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    Summary
    EudraCT Number:2014-001637-88
    Sponsor's Protocol Code Number:2014-650
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-06-24
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2014-001637-88
    A.3Full title of the trial
    A phase 2a study to explore treatment with Sodium Valproate in adults with McArdle Disease (Glycogen Storage Disorder Type V, GSDV)
    Et åbent, fase 2a pilotstudie, der undersøger effekten af behandling med sodium valproat på muskelfunktionen i voksne personer med McArdle sygdom (Glycogen storage disease type V)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effects on muscle function, in persons with McArdle disease, when treated with the drug Valproate.
    Effekten af behandling med lægemidlet Valproat på muskelfuntionen, hos personer med McArdle sygdom
    A.3.2Name or abbreviated title of the trial where available
    Valproate treatment in McArdle disease
    Behandling med Valproat ved McArdle sygdom
    A.4.1Sponsor's protocol code number2014-650
    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 SponsorJohn Vissing
    B.1.3.4CountryDenmark
    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 supportRigshospitalet
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNeuromuscular research unit, Rigshospitalet
    B.5.2Functional name of contact pointNeuromuscular research unit
    B.5.3 Address:
    B.5.3.1Street AddressBlegdamsvej 9, afsnit 3342
    B.5.3.2Town/ cityCopenhagen
    B.5.3.3Post code2100
    B.5.3.4CountryDenmark
    B.5.4Telephone number004535456135
    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 Deprakine
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi-aventis Denmark A/S
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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.3.4Pharmaceutical 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.3.9.4EV Substance CodeSUB12318MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number300 to 500
    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
    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 disorder type V)
    E.1.1.1Medical condition in easily understood language
    McArdle's disease, is a disorder of muscle energy metabolism caused by a genetic defect. Afflicted persons are unable to mobilize local carbohydrate stores in muscle cells to form energy.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    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 investigate, if administration of sodium valproate in patients with McArdle's disease improves exercise capacity, as measured during a cycle ergometer test, and to test feasibility of a larger scale study.
    E.2.2Secondary objectives of the trial
    To investigate, if administration of sodium valproate induces expression of an alternative isoform of myophoshporylase in muscles of patients with McArdle's disease, as seen in histochemically stained muscle biopsies.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects diagnosed with McArdle's disease. Diagnosis will have been 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 deletions in the muscle phophorylase gene.
    2. Subjects over 18 years of age
    3. Normal serum carnitine and acylcarnitine blood profiles at screening visit.
    E.4Principal exclusion criteria
    1. Children under the age of 18 years
    2. Pregnant women
    3. Known Diabetes mellitus
    4. Inflammatory disorders especially systemic lupus erythematosis.
    5. A previous history of sensitivity/allergy to sodium valproate.
    6. Patients treated with sodium valproate for epilepsy or a psychiatric disorder within the last 12 months prior to recruitment.
    7. Patients with pre-existing liver disease or a family history of severe liver disease affecting a first degree relative. Patients with GSDV may 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. Patients with mild elevation in bilirubin caused by clinically insignificant Gilbert’s syndrome (as demonstrated by a high ratio of unconjugated/conjugated billirubin) will also be included in the study.
    8. Patients prescribed other anti-convulsant medication or any other medication known to interact with sodium valproate.
    9. Patients who are sensitive to local anaesthetics that would prevent muscle biopsy.
    10. 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.
    11. Inability to exercise due to a lower limb fracture would be an exclusion criterion until there is complete recovery of the injury.
    12. Patients known to have porphyria or an affected first degree relative affected with porphyria will be excluded from the study.
    13. Patients known to have mitochondrial disease or where there is a first degree relative with mitochondrial disease.
    14. Patients with a history of abnormal acyl carnitine profile or low serum carnitine level
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure will be exercise endurance, measured on a cycle ergometer. Primary outcome measures will include changes in mean estimate and standard deviation from baseline to 6 months on full treatment in:
    • Workload measured in watts.
    • Maximum heart rate.
    • Oxygen consumption to calculate the respiratory quotient (RQ).
    • Rating of perceived exertion (RPE) during exercise.
    Before exercise an intravenous cannula/ butterfly will be inserted so that blood samples can be obtained for three laboratory measures of exercise endurance: glucose, ammonia and lactate. Samples will be drawn at rest t=0, 5, 10, 15 and 20 minutes or at exhaustion.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 6 months on full dose treatment (approximately 8 months after onset of treatment).
    E.5.2Secondary end point(s)
    1. Changes in number of muscle fibers that stain positively for muscle glycogen phosphorylase and total phosphorylase content, from before treatment to 6 months on full dose treatment. Muscle biopsies taken from the upper or lower limb will be performed before treatment and from the same muscle on the contralateral side after 7-8 months of treatment, after the final exercise assessment, while still under full dose sodium valproate treatment.
    2. Changes in performance in a 12-minute walk test at 0, 4 and 7 months. Outcome measures will include maximum heart rate and total distance walked.
    3. The ability to produce lactic acid, in working muscles, during a 1 minute forearm exercise test.
    4. SF36 scores and assessment of symptom diary for frequency of muscle cramps and myoglobinuria.
    5. Laboratory serum parameters for safety and compliance including: creatine kinase (CK), blood trough serum levels of sodium valproate, full blood count, liver function, ammonia and renal function.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 6 months on full dose treatment (approximately 8 months after onset of treatment).
    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 No
    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 Yes
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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
    LVLS; estimated to be 1st of February 2016.
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 7
    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 state7
    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)
    Not different from normal treatment.
    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 University College London Hospitals
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-08-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-08-10
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