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    Clinical Trial Results:
    A Randomised controlled trial to Evaluate the effectiveness and cost benefit of prescribing high dose FLuoride toothpaste in preventing and treating dEntal Caries in high-risk older adulTs (REFLECT trial)

    Summary
    EudraCT number
    		 2017-002402-13
    Trial protocol
    		 GB  
    Global end of trial date
    21 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Aug 2026
    First version publication date
    13 Aug 2026
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    R04684
    Additional study identifiers
    ISRCTN number
    		 ISRCTN11992428
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Manchester University NHS Foundation Trust
    Sponsor organisation address
    Oxford Road, Manchester, United Kingdom, M13 9WL
    Public contact
    Dr Lynne Webster, Manchester University NHS Foundation Trust, +44 01612764125, lynne.webster@mft.nhs.uk
    Scientific contact
    Dr Lynne Webster, Manchester University NHS Foundation Trust, +44 01612764125, lynne.webster@mft.nhs.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Dec 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of prescribing 5000ppm fluoride toothpaste with usual care on treatment for caries, including coronal/root restorations, endodontics or extractions To compare the costs and benefits, within a net benefit framework of prescribing 5000ppm fluoride toothpaste with usual care
    Protection of trial subjects
    Fluoride 5000ppm toothpaste is indicated in adults and adolescents aged 16 years and over for the prevention of dental caries, particularly amongst those at risk for multiple caries. The toothpaste was used within its licence within the REFLECT trial. Because of the high fluoride content, the SmPC recommends that the opinion of a dental specialist must be sought before the product used. Within REFLECT, all participants were assessed to be eligible by a general dental practitioner (GDP), and those randomised to the fluoride 5000ppm toothpaste had this prescribed to them by the GDP and dispensed by community pharmacists. The toothpaste is topically administered and known side effects are rare and minor. The CI and sponsor carried out a risk assessment and concluded this is a low-risk trial. At each routine follow-up appointment, dentists were asked to record any possible adverse reactions (serious or non-serious) to the toothpaste. In addition, all deaths were recorded. The study team monitored accruing safety data.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 1156
    Worldwide total number of subjects
    1156
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    660
    From 65 to 84 years
    479
    85 years and over
    17

    Subject disposition

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    Recruitment
    Recruitment details
    		 The clinical setting for the trial was general dental practices (primary care) in the UK (excluding N Ireland) providing NHS care. NHS patients 50 years or older, with active coronal caries in the last 12 months or any root caries; and\or other risk factors and for whom the dental practitioner decided were appropriate were invited to participate.

    Pre-assignment
    Screening details
    		 See published protocol (Tickle et al., 2019) for specific screening details and inclusion/exclusion criteria.

    Pre-assignment period milestones
    Number of subjects started
    		 1625 [1]
    Number of subjects completed
    		 1156

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Declined: Not want to participate in study: 346
    Reason: Number of subjects
    		 Ineligible: Already prescribed Fluoride toothpaste: 19
    Reason: Number of subjects
    		 Ineligible: Sodium fluoride hypersensitivity: 2
    Reason: Number of subjects
    		 Ineligible: Sharing abode with someone in trial: 6
    Reason: Number of subjects
    		 Ineligible: Unable to complete questionnaires: 4
    Reason: Number of subjects
    		 Ineligible: Unable to give informed consent: 8
    Reason: Number of subjects
    		 Other reason given: 81
    Reason: Number of subjects
    		 Post Randomisation Exclusions: 3
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1625 were the number screened for eligibility, 469 declined or were ineligible/post-randomisation exclusions, and 1156 is the final number randomised to the trial.
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Trial was open label so neither subject nor dentist were blinded. The trial statistician and the study team were blinded to the allocation during all analyses. Blinding to primary outcome was not possible but a more detailed clinical examination undertaken by independent (external to the trial dental practices) and blinded trained clinical examiners was conducted to collect secondary clinical outcomes in the Scottish practices only.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 High-dose fluoride plus usual care
    Arm description
    		 GDP prescription of 5000 parts per million (ppm) fluoride toothpaste, used as advised by the participant’s dentist, plus usual care
    Arm type
    		 Experimental

    Investigational medicinal product name
    5000ppm fluoride toothpaste
    Investigational medicinal product code
    A01AA01
    Other name
    Pharmaceutical forms
    Toothpaste
    Routes of administration
    Dental use
    Dosage and administration details
    GDP prescription of 5000 parts per million (ppm) fluoride toothpaste, used as advised by the participant’s dentist (twice a day), plus usual care

    Arm title
    		 Usual care only
    Arm description
    		 Any advice given by the GDP will be to use standard, off-the-shelf, fluoride toothpaste (1350-1500 ppm).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		High-dose fluoride plus usual care Usual care only
    Started
    579
    577
    Completed
    579
    577
    Period 2
    Period 2 title
    Trial follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 High-dose fluoride plus usual care
    Arm description
    		 GDP prescription of 5000 parts per million (ppm) fluoride toothpaste, used as advised by the participant’s dentist, plus usual care
    Arm type
    		 Experimental

    Investigational medicinal product name
    5000ppm fluoride toothpaste
    Investigational medicinal product code
    A01AA01
    Other name
    Pharmaceutical forms
    Toothpaste
    Routes of administration
    Dental use
    Dosage and administration details
    GDP prescription of 5000 parts per million (ppm) fluoride toothpaste, used as advised by the participant’s dentist (twice a day), plus usual care

    Arm title
    		 Usual care only
    Arm description
    		 Any advice given by the GDP will be to use standard, off-the-shelf, fluoride toothpaste (1350-1500 ppm).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		High-dose fluoride plus usual care Usual care only
    Started
    579
    577
    Completed
    420
    427
    Not completed
    159
    150
         Lost to follow-up
    159
    150

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    High-dose fluoride plus usual care
    Reporting group description
    		 GDP prescription of 5000 parts per million (ppm) fluoride toothpaste, used as advised by the participant’s dentist, plus usual care

    Reporting group title
    Usual care only
    Reporting group description
    		 Any advice given by the GDP will be to use standard, off-the-shelf, fluoride toothpaste (1350-1500 ppm).

    Reporting group values
    		 High-dose fluoride plus usual care Usual care only Total
    Number of subjects
    		 579 577 1156
    Age categorical
    NHS dental patients, 50 years of age or older, attending a GDP who are considered by their dentist to be at high risk of developing caries.
    Units: Subjects
        50-65
    		 359 354 713
        >65
    		 220 223 443
    Age continuous
    NHS dental patients, 50 years of age or older, attending a GDP who are considered by their dentist to be at high risk of developing caries.
    Units: years
        arithmetic mean (standard deviation)
    		 63.4 ( 8.9 ) 63.3 ( 8.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 282 286 568
        Male
    		 297 291 588
    Exemption from NHS charges
    Exempt from paying NHS dental treatment charges (minimisation variable).
    Units: Subjects
        Yes
    		 161 162 323
        No
    		 418 415 833
    Recruitment site
    Recruitment site split by geographic region
    Units: Subjects
        Scotland
    		 298 296 594
        Northern Ireland
    		 175 172 347
        England
    		 106 109 215
    Residential Setting
    Minimisation variable.
    Units: Subjects
        Own Home
    		 577 576 1153
        Care Home
    		 2 1 3
    Prevalence of coronal caries experience
    Cavitation into dentine
    Units: Subjects
        Yes
    		 578 577 1155
        No
    		 1 0 1
    Prevalence of recession with caries on root surfaces
    Units: Subjects
        No
    		 457 459 916
        Yes
    		 120 115 235
        Missing
    		 2 3 5
    Prevalence of active or untreated decay
    Units: Subjects
        No
    		 374 370 744
        Yes
    		 205 206 411
        Missing
    		 0 1 1
    Toothache in the previous 12 months
    Units: Subjects
        Yes
    		 188 182 370
        No
    		 366 375 741
        Missing
    		 25 20 45
    Best practice frequency brushing (Twice a day)
    Those following best practice in terms of brushing frequency (twice a day vs all other options)
    Units: Subjects
        Best practice
    		 390 355 745
        Not best practice
    		 168 199 367
        Missing
    		 21 23 44
    Best practice duration brushing (2 minutes)
    Those following best practice for brushing duration (2 minutes vs all other options)
    Units: Subjects
        Best practice
    		 193 211 404
        Not best practice
    		 363 340 703
        Missing
    		 23 26 49
    Best practice post-brushing behaviour (spit but not rinse)
    Those following best practice for post-brushing behaviour (spit, but not rinse vs all other options)
    Units: Subjects
        Best practice
    		 166 171 337
        Not best practice
    		 379 375 754
        Missing
    		 34 31 65
    Type of toothbrush
    Units: Subjects
        Power
    		 230 207 437
        Manual
    		 309 329 638
        Both
    		 14 11 25
        Missing
    		 26 30 56
    Dose of toothpaste on larger head
    Units: Subjects
        Full coverage of toothbrush head
    		 187 179 366
        Not full coverage
    		 196 211 407
        Missing
    		 196 187 383
    Dose of toothpaste on smaller head
    Units: Subjects
        Full coverage of toothbrush head
    		 242 216 458
        Not full coverage
    		 47 54 101
        Missing
    		 290 307 597
    Applies toothpaste more than once when brushing teeth
    Units: Subjects
        Yes
    		 51 48 99
        No
    		 503 504 1007
        Missing
    		 25 25 50
    Daily mouthwash contains fluoride
    Units: Subjects
        Yes
    		 83 77 160
        No
    		 19 23 42
        Don't know
    		 124 127 251
        Missing
    		 353 350 703
    DMFT Coronal
    Decayed, Missing or Filled coronal Teeth (DMFT) excluding wisdoms
    Units: Teeth
        arithmetic mean (standard deviation)
    		 19.2 ( 4.9 ) 18.8 ( 4.9 ) -
    DMFS Coronal
    Decayed, Missing or Filled coronal Surfaces (DMFT) excluding wisdoms
    Units: Surfaces
        arithmetic mean (standard deviation)
    		 67.4 ( 23.4 ) 65.9 ( 23.6 ) -
    DRT
    Root Decayed Teeth
    Units: Teeth
        arithmetic mean (standard deviation)
    		 0.5 ( 1.5 ) 0.4 ( 1.2 ) -
    Missing teeth
    Units: Teeth
        arithmetic mean (standard deviation)
    		 7.6 ( 5.5 ) 7.3 ( 5.5 ) -
    EQ-5D-5L
    Units: Utility value
        arithmetic mean (standard deviation)
    		 0.832 ( 0.227 ) 0.827 ( 0.220 ) -
    EQ-5D-5L-VAS
    Visual Analog Scale (VAS)
    Units: Utility Score
        arithmetic mean (standard deviation)
    		 79.595 ( 20.504 ) 79.017 ( 20.448 ) -
    OHIP-14
    Oral Health Impact Profile-14
    Units: Utility Score
        arithmetic mean (standard deviation)
    		 5.7 ( 7.9 ) 5.7 ( 7.3 ) -
    Sugar Intake
    Three questions covered frequency of consumption of sugary items (cakes, sweets, fizzy drinks) using five frequency categories. We calculated a score of exposure to sugar intake by coding the replies to each question as follows: we attributed a four to the maximum frequency of consumption (6 or more times a week) and three to the following category (3-5 times a week) and so on until the last category (rarely or never) which will be coded as zero. Final question asks sugar in hot drinks, if yes, coded as 0. Final score ranges from 0 (no exposure) to 16 (very frequent exposure to sugar intake)
    Units: Exposure score
        arithmetic mean (standard deviation)
    		 7.4 ( 3.7 ) 7.4 ( 3.5 ) -

    End points

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    End points reporting groups
    Reporting group title
    High-dose fluoride plus usual care
    Reporting group description
    		 GDP prescription of 5000 parts per million (ppm) fluoride toothpaste, used as advised by the participant’s dentist, plus usual care

    Reporting group title
    Usual care only
    Reporting group description
    		 Any advice given by the GDP will be to use standard, off-the-shelf, fluoride toothpaste (1350-1500 ppm).
    Reporting group title
    High-dose fluoride plus usual care
    Reporting group description
    		 GDP prescription of 5000 parts per million (ppm) fluoride toothpaste, used as advised by the participant’s dentist, plus usual care

    Reporting group title
    Usual care only
    Reporting group description
    		 Any advice given by the GDP will be to use standard, off-the-shelf, fluoride toothpaste (1350-1500 ppm).

