A Clinical Study to Evaluate Experimental Children's Toothpastes in an In-Situ Caries Model

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01607411
• Collaborator: (none)
• Enrollment: 55
• Location: 1
• Arms: 4
• Duration (Months): 3
• Patients Per Site Per Month: 18.6

Study Details

Study Description

Brief Summary

An in situ model will be used to evaluate and compare enamel remineralization of human enamel specimens after single use of experimental children's toothpastes.

Condition or Disease	Intervention/Treatment	Phase
Dental Caries	Drug: Fluoride; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• Official Title: A Clinical Study to Evaluate Experimental Children's Toothpastes in an In-Situ Caries Model
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: May 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Fluoride free toothpaste toothpaste with no fluoride	Drug: Placebo; Fluoride free toothpaste
Experimental: 1426ppm Fluoride Toothpaste Experimental toothpaste containing 1426 ppm Fluoride	Drug: Fluoride; Fluoride Toothpaste
Experimental: 1000 ppm Fluoride Toothpaste Experimental toothpaste containing 1000 ppm Fluoride	Drug: Fluoride; Fluoride Toothpaste
Experimental: 500 ppm Toothpaste Experimental toothpaste containing 500 ppm Fluoride	Drug: Fluoride; Fluoride Toothpaste

Outcome Measures

Primary Outcome Measures

1. Percentage Surface Microhardness Recovery of Test Dentifrices Relative to Placebo Dentifrice [Baseline to 4 hours]

   Surface microhardness recovery (SMHR) test was used to assess the changes in mineralization status of enamel specimens using a Wilson 2100 Hardness tester. SMHR was determined by measuring the length of the indentations of enamel specimens. An increase in the indentation length compared to the baseline indicates softening while decrease in the indentation length represents rehardening of enamel surface. Percent SMHR was calculated from indentation values of enamel specimens at baseline (B), after in-situ hardening (R) and after first demineralization challenge (D1) using formula: [(D1-R)/ (D1-B)]*100.

Secondary Outcome Measures

1. %SMHR of Enamel Specimens Exposed to Test Treatments [Baseline to 4 hours]

   Surface microhardness recovery (SMHR) test was used to assess the changes in mineralization status of enamel specimens using a Wilson 2100 Hardness tester. SMHR was determined by measuring the length of the indentations of enamel specimens. An increase in the indentation length compared to the baseline indicates softening while decrease in the indentation length represents rehardening of enamel surface. Percent SMHR was calculated from indentation values of enamel specimens at baseline (B), after in-situ hardening (R) and after first demineralization challenge (D1) using formula: [(D1-R)/ (D1-B)]*100.

2. Percent Net Acid Resistance (%NAR) of Enamel Specimens [Baseline to 4 hours]

   Changes in mineral content of enamel specimens exposed to dietary erosive challenge were determined by measuring the length of the indentations. Decrease in the indentation length compared to the baseline indicates hardening of enamel surface. Enamel specimens were exposed to second erosion challenge to determine NAR which compared the indentations values of sound enamel specimens at baseline (B), first demineralization challenge (D1) and second demineralization challenge (D2). Percent NAR was calculated by formula: [(D1-D2)/ (D1-B)]*100.

3. Enamel Fluoride Uptake [Baseline to 4 hours]

   Enamel fluoride uptake was determined using the microdrill enamel biopsy technique. The amount of fluoride uptake by enamel was calculated based on amount of F divided by volume of the enamel cores and expressed as micrograms (μg)* F/centimeters(cm)^2. Difference between treatments was calculated with respect to F uptake by enamel.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 11 Years to 14 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy males and females aged 11 to 14 inclusive who have an unstimulated salivary flow rate of at least 0.2 mL/minute and a stimulated salivary flow rate of at least 0.8 mL/minute (Screening Visit 1).

Exclusion Criteria:

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University School of Dentistry	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: NCT01607411
• Other Study ID Numbers: RH01390
• First Posted: May 30, 2012
• Last Update Posted: Aug 11, 2014
• Last Verified: Jul 1, 2014

• Additional relevant MeSH terms: Dental Caries; Fluorides

Study Results

Participant Flow

Recruitment Details	Participants were recruited at the clinical site.
Pre-assignment Detail	Of the 70 participants screened, 15 were not randomized into the study (12 did not meet study criteria and 3 withdrew the consent). A washout fluoride (F) toothpaste was used for a week prior treatment. In-situ appliances were prepared for participants to fit enamel specimens.

