Pilot Study of Triheptanoin in Patients With Glucose Transporter 1 Deficiency Syndrome (Glut1C7)
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|ClinicalTrials.gov Identifier: NCT02000960|
Recruitment Status : Unknown
Verified May 2016 by University of British Columbia.
Recruitment status was: Active, not recruiting
First Posted : December 4, 2013
Last Update Posted : June 1, 2016
|Condition or disease||Intervention/treatment||Phase|
|Glucose Transporter Type 1 Deficiency Syndrome||Drug: Triheptanoin||Phase 2|
BACKGROUND: Glucose transporter type 1 deficiency syndrome (Glut1-DS) is a metabolic epileptic encephalopathy caused by defects in the cerebral glucose transporter GLUT1. It is characterized by infantile seizures refractory to anticonvulsants, deceleration of head growth, and delays in mental and motor development. Low brain glucose and subsequent energy deficiency is considered the major pathogenic factor causing seizures. The ketogenic diet (KD) is the only causal treatment available for Glut1-DS, and its therapeutic effect resides in its ability to provide an alternate source of energy for the brain. However, seizure control with KD is not complete in many patients and the long-term cognitive outcome is not optimal. Biochemically, these observations can be explained by a lack of energy for metabolic functions provided by pathways derived exclusively from glucose, which the alternate energy from the KD fails to supplement.
HYPOTHESIS: We hypothesize that an anaplerotic agent adjunct to KD may be effective for controlling seizures and improving cognitive outcomes in children with Glut1-DS. Triheptanoin (C7) is a triglyceride containing the odd chain C7 (heptanoic) fatty acid, which occurs only in limited amounts in the natural diet. It improves the oxidation of acetyl CoA by the tricarbonic acid (TCA) cycle, leading to subsequent oxidative phosporylation by the electron transport chain to produce sufficient ATP for energy utilization. It also provides the TCA intermediates alpha ketoglutarate and oxaloacetate, which are important precursors for the neurotransmitters glutamate, GABA, and aspartate. Therefore, we expect these metabolic effects will enhance seizure control and/or neurodevelopmental function.
SPECIFIC AIMS: We aim to generate preliminary evidence on 1) the safety, 2) the clinical, and 3) the biochemical effects of C7 as an add on therapy in GLUT1-DS patients with inadequate response to ketogenic diet.
RESEARCH PLAN: To generate preliminary data and a better understanding of the precise biochemical mechanism of this novel treatment, we will conduct a pilot/proof of concept study using an open-label n-of-1 trial with 'an interrupted time-series before and after' design. We plan to enrol 3 Glut1-DS patients with incomplete seizure control, and the n-of-1 study design will help provide a distinct effectiveness estimate of C7 in each individual patient. As each participant acts as his/her own control, this design also supports an evidence-based, personalized medicine approach to treatment.
SIGNIFICANCE: If successful, this personalized treatment approach may be extended to GLUT1-DS patients with other symptoms refractory to the KD, or those who cannot tolerate the diet, and ultimately will serve as a model for eliminating seizures and side effects in other medically refractory epilepsies. The data generated with this study will be essential to design future trials for a larger number of Glut1-DS patients to create high-grade evidence.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||3 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Controlled N-of-1 Before-and-after Study to Determine Safety and Efficacy Triheptanoin in Patients With Glucose Transporter 1 Deficiency Syndrome|
|Study Start Date :||April 2014|
|Actual Primary Completion Date :||February 2016|
|Estimated Study Completion Date :||October 2016|
All subjects will receive the study treatment which includes adding triheptanoin to the ketogenic diet with a goal intake of 35% total calories provided by triheptanoin (max 100 ml oil/day.
Triheptanoin (C7 oil) is a triglyceride of the anaplerotic odd-chain fatty acid heptonate.
Other Name: C7 oil
- Seizure Control [ Time Frame: 8 months ]Complete seizure control (measured using seizure log book completed by the parents; defined by absence of clinical seizures and normalization of the EEG)
- Biochemical markers [ Time Frame: 8 months ]
Specific biochemical markers and metabolomics analysis to determine the metabolic fate of the administered Triheptanoate will be done at Case Western Reserve University, Cleveland.
TCA compounds: Succinate, fumarate, alphaketoglutarate Anaplerotic precursors: Propionate Ketone bodies: Betahydroxybutyrate, acetoacetate
Aminoacids: Glutamate, gluatamine, alanine Acylcarnitine/propionylcarnitine Beta hydroxypentanoate, beta ketopentanoate;
Aminoacids: Glutamate, gluatamine, alanine
- Neurodevelopmental function [ Time Frame: 8 months ]This will be measured by a psychologist using age-appropriate measurement scales from the NIH Toolbox (http://www.nihtoolbox.org).
- Movement Disorder [ Time Frame: 8 months ]assessed by neurological exam, Movement Disorder Childhood Rating Scale1 and tests from NIH Toolbox
- Seizure Frequency [ Time Frame: 8 months ]Median percent reduction in frequency of seizures from baseline from seizure log book.
- Clinical Global Impression-Improvement Scale [ Time Frame: 8 months ]Treatment response measured by Clinical Global Impression-Improvement Scale
- Patient specific outcomes of interest [ Time Frame: 8 months ]Patient specific outcomes of interest measured by Goal Attainment Scale
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02000960
|Canada, British Columbia|
|BC Children's Hospital|
|Vancouver, British Columbia, Canada, V6H 3V4|
|Principal Investigator:||Sylvia Stockler||The University of British Columbia/BC Children's Hospital|