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

• Sponsor: Juan Pascual (Other)
• Overall Status: Completed
• CT.gov ID: NCT02018315
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arm: 1
• Duration (Months): 26
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Glucose Transporter Type 1 Deficiency Syndrome; GLUT1 Deficiency Syndrome	Drug: Triheptanoin	Phase 1

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 Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• 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)
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Triheptanoin; Triheptanoin is a 7-carbon medium chain triglyceride; Other Names: C7 Heptanoate

Outcome Measures

Primary Outcome Measures

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

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

Secondary Outcome Measures

1. Number of Participants With Change in Brain Metabolic Rate After 3 Months [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Month to 20 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UT Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• Juan Pascual

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The G1D Registry

Publications

• 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.
• De Vivo DC, Wang D, Pascual JM, Ho YY. Glucose transporter protein syndromes. Int Rev Neurobiol. 2002;51:259-88. Review.
• 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. Epub 2002 May 24.
• 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, 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, 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. Review.
• 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. Review.
• 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. Review. Spanish.
• 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.
• 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. 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. Review.
• 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. Spanish.
• Pérez-Dueñas B, Prior C, Ma Q, Fernández-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.
• Wang D, Pascual JM, De Vivo D. Glucose Transporter Type 1 Deficiency Syndrome. 2002 Jul 30 [updated 2018 Mar 1]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from http://www.ncbi.nlm.nih.gov/books/NBK1430/
• 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. Epub 2003 Sep 16.
• 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.
• 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. Epub 2006 Feb 23.

• Responsible Party: Juan Pascual, Associate Professor, Director of the Rare Brain Disorders Program, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT02018315
• Other Study ID Numbers: UTSW 122010-186
• First Posted: Dec 23, 2013
• Last Update Posted: Oct 31, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Juan Pascual, Associate Professor, Director of the Rare Brain Disorders Program, University of Texas Southwestern Medical Center: G1D; Glut1 Disorder; Glucose Transporter Type 1 Disorder; Glucose Transporter Type I Disorder
• Additional relevant MeSH terms: Syndrome

Study Results

Participant Flow

Arm/Group Title	Experimental: Triheptanoin
Arm/Group Description	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.
Period Title: Overall Study
STARTED	14
COMPLETED	14
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Experimental: Triheptanoin
Arm/Group Description	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.
Overall Participants	14
Age (Count of Participants)
<=18 years	11 78.6%
Between 18 and 65 years	3 21.4%
>=65 years	0 0%
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	12.5
Sex: Female, Male (Count of Participants)
Female	6 42.9%
Male	8 57.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 7.1%
Not Hispanic or Latino	13 92.9%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 7.1%
White	12 85.7%
More than one race	1 7.1%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Reduction in Spike-wave Fraction of the EEG Recording Time
Description	Visual analysis of EEG recording to determine the fraction of spike-range within the area of recording.
Time Frame	1 day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental: Triheptanoin
Arm/Group Description	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.
Measure Participants	14
Count of Participants [Participants]	13 92.9%

2. Secondary Outcome

Title	Number of Participants With Change in Brain Metabolic Rate After 3 Months
Description	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.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

5 participants out of the 14 total participants enrolled completed the optional MRI . Reasons for participants electing to not participate in imaging included inability to remain immobile due to movement disorder or anxiety, immaturity, metal implants, and personal choice.

Arm/Group Title	Experimental: Triheptanoin
Arm/Group Description	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.
Measure Participants	5
Count of Participants [Participants]	5 35.7%

Adverse Events

Arm/Group Title	Triheptanoin
Arm/Group Description	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. Triheptanoin: Triheptanoin is a 7-carbon medium chain triglyceride
All Cause Mortality
	Triheptanoin
	Affected / at Risk (%)	# Events
Total	0/14 (0%)
Serious Adverse Events
	Triheptanoin
	Affected / at Risk (%)	# Events
Total	0/14 (0%)
Other (Not Including Serious) Adverse Events
	Triheptanoin
	Affected / at Risk (%)	# Events
Total	4/14 (28.6%)
Gastrointestinal disorders
Gastric discomfort	1/14 (7.1%)
Diarrhea	2/14 (14.3%)
Metabolism and nutrition disorders
weight gain	1/14 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.