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

Primary Purpose

Glucose Transporter Type 1 Deficiency Syndrome, GLUT1 Deficiency Syndrome

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Triheptanoin
Sponsored by
Juan Pascual
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Glucose Transporter Type 1 Deficiency Syndrome focused on measuring G1D, Glut1 Disorder, Glucose Transporter Type 1 Disorder, Glucose Transporter Type I Disorder

Eligibility Criteria

1 Month - 20 Years (Child, Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • UT Southwestern Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Triheptanoin

Arm 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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Number of Participants With Change in Brain Metabolic Rate After 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.

Full Information

First Posted
December 11, 2013
Last Updated
October 8, 2019
Sponsor
Juan Pascual
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1. Study Identification

Unique Protocol Identification Number
NCT02018315
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)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2019
Overall Recruitment Status
Completed
Study Start Date
January 2012 (undefined)
Primary Completion Date
January 2013 (Actual)
Study Completion Date
March 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Juan Pascual

4. Oversight

Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glucose Transporter Type 1 Deficiency Syndrome, GLUT1 Deficiency Syndrome
Keywords
G1D, Glut1 Disorder, Glucose Transporter Type 1 Disorder, Glucose Transporter Type I Disorder

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Triheptanoin
Arm Type
Experimental
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Triheptanoin
Other Intervention Name(s)
C7, Heptanoate
Intervention Description
Triheptanoin is a 7-carbon medium chain triglyceride
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Month
Maximum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Juan M. Pascual, MD, PhD
Organizational Affiliation
UT Southwestern Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
UT Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
23072752
Citation
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.
Results Reference
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PubMed Identifier
22683290
Citation
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.
Results Reference
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PubMed Identifier
20598931
Citation
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.
Results Reference
background
PubMed Identifier
20301603
Citation
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/
Results Reference
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PubMed Identifier
19901175
Citation
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.
Results Reference
background
PubMed Identifier
19225367
Citation
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.
Results Reference
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PubMed Identifier
17296829
Citation
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.
Results Reference
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PubMed Identifier
15132717
Citation
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.
Results Reference
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PubMed Identifier
18387950
Citation
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.
Results Reference
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PubMed Identifier
17169300
Citation
Pascual JM. [Glucose transport hereditary diseases]. Med Clin (Barc). 2006 Nov 11;127(18):709-14. doi: 10.1157/13095099. Spanish.
Results Reference
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PubMed Identifier
16497725
Citation
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.
Results Reference
background
PubMed Identifier
15622525
Citation
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.
Results Reference
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PubMed Identifier
15152356
Citation
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.
Results Reference
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PubMed Identifier
13129919
Citation
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.
Results Reference
background
PubMed Identifier
12325075
Citation
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.
Results Reference
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PubMed Identifier
12032147
Citation
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.
Results Reference
background
PubMed Identifier
12420362
Citation
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.
Results Reference
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PubMed Identifier
11603379
Citation
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.
Results Reference
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Links:
URL
http://www.g1dregistry.org
Description
The G1D Registry

Learn more about this trial

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

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