A 4-Week Randomised, Controlled, Examiner-blind, Clinical Study Investigating the Efficacy of an Experimental Toothpaste Containing Stannous Fluoride in Improving Gingival Health
Phase: NA
Conditions: Dental Plaque, Gingivitis
Sponsor: HALEON

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 1 of 53
CLINICAL PROTOCOL
A 4-Week Randomised, Controlled, Examiner-blind,
Clinical Study Investigating the efficacy of an
Experimental Toothpaste containing Stannous Fluoride in 
improving gingival health
Protocol Number:
300178
Compound/Product Name:
0.454% Stannous Fluoride
0.3% Zinc Chloride
1% Alumina
Phase:
Not applicable (N/A)
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
This document contains confidentiality statements that are not relevant for this publicly
available version
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 2 of 53
Sponsor Information
   
Sponsor Name & Legal 
Registered Address
Haleon (UK) 
Building 5, First Floor, 
The Heights, 
Weybridge, 
Surrey, 
KT13 0NY.
Sponsor Contact Details
Haleon (UK) 
St Georges Avenue,
Weybridge,
Surrey,
KT13 0DE,
United Kingdom (UK)
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 3 of 53
Document History
Document
Version
Summary of Changes 
Original protocol
1.0
Not applicable (N/A)
Amendment 1
2.0
To align baseline visit as Day 1 throughout (it was referred to as 
Day 0 in places).
To add comparison of pre-brushing at Day 1 and post-brushing at 
Week 4 to the exploratory analysis in section 8.3.1
Addition of prophy and snack consumption to sections 5.3 & 5.4
to align with rest of protocol.
Amendment 2
3.0
Change to protocol requirements on repeatability assessments 
(Sections 3, 6.2.7, 8.3.4 and Table 5.1 (Schedule)) from at least 
one subject per clinical assessment day to at least 3 subjects  
over the entire duration of each of visits 2&3.
Correction to typo in document history where V2.0 was described 
as a new version rather than as Amendment 1.
New versions incorporate all revisions to date prior to submission to institutional review 
boards/ethics committees (IRBs/ECs), etc.
Amendments incorporate all revisions to date, including amendments made at the request of 
institutional review boards/ethics committees (IRBs/ECs), etc.  
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 4 of 53
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
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
PPD
PPD
PPD
PPD

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 5 of 53
Table of Contents
Sponsor Information ................................................................................................... 2
Document History....................................................................................................... 3
Principal Investigator Protocol Agreement Page........................................................ 4
Table of Contents........................................................................................................ 5
1
INTRODUCTION ...................................................................................................... 8
1.1
Background & Study Rationale ...................................................................... 8
2
STUDY OBJECTIVES AND ENDPOINTS............................................................ 10
3
STUDY DESIGN ..................................................................................................... 11
4
STUDY POPULATION........................................................................................... 15
4.1
Type and Planned Number of Subjects......................................................... 15
4.2
Inclusion Criteria........................................................................................... 16
4.3
Exclusion Criteria ......................................................................................... 17
4.4
Lifestyle Considerations ............................................................................... 19
4.4.1
Dietary, Tobacco and Alcohol restrictions................................... 20
4.4.2
Oral Care Restrictions .................................................................. 20
5
STUDY PROCEDURES.......................................................................................... 21
5.1
Schedule of Activities................................................................................... 21
5.2
Visit 1/Screening........................................................................................... 23
5.2.1
Informed Consent ......................................................................... 23
5.2.2
Demographics............................................................................... 23
5.2.3
Review of subject’s current oral care product.............................. 23
5.2.4
Medical History and Prior Medication/Treatment ....................... 24
5.2.5
Oral examination/Assessments..................................................... 24
5.2.6
Inclusion/Exclusion Criteria......................................................... 24
5.2.7
Subject Eligibility......................................................................... 24
5.2.8
Enrolled Subjects and Screen Failures ......................................... 24
5.3
Visit 2/Day 1 (Baseline)................................................................................ 25
5.4
Visit 3/Day 28 (week 4)................................................................................ 25
6
STUDY ASSESSMENTS ........................................................................................ 26
6.1
Screening Assessments ................................................................................. 26
6.2
Efficacy Assessments.................................................................................... 27
6.2.1
Sampling and Laboratory Procedures .......................................... 27
6.2.2
Modified Gingival Index (MGI)................................................... 27
6.2.3
Bleeding Index (BI)...................................................................... 28
6.2.4
Basic Periodontal Examination (BPE) ......................................... 28
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 6 of 53
6.2.5
Plaque Disclosure Procedure........................................................ 29
6.2.6
Turesky Modification of the Quigley Hein Index (TPI) .............. 29
6.2.7
Repeatability Assessments ........................................................... 30
6.3
Safety and Other Assessments...................................................................... 30
6.3.1
Oral Soft Tissue (OST) Examination ........................................... 30
6.3.2
Oral Hard Tissue (OHT) Examination ......................................... 31
6.3.3
Pregnancy Testing ........................................................................ 31
6.4
Banked Bio specimens.................................................................................. 31
7
INVESTIGATIONAL/STUDY PRODUCTS.......................................................... 31
7.1
Investigational/Study Product Supplies ........................................................ 32
7.2
Product Supplies, Product Storage, Accountability, Returns and Destruction
....................................................................................................................... 33
7.3
Blinding and Allocation/Randomization ...................................................... 34
7.4
Breaking the Blind ........................................................................................ 34
8
STATISTICAL CONSIDERATIONS AND DATA ANALYSES.......................... 35
8.1
Sample Size Determination........................................................................... 35
8.2
Populations for Analysis............................................................................... 35
8.2.1
Definitions of Analysis Populations............................................. 35
8.2.2
Exclusions of Data from Analysis................................................ 36
8.3
Statistical Analyses ....................................................................................... 36
8.3.1
Primary Endpoint Analysis(es)..................................................... 37
8.3.2
Secondary Endpoint Analysis(es)................................................. 37
8.3.3
Safety Analysis(es)....................................................................... 37
8.3.4
Other Analysis(es)........................................................................ 38
8.3.5
Demographic and Baseline Characteristics.................................. 39
8.3.6
Use of Other Therapies................................................................. 40
8.3.7
Handling of Dropouts and Missing Data...................................... 40
9
APPENDICES .......................................................................................................... 40
9.1
Adverse Event (AE) and Serious AE (SAE)................................................. 40
9.2
Definition of an AE....................................................................................... 41
9.3
Definition of a SAE....................................................................................... 41
9.4
Pregnancy...................................................................................................... 41
9.5
Evaluating Adverse Events........................................................................... 42
9.5.1
Assessment of Intensity................................................................ 42
9.5.2
Assessment of Causality............................................................... 42
9.6
Follow-up of AEs and SAEs......................................................................... 43
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 7 of 53
9.7
DISCONTINUATION OF STUDY PRODUCT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL..................................................... 43
9.7.1
Discontinuation of Study Product ................................................ 44
9.7.2
Subject Discontinuation/Withdrawal............................................ 44
9.7.3
Lost to Follow up.......................................................................... 44
9.8
Data Management ......................................................................................... 45
9.8.1
Case Report Form......................................................................... 45
9.8.2
Data Handling............................................................................... 46
9.8.3
Data Queries ................................................................................. 46
9.9
Regulatory and Ethical Considerations......................................................... 46
9.9.1
Institutional Review Board/ Ethics Committee............................ 46
9.9.2
Ethical Conduct of the Study........................................................ 47
9.9.3
Subject Information...................................................................... 47
9.10
Records Retention......................................................................................... 47
9.11
Disclosure and Publication Policy ................................................................ 48
10 ABBREVIATIONS .................................................................................................. 48
11 REFERENCES ......................................................................................................... 50
List of in text tables
Table 2-1
Study Objectives and Endpoints................................................... 10
Table 5-1
Schedule of Activities................................................................... 21
Table 7-1
Investigational/Study Product Supplies........................................ 32
Table 7-2
Sundry Items................................................................................. 32
Table 9-1
Case Management Group mailbox............................................... 41
Table 10-1
Abbreviations ............................................................................... 48
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 8 of 53
1
INTRODUCTION
1.1
Background & Study Rationale
Gingivitis is a reversible inflammation of the periodontal tissues surrounding the tooth in 
response to the presence of dental plaque (Kinane 2001). It is reported to have a high prevalence 
worldwide in large population surveys (Albandar 2002) and by the World Health Organization
(Petersen and Ogawa 2012) but is also largely preventable. Left untreated, it is the main cause 
of tooth loss and considered one of the main threats to oral health (Murphy 2010). Gingivitis 
is in fact a pre-requisite for periodontitis (an irreversible severe inflammatory gum condition 
and major cause of tooth loss); while not all individuals with gingivitis go on to develop 
periodontitis, management of gingivitis is the primary measure employed in the prevention of 
this periodontal disease (Kinane, Attstr et al. 2005, Chapple, Van der Weijden et al. 2015). The 
prevalence of periodontitis has remained largely unchanged over the last 25 years and the 
evidence-base shows periodontitis has associations with certain non-communicable diseases. 
It is also important to highlight that the worldwide economic impact of unmanaged oral health
is large. The intangible cost (pain, difficulties with speech, low self-confidence, problems with 
expressing emotions such as smiling, etc.) of poor oral health on people’s self-confidence and 
quality of life should also be considered (Peres, Thomson et al. 2020).
Recent reports highlighted that prevention, diagnosis and management of periodontitis is cost-
effective and, preventing the progression of gingivitis to periodontitis, could save even many 
more costs associated with other health conditions that share risk factors with periodontitis 
(Murphy 2010).
Plaque-induced gingivitis is a reversible condition caused by the host’s inflammatory immune
response to the accumulation of dental plaque at the gingival margin and within the gingival
sulcus (Chapple, Mealey et al. 2018). Thus, gingivitis can be managed and prevented by 
removal of plaque with regular effective oral hygiene (Brook 2003, Ower 2003). While
mechanical plaque removal (i.e., toothbrushing) is fundamental to the successful control of
dental plaque, additional benefits can be achieved by adjunctive use of chemical anti-plaque
agents included in daily use dentifrices or mouth rinses (Chapple, Van der Weijden et al. 2015).
