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    Clinical Trial Results:
    Comparison of the caries-protective effect of fluoride varnish (Duraphat®) with treatment as usual in nursery school attenders receiving preventive oral health support through the Childsmile Programme: a Randomised Controlled Trial

    Summary
    EudraCT number
    		 2012-002287-26
    Trial protocol
    		 GB  
    Global end of trial date
    31 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Feb 2019
    First version publication date
    13 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GN12CO201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01674933
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Greater Glasgow & Clyde Health Board
    Sponsor organisation address
    Clinical Research & Development, Dalnair Street , Glasgow, United Kingdom, G3 8SW
    Public contact
    Paul Dearie, Clinical Research & Development, NHS Greater Glasgow & Clyde Health Board , +44 01412321810, paul.dearie@ggc.scot.nhs.uk
    Scientific contact
    Dr Marc Jones, Clinical Research & Development, NHS Greater Glasgow & Clyde Health Board , +44 07989470505, marc.jones@ggc.scot.nhs.uk
    Sponsor organisation name
    The University of Glasgow
    Sponsor organisation address
    University Avenue, Glasgow, United Kingdom, G12 8QQ
    Public contact
    William Wright, Glasgow Dental Hospital & School. University of Glasgow, Sauchiehall Street, Glasgow. G2 3JZ, +44 01412119802, william.wright@glasgow.ac.uk
    Scientific contact
    Professor Lorna Macpherson, Glasgow Dental Hospital & School. University of Glasgow, Sauchiehall Street, Glasgow. G2 3JZ, +44 01412119751, lorna.macpherson@glasgow.ac.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
    Interim
    Date of interim/final analysis
    22 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does Duraphat® fluoride varnish applied in addition to usual treatment provide additional protection against dental decay in children attending nursery school? Dental decay is measured by the d3mft score, based on the number of decayed (i.e. decay into the tooth dentine), missing or filled teeth. This score will be compared at baseline and 2 years later.
    Protection of trial subjects
    The participants' parents / guardians completed a contraindications checklist prior to each of the study interventions. Children were assessed for obvious temporary infections or injuries by dental nurses immediately before each of the study interventions and any child deemed too unwell or injured were excluded from that intervention, also children who were regarded as too distressed or nervous to undertake an intervention were excluded from that particular intervention. Children who were assessed as too nervous or distressed to undertake the baseline dental inspection were excluded from the trial and participants who were too nervous or distressed to undergo an endpoint dental inspection were excluded from that inspection. All children presented for inspections and study interventions in groups and dentists and dental nurses tried to ensure that the more confident and relaxed children were given the inspection or intervention first in order to provide an example for the others.
    Background therapy
    		 Background therapy is the Childsmile Core (CS) intervention, which is part of the Childsmile child oral health improvement programme. CS Core comprises supervised daily toothbrushing with fluoride toothpaste (circa 1000ppm F) in nursery schools, free dental packs of fluoride toothpaste, toothbrushes and advice. Participants in both arms of the trial receive CS Core as the treatment as usual (TAU).
    Evidence for comparator
    		 No treatment
    Actual start date of recruitment
    01 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 1284
    Worldwide total number of subjects
    1284
    EEA total number of subjects
    1284
    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)
    1284
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Consent was taken from parents / guardians using both postal and face-to-face recruitment methods. Participants were recruited from the ante pre-school classes in 65 public nursery schools in 13 Local Authorities in Scotland during the school years of 2012-13, 2013-14 and 2014-15. Children has were inspected and randomised in their nursery school

