The Effect of Triheptanoin on Fatty Acid Oxidation and Exercise Tolerance in Patients With Glycogenoses

Debrancher Deficiency Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03642860
• Other study ID #: #20171012 Trihep
• Secondary ID: 2017-004153-17
• Status: Completed
• Phase: Phase 2
• Start date: August 15, 2018
• Est. completion date: August 28, 2019

Study information

• Verified date: February 2024
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3
• Est. completion date: August 28, 2019
• Est. primary completion date: August 28, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Debrancher Deficiency
• Glycogen Storage Disease Type III
• Glycogen Storage Disease Type VII
• GYG1 DEFICIENCY
• Tarui Disease

Intervention

Drug:
• Triheptanoin
Daily treatment with Triheptanoin oil for 14 days (7 days titration period in addition to 7 days full dose period with 1g/kg/day).
• Placebo Oil
Daily treatment with Safflower oil for 14 days (7 days titration period in addition to 7 days full dose period with 1g/kg/day).

Locations

Country	Name	City	State
Denmark	Copenhagen Neuromuscular Center	Copenhagen

Sponsors (2)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	Ultragenyx Pharmaceutical Inc

Country where clinical trial is conducted

Denmark, 

References & Publications (35)

Akman HO, Aykit Y, Amuk OC, Malfatti E, Romero NB, Maioli MA, Piras R, DiMauro S, Marrosu G. Late-onset polyglucosan body myopathy in five patients with a homozygous mutation in GYG1. Neuromuscul Disord. 2016 Jan;26(1):16-20. doi: 10.1016/j.nmd.2015.10.01 — View Citation

Andersen ST, Haller RG, Vissing J. Effect of oral sucrose shortly before exercise on work capacity in McArdle disease. Arch Neurol. 2008 Jun;65(6):786-9. doi: 10.1001/archneur.65.6.786. — View Citation

Brunengraber H, Roe CR. Anaplerotic molecules: current and future. J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):327-31. doi: 10.1007/s10545-006-0320-1. — View Citation

Burke J, Hwang P, Anderson L, Lebo R, Gorin F, Fletterick R. Intron/exon structure of the human gene for the muscle isozyme of glycogen phosphorylase. Proteins. 1987;2(3):177-87. doi: 10.1002/prot.340020303. — View Citation

Coleman RA, Winter HS, Wolf B, Gilchrist JM, Chen YT. Glycogen storage disease type III (glycogen debranching enzyme deficiency): correlation of biochemical defects with myopathy and cardiomyopathy. Ann Intern Med. 1992 Jun 1;116(11):896-900. doi: 10.7326 — View Citation

Ding JH, de Barsy T, Brown BI, Coleman RA, Chen YT. Immunoblot analyses of glycogen debranching enzyme in different subtypes of glycogen storage disease type III. J Pediatr. 1990 Jan;116(1):95-100. doi: 10.1016/s0022-3476(05)81652-x. — View Citation

Haller RG, Lewis SF. Glucose-induced exertional fatigue in muscle phosphofructokinase deficiency. N Engl J Med. 1991 Feb 7;324(6):364-9. doi: 10.1056/NEJM199102073240603. — View Citation

Harris, R. & Devlin, T. Textbook of Biochemistry with Clinical Correlations. 1997, (Wiley-Liss).

Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, Chung WK, Desai DM, El-Gharbawy A, Haller R, Smit GP, Smith AD, Hobson-Webb LD, Wechsler SB, Weinstein DA, Watson MS; ACMG. Glycogen storage disease type III diagnosis and management guidelines. Ge — View Citation

Lamhonwah AM, Olpin SE, Pollitt RJ, Vianey-Saban C, Divry P, Guffon N, Besley GT, Onizuka R, De Meirleir LJ, Cvitanovic-Sojat L, Baric I, Dionisi-Vici C, Fumic K, Maradin M, Tein I. Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitin — View Citation

Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet. 2006 May 15;142C(2):77-85. doi: 10.1002/ajmg.c.30087. — View Citation

Luo S, Zhu W, Yue D, Lin J, Wang Y, Zhu Z, Qiu W, Lu J, Hedberg-Oldfors C, Oldfors A, Zhao C. Muscle pathology and whole-body MRI in a polyglucosan myopathy associated with a novel glycogenin-1 mutation. Neuromuscul Disord. 2015 Oct;25(10):780-5. doi: 10. — View Citation

