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    Summary
    EudraCT Number:2012-002933-12
    Sponsor's Protocol Code Number:11/0090
    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:2014-04-04
    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 number2012-002933-12
    A.3Full title of the trial
    A Phase II pilot study to explore treatment with Sodium Valproate in Adults with McArdle Disease (Glycogen Storage Disorder Type V, GSDV)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase II Pilot Study to Assess Safety and Efficacy of Sodium Valproate in Adults with McArdle Disease
    A.3.2Name or abbreviated title of the trial where available
    Sodium Valproate for GSDV Version 1.0 13th January 2014
    A.4.1Sponsor's protocol code number11/0090
    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 College London,
    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 supportMuscular Dystrophy Campaign
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMRC Centre for Neuromuscular Diseases
    B.5.2Functional name of contact pointTahera Hussain
    B.5.3 Address:
    B.5.3.1Street Address7 Queen Square
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeWC1N 3BG
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02076762113
    B.5.6E-mailtahera.hussain@ucl.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 Epilim Chrono 200 Controlled Released tablets
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi-Aventis
    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 nameEpilim Chrono 200 Controlled Released tablets
    D.3.4Pharmaceutical form Prolonged-release 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 INNSodium valproate
    D.3.9.1CAS number 1069-66-5
    D.3.9.3Other descriptive nameValproic acid
    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.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.IMP: 2
    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 Epilim Chrono 300 Controlled Released tablets
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi-Aventis
    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 nameEpilim Chrono 300 Controlled Released tablets
    D.3.4Pharmaceutical form Prolonged-release 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 INNSodium valproate
    D.3.9.2Current sponsor code11/0090
    D.3.9.3Other descriptive namevalproic acid
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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.IMP: 3
    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 Epilim Chrono 500 Controlled Released tablets
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi Aventis
    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 nameEpilim Chrono 500 Controlled Released tablets
    D.3.4Pharmaceutical form Prolonged-release 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 INNSodium valproate
    D.3.9.2Current sponsor code11/0090
    D.3.9.3Other descriptive namevalproic acid
    D.3.9.4EV Substance CodeAS3
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    McArdle disease (Glycogen storage disease type V, GSDV). The condition is an inherited disorder of skeletal muscle that causes exercise intolerance. The condition can give way to potential rhabdomyolysis which can cause acute renal failure and from middle age muscle wasting and weakness. Affected patients are unable to produce lactate during ischaemic exercise due to a congenital lack of the enzyme muscle glycogen phosphorylase which is essential for glycogen metabolism.
    E.1.1.1Medical condition in easily understood language
    McArdle disease. The condition is an inherited disorder of skeletal muscle that causes exercise intolerance. The condition can give way to renal failure and muscle wasting and weakness.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10026969
    E.1.2Term McArdle's disease
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether patients taking a medicine called sodium valproate can improve muscle function expressed by an increased number of normal muscle fibres on muscle biopsy.
    E.2.2Secondary objectives of the trial
    After at least 6 months of full dose treatment, secondary objectives include:
    1. Number of muscle fibres expressing Muscle Glycogen Phosphorylase
    2. Maximum walking distance in 12 minutes
    3. Forearm Exercise test
    4. Quality of life measure SF36 and symptom diary
    5. Safety including tolerability and adverse events
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male and infertile/ post menopausal female subjects diagnosed with GSDV and over 18 years of age.
    Diagnosis will be confirmed by either muscle biopsy showing subsarcolemmal blebs of glycogen with complete absence of skeletal muscle glycogen phosphorylase and/or DNA studies showing pathogenic homozygous or compound heterozygous mutations or deletion in the muscle phosphorylase gene (PYGM).
    2. Prior to recruitment all subjects will have been shown to have normal serum carnitine level and acylcarnitine blood profile.
    3. Patients with mild elevation in bilirubin caused by Gilbert's syndrome will be included following assessment and according to the clinical judgment of the investigator.
    E.4Principal exclusion criteria
    1. Children under the age of 18 years
    2. People older than 64 years
    3. Females of child bearing potential
    4. Patients with Diabetes
    5. Inflammatory disorders especially Systemic lupus erythematosis.
    6. A previous history of sensitivity/allergy to sodium valproate and its excipients
    7. Patients treated with sodium valproate for epilepsy or a psychiatric disorder within the last 12 months prior to recruitment
    8. Patients with pre-existenig liver disease or a family history of severe liver disease affecting a first degree relative. Liver disease will be defined by abnormal liver biopsy. Patients with GSDV will have raised serum transaminases that originate from muscle but which may cause abnormal liver function tests measured in serum, this will not be a reason for exclusion.
    9. Patients prescribed other anti-convulsant medication or any other medication known to interact with sodium valproate.
    10. Patients who are sensitive to local anaesthetics that would prevent a muscle biopsy.
    11. Subjects with any co-morbid illness or disability which would prevent an exercise assessment such as severe unstable/untreated ischaemic heart disease, lower limb disability such as severe muscle weakness with muscle strength assessed as worse than MRC scale 3 in any pelvic girdle muscle.
    12. Inability to exercise due to a lower limb fracture until there is a complete recovery of the injury.
    13. Patients known to have porphyria or an affected first degree relative affected with porphyria
    14. Patients known to have mitochondrial disease or where there is a first degree relative with mitochondrial disease
    15. Patients with an abnormal acyl carnitine profile or low serum carnitine levels
    16. Male participants unwilling to use contraception
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome will be an assessment of exercise endurance on a cycle ergometer by a number of physical and biochemical measures. We will determine changes in the mean estimate and standard deviation of the following parameters:
    - Rating of perceived exertion (RPE),
    - Oxygen consumption to calculate the respiratory quotient (RQ)
    - Maximum heart rate and workload from baseline to 6 months on full dose treatment
    - Laboratory measures associated with exercise endurance will include blood samples for glucose, lactate and ammonia taken at 0, 5, 10, 15, 20 minutes (or until exhaustion)during exercise.
    E.5.1.1Timepoint(s) of evaluation of this end point
    We will assess patients at baseline, 4 months and 7 months for primary and secondary outcome measures. There will be monthly telephone contact throughout the trial to assess for adverse events and compliance. There will be a post trial visit three months after the end of the trial.
    E.5.2Secondary end point(s)
    After at least 6 months on full dose treatment
    1. Number of muscle fibres expressing phosphorylase
    2. Maximum walking distance in 12 minutes
    3. Forearm exercise test
    3. Quality of life measure SF36 and symptom diary
    4. Safety including tolerability and adverse events
    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 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.8.5The 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
    The end of the trial will be the date when the last full dose treatment muscle biopsy has been performed on the 8th participant recruited in the UK to the study, which will be between 7- 8 months after the screening visit. Once treatment is discontinued there will be one follow up at 3 months +/- 21 days.
    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 months11
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days30
    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.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) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 8
    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 state8
    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)
    At the end of the study the patients will be asked to stop the study medication and return all the remaining pills. The researchers will not provide any further trial treatment but arrange for participants to return to their standard clinical care.

    As this is a pilot study it would not be considered appropriate to continue treatment without undertaking a larger placebo randomised controlled trial
    Should a positive effect be identified subjects who have participated in this study will be invited
    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 Decision2014-04-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-03-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-04-05
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