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    Summary
    EudraCT Number:2011-001319-30
    Sponsor's Protocol Code Number:CH/2011/3670
    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:2011-09-05
    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 number2011-001319-30
    A.3Full title of the trial
    A randomized, double-blind, parallel group, placebo-controlled trial of metformin in tuberous sclerosis complex.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Metformin as a treatment for people with the genetic disease Tuberous Sclerosis Complex.
    A.3.2Name or abbreviated title of the trial where available
    Metformin in Tuberous Sclerosis Complex (MiTS) V1.0
    A.4.1Sponsor's protocol code numberCH/2011/3670
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN92545532
    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 Hospitals Bristol 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 supportNational Institutes for Health Research (NIHR) Research for Patient Benefit grant
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Information not present in EudraCT
    D.2.1.1.1Trade name metformin (generic)
    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
    D.3.2Product code n/a
    D.3.4Pharmaceutical form Tablet
    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 657-24-9
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive name-
    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
    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 placeboTablet
    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
    Tuberous Sclerosis Complex
    E.1.1.1Medical condition in easily understood language
    A genetic condition called Tuberous Sclerosis Complex that causes benign tumours to grow throughout the body.
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10045138
    E.1.2Term Tuberous sclerosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Does the drug metformin reduce the size of kidney tumours in people with Tuberous Sclerosis Complex?
    E.2.2Secondary objectives of the trial
    -Is metformin safe and tolerable for people with TSC?
    -Does metformin reduce the size of TSC- related subependymal giant cell astrocytomas (SEGAs/brain tumours)?
    -Does metformin reduce the size of facial angiofibromata (disfiguring facial tumours) and ungal fibromas (nail tumours) in people with TSC?
    -Does metformin improve the quality of life of people with TSC?
    -Does metformin improve the control of epilepsy in people with TSC?
    -Does metformin improve the cognitive ability of people with TSC?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria:

    •Clinically definite diagnosis of TSC (modified Gomez criteria).
    •Age 10–65 years. The lower age limit of 10 years has been chosen because: 1.Metformin is currently licensed for use from age 10 (for obesity and/or diabetes). 2.Renal tumours in TSC tend to develop with age and are not present in the majority of young children although are present in over 90% of patients by age 14.
    •One or more renal AML of at least one centimetre in largest diameter.
    •Signed informed consent.
    E.4Principal exclusion criteria
    Exclusion Criteria:

    •Serious intercurrent illness or uncontrolled disease which could compromise participation in the study
    •Impairment of renal function (Metformin has a rare [incidence approx. 9 per 100,000 patient years](27) but serious [potentially leading to death] side-effect called lactic acidosis. The main risk of this side effect is in people with impaired renal function.)
    •Use of x-ray contrast medium containing iodine within the last 30 days (this can temporally impair renal function)
    •Multiple AMLs where individual lesions cannot be distinguished (distinguishing individual lesions will be required to assess the primary endpoint)
    •Renal haemorrhage within preceding year (patients with high risk of renal haemorrhage may require frequent assessment and intervention)
    •Known conservatively managed renal aneurysm(s) >10mm (as above)
    •Liver insufficiency (a contraindication for metformin)
    •Acute or chronic disease which may cause tissue hypoxia e.g.: cardiac/respiratory failure, recent myocardial infarction, shock (increases the risk of lactic acidosis)
    •Diabetes
    •Treatment with any injected or oral hypoglycaemic drug
    •Use of an investigational drug within the last 30 days.
    •Pregnancy, planning to become pregnant, or breastfeeding.
    E.5 End points
    E.5.1Primary end point(s)
    Mean kidney tumour (angiolipoma / AML) volume at 12 months as compared to baseline.

    The 5 largest AML will be identified from the baseline MRI. AML diameter and volume will be measured. Volumes are measured using a validated MRI stereology method. (Reliability coefficients are: Inter-rater –0.961, Intra-rater –0.962.) These are measured again at 12 months.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At baseline and 12 months.
    E.5.2Secondary end point(s)
    That in TSC, metformin will also:
    1. Reduce the size of subependymal giant-cell astrocytomas (SEGAs/brain tumours)
    2. Reduce the size of facial and nail hamartomas
    3. Improve control of epilepsy
    4. Improve cognitive ability
    5. Improve quality of life
    E.5.2.1Timepoint(s) of evaluation of this end point
    These are evaluated:
    1. At baseline and 12 months.
    2. At baseline, 6, 12 and 18 months.
    3. At baseline, 6, 12 and 18 months.
    4. At baseline and 12 months.
    5. At baseline and 12 months.
    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 Yes
    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 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 Yes
    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 concerned3
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA3
    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
    •Individual involvement for participants will end when they have completed the 18 month assessments.
    •Ethical approval will end when all participants continuing in the trial have completed their final assessments at 18 months.
    •Drug regulatory approval from the MHRA will end when all participants continuing in the trail have completed 12 months of treatment.
    •The sponsoring institution’s R&D approval will end when trial analysis, publication and archiving of trial data is complete.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 50
    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: 5
    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) Yes
    F.1.2.1Number of subjects for this age range: 50
    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 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 state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 100
    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)
    If active treatment is shown to be of benefit, patients will be offered the opportunity of continued therapy at the end of the trial.
    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 Western Comprehensive Local 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 Decision2012-04-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-09-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-02-28
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