Triheptanoin in Mc Ardle
关键词
抽象
描述
This project will investigate the treatment potential of the drug Triheptanoin in patients with the inborn defect in glycogen metabolism, McArdle Disease. There is currently no treatment available for this group of patients. The condition leads to intolerance to physical exercise with a risk of developing severe cramps and contractures followed by muscle damage and acute kidney failure. Also one third of the patients develop progressive muscle weakness and wasting.
The McArdle patients have an inherited defect in the enzyme, myofosforylase, an important link in the glycogenolysis within skeletal muscle. As a consequence, the patients lack substrates for glycolysis to fuel muscle work (1). The investigators have previously shown that patients with McArdle disease are unable to increase fat metabolism enough to compensate for the energy insufficiency that occurs in these patients in response to exercise (2).
A key limitation to exercise in McArdle disease is the reduced production of pyruvate, causing depletion of intermediates in the Citric Acid Cycle (CAC). Triheptanoin is a triglyceride of glycerol and three 7-carbon fatty acid chains (heptanoate). The breakdown of odd-number carbon fatty acids, such as heptanoate, generates CAC-intermediates. Triheptanoin can therefore potentially boost the flux through the CAC and increase the ATP and energy generation in the cells.
In other patients with inborn errors of metabolism, treatment with daily Triheptanoin supplement can increase metabolism of both fat and glucose. Triheptanoin treatment has reduced the symptom frequency and increased exercise tolerance and physical performance in these patients (3,4).
The aim of this study is to investigate the effect of Triheptanoin on exercise performance and tolerance and frequency of symptoms in patients with McArdle disease.
METHODS
The study will be designed as a double blinded placebo controlled cross-over study. During a 5 week trial period each study patient will go through a 2 week treatment period, a 1 week (+7days) wash-out period without treatment followed by another 2 week treatment period. In one treatment period, the patient takes a daily dietary oil supplement containing Triheptanoin and in the other period (2 weeks +7days), the oil contains regular safflower oil (placebo). Both Triheptanoin and placebo oil is manufactured, packed and handed out by the manufacturer, Ultragenyx Pharmaceuticals Inc. in a way that neither patients, nor the investigators will know in which period, which treatment is given to which patient.
Assessments:
The patients will meet at the laboratory for assessments on 5 occasions:
Screening visit: Patients perform a peak exercise test on a cycle ergometer wearing a mask that can measure oxygen and carbon dioxide exchange rates. Patients exercise with increasing workload until exhaustion to find their maximal oxidative capacity and maximal workload Test days 1-4: On one test day before and one after each treatment period, the patients perform a 30-minutes exercise test on a cycle ergometer working at a constant moderate intensity for 20-22 minutes followed by a 6-8 minutes stepwise increase to peak workload. Blood samples will be taken before, during and after exercise to measure concentrations of metabolic products. Patients report their current feeling of fatigue in a Fatigue Severity Scale (FSS-questionnaire)
Subjects:
A total number of 21-26 patients will be included in the study across three trial sites. From the French cohort of McArdle Patients; 10-15 patients will be included and from the Danish cohort; 11 patients have been already included.
日期
最后验证: | 06/30/2016 |
首次提交: | 09/27/2016 |
提交的预估入学人数: | 09/27/2016 |
首次发布: | 09/28/2016 |
上次提交的更新: | 09/27/2016 |
最近更新发布: | 09/28/2016 |
实际学习开始日期: | 09/30/2016 |
预计主要完成日期: | 08/31/2017 |
状况或疾病
干预/治疗
Drug: triheptanoin
Drug: placebo oil
相
手臂组
臂 | 干预/治疗 |
---|---|
Active Comparator: triheptanoin 14 days on Triheptanoin treatment including a 7 days titration period and a 7 days full dose treatment of 1mL/kg/day. | Drug: triheptanoin Anaplerotic dietary oil |
Placebo Comparator: placebo oil 14 days of diet on a placebo oil including 7 days titration period and 7 days full dose treatment of 1mL/kg/day | Drug: placebo oil Safflower oil |
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 or female between 18 and 65 years of age, - Genetically and/or biochemically verified diagnosis of McArdle disease - Body Mass Index of 18-32 - Women in child-bearing age on contraceptive treatment with: Birth control pills, coil, ring, transdermal hormone patch injection of gestagen or subdermal implant. - French national health insurance - Signed informed consent - Available for phone calls Exclusion Criteria: - Minor - Significant cardiac or pulmonary disease - Pregnancy (confirmed by urinary-HCG) or breastfeeding. Pregnancy not planned and to be avoided during the study by use of effective contraceptive methods. - Persons deprived of their liberty by judicial or administrative decision - Adult subject under legal protection or unable to consent - Treatment with beta-blockers - Inability to perform cycling exercise - Any other significant disorder that may confound the interpretation of the findings - Person subject to an exclusion period for a previous clinical trial |
结果
主要结果指标
1. Change in heart rate during constant load cycling exercise (HRconst) with Triheptanoin vs. placebo treatment. [Day 14 and Day 28]
次要成果指标
1. Change in maximal oxidative capacity (VO2max) with Triheptanoin vs. placebo treatment. [Day 14 and Day 28]
2. Change in self-rated severity of fatigue symptoms with Triheptanoin vs. placebo treatment. [Day 14 and 28]
3. Change in urine concentrations of organic acids with Triheptanoin vs. placebo treatment. Urine concentrations of: 3OH-propionate, heptanoate, methylmalonate, pimelate methylcitrate [Day 14 and 28]
4. Change in maximal workload capacity (Wmax) with Triheptanoin vs. placebo treatment. [Day 14 and Day 28]
5. Change in plasma concentrations of metabolites, citric acid cycle (CAC) intermediates with Triheptanoin vs. placebo treatment. [Day 14 and Day 28]