The Effect of Triheptanoin in Adults With McArdle Disease (Glycogen Storage Disease Type V)
Condition: Glycogen Storage Disease Type V
MeSH terms: Glycogen Storage Disease; Glycogen Storage Disease Type V; Metabolic Diseases; Disease
Study type: Interventional
Phase: Phase 2

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 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.
    

Detailed description: 
      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 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
      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, 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 21-28 patients will be included in the study across three trial sites. From
      the Danish cohort of McArdle Patients; 5-8 patients will be included and from the French
      cohort; 8-10 patients will be included and from the 8-10 American patients will be included.
    

Intervention name(s): Triheptanoin; Placebo oil
Intervention type(s): Drug; Other
Intervention description(s): Anaplerotic dietary oil; Safflower oil
Other intervention name(s): UX007; UX007 Placebo Oral Liquid
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Anaplerotic diet; McArdle Disease; Glycogen Storage Disease; Triheptanoin