Sodium Valproate for GSDV

McArdle Disease Clinical Trial

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

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Glycogen Storage Disease
• Glycogen Storage Disease Type V
• McArdle Disease

• NCT number: NCT03112889
• Study type: Interventional
• Source: University College, London
• Status: Completed
• Phase: Phase 2
• Start date: January 2015
• Completion date: April 5, 2017