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Triheptanoin in Mc Ardle

Primary Purpose

Glycogen Storage Disease Type V

Status
Unknown status
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Triheptanoin
Placebo oil
Sponsored by
Institut National de la Santé Et de la Recherche Médicale, France
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glycogen Storage Disease Type V

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Placebo Comparator

    Arm Label

    triheptanoin

    placebo oil

    Arm Description

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

    14 days of diet on a placebo oil including 7 days titration period and 7 days full dose treatment of 1mL/kg/day

    Outcomes

    Primary Outcome Measures

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

    Secondary Outcome Measures

    Change in maximal oxidative capacity (VO2max) with Triheptanoin vs. placebo treatment.
    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.
    Total score on a Fatigue Severity Scale (FSS)
    Change in urine concentrations of organic acids with Triheptanoin vs. placebo treatment. Urine concentrations of: 3OH-propionate, heptanoate, methylmalonate, pimelate methylcitrate
    Change in maximal workload capacity (Wmax) with Triheptanoin vs. placebo treatment.
    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.
    Plasma concentrations of metabolites and citric acid cycle (CAC) intermediates: Lactate, ammonia, glucose, Free Fatty Acids (FFA), acyl-carnitines and malate (a CAC intermediate).

    Full Information

    First Posted
    September 28, 2016
    Last Updated
    September 28, 2016
    Sponsor
    Institut National de la Santé Et de la Recherche Médicale, France
    Collaborators
    Rigshospitalet, Denmark
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02919631
    Brief Title
    Triheptanoin in Mc Ardle
    Official Title
    The Effect of Triheptanoin in Adults With Mc Ardle Disease (Glycogen Storage Disease Type V)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2016
    Overall Recruitment Status
    Unknown status
    Study Start Date
    October 2016 (undefined)
    Primary Completion Date
    September 2017 (Anticipated)
    Study Completion Date
    undefined (undefined)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Institut National de la Santé Et de la Recherche Médicale, France
    Collaborators
    Rigshospitalet, Denmark

    4. Oversight

    5. Study Description

    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. 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 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. Washout period (1 week +7 days): Subjects receive no treatment 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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Glycogen Storage Disease Type V

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Crossover Assignment
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    12 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    triheptanoin
    Arm Type
    Active Comparator
    Arm Description
    14 days on Triheptanoin treatment including a 7 days titration period and a 7 days full dose treatment of 1mL/kg/day.
    Arm Title
    placebo oil
    Arm Type
    Placebo Comparator
    Arm Description
    14 days of diet on a placebo oil including 7 days titration period and 7 days full dose treatment of 1mL/kg/day
    Intervention Type
    Drug
    Intervention Name(s)
    Triheptanoin
    Other Intervention Name(s)
    UX007
    Intervention Description
    Anaplerotic dietary oil
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo oil
    Other Intervention Name(s)
    UX007 Placebo Oral Liquid
    Intervention Description
    Safflower oil
    Primary Outcome Measure Information:
    Title
    Change in heart rate during constant load cycling exercise (HRconst) with Triheptanoin vs. placebo treatment.
    Description
    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).
    Time Frame
    Day 14 and Day 28
    Secondary Outcome Measure Information:
    Title
    Change in maximal oxidative capacity (VO2max) with Triheptanoin vs. placebo treatment.
    Description
    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.
    Time Frame
    Day 14 and Day 28
    Title
    Change in self-rated severity of fatigue symptoms with Triheptanoin vs. placebo treatment.
    Description
    Total score on a Fatigue Severity Scale (FSS)
    Time Frame
    Day 14 and 28
    Title
    Change in urine concentrations of organic acids with Triheptanoin vs. placebo treatment. Urine concentrations of: 3OH-propionate, heptanoate, methylmalonate, pimelate methylcitrate
    Time Frame
    Day 14 and 28
    Title
    Change in maximal workload capacity (Wmax) with Triheptanoin vs. placebo treatment.
    Description
    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.
    Time Frame
    Day 14 and Day 28
    Title
    Change in plasma concentrations of metabolites, citric acid cycle (CAC) intermediates with Triheptanoin vs. placebo treatment.
    Description
    Plasma concentrations of metabolites and citric acid cycle (CAC) intermediates: Lactate, ammonia, glucose, Free Fatty Acids (FFA), acyl-carnitines and malate (a CAC intermediate).
    Time Frame
    Day 14 and Day 28

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    65 Years
    Accepts Healthy Volunteers
    No
    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
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Pascal LAFORET, PH
    Phone
    + 33 (0)1 42 16 37 76
    Email
    pascal.laforet@psl.aphp.fr

    12. IPD Sharing Statement

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    Triheptanoin in Mc Ardle

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