Clinical trial NCT03642860: The Effect of Triheptanoin on Fatty Acid Oxidation and Exercise Tolerance in Patients With Glycogenoses
Official title: Triheptanoin's Effect on Fatty Acid Oxidation and Exercise Tolerance in Patients With Debrancher Deficiency, Glycogenin-1 Deficiency and Phosphofructoinase Deficiency at Rest and During Exercise. A Randomized, Double-blind, Placebo-controlled, Cross-over Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tarui Disease
Debrancher Deficiency
GYG1 DEFICIENCY
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Ultragenyx Pharmaceutical Inc
First posted: 2018-08-22
Enrollment: 3
Sex: ALL
Minimum age (years): 15
Maximum age (years): 85
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The study will be conducted as a randomized, placebo-controlled, double blind, crossover study consisting of two 14 days treatment periods set apart by minimum a 7-days wash-out period where no treatment is taken. In one treatment period, the subjects receive UX007 treatment and placebo treatment in the other. The study will consist of three separate groups; one group consisting of GSD III, one group of GSD VII, and one group of GSD XV subjects. Each of these groups will be blinded and randomized separately
Primary purpose: TREATMENT

Brief summary: The aim of this study is to investigate the effect of 14 days of treatment with the dietary oil-supplement Triheptanoin on fat metabolism and exercise tolerance in patients with Phosphofructokinase deficiency, Debrancher deficiency and Glycogenin-1 deficiency. The investigators wish to investigate whether a Triheptanoin diet can improve exercise capacity by measuring:

1. Heart rate during cycling exercise and maximal exercise capacity
2. Fat and glucose metabolism
3. Concentrations of metabolic substrates in blood during exercise
4. Perception of fatigue and symptoms by questionnaire
5. Degree of exhaustion during cycling exercise by Borg score

All measurements are done before and after 14 days with a Triheptanoin-oil diet, and before and after 14 days diet with safflower (Placebo-oil).

Triheptanoin-oil supplementation in the diet has been shown to increase metabolism of both fat and carbohydrates in patients with other metabolic myopathies. In these patients, Triheptanoin improved physical performance and has reduced the amount of symptoms experienced by patients.

Detailed description: BACKGROUND:

Neuromuscular diseases affect more than 5% of the population in Western countries. Some of the more rare neuromuscular disorders are patients with metabolic myopathies, which are hereditary disorders caused by enzymatic defects of intermediary metabolism. The disorders are generally subdivided in two major groups affecting either carbohydrate metabolism (the glycogenosis) or lipid metabolism. Patients suffer from recurrent episodes of exercise intolerance, muscle pain and muscle contractures/stiffness, and in severe cases rhabdomyolysis (breakdown of skeletal muscle fibers) and myoglobinuria. Recognition of the metabolic block in the metabolic myopathies has started the development of new therapeutic options. Enzyme replacement therapy with recombinant lysosomal acid alpha-glucosidase (rGAA) has revolutionized treatment of early onset Pompe's disease, glycogen storage disease (GSD) II.(1-3) Supplements of riboflavin, carnitine and sucrose show promise in patients with respectively riboflavin-responsive multiple acyl-Coenzyme A (CoA) dehydrogenase deficiency (4), primary carnitine deficiency (5-7) and McArdle disease (8). However, for many of the glycogenosis treatment primarily relies on avoiding precipitating factors, and dietary supplements that bypass the metabolic block.(9) Only a few of the used supplements are validated, and further studies are needed to define efficacious treatments.

