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    Summary
    EudraCT Number:2015-000748-41
    Sponsor's Protocol Code Number:15/135763
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-09-28
    Trial results View 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 number2015-000748-41
    A.3Full title of the trial
    Autoimmune Diabetes Accelerator Prevention Trial (adAPT)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Automimmune Diabetes Accelerator Prevention Trial (adAPT)
    A.3.2Name or abbreviated title of the trial where available
    adAPT
    A.4.1Sponsor's protocol code number15/135763
    A.5.4Other Identifiers
    Name:RECNumber:15/ES/0075
    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 SponsorUniversity of Exeter
    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 supportJuvenile Diabetes Research Foundation Ltd
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTayside Clinical Trials Unit
    B.5.2Functional name of contact pointDr Roberta Littleford
    B.5.3 Address:
    B.5.3.1Street AddressTASC, R&D Office Residence Block George Pirie Way Ninewells Hospital
    B.5.3.2Town/ cityDundee
    B.5.3.3Post code DD1 9SY
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01383383898
    B.5.6E-mailr.littleford@dundee.ac.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 Metformin Hydrochloride
    D.2.1.1.2Name of the Marketing Authorisation holderRosemount Pharmaceuticals
    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 nameMetformin Hydrochloride
    D.3.4Pharmaceutical form Oral liquid
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMetformin Hydrochloride
    D.3.9.1CAS number 1115-70-4
    D.3.9.2Current sponsor codeN/A
    D.3.9.3Other descriptive nameN/A
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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
    D.8.3Pharmaceutical form of the placeboOral liquid
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Children aged 5 to 16 on entry to the RCT with the presence of two or more islet-related autoantibodies which confers a 40% risk of developing type 1 diabetes in five years.
    E.1.1.1Medical condition in easily understood language
    Children at risk of developing diabetes.
    E.1.1.2Therapeutic area Body processes [G] - Biological Phenomena [G16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10036481
    E.1.2Term Pre-diabetes
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Can metformin, a drug known to reduce insulin demand in type 2 diabetes, reduce insulin demand in children at increased risk of developing type 1 diabetes (T1D)and prevent disease?

    Stage 1 (pilot) - Study and Participant Outcome Measures
    Feasibility of a randomised controlled trial in children who are at high risk of T1D comparing metformin and placebo. Specific outcome measures will include (1) recruitment rate, (2) attrition rate, (3) standard deviation of proposed participant outcome measures which are:
    Biomarker outcomes for HOMAR-IR (measures of insulin resistance), beta cell demand (glucose and c-peptide) and immunological down regulation in T-cell response to islet related antigens.
    Stage 2 (proof of concept) will continue with these outcomes measures. Outcome Measures will inform sample size for the fully powered trial (Stage 2 & 3).
    Stage 3 (definitive trial) will focus on the efficacy of Metformin to reduce HOMA2-IR. For purposes of assessing effect size, the HOMA2-I
    E.2.2Secondary objectives of the trial
    Secondary exploratory outcomes will include:
    Response rate of families to screening
    Response of families to participate in the intervention stage when a second sibling in the same family is found to be at high risk of T1D.
    Compliance with liquid formula metformin.
    Serum vitamin B12 as a fall in vitamin B12 levels have been reported in adults, currently no data for children.
    With safety endpoints:
    Haemoglobin (Hb) and Full Blood Count (FBC)
    Renal function tests: urea and electrolytes
    Liver function tests
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    FOR SCREENING PHASE (approx. ~3500)
    -Children/Adolescents aged 5-16 years at time of screening who are siblings of people whose T1D developed before the age of 25 years
    -Children/Adolescents aged 5-16 years who are the offspring of parents who themselves developed T1D before the age of 25 years
    -Parent/Participant is willing and able to give informed consent/assent
    -Multiple family members meeting eligibility criteria.
    FOR RCT PHASE (~ n= 90-200)
    - Children/adolescents identified by screening to be sero-positive for at least two of the four islet-related antibodies (IAA, GAD, IA-2, ZnT8).
    E.4Principal exclusion criteria
    For Screening Phase:

    -Parent /Participant is unwilling/unable to give informed consent/assent
    -Under 5y or over 16y at time of screening
    -Sibling or child of person who developed T1D after the age of 25y
    -Known to have physician diagnosed diabetes
    -Already taking metformin
    -Physically or psychologically unable to participate
    -Taking medication likely to increase insulin resistance (e.g. oral/systemic steroids or growth hormone)
    -Contraindication to metformin – anoxia, cardiovascular insufficiency, renal or hepatic disease, sepsis
    -Participating in another clinical trial (other than observational trials and registries) concurrently or within 30 days prior to screening for entry into this study

    Additional exclusions for RCT Phase:
    -Development of diabetes during the screening phase
    -Identified by screening to be sero-negative (fewer than two of the four islet-related antibodies (IAA, GAD, IA-2, ZnT8)
    -Pregnant or lactating
    -Known allergies to milk and soya

    For Randomisation:
    -fasting blood glucose (laboratory sample) greater than or equal to 7mmol/L
    E.5 End points
    E.5.1Primary end point(s)
    The trial is designed to establish whether metformin, an oral hypoglycaemic agent that is known to reduce insulin demand in type 2 diabetes (T2D), can do the same in children at risk of type 1 diabetes (T1D) and thereby prevent disease.

