Study Procedures
8.2.5.1
Diary Review
The diary should be reviewed at every visit by the investigator, or suitably qualified designee, 
with the subject. Any subject comment captured in the diary which is considered an AE will be 
assessed and reported as defined in the Adverse Event and Serious Adverse Events section of 
this protocol. 
Any additional comments relating to medications/treatments provided in the diary will be 
reviewed by the investigator or medically qualified designee with the subject and entered into 
the CRF as appropriate. 
Additional and missed product applications will be considered deviations from the protocol and 
will be recorded on the Deviations Log and as a deviation in the CRF.
8.2.5.2
Study Conclusion
The Study Conclusion page of the CRF will be completed for all subjects whether they 
completed all study procedures or if they were discontinued from the study early.  If the subject 
discontinued early, at any point during the study, the primary reason for withdrawal should be
recorded on the Study Conclusion page.
If a subject has any clinically significant, study related abnormalities or AEs at the end of the 
study, the Haleon medical monitor (or designated representative) should be notified and, the 
subject may be asked to remain at the clinical site or be asked to return for a follow-up visit to 
ensure any issue is resolved or deemed not clinically significant. 
8.2.5.3
Follow-up Visit / Phone Call
The study site may contact a subject to follow up an AE post-study completion/withdrawal and, 
in some circumstances, request they return to the site for additional follow-up visits (final safety 
assessments). If needed, additional clinical examinations may be carried out at such visits.
9
STUDY ASSESSMENTS
Every effort should be made to ensure that protocol-required examinations and assessments are 
completed as described.  However, it is anticipated that there may be circumstances outside the 
control of the investigator that may make it unfeasible to complete an assessment.  In these 
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cases, the investigator must take all steps necessary to ensure the safety and wellbeing of the 
subject.  When a protocol required assessment cannot be performed, the investigator (or 
designee) will document the reason for the missed assessment as a protocol deviation and any 
corrective and preventative actions that they have taken to ensure the required processes are 
adhered to as soon as possible.  The sponsor must be informed of any missed assessments in a 
timely manner.  The outcome of all examinations and assessments should be recorded in the 
CRF.  To facilitate subject flow, clinical assessments may be recorded on a paper source 
document and later transcribed into the CRF.
9.1
Screening Assessments
Screening examinations and assessments will be performed by appropriately trained 
staff/clinical examiners at the times, and in the order, defined in the Study Procedures section 
of this protocol.
9.1.1
OST Examination
The screening clinician will perform an initial oral soft tissue examination in agreement with 
Section 9.3.1 in order to record any abnormalities and assess the subject’s suitability and 
eligibility for enrollment into the study.
9.1.2
OHT Examination
The screening clinician will perform a visual examination of the oral hard tissues in agreement 
with Section 9.3.2 in order to record any abnormalities and assess the subject’s suitability and 
eligibility for enrollment into the study.
9.1.3
Dentine Hypersensitivity Assessments
At Visit 1, prior to randomization, subjects with a self-reported history of DH should undergo 
further clinical assessments.   For a subject to be clinically-diagnosed as having DH they must 
have at least one of the teeth that will be peroxide bleached to meet all of the following 
inclusion criteria and none of the following exclusion criteria:
Inclusion criteria for a tooth to be considered to have DH:
•
Tooth with exposed dentine due to facial/cervical erosion, abrasion or gingival 
recession (EAR).
•
Tooth with an MGI score=0 directly adjacent to the affected dentine.
•
Tooth with a clinical tooth mobility score=0.
•
Tooth demonstrating a positive response to the evaporative (air) sensitivity 
assessment [defined as those with a Schiff sensitivity score ≥2].
Exclusion criteria for a tooth to be considered to have DH:
•
Tooth with evidence of current or recent caries or reported treatment of decay.
•
Tooth with deep, defective or facial restorations, full crowns or veneers.
•
Tooth with contributing aetiologies other than erosion, abrasion or recession to 
exposed dentine.
9.1.3.1
Erosion, Abrasion and Recession (EAR) 
Teeth that will be peroxide bleached and that exhibit none of the dentition exclusion criteria for 
tooth DH (Section 9.1.3), will be examined for signs of cervical EAR (Addy et al., 2000). Only 
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teeth that demonstrate signs of EAR will be assessed further for DH.
9.1.3.2
Modified Gingival Index (MGI) 
The MGI is a non-invasive visual assessment of gingival health (Lobene, 1986). MGI will be 
assessed for teeth that will be peroxide bleached and that exhibit none of the dentition exclusion 
criteria for tooth DH (Section 9.1.3) and which show signs of EAR.  MGI should be scored for 
the facial gingiva, directly adjacent to the area of exposed dentine only, as described below. 
Score
Description
0
Absence of inflammation
1
Mild inflammation; slight change in colour, little change in colour; little change in 
texture of any portion of the marginal or papillary gingival unit.
2
Mild inflammation; criteria as above but involving the entire marginal or papillar 
gingival unit.
3
Moderate inflammation; glazing, redness, oedema, and/or hypertrophy of the marginal 
or papillary gingival unit.
4
Severe inflammation; marked redness, oedema and/or hypertrophy of the marginal or 
papillary gingival unit, spontaneous bleeding, congestion, or ulceration.
9.1.3.3
Clinical Mobility 
Clinical tooth mobility will be assessed for teeth that will be peroxide bleached and that exhibit 
none of the dentition exclusion criteria for tooth DH (Section 9.1.3), which show signs of EAR 
and which have an MGI=0 directly adjacent to the exposed dentine only, using a modification 
of the Miller Index (Laster et al., 1975) as described below. 
Degree
Description
0
No movement or mobility of the crown of the tooth < 0.2mm in a horizontal direction
1
Mobility of the crown of the tooth 0.2 - 1mm in a horizontal direction
2
Mobility of the crown of the tooth exceeding 1mm in a horizontal direction
3
Mobility of the crown of the tooth in a vertical direction as well.
9.1.3.4
Evaporative (Air) Sensitivity Assessment (Schiff sensitivity score)
The Evaporative (air) Sensitivity Assessment will be assessed for teeth that will be peroxide 
bleached and that exhibit none of the dentition exclusion criteria for tooth DH (Section 9.1.3), 
which show signs of EAR, which have an MGI=0 directly adjacent to the exposed dentine and 
which have clinical mobility = 0 only.
The examiner will apply an evaporative air stimulus by directing a maximum one second 
application of air from a dental air syringe to the exposed dentine surface from a distance of 
approximately 1 cm.  The subject response will be scored using the Schiff Sensitivity scale 
immediately following the evaporative air stimulus.  The Schiff Sensitivity scale is an examiner 
based index (Schiff et al., 1994) focusing on a combination of specific, observable, physical, 
behavioural and verbal responses from the subject as a result of the stimulation of exposed 
dentine, rather than solely an oral request from the subject to discontinue stimulation and may 
facilitate discrimination. The examiner will indicate the subject’s response to the evaporative 
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air stimulus, after the stimulation of each individual tooth, using the Schiff Sensitivity scale as 
below.
Score
Subject Response
0
Subject does not respond to air stimulation
1
Subject responds to air stimulus but does not request discontinuation of stimulus
2
Subject responds to air stimulus and requests discontinuation or moves from stimulus
3
Subject responds to stimulus, considers stimulus to be painful, and requests 
discontinuation of the stimulus
9.1.4
Assessment of Tooth Color and Extrinsic Tooth Stain
Tooth color will be assessed using the VITA Bleachedguide 3D Master shade guide as described 
in Section 9.2.2.  Extrinsic tooth stain will be assessed using the MLSI as described in Section 
9.2.1.
9.2
Efficacy Assessments
The following efficacy assessments will be performed by appropriately trained clinical 
examiner(s), at the times and in the order defined in the Study Procedures section of this 
protocol.
If in the opinion of the examiner a subject is between defined grades/scores, a conservative 
approach should be used to provide the final score.  The same approach should be applied 
throughout the study to ensure consistency in the grading of the scores at all timepoints. 
9.2.1
Tooth Color Assessment
Tooth color of the facial surfaces of the six anterior maxillary teeth (tooth numbers 6-11) 
[Universal tooth numbering system] will be assessed by a single, trained clinical examiner using 
the VITA Bleachedguide 3D-MASTER.  The arch tooth position will be parallel to the floor.  
Assessment conditions should be standardized: color corrected lighting in the range of 
5000Kelvin; a grey bib will be placed over the subject’s clothing; subjects will be asked not 
to wear lipstick; assessments will be performed in the same room (necessary) at approximately 
the same time of day (if possible); outside light will be controlled by covering the windows or 
using a windowless room. Color determination should be made within 5-7 seconds of starting 
an assessment to avoid eye fatigue.
The VITA Bleachedguide 3D-MASTER (Paravina, 2008) uses a value-ranked ordered scale 
from 1 (the lightest) to 29 (the darkest).  The shade level of each tooth surface is scored visually 
by the clinical examiner with reference to the Bleachedguide.
A single VITA Bleachedguide 3D Master Shade guide will be used for all assessments 
throughout the study wherever possible.
Subjects should have abstained from all oral hygiene procedures (including tooth brushing) for 
at least 6 hours prior to and during this assessment.  Additionally, subjects should have 
refrained from eating or drinking for at least 2 hours prior to and during this assessment, with 
the exception of small amounts of water required for taking medication.
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9.2.1.1
Repeatability of the Tooth Color Assessment
To assess the repeatability of the tooth color assessments, replicate examinations will be 
performed by the same clinical examiner using the same VITA Bleachedguide 3D Master shade 
guide.  Approximately ten subjects will be randomly selected for repeat shade assessments at 
each assessment time point (Visits 1-5), a total of 50 repeat shade assessments over the duration 
of the study.  Replicate assessments will be separated by a minimum of 10 minutes (maximum 
60 minutes) from the original assessment for a given subject and, where possible, separated by 
at least one subject.  
The scores of the initial assessment will not be visible to the examiner or scribe when the repeat 
assessment is carried out.
9.2.2
Macpherson Modification of the Lobene Stain Index (MLSI)
Extrinsic dental stain will be assessed on the facial surfaces of the 6 maxillary anterior teeth (6-
11) [Universal tooth numbering system] at Visits 1-5), using the MacPherson modification 
(Macpherson et al., 2000) of the Lobene stain index (Lobene, 1968) (MLSI). 
All assessments should be performed by a single, trained clinical examiner, with consistent 
lighting to standardize of the assessment conditions. If required, the examiner will brush the 
subject’s anterior teeth with a wetted toothbrush and/or floss to remove any debris which could 
impact the accuracy of the stain assessment.  Teeth will be air dried prior to and during the 
assessment as needed. 
The facial surfaces of each assessable tooth is divided into four regions. The ‘gingival’ region 
is defined as a crescent-shaped band, approximately 2 mm wide, adjacent to the free margin of 
the gingiva and extending to the crest of the interdental papillae of the adjacent teeth. The ‘body’ 
of the tooth is then sub-divided into three regions on the facial surfaces.
The facial surfaces of each assessable tooth will be divided into 2 regions, with a total of 4 sites 
per tooth surface (Figure 9-1).
•
Gingival Region: Defined as a crescent-shaped band (~ 2 mm wide) adjacent to the free 
margin of the gingiva and extending to the crest of the inter-dental papillae of the adjacent 
teeth (1 site). 
•
Body Region: The remainder of the tooth surface (the body) is further sub-divided into 3 
sites.
•
Distal facial, body facial, mesial facial sites
•
Distal lingual, body lingual, mesial lingual sites
Figure 9-1 MLSI Assessment Sites: Body (B), Gingival (G), Mesial (M), Distal (D)
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Area (A) and intensity (I) of extrinsic dental stain is scored separately for the four ‘gingival’ 
and ‘body’ sites, as follows. 
Score
Area
Intensity
0
No stain 
No stain
1
Stain covering up to one third of region
Light stain
2
Stain covering up to two thirds of region
Moderate stain
3
Stain covering more than two thirds of region
Heavy stain
Subjects should have abstained from all oral hygiene procedures (including tooth brushing) for 
at least 6 hours prior to and during this assessment.  Additionally, subjects should have 
refrained from eating or drinking for at least 2 hours prior to and during this assessment, with 
the exception of small amounts of water required for taking medication.
9.2.2.1
Repeatability of the MLSI Assessment
To assess the repeatability of the MLSI assessments, replicate examinations will be performed 
by the same clinical examiner.  Approximately ten subjects will be randomly selected for repeat 
MLSI assessments at each assessment time point (Visits 1-5), a total of approximately 50 repeat 
assessments over the duration of the study.  Replicate assessments will be separated by a 
minimum of 10 minutes (maximum 60 minutes) from the original assessment for a given subject 
and, where possible, separated by at least one subject.  
The scores of the initial assessment will not be visible to the examiner or scribe when the repeat 
assessment is carried out.
9.2.3
Tooth Sensitivity Questionnaire
The tooth sensitivity questionnaire (see Appendix 15.4) will be completed by the subject at the 
study site at Visits 1-3, to evaluate the overall tooth sensitivity experienced by the subject over 
the previous week.  Thus, the questionnaire should record the subject’s overall experience of 
the preceding 7 days.  The questionnaire will be completed at the study site without reference 
to other subjects and will be checked for completeness prior to the subject leaving the site.
Study personnel should demonstrate to subjects the correct completion of this questionnaire 
prior to administering.  
Subjects will indicate whether they have felt tooth sensitivity during the previous week.  Those 
who indicate they have not felt tooth sensitivity will not be required to complete the rest of the 
questionnaire.  Subjects who indicate they did feel tooth sensitivity will complete the remainder
of the questionnaire comprising the VAS, LMS and Bothersomeness numerical rating scale 
(NRS).
Subjects will rate their overall tooth sensitivity using a 100mm VAS with end anchors of ‘ No 
Sensitivity’ to ‘Extreme Sensitivity’.  
The LMS apply psychophysical procedures (magnitude estimation and cross-modality 
magnitude matching) to condition specific descriptive words relevant to the subject’s response
(Gracely et al., 1978).  The descriptive words are then aligned along a Visual Analogue Scale 
(VAS) at distances that reflect the psychological distances between words. These scales have 
been piloted and validated in a previously reported dentine hypersensitivity trials (Heaton et al., 
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2013, Mason et al., 2019).  The LMS will be used to rate the intensity, duration, tolerability and 
descriptive quality of their tooth sensitivity using the four individual 100 millimetre (mm) LMS. 
The study staff will measure the line segment marked-off in mm from bottom to top along the 
line (for LMS) and from left to right (for the VAS) and record this in the eCRF.
The subject will also complete a NRS for bothersomeness for which the subject should circle 
an appropriate number on the scale.
All questionnaire data shall be recorded in the CRF upon return of completed questionnaire.
9.2.4
Whitening History and Post-Whitening Questionnaires
Subjects will be dispensed the questionnaires to complete at Visits 2&3.  Subjects should 
complete these individually at the study site without reference to other subjects.  Site staff 
should ensure the questionnaires are fully completed before the subject leaves the site.
9.3
Safety and Other Assessments
The following safety assessments will be performed by appropriately trained clinical 
examiner(s), at the times and in the order defined in the Study Procedures section of this 
protocol.  Additionally, to help prevent COVID-19 or other disease transmission within the 
study, the measurement of the temperature of subjects and/or questioning of the subjects may 
be utilized at any site visit at the examiner’s discretion.
9.3.1
Oral Soft Tissue (OST) Examination
This procedure will be conducted by a qualified, experienced clinical examiner.  The OST 
examination will be accomplished by direct observation and palpation with retraction aids, as 
appropriate. The examination will cover the oral labial mucosa (including lips), buccal mucosa, 
mucogingival folds, gingival mucosa, hard palate, soft palate, tonsillar area, pharyngeal area, 
tongue, sublingual area, submandibular area and salivary glands.  Findings from the 
examination will be recorded in the CRF as either normal or abnormal, with details of any 
abnormalities. The results of the OST examination performed at screening will be used to 
determine subject eligibility. Any new OST abnormality or worsening of a pre-existing 
condition observed by the clinical examiner or reported by the subject after the screening 
examination will be recorded as an AE.
Where possible, this procedure should be conducted by a single clinical examiner.  
9.3.2
Oral Hard Tissue (OHT) Examination
This procedure should be conducted by a qualified, experienced clinical examiner.  The OHT 
examination will be accomplished by direct observation, using retraction aids as appropriate 
and will identify any grossly carious lesions, signs of erosive wear, enamel irregularities, tooth 
fracture, gross generalized dental caries decay, decalcification and faulty restorations. The 
presence of any implants, fixed or removable dentures, fixed or removable orthodontic 
braces/bands, fixed orthodontic retainers, full crowns or veneers will be recorded. Observations 
will be listed as either absent or present, and conditions noted as present will be described in 
the eCRF. Any change observed by the clinical examiner or reported by the subject after the 
screening examination will be recorded as an AE.
The results of the OHT examination performed at Screening will be used to determine subject 
eligibility.
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Where possible, this procedure should be conducted by a single clinical examiner. 
9.3.3
Pregnancy Testing
Urine pregnancy testing of subjects of child-bearing potential is not required for this study (see 
Section 4.2 for details).  Subjects of child-bearing potential will be asked to provide verbal 
confirmation of pregnancy status at screening (Visit 1) and to inform site staff if they find they 
are pregnant while participating in the study.  In case of a positive confirmed pregnancy, the 
subject will be withdrawn from the study.
10
ADVERSE EVENT AND SERIOUS ADVERSE EVENTS
The investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study product or the study, or that caused the 
subject to discontinue the study product or study.
10.1
Definition of an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study subject, temporally associated 
with the use of a study product including any washout or lead-in product (or medical device), 
whether or not considered related to the study product, including any washout or lead-in product 
(or medical device).
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a study product including any washout or lead-in product (or medical device).
Events Meeting the AE Definition:  
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g. ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (i.e., not related to progression of underlying 
disease).
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study product administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study product 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it 
is an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae.
•
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE if they fulfill the definition of an AE. 
Events NOT meeting the AE definition: 
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•
Any clinically significant abnormal laboratory findings (if applicable) or other abnormal 
safety assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 
•
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
•
Medical or surgical procedure (e.g. endoscopy, appendectomy) is not the AE. The 
condition that leads to the procedure is an AE (e.g. appendicitis).
•
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.2
Definition of a Serious Adverse Event (SAE)
A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse 
outcome is serious. If an event is not an AE per definition above, then it cannot be an SAE even 
if serious conditions are met (e.g. hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A serious adverse event is any untoward medical occurrence at any dose that:
•
Results in death
•
Is life-threatening 
•
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe;
•
Requires inpatient hospitalization or prolongation of existing hospitalization 
•
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred, or was necessary, 
the AE should be considered serious.
•
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
•
Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption
•
Results in congenital anomaly/birth defect
•
Other situations:
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
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not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Note: Classification of an AE as ‘serious’ is based on the outcome of the event and is a factor 
in determining reporting requirements.
10.3
Time Period and Frequency for Collecting AE and SAE 
Information
All AEs, and therefore all SAEs will be collected immediately after a subject provides consent 
to participate in the study by the completion (signature) of the ICF and until 5 days following 
last administration of the study product (or last procedure). 
Medical occurrences that began before obtaining informed consent will be recorded in the 
Medical History/Current Medical Conditions section of the CRF not the AE section.
Details recorded by the subject on a diary or similar document that meet the definition of an AE 
must also be discussed with the subjects and transcribed in the AE section of the CRF. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours. The investigator will submit any updated SAE data 
to the sponsor within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study product or study participation, the investigator must promptly 
