Efficacy of Three Toothpastes Using an in Situ Caries Model

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02751320
• Collaborator: (none)
• Enrollment: 58
• Location: 1
• Arms: 6
• Actual Duration (Months): 6.3
• Patients Per Site Per Month: 9.2

Study Details

Study Description

Brief Summary

This will be a single-centre, randomized, blinded, placebo-controlled, 6-treatment, 4-period crossover, incomplete block design, in situ caries study in healthy adults who wear a removable bilateral mandibular partial denture. The denture will be modified to accommodate 4 gauze-covered specimens of human dental enamel (4x3mm) that have been previously demineralized in vitro to form either S or low-R lesions (2 specimens of each lesion type will be used with each participant). After 14 days of twice daily product use off-site, the 2 S lesion specimens will be removed at the study site, with the remaining 2 low-R lesion specimens removed at the study site after a further 14 days of product use. To determine the remineralization ability of the treatments, all specimens will be analyzed by transverse microradiography (TMR) and enamel fluoride uptake (EFU), with the S lesions additionally analyzed by surface micro hardness (SMH) and the low-R lesions additionally analyzed by quantitative light fluorescence (QLF).

Condition or Disease	Intervention/Treatment	Phase
Dental Caries	Drug: 0.425 % w/w phytate,1150ppm F; Drug: 0.85 % w/w phytate,1150ppm F; Drug: 0.85 % w/w phytate,0.3%ZnCl2 0.5% sodium citrate, 1150ppm F; Other: 0 ppm F; Drug: 1150ppm F; Drug: 0.3%ZnCl2, 0.5% sodium citrate, 1150ppm F	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Clinical Efficacy of Three Experimental Toothpastes Using an in Situ Caries Model
• Actual Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Aug 11, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental Dentifrice1 Participants will brush their natural teeth with a pre-wetted toothbrush and their assigned dentifrice for one timed minute, ensuring the enamel specimens retained within their mouths are not directly brushed. Participants should then rinse their mouths with 15ml of tap water for approximately 10s.	Drug: 0.425 % w/w phytate,1150ppm F; Participants were assigned with 1.5±0.1g twice daily dentifrice for one timed minute.
Experimental: Experimental Dentifrice 2 Participants will brush their natural teeth with a pre-wetted toothbrush and their assigned dentifrice for one timed minute, ensuring the enamel specimens retained within their mouths are not directly brushed. Participants should then rinse their mouths with 15ml of tap water for approximately 10s.	Drug: 0.85 % w/w phytate,1150ppm F; Participants were assigned with 1.5±0.1g twice daily dentifrice for one timed minute.
Experimental: Experimental Dentifrice 3 Participants will brush their natural teeth with a pre-wetted toothbrush and their assigned dentifrice for one timed minute, ensuring the enamel specimens retained within their mouths are not directly brushed. Participants should then rinse their mouths with 15ml of tap water for approximately 10s.	Drug: 0.85 % w/w phytate,0.3%ZnCl2 0.5% sodium citrate, 1150ppm F; Participants were assigned with 1.5±0.1g twice daily dentifrice for one timed minute.
Placebo Comparator: Reference Product 1 Participants will brush their natural teeth with a pre-wetted toothbrush and their assigned dentifrice for one timed minute, ensuring the enamel specimens retained within their mouths are not directly brushed. Participants should then rinse their mouths with 15ml of tap water for approximately 10s.	Other: 0 ppm F; Participants were assigned with 1.5±0.1g twice daily dentifrice for one timed minute.
Active Comparator: Reference Product 2 Participants will brush their natural teeth with a pre-wetted toothbrush and their assigned dentifrice for one timed minute, ensuring the enamel specimens retained within their mouths are not directly brushed. Participants should then rinse their mouths with 15ml of tap water for approximately 10s.	Drug: 1150ppm F; Participants were assigned with 1.5±0.1g twice daily dentifrice for one timed minute.
Active Comparator: Reference Product 3 Participants will brush their natural teeth with a pre-wetted toothbrush and their assigned dentifrice for one timed minute, ensuring the enamel specimens retained within their mouths are not directly brushed. Participants should then rinse their mouths with 15ml of tap water for approximately 10s.	Drug: 0.3%ZnCl2, 0.5% sodium citrate, 1150ppm F; Participants were assigned with 1.5±0.1g twice daily dentifrice for one timed minute.