Anti-microbial agents have been incorporated into toothpastes for many years with a view to
enhancing plaque control and associated periodontal benefits (Cummins and Creeth 1992).
Their addition to toothpaste formulations complements mechanical plaque removal by helping 
to reduce/inhibit the growth of bacterial plaque in areas of the mouth less accessible to
toothbrushing, and by helping to prevent/slow subsequent re-colonization of ‘cleaned’ surfaces
by the plaque bacteria (Cummins and Creeth 1992, Teles and Teles 2009).
Stannous Fluoride (SnF2) is a well-known chemotherapeutic agent which has been incorporated 
into dentifrices since the 1940s for its oral health benefits (Van Loveren 1990, Miller, Truong 
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 9 of 53
et al. 1994, Van Loveren 2001, Makin 2013). The stannous ion (Sn[II]) is a broad-spectrum 
antimicrobial agent which has been shown to reduce bacterial biomass/ virulence and inhibit 
bacterial metabolism (Tinanoff 1990, Tinanoff 1995, Archila, Bartizek et al. 2004, Bellamy, 
Boulding et al. 2012, He, Barker et al. 2012). Sn [II] ions rapidly oxidize to “inactive” stannic 
ions (Sn [IV]) and hydrolyse to form insoluble tin compounds (for example, stannous 
hydroxide) in the presence of water derived ions (Makin 2013). To maximize the delivery of 
bioavailable Sn[II] ions to the oral cavity, SnF2 dentifrices are often “stabilized” by the addition 
of complexing agents or developed as low water content/anhydrous formulations.
Numerous clinical studies reported in the scientific literature demonstrate the anti-gingivitis/
anti-plaque efficacy of 0.4-0.454% SnF2 dentifrices, for example, (Mankodi, Petrone et al. 
1997, Mankodi, Bartizek et al. 2005, Mallatt, Mankodi et al. 2007, Parkinson, Targett et al. 
2014, Parkinson, Amini et al. 2018, Parkinson, Amini et al. 2018, Parkinson, Milleman et al. 
2020, Acherkouk, Patel et al. 2021) in a population with mild to moderate plaque-induced
gingivitis at timepoints ranging from 2 to 24 weeks.
. It provides cleaning and polishing action on the tooths surface 
with low abrasivity (Milleman, Milleman et al. 2016).
Zinc is known for its ability to reduce oral malodour, inhibiting the production of volatile sulfur 
compounds (VSCs). Zinc ion has also bacteriostatic properties, but it is not expected to impact 
the efficacy of stannous ions. Haleon have conducted 5 studies investigating the ability of zinc 
salts to reduce VSCs produced by oral bacteria. 
. Data from recent Haleon study 300025, have been 
generated in a population with clinical diagnosed gingivitis. Therefore, this formulation could 
offer reduction in breath odour (not investigated as part of this clinical study).
The aim of the current 4-week clinical study is to evaluate the ability of an experimental 
toothpaste, containing 0.454% SnF2, 0.3% ZnCl2 and 1% Alumina, to improve gingival health 
and plaque accumulation compared to a regular fluoride toothpaste (negative control) in 
subjects with plaque-induced mild to moderate gingivitis;
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 10 of 53
Although a diversity recruitment plan is not required for this study, the recruitment strategy
will include a diverse population, with balanced distribution of subjects based on the 
prevalence of gingivitis considering sex, age, race and ethnicity.
Research has found that periodontal disease is more prevalent in males (56.4%) than females 
(38.4%); five out of ten adult males are affected by gum diseases, while 4 out of 10 females
are affected. The difference has been found to be associated with females following better oral 
care regimens. Gingivitis prevalence is also positively associated with increasing age and
typically, it affects more Asians, White East European and Black African than White British 
(based on UK ethnicity) (Peres, Thomson et al. 2020, Rathee and Jain 2023).
2
STUDY OBJECTIVES AND ENDPOINTS
Table 2-1
Study Objectives and Endpoints
Objective(s)
Endpoint(s)
Primary
To evaluate gingival health, as measured by 
the Bleeding Index (BI), of an experimental
dentifrice 
containing 
0.454% 
Stannous 
Fluoride, 0.3% Zinc Chloride and 1% 
Alumina compared to a negative control 
following 4 weeks twice daily use
Mean BI at Week 4.
Secondary
To evaluate gingival health, as measured by 
the Number of Bleeding Sites (NBS) of an 
experimental dentifrice containing 0.454% 
Stannous Fluoride, 0.3% Zinc Chloride and 
1% Alumina compared to a negative control 
following 4 weeks twice daily use
Mean NBS at Week 4
To evaluate gingival health, as measured by 
Modified Gingival Index (MGI) of an 
experimental dentifrice containing 0.454% 
Stannous Fluoride, 0.3% Zinc Chloride and 
1% Alumina compared to a negative control 
following 4 weeks twice daily use
Mean MGI at Week 4.
To evaluate supragingival plaque levels, as 
measured by the Turesky Plaque Index 
(TPI), 
of 
an 
experimental
dentifrice 
containing 0.454% Stannous Fluoride, 0.3% 
Zinc Chloride and 1% Alumina compared to 
a negative control for following 4 weeks 
twice daily use 
•
Mean overall TPI at Week 4.
•
Mean interproximal TPI at Week 4.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 11 of 53
Exploratory
Safety
To evaluate the safety and oral tolerability of 
an 
experimental
dentifrice 
containing 
0.454% Stannous Fluoride, 0.3% Zinc 
Chloride and 1% Alumina following 4 weeks 
twice daily use
Treatment emergent adverse events 
(TEAEs) over 4 weeks
This study will be considered successful if there is a statistically significant difference in mean 
Bleeding Index (BI) after 4 weeks of twice daily brushing with the experimental toothpaste 
containing 0.454% SnF2, 0.3% ZnCl2 and 1% Alumina compared to the control toothpaste.
3
STUDY DESIGN 
This will be a single-center, 4 weeks, randomized, controlled, examiner-blind, 2 treatment 
arms, stratified, parallel group design clinical study, investigating gingival health and supra-
gingival plaque reduction on healthy subjects after using an experimental toothpaste containing 
0.454% SnF2, 0.3% ZnCl2 and 1% Alumina; the antimicrobial effect of the toothpaste will be 
also evaluated as exploratory objective.
Study subjects will be healthy adult volunteers, aged 18-70 years (inclusive), with mild to 
moderate plaque-induced gingivitis and with ≥ 20 natural teeth that meet all study criteria at 
both the Screening and Baseline visits (including ≥ 40 evaluable surfaces for Modified Gingival 
Index (MGI) Bleeding Index (BI), Basic Periodontal Examination (BPE) and Turesky Plaque 
Index (TPI) (BI and TPI will be performed at Baseline (V2), as part of the inclusion criteria, 
and BPE at Screening (V1) as per exclusion criteria).
This design is typical of many studies conducted to evaluate the clinical efficacy of dentifrices
for gingival health. A parallel group design has been selected as more appropriate for this 
investigation. Anticipated differential changes in clinical variables among treatment groups
could lead to carryover effects and an altered oral health state should a crossover design be 
employed. The dosage regimen of twice daily use (morning and evening) will be the same for 
each treatment group and is based on consumer habit and common practice within oral care 
clinical trials.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 12 of 53
Only study subjects with a pre-specified level of gingivitis will be randomized to study product.
The baseline levels of measures of gingivitis and plaque are consistent with previous Haleon
gingivitis studies with mean MGI 1.75-2.30 considered representative of generalised mild-
moderate gingivitis. Furthermore, a minimum of 20 permanent gradable teeth is 
representative of a minimum of a
“shortened dental arch” (Käyser 1989) equating to anywhere between 20-28 gradable teeth
(excluding 3rd molars) per subject.
Sufficient subjects will be screened to assess approximately 180 subjects so that at least 160 
subjects are randomized (approximately 80 per group) to ensure approximately 144 
(approximately 72 per group) evaluable subjects complete the entire study (allowing for 10% 
for drop-outs post-baseline).
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 13 of 53
The clinical efficacy of the experimental toothpaste will be compared with that of a regular 
fluoride toothpaste. A standard fluoride dentifrice has been chosen as the negative control 
dentifrice in this study, as this is likely to reflect a subject’s typical oral care product use.
This study will consist of 3 study visits: Screening (Visit 1), Baseline (Visit 2) and Week 4
(Visit 3). Gingival health will be assessed using MGI and BI; plaque will be assessed by TPI, 
overall and interproximal. 
At Screening visit (Visit 1), subjects will provide their written informed consent to participate 
in the study. Demographics, medical history, prior/current medications will be recorded,
subject’s current oral care product used, and inclusion and exclusion criteria will be checked 
followed by an oral examination consisting of oral soft tissue (OST), oral hard tissue (OHT) 
examination, MGI and BPE assessments (as per inclusion/exclusion criteria) to identify 
subjects likely to meet the qualifying levels of gingivitis at baseline. 
Subjects that show signs of periodontitis as assessed by BPE, with a score of 4 or above in one 
or more sextants will be excluded from the study. In addition, subjects with BPE ≥ 3 will 
undergo a pocket depth assessment, and those with ≥ 5mm pocket depth in a single tooth will 
be excluded.
Within approximately 3-5 weeks (21-35 days) of Screening (Visit 1), eligible subjects will 
return to the site for the Baseline visit (Visit 2), with overnight plaque (subjects will be 
instructed to abstain from oral hygiene for 12 hours [+3 hours; -2 hours] i.e., overnight 
immediately before the visit). At the Baseline visit, concomitant medication and 
inclusion/exclusion criteria will be checked and then subjects will undergo a full OST 
examination, 
, MGI, BI and TPI
assessments.
Subjects will be considered eligible with a minimum of 20 natural teeth, at least 40 evaluable 
surfaces, overall MGI ≥1.75 and ≤ 2.3 and overall TPI ≥ 1.5. Subjects with MGI and TPI score 
outside the study range will be discontinued from the study at this visit. 