    Primary: Number of participants requiring dental treatment of one or more teeth due to caries

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    End point title
    		 Number of participants requiring dental treatment of one or more teeth due to caries
    End point description
    The primary outcome measure, requirement for any dental treatment due to caries including restorations, endodontics or extraction, was analysed using a multilevel mixed-effects generalised linear model adjusting for minimisation variables and including a random effect intercept for centre (residential setting (own home/care home), exemption (including partial exemption) from dental treatment charges (yes/no) and age band (50-65; >65)). Analysis followed the intention-to-treat framework in accordance with the approved, pre-specified statistical plan.
    End point type
    Primary
    End point timeframe
    Up to 36 months post randomisation (with a 33-42 month acceptable follow-up window)
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    420
    427
    Units: Participants
        Yes
    279
    302
        No
    141
    125
    Statistical analysis title
    		 Generalised linear model
    Statistical analysis description
    A multilevel mixed-effects generalised linear model adjusting for minimisation variables and including a random effect intercept for centre was used to analyse the primary outcome.
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    847
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12

    Secondary: Difference in the OHIP-14 measure

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    End point title
    		 Difference in the OHIP-14 measure
    End point description
    End point type
    Secondary
    End point timeframe
    Oral health status using OHIP14, a measure of oral health-related Quality of Life (QoL), collected at baseline and annual follow up through patient administered questionnaires. The end point of interest is the 3 year follow up.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    396
    394
    Units: Score
        arithmetic mean (standard deviation)
    6.94 ( 9.89 )
    7.13 ( 9.23 )
    Statistical analysis title
    		 Linear mixed model
    Statistical analysis description
    Linear mixed model used to analyse the repeated measures of the OHIP-14 outcome adjusted for the minimisation variables; residential setting, age band, exemption from NHS dental charges, and centre (the latter via a random effect). Treatment effects at each time were derived from the interaction term for time by treatment.
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    790
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.235
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.53
         upper limit
    		 0.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.49

    Secondary: Difference in the EQ-5D-5L utility score

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    End point title
    		 Difference in the EQ-5D-5L utility score
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline and annual patient reported questionnaires during the 3 year follow up. The endpoint of interest is analysed at 3 years post randomisation.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    396
    397
    Units: Score
        arithmetic mean (standard deviation)
    0.743 ( 0.287 )
    0.747 ( 0.287 )
    Statistical analysis title
    		 Linear mixed model
    Statistical analysis description
    Linear mixed model used to analyse the repeated measures of the OHIP-14 outcome adjusted for the minimisation variables; residential setting, age band, exemption from NHS dental charges, and centre (the latter via a random effect). Treatment effects at each time were derived from the interaction term for time by treatment.
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    793
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.986
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.026
         upper limit
    		 0.025
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.013

    Secondary: Difference in the EQ-5D visual analog score (VAS)

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    End point title
    		 Difference in the EQ-5D visual analog score (VAS)
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline & each annual questionnaire during the 3 year trial follow up period. The endpoint of interest is analysed at 3 years post randomisation.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    397
    403
    Units: Score
        arithmetic mean (standard deviation)
    76.270 ( 20.386 )
    75.955 ( 19.510 )
    Statistical analysis title
    		 Linear mixed model
    Statistical analysis description
    Linear mixed model used to analyse the repeated measures of the OHIP-14 outcome adjusted for the minimisation variables; residential setting, age band, exemption from NHS dental charges, and centre (the latter via a random effect). Treatment effects at each time were derived from the interaction term for time by treatment.
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    800
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.795
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.294
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.921
         upper limit
    		 2.509
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.13

    Secondary: Number of participants following best dental practice: Toothbrush duration (2 minutes)

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    End point title
    		 Number of participants following best dental practice: Toothbrush duration (2 minutes)
    End point description
    End point type
    Secondary
    End point timeframe
    Recorded at baseline and annual patient questionnaire during the trial follow up period. The endpoint of interest is analysed at 3 years post randomisation.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    408
    414
    Units: Participants
        Best practice
    162
    142
        Not best practice
    246
    272
    Statistical analysis title
    		 Generalised linear model
    Statistical analysis description
    Generalised linear model - following a binary distribution - used to analyse the toothbrush duration best practice outcome at 3 years adjusted for toothbrush duration best practice at baseline and the minimisation variables; residential setting, age band, exemption from NHS dental charges, and centre (the latter via a random effect).
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    822
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.112
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19

    Secondary: Number of participants following best dental practice: Toothbrush frequency (twice a day)