Malfatti E, Nilsson J, Hedberg-Oldfors C, Hernandez-Lain A, Michel F, Dominguez-Gonzalez C, Viennet G, Akman HO, Kornblum C, Van den Bergh P, Romero NB, Engel AG, DiMauro S, Oldfors A. A new muscle glycogen storage disease associated with glycogenin-1 def — View Citation

Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D, Roe CR, Saudubray JM. Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab. 2005 Apr;84(4):305-12. doi: 10.1016/j.ymgme.2004.09 — View Citation

Moslemi AR, Lindberg C, Nilsson J, Tajsharghi H, Andersson B, Oldfors A. Glycogenin-1 deficiency and inactivated priming of glycogen synthesis. N Engl J Med. 2010 Apr 1;362(13):1203-10. doi: 10.1056/NEJMoa0900661. — View Citation

Olsen RK, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M, Merinero B, Frerman FE, Beresford MW, Dean JC, Cornelius N, Andersen O, Oldfors A, Holme E, Gregersen N, Turnbull DM, Morris AA. ETFDH mutations as a major cause of riboflavin-responsive mul — View Citation

Orngreen MC, Jeppesen TD, Andersen ST, Taivassalo T, Hauerslev S, Preisler N, Haller RG, van Hall G, Vissing J. Fat metabolism during exercise in patients with McArdle disease. Neurology. 2009 Feb 24;72(8):718-24. doi: 10.1212/01.wnl.0000343002.74480.e4. — View Citation

Orngreen MC, Madsen KL, Preisler N, Andersen G, Vissing J, Laforet P. Bezafibrate in skeletal muscle fatty acid oxidation disorders: a randomized clinical trial. Neurology. 2014 Feb 18;82(7):607-13. doi: 10.1212/WNL.0000000000000118. Epub 2014 Jan 22. — View Citation

ORngreen MC, Norgaard MG, Sacchetti M, van Engelen BG, Vissing J. Fuel utilization in patients with very long-chain acyl-coa dehydrogenase deficiency. Ann Neurol. 2004 Aug;56(2):279-83. doi: 10.1002/ana.20168. — View Citation

Orngreen MC, Schelhaas HJ, Jeppesen TD, Akman HO, Wevers RA, Andersen ST, ter Laak HJ, van Diggelen OP, DiMauro S, Vissing J. Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency? Neurology. 2008 May 13;70(20):1876-82. doi: 10.1 — View Citation

Orngreen MC, Vissing J. Treatment Opportunities in Patients With Metabolic Myopathies. Curr Treat Options Neurol. 2017 Sep 21;19(11):37. doi: 10.1007/s11940-017-0473-2. — View Citation

Preisler N, Laforet P, Madsen KL, Prahm KP, Hedermann G, Vissing CR, Galbo H, Vissing J. Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III. Neurology. 2015 Apr 28;84(17):1767-71. doi: 10.1212/WNL.0000000000001518. — View Citation

Preisler N, Pradel A, Husu E, Madsen KL, Becquemin MH, Mollet A, Labrune P, Petit F, Hogrel JY, Jardel C, Maillot F, Vissing J, Laforet P. Exercise intolerance in Glycogen Storage Disease Type III: weakness or energy deficiency? Mol Genet Metab. 2013 May; — View Citation

Roe CR, Bottiglieri T, Wallace M, Arning E, Martin A. Adult Polyglucosan Body Disease (APBD): Anaplerotic diet therapy (Triheptanoin) and demonstration of defective methylation pathways. Mol Genet Metab. 2010 Oct-Nov;101(2-3):246-52. doi: 10.1016/j.ymgme. — View Citation

Roe CR, Mochel F. Anaplerotic diet therapy in inherited metabolic disease: therapeutic potential. J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):332-40. doi: 10.1007/s10545-006-0290-3. — View Citation

Roe CR, Sweetman L, Roe DS, David F, Brunengraber H. Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride. J Clin Invest. 2002 Jul;110(2):259-69. doi: 10.1172/JCI15311. — View Citation

