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

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Basic Science
• Conditions: Glucose Transporter Type 1 Deficiency Syndrome; GLUT1 Deficiency Syndrome
• Intervention: Drug: Triheptanoin
• Enrollment: 14

Participant Flow

Recruitment Details
Pre-assignment Details

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 Number of Baseline Participants		14
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
	<=18 years	11 78.6%
	Between 18 and 65 years	3 21.4%
	>=65 years	0 0.0%
Age, Continuous [1]; Median (Full Range); Unit of measure: Years
	Number Analyzed	14 participants
		12.5; (2 to 27)
		[1] Measure Description: Confirm that 2 subjects were enrolled that were older than 20 years of age. Inclusion criteria was not updated to reflect this change in enrollment.
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
	Female	6 42.9%
	Male	8 57.1%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
	Hispanic or Latino	1 7.1%
	Not Hispanic or Latino	13 92.9%
	Unknown or Not Reported	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
	American Indian or Alaska Native	0 0.0%
	Asian	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 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 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	14 participants
		14

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.
Overall Number of Participants Analyzed	14
Measure Type: Count of Participants; Unit of Measure: 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.
Overall Number of Participants Analyzed	5
Measure Type: Count of Participants; Unit of Measure: Participants
	5 100.0%

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
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 (%)
Total	0/14 (0.00%)
Serious Adverse Events
	Triheptanoin
	Affected / at Risk (%)
Total	0/14 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Triheptanoin
	Affected / at Risk (%)
Total	4/14 (28.57%)
Gastrointestinal disorders
Gastric discomfort †	1/14 (7.14%)
Diarrhea †	2/14 (14.29%)
Metabolism and nutrition disorders
weight gain †	1/14 (7.14%)
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

Results Point of Contact

• Name/Title: Juan Pascual, M.D., Ph.D.
• Organization: University of Texas Southwestern Medical Center
• Phone: 214-648-3550
• EMail: juan.pascual@utsouthwestern.edu

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.

• Responsible Party: Juan Pascual, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT02018315
• Other Study ID Numbers: UTSW 122010-186
• First Submitted: December 11, 2013
• First Posted: December 23, 2013
• Results First Submitted: February 12, 2019
• Results First Posted: October 31, 2019
• Last Update Posted: October 31, 2019