Outcome Measures

Primary Outcome Measures

1. Percentage Surface Microhardness Recovery (SMHR) of Phyte (0% 0.425% and 0.85%) at 2 Weeks [Baseline upto 2 weeks]

   SMHR test was used to assess the changes in mineralization status of partially demineralized enamel specimens using a Wilson 2100 Hardness tester. SMH was determined by measuring the length of the indentations of enamel specimens. % SMHR was calculated from indentation length (micrometer [μm]) of sound enamel specimen at baseline (B), indentation length (μm) after in vitro demineralization(D), indentation length (μm) after intra-oral exposure (R): [D-R/D-B]*100.

Secondary Outcome Measures

1. % SMHR of 0.85% Phytate Compared to 0% Phytate, in Presence of 1150ppm Fluoride and 0.3% ZnCl2, 0.3% ZnCl2 Compared to 0% ZnCl2 in the Presence of 1150ppm Fluoride and 0.3% ZnCl2 Compared to 0% ZnCl2 in the Presence of 1150ppm Fluoride and 0.85% Phytate [Baseline upto 2 weeks]

   SMHR test was used to assess the changes in mineralization status of partially demineralized enamel specimens using a Wilson 2100 Hardness tester. SMH was determined by measuring the length of the indentations of enamel specimens. % SMHR was calculated from indentation length (μm) of sound enamel specimen at baseline (B), indentation length (μm) after in vitro demineralization(D), indentation length (μm) after intra-oral exposure (R): [D-R/D-B]*100.

2. Transverse Microradiography (TMR) Net Remineralization Change (ΔM) Value of Phytate (0% 0.452% and 0.85%) at 4 Weeks [Baseline upto 4 weeks]

   TMR was used to assess changes in the mineral status of partially demineralized enamel specimens. Lesions were analyzed at baseline and Integrated Mineral Loss (∆Z): (∆Z =(lesion depth x 87) - area under the curve [Area under the curve which relates volume % mineral at distances from the specimen surface with respect to section thickness]). After treatment a further section was taken from each lesion specimen for radiography assessment; ∆Z was calculated. The change which occurred in mineral content (∆M) of the lesions as a result of treatment was calculated by: ∆M= (baseline ∆Z - Post-treatment ∆Z).

3. TMR Δm Value of 0.85% Phytate Compared to 0% Phytate, in the Presence of 1150ppm F and 0.3% ZnCl2, 0.3% ZnCl2 Compared to 0% ZnCl2 in the Presence of 1150ppm F and 0.3% ZnCl2 Compared to 0% ZnCl2 in the Presence of 1150ppm F and 0.85% Phytate [Baseline upto 4 weeks]

   TMR was used to assess changes in the mineral status of partially demineralized enamel specimens. Lesions were analyzed at baseline and Integrated Mineral Loss (∆Z): (∆Z =(lesion depth x 87) - area under the curve [Area under the curve which relates volume % mineral at distances from the specimen surface with respect to section thickness]). After treatment a further section was taken from each lesion specimen for radiography assessment; ∆Z was calculated. The change which occurred in mineral content (∆M) of the lesions as a result of treatment was calculated by: ∆M= (baseline ∆Z - Post-treatment ∆Z).

4. Enamel Fluoride Uptake (EFU) of All Study Formulation Variables [At Week 2]

   The microdrill enamel biopsy technique was used to analyze the fluoride uptake by enamel. Each enamel specimen was mounted on the long axis of a drill attached to a microdrill and drilled to a depth of approximately 100 μm through the entire lesion (four cores per specimen). The enamel powder pooled from four drilling samples was then immediately analyzed for fluoride content using fluoride specific electrode and pH/ion meter. The amount of fluoride-uptake by enamel was calculated based on the amount of fluoride divided by the area of the enamel cores and expressed as μg/cm^2.

5. Enamel Fluoride Uptake (EFU) of All Study Formulation Variables [At Week 4]

   The microdrill enamel biopsy technique was used to analyze the fluoride uptake by enamel. Each enamel specimen was mounted on the long axis of a drill attached to a microdrill and drilled to a depth of approximately 100 μm through the entire lesion (four cores per specimen). The enamel powder pooled from four drilling samples was then immediately analyzed for fluoride content using fluoride specific electrode and pH/ion meter. The amount of fluoride-uptake by enamel was calculated based on the amount of fluoride divided by the area of the enamel cores and expressed as μg/cm^2.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Demonstrates understanding of the study.