notify the sponsor.
10.4
Reporting Procedures
The investigator and any designees are responsible for detecting, documenting and reporting 
events that meet the definition of an AE and remain responsible for following up on AEs that 
are serious, considered related to the study product(s), participation in the study, or a study 
procedure, or that caused the subject to discontinue the study product or study. 
Spontaneous reporting of adverse events and those elicited by asking subjects to respond to 
non-leading such as “How do you feel” will be assessed and any AE’s recorded in the CRF and 
reported appropriately.
The investigator (or medically qualified designee) is to report all directly observed AEs and all 
AEs spontaneously reported by the study subject. In addition, each study subject will be 
questioned about AEs. 
Each AE is to be assessed to determine if it meets the criteria for a SAE.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
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When an AE occurs, it is the responsibility of the investigator (or medically qualified designee) 
to review all documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
The investigator or site staff will then record all relevant information regarding an AE in the 
CRF and all details relating to an SAE in the paper SAE Form provided.
It is not acceptable for the investigator (or medically qualified designee) to send photocopies 
of the subject’s medical records to Haleon in lieu of completion of the AE CRF page/SAE form.
There may be instances when copies of medical records for certain cases are requested by 
Haleon.  In this instance, all subject identifiers, except for the subject number, will be redacted 
on the copies of the medical records prior to submission to Haleon.
The investigator (or medically qualified designee) will attempt to establish a diagnosis of the 
event based on signs, symptoms, and/or other clinical information.  The diagnosis will be the 
documented as the AE/SAE where known and not the individual signs/symptoms. (e.g. upper 
respiratory tract infection, seasonal allergy, etc. instead of runny nose).
AEs elicited by the investigator (or medically qualified designee) in a standard manner at the 
study visits should also be recorded in the AE section of the CRF and/or using the SAE form 
(subject to the classification of the AE). Care will be taken not to introduce bias when 
questioning a subject about any changes in their health. Open-ended and non-leading verbal 
questioning should be used.
10.4.1
Reporting of an Adverse Event
All AEs will be reported on the AE page of the CRF by the investigator or site staff.  It should 
be noted that the form for collection of SAE information is not the same as the AE CRF.  Where 
the same data are collected, the AE CRF page and the SAE form must be completed in a 
consistent manner.  For example, the same AE term should be used on both.  AEs should be 
reported using concise medical terminology on the CRF as well as on the form for collection of 
SAE information.
10.4.2
Reporting of a Serious Adverse Event
In addition to recording the details of each AE on the AE CRF page, an SAE form should be 
completed, as fully as possible. Hard copies of the ‘paper’ SAE form will be provided in the 
investigator study master file. Original SAE forms will be retained in the investigator study 
master file.
It is essential to enter the following information: 
•
Protocol and subject identifiers
•
Subject demography
•
Description of events, with diagnosis if available
•
Investigator opinion of relationship to study product (or study procedure, if appropriate)
•
Criterion for seriousness.
The following are desirable and are of particular relevance for investigator and Haleon
assessment of the SAE report:
•
Date of onset of AE 
•
Date AE stopped, if relevant
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•
Study product start date
•
Study product end date if relevant
•
Action taken in relation to the study product
•
Outcome if known
The SAE form, completed as fully as possible, must be scanned and e-mailed to the Case 
Management Group mailbox 
, with copy to the appropriate 
Study Manager, with the study number and subject number in the subject line of the email 
immediately and under no circumstance should this exceed 24 hours after study site 
personnel learn of the event. The investigator will submit any updated SAE data to the sponsor, 
immediately and under no circumstance should this exceed 24 hours of it being available. 
The initial report will be followed up with more information as relevant, or as requested by the 
study manager.
The Study Manager will be responsible for forwarding the SAE form to other Haleon personnel 
as appropriate.
10.5
Evaluating Adverse Events 
10.5.1
Assessment of Intensity
The investigator or medically qualified designee will make an assessment of intensity for each 
AE reported during the study and will assign it to one of the following categories:
•
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.
•
Moderate:  An event that is sufficiently discomforting to interfere with normal everyday 
activities
•
Severe:  An event that prevents normal everyday activities. 
NOTE: An AE that is assessed as severe should not be confused with an SAE. Severe is a 
category utilized for rating the intensity of an event; and both non-serious AEs and SAEs can 
be assessed as severe. For example, a headache may be severe (interferes significantly with the 
subject's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above. An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe.
10.5.2
Assessment of Causality
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
For each AE (serious and non-serious), the investigator (or medically qualified designee) must
provide an assessment of causality on the AE CRF page and the SAE form (subject to the 
classification of the AE). The investigator will also document in the medical notes that he/she 
has reviewed the AE and assessed causality, where applicable. 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
Generally, the facts (evidence) or arguments to suggest a causal relationship should be provided.
The investigator will use clinical judgment to determine the relationship and will also consult 
the Safety Statement and Product Information for marketed products, in the determination of 
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his/her assessment.  Alternative causes, such as underlying disease(s), concomitant therapy, 
other risk factors, and the temporal relationship of the event to the study product will be 
considered and investigated.
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality.
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the SAE reporting requirements if applicable.
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to Haleon.  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 Haleon. The investigator may change his/her opinion of 
causality in light of follow-up information and send an SAE follow-up report with the updated 
causality assessment. 
10.6
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow up with each 
subject and provide further information on the subject’s condition.
All AEs (serious and non-serious) will be followed until resolution, until the condition stabilizes, 
until the event is otherwise explained, or until the subject is lost to follow-up.  
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by Haleon to elucidate as 
fully as possible the nature and/or causality of the AE. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals.
New or updated information will be recorded on the AE CRF page and on the SAE form (subject 
to the classification of the AE).
The investigator will submit any updated SAE data to Haleon within 24 hours of receipt of the 
information.
Investigators are not obliged to actively seek AEs in former subjects.  However, if the 
investigator learns of a SAE, including death, at any time after a subject has been discharged 
from the study, and considers the event reasonably related to the study product or study 
participation, the investigator will promptly notify Haleon by emailing the information to the 
Case Management Group mailbox at Haleon
), with copy to 
the appropriate Study Manager.
The investigator will submit any updated SAE data to Haleon within the designated reporting 
time frames.
10.7
Withdrawal Due to an Adverse Event 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, according 
to the definition of an AE noted earlier, and recorded on the appropriate AE CRF page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined.
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10.8
Regulatory Reporting Requirements for SAEs
Haleon 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 Haleon is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects are met.
Haleon will comply with country specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/EC and investigators.
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information e.g. summary or listing of SAE from the sponsor will review and then file it 
along with the Investigator’s Brochure in the investigator study master file, and will notify the 
IRB/IEC, if appropriate according to local requirements.
10.9
Pregnancy
10.9.1
Time Period for Collecting Pregnancy Information
Pregnancy information will be collected on all pregnancies reported while a female subject is 
participating in the study from the signing of informed consent until 5 days after last 
administration of study product.
10.9.2
Action to be Taken if Pregnancy Occurs
The investigator will record pregnancy information on the appropriate form scan and e-mail it 
to the Case Management Group mailbox 
, with copy to the 
appropriate Study Manager. Original pregnancy information forms will be retained in the 
investigator study master file. 
The subject will be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and infant / neonate (including concomitant medications taken by the 
mother during the pregnancy) will be forwarded by the investigator to the Case Management 
Group mailbox at Haleon 
, with copy to the appropriate 
Study Manager. Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE, abnormal pregnancy outcomes (e.g. 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are, and 
should be recorded as an SAE.
Any subject who becomes pregnant while participating will be withdrawn from the study.
10.10
Medical Device Incidents
The definitions and procedures detailed are in accordance with ISO 14155.
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements.
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Medical devices are being provided by Haleon for use in this study; the medical device in this 
study is the study toothbrush.
10.10.1
Definition of an Incident
A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a subject/user/other 
person or to a serious deterioration in his/her state of health.
Not all incidents lead to death or serious deterioration in health. The nonoccurrence of such a 
result might have been due to other fortunate circumstances or to the intervention of health care 
personnel.
It is sufficient that:
An incident associated with a device happened and
•
The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
•
A serious deterioration in state of health can include any of the following:
•
Life-threatening illness
•
Permanent impairment of body function or permanent damage to body structure
•
Condition necessitating medical or surgical intervention to prevent one of the above 
•
Fetal distress, fetal death, or any congenital abnormality or birth defects
Examples of incidents:
•
A subject, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse.
•
A subject’s study treatment is interrupted or compromised by a medical device failure.
•
A misdiagnosis due to medical device failure leads to inappropriate treatment.
•
A subject’s health deteriorates due to medical device failure.
10.11
Reporting of Incidents and Malfunctions
All incidents must be reported to Haleon immediately and under no circumstance should 
this exceed 24 hours of the investigator or designee becoming aware of the situation.
Any medical device incident occurring during the study will be documented in the subject's 
medical records, if in accordance with the investigator's normal clinical practice, and on the 
appropriate Incident Report Form.  In addition, for incidents fulfilling the definition of an AE 
(serious and non-serious), the appropriate AE CRF page and SAE form will be completed and 
reported as per the AE and SAE reporting sections.
The Incident Report Form will be completed as thoroughly as possible and signed by the 
investigator before transmittal to Haleon.  It is very important that the investigator describes 
any corrective or remedial actions taken to prevent recurrence of the incident.
The completed Incident Report Form should be scanned and emailed to the Case Management 
Group mailbox 
, with copy to the appropriate   Study 
Manager, with the study number and subject number in the subject line of the email 
immediately and under no circumstance should this exceed 24 hours after study site 
personnel learn of the event. If there is an SAE, the completed SAE form should be sent together 
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with this report form.  However, if a copy of the SAE report is sent with this form, this does not 
replace the procedure to report an SAE.  The original Incident Report Form will be retained in 
the investigator study master file. 
The initial report will be followed up with more information as relevant, or as requested by the   
study manager.
The investigator will follow the following directions regarding the reporting of a device failure 
(malfunction):
•
Notify Haleon immediately (by following the process described above).
•
Schedule the subject to return to the site promptly to return the failed device.
•
Record any incidents on the CRF and Incident Report Form following instructions given 
in the section above.
•
For any incident/malfunction occurring with a medical device (including those that are 
part of combination products) supplied by Haleon, return the failed device to the sponsor 
as soon as possible, including documentation of the details of the failure.
•
For any incident/malfunction occurring with a medical device (including those that are 
part of combination products) supplied by the Investigator site, report the incident to the 
device manufacturer and follow the manufacturer instructions for the return of the failed 
device (whilst keeping Haleon informed).
10.12
Follow-up of Medical Device Incidents
Medical device incidents involving an AE will be followed and reported in the same manner as 
other AEs. This applies to all subjects, including those who discontinue study product or are 
withdrawn from the study.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident.
New or updated information will be recorded on the originally completed Incident Report form 
with all changes signed and dated by the investigator.
10.13
Regulatory Reporting Requirements for Medical Device Incidents
To fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction that 
occur during all periods of the study in which the medical device is used. 
The investigator will promptly report all incidents occurring with any medical device provided 
for use in the study in order for the sponsor to fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to medical 
devices being used in clinical studies.
The investigator, or responsible person according to local requirements (e.g. the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of incidents to the IRB/IEC.
11
DATA MANAGEMENT
As used in this protocol, the term CRF is understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method. 
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For this study, subject data will be entered into an electronic CRF (eCRF), using a validated 
system. Data relating to SAEs, pregnancy and incidents will also be collected on paper forms.
The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The source documents (e.g. hospital records, clinical and office charts, laboratory notes, 
memoranda, subject diaries, questionnaires, evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files and records kept at the pharmacy, at the laboratory and at 
the medico-technical departments involved in the clinical study) which contain the source of 
data recorded in the CRF should be specified.  The CRF and or diary can be used as a source 
document at the discretion of data management.
Each subject will be assigned and identified by a unique Screening Subject Number. Any 
reference made to an individual subject within the study must be done using their unique 
Screening Subject Number.
11.1
Case Report Form
A CRF is a printed, optical, or electronic document designed to record the protocol required 
information to be reported to the sponsor on each trial subject.
For each subject who has given informed consent/assent the CRF must be completed and signed 
by the Principal Investigator (or authorized designee) to certify that the data are complete and 
correct.  The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
Management of clinical data will be performed in accordance with Third Party BDM Vendor 
applicable standards and data cleaning procedures with oversight by Haleon to ensure integrity 
of the data, for example, to remove errors and inconsistencies in the data. 
To protect the privacy of subjects, no Personal Information (PI) (including the subject's name 
or initials or full birth date) is to be recorded in the CRF or as part of the query text.
All CRF pages should be completed during a subject assessment when the CRF has been 
designated as the source.  Data that is sourced elsewhere should be entered into the CRF in an 
agreed upon timeframe between the Investigator and Sponsor.  
Haleon will obtain and retain all CRFs and associated study data as applicable at the completion 
of the study. 
11.2
Data Handling
Documentation of all data management activities should allow step-by-step retrospective 
assessment of data quality and study performance. 
Any changes or corrections to data will be performed in the Electronic Data Capture (EDC) 
System, and it will include rationale for changes. The EDC system has an audit trail, which will 
provide a complete record of the changes and corrections endorsed by the Investigator.
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
and any concomitant medications terms (if applicable) using an internal validated medication 
dictionary, WHODrug.
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11.2.1
Data Queries
Programmed edit checks will be generated automatically, as the data are being entered into the 
system. Reports and listings on the CRF data will also be run, in addition to the queries already 
programmed and generated by the system, to raise manual queries as needed for site 
clarification or correction. The Clinical Dictionary Development and Management Group will 
raise queries as needed on safety data to code the terms (AEs and Drugs or concomitant 
medication) appropriately. 
The study monitor will perform ongoing review the of the CRFs in accordance with the 
monitoring plan, to confirm that data entered into the CRF by authorized site personnel are 
accurate, complete, and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.
Any queries will be generated in the EDC System to the Investigator or designee, enabling the 
errors to be addressed in parallel with Data Management review. The study monitor can also 
run reports and listings on the CRFs, to raise manual queries as needed for site clarification or 
correction.
11.3
Processing Patient Reported Outcomes
Paper based patient reported outcome (PRO) data may be recorded to a diary, tooth sensitivity 
questionnaire, or other specified document (eg questionnaires), etc. and entered into the data 
management system (DMS).
All PRO source data should be reviewed by the study staff and the study monitor to ensure 
accurate transcription of data and that any potential AEs or concomitant medications reported 
on these documents are discussed with the subject and transcribed accurately to the CRF and/or 
DMS. PROs that are classed as source data will be retained by the investigator and true/certified 
copies may be sent to a designated vendor or Haleon as required. Any AEs or concomitant 
medications collected as ePRO will be reviewed and transcribed to the eCRF by the site.
To protect the privacy of subjects, no Personal Information (PI) (including the subject's name 
or initials or birth date) is to be recorded on any PRO/ePRO/IoMT Devices Data that will be 
forwarded to Haleon or Third-Party Vendor.
12
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
12.1
Sample Size Determination
There were no previous directly comparable studies that have evaluated the effect of a dentifrice
on maintaining tooth whiteness after peroxide bleaching upon which to base an estimate of 
sample size. However, based on a previous study evaluating the tooth whitening abilities of the 
test dentifrice (Haleon Clinical Study 300024, 2023), a mean change (SD) of VITA scores of 1 
(±2) was assumed. Sufficient individuals will be screened to enroll approximately 160 subjects 
(approximately 80 per group) assuming an estimated 20% dropout rate; approximately 128 
completed subjects (approximately 64 per group) are deemed sufficient to detect a difference 
between the Test and Reference Dentifrices at 24 weeks with 80% power,
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12.2
Populations for Analysis
•
The Safety population will comprise all randomized subjects who receive at least one dose 
of the study product. This population will be based on the product the subject actually 
received.
•
The modified Intent-To-Treat (mITT) population will include all randomized subjects who 
complete at least one use of study product and have at least one assessment of tooth color 
after the bleaching period. This population will be based on the study product to which the 
subject was randomized. Any subject who receives a randomization number will be 
considered to have been randomized.
•
The Per-Protocol (PP) population will include all randomized subjects who do not have 
any protocol deviations that could confound the interpretation of analyses conducted on 
the mITT.
•
The repeatability population for tooth color is defined as all subjects who have at least one 
repeat tooth color clinical assessment at any visit.
•
The repeatability population for MLSI is defined as all subjects who have at least one 
repeat MLSI clinical assessment at any visit.
12.3
Statistical Analyses
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/analysis (as appropriate). This section is a summary of the planned statistical 
analyses for the primary and key secondary endpoints.
The mITT population will be used for all efficacy analyses. No repeat assessment data is to be 
used in any efficacy analyses.
12.3.1
Primary Analysis
The primary efficacy variable is mean Vita Bleachedguide shade at 24 weeks after tooth 
bleaching has completed, calculated at the subject level as the average Vita Bleachedguide 
shade over all sites assessed. The primary comparison will be the test dentifrice vs. the reference 
dentifrice. As there is only a single primary objective, no adjustment for multiple comparisons 
is required.
Mean Vita Bleached guide shade will be analyzed using a repeated measures ANOVA model 
with treatment group and time point as factors, and treatment group by time point as interaction.
The adjusted mean treatment difference at 24 weeks will be obtained from the model and 
presented, along with 95% confidence intervals (CIs) and p-values.  All p-values presented will 
be two-sided and assessed at the 5% significance level.
