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    Summary
    EudraCT Number:2017-002402-13
    Sponsor's Protocol Code Number:R04684
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-11-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2017-002402-13
    A.3Full title of the trial
    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)
    A.3.2Name or abbreviated title of the trial where available
    REFLECT
    A.4.1Sponsor's protocol code numberR04684
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN11992428
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorManchester University NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationManchester University NHS Foundation Trust
    B.5.2Functional name of contact pointDr Lynne Webster
    B.5.3 Address:
    B.5.3.1Street AddressThe Research Office, 1st Floor, the Nowgen Building, 29 Grafton Street
    B.5.3.2Town/ cityManchester
    B.5.3.3Post codeM13 9WU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01612764125
    B.5.6E-maillynne.webster@mft.nhs.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name 5000 ppm FLUORIDE TOOTHPASTE
    D.2.1.1.2Name of the Marketing Authorisation holderMorningside Healthcare Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product name5000 ppm FLUORIDE TOOTHPASTE
    D.3.4Pharmaceutical form Toothpaste
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPDental use
    Oral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSodium Fluoride
    D.3.9.1CAS number 7681-49-4
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500 mg fluoride to 100g toothpaste
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Dental caries in high-risk older adults
    E.1.1.1Medical condition in easily understood language
    Tooth decay in high-risk older adults
    E.1.1.2Therapeutic area Diseases [C] - Mouth and tooth diseases [C07]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10012318
    E.1.2Term Dental caries
    E.1.2System Organ Class 10017947 - Gastrointestinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary objectives of the trial
    Secondary objectives will evaluate the effect of prescribing 5000ppm fluoride toothpaste on caries (mean Decayed Missing Filled Surfaces [DMFS]) increment, progression of early caries lesions, bleeding on probing, quality of life (generic and condition specific), costs to the NHS and to individuals and society, oral health behaviour and episodes of pain. In addition, we will explore the attitudes of clinicians and patients to the prescribing and use of high fluoride toothpaste.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A more detailed clinical examination undertaken by independent (external to the trial dental practices) dentists will be used to repeat primary outcome measures and collect secondary outcomes (caries increment and bleeding on probing). This more detailed clinical examination will take place in Scottish practices only and the independent examiners will be blind to the allocation. All clinical outcomes will be assessed at baseline and three years by trained examiners. Training will be provided by an expert in caries assessment and the use of criteria in caries clinical trials.


    A detailed caries measurement will be made using the validated International Caries Detection and Assessment System (ICDAS) for coronal caries. The ICDAS criteria measure both early and more advanced stages of caries. For early caries, ICDAS measures the surface changes and potential histological depth of carious lesions by relying on surface characteristics related to the optical properties of sound and demineralised enamel prior to cavitation. The primary requirement for applying the ICDAS system is the examination of clean and dry teeth aided by a ball-ended explorer that is used to remove any remaining plaque and debris and to check for surface contour, minor cavitation or sealants. All surfaces of all teeth will be examined and the caries status recorded.

    Periodontal Gingival inflammation as bleeding will be measured according to the Gingival Index of Loe by running a UNC periodontal probe circumferentially around each tooth just within the gingival sulcus or pocket. After 30 seconds, bleeding will be recorded as being present or absent on the buccal and lingual surfaces.
    E.3Principal inclusion criteria
    • aged 50 years or older
    • with a diagnosis of active coronal caries (into dentine) in the last 12 months which may\may not have been treated, or any root caries; and\or other risk factors as determined by their GDP.
    • receive their dental care in part or fully as an NHS patient
    • living in any residential setting, and
    • for whom their GDP decides prescription of high concentration fluoride toothpaste is appropriate for the patient
    E.4Principal exclusion criteria
    • are currently prescribed (by General Dental Practice or General Practitioner) high concentration fluoride toothpaste (for GDPs prescription must have been issued at last examination visit)
    • hypersensitivity for Sodium Fluoride and\or other ingredients used in 5000ppm toothpaste
    • are living in the same household as someone already recruited to Reflect
    • are unable to provide informed consent
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of participants receiving any dental treatment due to caries; including restorations, endodontics or extraction.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At 12, 24 and 36 months after commencing treatment
    E.5.2Secondary end point(s)
    Secondary outcomes (patient reported):

    • 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 OHIP-14 is the most common, validated dental quality of life instrument and has been successfully used in previous HTA trials. It has been found to be sensitive to differences in oral health and is closely correlated with self-reported oral health outcomes.

    • The EQ-5D-5L profile measure of generic health status will be collected at baseline and annual follow up through patient questionnaires.

    • Any episode of dental pain (and total number per participant) during the 3 year follow up period severe enough to trigger an unscheduled visit to a healthcare profession (dentist, GP, community pharmacist). This will be recorded at scheduled and unscheduled dental visits by patient questionnaire.

    • Oral health behaviour, including self-reported brushing/other sources of fluoride. Evaluated at baseline and through annual questionnaires sent by mail to the home address of participants.


    Secondary outcomes (clinically assessed): The clinically assessed secondary outcomes will be measured in Scottish practices only. Clinically assessed secondary outcomes are:
    • Coronal caries increment, including dentist replacement restorations for caries, at tooth surface (DMFS) level by independent, trained and calibrated, clinical examiners at baseline and 3 year (+/- 3 months) follow-up. We will use the ICDAS method to assess caries as it provides flexibility to analyse and present caries data at different diagnostic thresholds.
    • Root caries increment, including dentist replacement restorations for caries, at tooth surface (DMFRS) level by independent, trained and calibrated, clinical examiners at baseline and 3 year (+/- 3 months) follow-up.
    • Early caries lesion progression data, using ICDAS.
    • Bleeding on probing (BoP) will also be recorded by the independent clinical examiners. BoP provides evidence of long term optimal brushing rather than transitory measures such as visible plaque scores.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At 12, 24 and 36 months after commencing treatment (secondary outcomes - patient reported)

    At baseline and 36 months (secondary outcomes - clinically assessed (Scottish sub-study))
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned60
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of trial is defined as end of funding
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 587
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 587
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1174
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1174
    F.4.2.2In the whole clinical trial 1174
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard clinical care (this may include prescription of 5000 ppm fluoride toothpaste by the participant's dentist).
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Greater Manchester Clinical Research Network
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-11-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-02-02
    P. End of Trial
    P.End of Trial StatusOngoing
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