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    Summary
    EudraCT Number:2015-001382-10
    Sponsor's Protocol Code Number:CS/2015/4775
    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:2015-08-24
    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 number2015-001382-10
    A.3Full title of the trial
    Treatment of Barth Syndrome by CARDIOlipin MANipulation (CARDIOMAN): A randomised placebo controlled pilot trial conducted by the nationally commissioned Barth Syndrome Service
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study comparing the drug 'bezafibrate' against a placebo in the treatment of Barth Syndrome
    A.3.2Name or abbreviated title of the trial where available
    CARDIOMAN
    A.4.1Sponsor's protocol code numberCS/2015/4775
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1168-5327
    A.5.4Other Identifiers
    Name:NIHR EME (funder)Number:12/205/56
    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 Institute of Health Research (NIHR) Efficacy and Mechanisms Evaluation Programme
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Bristol
    B.5.2Functional name of contact pointLucy Dabner
    B.5.3 Address:
    B.5.3.1Street AddressClinical Trials and Evaluation Unit, Level 7, Bristol Royal Infirmary
    B.5.3.2Town/ cityUpper Maudlin Street, Bristol
    B.5.3.3Post codeBS2 8HW
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01173422374
    B.5.6E-mailcardioman-trial@bristol.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 No
    D.2.1.1.1Trade name Bezafibrate
    D.2.1.1.2Name of the Marketing Authorisation holderGenerics [UK] Ltd T/A Mylan
    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 nameBezafibrate
    D.3.4Pharmaceutical form Coated 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 INNBezafibrate (INN 3968)
    D.3.9.1CAS number 41859-67-0
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number100 to 200
    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 placeboCoated tablet
    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
    Barth Syndrome is a rare, life threatening, genetic disease which affects young males. It is caused by abnormal fats (lipids) in the powerhouses of cells (mitochondria) and those who suffer with it often develop heart failure, heart rhythm abnormalities, bacterial infections, poor growth or feeding, weak muscles, developmental delay, severe exercise intolerance, lethargy and fatigue.
    E.1.1.1Medical condition in easily understood language
    Barth Syndrome is a rare, life threatening, genetic disease which affects young males. It is caused by abnormal fats in the cells and results in a variety of debilitating symptoms.
    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 20.0
    E.1.2Level SOC
    E.1.2Classification code 10010331
    E.1.2Term Congenital, familial and genetic disorders
    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
    What is the effect on clinical and biochemical outcomes and Quality of Life of bezafibrate treatment in comparison to placebo in Barth Syndrome patients?
    E.2.2Secondary objectives of the trial
    1. Is there a relationship between improvements in clinical outcomes (such as the ability to tolerate exercise) and laboratory measures of cardiolipin ratio/profile and mitochondrial morphology (shape and structure of the cells) when participants are exposed to bezafibrate.
    2. What are the most feasible methods and standardised ways of measuring outcomes that may allow better conduct of future trials (e.g. larger multinational trials) and evaluations in Barth syndrome?
    3. Is it possible to create a research infrastructure which optimises recruitment, retention and communication with families and people with Barth syndrome nationwide?
    5. What are the participant and family perceptions of research and are there any important potential barriers to participation?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Male aged ≥6 years old
    • Clinical diagnosis of Barth Syndrome with characteristic abnormality of the L4-cardiolipin/monolysocardiolipin ratio plus identified mutation in the tafazzin gene
    • Under the care of the NHS Barth Syndrome Service
    • Stable cardiac condition
    • Able to swallow bezafibrate tablets (similar size to Ibuprofen tablets)
    E.4Principal exclusion criteria
    1. Known hypersensitivity to bezafibrate, to any component of the product or to other fibrates
    2. Known photoallergic or phototoxic reactions to fibrates.
    3. Hepatic dysfunction and/or liver function tests greater than 2x normal
    4. Unstable cardiac status: a shortening fraction of <25 (or a significant drop in shortening fraction in the previous year)
    5. Documented atrial or ventricular arrhythmia (atrial/ventricular tachycardia or atrial/ventricular fibrillation) that has not been stabilised with treatment.
    6. Renal impairment (creatinine clearance < 90 mL/min)
    7. Pre-existing known gallbladder disease.
    8. Recent unspecified significant deterioration in general health
    9. Prisoners and adults lacking capacity to provide informed consent
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is peak oxygen consumption on bicycle ergometry. This will be assessed at baseline and in the final week of each treatment phase.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Peak oxygen consumption will be measured at baseline (before treatment starts), in the last week of the first 4 month treatment phase and then again in the last week of the second 4 month treatment phase.
    E.5.2Secondary end point(s)
    1. MLCL/L4-CL ratio/cardiolipin profile
    2. PCr/ATP ratio in cardiac muscle on 31P Magnetic Resonance Spectroscopy
    3. Skeletal muscle oxidative function/ATP production on 31P Magnetic Resonance Spectroscopy
    4. Quality of life (QOL) assessed using age-appropriate PedsQL or SF36 questionnaires
    5. Absolute neutrophil count
    6. Amino acid expression (serum arginine and cysteine levels)
    7. Cardiac function (LVEF and shortening fraction)
    8. Mitochondrial size
    9. Numbers of mitochondria (per lymphocyte)
    10. Total area of mitochondria per lymphocyte
    11. Area of mitochondria as proportion of cytoplasm
    12. Mitochondria function and cristae organisation in lymphocytes
    13. Arrhythmia profile from 12 lead ECG at rest and during exercise (for potential rhythm abnormalities)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary outcomes will be measured at baseline (before treatment starts), in the last week of the first 4 month treatment phase and then again in the last week of the second 4 month treatment phase.
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    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 Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 trial for participants will be after they have completed the treatment period and a one month follow-up period (or have been lost to follow-up or died).

    The end of the trial as a whole will be when all recruited participants have completed the treatment and follow-up period and all data has been collected, data queries answered and all laboratory samples have been processed and analysed.

    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days8
    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: 12
    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: 6
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 3
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female No
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 15
    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)
    Once the participants have completed the study treatment their medical care will revert back to the standard care received from the Barth Syndrome Service. However, if bezafibrate is shown to have a beneficial effect on individual participants, provision will be made for them to continue receiving bezafibrate, funded through NHS Specialised Services.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-11-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-21
    P. End of Trial
    P.End of Trial StatusOngoing
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