The assumption of normality and homogeneity of variance in the ANOVA will be investigated. 
In case of violation of these assumptions, a suitable nonparametric test will be performed; 
inferences drawn from non-parametric analysis will be considered as confirmatory results.
Summary statistics including mean, SD, standard error (SE), median, minimum, maximum will
be provided by visit and randomized treatment group. Raw means and SE will also be plotted
over time by treatment group.
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12.3.2
Secondary Analyses
The secondary efficacy variables are as follows:
Mean Vita Shade score at 12 weeks
MLSI score at 12 and 24 weeks:
o
Mean total MLSI (Area x Intensity)
o
Mean MLSI (AxI) for gingival sites
o
Mean MLSI (AxI) for interproximal sites)
o
Mean MLSI (AxI) for body sites
o
Mean total MLSI Area 
o
Mean Total MLSI Intensity
Secondary endpoints will be analyzed using the same model as used in the primary analysis. 
The comparisons of interest will be the test dentifrice vs. the reference dentifrice. Adjusted 
mean treatment differences will be provided, along with p-values and 95% CIs.
Summary statistics including mean, SD, standard error (SE), median, minimum, maximum will 
be provided by visit and randomized treatment group.  Raw means and SE will also be plotted 
over time by treatment group.  Summary statistics of the between-treatment results at each time 
point will also be obtained and tabulated.
12.3.3
Exploratory Analysis 
Tooth sensitivity questionnaire 
For the exploratory endpoints listed below, the mean scores of the responses to the sensitivity 
questionnaire scores will be summarized for each time point; screening (Visit 1), prior to the 
start of tooth bleaching (Visit 2) and at the completion of tooth bleaching (Visit 3) and analyzed.
o
Visual analogue scale
o
Labelled Magnitude scales
o
Bothersomeness score
These analyses will be performed for the mITT population and by strata group (clinically 
diagnosed DH (Y/N) (where applicable) at screening.
Additionally, the following data from the questionnaires will be presented with summary 
statistics.
o
Number of subjects who experienced tooth sensitivity by treatment group and stratum 
(Clinically-diagnosed DH [Y/N])
Whitening History Questionnaire
The data from this questionnaire will be presented with summary statistics.
Post-Whitening Questionnaire
The data from this questionnaire will be presented with summary statistics only by treatment 
group.
Tooth Whitening History Questionnaire
The data from this questionnaire will be presented with summary statistics.
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Change in VITA shade from pre-to post to bleaching
The mean Vita shade will be summarized for prior to the start of tooth bleaching (Visit 2) and 
at the completion of tooth bleaching (Visit 3) and analyzed. An Analysis of Covariance 
(ANCOVA) model will be applied to analyze the Change from pre-to-post bleaching treatment 
in the mean VITA-Shade color score with study product as a fixed effect and the mean VITA-
Shade color score prior to the start of tooth bleaching fitted as a covariate. The least square 
means for each study product will be presented along with the pairwise differences.
The assumption of normality and homogeneity of variance in will be investigated. In case of 
violation of these assumptions, a suitable non-parametric test will be performed, and results will 
be provided to support the parametric results.
Additional details of the proposed statistical analysis of the exploratory endpoints will be 
documented in the statistical analysis plan (SAP).
12.3.4
Safety Analyses
The Safety population will be used for safety analyses. Safety analyses will be performed 
according to study product received.
Safety analyses will focus on:
o
Exposure and compliance with study product
o
Adverse Events (AEs)
All AEs will be reviewed by the Clinical Research Scientist, or designee, prior to database lock 
and unblinding and will be coded using the 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 first use of study product at the Baseline visit.
The following AEs summaries (number of distinct AEs and frequency/proportion of subjects 
affected will be presented by study product group and overall:
o
Treatment emergent AEs
o
Treatment emergent AEs by System Organ Class (SOC) and Preferred Term (PT);
o
Treatment emergent AEs by Oral/Non-Oral and PT;
o
Treatment emergent treatment related AEs by Oral/Non-Oral and PT;
o
Treatment emergent treatment related serious AEs by SOC and PT
A listing of all AEs will be presented for all subjects in the Safety population. Separate listings 
will be presented for any deaths, serious AEs and AEs leading to study or product 
discontinuation.
A list of medical device incidents will also be included as part of the safety analyses.  No 
specific risks or anticipated adverse device effects are expected to be observed within this study, 
however all AEs and medical device incidents will be assessed to evaluate the tolerability and 
safety of the treatments.
No specific risks or anticipated adverse device effects are expected to be observed within this 
study, however all AEs and medical device incidents will be assessed to evaluate the tolerability 
and safety of the treatments.
12.3.5
Other Analyses
The repeat tooth stain and color assessments will be compared to the original assessments and 
will not be used in any efficacy analysis. The first and second assessments on each tooth site 
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will be cross tabulated. A weighted Kappa coefficient (κ), along with the 95% CI will be 
calculated to assess the intra-examiner reliability. Fleiss-Cohen weighted kappa will be 
calculated for the repeatability analysis. Reliability will be deemed-
•
Excellent if κ > 0.75
•
Fair-to-good if 0.4 ≤ κ ≤ 0.75
•
Poor if κ <0.4
All subjects who have repeatability data will be included in this analysis.
12.3.6
Exclusion of Data from Analysis 
Exclusion of any data from the analyses will be determined during a Blind Data Review (BDR) 
Meeting prior to database lock. Any reasons for exclusion from an analysis population will be 
listed, if applicable. 
12.3.7
Demographic and Baseline Characteristics
Demographic and randomized stratification data will be summarized descriptively.
12.3.8
Study Product Compliance
12.3.8.1 Study Product Compliance
Number of brushings, brushing compliance (%), number of missed/additional brushings will be 
summarized using descriptive statistics by cumulative visit. 
12.3.8.2 Prior and Concomitant Medications
Prior and Concomitant Medications will be listed.  Concomitant medications that have been 
taken to alleviate tooth sensitivity/pain will be summarized and listed separately.
12.3.8.3 Other Therapy
Number of bleaching occurrences, bleaching compliance (%), number of missed/additional 
bleaching occurrences will be summarized using descriptive statistics by cumulative visit.
12.3.9
Handling of Dropouts and Missing Data 
The use of ANOVA analyses account for missing data assuming a missing at random 
assumption, i.e., there is a systematic relationship between the propensity of missing values and 
the observed data, but not the missing data. 
It is therefore assumed that a subject with missing data would have obtained a similar efficacy 
result compared to a subject using the same study product with the same smoking status and 
similar non-missing results at other timepoints. Sensitivity analyses may be added to the SAP 
prior to unblinding in case of high drop-out rates and/or exclusion from PP population. 
12.3.10
Interim Analysis 
No interim analysis is planned for this study.
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13
STUDY GOVERNANCE CONSIDERATIONS
13.1
Quality Control 
In accordance with applicable regulations including GCP, and Haleon procedures, Haleon 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 Haleon 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.
Haleon 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 
Haleon. The investigator (or designee) agrees to allow the monitor direct access to all relevant 
documents and agrees to co-operate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved.
13.2
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, Haleon may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of the 
study. 
In the event of an assessment, audit or inspection, the investigator (and institution) must agree 
to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and 
to allocate their time and the time of their staff to discuss the conduct of the study, any 
findings/relevant issues and to implement any corrective and/or preventative actions to address 
any findings/issues identified.
The investigator(s) will notify Haleon or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Haleon 
or its agents to prepare the study site for the inspection and will allow Haleon or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly apply 
copies of the inspection finding to Haleon or its agent. Before response submission to the 
regulatory authority, the investigator will provide Haleon or its agents with an opportunity to 
review and comment on responses to any such findings. 
The sponsor will be available to help investigators prepare for an inspection.
13.3
Regulatory and Ethical Considerations
13.3.1
Institutional Review Board/ Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, investigator brochure/safety statement 
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(including any updates) and other relevant documents, e.g. recruitment advertisements, if 
applicable, from the IRB/EC.  All correspondence with the IRB/EC should be retained in the 
investigator file.  Copies of IRB/EC approvals should be forwarded to Haleon prior to the 
initiation of the study, and also when subsequent amendments to the protocol are made.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the investigator must notify the IRB/EC and Haleon in writing immediately after the 
implementation.
13.3.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol and legal and regulatory 
requirements, as well as the general principles set forth in the International Ethical Guidelines 
for Biomedical Research Involving Human Subjects (Council for International Organizations 
of Medical Sciences, 2002), International Ethical Guidelines for Health-Related Research 
Involving Humans), guidelines for GCP (Council for International Organizations of Medical 
Sciences, 2016, ICH, 1996), and the Declaration of Helsinki (World Medical Association, 2013).
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws.
13.3.3
Subject Information and Consent
not include subject names or other identifiable data in any reports, publications, or other 
disclosures, except where required by laws. 
When study data are compiled for transfer to Haleon and other authorized parties, subject names, 
addresses, and other identifiable data will be replaced by numerical codes based on a numbering 
system provided by Haleon in order to de-identify study subjects.  
The study site will maintain a confidential list of subjects who participated in the study, linking 
each subject’s numerical code to his or her actual identity.  In case of data transfer, Haleon will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be reviewed 
and approved by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study subject, is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed. The investigator will 
retain the original of each subject's signed informed consent document.
13.3.4
Subject Recruitment 
Advertisements approved by IRBs/ECs and investigator databases may be used as recruitment 
procedures.  Use of ethics committee approved, generic, prescreening questionnaire to assess 
basic subject characteristics to determine general eligibility for this study is allowed. This 
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generic questionnaire may be used by sites as a phone script and/or to review internal databases 
to identify subjects.  
Haleon will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used. 
13.3.5
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP 
Within Haleon a serious breach is defined as a breach likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated in Haleon -
sponsored human subject research studies. 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Haleon should be informed immediately. 
In addition, the investigator will inform Haleon immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13.4
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of subjects begins in accordance with applicable Haleon processes.
Haleon intends to make anonymized subject-level data from this trial available to external 
researchers for scientific analyses or to conduct further research that can help advance medical 
science or improve patient care. This helps ensure the data provided by trial participants are 
used to maximum effect in the creation of knowledge and understanding.
13.5
Provision of Study Results to Investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the opportunity 
to review the complete study results at a Haleon site or other mutually-agreeable location.
Haleon 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 Haleon Policy.
A manuscript will be progressed for publication in the scientific literature if the results provide 
important scientific or medical knowledge.
13.6
Records Retention
Following closure of the study, the investigator must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and secure location.  
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The records (study/ site master file) must be maintained to allow easy and timely retrieval, when 
needed (e.g. for a Haleon 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 Haleon, 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 Haleon, e.g. subjects’ written consent forms, 
should be maintained by the investigator in strict confidence.
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the investigator as per the signed contractual agreement, from the issue of the final 
Clinical Study Report (CSR) or equivalent summary, unless local regulations or institutional 
policies require a longer retention period. The minimum retention time will meet the strictest 
standard applicable to that site for the study, as dictated by any institutional requirements or 
local laws or regulations, Haleon standards/procedures, and/or institutional requirements.  
No study document should be destroyed without a prior written agreement between Haleon and 
the investigator. The investigator must notify Haleon of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with the site.
13.7
Conditions for Terminating the Study 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB, or study product safety problems, or at the discretion of Haleon.  
In addition, Haleon retains the right to discontinue development of potassium nitrate dentifrices 
at any time. 
If a study is prematurely terminated, Haleon will promptly notify the investigator.  After 
notification, the investigator must promptly contact all participating subjects and should assure 
appropriate therapy/ follow-up for the subjects.  As directed by Haleon, all study materials must 
be collected and all CRF’s completed to the greatest extent possible. Where required by the 
applicable regulatory requirements, Haleon should inform the regulatory authority(ies) and the 
investigator should promptly inform the IRB and provide the IRB a detailed written explanation 
of the termination or suspension. 
If the IRB terminates or suspends its approval/favorable opinion of a trial, the investigator 
should promptly notify the Haleon and provide Haleon with a detailed written explanation of 
the termination or suspension.
Upon completion or premature discontinuation of the study, the Haleon monitor will conduct 
site closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations including GCP, and Haleon Standard Operating Procedures.
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14
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nitrate desensitizing mouthwash and a toothpaste in the treatment of dentinal hypersensitivity. 
Journal of clinical and experimental dentistry; 4(1): e28.
[UK National Health Service (2023)]. Teeth Whitening [Online]. Available: 
https://www.nhs.uk/conditions/teeth-
whitening/#:~:text=Is%20teeth%20whitening%20permanent%3F,can%20all%20stain%20you
r%20teeth. [Accessed].
[US FDA (2005)] GUIDANCE FOR INDUSTRY: COLLECTION OF RACE AND 
ETHNICITY DATA IN CLINICAL TRIALS.
[West NX (2023a)] Manuscript Under Preparation.
[West NX (2023b)] Seven Country European Prevalence Data on Toothwear and Dentine 
Hypersensitivity. J Dent Res; 102(Spec Iss B): 0711-4.
[World Medical Association (2013)] Declaration of Helsinki, 64th General Assembly, Fortaleza.
15
APPENDICIES
15.1
ABBREVIATIONS
The following is a list of abbreviations that may be used in the protocol.
AE
adverse event
ANOVA
analysis of variance
BDR
blinded data review
CI
confidence interval
CRF
case report form
DH
Dentine Hypersensitivity
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EAR
Erosion, Abrasion or Recession
eCRF
Electronic Case Report Form
FDA
Food and Drug Administration (United States)
GCP
Good Clinical Practice
ICH
International Conference on Harmonisation
IRB
institutional review board
LSLV
last subject last visit 
MedDRA
medical Dictionary for Regulatory Activities
MGI
Modified Gingival Index
MLSI
Modified Lobene Stain Index
MMRM
Mixed model with repeated measures
N/A
not applicable
PI
principal investigator
SS
safety statement
USA
United States of America
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15.2
Study Product Usage Instructions Sheet
INSTRUCTIONS FOR PRODUCT USE
Brush your teeth twice a day (morning and evening).
Each time you brush:
•
Dispense a ribbon of toothpaste covering the length of the toothbrush head (see below 
picture). Only the supplied toothbrush may be used.
•
Set your timer for 2 minutes, and then brush your teeth in your usual manner for 2 timed 
minutes.
•
Record each brushing on the diary card. Note any changes to these brushing procedures 
and reasons for changes (e.g. missed brushings, extra brushings) in the ‘Comments’ 
column.
•
Record any changes in your smoking habits, health, medications (prescription and over the 
counter medications), or treatments on the diary card.
•
Bring your diary card (completed and not completed), toothpaste, toothbrush and tooth 
bleaching treatment to all study visits.
Peroxide bleaching usage
On days where the study staff have indicated you should use your peroxide tooth bleaching kit
after either your morning or evening toothbrushing:
•
Having brushed your teeth with the supplied toothpaste, floss your teeth. Use the peroxide 
bleaching gel according to the supplied manufacturer’s instructions.  You should use the 
peroxide once-per-day for a total of 7 days.  If possible, try to perform your tooth 
bleaching at roughly the same time each day (morning or evening after your tooth 
brushing).  You should bleach your teeth for 15 minutes (please use the supplied timer).  
Should you experience any gum soreness or irritation please apply a thin smear of the 
supplied petroleum jelly to your gums prior to wearing your tray.  Try to avoid getting the 
petroleum jelly in contact with your teeth.
•
Record each use of the peroxide bleaching treatment on the diary card. Note any changes 
to these procedures and reasons for changes (e.g. missed bleaching, only bleached for 10 
minutes etc) in the ‘Comments’ column.
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15.3
Tooth Sensitivity Questionnaire (EXAMPLE)
Subject #
Date:
When completing this form please consider your experience over the last week
Have your teeth been sensitive ?   Y/N      If NO do not complete any further questions.
Please make a single vertical mark at the point on the line which represents the degree of 
overall tooth sensitivity (eg twinges, pain and other sensations in your teeth) that you have 
experienced over the last week
No
Extreme
Sensitivity
Sensitivity
For Site use only:                         mm                                                            Initials
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TOLERABILITY
Labelled Magnitude Scales
TOLERABLE
UNCOMFORTABLE
UNNERVING
UNBEARABLE
NO PAIN
INTENSITY
DURATION
DIM
DULL
SHARP
STABBING
NO PAIN
TEMPORARY
QUICK
LINGERING
CHRONIC
NO PAIN
Screening No. S ___ ___ ___ ___
Protocol:  204930 
Visit No: ____ Date: __ __/ __ __/ __ __
Score:
Scorer initials (site staff):
mm
mm
mm
Tooth No:
mm
TWINGE
ACHE
THROBBING
SHOOTING
NO PAIN
DESCRIPTION
Please rate the INTENSITY/DURATION/TOLERABILITY/DESCRIPTION of this feeling or sensation.
Mark the scales below with an “X” to indicate the best description of that feeling or sensation. 
Remember, you can mark anywhere on the line, including between the descriptive words.
Final v1.0 16 Oct 15
NOT TO SCALE
On a scale of 1 to 10 how bothered have you been by any tooth sensitivity (eg 
twinges, pain, ache or other sensations in your teeth) that you have experienced
over the last week (please circle your answer)
Not at all
   1        2        3       4       5       6       7        8        9     10
Extremely
Bothered
Bothered
Please rate the INTENSITY/DURATION/TOLLERABILITY/DESCRIPTION of your 
overall tooth sensitivity (eg twinges, pain and other sensations in your teeth) experienced over 
the past week.  Mark the scales below with an “x” to indicate the best description of your 
sensitivity.  Remember you can mark anywhere on the line, including between the descriptive 
words.
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15.4
Whitening History Questionnaire.
To be completed at Visit 2 prior to first tooth whitening application
Have you ever had 
your teeth 
professionally 
whitened?
Yes  □
No  □
If you have had tooth 
whitening treatment 
previously, how many 
times?
If you previously had 
your teeth whitened
approximately how 
long ago was your last 
whitening treatment?
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15.5
Post-Whitening Questionnaire.
To be completed at Visit 3 after the completion of the peroxide tooth bleaching.
Please tick the boxes that best answers the statements:
Strongly 
Agree
Agree
Agree 
a Little
Neither 
Agree nor 
Disagree
Disagree 
a Little
Disagree
Strongly 
Disagree
(7)
(6)
(5)
(4)
(3)
(2)
(1)
1) I am satisfied 
with the results of 
my tooth whitening.
□
□
□
□
□
□
□
2) I found it 
inconvenient to 
switch my toothpaste 
for this study.
□
□
□
□
□
□
□
3) I found my teeth 
to be painful during 
the tooth whitening
treatment.
□
□
□
□
□
□
□
4) I would 
recommend tooth 
whitening to a friend 
or relative.
□
□
□
□
□
□
□
5) I would consider 
further tooth 
whitening treatments 
in the future.
□
□
□
□
□
□
□
6) I had to change 
the way I ate or 
drank certain things 
during the tooth 
whitening treatment.
□
□
□
□
□
□
□
7) Having sensations 
in my teeth during 
tooth whitening took 
pleasure out of 
eating and 
drinking.
□
□
□
□
□
□
□
8) Having sensations 
in my teeth during 
tooth whitening was 
worrying to me.
□
□
□
□
□
□
□
9) Having sensations 
in my teeth during 
tooth whitening was 
unpleasant for me.
□
□
□
□
□
□
□
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SAP_001.pdf: 
Potassium Nitrate Dentifrice
300109
Property of Haleon
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Haleon
Statistical Analysis Plan Template v7.0
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STATISTICAL ANALYSIS PLAN 
A Randomized, Controlled, Single-Blind Clinical Study Assessing
the Effects of an Experimental Dentifrice in Maintaining Tooth Color
Following Tooth Bleaching
Protocol Number:
300109
Phase:
N/A
This document contains confidentiality statements that are not relevant for this 
publicly available version
CCI