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    End point title
    		 Number of participants following best dental practice: Toothbrush frequency (twice a day)
    End point description
    End point type
    Secondary
    End point timeframe
    Recorded at baseline and annual patient questionnaire during the trial follow up period. The endpoint of interest is analysed at 3 years post randomisation.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    408
    414
    Units: Participants
        Best practice
    269
    266
        Not best practice
    139
    148
    Statistical analysis title
    		 Generalised linear model
    Statistical analysis description
    Generalised linear model - following a binary distribution - used to analyse the toothbrush frequency best practice outcome at 3 years adjusted for toothbrush frequency best practice at baseline and the minimisation variables; residential setting, age band, exemption from NHS dental charges, and centre (the latter via a random effect).
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    822
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.932
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.18

    Secondary: Number of participants following best dental practice: Post-brushing (Spit, but no rinse)

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    End point title
    		 Number of participants following best dental practice: Post-brushing (Spit, but no rinse)
    End point description
    End point type
    Secondary
    End point timeframe
    Recorded at baseline and annual patient questionnaire during the trial follow up period. The endpoint of interest is analysed at 3 years post randomisation.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    408
    412
    Units: Participants
        Best practice
    202
    163
        Not best practice
    206
    249
    Statistical analysis title
    		 Generalised linear model
    Statistical analysis description
    Generalised linear model - following a binary distribution - used to analyse the post-brushing best practice outcome at 3 years adjusted for post-brushing best practice at baseline and the minimisation variables; residential setting, age band, exemption from NHS dental charges, and centre (the latter via a random effect).
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    820
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.15
         upper limit
    		 2.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.23

    Secondary: Number of participants experiencing episodes of toothache (Recorded at least once during follow up)

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    End point title
    		 Number of participants experiencing episodes of toothache (Recorded at least once during follow up)
    End point description
    End point type
    Secondary
    End point timeframe
    Recorded at baseline and annual patient questionnaire during the trial follow up period. The endpoint of interest is analysed at 3 years post randomisation.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    418
    430
    Units: Participants
        Yes
    214
    250
        No
    204
    180
    Statistical analysis title
    		 Generalised linear model
    Statistical analysis description
    Generalised linear model - following a binary distribution - used to analyse the episodes of toothache outcome at 3 years adjusted for prior episodes of toothache at baseline and the minimisation variables; residential setting, age band, exemption from NHS dental charges, and centre (the latter via a random effect).
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    848
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09

    Secondary: Difference in Decayed, Missing or Filled Surfaces coronal increment cavitation level (Scottish subset)

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    End point title
    		 Difference in Decayed, Missing or Filled Surfaces coronal increment cavitation level (Scottish subset)
    End point description
    The increment score was calculated as the difference at follow up from baseline in the number of cavitated tooth surfaces calculated at the patient level. This increment was then supplemented by CRF information to account for coronal restorations due to caries (Filling, crown, extraction, veneer).
    End point type
    Secondary
    End point timeframe
    Recorded at baseline and 3 years post randomisation.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    106
    103
    Units: Surfaces
        arithmetic mean (standard deviation)
    2.26 ( 4.99 )
    3.20 ( 5.58 )
    Statistical analysis title
    		 Generalised linear model
    Statistical analysis description
    Generalised mixed model used to analyse the DMFS increment outcome adjusted for the minimisation variables; residential setting, age band, exemption from NHS dental charges, and centre (the latter via a random effect).
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.187
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.16
         upper limit
    		 0.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.66

    Secondary: Difference in Decayed, Filled Surface root increment cavitation level (Scottish subset)

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    End point title
    		 Difference in Decayed, Filled Surface root increment cavitation level (Scottish subset)
    End point description
    The increment score was calculated as the difference at follow up from baseline in the number of cavitated root surfaces at the patient level. This increment was then supplemented by CRF information to account for root restorations & root canal treatment due to caries.
    End point type
    Secondary
    End point timeframe
    Recorded at baseline and 3 years post randomisation.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    106
    103
    Units: Surfaces
        arithmetic mean (standard deviation)
    0.82 ( 1.32 )
    0.74 ( 1.41 )
    Statistical analysis title
    		 Generalised linear model
    Statistical analysis description
    Generalised mixed model used to analyse the DFS root increment outcome adjusted for the minimisation variables; residential setting, age band, exemption from NHS dental charges, and centre (the latter via a random effect).
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.182
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13

    Secondary: Difference in progression of early caries surfaces by ICDAS (Scottish subset)