A promising product for treatment of glycogenosis is Triheptanoin. Triheptanoin provides patients with medium-length, odd-chain fatty acids that are metabolized into ketones, which replace deficient intermediates in the Tricaboxylic acid (TCA) cycle, thus supporting glucose production through gluconeogenesis, resulting in a lower turnover of glycogen.(10) Triheptanoin has primarily been used in lipid metabolism disorders, where it has shown a remarkable improvement of cardiac and muscular symptoms in three children with VLCAD deficiency and in seven patients with Carnitine palmitoyltransferase (CPT) II deficiency after dietary Triheptanoin supplementation.(10,11)

Metabolic studies in patients with the glycogenosis McArdle disease and Debrancher deficiency has showed that these disorders are associated with an energy deficit caused by reduced skeletal muscle oxidation of carbohydrates and a compensatory increase in fatty acid oxidation. Despite increasing availability of free fatty acid (FFA) during exercise, fatty acid oxidation (FAO) is not increased further, even though the energy deficit is maintained.(12,13)

McArdle disease is one of the largest and most investigated groups of the muscle glycogenosis, caused by mutations in the myophosphorylase gene (PYGM) on chromosome 11 that encodes muscle glycogen phosphorylase.(14). It is know that TCA cycle intermediates are low during exercise in patients with McArdle disease, and most likely the impaired FAO relates to a slowing of the TCA-cycle by limited supply from glycolysis.(15) Triheptanoin, most likely can correct the suspected shortage of anaplerotic intermediates to spark the TCA-cycle in patients with glycogenosis as well, and studies are ongoing in patients with McArdle disease at our research unit Copenhagen Neuromuscular Center. Clinical-Trials.gov Identifier: NCT02432768.

Other glycogenoses as Debrancher deficiency, Phosphofructokinase deficiency and Glycogenin 1 deficiency, all involved in either glycogenolysis or gluconeogenesis might benefit from Triheptanoin treatment.

Glycogen storage disease III (GSD III) also known as Debrancher deficiency or Cori-Forbes disease is caused by deficient activity of glycogen debranching enzyme (GDE) due to mutations in the AGL gene on chromosome 1p21. (16) More than 20 different disease-causing mutations have been identified in this gene.(17) Debranching enzyme is required for complete hydrolysis of glycogen and GSD III is associated with an accumulation of abnormal glycogen with short outer chains.(18) Four subtypes are described:

1. Type IIIa (the most common) that affects enzymes in the liver and the skeletal and cardiac muscle.
2. Type IIIb (about 15% of patients) involves only the liver enzyme.
3. Type IIIc (rare) with a selective loss of only one of the two GDE activities affecting muscle.
4. Type IIId (rare) with loss of the transferase affecting muscle and liver (19) Dominant features during infancy and childhood are hepatomegaly, hypoglycaemia, hyperlipidaemia, and growth retardation.(16) Muscle weakness (myopathy) and wasting typically present in the third decade. Weakness can be both proximal and distal. Electromyography (EMG) and muscle histology show myopathic changes and large glycogen deposits in the muscle.(20) Treatment is symptomatic. GSD III is associated with fixed skeletal muscle weakness and some patients have exercise-related dynamic symptoms, most likely caused by a reduced skeletal muscle oxidation of carbohydrates and a compensatory increase in fatty acid oxidation.(13,21) Phosphofructokinase deficiency (GSD VII) is another glycogenosis inherited in an autosomal recessive manner causing a defect in the rate-limiting enzyme of glycolysis, phosphofructokinase (PFK).(22) The defect results in a complete block in muscle glycolysis and glycogenolysis. Clinical features are exercise intolerance, myopathy and muscle contractures that can lead to myoglobinuria. The exercise intolerance is due to a severely restricted oxidative metabolism. An increase in blood glucose will actually decrease exercise tolerance in GSD VII contrary to GSD IIIa where it has an increasing effect. Therefore, the GSD VII subjects depend on the availability of blood borne fuels such as free fatty acids and ketones seen during fasting. (23) Glycogenin-1(GYG1) deficiency (GSD XV) (OMIM #613507) is an inborn error of glycogen synthesis caused by mutations in the GYG1 gene. GYG1 works as the initial building block in the biosynthesis of glycogen in skeletal muscle. It is a glycosyl-transferase that uses UDP-glucose as substrate for autoglycosylation, forming an oligosaccharide by the process of UDP-alpha-D-glucose + glycogenin -\> UDP + alpha-D-glucosylglycogenin.(24) GYG1 deficiency is inherited autosomal recessively, and is the most recently discovered muscle glycogenosis.

