Treatment Development for Glucose Transporter Type I Deficiency Syndrome (G1D)

• ClinicalTrials.gov Identifier: NCT02018315
• Recruitment Status: Completed
• First Posted: December 23, 2013
• Results First Posted: October 31, 2019
• Last Update Posted: October 31, 2019
• Sponsor: Juan Pascual
• Information provided by (Responsible Party): Juan Pascual, University of Texas Southwestern Medical Center

Tracking Information

• First Submitted Date: December 11, 2013
• First Posted Date: December 23, 2013
• Results First Submitted Date: February 12, 2019
• Results First Posted Date: October 31, 2019
• Last Update Posted Date: October 31, 2019
• Study Start Date: January 2012
• Actual Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 8, 2019)

Number of Participants With Reduction in Spike-wave Fraction of the EEG Recording Time [ Time Frame: 1 day ]

Visual analysis of EEG recording to determine the fraction of spike-range within the area of recording.

Original Primary Outcome Measures (submitted: December 16, 2013)

Change in Brain Metabolic Rate [ Time Frame: Baseline, 90 minutes, 3 months ]

Magnetic Resonance Imaging (MRI) used to calculate brain metabolic rate before oil ingestion, 90 minutes after oil ingestion, and after 3 months of daily oil ingestion

Current Secondary Outcome Measures (submitted: October 8, 2019)

Number of Participants With Change in Brain Metabolic Rate After 3 Months [ Time Frame: 3 months ]

Magnetic Resonance Imaging (MRI) used to calculate brain metabolic rate. Brain metabolic rate compared before oil ingestion (Baseline), 90 minutes after oil ingestion, and after 3 months of daily oil ingestion in each participant. Triheptanoin metabolism may lead to increased oxygen consumption only while the brain undergoes a reduction of ictogenesis. We hypothesize that when ictogenesis is abolished by triheptanoin or absent at baseline, triheptanoin exerts little or no effect on CMR02.

• Original Secondary Outcome Measures (submitted: December 16, 2013): Change in Fasting Glucose [ Time Frame: Baseline, 3 months ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Treatment Development for Glucose Transporter Type I Deficiency Syndrome (G1D)
• Official Title: Clinical Trial of Citric Acid Cycle Stimulation in Energy-deficiency States: Treatment Development for Glucose Transporter Type I Deficiency Syndrome (G1D) (NMTUT 2010B)

Brief Summary

The purpose of this trial is to determine if an alternative energy source will impact brain metabolism in a disorder characterized by glucose metabolism failure in the brain.

The central hypothesis tested in this investigation is whether circumventing impaired glucose metabolism is feasible, safe and potentially promising by supplying anaplerotic precursors through metabolism of odd-carbon fatty acids that can enter the citric acid cycle (CAC) through alternative metabolic pathways.

• Detailed Description: Triheptanoin, a nutritional supplement long used in other metabolic disorders and also added to foods and cosmetics, will be used to complement any diet that G1D patients may be receiving at enrollment with the exception of the ketogenic diet.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Basic Science

Condition

• Glucose Transporter Type 1 Deficiency Syndrome
• GLUT1 Deficiency Syndrome

Intervention

Drug: Triheptanoin

Triheptanoin is a 7-carbon medium chain triglyceride

Other Names:

• C7
• Heptanoate

Study Arms

Experimental: Triheptanoin

Triheptanoin (C7 oil, liquid) dosed at 1 g/kg body weight divided and administered 4 times per day via mouth or g-tube for 3 months.

Intervention: Drug: Triheptanoin

Publications *

• 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.
• Marin-Valencia I, Good LB, Ma Q, Duarte J, Bottiglieri T, Sinton CM, Heilig CW, Pascual JM. Glut1 deficiency (G1D): epilepsy and metabolic dysfunction in a mouse model of the most common human phenotype. Neurobiol Dis. 2012 Oct;48(1):92-101. doi: 10.1016/j.nbd.2012.04.011. Epub 2012 Apr 23.
• Marin-Valencia I, Roe CR, Pascual JM. Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Genet Metab. 2010 Sep;101(1):9-17. doi: 10.1016/j.ymgme.2010.05.004. Epub 2010 Jun 9.
• Wang D, Pascual JM, De Vivo D. Glucose Transporter Type 1 Deficiency Syndrome. 2002 Jul 30 [updated 2018 Mar 1]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1430/
• Perez-Duenas B, Prior C, Ma Q, Fernandez-Alvarez E, Setoain X, Artuch R, Pascual JM. Childhood chorea with cerebral hypotrophy: a treatable GLUT1 energy failure syndrome. Arch Neurol. 2009 Nov;66(11):1410-4. doi: 10.1001/archneurol.2009.236.
• Pascual JM, Campistol J, Gil-Nagel A. Epilepsy in inherited metabolic disorders. Neurologist. 2008 Nov;14(6 Suppl 1):S2-S14. doi: 10.1097/01.nrl.0000340787.30542.41.
• Pascual JM, Wang D, Hinton V, Engelstad K, Saxena CM, Van Heertum RL, De Vivo DC. Brain glucose supply and the syndrome of infantile neuroglycopenia. Arch Neurol. 2007 Apr;64(4):507-13. doi: 10.1001/archneur.64.4.noc60165. Epub 2007 Feb 12.
• Pascual JM, Wang D, Lecumberri B, Yang H, Mao X, Yang R, De Vivo DC. GLUT1 deficiency and other glucose transporter diseases. Eur J Endocrinol. 2004 May;150(5):627-33. doi: 10.1530/eje.0.1500627.
• Pascual JM, Wang D, Yang R, Shi L, Yang H, De Vivo DC. Structural signatures and membrane helix 4 in GLUT1: inferences from human blood-brain glucose transport mutants. J Biol Chem. 2008 Jun 13;283(24):16732-42. doi: 10.1074/jbc.M801403200. Epub 2008 Apr 3.
• Pascual JM. [Glucose transport hereditary diseases]. Med Clin (Barc). 2006 Nov 11;127(18):709-14. doi: 10.1157/13095099. Spanish.
• Wang D, Pascual JM, Yang H, Engelstad K, Mao X, Cheng J, Yoo J, Noebels JL, De Vivo DC. A mouse model for Glut-1 haploinsufficiency. Hum Mol Genet. 2006 Apr 1;15(7):1169-79. doi: 10.1093/hmg/ddl032. Epub 2006 Feb 23.
• Wang D, Pascual JM, Yang H, Engelstad K, Jhung S, Sun RP, De Vivo DC. Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol. 2005 Jan;57(1):111-8. doi: 10.1002/ana.20331.
• Pascual JM, Lecumberri B, Wang D, Yang R, Engelstad K, De Vivo DC. [Type 1 glucose transporter (Glut1) deficiency: manifestations of a hereditary neurological syndrome]. Rev Neurol. 2004 May 1-15;38(9):860-4. Spanish.
• Wang D, Pascual JM, Iserovich P, Yang H, Ma L, Kuang K, Zuniga FA, Sun RP, Swaroop KM, Fischbarg J, De Vivo DC. Functional studies of threonine 310 mutations in Glut1: T310I is pathogenic, causing Glut1 deficiency. J Biol Chem. 2003 Dec 5;278(49):49015-21. doi: 10.1074/jbc.M308765200. Epub 2003 Sep 16.
• Pascual JM, Van Heertum RL, Wang D, Engelstad K, De Vivo DC. Imaging the metabolic footprint of Glut1 deficiency on the brain. Ann Neurol. 2002 Oct;52(4):458-64. doi: 10.1002/ana.10311.
• Iserovich P, Wang D, Ma L, Yang H, Zuniga FA, Pascual JM, Kuang K, De Vivo DC, Fischbarg J. Changes in glucose transport and water permeability resulting from the T310I pathogenic mutation in Glut1 are consistent with two transport channels per monomer. J Biol Chem. 2002 Aug 23;277(34):30991-7. doi: 10.1074/jbc.M202763200. Epub 2002 May 24.
• De Vivo DC, Wang D, Pascual JM, Ho YY. Glucose transporter protein syndromes. Int Rev Neurobiol. 2002;51:259-88. doi: 10.1016/s0074-7742(02)51008-4. No abstract available.
• Brockmann K, Wang D, Korenke CG, von Moers A, Ho YY, Pascual JM, Kuang K, Yang H, Ma L, Kranz-Eble P, Fischbarg J, Hanefeld F, De Vivo DC. Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. Ann Neurol. 2001 Oct;50(4):476-85. doi: 10.1002/ana.1222.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 16, 2013): 14
• Original Actual Enrollment: Same as current
• Actual Study Completion Date: March 2014
• Actual Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male or Female
• Ages 1 month to <21 years of age
• Diagnosed with glucose transporter type I deficiency.
• Age matched (within 1 year) controls not diagnosed with G1D.

Exclusion Criteria:

• All subjects carrying body metal implants incompatible with the exposure to a magnetic field
• Subjects unable to tolerate the MRI and MRS procedures due to anxiety
• Subjects receiving oxygen supplementation or those confined to a bed or stretcher
• Subjects currently receiving a ketogenic diet, due to a high risk of seizure recurrence while transitioning off ketosis.
• Patients behaviorally unable to hold still for imaging procedures (rather than limited by seizure activity) will be excluded.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Month to 20 Years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02018315
• Other Study ID Numbers: UTSW 122010-186
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Juan Pascual, University of Texas Southwestern Medical Center
• Original Responsible Party: Same as current
• Current Study Sponsor: Juan Pascual
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Juan M. Pascual, MD, PhD; UT Southwestern Medical Center

• PRS Account: University of Texas Southwestern Medical Center
• Verification Date: October 2019