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D o c u m e nt Hi st or y 
 
D oc u m e nt  
Versi o n D ate  
S u m m ar y of C h a n ges ( Ne w a n al ysis or 
C h a n ge i n pl a n ne d a n al ysis)  
Ori gi nal A nal ysis Pla n  
1 6 -J A N-2 0 2 4  
N ot a p plica ble ( N/ A)  
 
 
 
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T a bl e of c o nt e nt s 
D oc u me nt Hist or y ............................................................................................................... 2  
Ta ble of c o nt e nts  ................................................................................................................. 3  
List of Ta bles  ....................................................................................................................... 4  
A b bre viati o ns .............................................................................................................................. 5  
1  
S u m mar y of Ke y Pr ot oc ol I nf or mati o n  ............................................................................... 6  
1. 1  
St u d y Desi g n  ............................................................................................................ 6  
1. 2  
St u d y O bjecti ves  ...................................................................................................... 8  
1. 3  
Treat me nts  ............................................................................................................... 9  
1. 4  
Sa m ple Size Calc ulati o n  .......................................................................................... 9  
2  
Pla n ne d A nal yses  ................................................................................................................. 9  
2. 1  
I nteri m A nal ysis ....................................................................................................... 9  
2. 2  
Fi nal A nal yses  ......................................................................................................... 9  
3  
C o nsi derati o ns f or Data A nal yses a n d D ata Ha n dli n g C o n ve nti o ns ................................. 1 0  
3. 1  
Baseli ne Defi niti o n  ................................................................................................ 1 0  
3. 2  
S u b gr o u ps/ Stratificati o ns  ....................................................................................... 1 0  
3. 3  
Ce nters P o ols  ......................................................................................................... 1 0  
3. 4  
Ti me p oi nts a n d Visit Wi n d o ws  ............................................................................. 1 0  
4  
Data A nal ysis  ..................................................................................................................... 1 0  
4. 1  
P o p ulati o ns f or A nal ysis  ........................................................................................ 1 1  
4. 1. 1  
S u bject Dis p ositi o n  ............................................................................... 1 1  
4. 1. 2  
Pr ot oc ol De viati o ns ............................................................................... 1 1  
4. 1. 3  
A nal ysis P o p ulati o ns ............................................................................. 1 2  
4. 2  
S u bject De m o gra p hics a n d Ot her Baseli ne C haracteristics  ................................... 1 3  
4. 2. 1  
De m o gra p hic C haract eristics  ................................................................ 1 4  
4. 2. 2  
Ge ner al Me dical Hist or y  ....................................................................... 1 4  
4. 3  
Treat me nts ( St u d y Pr o d uct, Resc ue Me dicati o n, ot her C o nc o mita nt 
T hera pies, C o m plia nce)  ......................................................................................... 1 4  
4. 3. 1  
St u d y Pr o d uct C o m plia nce a n d E x p os ure  ............................................. 1 4  
4. 3. 2  
Bleac hi n g C o m plia nce a n d E x p os ure  ................................................... 1 5  
4. 3. 3  
Pri or a n d C o nc o mita nt Me dicati o n  ....................................................... 1 5  
4. 4  
A nal ysis of Efficac y  .............................................................................................. 1 5  
4. 4. 1  
Pri mar y Efficac y E n d p oi nt  .................................................................... 1 6  
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4. 4. 2  
Sec o n dar y Efficac y E n d p oi nts  .............................................................. 1 7  
4. 4. 3  
E x pl orat or y Effi cac y Varia bles  ............................................................. 2 0  
4. 4. 4  
Ha n dli n g of Missi n g Val ues/ Ce ns ori n g/ Disc o nti n uati o ns  .................... 2 1  
4. 5  
A nal ysis of Safet y  .................................................................................................. 2 1  
4. 5. 1  
A d verse E v e nts a n d Seri o us A d verse E v e nts  ........................................ 2 2  
4. 5. 2  
Me dical De vice I n ci de nts  ...................................................................... 2 2  
4. 5. 3  
Ot her Safet y V aria bles  .......................................................................... 2 2  
4. 6  
A nal ysis of Ot her V aria bles  ................................................................................... 2 3  
4. 6. 1  
Re peata bilit y of t he T o ot h C ol or Assess me nt ....................................... 2 3  
4. 6. 2  
Re peata bilit y of t he M L SI Assess me nt  ................................................. 2 4  
5  
C ha n ges t o t he Pr ot oc ol Defi ne d Statistical A nal ysis Pla n  ............................................... 2 4  
 
Li st of T a bl e s  
Fi g ure 1- 1  
Sc he matic of Fl o w of Ke y St u d y Assess me nts/ Pr oce d ures  .................... 7 
Ta ble 1 - 2 
St u d y O bjecti ves a n d E n d p oi nts ............................................................. 8  
A p pe n di x 1: List of Data Dis pla ys ........................................................................................... 2 5  
 
 
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A b br e vi ati o n s  
A b br e vi ati o n  
T er m  
A E  
A d v er s e E v e nt  
A N C O V A  
A n al y si s of C o v ari a n c e  
A N O V A  
A n al y si s of V ari a n c e  
A  ×  I 
Ar e a ×  I nt e n sit y 
B D R M  
Bli n d e d D at a R e vi e w M e eti n g  
CI  
C o nfi d e n c e I nt er v al  
D H  
D e nti n e H y p er s e n siti vit y  
e C R F  
El e ctr o ni c C a s e R e p ort F or m  
I C F 
I nf or m e d C o n s e nt F or m 
K N O 3  
P ot a s si u m Nitr at e  
L M S  
L a b ell e d M a g nit u d e S c al e  
M e d D R A  
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s  
mI T T  
M o difi e d I nt e n d -T o -Tr e at  
M L SI  
T ot al M o difi e d L o b e n e  St ai n I n d e x  
N/ A  
N ot A p pli c a bl e  
N A  
N ot A p pli c a bl e  
N a F  
S o di u m Fl u ori d e  
N R S  
N u m eri c al R ati n g  S c al e  
O H T  
Or al H ar d Ti s s u e  
O S T  
Or al S oft Ti s s u e  
P P  
P er -Pr ot o c ol  
P T  
Pr ef err e d T er m  
S A E  
S eri o u s A d v er s e E v e nt  
S A P  
St ati sti c al A n al y si s Pl a n  
S D  
St a n d ar d D e vi ati o n  
S E  
St a n d ar d Err or  
S O C  
S y st e m Or g a n Cl a s s  
S T P  
S o di u m Tri p ol y p h o s p h at e  
T E A E s  
Tr e at m e nt E m er g e nt A d v er s e E v e nt s  
V A S  
Vi s u al A n al o g u e S c al e  
W H O D D  
W orl d H e alt h Or g a ni z ati o n Dr u g Di cti o n ar y  
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T he p ur p ose of t his Statistical A nal ysis Pla n  is t o descri be t he pl a n ne d a n al yses a n d o ut p uts t o 
be i ncl u de d i n t he Cli nical St u d y Re p ort f or Pr ot oc ol  3 0 0 1 0 9 ( versi o n 2 . 0, d ate d 13- Oct - 2 0 2 3). 
1 
S u m m ar y of K e y Pr ot o c ol I nf or m ati o n  
T his will be a ra n d o mize d, si n gle -bli n d, si n gle -ce nter, c o ntr olle d, t w o ar m, stratifie d (cli nicall y  
dia g n ose d D H ( Y/ N)), parallel gr o u p st u d y t o e val uate t he efficac y of a n e x peri me ntal de ntifri ce  
c o ntai ni n g 5 % p otassi u m nitrate ( K N O 3), 1 % al u mi na a n d 5 % s o di u m tri p ol y p h os p hate ( S T P),  
t o mai ntai n t o ot h c ol or a n d re d uce t he acc u m ulati o n of e xtri nsic t o ot h stai n f oll o wi n g per o xi de 
t o ot h bleac hi n g c o m p are d t o a re g ular fl u ori de-c o ntai ni n g de ntifrice. T he st u d y will recr uit  
ge nerall y healt h y s u bjects w h o wis h t o u n der g o p er o xi de t o ot h bleac hi n g. 
A p pr o xi matel y 1 6 0 s u bjects ( 8 0 p er treat me nt gr o u p) will be ra n d o mize d t o st u d y treat me nt t o 
e ns ure 1 2 8 e val u a ble s u bjects c o m plete t h e st u d y b y  ass u mi n g dr o p o ut rate of 2 0 % . S u bjects 
will be stratifie d acc or di n g t o t heir cli nicall y dia g n ose d D H Stat us ( Y/ N). 
 
T he pri mar y ai m of t his st u d y is t o e val uate w het h er a n e x p eri me ntal de ntifrice c o ntai ni n g 5 % 
p otassi u m nitrate ( K N O 3), 1 % al u mi na a n d 5 % s o di u m tri p ol y p h os p hate ( S T P) mai ntai ns 
t o ot h c ol or after p er o xi de t o ot h bleac hi n g c o m pare d t o re g ular fl u ori d e de ntifrice . 
1. 1   
St u d y De si g n  
T his will be a ra n d o mize d, si n gle -bli n d, si n gle -ce nter, c o ntr olle d, t w o -ar m, stratifie d (cli nicall y  
dia g n ose d D H ( Y/ N)), parallel gr o u p st u d y t o e val uate t he efficac y of a n e x peri me ntal de ntifri ce  
c o ntai ni n g 5 % p otassi u m nitrate ( K N O 3), 1 % al u mi na a n d 5 % s o di u m tri p ol y p h os p hate ( S T P),  
t o mai ntai n t o ot h c ol or a n d re d uce t he acc u m ulati o n of e xtri nsic t o ot h stai n f oll o wi n g per o xi de 
t o ot h bleac hi n g c o m p are d t o a re g ular fl u ori de-c o ntai ni n g de ntifrice. T he st u d y will recr uit  
ge nerall y  healt h y  s u bjects  of  a ge d  1 8- 6 5  i ncl usi ve  w h o  wis h  t o  u n der g o  per o xi de  t o ot h  
bleac hi n g. 
P ote ntial s u bjects will atte n d a scree ni n g visit  ( Visit 1, Da y 1) t o deter mi ne t heir s uita bilit y t o 
partici pate.  Ha vi n g  o btai ne d  t heir  writte n  i nf or me d  c o nse nt,  rele va nt  details  of  t heir  
de m o gra p h y, m e dical hist or y a n d c urre nt me dicati o ns will be rec or de d, f oll o we d b y O S T a n d 
O H T e xa mi nati o ns.  
S u bjects meeti n g all st u d y criteria, will be c o nsi dere d as eli gi ble t o pr ocee d, stratifie d ( base d  
u p o n  t heir  cli nicall y  dia g n ose d  D H  stat us  [ Y/ N])  a n d  ra n d o mize d  t o  treat me nt  gr o u p.  
Ra n d o mize d s u bjects will t he n c o m plete t he t o ot h se nsiti vit y q uesti o n naire. S u bjects will be  
dis pe nse d t heir st u d y pr o d ucts (i ncl u di n g diar y a n d s u n dr y ite ms) a n d u n d erta ke a s u p er vise d  
br us hi n g wit h t heir all ocate d de ntifrice at t he cli nical site a n d be sc he d ule d t o atte n d Visit 2 ( 2  
wee ks ± 2 da ys after Scr ee ni n g/ Ra n d o mizati o n). S u bjects will c o nti n ue t o use t heir all ocat e d  
st u d y pr o d ucts (t wice-d ail y) t hr o u g h o ut t he st u d y a n d will rec or d t his usa ge i n t heir st u d y  diar y.  
D etaile d i nf or mati o n  is pr o vi de d i n secti o n 4. 1 of Pr ot oc ol ( v 2. 0 date d 1 3- N o v - 2 0 2 3).  
Fi g ure 1- 1  prese nt s t he k e y st u d y assess me nts. 
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1. 2   
St u d y Obj e cti v e s  
St u d y o bjecti ves a n d e n d p oi nts are defi ne d i n  T a ble 1 - 2 
T a bl e 1- 1 
St u d y O bj e cti v e s a n d E n d p oi nt s  
O bj e cti ve s  
E n d p oi nt s  
Pri m ary O bj ecti ve  
Pri m ary E n d p oi nt  
T o c o m p ar e t o ot h c ol or aft er 2 4 w e e k s t wi c e 
d ail y u s e of a ‘ 5 %  K N O 3 / 1 % al u mi n a/ 5 % S T P’ 
d e ntifri c e  c o m p ar e d  t o  a  r e g ul ar  fl u ori d e 
d e ntifri c e  f oll o wi n g  p er o xi d e  t o ot h  bl e a c hi n g  
a s  m e a s ur e d  b y  VI T A  Bl e a c h e d  g ui d e  3 D -
M a st er.  
M e a n VI T A s h a d e s c or e at 2 4  w e e k s aft er t o ot h 
bl e a c hi n g.  
S e c o n d ary O bje cti ve s  
S e c o n d ary  E n d p oi nt s 
T o c o m p ar e t o ot h c ol or aft er 1 2 w e e k s t wi c e 
d ail y u s e of a ‘ 5 %  K N O 3 / 1 % al u mi n a/ 5 % S T P’ 
d e ntifri c e  c o m p ar e d  t o  a  r e g ul ar  fl u ori d e 
d e ntifri c e  f oll o wi n g  p er o xi d e  t o ot h  bl e a c hi n g  
a s  m e a s ur e d  b y  VI T A  Bl e a c h e d  g ui d e  3 D -
M a st er.  
M e a n VI T A s h a d e s c or e at 1 2  w e e k s aft er t o ot h 
bl e a c hi n g.  
T o c o m p ar e e xtri n si c d e nt al st ai n aft er 1 2 a n d 
2 4 w e e k s, t wi c e  d ail y u s e of a ‘ 5 % K N O 3 / 1 % 
al u mi n a/ 5 %  S T P’  d e ntifri c e  c o m p ar e d  t o  a  
r e g ul ar  fl u ori d e  d e ntifri c e  f oll o wi n g  p er o xi d e  
t o ot h  bl e a c hi n g a s  m e a s ur e d  b y  M o difi e d  
L o b e n e St ai n I n d e x.  
M e a n M L SI at 1 2 a n d 2 4  w e e k s aft er t o ot h 
bl e a c hi n g i n : 
•  
T ot al M L SI ( Ar e a ( A) x  I nt e n sit y (I)) 
•  
Gi n gi v al sit e s ( A xI)  
•  
I nt er pr o xi m al sit e s ( A xI) 
•  
B o d y sit e s ( A xI)  
•  
M L SI ( A)  
•  
M L SI (I)  
E x pl or at or y O bj ecti v es  
E x pl or at or y E n d p oi nt s  
T o c o m p ar e s u bj e ct -p er c ei v e d t o ot h 
s e n siti vit y d uri n g p er o xi d e  t o ot h bl e a c hi n g 
wit h t wi c e d ail y u s e of a ‘ 5 % K N O 3 / 1 % 
al u mi n a/ 5 % S T P’ d e ntifri c e c o m p ar e d t o a 
r e g ul ar fl u ori d e d e ntifri c e, a s m e a s ur e d b y 
s u bj e ct -c o m pl et e d s e n siti vit y  q u e sti o n n air e 
o v er all a n d wit hi n str at a ( cli ni c all y -di a g n o s e d 
D H  [Y/ N ]) 
M e a n s e n siti vit y q u e sti o n n air e  s c or e s pr e a n d 
p o st p er o xi d e  t o ot h bl e a c hi n g i n: 
•  
Vi s u al a n al o g u e s c al e  ( V A S) 
•  
L a b ell e d M a g nit u d e s c al e s  (I nt e n sit y, 
D ur ati o n , T ol er a bilit y, D e s cri pti o n) –   
•  
B ot h er s o m e n e s s s c or e -N R S  
T o  e x pl or e  s u bj e ct’ s  e x p eri e n c e  of  p er o xi d e  
t o ot h  bl e a c hi n g  w h e n si m ult a n e o u sl y  u si n g  
eit h er a ‘ 5 % K N O 3 / 1 % al u mi n a/ 5 % S T P’ 
d e ntifri c e or a r e g ul ar fl u ori d e d e ntifri c e.  
P o st -w hit e ni n g q u e sti o n n air e  
T o  c o nfir m  t h e  t o ot h  w hit e ni n g  effi c a c y  of  
p er o xi d e  t o ot h  bl e a c hi n g  wit h  c o n c urr e nt,  
t wi c e d ail y u s e of ‘ 5 % K N O 3/ 1 % al u mi n a/ 5 % 
S T P’ d e ntifri c e a n d a r e g ul ar fl u ori d e  d e ntifri c e 
a s  m e a s ur e d  b y  VI T A  Bl e a c h e d  g ui d e  3 D  
M a st er.  
C h a n g e i n m e a n VI T A s h a d e  s c or e fr o m pr e t o 
p o st t o ot h  bl e a c hi n g  
S af et y  
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O bj e cti ve s  
E n d p oi nt s  
S af et y  
T o a s s e s s t h e s af et y a n d t ol er a bilit y of a ‘ 5 % 
K N O 3 / 1 % al u mi n a/ 5 % S T P’ d e ntifri c e . 
Tr e at m e nt e m er g e nt a d v er s e  e v e nt s  
 
T his st u d y will be c o nsi dere d s uccessf ul if t he T est de ntifrice c o ntai ni n g 5 % K N O 3, 1 % 
al u mi na a n d 5 % S T P de m o nstrates statisticall y si g nifica nt w hit her teet h as meas ure d b y VI T A  
Bleac he d  g ui de S ha d e i n c o m paris o n wit h t he refere nce d e ntifrice 2 4 wee ks after per o xi de 
t o ot h bleac hi n g. 
1. 3   
Tr e at m e nt s 
T he st u d y pr o d uct will be Test De ntifri ce w hic h is De ntifrice c o ntai ni n g 5 % w/ w K N O 3, 1 % 
al u mi na, 5 % S T P a n d 1 1 5 0 p p m fl u ori de as s o di u m fl u ori de a n d Refere n ce pr o d uct will be 
De ntifrice c o ntai ni n g 1 1 5 0 p p m fl u ori de as s o di u m fl u ori de. S u bjects will br us h f or t w o ti me d 
mi n utes t wice dail y ( m or ni n g a n d e ve ni n g).  
1. 4   
S a m pl e Si z e C al c ul ati o n 
T here w ere n o pre vi o us directl y c o m para ble st u dies t hat ha ve e val u ate d t he effect of de ntifri ce 
o n mai ntai ni n g t o ot h w hite ness aft er p er o xi de bl eac hi n g u p o n w hic h t o base a n esti mate of 
sa m ple size. H o we ver, base d o n a pre vi o us st u d y e val uati n g t he t o ot h w hite ni n g a bilities of t he 
test de ntifrice (Hal e o n Cli nical St u d y 3 0 0 0 2 4, 2 0 2 3 ), a mea n c h a n ge ( S D) of VI T A sc ores of 1 
( ± 2) was ass u me d. S ufficie nt i n di vi d uals will be scree n e d t o e nr oll a p pr o xi matel y 1 6 0 s u bjects 
(a p pr o xi matel y 8 0 per gr o u p) ass u mi n g a n esti mate d 2 0 % dr o p o ut rate; a p pr o xi matel y 1 2 8 
c o m plete d s u bjects (a p pr o xi matel y 6 4 per gr o u p) are d ee me d s uffici e nt t o detect a differe n ce  
bet wee n t he T est a n d Ref ere nce De ntifrices at 2 4 wee ks wit h 8 0 % p o w er . 
2 
Pl a n n e d A n al y s e s  
2. 1   
I nt eri m A n al y si s 
N o i nteri m a nal ysis is pla n ne d  f or t his st u d y. 
2. 2   
Fi n al A n al y s e s 
T he fi nal pla n n e d pri mar y a nal yses will be perf or me d aft er t he c o m pleti o n of t he f oll o wi n g 
se q ue ntial ste ps: 
1.  All s u bjects ha ve c o m plete d t he st u d y as defi ne d i n t he pr ot oc ol . 
2.  All re q uire d dat a base clea ni n g acti vities i ncl u di n g a n y e xter n al data rec o nciliati o n ha ve 
bee n c o m plete d a n d data base has bee n l oc ke d. 
3.  All criteria f or u n bli n di n g t he ra n d o mizati o n c o d es ha ve bee n m et a n d t he ra n d o mizati o n 
c o des ha ve b ee n distri b ut e d. 
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3  
C o n si d er ati o n s f or D at a A n al y s e s  a n d D at a  H a n dli n g 
C o n v e nti o n s  
3. 1   
B a s eli n e D efi niti o n 
T here will be n o c ha n ge- fr o m-baseli ne assess me nts d o ne f or t his st u d y. 
3. 2   
S u b gr o u p s/ Str atifi c ati o n s 
S u bjects w h o satisf y all selecti o n criteria will be ra n d o mize d i nt o t he st u d y. Ra n d o mi zati o n 
n u m bers will be assi g ne d i n asce n di n g n u merical or der as eac h s u bject is det er mi ne d t o be f ull y  
eli gi ble. 
S u bjects will be  str atifie d base d o n cli nicall y di a g n ose d D H  stat us ( Y es/ N o). T he stratificati o n 
fact or will gi ve rise t o t w o strata. 
•  Str at u m 1 : D e nti ne H y perse nsiti vit y Prese nt  
•  Str at u m 2 : De nti ne H y perse nsiti vit y  N ot Prese nt  
Wit h eac h strat u m , s u bject will be ra n d o mize d t o Test De ntifrice a n d Refere nce D e ntifrice  wit h 
1: 1 all ocati o n rati o.  
I n t he e v e nt of mis-stratificati o n, t he c orrect strat a acc or di n g t o C R F i nf or mati o n will be use d 
i n t he a nal ysis (i.e., deri v e d stratificati o n varia ble fr o m A D S L will be use d f or a nal ysis ). 
3. 3   
C e nt er s P o ol s 
Si nce t his is si n gle ce nter  st u d y, p o oli n g of ce nters is n ot a p plica ble. 
3. 4   
Ti m e p oi nt s a n d Vi sit Wi n d o w s 
T he ti me p oi nts a n d visits f or t his st u d y are defi ne d i n  “ Sc he d ule of Acti vities”  defi ne d i n secti o n 
1. 2 of st u d y Pr ot oc ol  ( v 2. 0 date d 1 3-N o v - 2 0 2 3). A n y de viati o n fr o m t he st u d y sc he d ule ma y 
be re vie w e d o n case - b y-case basis at t he Bli n de d Data Re vie w Meeti n g ( B D R M) t o deter mi ne 
w het her t he d ata s h o ul d be e xcl u de d fr o m t he Per- Pr ot oc ol ( P P) a nal yses . 
4 
D at a A n al y si s  
Data a nal ysis will be perf or me d b y 
 wit h o versi g ht fr o m Hale o n . T he statistical 
a nal ysis s oft war e use d will be S A S versi o n 9. 4  or hi g her. 
Pri or t o data base cl os ur e a B D R M will be c o n d ucte d i n w hic h vari o us as pects of t he trial will 
be disc usse d a n d a gree d. 
O ne as pect t hat will be c o nsi dere d pri or t o or d uri n g t he B D R M is t he assess me nt of t he n u m ber 
of s u bjects w h o ha ve dr o p pe d or disc o nti n ue d fr o m t he st u d y d ue t o p a n d e mic rel ate d e v e nts 
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a n d t he p ote ntial nee d of a se nsiti vit y a nal ysis. A n y  maj or c ha n ges  t o pla n n e d  a nal yses will  
ne e d  a n  a me n d me nt  t o S A P.  
E xce pt as des cri be d b el o w, all listi n gs will be pr o d uce d f or all ra n d o mize d s u bjects.  
4. 1   
P o p ul ati o n s f or An al y si s  
Ta bles descri be d i n t his secti o n will be pr o d uce d f or all ra n d o mize d s u bjects. 
4. 1. 1  S u bj e ct D i s p o siti o n 
Scree n f ail ures ar e defi n e d as s u bjects w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y ra n d o mize d. A n e nr olle d s u bject is a s u bject w h o has si g ne d i nf or me d c o nse nt 
a n d is eli gi ble t o pr ocee d be y o n d t he scree ni n g visit. 
T he n u m ber of s u bjects scree n e d, e nr olle d, a n d ra n d o mize d will be prese nt e d i n Ta ble 1 4. 1. 1. 
T he n u m ber a n d perce nt a ge of scr ee n fail ure s u bjects (s u bjects n ot ra n d o mize d) wit h reas o ns 
w h y s u bjects are n ot will be dis pla ye d. Perce nta g es f or scree n fail ure s u bjects will be base d o n 
t he t otal n u m ber of s u bjects scree n e d. 
T he n u m ber a n d per ce nt a ge of ra n d o mize d s u bjects w h o c o m plete a n d disc o nti n ue t he st u d y, 
br o ke n d o w n b y r eas o n f or disc o nti n uati o n b y st u d y pr o d uct a n d o verall will als o be dis pla ye d. 
T he per ce nta g es will be base d o n t he n u m ber of s u bjects ra n d o mize d. 
Ta ble 1 4. 1. 1 will als o pr ese nt t he n u m ber a n d perce nta g e of s u bjects i n eac h of t he d efi ne d 
a nal ysis p o p ulati o ns (as d efi ne d i n Secti o n 4. 1. 3 ) b y st u d y pr o d uct a n d o v erall. Perce nta g es will 
be base d o n t he n u m ber of s u bjects ra n d o mize d. 
S u bject dis p ositi o n i ncl u di n g de m o gra p hic data (a ge, se x, race a n d et h nicit y), scree ni n g d ate, 
st u d y  pr o d uct  start  date  a n d  ti me,  s u bject  stat us  (c o m pleter,  Y es/ N o),  st u d y  c o m pleti o n  
/ wit h dra wal date, d urati o n (i n da ys) i n t he st u d y ( d efi ne d as [( date of c o m pl eti o n or wit h dra wal 
– start dat e of st u d y pr o d uct) + 1], a n d t h e pri mar y reas o n f or wit h dra wal will be liste d ( Listi n g 
1 6. 2. 1. 1) b y st u d y pr o d uct f or all ra n d o mize d s u bjects. 
S u bject dis p ositi o n i nf or mati o n will be liste d f or n o n -ra n d o mize d s u bjects ( Listi n g 1 6. 2. 1. 2), 
dis pla yi n g s u bject n u m ber, de m o gr a p hic i nf or mati o n (a ge, se x, race a n d et h nicit y), scree ni n g 
date,  reas o n  f or  scree n  fail ure  a n d  a n y  f urt her  details  of  reas o n  f o r  scree n  fail ure  a n d  
disc o nti n uati o n stat us. 
4. 1. 2  Pr ot o c ol D e vi ati o n s  
Pr ot oc ol de viati o ns will be trac k e d b y t he st u d y tea m t hr o u g h o ut t he c o n d uct of t he st u d y. Dat a 
will  be  re vie we d  pri or  t o  u n bli n di n g  a n d  cl os ure  of  t he  data base  t o  e ns ure  all  i m p orta nt  
de viati o ns are ca pt ure d a n d cate g orise d. S u bjects wit h i m p orta nt pr ot oc ol de viati o ns lia ble t o 
i nfl ue nce t he effi cac y o ut c o mes will ha ve affecte d data e xcl u d e d fr o m t he P P a nal yses . S u bjects 
ma y als o be i de ntifie d as ha vi n g i m p orta nt pr ot oc ol de viati o ns n ot lea di n g t o e xcl usi o n of dat a 
fr o m t he P P a nal yses . 
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I m p ort a nt de viati o ns of t he pr ot oc ol pr oce d ures m a y i ncl u de, b ut will n ot n ecessaril y be li mite d 
t o t he f oll o wi n g: 
•  C o nse nt pr oce d ur es 
•  I n cl usi o n/ E xcl usi o n criteria 
•  St u d y pr oce d ures 
•  Ra n d o mizati o n pr oce d ur es 
•  N o n -c o m plia nce wit h pr o d uct a d mi nistrati o n  
•  I n a d missi ble c o nc o mita nt me dicati o n 
•  Visit sc he d ule/i nter val  
•  Ot her  
T he s pecific d etails of t he i m p orta nt pr ot oc ol de viati o ns will be liste d i n Pr ot oc ol De viati o n 
Ma na ge me nt Pla n a n d assess me nt pr ocess will be s pecifie d i n t he Bli n d Data Re vie w Pla n a n d 
s u bjects wit h i m p orta nt pr ot oc ol de viati o ns will be i de ntifie d at t he B D R M. 
T he n u m ber a n d per ce nt a ge of s u bjects wit h at least o ne i m p orta nt pr ot oc ol de viati o n, at least 
o ne i m p orta nt pr ot oc ol d e viati o n n ot lea di n g t o e x cl usi o n  of dat a  fr o m P P a nal yses  ( o verall a n d 
b y eac h de viati o n reas o n) a n d at least o ne i m p orta nt pr ot oc ol de viati o n lea di n g t o e xcl usi o n of 
data  fr o m t he P P a nal yses  ( o ver all a n d b y eac h de viati o n reas o n) will be prese nte d b y st u d y 
pr o d uct  ( Ta ble 1 4. 1. 2) a n d liste d i n Listi n g 1 6. 2. 2. 1. 
All pr ot oc ol de viati o ns c ollecte d o n t he pr ot oc ol de viati o n case re p ort f or m pa ge will be liste d 
i n Listi n g 1 6. 2. 2. 2. T he listi n g will prese nt date of de viati o n, t y pe of d e viati o n, a n d de viati o n 
descri pti o n. 
4. 1. 3  A n al y si s P o p ul ati o n s  
 A nal ysis p o p ulati o ns are defi ne d as   
 
P o p ul ati o n  
D efi niti o n / Crit eri a  
A n al y s e s E v al u at e d  
Safet y  
C o m prise of all ra n d o mize d s u bjects w h o 
c o m plete at least o ne us e of st u d y pr o d uct. 
T his p o p ulati o n will be base d o n t he pr o d u ct 
t he s u bject act uall y recei ve d *. 
A n y s u bject w h o recei ves a ra n d o mizati o n 
n u m ber will be c o nsi dere d t o ha ve bee n 
ra n d o mize d. 
De m o gra p hics 
Safet y   
M o difie d I nte nt -
T o -Treat 
( mI T T) 
C o m prise all ra n d o mize d s u bjects w h o 
c o m plete at least o ne us e of st u d y pr o d uct a n d 
ha ve at least o ne assess m e nt of t o ot h c ol or 
after t he bl eac hi n g peri o d . 
De m o gra p hics 
C o m plia nce 
Efficac y A nal ysis  
E x pl orat or y A nal ysis  
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P o p ul ati o n  
D efi niti o n / Crit eri a  
A n al y s e s E v al u at e d  
T his p o p ulati o n will be base d o n t he st u d y 
pr o d uct t o w hic h t he s u bj ect was ra n d o mize d. 
A n y s u bject w h o recei ves a ra n d o mizati o n 
n u m ber will be c o nsi dere d t o ha ve bee n 
ra n d o mize d. 
 
