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The European Union Clinical Trials Register   allows you to search for protocol and results information on:
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    The EU Clinical Trials Register currently displays   43694   clinical trials with a EudraCT protocol, of which   7248   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2015-000508-24
    Sponsor's Protocol Code Number:7406
    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:2015-05-07
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-000508-24
    A.3Full title of the trial
    A Feasibility Study of Bezafibrate in Mitochondrial Myopathy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Feasibility Study of Bezafibrate in Mitochondrial Myopathy
    A.3.2Name or abbreviated title of the trial where available
    A Feasibility Study of Bezafibrate in Mitochondrial Myopathy
    A.4.1Sponsor's protocol code number7406
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02398201
    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 SponsorNewcastle Upon Tyne Hospitals NHS 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 supportNewcastle University, Confidence in Concept Fund
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNewcastle University
    B.5.2Functional name of contact pointPatrick Chinnery
    B.5.3 Address:
    B.5.3.1Street AddressInstitute of Genetic Medicine
    B.5.3.2Town/ cityNewcastle University
    B.5.3.3Post codeNE1 3BZ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number441912418611
    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. name Bezafibrate
    D. of the Marketing Authorisation holderActavis Group PTC EHF
    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 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
    D.3.9.1CAS number CAS41859-67
    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 number200
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Mitochondrial myopathy due to mt.3243A>G mutation
    E.1.1.1Medical condition in easily understood language
    Mitochondrial myopathy is an inherited muscle disease due to impaired energy production
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10027710
    E.1.2Term Mitochondrial myopathy
    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
    The main aim of this research is to determine whether bezafibrate has an effect on the way mitochondria in muscle cells produce energy.

    Our hypothesis, based on pre-clinical data is that bezafibrate will improve mitochondrial function in people with muscle disease due to mitochondrial disease.
    E.2.2Secondary objectives of the trial
    There are several secondary aims of this project:

    • To characterise changes in mitochondria in relation to bezafibrate use;
    • To obtain preliminary safety and tolerability data of bezafibrate in patients with mitochondrial muscle disease;
    • To identify and characterise new blood markers of mitochondrial disease in relation to bezafibrate use and dosage;
    • To assess possible magnetic resonance markers of mitochondrial disease in relation to bezafibrate use and dosage;
    • To assess a high speed magnetic resonance imaging technique in mitochondrial myopathy;
    • To assess the effect of bezafibrate on measures of aerobic respiration using sub-maximal exercise testing on a cycle ergometer;
    • To assess the use of different functional outcome measures encompassing disease burden, activity levels and quality of life;
    • To provide us with data to estimate a treatment effect size so that, if appropriate, we can determine how many patients we need to recruit to a future randomised controll
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The inclusion criteria are:

    • The participant is willing and able to give informed consent for participation in the trial.

    As an experimental trial, there is an inherent degree of risk. We therefore believe that all participants should have capacity to consent to the trial.

    • Male or Female, aged 18 years or over and less than 65 years.

    No minors will be recruited to this trial for the reasons stated above. The Summary of Product Characteristics for bezafibrate identifies that there is an increased risk of muscle complications in those over the age of 65 years. It is for this reason we have used this as the upper age limit for inclusion.

    • Confirmed mt.3243A>G mutation.

    We wanted to have a genetically homogeneous population. The mt.3243A>G mutation is the most common cause of muscle disease in our mitochondrial population.

    • Evidence of myopathy as determined by the investigator.

    The mt.3243A>G mutation can manifest in a variety of clinical ways. We wanted to ensure that participants in the trial had at least some clinical similarity in their presentation.

    Additionally, we felt that participants manifesting muscle disease would be most appropriate to recruit and study given the investigative tools available to us. These include respiratory chain enzyme analysis and MRS (magnetic resonance spectroscopy) of skeletal muscle.

    • Stable dose of current regular medication for at least 4 weeks prior to trial entry.

    We wish to avoid recruiting participants who are likely to require frequent changes to their medication regimes. This will facilitate analysis of any changes seen in the muscle biopsies and imaging studies. In addition, there are restrictions on certain concomitant medications during the trial period. By ensuring the participant body are on relatively stable medications, we can help avoid prescribing errors.

    • Not already taking fibrates.

    Participants should be naive to fibrate treatment so that the baseline muscle biopsy accurately reflects their mitochondrial disease. This will enable comparison between muscle biopsy samples pre and post treatment.

    • No evidence of liver impairment.

    Liver impairment is a contraindication to use of bezafibrate according to the Summary of Product Characteristics. Although bezafibrate is excreted renally, it accumulates in the liver. Impaired liver function can increase liver toxicity.

    • Normal renal function, with a creatinine clearance of >60ml/minute.

    Bezafibrate is excreted almost entirely by the kidneys. Drug accumulation and toxicity may occur in impaired renal function.

    The Summary of Product Characteristics for bezafibrate identifies that impaired renal function is a predisposing factor for muscle complications such as (worsening) myopathy and rhabdomyolysis. Given participants already have a clinically relevant myopathy, and we are using higher than licensed doses of bezafibrate in this feasibility study, we wanted to control other risk factors where possible.

    • Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the trial and for 3 months thereafter.

    In animal reproductive studies, although bezafibrate did not appear to affect fertility, it did demonstrate teratogenicity. Therefore, it is a requirement of the study that sexually active participants avoid conception during use of the trial drug. Clear guidance will be provided regarding contraception. In female participants, this may not include oestrogen containing contraceptives.

    • In the Investigator’s opinion, is able and willing to comply with all trial requirements.

    There is a considerable patient burden associated with this trial. Participants may be required to attend the Clinical Research Facility on a weekly basis for a period of 3 months. This is necessary for safety purposes and therefore participants who are unlikely or unwilling to comply with these requirements will not be recruited to the trial.

    • Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the trial.

    Given the complexity of mitochondrial disorders, coupled with the restrictions on certain drug prescriptions during the trial, the trial team feel it is necessary to include other health care professionals involved in the health care delivery of all participants.
    E.4Principal exclusion criteria
    The exclusion criteria are:

    • Unstable, or poorly controlled diabetes, as determined by the investigator. Participants with diabetes cannot be taking insulin or oral anti-diabetic agents.

    Insulin and oral anti-diabetic agents are contraindicated with bezafibrate use. Futhermore, poorly controlled diabetes may contribute to poor muscle biopsy site healing.

    • History of rhabdomyolysis

    Bezafibrate can rarely cause rhabdomyolysis. As such, anyone with a previous episode of rhabdomyolysis will be excluded from the trial.

    • History of sensitivity to fibrates (including photosensitivity)

    This is a contraindication to bezafibrate use according to the SPC (summary of product characteristics).

    • Gallbladder disease with or without cholelithiasis

    This is a contraindication to bezafibrate use according to the SPC (summary of product characteristics) as bezafibrate may contribute to gallstone formation.

    • History of liver impairment or disease

    This is a contraindication to bezafibrate use according to the SPC (summary of product characteristics).

    • Alcohol misuse

    Bezafibrate can rarely cause rhabdomyolysis. Excess alcohol intake is a risk factor for rhabdomyolysis with vibrates. Alcohol misuse will be determined by the investigators.

    • Nephrotic syndrome

    This increases the risks of drug induced side effects, in particular rhabdomyolysis.

    • Significant renal impairment, or creatine clearance <60ml/minute

    This increases the risks of drug induced side effects, in particular rhabdomyolysis.

    • Untreated hypothyroidism

    Bezafibrate can rarely cause rhabdomyolysis. Untreated hypothyroidism increases the risk of rhadomyolysis with bezafibrate use. All individuals will be required to have satisfactory thyroid function tests at screening before proceeding in the trial.

    • Use of another medication that interacts with bezafibrate: colestyramine, insulin, anion exchange resins, coumarin anticoagulants, anti-diabetics, monoamine oxidase inhibitors, oestrogens, immunosuppressants, statins.

    These medications are not to be used with bezafibrate concomitantly according to the SPC. These medications either affect bezafibrate metabolism; or bezafibrate affects their metabolism. Consequently, participants cannot be taking these.

    • A female participant who is pregnant, lactating or planning pregnancy during the course of the trial or a male participant who is planning to conceive with their female partner.

    Pre-clinical studies demonstrate teratogenic effects for both males and females taking bezafibrate at conception or during pregnancy. Consequently, anyone planning a family during the trial will not be eligible for inclusion.

    • Elective or emergency surgery in the past 12 weeks.

    This is to ensure validity of the results, as well as participant safety.

    • Scheduled elective surgery or other procedures requiring general anaesthesia during the trial.

    This is to ensure validity of the results, as well as participant safety.

    • Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial.

    The trial requires considerable personal commitment by participants. As such, if the investigators have concerns about a participant's medical history, ability to co-operate with the trial procedures, or any other concerns, the individual will not be eligible for inclusion.

    • Participants who have participated in another research trial involving an investigational product in the past 12 weeks.

    This ensures participant safety.

    • Participants will be unable to undergo MRI if they have any contra-indication to MRI scanning e.g. implantable medical device, cranial aneurysm clips, metallic foreign body, however will be able to participate in other areas of the study if they meet the remaining inclusion/exclusion criteria.

    • For exercise testing – any participant with ischaemic heart disease, or symptoms suggestive of this. Again, participants will be able to participate in other areas of the study if they meet the remaining inclusion/exclusion criteria.
    E.5 End points
    E.5.1Primary end point(s)
    Change in respiratory chain enzyme activity (measured in mean percentage and absolute terms; and individual percentage and absolute terms).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Comparison will be made between measurements obtained at week 0 (baseline) and week 12 (after bezafibrate treatment).
    E.5.2Secondary end point(s)
    1) The individual and mean absolute and percentage change and inter-individual variability of mitochondrial biogenesis markers:
    • Citrate synthase quantification;
    • Mitochondrial DNA copy number quantification.

    2) The individual and mean absolute and percentage change in levels and inter-individual variability of serum biomarkers including:
    • serum fibroblast growth factor-21 (FGF-21);
    • serum PGC-1α;
    • serum microRNAs.

    3) The individual and mean absolute & percentage change, and inter-individual variability, in t 1/2 PCr measurements of skeletal muscle obtained during 31P –MRS.

    4) The individual and mean absolute & percentage change, and inter- individual variability, in ATP production and muscle phosphocreatine of cardiac muscle during 31P–MRS.

    5) The individual and mean absolute & percentage change, and inter-individual variability, in cardiac LV torsion measured during cine-gated cardiac MRI.

    6) The individual and mean absolute & percentage change, and inter-individual variability, in skeletal muscle lipid content and volume assessed during an accelerated MRI technique.

    7) The individual and mean absolute & percentage change in peak VO2; peak W and peak a-VO2 diff determined during sub-maximal exercise testing on a stationary cycle.

    8) Disease burden
    Individual and mean absolute and percentage change, and inter-individual variability, in NMDAS score, timed up and go (TUG), heteroplasmy levels in blood, urine and muscle and COX negative, positive and intermediate fibre quantification.

    9) Activity levels
    The individual and mean absolute and percentage change, and inter-individual variability, in IPAQ score, total number of daily steps, total energy expenditure, active energy expenditure and physical activity duration.

    10) Quality of life measures
    The individual and mean absolute and percentage change, and inter-individual variability, in NMQ , SF-12 and FIS scores.

    11) Safety & Tolerability Data
    Bloods (FBC, PT, U&E, LFTs, CK) will be assessed weekly throughout the trial and compared to normal reference ranges.
    Adverse Event reporting will be undertaken as required and with opportunistic capture throughout the trial.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The following secondary outcome measures will be compared at week 0 (baseline) and week 12 (after bezafibrate treatment):

    • Mitochondrial biogenesis markers (as above);
    • Skeletal and cardiac muscle MRI/MRS (points 3,4,5 & 6 above);
    • Exercise testing;

    The following outcome measures will be assessed at weeks 0, 3, 6, 9 and 12:

    • Serum Biomarkers (as above)

    The following outcome measures will be assessed at weeks 0, 6 and 12:
    • Disease burden (as above, excluding COX fibre analysis which will be done at weeks 0 & 12 only).
    • Activity levels (as above)
    • Quality of life (as above)

    The following outcome measures will be assessed weekly throughout the trial, and as required:
    • Bloods
    • Adverse Event Reporting
    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 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. 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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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.8.4.1Number of sites anticipated in Member State concerned1
    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 No
    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
    Last telephone contact with last subject.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years1
    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 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F. of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F. of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F. of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F. of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F. of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F. of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 10
    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)
    This study is not designed to provide evidence of efficacy. Therefore, at the end of this feasibility study, bezafibrate will not be routinely provided to participants. If a positive effect is demonstrated on respiratory chain enzyme activity, a larger randomised controlled trial will be designed and participants may be eligible for entry into this.
    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 Decision2015-06-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-06-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-03-23
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