    Stage 1 (pilot) which will test
    1. Study Outcome Measures:
    Feasibility of a randomised controlled trial in children who are at high risk of T1D comparing metformin and placebo. Specific outcome measures will include (1) recruitment rate, (2) attrition rate, (3) standard deviation of proposed participant outcome measures
    2. Participant Outcome Measures:
    Biomarker outcomes for HOMAR-IR (measure of insulin resistance), beta cell demand (glucose and c-peptide) and immunological t-cell response to diabetes antigens.

    Following 4 months treatment, for a minimum of 90 evaluable participants, Stage 1 evalutation will be undertaken. The design does not propose formally statistical testing for differences in outcomes between or within groups. Instead, for all groups, estimates of metformin and placebo group mean and standard deviation (or frequency) for all outcomes at each assessment point. Count data will be expressed both as a percentage of the total number of participants approached and in relation to the preceding step in recruitment. With regard to attrition, for both groups, the number of participants who withdrew, could not be contacted or did not provide four month follow up data for another reason will be quantified. In addition the total number of participants in each of the two groups will be presented. The primary analyses will be conducted according to the intention to treat (ITT) principle.

    For purposes of assessing effect size, the HOMA2-IR levels obtained on metformin in adAPT will be compared with those modelled values for 1990, when the incidence of T1D was half that of today. A return to these IR levels would indicate a modest insulin resistance change, in response the study intervention.

    Stages 2 and 3 are part of the adaptive design. Stage 1 data will be used to calculate participant numbers needed to ensure statistical reliability in Stages 2 & 3. It is planned that all participants receive 60 months of treatment (to end of Stage 3) irrespective at what juncture they join the study. Stopping rules are in place. Those participants already participating and entered into Stage 2 from Stage 1 will be invited and asked to consent to continue into Stage 3 (subsequently Stage 3 will require a substantial amendment).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Stage 1 primary outcomes will be evaluated after a minimum of 90 sero-positive complete Stage 1.
    Maximum Stage 1 treatment will be 21 months while minimum treatment will be 6 months The time-frame allows for a 15 month recruitment period, 4 months minimum treatment and 2 month analysis period). Participants will continue treatment during the analysis period (with the aim of continuing to month 60, Stage 2 & 3.)

    Participant outcomes measures: standard deviations of HOMA-IR and other indices of beta cell demand in pre-diabetic children (glucose, C-peptide) and immulogical down regulation in T-cell response to islet related antigens.

    Stage 2 and 3, will review outcomes at 36 and 60 months (respectively) of intervention.
    E.5.2Secondary end point(s)
    Stage 1 Secondary exploratory objectives are screening response rates, response to participate in the treatment study when a second child in the same family is found to be at high risk of T1D (double-antibody positive) and are compliance of liquid metformin/placebo and review of Vitamin B12 serum levels.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Similarly secondary outcome of Stage 1 can only be known after all participants have completed 4 months treatment. We plan that by month 21, feasibility and efficacy secondary outcomes will be established.

    Stages 2 and 3 will review outcomes at 36 and 60 months (respectively) of intervention.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    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 No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned15
    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
    The end of the study is defined as the date of the last participant last visit(LPLV). This application is for entire study totaling 60 months/5 years however the RCT/CTIMP spans 3 distinct stages. Subsequent stage 2&3 amendments to the CTA, REC and R&D applications will be required/submitted
    Remote data-linkage monitoring will follow-up participants (with consent) for 10 years (to time of T1D diagnosis) - this will fall outwith the end of trial definition.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 90
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 45
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 45
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2015-09-28. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children aged 5-16. Relevant Scotland/England consent/assent guidance applies. Assessment of competence will be carried out, where present consent will be obtained from the child with parental assent for screening and parental consent for RCT.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state90
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 90
    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)
    Participants will not be given metformin by the study team after their participation has ended. If the trial is successful, appropriate consideration will be given by the authorities to licence metformin as a means of preventing diabetes in children at risk.
    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 ScotCRN
    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 Decision2015-09-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-12-01
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