After 
all initial clinical assessments, eligible subjects will receive
a standardise snack followed by a full mouth dental prophylaxis to remove sub and supra-
gingival calculus, stain, plaque and debris from the teeth. Post-prophylaxis, the subject’s teeth 
will be re-disclosed, and a second clinician will check all plaque and calculus has been 
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI
CCI
CCI
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 14 of 53
removed. Any residual plaque and/or calculus will be removed to bring the subject to zero 
plaque (TPI = 0) before entering the treatment period.  
Subjects will be then stratified based on gender and baseline mean whole mouth MGI score 
(Low: ≤2.00/High >2.00), to ensure a balance of gingivitis across both treatment groups and 
will be then randomized to study products. Gender is a known modifier of the initiation and 
outcome of conditions related to gingival health (Alam, Mishra et al. 2012). Stratifying by MGI 
will facilitate evaluation of BI and MGI in low and high MGI subgroups.
The MGI and the BI are established clinical measures of gingival inflammation and gingival
bleeding, respectively (i.e. gingival health); the TPI is an established clinical measure of supra-
gingival plaque accumulation. To avoid inter-examiner variability, a single examiner will be 
responsible for the conduct of each of the clinical indices (MGI, BI, TPI).
Randomized subjects will then receive their assigned study product, a toothbrush, rinsing cups 
and instructions on product usage. Subjects will be instructed to brush twice daily (morning 
and evening) with their allocated study product, in their usual manner, for 1-timed minute for 
the next 4 weeks. They will complete the first brushing at the study site, under supervision.
After using the study products for 4 weeks, subjects will return to the study site (Visit 3) with 
overnight plaque (subjects will be instructed to abstain from overnight toothbrushing for 12 
hours [+3 hours; -2 hours] immediately before each assessment visit), at approximately the 
same time of day as the Baseline visit. Changes in health/concomitant medications will be 
recorded and compliance check will be performed by visual inspection of study products by 
study stuff to ensure adequate brushing. Subjects will then have a full OST examination 
followed by a
, MGI, BI and TPI assessments. 
Subjects will be offered a standardised snack and then will be asked to brush their teeth on site,
under supervision, with the assigned toothpaste.
. Subjects will also have a full 
final OST/OHT examination.
At the end of V3 (Week 4), study closeout procedures (return of study product etc.) will take 
place and the subject may undergo an additional prophylaxis if it is deemed necessary by the 
examiner. Adverse events (AEs) will be recorded from informed consent and at the end of each 
study visit.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI
CCI
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 15 of 53
To assess examiner reproducibility across the treatment period, repeat MGI and TPI 
assessments will be performed on selected subjects at Visits 2-3. (Replicate BI examinations 
cannot be performed due to the inherent invasiveness of this measure). At least 3 subjects will 
be selected for repeatability examinations for each of the 2 clinical measures over the duration 
of each of visits 2 and 3. This will give a total of at least 6 subjects with repeatability 
examinations for each of the MGI and TPI assessments across the entire study.  Repeatability 
examinations should be separated by a minimum of 10 minutes and, where possible, separated 
by another subject. MGI and TPI repeat assessments should be performed on different subjects.
All assessments will be carried out on the facial and lingual/palatal surfaces of each incisor, 
canine, pre-molar and molar, excluding third molars. To control inter-examiner variability, the 
same examiner will be used throughout the study for each clinical index.
Subjects will not be able to eat or drink, except for small sips of water used to alleviate thirst 
or to aid with medication, following supervised brushing at V2 and V3
.
4
STUDY POPULATION
4.1
Type and Planned Number of Subjects
Subjects will be male or female, non-smokers, aged 18-70 years (inclusive), with a minimum 
of 20 natural teeth and generalized mild-moderate plaque-induced gingivitis. At Baseline (pre-
prophylaxis), qualifying subjects will have a mean overall MGI ≥ 1.75 to ≤ 2.30 and an overall 
mean TPI ≥1.5.
Sufficient subjects will be screened to assess approximately 180 subjects so that at least 160 
subjects are randomized (approximately 80 per group) to ensure approximately 144 
(approximately 72 per group) evaluable subjects complete the entire study (allowing for 10% 
for drop-outs post-baseline).
An enrolled subject is one who has agreed to participate in the clinical study following 
completion of the informed consent process and has successfully met the eligibility criteria to 
proceed beyond the screening visit, as described in this protocol.
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.  
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 16 of 53
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.
4.2
Inclusion Criteria
An individual must meet all the following inclusion criteria to be eligible to be included into 
the study:
1. 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. Biological sex at birth was male or female.
3. Aged 18 to 70 years inclusive, at the signing of the informed consent.
4. Willing and able to comply with scheduled visits, treatment plan, saliva sample collection,
study restrictions, Lifestyle Considerations and other study procedures.
5. In good general and mental health with, in the opinion of the investigator or medically 
qualified designee, no clinically significant or relevant abnormalities in medical history or 
upon oral examination, or condition, that would impact the subject’s safety, wellbeing or 
the outcome of the study, if they were to participate in the study, or affect the individual’s 
ability to understand and follow study procedures and requirements.
6. Subject oral health that meets all the following:
AT SCREENING (Visit 1) 
7. Subject with at least 20 natural, permanent teeth, (excluding 3rd molars).
8. Subject with at least 40 evaluable surfaces for MGI, BI, and TPI.
An evaluable surface is defined as having 2/3rds of the natural tooth surface gradable for the 
selected clinical indices. The following should not be included in the evaluable surface count-
third molars; fully crowned/extensively restored, grossly carious, orthodontically 
banded/bonded or abutment teeth; surfaces with calculus deposits which, in the opinion of the 
clinical examiner, would interfere with the baseline assessments of the selected clinical indices.
9. A healthy subject with mild to moderate plaque-induced gingivitis in the opinion of the 
clinical examiner
10. Overall MGI ≤1.75 to ≤ 2.30 
AT BASELINE (V2):
11. Overall MGI ≥1.75 to ≤2.30 
12. Overall TPI score ≥ 1.5
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 17 of 53
4.3
Exclusion Criteria
An individual who meets any of the following exclusion criteria will be excluded from the 
study:
1. 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. A subject who has participated in other studies (including non-medicinal studies) involving 
investigational product(s) within 30 days prior to study entry and/or during study 
participation.
3. A subject with, in the opinion of the investigator (or medically qualified designee), an acute 
or chronic medical or psychiatric condition or laboratory abnormality that may increase the 
risk associated with study participation or investigational product administration or may 
interfere with the interpretation of study results and, in the judgment of the investigator or 
medically qualified designee, would make the subject inappropriate for entry into this study.
4. A subject who has any other clinical serious or unstable conditions (e.g., cardiovascular 
diseases, diabetes, liver disorders, and kidney disorders) which could have affected study 
out comes and/or subject safety.
5. A subject who is pregnant (self-reported) or intending to become pregnant over the duration 
of the study.
6. A subject who is breastfeeding.
7. A subject with known or suspected intolerance or hypersensitivity to any study materials 
(or closely related compounds) or any of their stated ingredients. 
8. A subject unwilling or unable to comply with the Lifestyle Considerations described in 
this protocol.
9. A subject who is a current smoker or an ex-smoker (including vaper) who stopped within 
6 months of Screening.
10. A subject who is using smokeless forms of tobacco (e.g., chewing tobacco, gutkha, pan 
containing tobacco, nicotine-based e-cigarettes).
11. A subject who is diagnosed xerostomia or is taking any medication that in the view of the
     investigator is causing xerostomia.
12. A subject who has a medical condition which could have directly influenced gingival 
bleeding.
13. A subject who has a bleeding disorder that could have affected study outcomes and/or 
subject safety.
14. A subject who has a recent history (within the last year) of alcohol or other substance abuse.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 18 of 53
15. A subject who has a severe oral condition (e.g., acute necrotizing ulcerative gingivitis or 
oral or peri-oral ulceration including herpetic lesions) that could, in the opinion of the 
investigator, compromise study outcomes or the oral health of the subject/examiner if they 
participate in the study.
16. Presence of a tongue or lip piercing, or any other oral feature that could interfere with the 
usage of a toothbrush.
17. Medication exclusions:
At screening (Visit 1):
a.
A subject using any antibiotic medication within 28 days prior to screening or at 
any time during the study.
b. Subject who has used an anti-bacterial toothpaste/mouthwash (e.g., chlorhexidine) 
or another oral care product within 2 weeks of Screening that, in the opinion of the 
investigator or dentally qualified designee, could affect gingival health, plaque 
formation or oral bacteria.
c.
A subject currently taking an anti-inflammatory medication which, in the opinion 
of the Investigator, could affect gingival condition.
d. A subject currently taking a systemic medication (e.g., anti-inflammatory, 
anticoagulant, immunosuppressants) or traditional/ herbal remedy which, in the 
opinion of the Investigator, could affect plaque/ gingival condition (e.g., ibuprofen, 
aspirin, warfarin, cyclosporin, phenytoin, calcium channel blockers, statins).
18. Medication exclusions:
At Baseline (Visit 2):
a.
A subject who has taken any antibiotics during the washout period (between 
Screening and Baseline).
b. A subject who has taken (in the previous 14 days) a systemic medication (e.g., anti-
inflammatory, anti-coagulant, immunosuppressants) or traditional/ herbal remedy 
which, in the opinion of the Investigator, could affect plaque/ gingival condition 
(e.g., ibuprofen, aspirin, warfarin, cyclosporin, phenytoin, calcium channel 
blockers).
c.
A subject who has used an antibacterial dentifrice or mouthwash (e.g., 
chlorhexidine) or any oral care product that in the view of the investigator could 
interfere with gingival health, plaque formation and oral bacteria, in the period 
between Screening and the Baseline visit.
19. Periodontal exclusions:
a.
A subject who shows signs of periodontitis (at both Screening (V1) and Baseline 
visits (V2)).
b. A subject with a BPE score of 4 or above in one or more sextants.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 19 of 53
c.