Arm/Group Title	Sodium Fluoride(NaF) Toothpaste (1426parts Per Million(Ppm) F)	NaF Toothpaste (1000 Ppm F)	NaF Toothpaste (500 Ppm F)	Placebo Toothpaste (0 Ppm F)
Arm/Group Description	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 grams (g) ± 0.1g of NaF toothpaste(1426 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (1000 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (500 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (0ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided
Period Title: Period I
STARTED	14	13	14	14
COMPLETED	14	13	14	14
NOT COMPLETED	0	0	0	0
Period Title: Period I
STARTED	14	14	13	14
COMPLETED	14	14	13	14
NOT COMPLETED	0	0	0	0
Period Title: Period I
STARTED	14	14	14	13
COMPLETED	14	14	14	13
NOT COMPLETED	0	0	0	0
Period Title: Period I
STARTED	13	14	14	14
COMPLETED	13	14	14	14
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Overall
Arm/Group Description	All randomized participants who received atleast one dose of the study treatments
Overall Participants	55
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	12.4 (1.12)
Sex: Female, Male (Count of Participants)
Female	31 56.4%
Male	24 43.6%
Race/Ethnicity, Customized (Number) [Number]
Black or African American	9 16.4%
White	41 74.5%
More than one race	5 9.1%

Outcome Measures

1. Primary Outcome

Title	Percentage Surface Microhardness Recovery of Test Dentifrices Relative to Placebo Dentifrice
Description	Surface microhardness recovery (SMHR) test was used to assess the changes in mineralization status of enamel specimens using a Wilson 2100 Hardness tester. SMHR was determined by measuring the length of the indentations of enamel specimens. An increase in the indentation length compared to the baseline indicates softening while decrease in the indentation length represents rehardening of enamel surface. Percent SMHR was calculated from indentation values of enamel specimens at baseline (B), after in-situ hardening (R) and after first demineralization challenge (D1) using formula: [(D1-R)/ (D1-B)]*100.
Time Frame	Baseline to 4 hours

Outcome Measure Data

Analysis Population Description

Per Protocol (PP) Population: All randomized participants who received at least one study product, had one efficacy assessment and did not have any protocol violations deemed to affect efficacy. Missing enamel specimen values were imputed, by averaging over the available enamel specimens.

Arm/Group Title	NaF Toothpaste (1426 Ppm F)	NaF Toothpaste (1000 Ppm F)	NaF Toothpaste (500 Ppm F)	Placebo Toothpaste (0 Ppm F)
Arm/Group Description	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (1426 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (1000 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (500 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (0ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided
Measure Participants	55	55	55	55
Mean (Standard Error) [%SMHR]	30.72 (0.87)	29.49 (0.87)	28.29 (0.87)	25.13 (0.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1426 Ppm F), Placebo Toothpaste (0 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified.
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	5.59
	Confidence Interval	(2-Sided) 95%; 3.60 to 7.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1000 Ppm F), Placebo Toothpaste (0 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	4.36
	Confidence Interval	(2-Sided) 95%; 2.37 to 6.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (500 Ppm F), Placebo Toothpaste (0 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	3.16
	Confidence Interval	(2-Sided) 95%; 1.17 to 5.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

2. Secondary Outcome

Title	%SMHR of Enamel Specimens Exposed to Test Treatments
Description	Surface microhardness recovery (SMHR) test was used to assess the changes in mineralization status of enamel specimens using a Wilson 2100 Hardness tester. SMHR was determined by measuring the length of the indentations of enamel specimens. An increase in the indentation length compared to the baseline indicates softening while decrease in the indentation length represents rehardening of enamel surface. Percent SMHR was calculated from indentation values of enamel specimens at baseline (B), after in-situ hardening (R) and after first demineralization challenge (D1) using formula: [(D1-R)/ (D1-B)]*100.
Time Frame	Baseline to 4 hours

Outcome Measure Data

Analysis Population Description

Per Protocol (PP) Population: All randomized participants who received at least one study product, had one efficacy assessment and did not have any protocol violations deemed to affect efficacy. Missing enamel specimen values were imputed, by averaging over the available enamel specimens.

