Clinical Trial: Sodium Valproate for GSDV

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

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 Summary:

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.


Sponsor: University College, London

Current Primary Outcome: 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.


Original Primary Outcome: Same as current

Current Secondary Outcome:

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


Original Secondary Outcome: Same as current

Information By: University College, London

Dates:
Date Received: August 11, 2015
Date Started: January 2015
Date Completion: July 2017
Last Updated: May 11, 2017
Last Verified: March 2017