A subject with BPE score ≥ 3, if with probing pocket, a single tooth dept is ≥ 5mm.
d. A subject who is receiving or has received treatment for periodontal disease 
(including surgery) within 12 months of Screening.
e.
A subject who has gingivitis, which in the opinion of the investigator, is not 
expected to respond to treatment with an over the counter (OTC) dentifrice.
20. Dental Exclusions: 
a.
A subject who has active caries that could, in the opinion of the investigator, 
compromise study outcomes or the oral health of the subject if they participate in 
the study.
b. A subject who has dentures (partial or full).
c.
A subject who has an orthodontic appliance (bands, appliances, or fixed/ removable
retainers).
d. A subject who received orthodontic therapy within 3 months of Screening.
e.
A subject who has numerous restorations in a poor state of repair.
f.
A subject who has any dental condition (e.g., overcrowding) that could, in the 
opinion of the investigator, compromise study outcomes or the oral health of the 
subject if they participate in the study.
g. A subject who has had dental prophylaxis within 12 weeks of Screening.
h. A subject who has had teeth bleaching within 12 weeks of Screening.
i.
A subject who has high levels of extrinsic stain or calculus deposits, in the opinion 
of the investigator, that could have interfered with plaque assessments.
21. A subject who has previously been enrolled in this study. 
22. A subject who, in the opinion of the investigator or medically qualified designee, should 
not participate in the study.
4.4
Lifestyle Considerations
If, in the opinion of the investigator or medically qualified designee, a subject has not complied
with a study restriction (e.g., oral hygiene, dietary or alcohol-related) prior to a study visit or
cannot attend a study visit, every effort will be made to reappoint them within the permitted
visit tolerances (see Schedule of Activities, Table 5-1). The reason for re-appointment will be
documented in the electronic case report form (eCRF).
If re-appointment is not possible, the following visit specific actions should be taken:
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 20 of 53
•
Baseline (Visit 2): if the subject cannot be reappointed (within the 3-5 weeks visit 
tolerance), they will be withdrawn from the study. No clinical efficacy assessments will 
be performed. The subject may be replaced.
•
Week 4 (Visit 3): if the subject cannot be reappointed (within the visit tolerance), they 
will be withdrawn from the study. No clinical efficacy assessments will be performed.
The subject will not be replaced.
4.4.1
Dietary, Tobacco and Alcohol restrictions
Before a Clinical Assessment Visit: Baseline (Visit 2) and Week 4 (Visit 3)
•
Subjects must not eat or drink for at least 4 hours before a clinical assessment visit and 
until all clinical assessments are complete during visit day.
Note: Small sips of room-temperature water are permitted, if required, to take medications or to relieve 
a dry mouth up to 1 hour before their appointment time
Note: A standardize snack will be offered after clinical assessments have been completed and before 
brushing on site
•
Subjects will not be permitted to smoke, vape or use tobacco (e.g., chewing tobacco, 
gutkha, pan containing tobacco, nicotine-based e-cigarettes) products during their 
scheduled visits to the study site.
•
Subjects should refrain from alcohol consumption for 24 hours before the clinical 
assessment visits.
4.4.2
Oral Care Restrictions
From Screening (Visit 1) to the Subject’s Last Study Visit (Visit 3):
•
Subjects should not carry out any interproximal dental cleaning. Use of dental floss,
toothpicks, waterpicks or inter-dental brushes is prohibited (except for the removal of
impacted food with non-antimicrobial products only).
•
Subjects should not chew gum or consume confectionery containing xylitol (e.g., sugar-
free mints).
•
Subjects should delay any non-emergency dental treatment until after study completion
(including dental prophylaxis).
From Baseline (Visit 2) to the Subject’s Last Study Visit (Visit 3):
•
Subjects should not use any other oral care products (e.g., toothpastes, toothbrushes,
mouthrinses) than those provided during the study.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 21 of 53
Before Clinical Efficacy Assessment Visits: Baseline (Visit 2) and Week 4 (Visit 3)
•
Subjects should refrain from oral hygiene procedures for 12 hours (+3 hours, -2 hours)
before their visit and attend the study site with overnight plaque growth.
5
STUDY PROCEDURES
This section lists the procedures to be completed at each planned study visit.  Each procedure 
is listed in Table 5-1
Schedule of Activities.
Adherence to the study design requirements, including all procedures are essential and required 
for study conduct.
All information and data collected at each study visit will be documented in the eCRF, unless 
stated otherwise.
5.1
Schedule of Activities
Table 5-1
Schedule of Activities
The schedule of activities table provides an overview of the protocol visits and procedures.  
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the 
well-being of the subject.
Procedure/Assessment
Screening
Visit 1
Visit 2
Baseline
Day 1
Visit 3
Week 4
Day 28 (± 
2)
Informed Consent
X
Lead in period [approximately 3-5 weeks (21-
35 days)
Demographics 
X
Medical History
X
Current/Prior Medication Review 
X
Review subject’s current oral care 
products
X
Oral soft tissue (OST) 
examination
X
X
X
Oral hard tissue (OHT) 
examination
X
X
Inclusion/exclusion criteria 
X
X
Modified Gingival Index (MGI)
X1
X1
X
Basic Periodontal Examination 
(BPE)
X1
BI (Bleeding index)
X
X
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 22 of 53
X
X
Disclose dental plaque
X
X
Turesky Plaque Index (TPI) 
assessment
X
X
Subject eligibility
X
X
Repeat MGI assessment3
X
X
Repeat TPI assessment4
X
X
Compliance Checks
X
X
Concomitant medications and 
treatments
X
X
Subject Continuance
X
Dental prophylaxis
X
2nd clinician check to confirm 
TPI=0 (additional dental cleaning 
will be performed as required)  
X
Randomization
X
Dispense study product,
toothbrush, rinsing cups and oral 
hygiene instructions
X
Supervised brushing with study 
product
X
X
X
X
Subject brings study product, 
toothbrush for brushing on site 
X
Visual inspection of study product 
to check compliance
X
Adverse Events (AEs) Review5
X
X
X
Optional dental prophylaxis at the 
end of Visit 3
X
Study Conclusion/Subject Exit 
from Study
X
Footnotes:
1.
In relation to the general dentition inclusion/ exclusion criteria
2.
Subjects will abstain from overnight toothbrushing for a minimum of 12hrs (+3hr, -2hr) immediately prior to the assessment 
visits (Visits 2-3)
3.
At least 3 subjects at each of visits 2&3 will be selected for repeat MGI assessments.
4.
At least 3 subjects at each of visits 2&3 will be selected for repeat TPI assessments.
5.
Adverse Events (AEs) and therefore all Serious Adverse Events (SAEs) will be collected immediately after a subject provides 
consent to participate in the study by the completion of the Informed Consent Form (ICF).
The site may contact subjects prior to study visits, either as part of pre-screening activities or 
as a reminder of the approaching scheduled visit. Further details included in the ICF. 
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 23 of 53
5.2
Visit 1/Screening
Screening procedures will be conducted by the Investigator (or suitably qualified designee), 
prior to randomization to study product. Where practically feasible, they should be completed 
in the order listed below. 
1) Informed consent
2) Demographics
3) Medical history and prior/concomitant medication/treatment
4) Review of subject’s current oral care product
5) OST examination 
6) OHT examination 
7) Inclusion/exclusion criteria (including MGI and BPE)
8) Subject eligibility
9) Record Adverse Events.
5.2.1
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, potential hazards of the 
study and their rights to refuse to enter the study or to withdraw from it at any time. 
Informed consent must be obtained before any study specific activity is performed. Two copies 
of the informed consent form (ICF) will be signed and dated by the subject, and the subject 
will be provided with one copy and the other will be kept at site.
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. 
5.2.2
Demographics
The following demographic information will be collected: year of birth, sex at birth, race and 
ethnicity.
5.2.3
Review of subject’s current oral care product
Subjects will be encouraged to bring their current oral care products to the study site to enable 
staff to check the ingredient listings for compliance with Exclusion Criterion 19. Ingredient 
listings and on-pack claims will be reviewed to confirm that products do not contain any anti-
bacterial ingredients (e.g. Stannous Fluoride, chlorhexidine, cetyl pyridinium chloride, zinc 
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 24 of 53
salts) or make any antibacterial/ anti-gingivitis claims. Subjects using any oral care product 
that, in the opinion of the investigator, could interfere with plaque formation or measures of 
gingivitis will be excluded.
5.2.4
Medical History and Prior Medication/Treatment
Relevant medical and/or surgical history (in the last 1 year), including allergies or drug 
sensitivity and prior medications/treatments, including prescription and non-prescription drugs, 
dietary supplements and herbal remedies, taken in the last 30 days, that began before obtaining 
informed consent will be recorded as the Medical History/Current Medical Conditions. 
5.2.5
Oral examination/Assessments
The following procedures will be completed, and data recorded in the eCRF. The following
screening procedures should be carried out by a qualified dental professional:
•
OST examination
•
OHT examination 
•
MGI and BPE assessments (as part of the eligibility criteria)
The oral examinations/assessments should be carried out as described in Section 6.
All findings will be recorded in the eCRF.
5.2.6
Inclusion/Exclusion Criteria
Inclusion and exclusion criteria as per Section 4.2 and 4.3.
5.2.7
Subject Eligibility
The investigator and/or medically qualified designee will review inclusion/exclusion criteria, 
medical history and prior medications and oral examinations to confirm subject eligibility to 
participate in the study.
5.2.8
Enrolled Subjects and Screen Failures
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 to proceed beyond the screening visit.
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.
Individuals who do not meet the criteria for participation in this study (screen failure) will not 
be re-screened.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 25 of 53
5.3
Visit 2/Day 1 (Baseline)
1) Review of concomitant medication or non-drug treatments/procedures, adverse events,
and lifestyle restrictions.
2) OST examination 
3)
4) MGI assessment 
5) BI assessment (including number of bleeding sites which is derived from BI assessment)
6) Plaque disclosure 
7) TPI assessment 
8) Inclusion/exclusion criteria
9) Subject eligibility
10) MGI repeatability assessment (where applicable) 
11) TPI repeatability assessment (where applicable) 
12) Subject is offered snack to consume
13) Prophylaxis tooth cleaning followed by confirmation of zero plaque by second clinician
14) RandomizationDispense study product, toothbrush, rinsing cups and oral hygiene
instructions 
15) Supervised brushing at site
16)
17) AE recording (if applicable)
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 any AEs recorded in the 
eCRF.
5.4
Visit 3/Day 28 (week 4)
1) Collection and visual inspection of study products returned by subjects to assess 
compliance
2) Review of concomitant medication or non-drug treatments/procedures, adverse events,
and lifestyle restrictions.
3) Subject continuance confirmation
4) OST examination 
5)
6) MGI assessment 
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 26 of 53
7) BI assessment (including number of bleeding sites which is derived from BI assessment)
8) Plaque disclosure 
9) TPI assessment 
10) MGI repeatability assessment (where applicable) 
11) TPI repeatability assessment (where applicable) 
12) Subject is offered snack to consume
13) Supervised brushing at site
14)
15) Optional dental prophylaxis (if deemed necessary by examiner)
16) AE recording (if applicable)
17) Study conclusion
Changes in concomitant medication or non-drug treatments/procedures will be documented in 
the eCRF.
Spontaneous reporting of adverse events and those elicited by asking subjects to respond to a 
non-leading question such as “How do you feel?” will be assessed and any AEs recorded in the 
eCRF.
6
STUDY ASSESSMENTS
Every effort should be made to ensure that protocol required tests and procedures are completed 
as described.  However, it is anticipated that from time to time there may be circumstances, 
outside the control of the investigator that may make it unfeasible to complete an assessment.  
In these cases, the investigator must take all steps necessary to ensure the safety and 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 he or she has taken to ensure that required processes 
are adhered to as soon as possible.  The Sponsor must be informed of any missed assessments 
in a timely manner.
6.1
Screening Assessments
Screening assessments will be performed by appropriately trained staff/clinical examiners at 
the times, and in the order, defined in the STUDY PROCEDURES section of this protocol.
A single examiner will be responsible for the conduct of the clinical measures of gingivitis/ 
plaque accumulation 
for the duration of the study.
Eligible tooth assessments will be accomplished by oral examination and will evaluate 
dentition exclusions along with a gross gingival assessment in relation to the general dentition 
inclusion/exclusion criteria.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 27 of 53
Assessments will be carried out by the investigator, or qualified designee, against the inclusion/
exclusion criteria. Ineligible subjects will not be re-screened.
Findings from these examinations will be used to determine subject eligibility.
6.2
Efficacy Assessments
The following efficacy 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.
6.2.1
Sampling and Laboratory Procedures
All sampling and laboratory procedures will be provided in separate work instruction 
documents. They will be prepared by PI or designee and reviewed by Haleon, and they will be
approved by PI or designee and CRS or designee and stored in eDMS prior to Screening Visit.
The work instruction documents will cover, but not limited, the following elements:
•
•
•
Sample destruction at the clinical site
6.2.2
Modified Gingival Index (MGI)
The MGI is a non-invasive visual assessment of gingival inflammation (Lobene 1986).
MGI will be assessed for all evaluable surfaces of the facial and lingual/palatal gingiva, four 
sites per tooth (facial gingiva: papilla and margin; lingual/palatal gingiva: papilla and margin) 
and scored as follows.
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.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 28 of 53
6.2.3
Bleeding Index (BI)
The BI is an invasive assessment of gingival bleeding (Saxton and Van der Ouderaa 1989).
BI will be assessed for all evaluable surfaces of the facial and lingual/palatal gingiva, six sites 
per tooth (mesiobuccal, buccal and distobuccal; mesiolingual/palatal, lingual/palatal and 
distolingual/palatal) and scored as follows.
Score
Description
0
Absence of bleeding on probing
1
Bleeding observed within 30 seconds of probing
2
Bleeding observed immediately on probing
Sites with a score of 1 or 2 will be classified as ‘bleeding’ sites.
To perform the bleeding assessment, a round-end probe (e.g., CPITN* probe) is inserted
approximately 1 millimetre (mm) into the gingival sulcus (at approximately 60 degrees) and
moved around the tooth from the distal interproximal area to the mesial interproximal area,
gently stretching the gingival epithelium. Contact with the tooth surface should be avoided.
Presence/absence of gingival bleeding is assessed for 30 secs after probing.
Assessments should be performed one quadrant at a time, with BI scores recorded for the most
recently probed quadrant before moving on to the next.
*CPITN = Community Periodontal Index of Treatment Needs
6.2.4
Basic Periodontal Examination (BPE)
The BPE is a simple, rapid and routinely used screening tool for periodontitis. The mouth is 
divided into sextants and the highest BPE score per sextant is recorded (on all teeth in that 
sextant, excluding wisdom teeth).
To perform BPE assessment, a BPE probe is used. This has a ‘ball end’ 0.5mm in diameter and 
a black band from 3.5mm to 5.5mm. Light probing force should be used (20-25 grams). The 
probe should be ‘walked around’ the teeth in each sextant. All sites should be examined to 
ensure that the highest score in the sextant is recorded before moving on to the next sextant.
The BPE scores are: 
0
Probing depth <3.5mm, no bleeding on probing and no plaque retentive factors
1
Probing depth <3.5mm, bleeding on probing and no plaque retentive factors
2
Probing depth <3.5mm, and presence of plaque retentive factors
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 29 of 53
3
Probing depth ≥3.5mm but <5.5 mm
4
Probing depth ≥5.5mm
*
Presence of furcation involvement (can be added to any BPE score)
Both the number and the * should be recorded if a furcation is detected - e.g. the score for a 
sextant could be 3* (e.g. indicating probing depth 3.5-5.5 mm PLUS furcation involvement in 
the sextant).
6.2.5
Plaque Disclosure Procedure
Dental plaque forms as a colourless deposit on the teeth and so requires ‘staining’ with 
disclosing solution prior to TPI assessment. The disclosing solution supplied by the sponsor 
will be used according to the manufacturer’s instructions.
At the request of the subject, to minimize staining of the lips, the clinical assessor may apply a 
thin layer of petroleum jelly to the subject’s lips as a barrier, prior to applying the disclosing 
solution.
Care should be taken to ensure no petroleum jelly comes into contact with the labial surfaces 
of the anterior teeth as this could impact TPI assessment for these surfaces.
Subject rinses with 10 mL tap water for 10 seconds and expectorates to remove any food debris 
from the mouth.
Disclosing solution will be dispensed into a dispensing cup (~2.5 ml) and subject rinses for 10 
seconds to distribute this solution around their mouth. Care should be taken not to dislodge the 
plaque during this process.
Subject rinses with another 10 mL tap water for 10 seconds and expectorates to remove excess 
solution from the mouth.
6.2.6
Turesky Modification of the Quigley Hein Index (TPI)
The TPI is a non-invasive assessment of supra-gingival plaque accumulation (Turesky 1970, 
Lobene 1986). TPI will be assessed for all evaluable surfaces of the facial and lingual surfaces 
of the teeth (7-7 in each arch). Each tooth surface is divided into 3 areas; three scores are 
recorded facially (mesiofacial, facial, distofacial) and three scores lingually (mesiolingual, 
lingual and distolingual), generating six scores per tooth.
The plaque is first disclosed, as described in Section 6.2.5, then each evaluable site is scored 
as follows:
Score
Description
0
No plaque
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 30 of 53
1
Slight flecks of plaque at the cervical margin of the tooth
2
Thin, continuous band of plaque (1millimetre (mm) or smaller) at the 
cervical margin of the tooth
3
Band of plaque wider than 1mm but covering less than 1/3 of the area
4
Plaque covering at least 1/3 but less than 2/3 of the area
5
Plaque covering 2/3 or more of the crown of the tooth
6.2.7
Repeatability Assessments
Repeat MGI and TPI assessments will be performed by the clinical examiners at Visits 2 and 
3. At least 3 subjects will be selected for repeat assessments over the duration of each of visit 
2 and 3.  Thus a total of at least 6 subjects repeat assessments for each endpoint will be collected 
during this study. ‘Repeat’ subjects will be selected at random from those in attendance on any 
given assessment day. Different subjects should be used for repeat MGI and TPI assessments.
There should be a delay of at least 10 minutes between the original and the repeat assessment 
for a given subject; ideally, repeat assessments should be separated by another subject. No 
other clinical procedure should be carried out on the selected subject between repeat 
assessments. 
Scores from the first assessment must not be visible to the examiner/scribe when the repeat 
assessment is carried out.
6.3
Safety and Other Assessments
The following safety assessments will be performed by appropriately trained staff/clinical 
examiners, at the times and in the order defined in the STUDY PROCEDURES section of this 
protocol.  
6.3.1
Oral Soft Tissue (OST) Examination
The OST examination will be accomplished by direct observation and palpation, using
retraction aids as appropriate. It will include examination of the labial mucosa (including lips),
buccal mucosa, mucogingival folds, gingival mucosa, hard palate, soft palate, tonsillar area,
pharyngeal area, tongue, sublingual area, submandibular area and salivary glands. The results
of the examination will be recorded in the eCRF as either ‘normal’ or ‘abnormal’; the details 
of any abnormalities will be described in the eCRF.
Any OST observation that changes from ‘normal’ to ‘abnormal’, or worsens, from Screening
will be recorded as an AE in the eCRF.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 31 of 53
6.3.2
Oral Hard Tissue (OHT) Examination
The OHT examination will be accomplished by direct observation, using retraction aids as 
appropriate. It will identify enamel irregularities, tooth fractures, grossly carious lesions/gross 
decay, defective/faulty restorations, direct & indirect restorations including fixed/removal 
prostheses, non-carious tooth surface loss (abrasion, attrition, abfraction and erosion), any other
hard tissue irregularities (e.g., hypo/hypermineralisation, decalcification) and significant tooth 
staining. Conditions will be listed as ‘absent’ or ‘present’; those noted as ‘present’ will be 
described in the eCRF. Any OHT observation that changes from ‘absent’ to ‘present’, or 
worsens, from Screening will be recorded as an AE in the eCRF.