Most patients present with a slowly progressive adult-onset myopathy with a variable clinical presentation.(25) Some adult patients also report exercise intolerance.(26-28) Metabolic studies show that patients with GYG1 deficiency, not only have abnormal formation of glycogen, but also have impaired muscle glycogenolysis, as suggested by impaired lactate production during exercise and improved exercise tolerance with glucose infusion; results are accepted for publication in Neurology.

At present, there is only 1 known patient with Debrancher deficiency, no patients with PFK deficiency and two patients with GYG1 deficiency in Denmark. Therefore the study will aim to include patients from abroad. Patients will fly in for studies in Copenhagen, as the investigators have done many times before.(12,29-31)

Based on observation from Roe et al. and Mochel et al. the first effects of Triheptanoin appears within 48 hrs of treatment. Furthermore, based on these observations the treatment period will consist of a week of dosage escalation to avoid potential gastro-intestinal side effects.(10,11,32-34) Therefore, the investigators hypothesize that 14 days of treatment with Triheptanoin oil will improve exercise tolerance, indicated by heart rate, and fatty acid oxidation during steady state cycling exercise using indirect calorimetry and stable isotope technique in patients with the glycogenosis Debrancher deficiency, PFK deficiency and GYG1 deficiency.

INVESTIGATIONAL PRODUCT:

UX007 (Triheptanoin) is an artificially made oil of a triglyceride of three 7-carbon fatty acid chains (heptanoate) that can be used in the treatment of patients with several types of inborn errors of metabolism associated with an impaired functioning of the TCA.(10,11,32-34)(See Investigator's Brochure). UX007 (Triheptanoin) is a liquid, intended for PO administration. UX007 is a colorless to yellow oil supplied in 1 L round amber-colored glass bottles. UX007 is manufactured, packaged, and labeled according to Good Manufacturing Procedure (GMP) regulations.

Processes that replenish the stores of TCA-intermediates are called anaplerosis. Metabolism of odd-numbered carbon fatty acids such as Triheptanoin provides anaplerotic substrates through ketone body production in the liver and beta-oxidation in peripheral tissues, which forms propionyl- and acetyl-CoA that both enter the TCA-cycle.(32-35) The effect of the UX007-intake will be compared to intake of a placebo substance. Placebo will consist of safflower oil and will match the appearance of UX007, which is orally administered in the same manner as UX007.

Eligibility criteria: Inclusion Criteria:

* Males and females age \>15 years
* Genetically and/or biochemically verified diagnosis of Debrancher deficiency or Phosphofructokinase deficiency or Glycogenin 1 deficiency
* Capacity to consent
* All women in fertile age must be on contraceptive treatment with: Birth control pills, coil, ring, transdermal hormone patch injection of synthetic progesterone or subdermal implant.

Exclusion Criteria:

* Significant cardiac or pulmonary disease
* Pregnancy (confirmed by urine stick) or breastfeeding.
* Treatment with beta-blockers
* Inability to perform cycling exercise
* Any other significant disorder that may confound the interpretation of the findings.
* Subjects at risk of musculoskeletal injury, i.e. with disease in joints or muscle.

Primary outcomes:
measure: Heart rate
timeFrame: 60 min
measure: Palmitate oxidation
timeFrame: 60 min
Secondary outcomes:
measure: Short Form-36 Questionnaire
timeFrame: 2 weeks
measure: Maximal workload capacity
timeFrame: 60 min
measure: Plasma concentrations of lactate, ammonia, glucose, FFA, acyl-carnitines, malate, C5, insulin, adrenalin and noradrenalin.
timeFrame: 60 min
measure: Rate of Perceived Exertion (RPE)
timeFrame: 60 min
measure: Bouchards energy expenditure questionnaire
timeFrame: 3 days
measure: Glucose rate of appearance and disappearance
timeFrame: 60 min
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Copenhagen Neuromuscular Center
Study officials:
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