2. Aged 18 to 85 years.

3. Understands and is willing, able and likely to comply with all study procedures and restrictions.

4. Has good general health (in the opinion of the investigator or medically qualified designee).

5. A salivary flow-rate in the range of normal values (unstimulated whole saliva flow- Rate ≥ 0.2 g/minute (min); gum base stimulated whole saliva flow-Rate ≥ 0.8 g/min).

6. Currently wearing a removable mandibular partial denture with sufficient room in the posterior buccal flange area to accommodate two enamel specimens.

7. Have no current active caries or periodontal disease and all restorations in a good state of repair.

8. Willing and capable of brushing their natural teeth with the lower partial denture in place.

Exclusion Criteria:

1. Pregnant or breast feeding women.

2. Known or suspected intolerance or hypersensitivity to the study materials or their stated ingredients.

3. Currently taking antibiotics or have taken antibiotics in the two weeks prior to the screening visit.

4. Unable to measure product weights accurately using the assigned study scale as determined by the study staff as demonstrated.

5. Participation in another clinical study or receipt of an investigational drug within 30 days of the screening visit.

6. Have received a professional fluoride treatment within 14 days of randomization to the first treatment.

7. Recent history (within the last year) of alcohol or other substance abuse.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Indianapolis	Indiana	United States	46202

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02751320
• Other Study ID Numbers: 202301
• First Posted: Apr 26, 2016
• Last Update Posted: Oct 13, 2017
• Last Verified: Jul 1, 2017

• Additional relevant MeSH terms: Dental Caries; Citric Acid; Sodium Citrate

Study Results

Participant Flow

Recruitment Details	Participants were recruited at one center in United States.
Pre-assignment Detail	A total of 58 participants were screened, of which 45 participants were randomized and 42 completed the study.

Arm/Group Title	Overall Study
Arm/Group Description	This was a single-centre, randomized, blinded (examiner and laboratory analyst), placebo-controlled, 6-treatment, 4-period cross-over, incomplete block design, in situ caries study in healthy adults who wore a removable bilateral mandibular partial denture. Each participant received Test Product 1 (Dentifrice containing 0.425 % weight by weight (w/w) phytate, and 1150 parts per million [ppm] fluoride [F]), Test Product 2 (Dentifrice containing 0.85 % w/w phytate, and 1150 ppm fluoride), Test Product 3 (Dentifrice containing 0.85 % w/w phytate, 0.3% zinc chloride, 0.5% sodium citrate, and 1150 ppm fluoride), Reference Product 1 (0 ppm fluoride), Reference Product 2 (Dentrifrice containing 1150 ppm fluoride toothpaste and Reference Product 3 (Dentrifrice containing 0.3% zinc chloride , 0.5% sodium citrate, and 1150 ppm fluoride).
Period Title: Overall Study
STARTED	45
Received Test Product 1	29
Received Test Prodcut 2	28
Received Test Prodcut 3	28
Received Reference Product 1	29
Received Reference Product 2	28
Received Reference Product 3	28
COMPLETED	42
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	All Randomized Participants
Arm/Group Description	All randomized participants were included for baseline evaluation.
Overall Participants	45
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.3 (9.69)
Sex: Female, Male (Count of Participants)
Female	25 55.6%
Male	20 44.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	20 44.4%
White	24 53.3%
More than one race	1 2.2%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage Surface Microhardness Recovery (SMHR) of Phyte (0% 0.425% and 0.85%) at 2 Weeks
Description	SMHR test was used to assess the changes in mineralization status of partially demineralized enamel specimens using a Wilson 2100 Hardness tester. SMH was determined by measuring the length of the indentations of enamel specimens. % SMHR was calculated from indentation length (micrometer [μm]) of sound enamel specimen at baseline (B), indentation length (μm) after in vitro demineralization(D), indentation length (μm) after intra-oral exposure (R): [D-R/D-B]*100.
Time Frame	Baseline upto 2 weeks

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population, all participants who were randomized, received the study products at least once and provided at least one post-baseline assessment of efficacy. Number of participants who missed enamel specimens were: Test product 1- [1], Test product 2- [1], Reference Product 1- [1], and Reference Product 2- [1].

