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

NCT03642860 | Completed Phase 2

• 2 other identifiers: #20171012 Trihep2017-004153-17
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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

Conditions

Tarui Disease; Debrancher Deficiency; GYG1 DEFICIENCY

Outcome Measures

Primary Outcomes (2)

• Heart rate

  Heart rate during constant load cycling exercise.

  60 min

• Palmitate oxidation

  Palmitate oxidation measured via stable isotope technique and indiret calorimetry during constant load exercise.

  60 min

Secondary Outcomes (6)

• Short Form-36 Questionnaire

  2 weeks

• Maximal workload capacity

  60 min

• Plasma concentrations of lactate, ammonia, glucose, FFA, acyl-carnitines, malate, C5, insulin, adrenalin and noradrenalin.

  60 min

• Rate of Perceived Exertion (RPE)

  60 min

• Bouchards energy expenditure questionnaire

  3 days

Study Arms (2)

Active treatment

EXPERIMENTAL

Triheptanoin oil

Drug: Triheptanoin

Placebo treatment

PLACEBO COMPARATOR

Safflower oil

Drug: Placebo Oil

Interventions

Triheptanoin DRUG

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

Also known as: Trioctanoin

Active treatment

Placebo Oil DRUG

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

Placebo treatment

Eligibility Criteria

• Age: 15 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• Ultragenyx Pharmaceutical Inc: collaborator

Study Sites (1)

Copenhagen Neuromuscular Center

Copenhagen, 2200, Denmark

Location

Related Publications (35)

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

  BACKGROUND

• 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 alglucosidase alfa. Mol Genet Metab. 2012 Nov;107(3):456-61. doi: 10.1016/j.ymgme.2012.09.015. Epub 2012 Sep 17.

  PMID: 23031366 RESULT

• 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, Wasserstein M, Zivkovic SA. A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med. 2010 Apr 15;362(15):1396-406. doi: 10.1056/NEJMoa0909859.

  PMID: 20393176 RESULT

• 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.

  PMID: 18929906 RESULT

• 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 multiple acyl-CoA dehydrogenation deficiency. Brain. 2007 Aug;130(Pt 8):2045-54. doi: 10.1093/brain/awm135. Epub 2007 Jun 20.

  PMID: 17584774 RESULT

• 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.

  PMID: 16602102 RESULT

• 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.

  PMID: 2199596 RESULT

• 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 carnitine therapy prevents cardiomyopathy. Am J Med Genet. 2002 Aug 15;111(3):271-84. doi: 10.1002/ajmg.10585.

  PMID: 12210323 RESULT

• 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.

  PMID: 18541798 RESULT

• 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.

  PMID: 28932990 RESULT

• 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.

  PMID: 18645163 RESULT

• 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.

  PMID: 12122118 RESULT

• 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.

  PMID: 19237700 RESULT

• 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. Epub 2015 Apr 1.

  PMID: 25832663 RESULT

• 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.

  PMID: 3447177 RESULT

• 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.

  PMID: 7634753 RESULT

• 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: 10.7326/0003-4819-116-11-896.

  PMID: 1580445 RESULT

• 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):352-7. doi: 10.1172/JCI118799.

  PMID: 8755644 RESULT

• 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.

  PMID: 5235982 RESULT

• 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.

  PMID: 2295969 RESULT

• 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. Genet Med. 2010 Jul;12(7):446-63. doi: 10.1097/GIM.0b013e3181e655b6.

  PMID: 20631546 RESULT

• 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;109(1):14-20. doi: 10.1016/j.ymgme.2013.02.008. Epub 2013 Feb 19.

  PMID: 23507172 RESULT

• 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.

  PMID: 1824792 RESULT

• 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.

  PMID: 1281472 RESULT

• 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.

  PMID: 20357282 RESULT

• 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 deficiency. Ann Neurol. 2014 Dec;76(6):891-8. doi: 10.1002/ana.24284. Epub 2014 Oct 31.

  PMID: 25272951 RESULT

• 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.2015.10.012. Epub 2015 Nov 10.

  PMID: 26652229 RESULT

• 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: 10.1016/j.nmd.2015.07.007. Epub 2015 Jul 15.

  PMID: 26255073 RESULT

• 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.

  PMID: 24453079 RESULT

• 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.

  PMID: 15293280 RESULT

• 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: 10.1212/01.wnl.0000289190.66955.67. Epub 2008 Apr 9.

  PMID: 18401027 RESULT

• 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.

  PMID: 16763896 RESULT

• 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.2004.09.007.

  PMID: 15781190 RESULT

• 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.2010.06.017. Epub 2010 Jul 6.

  PMID: 20655781 RESULT

• 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.

  PMID: 16763895 RESULT

MeSH Terms

Conditions

Glycogen Storage Disease Type VII; Glycogen Storage Disease Type III

Interventions

triheptanoin; tricaprylin

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Glycogen Storage Disease; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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

Study Record Dates

• First Submitted: August 20, 2018
• First Posted: August 22, 2018
• Study Start: August 15, 2018
• Primary Completion: August 28, 2019
• Study Completion: August 28, 2019
• Last Updated: February 22, 2024

Record last verified: 2024-02

Locations

DK (1)