Sodium Valproate for GSDV
关键词
抽象
描述
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.
日期
| 最后验证: | 01/31/2018 |
| 首次提交: | 08/10/2015 |
| 提交的预估入学人数: | 04/06/2017 |
| 首次发布: | 04/12/2017 |
| 上次提交的更新: | 02/01/2018 |
| 最近更新发布: | 02/04/2018 |
| 实际学习开始日期: | 12/31/2014 |
| 预计主要完成日期: | 04/04/2017 |
| 预计完成日期: | 04/04/2017 |
状况或疾病
干预/治疗
Drug: Sodium Valproate
相
手臂组
| 臂 | 干预/治疗 |
|---|---|
| Experimental: Sodium Valproate Subjects will receive sodium valproate modified release 20mg/kg/day (maximum dose 2.0g/day) administered orally once daily for six months. | Drug: Sodium Valproate Subjects will receive sodium valproate modified release 20mg/kg/day (maximum dose 2.0g/day) administered orally once daily for six months. |
资格标准
| 有资格学习的年龄 | 18 Years 至 18 Years |
| 有资格学习的性别 | All |
| 接受健康志愿者 | 是 |
| 标准 | 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 |
结果
主要结果指标
1. Change in VO2peak [Week 1, Week 16 and Week 28]
次要成果指标
1. Presence of phosphorylase positive fibres [Week 0 and Week 28]
2. Change in total walked distance [Week 1, Week 16 and Week 28]
3. Blood lactate responses to exercise [Week 1, Week 16 and Week 28]
4. Safety of sodium valproate assessed by blood exams and self-reported adverse events [For the duration of the trial and within 3 months of Visit 3 (+- Week 40)]
5. Adverse events log [Week 4, Week 8, Week 16, Week 20, Week 24, Week 28, +- Week 40]
6. Quality of life [Week 1, Week 16 and Week 28]
