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Sodium Valproate for GSDV

Primary Purpose

Glycogen Storage Disease Type V, McArdle Disease

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Sodium Valproate

About this trial

This is an interventional treatment trial for Glycogen Storage Disease Type V focused on measuring McArdle Disease, McArdle's Disease, Glycogen Storage Disease Type V, GSDV, Sodium Valproate, Valproic Acid, Myophosphorylase Deficiency, Muscle Phosphorylase Deficiency, Glycogenosis, Glycogen Storage Disorder

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Rigshospitalet
MRC Centre for Neuromuscular Diseases

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sodium Valproate

Arm Description

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

Outcomes

Primary Outcome Measures

Change in VO2peak

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

Presence of phosphorylase positive fibres

Pre and post-treatment muscle biopsies will be evaluated for phosphorylase enzyme activity

Change in total walked distance

The total walked distance will be measured by the 12 minute walk test (corridor).

Blood lactate responses to exercise

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

Adverse events log

Assessed during each study visit, monthly phone calls and symptoms diary

Quality of life

Total score on SF36 questionnaire

Full Information

NCT ID

NCT03112889

First Posted

August 11, 2015

Last Updated

February 2, 2018

Sponsor

University College, London

1. Study Identification

Unique Protocol Identification Number

NCT03112889

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)

Study Type

Interventional

2. Study Status

Record Verification Date

February 2018

Overall Recruitment Status

Completed

Study Start Date

January 2015 (Actual)

Primary Completion Date

April 5, 2017 (Actual)

Study Completion Date

April 5, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University College, London

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glycogen Storage Disease Type V, McArdle Disease

Keywords

McArdle Disease, McArdle's Disease, Glycogen Storage Disease Type V, GSDV, Sodium Valproate, Valproic Acid, Myophosphorylase Deficiency, Muscle Phosphorylase Deficiency, Glycogenosis, Glycogen Storage Disorder

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

8 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Sodium Valproate

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Sodium Valproate

Intervention Description

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

Primary Outcome Measure Information:

Title

Change in VO2peak

Description

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.

Time Frame

Week 1, Week 16 and Week 28

Secondary Outcome Measure Information:

Title

Presence of phosphorylase positive fibres

Description

Pre and post-treatment muscle biopsies will be evaluated for phosphorylase enzyme activity

Time Frame

Week 0 and Week 28

Title

Change in total walked distance

Description

The total walked distance will be measured by the 12 minute walk test (corridor).

Time Frame

Week 1, Week 16 and Week 28

Title

Blood lactate responses to exercise

Description

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).

Time Frame

Week 1, Week 16 and Week 28

Title

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)

Title

Adverse events log

Description

Assessed during each study visit, monthly phone calls and symptoms diary

Time Frame

Week 4, Week 8, Week 16, Week 20, Week 24, Week 28, +- Week 40

Title

Quality of life

Description

Total score on SF36 questionnaire

Time Frame

Week 1, Week 16 and Week 28

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

64 Years

Accepts Healthy Volunteers

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 level Male participants unwilling to use contraception

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ros Quinlivan, FRCPCH, MD

Organizational Affiliation

University College, London

Official's Role

Principal Investigator

Facility Information:

Facility Name

Rigshospitalet

City

Copenhagen

Country

Denmark

Facility Name

MRC Centre for Neuromuscular Diseases

City

London

ZIP/Postal Code

WC1N 3BG

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

25455802

Citation

Howell JM, Dunton E, Creed KE, Quinlivan R, Sewry C. Investigating sodium valproate as a treatment for McArdle disease in sheep. Neuromuscul Disord. 2015 Feb;25(2):111-9. doi: 10.1016/j.nmd.2014.10.002. Epub 2014 Oct 13.

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Sodium Valproate for GSDV

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