An Open-Label Trial of Triheptanoin in Patients With Glucose Transporter Type-1 Deficiency Syndrome
NCT ID: NCT02036853
Last Updated: 2021-01-28
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
20 participants
INTERVENTIONAL
2014-02-20
2019-06-30
Brief Summary
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Glut1 DS is a severely debilitating disease characterized by seizures, developmental delay and movement disorder. There are currently no approved treatments specific to Glut1 DS. Treatment generally includes medications for control of seizures. The use of a ketogenic diet can be effective in controlling seizures when medications are ineffective or provide insufficient control. However, the ketogenic diet may be very difficult for patients to maintain for long periods of time, and there may be negative secondary long-term effects of ketogenic diet.. Triheptanoin is metabolized to molecules that can provide an alternative energy source to the brain, and appears to help in controlling seizures without many of the difficulties of the ketogenic diet.
Eligible patients may be those who have been diagnosed with GLUT1 DS, and have discontinued or are not currently on ketogenic diet, or are able to tolerate triheptanoin if they have been treated or are currently being treated with triheptanoin and do not qualify for any other clinical trial.
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Detailed Description
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The proposed study is an open-label study to assess the safety and long-term efficacy of triheptanoin in patients with Glut1 DS over a 5-year treatment period. Eligible patients may be those who are able to tolerate triheptanoin if they have been treated or are currently being treated with triheptanoin and do not qualify for any other clinical trial. Subjects previously treated with triheptanoin will continue to dose at approximately 35% of total daily calories (\~1-4g/kg/day, depending on age). Subjects who are naïve to triheptanoin will begin a 2-week fixed titration schedule up until they have reached 35% of total daily calories.
The primary objective of the study is to evaluate the safety of triheptanoin via adverse event rates and laboratory values. The secondary objective is to evaluate the long-term efficacy of triheptanoin as measured by the change in seizure frequency from historical baseline.
Conditions
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Schedule A
Subjects previously treated with triheptanoin
Triheptanoin
Schedule A: Subjects previously treated with triheptanoin will continue to dose at approximately 35% of total daily calories (\~1-4g/kg/day, depending on age).
Schedule B: Subjects who are naïve to triheptanoin will begin a 2-week fixed titration schedule up until they have reached 35% of total daily calories (\~1-4 g/kg/day depending on age). If a subject has not reached the target of 35% of total daily calories, by the end of the 2-week fixed titration period, dose titration should continue until achieved or until the maximally tolerated dose has been established.
Schedule B
Naïve to triheptanoin
Triheptanoin
Schedule A: Subjects previously treated with triheptanoin will continue to dose at approximately 35% of total daily calories (\~1-4g/kg/day, depending on age).
Schedule B: Subjects who are naïve to triheptanoin will begin a 2-week fixed titration schedule up until they have reached 35% of total daily calories (\~1-4 g/kg/day depending on age). If a subject has not reached the target of 35% of total daily calories, by the end of the 2-week fixed titration period, dose titration should continue until achieved or until the maximally tolerated dose has been established.
Interventions
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Triheptanoin
Schedule A: Subjects previously treated with triheptanoin will continue to dose at approximately 35% of total daily calories (\~1-4g/kg/day, depending on age).
Schedule B: Subjects who are naïve to triheptanoin will begin a 2-week fixed titration schedule up until they have reached 35% of total daily calories (\~1-4 g/kg/day depending on age). If a subject has not reached the target of 35% of total daily calories, by the end of the 2-week fixed titration period, dose titration should continue until achieved or until the maximally tolerated dose has been established.
Eligibility Criteria
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Inclusion Criteria
1. Patients with GLUT1 DS by physician diagnosis
2. Males and females, aged 1 to 50 years
3. Allowed to be on concomitant AEDs
4. Patients are able to tolerate triheptanoin if they have been (or are currently being) treated with this medication
5. Must, in the opinion of the investigator, be willing and able to comply with study procedures and schedule
6. Provide written assent (if appropriate) and written informed consent by a Legally Authorized Representative (LAR) after the nature of the study has been explained, and prior to any research-related procedures
7. Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study
8. Females of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study
Exclusion Criteria
2. Concomitant administration of a ketogenic diet for the treatment of GLUT1 deficiency
3. Concomitant administration of valproic acid
4. In the Investigator's opinion, the patient may not be compliant
5. Pregnant or breastfeeding an infant at screening
6. Has a concurrent disease or condition, or laboratory abnormality that, in the view of the Investigator, places the subject at high risk for adverse events, or introduces additional safety concerns
7. History of or current suicidal ideation, behavior and attempts
8. Patient qualifies for any other clinical trial designed to progressively evaluate the safety and efficacy of triheptanoin as approved by the FDA under a separate IND which is open at Cook Children's
1 Year
50 Years
ALL
No
Sponsors
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Ultragenyx Pharmaceutical Inc
INDUSTRY
Adrian Lacy
OTHER
Responsible Party
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Adrian Lacy
Principal Investigator
Principal Investigators
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Adrian Lacy, MD
Role: PRINCIPAL_INVESTIGATOR
Cook Children's Medical Center
Locations
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Cook Childrens Medical Center
Fort Worth, Texas, United States
Countries
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References
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Johnson W Jr; Cosmetic Ingredient Review Expert Panel. Final report on the safety assessment of trilaurin, triarachidin, tribehenin, tricaprin, tricaprylin, trierucin, triheptanoin, triheptylundecanoin, triisononanoin, triisopalmitin, triisostearin, trilinolein, trimyristin, trioctanoin, triolein, tripalmitin, tripalmitolein, triricinolein, tristearin, triundecanoin, glyceryl triacetyl hydroxystearate, glyceryl triacetyl ricinoleate, and glyceryl stearate diacetate. Int J Toxicol. 2001;20 Suppl 4:61-94.
