Glycogen Storage Disease Type VPhase 2NCT03112889
Sodium Valproate for GSDV
A Phase 2 study testing Sodium Valproate in people with Glycogen Storage Disease Type V and McArdle Disease, run by University College, London at 2 sites in 2 countries.
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. Read more about this study
- Who is it for?
- Ages 18 to 64 years
- Conditions the study is for
- Glycogen Storage Disease Type V, McArdle Disease
- What is being tested?
- Sodium Valproate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 2 sitesin 2 countries
- Study dates
- Jan 2015to 5 Apr 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 64 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 16Show fewer
- 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
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
United Kingdom1 site
MRC Centre for Neuromuscular Diseases
London, WC1N 3BG
About this study
Official title: A Phase II Pilot Study to Explore Treatment With Sodium Valproate in Adults With McArdle Disease (Glycogen Storage Disorder Type V, GSDV)
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.
Read the 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.
- Conditions
- Glycogen Storage Disease Type V, McArdle Disease
- Being tested
- Sodium Valproate
- 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
- Medical subject headings
- Glycogen Storage Disease Type V, Glycogen Storage Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sodium ValproateDrug
Subjects will receive sodium valproate modified release 20mg/kg/day (maximum dose 2.0g/day) administered orally once daily for six months.
| Study group | Role | What they receive |
|---|---|---|
| Sodium Valproate | Experimental | Subjects will receive sodium valproate modified release 20mg/kg/day (maximum dose 2.0g/day) administered orally once daily for six months. Receives: Drug: Sodium Valproate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Week 1, Week 16 and Week 28
Secondary outcomes (6)
Presence of phosphorylase positive fibres
Pre and post-treatment muscle biopsies will be evaluated for phosphorylase enzyme activity
Measured: Week 0 and Week 28
Change in total walked distance
The total walked distance will be measured by the 12 minute walk test (corridor).
Measured: Week 1, Week 16 and Week 28
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).
Measured: Week 1, Week 16 and Week 28
Safety of sodium valproate assessed by blood exams and self-reported adverse events
Measured: For the duration of the trial and within 3 months of Visit 3 (+- Week 40)
Adverse events log
Assessed during each study visit, monthly phone calls and symptoms diary
Measured: Week 4, Week 8, Week 16, Week 20, Week 24, Week 28, +- Week 40
Quality of life
Total score on SF36 questionnaire
Measured: Week 1, Week 16 and Week 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Apr 2017
- Study startJan 2015
- Primary completion5 Apr 2017
- Study completion5 Apr 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Glycogen Storage Disease Type VStudies of the same condition, open and under way.
- More trials run by University College, LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 8 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University College, London
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ros Quinlivan, FRCPCH, MD, Principal investigator, University College, London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03112889
- Sponsor's protocol ID
- 11/0090
- Status last verified
- Feb 2018
- First submitted
- 11 Aug 2015
- Last updated
- 5 Feb 2018
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 25455802
Study at a glance
From the registry record, last updated by the sponsor on 5 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Pilot Study to Explore Treatment With Sodium Valproate in Adults With McArdle Disease (Glycogen Storage Disorder Type V, GSDV)
- ClinicalTrials.gov ID
- NCT03112889
- Acronym / sponsor ID
- 11/0090
- Conditions
- 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
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (estimated)
- Lead sponsor
- University College, LondonUniversity, hospital or other
- Study start
- Jan 2015 (actual)
- Primary completion
- 5 Apr 2017 (actual)
- Study completion
- 5 Apr 2017 (actual)
- First posted
- 13 Apr 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Sodium Valproate | Experimental | Drug: Sodium ValproateSubjects will receive sodium valproate modified release 20mg/kg/day (maximum dose 2.0g/day) administered orally once daily for six months. |
Who may qualify
- Ages
- 18 to 64 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (16 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sodium ValproateSubjects will receive sodium valproate modified release 20mg/kg/day (maximum dose 2.0g/day) administered orally once daily for six months. | Drug | Sodium Valproate |
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.
6 secondary outcomes
Presence of phosphorylase positive fibres
Time frame: Week 0 and Week 28
Change in total walked distance
Time frame: Week 1, Week 16 and Week 28
Blood lactate responses to exercise
Time frame: Week 1, Week 16 and Week 28
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
Quality of life
Time frame: Week 1, Week 16 and Week 28
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Feb 2018.
- Background: PubMed 25455802Howell 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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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ros Quinlivan, FRCPCH, MD principal investigator
University College, London
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Sodium Valproate in people with Glycogen Storage Disease Type V and McArdle Disease, run by University College, London at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Denmark, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in VO2peak (time frame: Week 1, Week 16 and Week 28). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03112889, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Feb 2018.