The presence of implants, fixed or removable dentures, fixed or removable orthodontic 
braces/bands, fixed orthodontic retainers, full crowns or veneers will be recorded, along with 
evidence of gross intra-oral neglect or the need for extensive dental therapy.
6.3.3
Pregnancy Testing
For Haleon studies in which no drug is utilized or studies of single-use marketed products that 
are classified as a non-medicinal product in the market where the testing is occurring and there 
is no pregnancy warning on labelling, a pregnancy test will not be required.
Female subjects will provide verbal confirmation of pregnancy status at Screening (Visit 1) 
and will be asked to inform study staff immediately should this change at any point during the 
study. Female subjects who are pregnant or intending to become pregnant during the study 
(self-reported) will be excluded.
6.4
Banked Bio specimens
Aliquots of saliva samples collected during the study will be stored at the study site Biobank 
for future additional analysis (i.e microbiome analysis). Unless prohibited by local regulations 
or ethics committee decision, subjects will be asked to indicate on the consent form whether 
they will allow the banked biospecimens to also be used for the specified research.
7
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 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. 
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 32 of 53
7.1
Investigational/Study Product Supplies
The following study products will be supplied by the Clinical Supplies Department, Haleon:
Table 7-1
Investigational/Study Product Supplies
Test Product
Reference Product 
(Negative Control) 
Product Name
Experimental toothpaste 
containing 0.454% Stannous 
Fluoride, 0.3% Zinc 
Chloride,1% Alumina
Colgate Cavity Protection (UK 
Marketplace)
Pack Design
Carton of 2 over-wrapped tubes
Dispensing Details
One carton – baseline visit
Product Master 
Formulation Code (MFC)
Commercial Product
Fluoride concentration
1100ppm
1450ppm 
Dose/Application
Full ribbon of toothpaste on head of toothbrush provided
Route of Administration
Oral
Usage Instructions
Subjects will brush their teeth for one timed minute twice a 
day (morning and evening)
Rinsing is not a study requirement. Subjects who wish to rinse 
after brushing will be provided with a measuring cup to rinse 
once with 10mL water.
Return Requirements
All used/unused samples to be returned
Table 7-2
Sundry Items
Item
Supplied 
By
Pack 
Design
Dispensing 
Details
Return/Disposal Details
Used 
Samples
Unused 
Samples
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 33 of 53
Aquafresh® Clean 
Control toothbrush
(medium)
Haleon
Individual 
commercial 
pack 
One at baseline 
for use with 
test/reference 
product
Destroy at site 
using site 
disposal 
procedures-
following 
approval from 
Haleon 
Clinical 
Supplies
Return
Opaque Carrier bag
Haleon
Individual 
bags
One at Baseline 
visit
Subject to 
keep or 
destroyed at 
site using site 
disposal 
procedures 
following 
approval from 
Haleon 
Clinical 
Supplies
Return
7.2
Product Supplies, Product Storage, Accountability, Returns and
Destruction
All study products supplied are for use only in this clinical study and should not be used for 
any other purpose. 
Guidance will be provided to the Investigator and site staff for the receipt, storage and 
management of products for the duration of the trial by Haleon Clinical Supplies during the 
Site Initiation Visit and with further instructions included with the shipping documentation.
The site should ensure that the room or area set aside for storage is able to maintain the correct 
temperature to meet the product label storage conditions, is sufficient to store all products and 
is secure and access controlled.
Any temperature excursions or discrepancies during transit or whilst study products are stored 
at site require the affected products to be quarantined and this must be communicated 
immediately to the Sponsor who will provide documentation to approve further usage.
Use of any of the affected product(s) prior to sponsor approval will be considered a protocol 
deviation.
Study products are to be dispensed only to subjects enrolled in the study in accordance with 
the protocol, by authorised site staff. Subjects will be informed on product usage, storage, 
return and what to do in the event of product loss when they are first dispensed after enrolment.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 34 of 53
All study products will be accounted for using the investigational/study product accountability 
form/record. The Investigator is responsible for study product accountability, reconciliation, 
and record maintenance.  
Detailed instructions for the return of study product/study supplies will be provided by Haleon 
during the study in time for study close out. Investigational products can only be destroyed at 
site in agreement with and after approval from the Sponsor.
7.3
Blinding and Allocation/Randomization
Subjects will be randomized into the study provided they have satisfied all subject selection 
criteria.
All subjects will be centrally randomized using an Interactive Response Technology (IRT). 
Returned study products should not be re-dispensed to any subject.
The investigator’s knowledge of the product allocation should not influence the decision to 
enroll a subject or affect the order in which subjects are enrolled.
This study is described as examiner-blind (the examiner will be blinded to the product received). 
To ensure the examiner remains blinded throughout the study, staff involved in the preparation 
and dispensing of study products will work in a separate area. 
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.  
Qualifying subjects will be stratified by their gender and Baseline Mean MGI resulting in the 
following stratum:
•
Male, baseline Mean MGI ≤2.00 (low)
•
Male, baseline Mean MGI >2.00 (high)
•
Female, baseline Mean MGI ≤2.00 (low)
•
Female, baseline Mean MGI >2.00 (high)
This study is described as examiner-blind (the clinical examiner(s) will be blinded to treatment
received). However, study subjects, investigator site staff involved in safety or efficacy
assessments, study statistician(s), data management staff, other employees of the Sponsor
(including the clinical research scientist (CRS)) and vendors acting on behalf of the sponsor 
who may influence study outcomes will also be blinded to treatment allocation. 
7.4
Breaking the Blind
In case of an emergency, the investigator or designee has the sole responsibility for determining 
if unblinding of a subject’s product assignment is warranted. Subject safety must always be the 
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 35 of 53
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.
8
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
8.1
Sample Size Determination
Sufficient subjects will be screened to assess approximately 180 subjects so that at least 160 
subjects are randomized (approximately 80 per group) to ensure approximately 144 
(approximately 72 per group) evaluable subjects complete the entire study (allowing for 10% 
for drop-outs post-baseline).
The study will be sufficiently powered to demonstrate statistically significant differences 
between Test Product compared to the Reference Product (negative control) for mean BI at 
Week 4 (primary objective). A sample size of 72 evaluable subjects per treatment group will 
provide at least 90% power to detect a mean difference of 0.07 units (SD = 0.128) in mean BI
score after 4 weeks of treatment, using a 2-tailed 2-sample t-test with a 5% significance level. 
The sample size calculation was performed using PASS software version 23.0.1.
The assumed treatment efficacy estimates come from a review of sponsor clinical studies 
(
 and 212537, sponsor data held on file and available on request) where the mean 
difference (SD) between the test and reference product reported a mean difference in BI of 0.07 
between groups with standard deviation ranging from 0.04 to 0.128 at 12 weeks. The higher 
SD of 0.128 was used to calculate the sample size for this study.
8.2
Populations for Analysis
8.2.1
Definitions of Analysis Populations
The Safety population will comprise all randomized subjects who receive at least one dose of
investigational product. Summaries and analyses of this population will be based on the
investigational product the subject received.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 36 of 53
The primary population for the assessment of efficacy will be a modified intention-to-treat
(mITT) population. The mITT population will comprise all randomized subjects who receive
at least one dose of investigational product and complete at least one-post Baseline BI 
assessment. This population will be based on the investigational product the subject was
randomized to. All subjects who receive a randomization number will be considered 
randomized.
The Per-Protocol (PP) population will comprise all subjects in the mITT population who have 
at least one non-missing BI assessment considered to be unaffected by protocol deviations.
The repeatability population for MGI is defined as all subjects who have at least one repeat
MGI clinical assessment at any visit.
The repeatability population for TPI is defined as all subjects who have at least one repeat TPI 
clinical assessment at any visit.
8.2.2
Exclusions of Data from Analysis
Exclusion of any data from the analyses will be agreed during a Blinded Data Review (BDR) 
Meeting prior to database lock. Any reasons for exclusion of a subject from an analysis 
population or data from an analysis will be listed, if applicable.
A PP analysis will be performed for the primary endpoint if ≥10% subjects in the mITT
population are excluded from the PP population. Efficacy data determined to have been
potentially impacted by a protocol deviation will be excluded from the PP analysis. The
decisions as to whether or not a protocol deviation impacts efficacy data and whether to
perform a PP analysis will be made during BDR, prior to database lock.
8.3
Statistical Analyses
This is a summary of the planned statistical analyses; the detail of the proposed statistical
analyses will be documented in the Statistical Analysis Plan (SAP), to be written following
finalization of the protocol and prior to study unblinding.
The mITT population will be used for all efficacy analyses.
All p-values presented will be two-sided and assessed at the 5% significance level. No 
adjustments will be made for multiple comparisons in this study. 
Summary statistics (mean, median, SE, SD, minimum, maximum) will be presented for the 
primary and secondary endpoints at each assessment time point for both the observed value 
and change from baseline.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 37 of 53
Raw means (± SE) of primary and secondary endpoints will be plotted by treatment group at 
each assessment timepoint.
8.3.1
Primary Endpoint Analysis(es) 
The primary endpoint of this study Mean BI at Week 4; the primary hypothesis test will be the 
comparison between the Test product and the Reference product (negative control) in the mITT 
population as follows:
Mean BI will be calculated by taking the average over all tooth sites assessed for a subject.
Mean BI at Week 4 will be analysed using an ANCOVA Model with treatment group as fixed 
effects and Baseline Mean BI and Baseline Mean MGI as a covariate. Gender will also be 
included as stratification factor. The MGI stratificationfactor is not included in the model as 
the actual value is included as a covariate. The adjusted mean treatment difference will be
presented, along with the two-sided p-value and 95% CIs. The observed margin (OM) option 
in SAS will be used when estimating least square means.
The assumptions of normality and homogeneity of variance in the model will be investigated.
In case of violation of these assumptions, a data transformation, or a suitable non-parametric 
test (adjusted for the randomization stratification) will be performed; the results will be 
provided to support the ANCOVA results.