    Pre-assignment
    Screening details
    		 Inclusion criteria: provision of a signed informed consent form from a parent or legal guardian; children in the first year of nursery school; Exclusion criteria: hypersensitivity to colophony and / or any other constituents; a history of bronchial asthma requiring hospitalisation; and history of allergic episodes requiring hospital admission.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    Assessors in this instance are the dentists conducting the baseline and endpoint dental inspections and they were not made aware of the participants allocation to either study arm. Dental nurses applied the study intervention (fluoride varnish) so were aware. All trial data was recorded on paper case report forms and transferred from the study sites to the central trial management site for checking and transfer to an independent clinical trials unit.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 Participants in the intervention arm will receive, at each treatment, a total volume of 0.25ml of Duraphat® Dental Suspension. Each 1 ml of Duraphat® Dental Suspension contains 50mg sodium fluoride which is equivalent to 22.6mg of fluoride. The treatments will be applied at approximately six monthly intervals for 18 months i.e. baseline, and at 6 months, 12 months and finally 18 months post-baseline. Participants also received supervised daily toothbrushing with fluoride toothpaste (1000 ppm).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Duraphat dental suspension
    Investigational medicinal product code
    A01AA
    Other name
    Duraphat 50/mg/ml Dental Suspension, Colgate Duraphat Varnish 50mg/ml Dental Suspension
    Pharmaceutical forms
    Dental suspension
    Routes of administration
    Dental use
    Dosage and administration details
    At each treatment, a total volume of 0.25ml of Duraphat® Dental Suspension will be applied by study dental nurses to the teeth of children using an applicator brush. Each 1 ml of Duraphat® Dental Suspension contains 50mg sodium fluoride which is equivalent to 22.6mg of fluoride. Participants will receive 4 applications at approximately 6 monthly intervals over an 18 month period.

    Arm title
    		 Treatment as Usual
    Arm description
    		 All children receive treatment as usual (TAU), namely supervised toothbrushing in their nursery school. TAU is the Childsmile Core intervention comprising supervised daily toothbrushing with fluoride toothpaste (circa 1000ppm F), free dental packs of fluoride toothpaste, toothbrushes and advice. Children in the TAU arm will receive the same series of contacts as those in the intervention arm, including the Childsmile Core intervention, without the application of varnish.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The dentists / assessors who undertook the baseline and the endpoint dental inspections were not made aware which trial arm participants were allocated to. This was undertaken to avoid any potential influence or bias this knowledge might have had during both dental inspections. Dental nurses applied the varnish at the interventions and therefore had to be aware. The participants would also have been aware if fluoride varnish had been applied to their teeth or not.
    Number of subjects in period 1
    		Intervention Treatment as Usual
    Started
    643
    641
    Completed
    577
    573
    Not completed
    66
    68
         Consent withdrawn by subject
    8
    13
         Contraindication
    2
    1
         Missing final inspection case report form
    -
    5
         Final inspection visit not undertaken
    1
    -
         Incomplete data excluded from analyses
    1
    1
         Lost to follow-up
    42
    35
         Incomplete case report form
    1
    -
         Refused final inspection
    2
    2
         Absent final inspection
    9
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Participants were screened and given a baseline dental inspection prior to randomisation into one of the two trial arms. The number of subjects reported here are those randomised into the trial after screening and baseline inspections had been completed.

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 1284 1284
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.52 ( 0.28 ) -
    Gender categorical
    Units: Subjects
        Female
    		 673 673
        Male
    		 611 611

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Participants in the intervention arm will receive, at each treatment, a total volume of 0.25ml of Duraphat® Dental Suspension. Each 1 ml of Duraphat® Dental Suspension contains 50mg sodium fluoride which is equivalent to 22.6mg of fluoride. The treatments will be applied at approximately six monthly intervals for 18 months i.e. baseline, and at 6 months, 12 months and finally 18 months post-baseline. Participants also received supervised daily toothbrushing with fluoride toothpaste (1000 ppm).

    Reporting group title
    Treatment as Usual
    Reporting group description
    		 All children receive treatment as usual (TAU), namely supervised toothbrushing in their nursery school. TAU is the Childsmile Core intervention comprising supervised daily toothbrushing with fluoride toothpaste (circa 1000ppm F), free dental packs of fluoride toothpaste, toothbrushes and advice. Children in the TAU arm will receive the same series of contacts as those in the intervention arm, including the Childsmile Core intervention, without the application of varnish.