Roe CR, Yang BZ, Brunengraber H, Roe DS, Wallace M, Garritson BK. Carnitine palmitoyltransferase II deficiency: successful anaplerotic diet therapy. Neurology. 2008 Jul 22;71(4):260-4. doi: 10.1212/01.wnl.0000318283.42961.e9. — View Citation

Sahlin K, Jorfeldt L, Henriksson KG, Lewis SF, Haller RG. Tricarboxylic acid cycle intermediates during incremental exercise in healthy subjects and in patients with McArdle's disease. Clin Sci (Lond). 1995 Jun;88(6):687-93. doi: 10.1042/cs0880687. — View Citation

Scholte HR, Rodrigues Pereira R, de Jonge PC, Luyt-Houwen IE, Hedwig M, Verduin M, Ross JD. Primary carnitine deficiency. J Clin Chem Clin Biochem. 1990 May;28(5):351-7. — View Citation

Shen J, Bao Y, Liu HM, Lee P, Leonard JV, Chen YT. Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle. J Clin Invest. 1996 Jul 15;98(2):352 — View Citation

van der Ploeg AT, Barohn R, Carlson L, Charrow J, Clemens PR, Hopkin RJ, Kishnani PS, Laforet P, Morgan C, Nations S, Pestronk A, Plotkin H, Rosenbloom BE, Sims KB, Tsao E. Open-label extension study following the Late-Onset Treatment Study (LOTS) of algl — View Citation

van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, Herson S, Kishnani PS, Laforet P, Lake SL, Lange DJ, Leshner RT, Mayhew JE, Morgan C, Nozaki K, Park DJ, Pestronk A, Rosenbloom B, Skrinar A, van Capelle CI, van der Beek NA, Wa — View Citation

van der Ploeg AT, Reuser AJ. Pompe's disease. Lancet. 2008 Oct 11;372(9646):1342-53. doi: 10.1016/S0140-6736(08)61555-X. — View Citation

Van Hoof F, Hers HG. The subgroups of type 3 glycogenosis. Eur J Biochem. 1967 Oct;2(3):265-70. doi: 10.1111/j.1432-1033.1967.tb00134.x. No abstract available. — View Citation

Viskupic E, Cao Y, Zhang W, Cheng C, DePaoli-Roach AA, Roach PJ. Rabbit skeletal muscle glycogenin. Molecular cloning and production of fully functional protein in Escherichia coli. J Biol Chem. 1992 Dec 25;267(36):25759-63. — View Citation

* Note: There are 35 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Heart rate	Heart rate during constant load cycling exercise.	60 min
Primary	Palmitate oxidation	Palmitate oxidation measured via stable isotope technique and indiret calorimetry during constant load exercise.	60 min
Secondary	Short Form-36 Questionnaire	The Short form-36 assesses eight health concepts: limitations in Quality of life physical activities because of health problems; limitations in social activities because of physical or emotional problems; limitations in usual role activities because of physical health problems); bodily pain; general mental health (psychological distress and well-being); limitations in usual role activities because of emotional problems; vitality (energy and fatigue); and general health perceptions. The standard form of the instruments asks for participants to reply to questions according to how they have felt over the previous week. The items use Likert-type scales, from 1-5 points, where 1 usually indicates that the patient is feeling worse.	2 weeks
Secondary	Maximal workload capacity	During cycle exercise	60 min
Secondary	Plasma concentrations of lactate, ammonia, glucose, FFA, acyl-carnitines, malate, C5, insulin, adrenalin and noradrenalin.		60 min
Secondary	Rate of Perceived Exertion (RPE)	Borg Score during constant workload cycling. The Borg RPE scale is a numerical scale that ranges from 6 to 20, where 6 means "no exertion at all" and 20 means "maximal exertion. The Borg scale is named after Borg GA 1982.	60 min
Secondary	Bouchards energy expenditure questionnaire	Bouchard's Physical Activity Record (BAR) is a widely used diary in which participants report physical activity for each 15 minute interval over three days. Activities are rated on a scale of 1 to 9 (1 = sedentary activity, 9 = intense manual work or high intensity sports) to yield a total energy expenditure score.	3 days
Secondary	Glucose rate of appearance and disappearance		60 min