Arm/Group Title	NaF Toothpaste (1426 Ppm F)	NaF Toothpaste (1000 Ppm F)	NaF Toothpaste (500 Ppm F)
Arm/Group Description	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (1426 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (1000 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (500 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided
Measure Participants	55	55	55
Mean (Standard Error) [%SMHR]	30.72 (0.87)	29.49 (0.87)	28.29 (0.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1426 Ppm F), NaF Toothpaste (1000 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2225
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; -0.76 to 3.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1426 Ppm F), NaF Toothpaste (500 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0168
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	2.44
	Confidence Interval	(2-Sided) 95%; 0.44 to 4.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1000 Ppm F), NaF Toothpaste (500 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2352
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; -0.79 to 3.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

3. Secondary Outcome

Title	Percent Net Acid Resistance (%NAR) of Enamel Specimens
Description	Changes in mineral content of enamel specimens exposed to dietary erosive challenge were determined by measuring the length of the indentations. Decrease in the indentation length compared to the baseline indicates hardening of enamel surface. Enamel specimens were exposed to second erosion challenge to determine NAR which compared the indentations values of sound enamel specimens at baseline (B), first demineralization challenge (D1) and second demineralization challenge (D2). Percent NAR was calculated by formula: [(D1-D2)/ (D1-B)]*100.
Time Frame	Baseline to 4 hours

Outcome Measure Data

Analysis Population Description

Per Protocol (PP) Population: All randomized participants who received at least one study product, had one efficacy assessment and did not have any protocol violations deemed to affect efficacy. Missing enamel specimen values were imputed, by averaging over the available enamel specimens.

Arm/Group Title	NaF Toothpaste (1426 Ppm F)	NaF Toothpaste (1000 Ppm F)	NaF Toothpaste (500 Ppm F)	Placebo Toothpaste (0 Ppm F)
Arm/Group Description	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (1426 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (1000 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (500 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (0ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided
Measure Participants	55	55	55	55
Mean (Standard Error) [%NAR]	-19.72 (1.90)	-19.52 (1.90)	-25.82 (1.90)	-54.38 (1.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1426 Ppm F), Placebo Toothpaste (0 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	34.65
	Confidence Interval	(2-Sided) 95%; 30.07 to 39.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1000 Ppm F), Placebo Toothpaste (0 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean difference
	Estimated Value	34.86
	Confidence Interval	(2-Sided) 95%; 30.28 to 39.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (500 Ppm F), Placebo Toothpaste (0 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	28.55
	Confidence Interval	(2-Sided) 95%; 23.97 to 33.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1426 Ppm F), NaF Toothpaste (1000 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9292
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -4.79 to 4.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1426 Ppm F), NaF Toothpaste (500 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0094
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	6.10
	Confidence Interval	(2-Sided) 95%; 1.52 to 10.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1000 Ppm F), NaF Toothpaste (500 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0073
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	6.31
	Confidence Interval	(2-Sided) 95%; 1.72 to 10.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

4. Secondary Outcome

Title	Enamel Fluoride Uptake
Description	Enamel fluoride uptake was determined using the microdrill enamel biopsy technique. The amount of fluoride uptake by enamel was calculated based on amount of F divided by volume of the enamel cores and expressed as micrograms (μg)* F/centimeters(cm)^2. Difference between treatments was calculated with respect to F uptake by enamel.
Time Frame	Baseline to 4 hours

Outcome Measure Data

Analysis Population Description

Per Protocol (PP) Population: All randomized participants who received at least one study product, had one efficacy assessment and did not have any protocol violations deemed to affect efficacy. Missing enamel specimen values were imputed, by averaging over the available enamel specimens