Arm/Group Title	Test Product 1	Test Product 2	Reference Product 1	Reference Product 2
Arm/Group Description	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned experimental dentifrice (containing 0.425 % phytate, 1150 ppm F) for one timed minute twice daily, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15 milliliters (ml) of tap water for approximately 10 seconds (s).	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned experimental dentifrice (containing 0.85 % phytate, 1150 ppm F) for one timed minute twice daily, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned reference dentifrice (containing 0 ppm fluoride) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned reference dentifrice (containing 1150ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.
Measure Participants	28	28	29	28
Mean (Standard Deviation) [% SMHR]	25.53 (21.513)	26.81 (18.059)	7.41 (18.648)	28.88 (21.046)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Product 1, Reference Product 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7603
	Comments	From ANCOVA: Participant (random), treatment & period (fixed), subject-level baseline SMH, period-level baseline SMH, subject-level pre-treatment acid challenge SMH and period-level pre-treatment acid challenge SMH (covariates).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.09
	Confidence Interval	(2-Sided) 95%; -8.11 to 5.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that positive difference favors the first named treatment.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Test Product 2, Reference Product 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3555
	Comments	From ANCOVA: Participant (random), treatment & period (fixed), subject-level baseline SMH, period-level baseline SMH, subject-level pre-treatment acid challenge SMH and period-level pre-treatment acid challenge SMH (covariates).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.30
	Confidence Interval	(2-Sided) 95%; -10.34 to 3.74
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that positive difference favors the first named treatment.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Test Product 1, Test Product 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5335
	Comments	ANCOVA: Participant (random), treatment & period (fixed), Participant-level baseline SMH, period-level baseline SMH, Participant-level pre-treatment acid challenge SMH and period-level pre-treatment acid challenge SMH (covariates)
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.21
	Confidence Interval	(2-Sided) 95%; -4.81 to 9.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that positive difference favors the first named treatment.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Reference Product 1, Reference Product 2
	Comments	Treatment comparison corresponding to qualifying criteria for the analysis
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	From ANCOVA: Participant (random), treatment & period (fixed), Participant -level baseline SMH, period-level baseline SMH, Participant -level pre-treatment acidchallenge SMH and period-level pre-treatment acid challenge SMH (covariates) .
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	22.96
	Confidence Interval	(2-Sided) 95%; 16.02 to 29.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that positive difference favors the first named treatment.

2. Secondary Outcome

Title	% SMHR of 0.85% Phytate Compared to 0% Phytate, in Presence of 1150ppm Fluoride and 0.3% ZnCl2, 0.3% ZnCl2 Compared to 0% ZnCl2 in the Presence of 1150ppm Fluoride and 0.3% ZnCl2 Compared to 0% ZnCl2 in the Presence of 1150ppm Fluoride and 0.85% Phytate
Description	SMHR test was used to assess the changes in mineralization status of partially demineralized enamel specimens using a Wilson 2100 Hardness tester. SMH was determined by measuring the length of the indentations of enamel specimens. % SMHR was calculated from indentation length (μm) of sound enamel specimen at baseline (B), indentation length (μm) after in vitro demineralization(D), indentation length (μm) after intra-oral exposure (R): [D-R/D-B]*100.
Time Frame	Baseline upto 2 weeks

Outcome Measure Data

Analysis Population Description

ITT population, all participants who were randomized, received the study products at least once and provided at least one post-baseline assessment of efficacy. Number of participants who missed enamel specimens were: Test product 2- [1], Test product 3- [2], Reference Product 2- [1], and Reference Product 3- [1].

