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
About this trial
This is an interventional treatment trial for Glycogen Storage Disease Type V
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
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
NCT ID
NCT02919631
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
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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