Pearson TS, Akman C, Hinton VJ, Engelstad K, De Vivo DC. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep. 2013 Apr;13(4):342. doi: 10.1007/s11910-013-0342-7.
Pong AW, Geary BR, Engelstad KM, Natarajan A, Yang H, De Vivo DC. Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes. Epilepsia. 2012 Sep;53(9):1503-10. doi: 10.1111/j.1528-1167.2012.03592.x. Epub 2012 Jul 19.
Roe CR. Inherited disorders of mitochondrial fatty acid oxidation: a new responsibility for the neonatologist. Semin Neonatol. 2002 Feb;7(1):37-47. doi: 10.1053/siny.2002.0097.
Kinman RP, Kasumov T, Jobbins KA, Thomas KR, Adams JE, Brunengraber LN, Kutz G, Brewer WU, Roe CR, Brunengraber H. Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats. Am J Physiol Endocrinol Metab. 2006 Oct;291(4):E860-6. doi: 10.1152/ajpendo.00366.2005. Epub 2006 May 16.
Deng S, Zhang GF, Kasumov T, Roe CR, Brunengraber H. Interrelations between C4 ketogenesis, C5 ketogenesis, and anaplerosis in the perfused rat liver. J Biol Chem. 2009 Oct 9;284(41):27799-27807. doi: 10.1074/jbc.M109.048744. Epub 2009 Aug 8.
Gu L, Zhang GF, Kombu RS, Allen F, Kutz G, Brewer WU, Roe CR, Brunengraber H. Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats. II. Effects on lipolysis, glucose production, and liver acyl-CoA profile. Am J Physiol Endocrinol Metab. 2010 Feb;298(2):E362-71. doi: 10.1152/ajpendo.00384.2009. Epub 2009 Nov 10.
Marin-Valencia I, Good LB, Ma Q, Malloy CR, Pascual JM. Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain. J Cereb Blood Flow Metab. 2013 Feb;33(2):175-82. doi: 10.1038/jcbfm.2012.151. Epub 2012 Oct 17.
Willis S, Stoll J, Sweetman L, Borges K. Anticonvulsant effects of a triheptanoin diet in two mouse chronic seizure models. Neurobiol Dis. 2010 Dec;40(3):565-72. doi: 10.1016/j.nbd.2010.07.017. Epub 2010 Aug 4.
Samala R, Willis S, Borges K. Anticonvulsant profile of a balanced ketogenic diet in acute mouse seizure models. Epilepsy Res. 2008 Oct;81(2-3):119-27. doi: 10.1016/j.eplepsyres.2008.05.001. Epub 2008 Jun 18.
Kim TH, Borges K, Petrou S, Reid CA. Triheptanoin reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy. Epilepsy Res. 2013 Jan;103(1):101-5. doi: 10.1016/j.eplepsyres.2012.09.016. Epub 2012 Nov 26.
Ataíde TdaR, de Olivera SK, da Silva FM, Vitorino Filha LGC, do N Tavares MC, Sant'Ana AEG. Toxicological analysis of the chronic consumption of diheptanoin and triheptanoin in rats. Intl J Food Sci Tech. 2009;44:484-492
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.
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.
Mochel F, Duteil S, Marelli C, Jauffret C, Barles A, Holm J, Sweetman L, Benoist JF, Rabier D, Carlier PG, Durr A. Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington's disease. Eur J Hum Genet. 2010 Sep;18(9):1057-60. doi: 10.1038/ejhg.2010.72. Epub 2010 May 26.
Baruteau J, Sachs P, Broue P, Brivet M, Abdoul H, Vianey-Saban C, Ogier de Baulny H. Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation defects: a French pediatric study of 187 patients. J Inherit Metab Dis. 2013 Sep;36(5):795-803. doi: 10.1007/s10545-012-9542-6. Epub 2012 Oct 3.
Goldstein A, Barone AR, DeWard SJ, Payne N, Vockley J. Triheptanoin therapy for inherited disorders of fatty acid oxidation. Mitochondrion. 2012;12(5):566
Sparrow, SS, Cicchetti D, & Balla DA. Vineland Adaptive Behavior Scales - 2nd Edition manual. Minneapolis, MN: NCS Pearson, Inc; 2005
Barry MJ, VanSwearingen JM, Albright AL. Reliability and responsiveness of the Barry-Albright Dystonia Scale. Dev Med Child Neurol. 1999 Jun;41(6):404-11. doi: 10.1017/s0012162299000870.
Varni JW, Burwinkle TM, Seid M. The PedsQL as a pediatric patient-reported outcome: reliability and validity of the PedsQL Measurement Model in 25,000 children. Expert Rev Pharmacoecon Outcomes Res. 2005 Dec;5(6):705-19. doi: 10.1586/14737167.5.6.705.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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2013-NEUR-001
Identifier Type: -
Identifier Source: org_study_id
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