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    End point title
    		 Difference in progression of early caries surfaces by ICDAS (Scottish subset)
    End point description
    Progression of early caries from baseline to 36 months. Those surfaces progressing from Tooth Surface Code = Caries & ICDAS code = First change in enamel/distinct visual change in enamel at baseline to more severe decay at 36 months. The analysis accounts for number of early caries at baseline since everyone has a different starting point.
    End point type
    Secondary
    End point timeframe
    Recorded at baseline and 3 years post randomisation.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    97
    97
    Units: Surfaces
        arithmetic mean (standard deviation)
    0.96 ( 1.03 )
    1.04 ( 1.17 )
    Statistical analysis title
    		 Generalised linear model
    Statistical analysis description
    Generalised mixed model used to analyse the progression of early caries outcome adjusted for the minimisation variables; residential setting, age band, exemption from NHS dental charges, and centre (the latter via a random effect).
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.099
    Method
    		 Mixed models analysis
    Parameter type
    		 Incidence Rate Ratio
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13

    Secondary: Difference in bleeding on probing surfaces (Scottish subset)

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    End point title
    		 Difference in bleeding on probing surfaces (Scottish subset)
    End point description
    The number of surfaces with bleeding on probing at 36 months, analysis accounts for differences in number of surfaces measured for BOP at 36 months, and the analysis model includes the number of bleeding surfaces at baseline as a predictor variable.
    End point type
    Secondary
    End point timeframe
    Recorded at baseline and 3 years post randomisation.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    106
    103
    Units: Surfaces
        arithmetic mean (standard deviation)
    2.40 ( 4.42 )
    1.97 ( 3.60 )
    Statistical analysis title
    		 Generalised linear model
    Statistical analysis description
    Generalised mixed model used to analyse the bleeding surfaces outcome adjusted for total surfaces bleeding at baseline and the minimisation variables; residential setting, age band, exemption from NHS dental charges, and centre (the latter via a random effect).
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.263
    Method
    		 Mixed models analysis
    Parameter type
    		 Incidence Rate Ratio
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 2.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3

    Other pre-specified: Sensitivity analysis: Number of participants requiring dental treatment on one or more teeth due to caries

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    End point title
    		 Sensitivity analysis: Number of participants requiring dental treatment on one or more teeth due to caries
    End point description
    A sensitivity analysis of the primary outcome up to 36 months post randomisation, using the same analysis as the primary outcome, where participants that did not require treatment will be included as such in the extended acceptable window of 30-48 months post randomisation.
    End point type
    Other pre-specified
    End point timeframe
    Up to 36 months post randomisation with an extended acceptable window of 30-48 months post randomisation.
    End point values
    		 High-dose fluoride plus usual care Usual care only
    Number of subjects analysed
    432
    442
    Units: Participants
        Yes
    282
    305
        No
    150
    137
    Statistical analysis title
    		 Generalised linear model
    Comparison groups
    High-dose fluoride plus usual care v Usual care only
    Number of subjects included in analysis
    874
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.159
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation to end of trial follow up period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    High-dose fluoride plus usual care
    Reporting group description
    		 GDP prescription of 5000 parts per million (ppm) fluoride toothpaste, used as advised by the participant’s dentist, plus usual care

    Reporting group title
    Usual care only
    Reporting group description
    		 Any advice given by the GDP will be to use standard, off-the-shelf, fluoride toothpaste (1350-1500 ppm).

    Serious adverse events
    		 High-dose fluoride plus usual care Usual care only
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 579 (0.00%)
    0 / 577 (0.00%)
         number of deaths (all causes)
    13
    13
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 High-dose fluoride plus usual care Usual care only
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 579 (1.55%)
    0 / 577 (0.00%)
    Gastrointestinal disorders
    Oral mucosal erythema
    Additional description: Symptom described on form as: "redness"
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Oral discomfort
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Hyperaesthesia teeth
         subjects affected / exposed
    4 / 579 (0.69%)
    0 / 577 (0.00%)
         occurrences all number
    5
    0
    Oropharyngeal plaque
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Tongue exfoliation
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Gingival pain
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Gingival bleeding
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Abdominal discomfort
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Lip swelling
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    2
    0
    Paraesthesia oral
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    2
    0
    Chapped lips
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Tooth discolouration
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    1 / 579 (0.17%)
    0 / 577 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    22 Mar 2020
    Onset of the COVID-19 pandemic and subsequent social restrictions. Time periods are as follows: Pre-restrictions (Randomisation - 22March2020), During-restrictions (23March2020 - 31October2020), Post-restrictions (1November2020 - 42 months post randomisation)
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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