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Sodium Valproate for GSDV

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03112889
Recruitment Status : Completed
First Posted : April 13, 2017
Last Update Posted : February 5, 2018
Information provided by (Responsible Party):
University College, London

Brief Summary:

McArdle disease is a metabolic myopathy characterised by the absence of glycogen phosphorylase in skeletal muscle. Sodium Valproate is part of a group of drugs known as histone deacetylase inhibitors, which have a direct effect on chromatin. Recently a drug trial in an animal model of McArdle disease showed that sodium valproate stimulated the expression of a different isoform of the missing enzyme in skeletal muscle.

A safety and feasibility study of sodium valproate in people with McArdle disease has been carried out in London (UK) and Copenhagen (DK) since January 2015. Participants will receive 20mg/Kg/day of sodium valproate for 6 months. The primary outcome measure is exercise performance assessed by cycle ergometry. Pre and post-treatment skeletal muscle biopsies will be performed to assess for glycogen phosphorylase. Together with blood analyses for safety. Additional functional exercise tests will be performed.

Condition or disease Intervention/treatment Phase
Glycogen Storage Disease Type V McArdle Disease Drug: Sodium Valproate Phase 2

Detailed Description:

McArdle disease (Glycogen storage disease type V, GSDV) is an inherited metabolic disorder of skeletal muscle. Affected patients are unable to perform strenuous exercise due to a congenital absence of the enzyme muscle glycogen phosphorylase, essential for glycogen metabolism. This enzyme deficiency results in the inability to mobilise muscle glycogen stores from muscle, required for energy during strenuous exercise. In affected people symptoms of fatigue and cramps occur within minutes of initiating any activity and during strenuous activity such as lifting heavy weights or walking uphill, if activity is continued despite severe cramping, a contracture occurs which leads to muscle damage (rhabdomyolysis), myoglobinuria (dark brown/black discolouration of urine) and, when severe, acute renal failure.

Currently no satisfactory treatment can be recommended other than aerobic exercise. Although most people with McArdle disease have complete absence of skeletal muscle phosphorylase, there are a small minority of patients who possess splice site mutations that enable production of very small amounts (1-2%) of functional enzyme. These people have a milder phenotype with less severe symptoms, and functional exercise assessments have shown better exercise capacity than typical patients with the condition. Findings from these atypical individuals suggest potential therapeutic agents might only need to produce very small amounts of enzyme for significant functional improvement. Furthermore, finding a therapeutic agent to 'switch on' expression of the foetal isoenzyme may be a potential therapeutic strategy. There is some evidence from animal studies to suggest that sodium valproate can 'switch on' the foetal phosphorylase isoenzyme. The current proposes to undertake a feasibility study of 8 participants recruited in the UK and 7 in Denmark.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 8 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Pilot Study to Explore Treatment With Sodium Valproate in Adults With McArdle Disease (Glycogen Storage Disorder Type V, GSDV)
Actual Study Start Date : January 2015
Actual Primary Completion Date : April 5, 2017
Actual Study Completion Date : April 5, 2017

Arm Intervention/treatment
Experimental: Sodium Valproate
Subjects will receive sodium valproate modified release 20mg/kg/day (maximum dose 2.0g/day) administered orally once daily for six months.
Drug: Sodium Valproate
Subjects will receive sodium valproate modified release 20mg/kg/day (maximum dose 2.0g/day) administered orally once daily for six months.

Primary Outcome Measures :
  1. Change in VO2peak [ Time Frame: Week 1, Week 16 and Week 28 ]
    The aerobic power will be measured at peak workload after a +- 15 minutes incremental cycle test performed on a cycle ergometer after 15 minutes constant load cycling.

Secondary Outcome Measures :
  1. Presence of phosphorylase positive fibres [ Time Frame: Week 0 and Week 28 ]
    Pre and post-treatment muscle biopsies will be evaluated for phosphorylase enzyme activity

  2. Change in total walked distance [ Time Frame: Week 1, Week 16 and Week 28 ]
    The total walked distance will be measured by the 12 minute walk test (corridor).

  3. Blood lactate responses to exercise [ Time Frame: Week 1, Week 16 and Week 28 ]
    Lactate will be measured at rest, during a non-ischameic forearm exercise test (0, 2 and 5 minutes post exercise) and during a cycle test (5, 10 and 15 minutes during exercise and at exhaustion).

  4. Safety of sodium valproate assessed by blood exams and self-reported adverse events [ Time Frame: For the duration of the trial and within 3 months of Visit 3 (+- Week 40) ]
  5. Adverse events log [ Time Frame: Week 4, Week 8, Week 16, Week 20, Week 24, Week 28, +- Week 40 ]
    Assessed during each study visit, monthly phone calls and symptoms diary

  6. Quality of life [ Time Frame: Week 1, Week 16 and Week 28 ]
    Total score on SF36 questionnaire

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Male subjects and post-menopausal or infertile females
  • Diagnosed with GSDV and over 18 years of age
  • Normal serum carnitine level and acylcarnitine blood profile at screening visit

Exclusion Criteria:

  • Children under the age of 18 years
  • People older than 64 years
  • Females of child bearing potential
  • Patients with Diabetes
  • Inflammatory disorders especially systemic lupus erythematosis.
  • A previous history of sensitivity/allergy to sodium valproate and its excipients
  • Patients treated with sodium valproate for epilepsy or a psychiatric disorder within the last 12 months prior to screening
  • Patients with pre-existing 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 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 prescribed other anti-convulsant medication or any other medication known to interact with sodium valproate (see section 9.3).
  • Patients who are sensitive to local anaesthetics that would prevent muscle biopsy.
  • 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.
  • Inability to exercise due to a lower limb fracture would be an exclusion criterion until there is complete recovery of the injury.
  • Patients known to have porphyria or an affected first degree relative affected with porphyria will be excluded from the study.
  • Patients known to have mitochondrial disease or where there is a first degree relative with mitochondrial disease.
  • Patients with a history of abnormal acyl carnitine profile or low serum carnitine level
  • Male participants unwilling to use contraception

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03112889

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Copenhagen, Denmark
United Kingdom
MRC Centre for Neuromuscular Diseases
London, United Kingdom, WC1N 3BG
Sponsors and Collaborators
University College, London
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Principal Investigator: Ros Quinlivan, FRCPCH, MD University College, London
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Responsible Party: University College, London Identifier: NCT03112889    
Other Study ID Numbers: 11/0090
First Posted: April 13, 2017    Key Record Dates
Last Update Posted: February 5, 2018
Last Verified: February 2018
Keywords provided by University College, London:
McArdle Disease
McArdle's Disease
Glycogen Storage Disease Type V
Sodium Valproate
Valproic Acid
Myophosphorylase Deficiency
Muscle Phosphorylase Deficiency
Glycogen Storage Disorder
Additional relevant MeSH terms:
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Glycogen Storage Disease
Glycogen Storage Disease Type V
Genetic Diseases, Inborn
Metabolic Diseases
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Valproic Acid
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs