An Open-Label Trial of Triheptanoin in Patients With Glucose Transporter Type-1 Deficiency Syndrome

NCT02036853 | Completed Phase 2 Results DMC

• 1 other identifier: 2013-NEUR-001
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being done to assess the safety and long-term efficacy of triheptanoin in pediatric patients with Glut1 DS over a 5-year treatment period. Glut 1 is a protein that helps transport glucose to the brain. Glucose is the brain's primary source of energy. Glut 1 DS prevents this protein from being effectively produced, causing deprivation of energy to the neurons of the of the brain. 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.

Conditions

Glucose Transporter Type-1 Deficiency Syndrome (Glut1 DS)

Keywords

Triheptanoin; Glut1 DS; Epilepsy; Seizures

Outcome Measures

Primary Outcomes (8)

• Reported Change in Seizures Frequency From Baseline at 13 Weeks

  A seizure diary was used to track date, type, number, and unusual presentation of seizures. Subjects were given a seizure diary at screening to record daily seizure activity for incremental periods of time. Unless otherwise waived, subjects complete this form daily during the screening period and for two weeks prior to each subsequent study visit.

  Baseline and 13 weeks

• Reported Change in Seizures Frequency From Baseline at 26 Weeks

  A seizure diary was used to track date, type, number, and unusual presentation of seizures. Subjects were given a seizure diary at screening to record daily seizure activity for incremental periods of time. Unless otherwise waived, subjects complete this form daily during the screening period and for two weeks prior to each subsequent study visit. The table below represents the change in seizure frequency from baseline for each time point.

  Baseline and 26 weeks

• Reported Change in Seizures Frequency From Baseline at 1 Year

  A seizure diary was used to track date, type, number, and unusual presentation of seizures. Subjects were given a seizure diary at screening to record daily seizure activity for incremental periods of time. Unless otherwise waived, subjects complete this form daily during the screening period and for two weeks prior to each subsequent study visit. The table below represents the change in seizure frequency from baseline for each time point.

  Baseline and one yr

• Reported Change in Seizures Frequency From Baseline at 18 Months

  A seizure diary was used to track date, type, number, and unusual presentation of seizures. Subjects were given a seizure diary at screening to record daily seizure activity for incremental periods of time. Unless otherwise waived, subjects complete this form daily during the screening period and for two weeks prior to each subsequent study visit. The table below represents the change in seizure frequency from baseline for each time point.

  Baseline and 18 months

• Reported Change in Seizures Frequency From Baseline at 2 Years

  A seizure diary was used to track date, type, number, and unusual presentation of seizures. Subjects were given a seizure diary at screening to record daily seizure activity for incremental periods of time. Unless otherwise waived, subjects complete this form daily during the screening period and for two weeks prior to each subsequent study visit. The table below represents the change in seizure frequency from baseline for each time point.

  Baseline and two yrs

• Reported Change in Seizures Frequency From Baseline at 3 Years

  A seizure diary was used to track date, type, number, and unusual presentation of seizures. Subjects were given a seizure diary at screening to record daily seizure activity for incremental periods of time. Unless otherwise waived, subjects complete this form daily during the screening period and for two weeks prior to each subsequent study visit. The table below represents the change in seizure frequency from baseline for each time point.

  Baseline and three yrs

• Reported Change in Seizure Frequency From Baseline at 4 Years

  A seizure diary was used to track date, type, number, and unusual presentation of seizures. Subjects were given a seizure diary at screening to record daily seizure activity for incremental periods of time. Unless otherwise waived, subjects complete this form daily during the screening period and for two weeks prior to each subsequent study visit. The table below represents the change in seizure frequency from baseline for each time point.

  Baseline and four yrs

• Reported Change in Seizure Frequency From Baseline at 5 Years

  A seizure diary was used to track date, type, number, and unusual presentation of seizures. Subjects were given a seizure diary at screening to record daily seizure activity for incremental periods of time. Unless otherwise waived, subjects complete this form daily during the screening period and for two weeks prior to each subsequent study visit. The table below represents the change in seizure frequency from baseline for each time point.

  Baseline and five yrs

Study Arms (2)

Schedule A

EXPERIMENTAL

Subjects previously treated with triheptanoin

Drug: Triheptanoin

Schedule B

EXPERIMENTAL

Naïve to triheptanoin

Drug: Triheptanoin

Interventions

Triheptanoin DRUG

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 A; Schedule B

Eligibility Criteria

• Age: 1 Year - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Individuals eligible to participate in this study must meet all of the following criteria:
• Patients with GLUT1 DS by physician diagnosis
• Males and females, aged 1 to 50 years
• Allowed to be on concomitant AEDs
• Patients are able to tolerate triheptanoin if they have been (or are currently being) treated with this medication
• Must, in the opinion of the investigator, be willing and able to comply with study procedures and schedule
• 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
• Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study
• Females of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study

You may not qualify if:

• Patients and their Legally Authorized Representatives (as appropriate) not willing or able to give written or verbal assent or written informed consent.
• Concomitant administration of a ketogenic diet for the treatment of GLUT1 deficiency
• Concomitant administration of valproic acid
• In the Investigator's opinion, the patient may not be compliant
• Pregnant or breastfeeding an infant at screening
• 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
• History of or current suicidal ideation, behavior and attempts
• 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

Sponsors & Collaborators

• Adrian Lacy: lead
• Ultragenyx Pharmaceutical Inc: collaborator

Study Sites (1)

Cook Childrens Medical Center

Fort Worth, Texas, 76104, United States

Location

Related Publications (20)

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  PMID: 11800053 BACKGROUND

• 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.

  PMID: 23443458 BACKGROUND

• 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.

  PMID: 22812641 BACKGROUND

• 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.

  PMID: 12069537 BACKGROUND

• 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.

  PMID: 16705058 BACKGROUND

• 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.

  PMID: 19666922 BACKGROUND

• 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.

  PMID: 19903863 BACKGROUND

• 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.

  PMID: 23072752 BACKGROUND

• 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.

  PMID: 20691264 BACKGROUND

• 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.

  PMID: 18565731 BACKGROUND

• 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.

  PMID: 23196212 BACKGROUND

• 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

  BACKGROUND

• 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.

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• Goldstein A, Barone AR, DeWard SJ, Payne N, Vockley J. Triheptanoin therapy for inherited disorders of fatty acid oxidation. Mitochondrion. 2012;12(5):566

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MeSH Terms

Conditions

Glut1 Deficiency Syndrome; Epilepsy; Seizures

Interventions

triheptanoin

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Director of Research Operations
• Organization: Cook Children's Health Care System

CookChildrensResearch@cookchildrens.org

682-885-2103

Study Officials

• Adrian Lacy, MD

  Cook Children's Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 13, 2014
• First Posted: January 15, 2014
• Study Start: February 20, 2014
• Primary Completion: June 30, 2019
• Study Completion: June 30, 2019
• Last Updated: January 28, 2021
• Results First Posted: January 28, 2021

Record last verified: 2021-01

Locations

US (1)