Triheptanoin in Mc Ardle

The Effect of Triheptanoin in Adults With Mc Ardle Disease (Glycogen Storage Disease Type V)

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.

Study Overview

• Status: Unknown
• Conditions: Glycogen Storage Disease Type V
• Intervention / Treatment: Drug: Triheptanoin; Drug: Placebo oil

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 Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pascal LAFORET, PH; Phone Number: + 33 (0)1 42 16 37 76; Email: pascal.laforet@psl.aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: triheptanoin; 14 days on Triheptanoin treatment including a 7 days titration period and a 7 days full dose treatment of 1mL/kg/day.	Drug: Triheptanoin; Anaplerotic dietary oil; Other Names: UX007
Placebo Comparator: placebo oil; 14 days of diet on a placebo oil including 7 days titration period and 7 days full dose treatment of 1mL/kg/day	Drug: Placebo oil; Safflower oil; Other Names: UX007 Placebo Oral Liquid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Day 14 and Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 14 and Day 28
Change in self-rated severity of fatigue symptoms with Triheptanoin vs. placebo treatment.	Total score on a Fatigue Severity Scale (FSS)	Day 14 and 28
Change in urine concentrations of organic acids with Triheptanoin vs. placebo treatment. Urine concentrations of: 3OH-propionate, heptanoate, methylmalonate, pimelate methylcitrate		Day 14 and 28
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.	Day 14 and Day 28
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).	Day 14 and Day 28

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Collaborators: Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start: October 1, 2016
• Primary Completion (Anticipated): September 1, 2017

Study Registration Dates

• First Submitted: September 28, 2016
• First Submitted That Met QC Criteria: September 28, 2016
• First Posted (Estimate): September 29, 2016

Study Record Updates

• Last Update Posted (Estimate): September 29, 2016
• Last Update Submitted That Met QC Criteria: September 28, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Disease; Glycogen Storage Disease; Glycogen Storage Disease Type V
• Other Study ID Numbers: C15-54'