    Primary: Occurrence of new caries lesions

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    End point title
    		 Occurrence of new caries lesions
    End point description
    The primary endpoint for each individual child is whether or not there has been any occurrence of new caries lesions over the two year period, as measured by any increase in d3mft at two years of follow up compared to the d3mft at baseline (d3mft is dental decay as measured by the dmft scale in the dentine).
    End point type
    Primary
    End point timeframe
    The primary endpoint for each individual child is whether or not there has been any occurrence of new caries lesions over a two year period.
    End point values
    		 Intervention Treatment as Usual
    Number of subjects analysed
    643
    641
    Units: d3mft scores
    577
    573
    Statistical analysis title
    		 Analyses - clinical trial with a binary endpoint
    Statistical analysis description
    Binary endpoints will be analysed by Mantel-Haenszel Chi-squared tests and odds-ratios, with the attendant 95% confidence intervals. Changes in d3mft will be analysed by Wilcoxon tests, unless these changes are normally distributed and therefore suitable for analysis by Analysis of Covariance. Compliance will be compared with a chi-squared test. Null hypothesis: dental health of children in the FV arm of study is no better after 18m of varnish application than that of the children in the TAU arm
    Comparison groups
    Intervention v Treatment as Usual
    Number of subjects included in analysis
    1284
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0782 [1]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.7955
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6166
         upper limit
    		 1.0263
    Variability estimate
    Standard error of the mean
    Notes
    [1] - All statistical tests will be two-tailed tests at the 5% significance level.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Any adverse reaction is extremely likely to be seen within a maximum of 24 hours post application. Any adverse events reported by parents during that time will be recorded and evaluated by the Childsmile coordinator and the local Principal Investigator.
    Adverse event reporting additional description
    Any adverse reactions whether noted by Childsmile staff or reported to Childsmile staff by parents or the staff at the nursery school, will cause either the study dental nurse or dental health support worker to record details in the relevant Case Report Form and to inform the site Principal Investigator.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0 2017
    Reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Participants in the intervention arm will receive at each treatment, a total volume of 0.25ml of Duraphat® Dental Suspension. Each 1 ml of Duraphat® Dental Suspension contains 50mg sodium fluoride which is equivalent to 22.6mg of fluoride. The treatments will be applied at approximately six monthly intervals for 18 months i.e. baseline, and at 6 months, 12 months and finally 18 months post-baseline. Participants also received supervised daily toothbrushing with fluoride toothpaste (1000 ppm).

    Reporting group title
    Treatment as Usual
    Reporting group description
    		 Treatment as usual (TAU) is the Childsmile Core intervention comprising supervised daily toothbrushing with fluoride toothpaste (circa 1000ppm F), free dental packs of fluoride toothpaste, toothbrushes and advice. Children in the TAU arm will receive the same series of contacts as those in the intervention arm, including the Childsmile Core intervention, without the application of varnish.

    Serious adverse events
    		 Intervention Treatment as Usual
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 643 (0.00%)
    0 / 641 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intervention Treatment as Usual
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 643 (0.00%)
    0 / 641 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: The reporting period for any adverse events or adverse reactions in this trial was set at 24 hours post-application of the fluoride varnish, which is a relatively short length of time. We did not have any adverse events (non-serious or serious) reported to trial staff, by parents or nursery staff, during this period and nor did any of the trial staff record an adverse event (non-serious or serious) during any of the intervention or inspection visits.

    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
    26 Jun 2015
    On Friday 26th of June 2015, the Chief Investigator notified our co-sponsor (NHS Health Board Greater Glasgow and Clyde) of the suspension of the trial pending clarification of a potential trial medication safety issue. This centered around the possibility that a component of the packaging of the Duraphat® fluoride varnish (the ‘0’ ring seal) used in the study contained latex, and this could constitute a possible risk of an allergic reaction among children given the product. Following consultation with the manufacturer, the co-sponsor notified the Research Ethics Committee (REC) and the Medicines and Healthcare products Regulatory Agency (MHRA) by a substantial amendment, dated 09/07/2015, of the temporary suspension of recruitment and treatment of study participants. After assessing the potential safety implication of this new information the co-sponsor concluded that overall there is no fundamental change to the risk-benefit assessment of the trial based on the new information. In addition the manufacturer, Colgate Palmolive, considers it unlikely under normal or extraordinary circumstances that a latex sensitivity or reaction could arise through use of the product. Accordingly, the co-sponsor did not consider that the exclusion criteria of the protocol needed to be amended. The current protocol already excluded children with serious allergy. The co-sponsor made an application to the MHRA to restart the trial on the 8th of August 2015, permission was granted to re-start by the Agency on the 3rd of September 2015.
    03 Sep 2015

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26681191
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