Arm/Group Title	Test Product 2	Test Product 3	Reference Product 2	Reference Product 3
Arm/Group Description	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.85 % phytate, 1150 ppm F) for one timed minute twice daily, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.85 % phytate, 1150 ppm F, 0.3% ZnCl2) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 1150ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 1150ppm F, 0.3% ZnCl2) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.
Measure Participants	28	28	28	28
Mean (Standard Deviation) [% SMHR]	26.81 (18.059)	23.38 (20.177)	28.88 (21.046)	28.80 (20.830)

3. Secondary Outcome

Title	Transverse Microradiography (TMR) Net Remineralization Change (ΔM) Value of Phytate (0% 0.452% and 0.85%) at 4 Weeks
Description	TMR was used to assess changes in the mineral status of partially demineralized enamel specimens. Lesions were analyzed at baseline and Integrated Mineral Loss (∆Z): (∆Z =(lesion depth x 87) - area under the curve [Area under the curve which relates volume % mineral at distances from the specimen surface with respect to section thickness]). After treatment a further section was taken from each lesion specimen for radiography assessment; ∆Z was calculated. The change which occurred in mineral content (∆M) of the lesions as a result of treatment was calculated by: ∆M= (baseline ∆Z - Post-treatment ∆Z).
Time Frame	Baseline upto 4 weeks

Outcome Measure Data

Analysis Population Description

ITT population, all participants who were randomized, received the study products at least once and provided at least one post-baseline assessment of efficacy. Number of participants who missed enamel specimens were: Test product 1- [1], Test product 2- [1], and Reference Product 2- [1].

Arm/Group Title	Test Product 1	Test Product 2	Reference Product 1	Reference Product 2
Arm/Group Description	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.425 % phytate, 1150 ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.85 % phytate, 1150 ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned reference dentifrice (containing 0 ppm fluoride) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 1150ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.
Measure Participants	28	27	29	28
Mean (Standard Deviation) [[%vol mineral x µm]	3055.36 (1459.283)	2772.96 (989.567)	3849.83 (1978.088)	2720.00 (1151.914)

4. Secondary Outcome

Title	TMR Δm Value of 0.85% Phytate Compared to 0% Phytate, in the Presence of 1150ppm F and 0.3% ZnCl2, 0.3% ZnCl2 Compared to 0% ZnCl2 in the Presence of 1150ppm F and 0.3% ZnCl2 Compared to 0% ZnCl2 in the Presence of 1150ppm F and 0.85% Phytate
Description	TMR was used to assess changes in the mineral status of partially demineralized enamel specimens. Lesions were analyzed at baseline and Integrated Mineral Loss (∆Z): (∆Z =(lesion depth x 87) - area under the curve [Area under the curve which relates volume % mineral at distances from the specimen surface with respect to section thickness]). After treatment a further section was taken from each lesion specimen for radiography assessment; ∆Z was calculated. The change which occurred in mineral content (∆M) of the lesions as a result of treatment was calculated by: ∆M= (baseline ∆Z - Post-treatment ∆Z).
Time Frame	Baseline upto 4 weeks

Outcome Measure Data

Analysis Population Description

ITT population, all participants who were randomized, received the study products at least once and provided at least one post-baseline assessment of efficacy. Number of participants who missed enamel specimens were: Test product 2 - [1], Test product 3 - [2], Reference Product 2 - [1] and Reference Product 3 [1].

Arm/Group Title	Test Product 2	Test Product 3	Reference Product 2	Reference Product 3
Arm/Group Description	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.85 % phytate, 1150 ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.85 % phytate, 1150 ppm F, 0.3% ZnCl2) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 1150ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 1150ppm F, 0.3% ZnCl2) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.
Measure Participants	27	27	28	28
Mean (Standard Deviation) [[%vol mineral x µm]	2772.96 (989.567)	2733.33 (1051.738)	2720.00 (1151.914)	2421.25 (677.286)

5. Secondary Outcome

Title	Enamel Fluoride Uptake (EFU) of All Study Formulation Variables
Description	The microdrill enamel biopsy technique was used to analyze the fluoride uptake by enamel. Each enamel specimen was mounted on the long axis of a drill attached to a microdrill and drilled to a depth of approximately 100 μm through the entire lesion (four cores per specimen). The enamel powder pooled from four drilling samples was then immediately analyzed for fluoride content using fluoride specific electrode and pH/ion meter. The amount of fluoride-uptake by enamel was calculated based on the amount of fluoride divided by the area of the enamel cores and expressed as μg/cm^2.
Time Frame	At Week 2

Outcome Measure Data

Analysis Population Description

ITT population, all participants who were randomized, received the study products at least once and provided at least one post-baseline assessment of efficacy. Number of participants who missed enamel specimens were: Test product1-[1], Test product2-[1], Test product3-[2], Reference Product1-[1], Reference Product2-[1] and Reference Product3-[1].

