Clinical Trial: The Effect of Triheptanoin in Adults With McArdle Disease (Glycogen Storage Disease Type V)

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: The Effect of Triheptanoin in Adults With McArdle Disease (Glycogen Storage Disease Type V)

Brief Summary:

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.

  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 s

    Detailed Summary:

    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).

    The aim of this
    Sponsor: Rigshospitalet, Denmark

    Current Primary Outcome: Change in heart rate during constant load cycling exercise (HRconst) with Triheptanoin vs. placebo treatment [ Time Frame: 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).


    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • Change in maximal oxidative capacity (VO2max) with Triheptanoin vs. placebo treatment [ Time Frame: Day 14 and day 28 ]
      The maximal oxidative capacity measured at peak workload after a 6 minutes ramp test performed on a cycle ergometer after 20 minutes constant load cycling.
    • Change in self-rated severity of fatigue symptoms with Triheptanoin vs. placebo treatment [ Time Frame: Day 14 and day 28 ]
      Total score on a Fatigue Severity Scale (FSS)
    • Change in urine concentrations of organic acids with Triheptanoin vs. placebo treatment [ Time Frame: Day 14 and day 28 ]
      Urine concentrations of: 3OH-propionate, heptanoate, methylmalonate, pimelate methylcitrate
    • Change in maximal workload capacity (Wmax) with Triheptanoin vs. placebo treatment [ Time Frame: Day 14 and day 28 ]
      The maximal workload capacity (Wmax) is measured at peak workload after a 6 minutes ramp test performed on a cycle ergometer after 20 minutes constant load cycling.
    • Change in plasma concentrations of metabolites, citric acid cycle (CAC) intermediates with Triheptanoin vs. placebo treatment [ Time Frame: Day 14 and day 28 ]
      Plasma concentrations of metabolites and citric acid cycle (CAC) intermediates: Lactate, ammonia, glucose, Free Fatty Acids (FFA), acyl-carnitines and malate (a CAC intermediate).


    Original Secondary Outcome: Same as current

    Information By: Rigshospitalet, Denmark

    Dates:
    Date Received: November 4, 2014
    Date Started: April 2015
    Date Completion: July 2017
    Last Updated: October 28, 2015
    Last Verified: October 2015