The Effect of Triheptanoin in Adults With McArdle Disease (Glycogen Storage Disease Type V)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 22
- 试验地点
- 1
- 主要终点
- Change in heart rate during constant load cycling exercise (HRconst) with Triheptanoin vs. placebo treatment
研究概览
简要总结
Background: Patients with the sugar metabolism disorder, Glycogen Storage Disease Type V, have insufficient breakdown of sugar stored as, glycogen, within the cells. The investigators know from previous studies with McArdle patients, that they not only have a reduced sugar metabolism, both also have problems in increasing their fat metabolism during exercise to fully compensate for the energy deficiency.
Studies on Triheptanoin diet used in patients with other metabolic diseases have shown that Triheptanoin can increase metabolism of both fat and sugar. In these patients, Triheptanoin has had a positive effect on the physical performance and has reduces the level of symptoms experienced by patients.
Aim: To investigate the effect of treatment with the dietary oil, Triheptanoin, in patients with McArdle disease on exercise capacity.
Methods: 20-30 adult patients will be recruited through Rigshospitalet in Copenhagen, Denmark, Hopital Pitié-Sapêtrière in Paris, France and through The University of Texas Southwestern Medical Center in Dallas, Texas.
- Pre-experimental testing (1 day):
Baseline blood samples are collected to obtain baseline values of safety parameters: Plasma-acylcarnitines, free fatty acids and creatine kinase.
Subjects perform a max-test to determine their VO2max 2. Treatment period #1 (2 weeks):
Subjects follow a diet consuming a dietary treatment oil. Neither patients nor members of the study group know who receive which type of oil. 3. Washout period (1 week):
Subjects receive no treatment 4. Treatment period #2 (2 weeks):
Subjects who received Triheptanoin oil in the first treatment period, now receive placebo oil and vice versa.
Assessments: Before and after each treatment periods, subjects perform a 30-minutes exercise test on a cycle ergometer, comprising of 20-22 minutes of constant load exercise and 6-8 minutes increasing load to peak. Subjects will complete a Fatigue Severity Scale questionnaire and metabolic products will be measured in blood and urine.
详细描述
BACKGROUND
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Genetically and/or biochemically verified diagnosis of McArdle disease
- •Body Mass Index of 18-32
- •Capacity to consent
排除标准
- •Significant cardiac and pulmonary disease
- •Pregnancy
- •Treatment with beta-blockers
- •Inability to perform cycling exercise
- •Any other significant disorder that may confound the interpretation of the findings
研究组 & 干预措施
Triheptanoin
14 days on Triheptanoin treatment including a 7 days titration period and a 7 days full dose treatment of 1mL/kg/day.
干预措施: Triheptanoin (Drug)
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.
干预措施: Placebo oil (Other)
结局指标
主要结局
Change in heart rate during constant load cycling exercise (HRconst) with Triheptanoin vs. placebo treatment
时间窗: Day 14 and day 28
Subject heart rate will be measured during 20 minutes exercise test performed on a cycle ergometer at a workload corresponding to approximately 60% of maximal oxidative capacity (VO2max).
次要结局
- Change in urine concentrations of organic acids with Triheptanoin vs. placebo treatment(Day 14 and day 28)
- Change in maximal workload capacity (Wmax) with Triheptanoin vs. placebo treatment(Day 14 and day 28)
- Change in maximal oxidative capacity (VO2max) with Triheptanoin vs. placebo treatment(Day 14 and day 28)
- Change in self-rated severity of fatigue symptoms with Triheptanoin vs. placebo treatment(Day 14 and day 28)
- Change in plasma concentrations of metabolites, citric acid cycle (CAC) intermediates with Triheptanoin vs. placebo treatment(Day 14 and day 28)
研究者
Karen Lindhardt Madsen
MD
Rigshospitalet, Denmark