Triheptanoin in Mc Ardle

Brief Title

Triheptanoin in Mc Ardle

Official Title

The Effect of Triheptanoin in Adults With Mc Ardle 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
      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.
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Change in heart rate during constant load cycling exercise (HRconst) with Triheptanoin vs. placebo treatment.

Secondary Outcome

 Change in maximal oxidative capacity (VO2max) with Triheptanoin vs. placebo treatment.

Condition

Glycogen Storage Disease Type V

Intervention

Triheptanoin

Study Arms / Comparison Groups

 triheptanoin
Description:  14 days on Triheptanoin treatment including a 7 days titration period and a 7 days full dose treatment of 1mL/kg/day.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

12

Start Date

October 2016


Primary Completion Date

September 2017

Eligibility Criteria

        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
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

, + 33 (0)1 42 16 37 76, [email protected]



Administrative Informations


NCT ID

NCT02919631

Organization ID

C15-54'


Responsible Party

Sponsor

Study Sponsor

Institut National de la Santé Et de la Recherche Médicale, France

Collaborators

 Rigshospitalet, Denmark

Study Sponsor

, , 


Verification Date

July 2016