Per - Pr ot oc ol 
C o m prise all s u bjects i n t he mI T T  p o p ulati o n 
w h o ha ve at least o ne ass ess me nt of effi cac y 
c o nsi dere d u n affecte d b y pr ot oc ol vi olati o ns. 
Pr ot oc ol de viati o ns t hat ma y e xcl u de s u bjects 
fr o m t he P P p o p ulati o n are defi n e d i n Secti o n 
4. 1. 2  ( Pr ot oc ol De viati o ns). 
T his p o p ulati o n will be base d o n t he st u d y 
pr o d uct t o w hic h t he s u bj ect was ra n d o mize d.  
Efficac y A nal ysis   
Re peata bilit y 
P o p ulati o n 
T o ot h C ol or Re peata bilit y P o p ulati o n: 
s u bjects w h o ha ve at least o ne re peat t o ot h 
c ol or cli nical assess me nt at a n y visit.  
M L SI Re peata bilit y P o p ulati o n: S u bjects w h o 
ha ve at least o ne  re p eat M L SI cli nical 
assess me nt at a n y visit.  
Re peata bilit y 
Assess me nt A nal ysis  
N O T E S:  
* T h e tr e at m e nt a ct u all y r e c ei v e d will b e a s s u m e d t o b e t h e s a m e a s t h e r a n d o mi z e d tr e at m e nt 
u nl e s s a pr ot o c ol d e vi ati o n i s r e c or d e d t o i n di c at e t h at i n c orr e ct tr e at m e nt w a s di s p e n s e d t o t h e 
s u bj e ct.  
Pl e a s e r ef er t o  A p p e n di x 1 : Li st of D at a Di s pl a y s w hi c h d et ail s t h e p o p ul ati o n t o b e u s e d f or e a c h 
di s pl a y b ei n g g e n er at e d.  
T he n u m bers of s u bjects i ncl u de d i n eac h of t he a nal ysis p o p ulati o ns, will be s u m marize d 
(Ta ble 1 4. 1. 1). S u bjects e xcl u de d fr o m a n y of t h e a nal ysis p o p ulati o ns will be liste d i n Listi n g 
1 6. 2. 3. 1. 
T he pri mar y p o p ulati o n f or assess me nt of efficac y will be t he mI T T P o p ulati o n. A P P a nal ysis 
will be perf or me d o n t h e pri mar y e n d p oi nt o nl y if m ore t ha n 1 0 % of mI T T s u bjects are e x cl u de d  
fr o m t he P P P o p ulati o n. A decisi o n o n w het her a P P a nal ysis will be perf or me d will be ma de 
pri or t o st u d y u n bli n di n g (release of t he ra n d o mizati o n c o des).  
4. 2   
S u bj e ct D e m o gr a p hi c s a n d O t h er Ba s eli n e C h ar a ct eri sti c s  
De m o gra p hic a n d bas eli ne c haracteristics s u m maries will be pr o d uce d f or Safet y a n d  mI T T 
P o p ulati o n. 
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4. 2. 1  D e m o gr a p hi c C h ar a ct eri sti c s  
Descri pti ve statistics ( n u m ber of s u bjects [ n], mea n, sta n dar d de viati o n [ S D], me dia n, mi ni m u m 
a n d ma xi m u m f or c o nti n u o us varia bles a n d fre q u e nc y c o u nt [ n] a n d perce nt a ge [ %] of s u bjects 
f or cate g orical varia bles) will be pr ese nte d f or de m o gra p hic varia bles b y st u d y pr o d uct. T h ese 
varia bles i n cl u de a ge, s e x, race, et h nicit y, a n d stratificati o n gr o u p a n d will be prese nte d f or t he 
Safet y p o p ulati o n ( Ta ble 1 4. 1. 3. 1 ), a n d t he mI T T p o p ulati o n ( Ta ble 1 4. 1. 3. 2 ). 
De m o gra p hic i nf or mati o n will be liste d ( Listi n g 1 6. 2. 4. 1 ) f or all ra n d o mize d s u bjects. 
 
4. 2. 2  G e n er al M e di c al H i st or y 
Me dical a n d s ur gical hist or y (i n t he last y ear) i n cl u di n g aller gies or dr u g  se nsiti vit y will be 
liste d i n Listi n g 1 6. 2. 4. 2, wit h start date a n d e n d d ate or o n g oi n g at t he start of st u d y pr o d uct 
4. 3   
Tr e at m e nt s ( St u d y Pr o d u ct, Re s c u e M e di c ati o n, ot h er C o n c o mit a nt 
T h er a pi e s, C o m pli a n c e) 
Ra n d o mizati o n details will be liste d, i ncl u di n g t he ra n d o mizati o n n u m ber, stratificati o n gr o u p, 
t he pla n ne d st u d y pr o d u ct, t he act ual st u d y pr o d uct t he s u bject w as ra n d o mize d t o a n d t he 
ra n d o mizati o n date (Listi n g 1 6. 1. 7. 1 ) f or all ra n d o mize d s u bjects. 
T he st u d y pr o d uct kit all ocati o ns will be liste d ( Listi n g 1 6. 1. 7. 2), i ncl u di n g kit n u m ber a n d 
st u d y pr o d uct i nf or mati o n. 
4. 3. 1  St u d y Pr o d u ct  C o m pli a n c e  a n d E x p o s ur e  
C o m plia nce data will als o be s u m marize d f or t h e mI T T p o p ulati o n a n d will be assesse d b y 
n u m ber of br us hi n gs. 
N u m ber  of  br us hi n gs,  br us hi n g  c o m plia nce  ( %),  n u m ber  of  misse d  br us hi n gs,  n u m ber  of  
a d diti o nal br us hi n gs will be s u m marize d usi n g descri pti ve statistics as se parate cate g ories b y 
st u d y pr o d uct i n Ta ble 1 4. 2. 1. 1 b y c u m ulati ve visit.  
N u m ber of br us hi n gs is d efi ne d as: [( date of Visit  N – date of Visit 1 ) m ulti plie d b y 2 – n u m ber 
of missi n g br us hi n gs + n u m ber of a d diti o nal br us hi n gs]. 
Br us hi n g c o m plia nce ( %) is defi ne d as: [ 1 0 0 x ( N u m ber of br us hi n gs / E x pecte d n u m ber of 
br us hi n gs)], w here e x pecte d n u m ber of br us hi n gs is defi ne d as: [( d ate of Visit N – date of Visit 
1) m ulti plie d b y 2]. 
St u d y pr o d uct c o m plia nce ( n u m ber of br us hi n gs / br us hi n g c o m plia nce [ %] / n u m ber of misse d 
br us hi n gs / n u m bers of a d diti o nal br us hi n gs) will be liste d i n Listi n g  1 6. 2. 5. 1 f or all ra n d o mize d 
s u bjects b y st u d y pr o d uct. 
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4. 3. 2  Bl e a c hi n g  C o m pli a n c e a n d E x p o s ur e  
Bleac h i n g C o m plia nce will be s u m marize d f or mI T T P o p ulati o n w here n u m ber of bleac hi n g, 
bleac hi n g  c o m plia nce ( %) a n d misse d/a d diti o nal bleac hi n g occ urre n ce will be  s u m marize d 
usi n g  descri pti ve  statistics  as  se parate  cate g ori es  b y  st u d y  pr o d uct  i n  Ta ble  1 4. 2. 1. 2  b y 
c u m ulati ve visit.   
N u m ber of bleac hi n g is defi ne d as: [( date of Visit 3 – date of Visit 2) – n u m ber of missi n g 
bleac hi n g + n u m ber of a d diti o nal bleac hi n g ]. 
Bleac hi n g c o m plia nce ( %) is defi ne d as: [ 1 0 0 x ( N u m ber of bleac hi n g / E x pecte d n u m ber of 
bleac hi n g )], w h ere e x pecte d n u m ber of bleac hi n g is defi ne d as: ( date of Visit 3 – date of Visit 
2).  
Bleac hi n g  c o m plia nce ( n u m ber of b leac hi n g / b leac hi n g c o m plia nce [ %] / n u m ber of misse d 
b leac hi n g / n u m b ers of a d diti o nal b leac hi n g) will be liste d i n Listi n g 1 6. 2. 5. 2 f or all ra n d o mize d 
s u bjects b y st u d y pr o d uct. 
4. 3. 3  Pri or a n d C o n c o mit a nt M e di c ati o n  
Pri or  me dicati o ns/treat me nts,  i ncl u di n g  prescri pti o n  a n d  n o n -prescri pti o n  dr u gs,  dietar y  
s u p ple me nts a n d her b al r e me dies, ta ke n i n t he l ast 2 8 da ys a n d pri or t o si g ni n g t he i nf or me d 
c o nse nt f or m, will be d oc u me nte d i n t he C R F. T he pri or a n d c o nc o mita nt me d icati o ns will be 
c o de d usi n g a vali date d me dicati o n dicti o nar y, W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y 
( W H O D D). 
Pri or me dicati o ns a n d pri or n o n -dr u g treat me nts will be liste d b y s u bject, wit h dr u g na me, 
W H O D D Dr u g S y n o n y m, reas o n, r o ute, d os e,   u nit, fre q ue n c y, start dat e a n d e n d d ate b ot h 
relati ve  t o  st u d y  pr o d u ct  start  date  ( Listi n g  1 6. 2. 4. 3)  f or  all  ra n d o mi ze d s u bjects.  Pri or  
me dicati o ns are d efi ne d as t h ose w hic h st o p pe d b ef ore t h e first use of t he st u d y pr o d uct. 
C o nc o mita nt me dicati o ns a n d c o nc o mita nt n o n- dr u g treat me nts/si g nifica nt n o n- dr u g t hera pies 
ta ke n d uri n g treat me nt will be liste d si milarl y ( Listi n g 1 6. 2. 4. 4) f or all ra n d o mize d s u bjects 
wit h eit her o n g oi n g or e n d date dis pla ye d.  
C o nc o mita nt  me dicati o ns  t hat  ha ve  bee n  ta ke n  t o  alle viate  t o ot h  se nsiti vit y/ pai n  will  be  
s u m marize d i n T a ble 1 4 . 3. 4. 2 f or all ra n d o mize d p o p ulati o n a n d will be liste d i n Listi n g 
1 6. 2. 4. 5. 
C o nc o mita nt me dicati o ns are defi ne d as me di cati o ns t hat starte d or st o p pe d o n or after t h e 
first use of t he st u d y pr o d uct or ar e o n g oi n g. 
U n k n o w n dates will n ot be i m p ute d, h o we ver if t he start or st o p date is u n k n o w n, t he n it will 
be ass u me d t o be c o n c o mita nt me dicati o n u nless t he p artial start date or st o p date i n dicates 
differe ntl y.  
4. 4   
A n al y si s of Effi c a c y  
T he pri mar y p o p ulati o n f or assess me nt of efficac y will be t he mI T T P o p ulati o n.  
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4. 4. 1  Pri m ar y E ffi c a c y E n d p oi nt  
4. 4. 1. 1  
Pri m ar y E ffi c a c y E n d p oi nt D efi niti o n  
T he pri mar y efficac y v aria ble is mea n Vita Bleac he d g ui de s h a de at 2 4 wee ks after t o ot h 
bleac hi n g h as  c o m plet e d , calc ul ate d at t he s u bject le vel as t he a vera ge Vita Bleac h e d  g ui de 
s ha de o ver all sites assesse d. 
 
T o ot h c ol or of t he f acial s urfaces of t he si x a nteri or ma xillar y teet h (t o ot h n u m bers 6- 1 1) 
[ U ni versal t o ot h n u m beri n g s yste m] will be assesse d b y a si n gle, trai ne d cli nical e xa mi ner usi n g 
t he VI T A Bleac he d g ui de 3 D -M A S T E R.  T he VI T A Bleac he d  g ui de 3 D -M A S T E R uses a val ue -
ra n ke d or der e d s cale fr o m 1 (t he li g htest) t o 2 9 (t he dar kest). T h e s ha d e le vel of eac h t o ot h 
s urface is sc ore d vis u all y b y t he cli nical e xa mi ner wit h refere nce t o t he Bleac he d g ui de. 
T he mea n  VI T A s ha d e s c ore f or eac h s u bject at eac h visit is calc ulat e d as t he mea n VI T A s ha de 
sc ore o ver all n o n-missi n g facial s urfaces of si x a nteri or ma xillar y teet h (t o ot h n u m bers 6- 1 1). 
Descri pti ve  statistics  ( n,  missi n g,  mea n,  S D,  st a n dar d  err or  [ S E],  me di a n,  mi ni m u m,  a n d  
ma xi m u m) will be prese nte d f or mea n VI T A s h a de  sc ore at eac h assess me nt ti me p oi nt i n 
Ta ble  1 4. 2. 2. 1. 1 f or all s u bjects i n t he mI T T p o p ulati o n b y st u d y pr o d uct.  
Ra w mea ns ( ± S E) of t h e mea n VI T A s h a de  s c ore at eac h ti me p oi nt will be pl otte d b y st u d y 
pr o d uct i n Fi g ure 1 4. 2. 1. 1 f or all s u bjects i n t he mI T T p o p ul ati o n. 
 
I n di vi d ual dat a f or mea n VI T A s ha d e  sc ore will be liste d f or eac h s u bject b y st u d y pr o d uct 
gr o u p a n d visit i n Listi n g 1 6. 2. 6. 1 f or all ra n d o mize d s u bjects. 
4. 4. 1. 2  
St ati sti c al H y p ot h e si s, M o d el, a n d M et h o d of A n al y si s  
T he pri mar y c o m paris o n is bet wee n t he T est De ntifrice  a n d t h e Refere n ce D e ntifrice  i n t h e 
mI T T p o p ulati o n. As t h ere is o nl y a si n gle pri mar y o bjecti ve , n o a dj ust me nt f or m ulti ple 
c o m paris o ns is re q uire d. 
St u d y pr o d uct differe n ces will be teste d u n der t he n ull h y p ot hesis  at 2 4 wee ks after t o ot h 
bleac hi n g  has c o m plet e d : 
•  H 0: t here is n o differe n ce i n mea n VI T A sh a de sc ore bet wee n T est D e ntifrice  a n d 
Refere n ce D e ntifrice  
•  H 1: t here is a differ e nce i n mea n VI T A sh a de sc ore bet wee n T est De ntifrice  a n d Refere n ce 
De ntifrice  
 
Mea n V I T A Bleac he d g ui de s ha de will be a nal yze d usi n g a re peate d meas ures A N O V A m o del  
wit h treat me nt gr o u p a n d st u d y ti me p oi nts ( Visit 2 t o 5) as fact or a n d treat me nt gr o u p b y ti me 
p oi nt ( Visit  2  t o 5) as i nteracti o n. S u bject  will  be  i ncl u de d  as  a  re p eate d  meas ure  wit h  
u nstr uct ure d c o v aria n ce matri x ; t he Ke n w ar d R o gers de grees of free d o m a p pr oac h will be 
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a p plie d ( Ke n w ar d a n d R o ger, 1 9 9 7). If t he m o del wit h u nstr uct ure d c o vari a nce matri x d oes n ot 
c o n ver ge t h e n c o m p o u n d s y m metr y c o varia n ce m atri x will be use d.  
 
Usi n g t he a b o ve m o del, m ea n differe nce s bet w ee n  Test De ntifrice c o m pare d t o Refere n ce 
De ntifrice i n Mea n VI T A s ha de sc or e will be re p orte d b y st u d y pr o d uct gr o u p al o n g wit h 9 5 % 
CIs  a n d p-v al ues  will be pr o vi de d i n Ta ble 1 4. 2. 2. 2. 1 . All p -val ues prese nte d will be t w o -si de d 
a n d assesse d at t he 5 % si g nifica nce l e vel.  
T he ass u m pti o n of n or malit y a n d h o m o ge neit y of varia nce i n re peate d meas ures A N O V A will 
be   i n vesti gate d. I n case of vi olati o n of t hese ass u m pti o ns, a s uita ble n o n para metri c test ( V a n 
Elter e n Test  a dj uste d f or ra n d o mizati o n stratificati o n) will be perf or me d,  a n d t he res ults will be 
pr o vi de d t o s u p p ort t he r e peate d meas ures A N O V A res ults. T he n o n-para m etric res ults will be 
c o nsi dere d c o nfir mat or y u n der t he o bser vati o n of str o n g vi olati o ns of t he ass u m pti o ns. 
If t here is m ore t ha n 1 0 % differe n ce i n t he o verall n u m ber of s u bjects bet wee n P P a n d mI T T 
p o p ulati o ns, a s u m mar y a n d a nal ysis of t he pri mar y efficac y varia ble  will be prese nte d f or t he 
P P p o p ulati o n i n Ta ble 1 4. 2. 2. 1. 2 a n d Ta ble 1 4. 2. 2. 2. 2 res pecti vel y. 
4. 4. 2  S e c o n d ar y Effi c a c y E n d p oi nt s  
4. 4. 2. 1  
S e c o n d ar y E ffi c a c y V ari a bl e 1  
T he Sec o n dar y Efficac y E n d p oi nt 1 will be m ea n VI T A s ha d e sc ore at 1 2 wee ks after t o ot h 
bleac hi n g  a n d t he c o m paris o n of Test De ntifrice t o t he Refere nce De ntifrice.  
4. 4. 2. 1. 1  St ati sti c al H y p ot h e si s, M o d el a n d M et h o d of A n al y si s  
St u d y pr o d uct differe nces will be teste d u n der sa me h y p ot hesis state d i n Secti o n 4. 4. 1. 2 . Mea n 
VI T A Bleac he d g ui de s h a de will be a nal yze d usi n g a re peate d meas ures A N O V A m o del wit h 
treat me nt gr o u p a n d st u d y ti me p oi nts ( Visit 2 t o 5) as fact or a n d treat me nt gr o u p b y ti me p oi nt 
( Visit 2 t o 5) as i nteracti o n. S u bject will be i ncl u de d as a re p eate d meas ure wit h u nstr uct ure d 
c o varia n ce matri x; t he Ke n war d R o gers de grees of free d o m a p pr o ac h will be a p plie d ( Ke n war d 
a n d R o ger, 1 9 9 7). If t he m o del wit h u nstr uct ure d c o varia nce matri x d oes n ot c o n ver ge t he n 
c o m p o u n d s y m metr y c o v aria nce matri x will be us e d.  
Refer t o Secti o n 4. 4. 1. 2 . Mea n differe n ces bet w ee n Test De ntifrice c o m pare d t o Refer e nce 
De ntifrice i n Mea n VI T A s ha de sc ore at 1 2 wee ks after t o ot h bleac hi n g will be prese nte d al o n g 
wit h 9 5 % CIs a n d p -v al ues i n Ta ble 1 4. 2. 2. 2. 1 . All p -val ues prese nt e d will be t w o -si de d a n d 
assesse d at t he 5 % si g nifica nce le vel.  
T he ass u m pti o n of n or malit y a n d h o m o ge neit y of varia nce i n re peate d meas ures A N O V A will 
be   i n vesti gate d. I n case of vi olati o n of t hese ass u m pti o ns, a s uita ble n o n para metri c test ( V a n 
Elter en Test a dj uste d f or ra n d o mizati o n stratificati o n) will be perf or m e d t o assess c o m paris o ns 
( Test De ntifrice vs. Ref er e nce D e ntifrice at Wee k 1 2) a n d t he res ults will be pr o vi de d t o s u p p ort 
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t he re p eate d  meas ur es  A N O V A  res ults.  T h e  n o n-para m etric  res ults  will  be  c o nsi dere d  
c o nfir mat or y u n der t he o bser vati o n of str o n g vi olati o ns of t he ass u m pti o ns. 
4. 4. 2. 2  
S e c o n d ar y E ffi c a c y V ari a bl e 2 
F or c o m paris o n of e xtri nsic de ntal after stai n t he Sec o n dar y Efficac y E n d p oi nt 2 will be mea n 
sc ores at 1 2 a n d 2 4 wee k s after t o ot h bleac hi n g i n: 
o  T otal M L SI ( Area ( A) x I nte nsit y (I))  
o  M L SI ( A xI) f or g i n gi val sites ( A xI) 
o  M L SI ( A xI) f or inter pr o xi mal sites ( A xI)  
o  M L SI ( A xI) f or b o d y sites ( A xI) 
o  T otal M L SI Area ( A) 
o  T otal M L SI I nte nsit y (I) 
E xtri nsic de ntal stai n will be assesse d o n t he facial s urfaces of t he 6 m a xillar y a nteri or teet h ( 6 -
1 1) [ U ni versal t o ot h n u m beri n g s yste m] at Visits 1 -5), usi n g ( M L SI)  descri be d i n secti o n 9. 2. 2  
of t he st u d y Pr ot oc ol ( v 2. 0, date d 1 3- N o v - 2 0 2 3). 
 
4. 4. 2. 2. 1  St ati sti c al H y p ot h e si s, M o d el a n d M et h o d of A n al y si s  
T he res ults f or mea n tot al M L SI Area x I nte nsit y  ( A xI), mea n t otal M L SI ( A xI) f or gi n gi val 
sites ( A xI), mea n t otal M L SI ( A xI) f or i nter pr o xi mal sites ( A xI) , m ea n t otal M L SI ( A xI) f or 
b o d y sites ( A xI) , mea n total M L SI Area ( A) , a n d mea n t otal M L SI I nte nsit y (I)  will be o btai ne d 
fr o m t he Re peate d Meas ures A N O V A detaile d i n Secti o n 4. 4. 1. 2. Mea n differe n ces b et wee n 
Test De ntifrice c o m par e d t o t he Refere n ce De ntifrice i n mea n T otal M L SI ( A ×I) sc ore at 1 2 
a n d 2 4 wee ks after t o ot h bleac hi n g will be prese nt e d al o n g wit h 9 5 % CIs a n d p -val ues i n Ta bl e 
1 4. 2. 3. 2 f or all s u bjects i n t he mI T T p o p ulati o n. Si g nifica nce testi n g will be c o n d ucte d at t he 
t w o-si de d 5 % si g nifica n ce le vel. St u d y pr o d uct differe n ces f or eac h of t he af ore me nti o ne d 
efficac y varia bl es will be teste d u n der t he n ull h y p ot hes es descri be d bel o w at 1 2 a n d 2 4 Wee ks: 
•  T ot al M L SI ( Are a ( A) x I nte nsit y (I))  
H 0: t here is n o diff ere n ce i n mea n total M L SI  Area x I nte nsit y  ( A ×I) sc ores bet wee n T est 
De ntifrice a n d Ref ere n ce De ntifrice;  
H 1: t here is a differ e nce i n mea n total M L SI Area x I nte nsit y ( A ×I) sc ores bet wee n T est 
De ntifrice a n d Ref ere n ce De ntifrice;  
Descri pti ve statistics ( n, mea n, S D, Sta n dar d Err or [ S E], me dia n, mi ni m u m, a n d ma xi m u m) 
will be prese nte d f or Mea n T otal M L SI ( A xI) sc ore at eac h assess me nt ti me p oi nt  i n Ta ble 
1 4. 2. 3 . 1 f or all s u bjects i n mI T T P o p ulati o n b y st u d y pr o d uct.  Ra w mea n ±  ( S E) of mea n 
T otal M L SI ( A xI) s c ore at eac h ti me p oi nt will be pl otte d b y st u d y pr o d uct i n Fi g ure 1 4. 2. 2. 1 
f or all s ubjects i n t he mI T T p o p ulati o n. 
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•  Gi n gi v al sites ( A xI)  
H 0: t here is n o diff ere n ce i n mea n M L SI ( A ×I) sc ores f or gi n gi val sites bet wee n T est 
De ntifrice a n d Ref ere n ce De ntifrice;  
H 1:  t here is  a differ e nce i n  mea n  M L SI ( A ×I)  sc ores f or gi n gi val sites bet wee n  T est  
De ntifrice a n d Ref ere n ce De ntifrice;  
•  I nter pr o xi m al sites ( A xI) 
H 0: t here is n o differe nce i n mea n M L SI ( A ×I) sc ores f or i nter pr o xi mal sites bet wee n Test 
De ntifrice a n d Ref ere n ce De ntifrice;  
H 1: t here is a differe nce i n mea n M L SI ( A ×I)  sc ores f or i nter pr o xi mal sites bet wee n Test 
De ntifrice a n d Ref ere n ce De ntifrice;  
•  B o d y sites ( A xI) 
H 0: t here is n o differe n ce i n mea n M L SI ( A ×I) sc ores f or b o d y sites bet wee n Test De ntifrice 
a n d Refer e nce De ntifri ce;  
H 1: t here is a differe nce i n mea n M L SI ( A ×I) sc ores f or b o d y sites bet wee n Test De ntifrice 
a n d Refer e nce De ntifri ce;  
•  M L SI ( A) 
H 0: t here is n o diff ere n ce i n mea n t otal M L SI Area  ( A) sc ores b et wee n Test De ntifrice a n d 
Refere n ce D e ntifrice;  
H 1: t here is a differ e nce i n mea n t otal M L SI  Area  ( A) sc ores bet w ee n T est De ntifrice a n d 
Refere n ce D e ntifrice;  
 
•  M L SI (I)  
H 0: t here is n o diff ere n ce i n mea n t otal M L SI I nt e nsit y (I) sc ores bet w ee n Test De ntifrice 
a n d Refer e nce De ntifri ce;  
H 1: t here is a diff er e nce i n mea n t otal M L SI I nt e nsit y (I) sc ores bet w ee n Test De ntifrice 
a n d Refer e nce De ntifri ce;  
Descri pti ve statistics ( n, mea n, S D, Sta n dar d Err or [ S E], me dia n, mi ni m u m, a n d ma xi m u m) 
will be pres e nte d f or all t he af ore me nti o ne d efficac y vari a bles at eac h assess me nt ti me p oi nt  i n 
Ta ble 1 4. 2. 3 . 1 f or all s u bjects i n mI T T  P o p ulati o n b y st u d y pr o d uct.  Ra w mea n ±  ( S E) of mea n 
T otal M L SI ( A xI) s c ore at eac h ti me  p oi nt will b e pl otte d b y st u d y pr o d uct i n Fi g ure 1 4. 2. 2. 1 
f or all s u bjects i n t he mI T T p o p ulati o n. 
I n di vi d ual a n d deri v e d M L SI ( A ×I) sc ore data will be liste d f or eac h s u bject b y visit a n d st u d y 
pr o d uct gr o u p i n Listi n g 1 6. 2. 6. 2 . 1 a n d Listi n g 1 6. 2. 6. 2. 2 res pecti vel y f or all ra n d o mize d 
s u bjects. 
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T he ass u m pti o n of n or m alit y a n d h o m o ge n eit y of varia n ce i n t he re peate d meas ures A N O V A 
m o del will be i n vesti gate d. I n case of vi olati o n of t hese ass u m pti o ns, a s uit a ble n o n para metric 
test (t he Va n Eltere n test, a dj uste d f or t he ra n d o mizati o n stratificati o n) will be perf or me d f or 
eac h c o m p aris o n at wee k 1 2 a n d 2 4 a n d res ults will be pr o vi de d t o s u p p ort t he re peat e d 
meas ures A N O V A res ults. 
4. 4. 3  E x pl or at or y Effi c a c y V ari a bl e s  
T here will be n o a dj ust me nt f or m ulti plicit y i n t he a nal yses f or e x pl orat or y efficac y varia bles. 
4. 4. 3. 1  
E x pl or at or y Effi c a c y V ari a bl e 1  
T he  E x pl orat or y  E n d p oi nt  1 will  be  Mea n  se nsiti vit y  q uesti o n naire  sc ores  pre  a n d  p ost  
bleac hi n g t o access t o ot h se nsiti vit y of s u bjects a n d c o m paris o n bet w ee n Test De ntifrice a n d 
R efere n ce D e ntifrice . T o assess t o ot h se nsiti vit y  bel o w  q uesti o n naire will b e use d:   
•  Vis ual A nal o g ue Scale  ( V A S) 
•  La belle d  Ma g nit u de Scale (I nte nsit y, D urati o n, T olera bilit y, Descri pti o n) - L M S   
•  B ot hers o me ness Sc ore ( N R S)  
Descri pti ve  statistics  ( n,  missi n g,  mea n,  S D,  st a n dar d  err or  [ S E],  me di a n,  mi ni m u m,  a n d  
ma xi m u m) will  be  prese nte d  f or  V A S  sc ore,  N R S  Sc ore  a n d  L M S  (I nte nsit y,  D urati o n,  
T olera bilit y, Descri pti o n) sc ore at eac h assess me nt ti me p oi nt i n Ta ble  1 4. 2. 4. 1 f or all s u bjects 
i n t he mI T T p o p ulati o n b y st u d y pr o d uct wit hi n Strata . 
A d diti o nall y ,  nu m ber of s u bjects w h o e x peri e nce d t o ot h se nsiti vit y will be s u m marize d b y 
st u d y pr o d uct gr o u p a n d stratu m [ D H ( Y/ N)]  i n T a ble 1 4. 2. 4. 1.  
I n di vi d ual data f or V A S sc ore, L M S sc ore a n d N R S sc ore will be liste d f or eac h s u bject b y 
st u d y pr o d uct gr o u p a n d visit i n Listi n g 1 6. 2. 6. 3 f or all ra n d o mize d s u bjects. 
4. 4. 3. 2  
E x pl or at or y Effi c a c y V ari a bl e 2 
T he E x pl orat or y E n d p oi nt 2 will be P ost W hite ni n g Q uesti o n nai re a n d W hite ni n g Hist or y 
Q uesti o n naire t o e x pl ore s u bject’s e x peri e nce of p er o xi de t o ot h bleac hi n g w he n si m ulta ne o usl y 
usi n g eit her Test De ntifri ce or Ref er e nce D e ntifrice. 
•  W hite ni n g Hist or y Q uesti o n naire 
 
I n di vi d ual d ata fr o m q u esti o n naire will be liste d f or eac h s u bject b y st u d y pr o d uct gr o u p i n 
Listi n g 1 6. 2. 6. 5 f or all ra n d o mize d s u bjects.  
•  P ost W hite ni n g Q uesti o n naire  
 
T he q uesti o n naire will be s u m marize d [ n ( %)] f or all q uesti o ns a n d s u bject’s res p o nse i n 
Ta ble 1 4. 2. 4. 2 f or all s u bjects i n t he mI T T P o p ulati o n b y st u d y pr o d uct gr o u p. 
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I n di vi d ual dat a will be liste d f or eac h s u bject b y st u d y pr o d uct gr o u p i n Listi n g 1 6. 2. 6. 4 f or all 
ra n d o mize d s u bjects. 
4. 4. 3. 3  
E x pl or at or y Effi c a c y V ari a bl e 3 
 
T he e x pl or at or y e n d p oi nt 3 will be c h a n ge i n m ea n VI T A s ha d e sc ore fr o m pre t o p ost bleac hi n g  
Treat me nt . 
 
Descri pti ve  statistics  ( n,  missi n g,  mea n,  S D,  st a n dar d  err or  [ S E],  me di a n,  mi ni m u m,  a n d  
ma xi m u m) will be prese nte d f or mea n VI T A s ha de s c ore at visit 2 ( pre bleac hi n g) a n d visit 3  
( p ost bleac hi n g) t o get her wit h c ha n ge fr o m Visit 2 t o Visit 3 will be prese nte d i n  Ta ble  1 4. 2. 4. 3 
f or all s u bjects i n t he mI T T p o p ulati o n b y st u d y pr o d uct gr o u p. 
T he res ults f or t his e n d p oi nt will be a nal yze d fr o m a n A N C O V A m o del w here st u d y pr o d u ct 
gr o u p will be fi xe d effect  a n d mea n VI T A s ha d e sc ore pri or t o t he start of t o ot h bleac hi n g fitte d 
as a c o variate.   
Usi n g t he a b o ve m o del,  least s q uared mea n, pair wise differe nce  al o n g wit h 9 5 % CIs will be 
re p orte d b y st u d y pr o d uct i n Ta ble  1 4. 2. 4. 4 f or all s u bjects i n t he mI T T p o p ul ati o n. Si g nifica nce 
testi n g will be c o n d ucte d at t he t w o-si de d 5 % si g nifica nce l e vel. 
T he ass u m pti o n of n or malit y a n d h o m o ge neit y of varia nce i n will be i n vesti gate d. I n cas e of 
vi olati o n of t hese ass u m pti o ns, a s uita ble n o n- para metric test ( Va n Elter en) will be perf or me d, 
a n d res ults will  be pr o vi d e d t o s u p p ort t he para m etric res ults. 
4. 4. 4  
H a n dli n g of M i s si n g V al u e s/ C e n s ori n g/ D i s c o nti n u ati o n s 
Missi n g  data  will  n ot  be  r e place d  or  i m p ute d.  S u bjects  w h o  wit h dra w  fr o m  t he  st u d y  
pre mat urel y will be i ncl u de d i n t he statistical a nal yses u p t o t he p oi nt of disc o nti n uati o n. 
T he use of r e peate d meas ures a nal yses acc o u nts f or missi n g data ass u mi n g a missi n g at ra n d o m 
ass u m pti o n, i.e., t here is a s yste matic relati o ns hi p bet wee n t he pr o pe nsit y of missi n g val ues a n d 
t he o bser ve d d ata, b ut n ot t he missi n g data. 
It is t her ef or e ass u me d t h at a s u bject wit h missi n g data w o ul d ha v e o btai ne d a si milar effi cac y 
res ult c o m pare d t o a s u bject usi n g t he sa me st u d y pr o d uct wit h si milar n o n -missi n g res ults at 
ot her ti me p oi nts ( Baseli ne a n d  t he ot her p ost-B aseli ne visit).  
Se nsiti vit y a nal yses ma y be a d de d t o t he S A P pri or t o u n bli n di n g i n case of hi g h dr o p -o ut rates 
a n d/ or e xcl usi o n fr o m P P a nal yses . 
4. 5   
A n al y si s of S af et y  
T he safet y pr ofile of t he st u d y treat me nts will be assesse d wit h res pect t o A Es or i nci de nts or 
ot hers s uc h as O S T/ O H T a b n or malities i n oral healt h st u d y  a n d i nci de nts relate d t o me dical 
de vice s. 
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4. 5. 1  
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  
All A Es will be re vie we d b y t he Cli nical Researc h Scie ntist or Desi g nee pri or t o data base l oc k 
a n d will be c o de d t o a s yste m or ga n class ( S O C) a n d preferre d ter m ( P T) usi n g t he Me dical 
Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A). 
A Es will be classifie d as oral a n d n o n - oral o n t he A E pa ge of e C R F. 
Treat me nt e mer ge nt a d v erse e ve nts ( T E A Es) are d efi ne d as n e w A Es t hat o cc ur o n or after t he 
first st u d y pr o d uct use  (if t his date is missi n g a s uita ble alter nati ve will be use d e. g., date of 
ra n d o mizati o n).  A Es  wit h  a n  o nset  date/ti me  pri or  t o  t he  first  st u d y  pr o d uct use  will  be  
c o nsi dere d as n o n- treat me nt e mer ge nt. 
T he f oll o wi n g s u m mar y ta bles a n d listi n gs will be prese nte d b y st u d y pr o d u ct gr o u p. 
•  Ta ble of All A Es  ( T a ble 1 4. 3. 1. 1). 
•  Ta ble of T E A Es b y S O C a n d P T ( Ta ble 1 4. 3. 1. 2 ). 
•  Ta ble of T E A Es b y Oral/ N o n- Oral a n d P T ( Ta ble 1 4. 3. 1. 3) 
•  Ta ble of treat me nt relat e d T E A Es b y S O C a n d P T ( Ta ble 1 4. 3. 1. 4) 
•  Ta ble of treat me nt relat e d T E A Es b y Oral/ N o n - Oral a n d P T ( Ta bl e 1 4. 3. 1. 5) 
•  Listi n g of all A Es ( Listi n g 1 6. 2. 7. 1 f or all ra n d o mize d s u bjects; Listi n g 1 6. 2. 7. 2 f or 
n o n-ra n d o mize d s u bjects) 
•  Listi n g of deat hs ( Listi n g 1 4. 3. 2. 1) 
•  Listi n g of n o n-fatal S A Es ( Listi n g 1 4. 3. 2. 2) 
•  Listi n g of T E A Es lea di n g t o st u d y or pr o d uct disc o nti n uati o n ( Listi n g 1 4. 3. 2. 3) 
•  Listi n g of T E A Es classifie d as Oral ( Listi n g 1 4. 3. 2. 4) 
I n t he e ve nt t here is n ot hi n g t o re p ort, a n ull ta ble or listi n g will be pr o d uce d. 
4. 5. 2  
M e di c al D e vi c e I n ci d e nt s 
 