Arm/Group Title	NaF Toothpaste (1426 Ppm F)	NaF Toothpaste (1000 Ppm F)	NaF Toothpaste (500 Ppm F)	Placebo Toothpaste (0 Ppm F)
Arm/Group Description	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (1426 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (1000 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (500 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (0ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided
Measure Participants	55	55	55	55
Mean (Standard Error) [μg*F/cm^2]	1.76 (0.08)	1.77 (0.08)	1.47 (0.08)	0.98 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1426 Ppm F), Placebo Toothpaste (0 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random factor
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1000 Ppm F), Placebo Toothpaste (0 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (500 Ppm F), Placebo Toothpaste (0 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; 0.29 to 0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1426 Ppm F), NaF Toothpaste (1000 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9631
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.005
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1426 Ppm F), NaF Toothpaste (500 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0047
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; 0.09 to 0.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	NaF Toothpaste (1000 Ppm F), NaF Toothpaste (500 Ppm F)
	Comments	Null hypothesis was no difference between treatments, being compared. Tests were 2 sided at 5% significance levels
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0040
	Comments	No adjustment was required for multiple comparisons as the primary comparison was pre-specified
	Method	ANOVA
	Comments	The fixed factors for ANOVA were study period and treatment and the subject was random effect
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95%; 0.10 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is first named treatment minus second named treatment such that a positive difference favors the first named treatment

Adverse Events

Time Frame	Baseline through 5 days post administration of last treatment
Arm/Group Title	NaF Toothpaste (1426 Ppm F)		NaF Toothpaste (1000 Ppm F)		NaF Toothpaste (500 Ppm F)		Placebo Toothpaste (0 Ppm F)
Arm/Group Description	Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (1426 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided		Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (1000 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided		Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (500 ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided		Participants were fitted with enamel specimen appliance in the palatal surface 5 minutes before treatment initiation. Participants brushed their teeth for one timed minute with 1.0 g ± 0.1g of NaF toothpaste (0ppm F) and expectorated. The direct contact between palatal appliance and toothbrush was avoided
All Cause Mortality
	NaF Toothpaste (1426 Ppm F)		NaF Toothpaste (1000 Ppm F)		NaF Toothpaste (500 Ppm F)		Placebo Toothpaste (0 Ppm F)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	NaF Toothpaste (1426 Ppm F)		NaF Toothpaste (1000 Ppm F)		NaF Toothpaste (500 Ppm F)		Placebo Toothpaste (0 Ppm F)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/55 (0%)		0/55 (0%)		0/55 (0%)		0/55 (0%)
Other (Not Including Serious) Adverse Events
	NaF Toothpaste (1426 Ppm F)		NaF Toothpaste (1000 Ppm F)		NaF Toothpaste (500 Ppm F)		Placebo Toothpaste (0 Ppm F)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/55 (7.3%)		6/55 (10.9%)		7/55 (12.7%)		6/55 (10.9%)
Ear and labyrinth disorders
Sinusitis	0/55 (0%)	0	1/55 (1.8%)	1	1/55 (1.8%)	1	0/55 (0%)	0
Ear infection	1/55 (1.8%)	1	0/55 (0%)	0	0/55 (0%)	0	0/55 (0%)	0
Gastrointestinal disorders
Oral herpes	0/55 (0%)	0	0/55 (0%)	0	1/55 (1.8%)	1	1/55 (1.8%)	1
Musculoskeletal and connective tissue disorders
Myalgia	0/55 (0%)	0	1/55 (1.8%)	1	0/55 (0%)	0	0/55 (0%)	0
Gingival erythema	0/55 (0%)	0	0/55 (0%)	0	0/55 (0%)	0	1/55 (1.8%)	1
Nervous system disorders
Headache	1/55 (1.8%)	1	2/55 (3.6%)	2	2/55 (3.6%)	2	0/55 (0%)	0
Renal and urinary disorders
Blood urine present	0/55 (0%)	0	0/55 (0%)	0	0/55 (0%)	0	1/55 (1.8%)	1
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis	0/55 (0%)	0	0/55 (0%)	0	2/55 (3.6%)	2	1/55 (1.8%)	1
Pharyngitis streptococcal	0/55 (0%)	0	1/55 (1.8%)	1	1/55 (1.8%)	1	0/55 (0%)	0
Skin and subcutaneous tissue disorders
Lip injury	2/55 (3.6%)	2	0/55 (0%)	0	0/55 (0%)	0	1/55 (1.8%)	1
Rash	0/55 (0%)	0	1/55 (1.8%)	1	0/55 (0%)	0	0/55 (0%)	0
Chapped lips	0/55 (0%)	0	0/55 (0%)	0	0/55 (0%)	0	1/55 (1.8%)	1

Limitations/Caveats

[Not Specified]

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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.