Sodium Valproate for GSDV

Brief Title

Sodium Valproate for GSDV

Official Title

A Phase II Pilot Study to Explore Treatment With Sodium Valproate in Adults With McArdle Disease (Glycogen Storage Disorder Type V, GSDV)

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.

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

      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.

Study Phase

Phase 2

Study Type


Primary Outcome

Change in VO2peak

Secondary Outcome

 Presence of phosphorylase positive fibres


Glycogen Storage Disease Type V


Sodium Valproate

Study Arms / Comparison Groups

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


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

January 2015

Completion Date

April 5, 2017

Primary Completion Date

April 5, 2017

Eligibility Criteria

        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

          -  Male participants unwilling to use contraception




18 Years - 64 Years

Accepts Healthy Volunteers



Ros Quinlivan, FRCPCH, MD, , 

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party


Study Sponsor

University College, London

Study Sponsor

Ros Quinlivan, FRCPCH, MD, Principal Investigator, University College, London

Verification Date

February 2018