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    Summary
    EudraCT Number:2018-002721-29
    Sponsor's Protocol Code Number:08486
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-06-18
    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 number2018-002721-29
    A.3Full title of the trial
    Randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in patients with Mitochondrial Myopathy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomised double-blinded control adaptive trial to measure of the effectiveness of acipimox in patients with Mitochondrial Myopathy
    A.3.2Name or abbreviated title of the trial where available
    AIMM: Acipimox in Mitochondrial Myopathy
    A.4.1Sponsor's protocol code number08486
    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 Foundation Trust
    B.1.3.4Country
    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 organisationNewccastle Clinical Trials Unit
    B.5.2Functional name of contact pointRachel Lakey
    B.5.3 Address:
    B.5.3.1Street Address1 - 4 Claremont Terrace
    B.5.3.2Town/ cityNewcastle upon Tyne
    B.5.3.3Post codeNE2 4AE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01912085364
    B.5.6E-mailrachel.lakey@newcastle.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 Olbetam 250mg Capsules
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    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 nameOlbetam 250mg Capsules
    D.3.4Pharmaceutical form Capsule
    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 INNAcipimox
    D.3.9.1CAS number 51037-30-0
    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 number250
    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 placeboCapsule
    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
    Mitochondrial Myopathy
    E.1.1.1Medical condition in easily understood language
    Mitochondrial diseases are a group of rare, neurogenetic disorders, often found in tissues with high-energy demands. In the muscle, it displays as fatigue, exercise intolerance, myalgia and weakness.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary outcome is to establish if acipimox can increase energy (ATP content) in skeletal muscle in adult patients with mitochondrial disease and muscle involvement.
    E.2.2Secondary objectives of the trial
    The secondary objectives will determine any changes in the following, between the baseline visit and the end of treatment(week 12):
    1. Health-related Quality of Life
    2. Reported perceived fatigue
    3. Symptom-limited cardiopulmonary fitness
    4. Disease burden
    5. Upper and lower limb function, balance and walking
    6. Skeletal muscle analyses
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Must be able to provide full informed consent.
    2. Male or female patients ≥ 16 years of age.
    3. Patients must fulfil the following:
    i) Genetically proven diagnosis of m.3243A>G mutation or single large-scale mtDNA deletion, and
    ii)Evidence of myopathy as confirmed by the investigator
    4. Able and willing, in the opinion of the investigator, to comply with all
    trial requirements.
    5. Willing for their GP and Specialist (if applicable), to be
    informed of their participation in the trial.
    6. Be on a stable dose of any current regular medication for at least four
    weeks prior to trial entry.
    E.4Principal exclusion criteria
    1. Patients who are currently participating or have participated in a clinical
    trial of an investigational medicinal product within the 12 week period prior to the date of informed consent.
    2. Patients who have had an elective or emergency admission to hospital within
    the 4 week period prior to the date of informed consent.
    3. Patients with other known uncontrolled medical problems, which, in the
    opinion of the investigator, would preclude participation in the trial.
    4. Patients who are:
    a) pregnant
    b) breast feeding
    c) of childbearing potential with a positive urine pregnancy test
    prior to starting trial IMP or;
    d) male or female of childbearing potential unwilling to use a double
    barrier method of contraception throughout the trial (postmenopausal women
    must be amenorrhoeic for at least 12 months to be considered of non-
    childbearing potential).
    5. Patients with moderate to severe renal impairment (creatinine clearance < 60
    ml/min).
    6. Patients with a screening AST, ALT or Gamma GT result of more than 3 times
    the upper limit of normal.
    7. Patients with a platelet count of <50 platelets/ ul of blood
    8. Patients on treatment with methotrexate or other immunosuppressant
    medications.
    9. Patients with active known peptic ulcer or history of recurrent ulceration.
    10. Patients on treatment with warfarin, clopidogrel, regular high-dose (≥300 mg
    OD) aspirin or other anticoagulant medications which in the opinion of the
    investigator precludes entry into the trial. Patients receiving high-dose aspirin
    who are able to come off aspirin for a period of 72 hours prior to any muscle biopsy sample will be eligible to participate.
    11. Patients with a medical history which in the opinion of the investigator
    contraindicates the use of low-dose aspirin.
    12. Patients who are already taking acipimox.
    13. Patients with an elective hospital admission scheduled during the trial
    period, which in the opinion of the investigator would preclude participation.
    E.5 End points
    E.5.1Primary end point(s)
    Change in ATP content in skeletal muscle biopsy specimens, between baseline and end of treatment visit at week 12.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary outcome measure is the change in ATP content in skeletal muscle biopsy specimens. Samples for analysis will be taken at baseline and end of treatment (week 12).
    E.5.2Secondary end point(s)
    1. Health-related Quality of life:

    - NeuroQol.
    - Newcastle Mitochondrial Quality of Life questionnaire (NMQ).
    - Visual Analogue Scales (VAS) for pain and most bothersome symptom.

    2. Reported perceived fatigue:
    - Fatigue Impact Scale (FIS).
    - Fatigue Severity Scale (FSS).

    3. Symptom-limited cardiopulmonary fitness. Cardiopulmonary exercise testing (CPET) to include assessments at rest, during and/or at exhaustion (peak):
    - VO2.
    - VCO2.
    - Anaerobic Threshold (AT).
    - Pulmonary Ventilation (VE).
    - Respiratory Exchange Ratio (RER).
    - Breathing Frequency (f) via breath-by-breath indirect calorimetry.
    - Work rate (Power measured in watts).
    - Heart Rate (HR).
    - Stroke Volume (SV).
    - Cardiac Output (Q).
    - Arteriovenous Oxygen Difference (a-VO2 difference) via non-invasive bioreactance cardiac output.
    - Rate of Perceived Exertion.
    - Blood lactate via ear prick and/ or blood test

    4. Disease burden:

    - Newcastle Mitochondrial Disease Adult Scale (NMDAS).

    5. Upper and lower limb function, balance and walking:

    - 6 Minute Walk Test (6MWT).
    - 10 metre timed walk (10MWT).

    - Mini Balance Evaluation Systems Test (Mini-BESTest).
    - 9 hole peg test (9HPT).
    - 30 second Sit To Stand (STS).

    - Ataxia Rating Scale (SARA).

    6. Skeletal muscle analyses:

    - ATP/ADP ratio via luminescence assay or metabolomics.

    - NAD+/NADH ratio via metabolomics.

    - mtDNA copy number via quantitative PCR.

    - Respiratory chain deficiency via histochemistry and quadruple immunofluorescence.

    - mtDNA heteroplasmy via q-RT PCR (single deletion) or pyro sequencing (m.3243A>G).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluation of secondary endpoints will occur at the baseline visit and at the end of treatment visit (week 12).
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Adaptive
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA1
    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 trial will be defined as the last patient last visit (LPLV), which will be when the last trial participant completes the telephone follow-up ‘visit’ at week 16.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days24
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days24
    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: 10
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state120
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    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 trial will generate important evidence that will establish the clinical efficacy of acipimox in adult patients with mitochondrial disease and muscle involvement. If successful then these results could be used to inform an international, multicentre study trial of acipimox in which we would explore the potential benefit of acipimox, longer term, and its effect on other clinical features in patients with mitochondrial disease.
    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 Decision2018-12-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-04
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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