Arm/Group Title	Test Product 1	Test Product 2	Test Product 3	Reference Product 1	Reference Product 2	Reference Product 3
Arm/Group Description	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.425 % phytate, 1150 ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.85 % phytate, 1150 ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.85 % phytate, 1150 ppm F, 0.3% ZnCl2) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0 ppm fluoride) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 1150ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 1150ppm F, 0.3% ZnCl2) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.
Measure Participants	28	28	28	29	28	28
Mean (Standard Deviation) [μg/cm^2]	5.35 (2.038)	4.78 (2.655)	5.02 (2.499)	1.09 (0.397)	5.87 (2.772)	5.37 (2.384)

6. Secondary Outcome

Title	Enamel Fluoride Uptake (EFU) of All Study Formulation Variables
Description	The microdrill enamel biopsy technique was used to analyze the fluoride uptake by enamel. Each enamel specimen was mounted on the long axis of a drill attached to a microdrill and drilled to a depth of approximately 100 μm through the entire lesion (four cores per specimen). The enamel powder pooled from four drilling samples was then immediately analyzed for fluoride content using fluoride specific electrode and pH/ion meter. The amount of fluoride-uptake by enamel was calculated based on the amount of fluoride divided by the area of the enamel cores and expressed as μg/cm^2.
Time Frame	At Week 4

Outcome Measure Data

Analysis Population Description

ITT population, all participants who were randomized, received the study products at least once and provided at least one post-baseline assessment of efficacy. Number of participants who missed enamel specimens were: Test product1-[1], Test product2-[2], Test product3-[3], Reference Product1-[1], Reference Product2-[1] and Reference Product3-[1].

Arm/Group Title	Test Product 1	Test Product 2	Test Product 3	Reference Product 1	Reference Product 2	Reference Product 3
Arm/Group Description	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.425 % phytate, 1150 ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.85 % phytate, 1150 ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.85 % phytate, 1150 ppm F, 0.3% ZnCl2) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0 ppm fluoride) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 1150ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 1150ppm F, 0.3% ZnCl2) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.
Measure Participants	28	27	27	29	28	28
Mean (Standard Deviation) [μg/cm^2]	12.28 (6.756)	11.09 (6.336)	14.16 (12.851)	1.64 (0.974)	15.29 (10.177)	15.11 (10.180)