8.3.2
Secondary Endpoint Analysis(es)
The secondary endpoints will be analysed using the same ANCOVA model described above 
for the primary endpoint, but with Baseline Mean BI replaced with the Baseline of the 
respective endpoint (Baseline Mean overall TPI for Mean overall TPI at Week 4; Baseline
Mean interproximal TPI for Mean interproximal TPI at Week 4; Baseline NBS for NBS at 
Week 4. For Mean MGI at Week 4, no additional term will be added as Baseline Mean MGI is 
already included in the model as a covariate).
8.3.3
Safety Analysis(es)
Safety analyses will be performed on the Safety population, according to investigational
product received. AEs will be regarded as ‘treatment emergent’ if they occur on or after the 
first use of investigational product at Baseline. In the event of a missing start date, an AE will 
be assumed to be ‘treatment emergent’ unless the end date is prior to starting treatment. In case 
of misallocation, compared to the randomization schedule, TEAEs will be associated with the
most recent study investigational received.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 38 of 53
Each AE will be categorized as oral or non-oral by the investigator or medically qualified
designee. All will be reviewed by the CRS and coded using the MedDRA prior to database 
lock and unblinding.
A listing of all AEs will be presented for all subjects in the Safety population with the following
AE summaries (number of distinct AEs and frequency/proportion of subjects affected)
presented by treatment group and overall:
• TEAEs
• TEAEs by System Organ Class (SOC) and Preferred Term (PT)
• TEAEs by Oral/Non-Oral and PT
• Treatment emergent treatment related AEs by Oral/Non-Oral and PT
• Treatment emergent treatment related serious AEs by SOC and PT
Separate listings will be presented for:
• Deaths, SAEs and any AEs leading to product or study discontinuation.
• OST findings (with a summary of abnormalities by visit)
8.3.4
Other Analysis(es)
Exploratory Analysis
•
Day 1 post-brushing compared to Day 1 pre-brushing
•
Week 4 post-brushing compared to Week 4 pre-brushing
•
Week 4 pre-brushing compared to Day 1 pre-brushing
•
Week 4 post-brushing compared to Day 1 pre-brushing
Note: post-brushing is 3 hours post-brushing on site
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 39 of 53
Between treatment difference will be analysed using a Mixed Model with Repeated Measures 
(MMRM) with investigational product, visit and [investigational product x visit] as fixed 
effects and Baseline 
as a covariate. Gender and Baseline MGI will also be 
included as stratification covariates. Subject will be included as a repeated measure with 
unstructured covariance matrix. Kenward Rogers degrees of freedom approach will be applied 
(Kenward and Roger 1997). The difference between the least square mean changes from 
Baseline for the Test Product compared to Reference Product (negative control) at Week 4 
from the MMRM will be presented, along with the two-sided p-value and 95% CIs.
The assumptions of normality and homogeneity of variance in the MMRM will be investigated. 
Similarly, the assumptions for the paired t-test will be investigated. In case of violation of these 
assumptions, a suitable non-parametric test will be performed to support the results.
Repeatability of Examiner
The repeatability of the examiner in conducting the MGI and TPI assessments will also be
performed for at least 3 subjects (for each index) over the duration of each of visit 2 and 3. The 
repeat assessments will be compared to the original assessments. The repeat assessments will 
not to be used in any efficacy analysis.
The first and second assessments of each index will be analyzed with a Fleiss-Cohen weighted 
kappa coefficient (κ), along with the 95% CI, to assess the intra-examiner reliability. Reliability 
will be deemed: Excellent if κ > 0.75, Fair to good if 0.4 ≤ κ ≤ 0.75 and Poor if κ<0.4. 
This analysis will be conducted on each respective index repeatability population (MGI 
population and TPI population).
8.3.5
Demographic and Baseline Characteristics
Demographic and Baseline characteristics will be summarized by treatment group for the 
Safety and mITT populations (and for the PP population, if a PP analysis is performed) using
descriptive statistics.
Categorical variables (such as sex, race, ethnicity and Baseline Mean MGI stratification value) 
will be summarized by the number and percentage of subjects with each relevant characteristic 
in each treatment group. Continuous variables such as (age) will be summarized by mean, SD, 
median, minimum and maximum values in each treatment group.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 40 of 53
8.3.6
Use of Other Therapies
8.3.6.1
Prior and Concomitant Medications
Prior medications/non-drug therapies and concomitant medications/significant non-drug
therapies taken during the study will be listed for the Safety population.
8.3.7
Handling of Dropouts and Missing Data 
Primary and Secondary Analysis:
Subjects who withdraw from the study early will be included in the statistical analysis up to 
the point of when they withdraw. There will be no imputation for missing data (i.e. analyses 
will be conducted on an observed case basis).
Exploratory Analysis:
9
APPENDICES
9.1
Adverse Event (AE) and Serious AE (SAE)
The investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an adverse event (AE) or serious AE (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.
All AEs will be reported on the AE page of the eCRF by the investigator or site staff from the 
completion (signature) of the ICF and until 5 days following last administration of the study 
product (or last procedure).  
In addition to that, a SAE form should be completed (if required). 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.
The SAE form, completed as fully as possible, must be scanned and e-mailed to the Case 
Management Group mailbox (see Table 9-1), with a copy to the appropriate Haleon 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 
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 41 of 53
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. 
Table 9-1
Case Management Group mailbox
EMEA: Europe, Middle East, Commonwealth of 
Independent State (CIS), Africa
9.2
Definition of an 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).
9.3
Definition of a SAE
A 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
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Results in congenital anomaly/birth defect
•
Other serious (important) medical events
Note: Classification of an AE as ‘serious’ is based on the outcome of the event and is a factor 
in determining reporting requirements.
9.4
Pregnancy
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.
The investigator will record pregnancy information on the appropriate form scan and e-mail it 
to the Case Management Group mailbox (see Table 9-1), with copy to the appropriate Study 
Manager, within 24 hours. Original pregnancy information forms will be retained in the 
investigator study master file. 
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI
PPD

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 42 of 53
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 (see Table 9-1), 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 female subject who becomes pregnant while participating 
will be withdrawn.
9.5
Evaluating Adverse Events 
9.5.1
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.
9.5.2
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 eCRF 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.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 43 of 53
The investigator will use clinical judgment to determine the relationship and will also consult 
the Safety Statement, in the determination of his/her assessment.  Alternative causes, such as 
underlying disease(s), concomitant therapy, other risk factors, and the temporal relationship of 
the event to the study product will be considered and investigated.
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in the eCRF, 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. 
9.6
Follow-up of AEs and SAEs 
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 SAE or 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 eCRF 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.
The investigator will submit any updated SAE data to Haleon within 24 hours.
9.7
DISCONTINUATION OF STUDY PRODUCT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL
If a subject is discontinued early from the study product (Section 9.7.1) or discontinued or 
prematurely withdraws from the study (Section 9.7.2), the reason(s) for intervention 
discontinuation or withdrawal and the associated date must be documented in the relevant 
section(s) of the eCRF. If a subject is discontinued early from the study product, the subject 
should stay in the study and complete the remaining assessments unless they need to be 
withdrawn (see Section 9.7.2).
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 44 of 53
9.7.1
Discontinuation of Study Product 
A subject may be discontinued from the study product at any time whilst still in the study at 
the discretion of the investigator related to safety, subject consent or a potential worsening of 
the risk / benefit assessment from the subject of remaining on the intervention for the following 
reasons:
•
Adverse Event
•
Lack of efficacy from the intervention
•
Subject request
•
Subject to be withdrawn from the study (see Section 9.7.2)
9.7.2
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 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.
9.7.3
Lost to Follow up
If a subject fails to return to the site for a required study visit, the investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone calls or emails 
or local equivalent methods) 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.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 45 of 53
A subject will be considered lost to follow up and withdrawn from the study if he or she 
repeatedly fails to return for scheduled visits and is unable to be contacted by the study site. 
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).
9.8
Data Management
As used in this protocol, the term CRF is understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method. 
For this study, subject data will be entered into an electronic CRF (eCRF), using a validated 
system. Data relating to SAEs, pregnancy and incidents will also be collected on paper forms.
The source documents which contain the source of data recorded in the CRF should be 
specified.  The CRF can be used as a source document at the discretion of data management.
Each subject will be assigned and identified by a unique Screening Subject Number. Any 
reference made to an individual subject within the study must be done using their unique 
Screening Subject Number.
9.8.1
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 Biostatistics 
and Data Management (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.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 46 of 53
9.8.2
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 dictionary).  
9.8.3
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 third-party BDM vendor 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.
9.9
Regulatory and Ethical Considerations
9.9.1
Institutional Review Board/ Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent document, investigator brochure/safety statement 
(including any updates) and other relevant documents, e.g. recruitment advertisements, if 
applicable, from the IRB/EC.  All correspondence with the IRB/EC should be retained in the 
investigator file.  Copies of IRB/EC approvals should be forwarded to 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 
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 47 of 53
event, the investigator must notify the IRB/EC and Haleon in writing immediately after the 
implementation.
9.9.2
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 (Council for International Organizations of Medical Sciences, 2016), 
guidelines for GCP (ICH 1996 and revision 2), and the Declaration of Helsinki (World Medical 
Association 2013). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP and applicable local regulatory requirements and laws.
9.9.3
Subject Information 
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by laws. 
When study data are compiled for transfer to 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.
9.10
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.  
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 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.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 48 of 53
9.11
Disclosure and Publication Policy
Study information from this protocol may be posted on publicly available clinical trial registers 
before enrollment of subjects begins in accordance with applicable Haleon policies.
Haleon intends to make anonymized subject-level data from this study available to external 
researchers for scientific analyses or to conduct further research that can help advance medical 
science. This helps ensure the data provided by study participants are used to maximum effect 
in the creation of knowledge and understanding.
The procedures and timing for public disclosure of the results summary and for development 
of a manuscript for publication will be in accordance with sponsor policy and as per the country 
specific requirements for disclosure.
10
ABBREVIATIONS
The following is a list of abbreviations that may be used in the protocol.
