The Effect of Triheptanoin in Adults With Mc Ardle Disease (Glycogen Storage Disease Type V)
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
and Hopital Pitié-Sapêtrière in Paris, France.
1. 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 +7 days): Subjects receive no treatment
4. Treatment period #2 (2 weeks +7days): 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.
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.
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.
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
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.
Change in heart rate during constant load cycling exercise (HRconst) with Triheptanoin vs. placebo treatment.
Change in maximal oxidative capacity (VO2max) with Triheptanoin vs. placebo treatment.
Glycogen Storage Disease Type V
Study Arms / Comparison Groups
Description: 14 days on Triheptanoin treatment including a 7 days titration period and a 7 days full dose treatment of 1mL/kg/day.
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Primary Completion Date
- 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
- 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