Adverse Events

Arm/Group Title	Test Product 1		Test Product 2		Test Product 3		Reference Product 1		Reference Product 2		Reference Product 3
Arm/Group Description	Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.425 % phytate, 1150 ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.		Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.85 % phytate, 1150 ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.		Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0.85 % phytate, 1150 ppm F, 0.3% ZnCl2) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s		Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 0 ppm fluoride) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.		Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 1150ppm F) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.		Participants brushed their natural teeth with a pre-wetted toothbrush and their assigned dentifrice (containing 1150ppm F, 0.3% ZnCl2) for one timed minute, ensuring the enamel specimens retained within their mouths were not directly brushed. Participants then rinsed their mouths with 15ml of tap water for approximately 10s.
All Cause Mortality
	Test Product 1		Test Product 2		Test Product 3		Reference Product 1		Reference Product 2		Reference Product 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/28 (0%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Serious Adverse Events
	Test Product 1		Test Product 2		Test Product 3		Reference Product 1		Reference Product 2		Reference Product 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/28 (3.6%)		0/28 (0%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
INVASIVE DUCTAL BREAST CARCINOMA	1/28 (3.6%)		0/28 (0%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	Test Product 1		Test Product 2		Test Product 3		Reference Product 1		Reference Product 2		Reference Product 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/28 (32.1%)		9/28 (32.1%)		10/28 (35.7%)		7/29 (24.1%)		4/27 (14.8%)		8/28 (28.6%)
Gastrointestinal disorders
GINGIVAL ERYTHEMA	2/28 (7.1%)		3/28 (10.7%)		2/28 (7.1%)		1/29 (3.4%)		1/27 (3.7%)		1/28 (3.6%)
Mouth ulceration	2/28 (7.1%)		1/28 (3.6%)		1/28 (3.6%)		1/29 (3.4%)		0/27 (0%)		0/28 (0%)
Dry mouth	1/28 (3.6%)		0/28 (0%)		1/28 (3.6%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Gingival ulceration	1/28 (3.6%)		0/28 (0%)		1/28 (3.6%)		0/29 (0%)		0/27 (0%)		2/28 (7.1%)
Oral mucosal erythema	1/28 (3.6%)		2/28 (7.1%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		1/28 (3.6%)
Toothache	1/28 (3.6%)		0/28 (0%)		1/28 (3.6%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Gastrooesophageal reflux disease	0/28 (0%)		0/28 (0%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		1/28 (3.6%)
Gingival oedema	0/28 (0%)		1/28 (3.6%)		0/28 (0%)		0/29 (0%)		1/27 (3.7%)		0/28 (0%)
Gingival pain	0/28 (0%)		0/28 (0%)		1/28 (3.6%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Gingival swelling	0/28 (0%)		0/28 (0%)		0/28 (0%)		1/29 (3.4%)		0/27 (0%)		0/28 (0%)
Leukoplakia oral	0/28 (0%)		0/28 (0%)		0/28 (0%)		1/29 (3.4%)		0/27 (0%)		1/28 (3.6%)
Lip dry	0/28 (0%)		1/28 (3.6%)		0/28 (0%)		0/29 (0%)		1/27 (3.7%)		0/28 (0%)
Noninfective gingivitis	0/28 (0%)		1/28 (3.6%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Tongue coated	0/28 (0%)		0/28 (0%)		0/28 (0%)		1/29 (3.4%)		0/27 (0%)		0/28 (0%)
Tongue oedema	0/28 (0%)		0/28 (0%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		1/28 (3.6%)
General disorders
Injury Associated With Device	0/28 (0%)		1/28 (3.6%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Immune system disorders
Seasonal Allergy	0/28 (0%)		0/28 (0%)		0/28 (0%)		1/29 (3.4%)		0/27 (0%)		0/28 (0%)
Infections and infestations
Angular cheilitis	0/28 (0%)		1/28 (3.6%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Nasopharyngitis	0/28 (0%)		0/28 (0%)		0/28 (0%)		1/29 (3.4%)		0/27 (0%)		0/28 (0%)
Oral herpes	0/28 (0%)		0/28 (0%)		1/28 (3.6%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Pneumonia	0/28 (0%)		1/28 (3.6%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Urinary tract infection	0/28 (0%)		0/28 (0%)		1/28 (3.6%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Injury, poisoning and procedural complications
Thermal burn	1/28 (3.6%)		0/28 (0%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Laceration	0/28 (0%)		0/28 (0%)		1/28 (3.6%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Lip injury	0/28 (0%)		0/28 (0%)		1/28 (3.6%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Muscle strain	0/28 (0%)		0/28 (0%)		0/28 (0%)		1/29 (3.4%)		0/27 (0%)		0/28 (0%)
Traumatic ulcer	0/28 (0%)		1/28 (3.6%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Metabolism and nutrition disorders
Glucose Tolerance Impaired	0/28 (0%)		0/28 (0%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		1/28 (3.6%)
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain	0/28 (0%)		1/28 (3.6%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin cancer	0/28 (0%)		1/28 (3.6%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Nervous system disorders
Headache	1/28 (3.6%)		0/28 (0%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Migraine	0/28 (0%)		0/28 (0%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		1/28 (3.6%)
Product Issues
Device Failure	1/28 (3.6%)		1/28 (3.6%)		0/28 (0%)		0/29 (0%)		1/27 (3.7%)		0/28 (0%)
Respiratory, thoracic and mediastinal disorders
Allergic sinusitis	0/28 (0%)		0/28 (0%)		0/28 (0%)		0/29 (0%)		1/27 (3.7%)		0/28 (0%)
Asthma	0/28 (0%)		0/28 (0%)		1/28 (3.6%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Cough	0/28 (0%)		1/28 (3.6%)		0/28 (0%)		0/29 (0%)		0/27 (0%)		0/28 (0%)
Oropharyngeal pain	0/28 (0%)		0/28 (0%)		0/28 (0%)		1/29 (3.4%)		0/27 (0%)		0/28 (0%)
Pharyngeal erythema	0/28 (0%)		0/28 (0%)		0/28 (0%)		1/29 (3.4%)		0/27 (0%)		0/28 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.