Me dical d e vice i nci de nts i n v ol vi n g a n A E will be f oll o we d a n d re p orte d i n t he sa me ma n ner as 
ot her A Es. T his a p plies t o all s u bjects, i ncl u di n g t h ose w h o disc o nti n ue st u d y pr o d uct or are 
wit h dra w n fr o m t he st u d y. 
All re p orte d i nci de nts i ncl u di n g o nset date /ti me, o utc o me, e n d date/ti me, deat h date/ti me if a n y, 
treat me nt  pr o vi d e d, r eas o n  of  st u d y  wit h dra w n will  be  liste d  i n  Listi n g  1 6. 2. 7. 3 f or  all  
Ra n d o mize d s u bjects. 
4. 5. 3  
Ot h er S af et y V ari a bl e s  
Ot her saf et y varia bl es ar e liste d bel o w:  
•  O S T e xa mi nati o n  
•  O H T e xa mi nati o n  
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4. 5. 3. 1  
O S T E x a mi n ati o n  
T he  O S T  e xa mi nati o n  will  be  acc o m plis he d  b y  direct  o bser v ati o n  a n d  pal pati o n,  usi n g  
retracti o n ai ds as a p pr o priate, a n d will i ncl u de e xa mi nati o n of t he la bial m uc osa (i ncl u di n g 
li ps), b uccal m uc osa, m uc o gi n gi val f ol ds, gi n gi val m uc osa, har d p alate, s oft palate, t o nsillar 
area, p har y n geal ar ea, t o n g ue, s u bli n g ual area, s u b ma n di b ular area a n d s ali var y gla n ds. T h e 
res ults of t he e x a mi nati o n will be rec or de d i n t he e C R F as eit her ‘ n or m al’ or ‘a b n or mal’; wit h 
details of a n y a b n or m alities. 
A n y  o bser v ati o n  t hat  c ha n ges  fr o m  ‘ n or mal’  t o  ‘a b n or m al’,  or  w ors e ns,  fr o m  t he  O S T  
e xa mi nati o n c o m plete d at Scree ni n g will be rec or de d as a n A E. 
O S T will be s u m marize d ( n u m ber of s u bjects a n d perce nta ges wit h a b n or malities, wit h o ut 
a b n or malities , or O S T n ot e xa mi ne d) b y visit a n d st u d y pr o d uct i n Ta ble 1 4. 3. 4. 1 f or all s u bjects 
i n t he Safet y P o p ulati o n. O S T e xa mi nati o n will be liste d ( Listi n g 1 6. 2. 8. 1 . 1) wit h all rec or ds 
(' n or mal’, ‘ a b n or mal’ a n d ‘ n ot e xa mi ne d’) f or all ra n d o mize d s u bjects, a n d a se parate listi n g 
will be prese nte d f or ‘a b n or mal’ rec or ds o nl y ( Listi n g 1 6. 2. 8. 1. 2) f or all ra n d o mize d s u bjects. 
4. 5. 3. 2   
O HT E x a mi n ati o n  
 
T he O H T e xa mi nati o n will be acc o m plis he d b y direct o bser vati o n, usi n g retracti o n ai ds as 
a p pr o priate,  a n d  will  i de ntif y  gr ossl y  cari o us  lesi o ns,  si g ns  of  er osi ve  wear,  e na m el  
irre g ularities, t o ot h fract ure, gr oss ge neralize d de ntal cari es deca y, d ecalcificati o n a n d fa ult y 
rest orati o ns. T he pres e nce of a n y i m pla nts, fi xe d or re m o va ble de nt ures, fi xe d or re m o va ble 
ort h o d o ntic braces/ ba n ds, fi xe d ort h o d o ntic retai ners, f ull cr o w ns or ve neers  will be rec or de d. 
O bser vati o ns  will  b e liste d as  ‘a bse nt’ or  ‘ pres e nt’;  c o n diti o ns n ote d  as ‘ pres e nt’ will  b e 
descri be d i n t he e C R F. A n y o bser v ati o n t hat c h a n ges fr o m ‘a bse nt’ t o ‘ prese nt’, or w orse ns, 
fr o m t he O H T e xa mi nati o n c o m plete d at Scree ni n g will be rec or d e d as a n AE.  
O H T e xa mi nati o n will be liste d ( Listi n g 1 6. 2. 8. 2) f or all ra n d o mize d s u bjects. 
4. 6   
A n al y si s of Ot h er V ari a bl e s 
4. 6. 1  
R e p e at a bilit y of t h e T o ot h C ol or A s s e s s m e nt  
 
A p pr o xi matel y te n s u bjects will be ra n d o ml y selecte d f or re peat s ha d e assess me nts at eac h 
assess me nt ti me p oi nt ( Visits 1 - 5) t o test t he c o nsiste nc y of t he e x a mi ner.  
 
T he re p eat t o ot h stai n ass ess me nts will be c o m pare d t o t he ori gi nal assess m e nts a n d will n ot be 
use d i n a n y effi cac y a nal ysis. T he first a n d sec o n d assess me nts o n eac h t o ot h site will be cr oss 
ta b ulate d. A wei g hte d Ka p pa c oefficie nt ( κ), al o n g wit h t he 9 5 % CI will be  calc ulate d t o assess 
t he i ntra-e x a mi ner r elia bilit y  i n Ta ble 1 4. 2. 5. 1 f or all s u bject i n VI T A S ha de re p eata bilit y 
p o p ulati o n b y st u d y Pr o d uct Gr o u p . Fleiss-C o he n wei g hte d ka p p a will be  calc ul ate d f or t he 
re peat a bilit y a nal ysis. Relia bilit y will be dee me d- 
•  E xcelle nt if κ > 0. 7 5  
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•  Fair -t o-g o o d if 0. 4 ≤ κ ≤ 0. 7 5  
•  P o or if κ < 0. 4  
 
All s u bjects w h o ha ve r e peata bilit y data will be i ncl u de d i n t his a nal ysis.  
If t he sa me s u bject is selecte d at r a n d o m f or re p eata bilit y assess me nts at m ulti ple visits, t he 
pairs  of  o bser v ati o ns  will  be  c o nsi dere d  as  i n d e pe n de nt  f or  t h e  p ur p os es  of  re p eata bilit y  
a nal ysis; t hat is, a n y p ote ntial wit h  s u bject c orrelati o n will be i g n ore d. 
4. 6. 2  
R e p e at a bilit y of t h e M L SI  A s s e s s m e nt  
 
A p pr o xi matel y te n s u bjects will be ra n d o ml y selecte d f or re peat M L SI assess me nts at eac h 
assess me nt ti me p oi nt ( Visits 1 -5) t o test t he c o nsiste nc y of t he e x a mi ner. 
 
T he r e peat c ol or assess m e nts will be c o m pare d t o t he ori gi nal assess me nts a n d will n ot b e use d 
i n a n y efficac y a n al ysis. T he first a n d sec o n d assess me nts o n eac h t o ot h site will be cr oss 
ta b ulate d. A wei g hte d Ka p pa c oefficie nt ( κ), al o n g wit h t he 9 5 % CI will be calc ulate d t o assess 
t he i ntra-e xa mi ner relia bilit y  i n Ta ble 1 4. 2. 5. 2 f or all s u bject i n M L SI re p eata bilit y p o p ulati o n 
b y st u d y Pr o d uct Gr o u p . Fleiss -C o he n w ei g hte d ka p pa will be  calc ulate d f or t he re peata bilit y 
a nal ysis. Relia bilit y will be dee me d - 
•  E xcelle nt if κ > 0. 7 5  
•  Fair -t o-g o o d if 0. 4 ≤ κ ≤ 0. 7 5 
•  P o or if κ < 0. 4  
 
All s u bjects w h o ha ve r e peata bilit y data will be i ncl u de d i n t his a nal ysis.  
If t he sa me s u bject is selecte d at r a n d o m f or re p eata bilit y assess me nts at m ulti ple visits, t he 
pairs  of  o bser v ati o ns  will  be  c o nsi dere d  as  i n d e pe n de nt  f or  t h e  p ur p os es  of  re p eata bilit y  
a nal ysis; t hat is, a n y p ote ntial wit h  s u bject c orrelati o n will be i g n ore d. 
 
5 
C h a n g e s t o t h e Pr ot o c ol D efi n e d St ati sti c al A n al y si s Pl a n  
T here w ere n o c ha n g es or de viati o ns t o t he ori gi nall y pla n ne d statistical a n al ysis s pecifie d i n 
t he pr ot oc ol a me n d me nt ( Date d: 1 3-N o v - 2 0 2 3). 
 
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<Compound/Product>
<Protocol Number>
 
 
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Statistical Analysis Plan template v7.0
Page 25 of 31
Appendix 1: List of Data Displays
CSR Section
TLF
Number
Title
Population
Template
Topline
14.1 Demographic Data Summary Tables and Figures
Table
14.1.1
Subject Disposition
All Screened Subjects
14.1.1
Yes
Table
14.1.2
Incidence of Important Protocol Deviations
All Randomized Subjects
14.1.2
Table
14.1.3.1
Demographic and Baseline Characteristics
Safety Population
14.1.3.1
Table
14.1.3.2
Demographic and Baseline Characteristics
mITT Population
14.1.3.1
Yes
14.2 Efficacy Data Summary Tables and Figures
Table
14.2.1.1
Summary of Brushing Compliance
mITT Population
14.2.1.1
Table
14.2.1.2
Summary of Bleaching Compliance
mITT Population
14.2.1.2
Table
14.2.2.1.1
Summary of Mean VITA Shade Score
mITT Population
14.2.2.1.1
Yes
Table
14.2.2.1.2
Summary of Mean VITA Shade Score
PP Population
14.2.2.1.1
Table
14.2.2.2.1
Statistical Analysis of Mean VITA Shade Score 
(Repeated Measures ANOVA)
mITT Population
14.2.2.2.1
Yes
Table
14.2.2.2.2
Statistical Analysis of Mean VITA Shade Score 
(Repeated Measures ANOVA)
PP Population
14.2.2.2.1
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Statistical Analysis Plan Template v7.0
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CSR Section
TLF
Number
Title
Population
Template
Topline
Table
14.2.3.1
Summary of Mean Total MLSI Score
mITT Population
14.2.3.1
Yes
Table
14.2.3.2
Statistical Analysis of Mean Total MLSI Score 
(Repeated Measures ANOVA)
mITT Population
14.2.3.2
Yes
Table
14.2.4.1
Summary of Sensitivity Questionnaire Score
mITT Population
14.2.4.1
Yes
Table
14.2.4.2
Post Whitening Questionnaire
mITT Population
14.2.4.2
Yes
Table
14.2.4.3
Summary of Mean VITA Shade Score at Pre to Post 
Bleaching
mITT Population
14.2.2.1.1
Yes
Table
14.2.4.4
Statistical Analysis of Change in Mean VITA Shade 
Score Pre to Post Bleaching
mITT Population
14.2.4.4
Yes
Table
14.2.5.1
Intra-examiner Repeatability Analysis of VITA Shade 
Score 
VITA Shade Repeatability
Population
14.2.5.1
Yes
Table
14.2.5.2
Intra-examiner Repeatability Analysis of MLSI 
MLSI Repeatability
Population
14.2.5.2
Yes
Figure
14.2.1.1
Mean VITA Shade Score Mean (±SE) Plot Over Time 
by Product Group
mITT Population
14.2.1.1
Figure
14.2.1.2
Mean VITA Shade Score Mean (±SE) Plot Over Time 
by Product Group
PP Population
14.2.1.1
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Template
Topline
Figure
14.2.2.1
Mean Total MLSI (A*I) Score Mean (±SE) Plot Over 
Time by Product Group
mITT Population
14.2.2.1
14.3 Safety Data Summary Tables and Figures
14.3.1 Displays of Adverse Events 
Table
14.3.1.1
Summary of All Adverse Events
Safety Population
14.3.1.1
Table
14.3.1.2
Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety Population
14.3.1.2
Yes
Table
14.3.1.3
Treatment Emergent Adverse Events by Oral/Non-Oral 
and Preferred Term 
Safety Population
14.3.1.3
Table
14.3.1.4
Treatment Related Treatment Emergent Adverse 
Events by System Organ Class and Preferred Term
Safety Population
14.3.1.2
Table
14.3.1.5
Treatment Related Treatment Emergent Adverse 
Events by Oral/Non-Oral and Preferred Term
Safety Population
14.3.1.3
14.3.2 Listings of Deaths, Other Serious and Significant Adverse Events
Listing
14.3.2.1
Deaths
All Randomized Subjects
16.2.7.1
---
Listing
14.3.2.2
Non-fatal Serious Adverse Events
All Randomized Subjects
16.2.7.1
Listing
14.3.2.3 
Treatment Emergent Adverse Events Leading to Study 
or Product Discontinuation
All Randomized Subjects
16.2.7.1
Listing
14.3.2.4 
Treatment Emergent Adverse Events Classified as 
Oral
All Randomized Subjects
16.2.7.1
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14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events
14.3.4 Other Observations Related to Safety and Abnormal Laboratory Values 
Table
14.3.4.1
Summary of Oral Soft Tissue Examination 
Safety Population
14.3.4.1
Table
14.3.4.2
Concomitant Medication taken to alleviate Tooth 
Sensitivity
Safety Population
14.3.4.2
APPENDIX
16.1.6 Listing of Subjects Receiving Test Drug(s)/Investigational Product(s) from Specific Batches, where more than one batch was used
NA
16.1.7 Randomization Scheme and Codes (Subject identification and treatment assigned)
Listing
16.1.7.1
Randomization Information
All Randomized Subjects
16.1.7.1
Listing
16.1.7.2
Kit List Allocation
All Randomized Subjects
16.1.7.2
16.1.9 Documentation of Statistical Methods
Raw output
16.1.9.1.1
Statistical Analysis in Mean VITA Shade Score 
(Repeated Measures ANOVA)
(Reference: Table 14.2.2.2.1)
mITT Population
SAS Output
Yes
Raw output
16.1.9.1.2
Statistical Analysis in Mean VITA Shade Score 
(Repeated Measures ANOVA)
(Reference: Table 14.2.2.2.2)
PP Population
SAS Output
Raw output
16.1.9.2
Statistical Analysis in Mean Total MLSI Score 
(Repeated Measures ANOVA)
mITT Population
SAS Output
Yes
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(Reference: Table 14.2.3.2)
Raw output
16.1.9.3
Statistical Analysis of Change in Mean VITA Shade 
Score Pre to Post Bleaching
(Reference: Table 14.2.4.4)
mITT Population
SAS Output
Yes
16.2 Subject Data Listings
16.2.1 Discontinued Subjects
Listing
16.2.1.1
Subject Disposition
All Randomized Subjects
16.2.1.1
---
Listing
16.2.1.2
Subject Disposition
Non- Randomized 
Subjects
16.2.1.2
16.2.2 Protocol Deviations
Listing
16.2.2.1
Important Protocol Deviations 
All Randomized Subjects
16.2.2.1
---
Listing
16.2.2.2
All Protocol Deviations 
All Randomized Subjects
16.2.2.2
16.2.3 Patients Excluded from the Efficacy Analysis 
Listing
16.2.3.1
Exclusions from Analysis Populations 
All Randomized Subjects
16.2.3.1
---
16.2.4 Demographic Data 
Listing
16.2.4.1
Demographic Characteristics
All Randomized Subjects
16.2.4.1
---
Listing
16.2.4.2
Medical History and Current Medical Conditions
All Randomized Subjects
16.2.4.2
Listing
16.2.4.3
Prior Medications
All Randomized Subjects
16.2.4.3
Listing
16.2.4.4
Concomitant Medications and Concomitant Non-Drug 
Therapies
All Randomized Subjects
16.2.4.4
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Listing
16.2.4.5
Concomitant Medications used to Alleviate Tooth 
Sensitivity
All Randomized Subjects
16.2.4.5
16.2.5 Compliance and/or Drug Concentration Data (if available)
Listing
16.2.5.1
Brushing Compliance
All Randomized Subjects
16.2.5.1
---
Listing
16.2.5.2
Peroxide Bleaching Compliance
All Randomized Subjects
16.2.5.2
Listing
16.2.5.3
Supervised Brushing
All Randomized Subjects
16.2.5.3
16.2.6 Individual Efficacy Response Data
Listing
16.2.6.1
VITA Shade Score Data
All Randomized Subjects
16.2.6.1
---
Listing
16.2.6.2.1
MLSI (AxI) Score Data
All Randomized Subjects
16.2.6.2.1
Listing
16.2.6.2.2
Derived MLSI (AxI) Score Data
All Randomized Subjects
16.2.6.2.2
Listing
16.2.6.3
Tooth Sensitivity Questionnaire
All Randomized Subjects
16.2.6.3
Listing
16.2.6.4
Post Whitening Questionnaire
All Randomized Subjects
16.2.6.4
Listing
16.2.6.5
Whitening History Questionnaire
All Randomized Subjects
16.2.6.5
16.2.7 Adverse Event Listings 
Listing
16.2.7.1
All Adverse Events 
All Randomized Subjects
16.2.7.1
---
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Listing
16.2.7.2
All Adverse Events 
Non- Randomized
16.2.7.1
Listing
16.2.7.3
Incidents due to medical device
All Randomized Subjects
16.2.7.3
16.2.8 Other Listings and Listing of Laboratory Measurements, when required by regulatory authorities (if applicable) 
Listing
16.2.8.1.1
Oral Soft Tissue Examination (All Result)
All Randomized Subjects
16.2.8.1.1
---
Listing
16.2.8.1.2
Oral Soft Tissue Examination (Abnormal Result)
All Randomized Subjects
16.2.8.1.1
Listing
16.2.8.2
Oral Hard Tissue Examination 
All Randomized Subjects
16.2.8.2
16.4 Individual Subject Data Listings
NA
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