Table 10-1
Abbreviations
Abbreviation
Term
AE
Adverse Event 
ACNOVA
Analysis Of Covariance
BPE
Basic Periodontal Examination
BDM 
Biostatistics and Data Management
BDR
Blinded Data Review
BI
Bleeding Index
CFU
Colony Forming Unit
CRF
Case Report Form
CRS
Clinical Research Scientist
DMS
Data Management System
EC
Ethics Committee
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent To Treat
MedDRA
medical Dictionary for Regulatory Activities
MFC
Manufacturing Formulation Code
MGI
Modified Gingival Index
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 49 of 53
Abbreviation
Term
mITT
Modified Intent-To-Treat
mm
Millimetre
MMRM
Mixed Model with Repeated Measures
N/A
Not Applicable
NBS
Number of Bleeding Sites
OH
Oral Health
OHT
Oral Hard Tissue
OST
Oral Soft Tissue
PI
Principal Investigator
PI
Personal Information
PP
Per Protocol
SAE
Serious Adverse Event
SD SE
Standard Deviation
SE
Standard Error
SnF2
Stannous Fluoride
SS
Safety Statement
TEAE
Treatment Emergent Adverse Event
TPI
Turesky Modification of The Quigley Hein Plaque Index
VSCs
Volatile Sulphur Compounds
w/w
Weight For Weight
ZnCl2
Zinc Chloride
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 50 of 53
11
REFERENCES
Acherkouk, A., et al. (2021). "A randomised clinical study investigating efficacy of a stannous 
fluoride toothpaste in improving gingival health after 3 weeks’ use." BMC Oral Health 21: 1-
8.
Alam, M. N., et al. (2012). "Gender basis of periodontal diseases." Indian J Basic Appl Med 
Res 2(1): 128-135.
Albandar, J. M. (2002). "Periodontal diseases in North America." Periodontology 2000 29(1).
Archila, L., et al. (2004). "The comparative efficacy of stabilized stannous fluoride/sodium 
hexametaphosphate dentifrice and sodium fluoride/triclosan/copolymer dentifrice for the 
control of gingivitis: A 6‐month randomized clinical study." Journal of periodontology 75(12): 
1592-1599.
Bellamy, P., et al. (2012). "Randomized digital plaque imaging trial evaluating plaque 
inhibition efficacy of a novel stabilized stannous fluoride dentifrice compared with an amine 
fluoride/stannous fluoride dentifrice." Journal of Clinical Dentistry 23(3): 71.
Brook, I. (2003). "Microbiology and management of periodontal infections." General dentistry
51(5): 424-428.
Chapple, I. L., et al. (2018). "Periodontal health and gingival diseases and conditions on an 
intact and a reduced periodontium: Consensus report of workgroup 1 of the 2017 World 
Workshop on the Classification of Periodontal and Peri‐Implant Diseases and Conditions." 
Journal of periodontology 89: S74-S84.
Chapple, I. L., et al. (2015). "Primary prevention of periodontitis: managing gingivitis." Journal 
of Clinical Periodontology 42: S71-S76.
Cummins, D. and J. Creeth (1992). "Delivery of antiplaque agents from dentifrices, gels, and 
mouthwashes." Journal of dental research 71(7): 1439-1449.
Figuero, E., et al. (2010). "Gingival changes during pregnancy: I. Influence of hormonal 
variations on clinical and immunological parameters." Journal of Clinical Periodontology 37(3): 
220-229.
Guideline, I. H. T. (2001). "Guideline for good clinical practice." J Postgrad Med 47(3): 199-
203.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 51 of 53
He, T., et al. (2012). "Anti-gingivitis effects of a novel 0.454% stabilized stannous fluoride 
dentifrice relative to a positive control." American Journal of Dentistry 25(3): 136.
Health, U. D. o., et al. (2014). Guidance for industry. Gingivitis: Development and evaluation 
of drugs for treatment or prevention.
Käyser, A. F. (1989). "The Shortened Dental Arch: A Therapeutic Concept in Reduced 
Dentitions and Certain High-Risk Groups." International Journal of Periodontics & Restorative 
Dentistry 9(6).
Kenward, M. G. and J. H. Roger (1997). "Small sample inference for fixed effects from 
restricted maximum likelihood." Biometrics: 983-997.
Kinane, D., et al. (2005). "Advances in the pathogenesis of periodontitiss." Journal of Clinical 
Periodontology 32.
Kinane, D. F. (2001). "Periodontal disease in children and adolescents: introduction and 
classification." Periodontology 2000 26(1).
Lie, M., et al. (1998). "Oral microbiota in smokers and non ‐ smokers in natural and 
experimentally‐induced gingivitis." Journal of Clinical Periodontology 25(8): 677-686.
Lobene, R. (1986). "A modified gingival index for use in clinical trials." Clin. Prevent. Dent.
8: 3-6.
Machuca, G., et al. (2000). "Effect of cigarette smoking on periodontal status of healthy young 
adults." Journal of periodontology 71(1): 73-78.
Makin, S. A. (2013). "Stannous fluoride dentifrices." American Journal of Dentistry 26: 3A-
9A.
Mallatt, M., et al. (2007). "A controlled 6‐month clinical trial to study the effects of a stannous 
fluoride dentifrice on gingivitis." Journal of Clinical Periodontology 34(9): 762-767.
Mankodi, S., et al. (2005). "Anti ‐ gingivitis efficacy of a stabilized 0.454% stannous 
fluoride/sodium hexametaphosphate dentifrice: a controlled 6‐month clinical trial." Journal 
of Clinical Periodontology 32(1): 75-80.
Mankodi, S., et al. (1997). "Clinical efficacy of an optimized stannous fluoride dentifrice, Part 
2: A 6-month plaque/gingivitis clinical study, northeast USA." Compendium of Continuing 
Education in Dentistry (Jamesburg, NJ: 1995) 18: 10-15.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 52 of 53
Milleman, K. R., et al. (2016). "A Randomized Clinical Study to Evaluate the Effect of Two 
Experimental Toothpastes on Tooth Enamel Gloss and Smoothness." The Journal of clinical 
dentistry 27(1): 7-12.
Miller, S., et al. (1994). "Recent advances in stannous fluoride technology: antibacterial 
efficacy and mechanism of action towards hypersensitivity." International dental journal 44(1 
Suppl 1): 83-98.
Murphy, N. C. (2010). "Understanding Periodontal Disease and Gum Infections While They 
Can Still be Treated Early & Easily with an Excellent Prognosis©."
Obeid, P. and P. Bercy (2000). "Effects of smoking on periodontal health: a review." Advances 
in therapy 17: 230-237.
Ower, P. (2003). "The Role of Self-Administered Plaque Control in the Management of 
Periodontal Diseases: 1. A Review of the Evidence." Dental update 30(2): 60-68.
Parkinson, C., et al. (2018). "A 24-week randomized clinical study investigating the anti-
gingivitis efficacy of a 0.454% w%# 47; w stannous fluoride dentifrice." American Journal of 
Dentistry 31(1): 17-23.
Parkinson, C., et al. (2014). Clinical Study Investigating the Gingivitis Efficacy of an 
Experimental Toothpaste.
Parkinson, C. R., et al. (2018). "A 12-week randomized clinical study investigating the anti-
gingivitis efficacy of a 0.454% w/w stannous fluoride dentifrice." American Journal of 
Dentistry 31(2): 81-85.
Parkinson, C. R., et al. (2020). "Gingivitis efficacy of a 0.454% w/w stannous fluoride 
dentifrice: a 24-week randomized controlled trial." BMC Oral Health 20: 1-8.
Peres, K., et al. (2020). "Oral health birth cohort studies: achievements, challenges, and 
potential." Journal of dental research 99(12): 1321-1331.
Petersen, P. E. and H. Ogawa (2012). "The global burden of periodontal disease: towards 
integration with chronic disease prevention and control." Periodontology 2000 60(1): 15-39.
Rathee, M. and P. Jain (2023). Gingivitis. StatPearls [Internet], StatPearls Publishing.
Saxton, C. and F. Van der Ouderaa (1989). "The effect of a dentifrice containing zinc citrate 
and Triclosan on developing gingivitis." Journal of periodontal research 24(1): 75-80.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Haleon
Clinical Protocol
Protocol Number: 300178
Property of Haleon- Confidential
May not be used, divulged, published or otherwise disclosed without the consent of Haleon
Abbreviated Clinical Protocol Template v1.0
Page 53 of 53
Teles, R. P. and F. R. F. Teles (2009). "Antimicrobial agents used in the control of periodontal 
biofilms: effective adjuncts to mechanical plaque control?" Brazilian Oral Research 23: 39-48.
Tinanoff, N. (1990). "Review of the antimicrobial action of stannous fluoride." The Journal of 
clinical dentistry 2(1): 22-27.
Tinanoff, N. (1995). "Progress regarding the use of stannous fluoride in clinical dentistry." The 
Journal of clinical dentistry 6: 37-40.
Turesky, S. (1970). "Reduced plaque formation by the chloromethyl analogue vitamine C." J 
periodontol 41: 41-43.
Van Loveren, C. (1990). "The antimicrobial action of fluoride and its role in caries inhibition." 
Journal of dental research 69(2_suppl): 676-681.
Van Loveren, C. (2001). "Antimicrobial activity of fluoride and its in vivo importance: 
identification of research questions." Caries research 35(Suppl. 1): 65-70.
300178 Protocol  14 Nov 2024 | TMF-254788 | 3.0
CCI

Si g nat ure Pa ge f or  3 0 0 1 7 8 T M F- 2 5 4 7 8 8 v 3. 0
Si g nat ure Pa ge f or T M F- 2 5 4 7 8 8 v 3. 0
Reas o n f or si g ni n g: A p pr o ve d
Na me:
R ole: A p pr o ver
Date of si g nat ure:
G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Na me: 
R ole: A p pr o ver
Date of si g nat ure:
G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Na me:
R ole: A p pr o ver
Date of si g nat ure: 
G M T + 0 0 0 0
3 0 0 1 7 8 Pr ot oc ol  1 4 N o v 2 0 2 4 | T M F- 2 5 4 7 8 8 | 3. 0
P P D
P P D
P P D
P P D
P P D
P P D