Pilot Study of Triheptanoin in Patients With Glucose Transporter 1 Deficiency Syndrome (Glut1C7)

May 30, 2016 updated by: University of British Columbia

A Controlled N-of-1 Before-and-after Study to Determine Safety and Efficacy Triheptanoin in Patients With Glucose Transporter 1 Deficiency Syndrome

Glucose transporter deficiency syndrome (Glut1-DS) is a form of pediatric epilepsy caused by a genetic mutation that disrupts the body's ability to process food from the child's diet into sugar (energy) needed to support brain function. Children with Glut1-DS experience seizures that are not controlled by anticonvulsant medications, as well as delays in cognitive and motor development. Currently, Glut1-DS is treated with the ketogenic diet, a high-fat, low-sugar diet that provides the brain with an alternate source of energy. Despite the significant improvement of seizures upon this diet, seizure control is incomplete in a majority of children, and they continue to experience problems with brain development. Our team of researchers and clinicians with expertise in metabolic diseases, neurology, pediatrics, biochemistry, and genetics believes that there is an opportunity to achieve CURE's goal of "No Seizures/No Side Effects" for children with Glut1-DS by investigating the use of a new treatment option that is designed to compensate for the underlying biochemical deficiency thought to contribute both to the seizures and to the impaired brain development associated with Glut1-DS. The proposed treatment involves incorporating a special type of oil, called triheptanoin, into the ketogenic diet as a way to make up for a specific biochemical deficit affecting kids with Glut1-DS that the standard ketogenic diet fails to address. Our goal is to do a pilot study to test the safety and effectiveness of this promising new treatment option in a small group of children with Glut1-DS.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
3

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V6H 3V4
        • BC Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

1 year to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Confirmed diagnosis of Glut1-DS with mutation(s) in SLC2A1 gene.
  • Male or female age 1-18 years.
  • Glut1-DS is currently managed with ketogenic diet for a minimum of 4 months prior to baseline visit and patient is willing to maintain this diet for the study duration..
  • Inadequate response to ketogenic diet defined by clinical 'breakthrough seizures', confirmed by EEG and at least 1 clinical seizure episode documented in the seizure logbook during the baseline period.
  • For participants taking anticonvulsants for their seizures, anti-seizure medication should not be changed at least 4 weeks prior to starting triheptanoin treatment and the participant is willing to maintain the same dosing of all medication(s) during study participation.
  • Willing and able to provide written informed consent by parent(s) or guardian(s) or assent by the participant, depending on the age, after the nature of the study has been explained, and prior to any research related-procedures.

Exclusion Criteria:

  • Participants with medium chain acyl-CoA dehydrogenase (MCAD) and propionyl CoA carboxylase (PCC) deficiency will be excluded from the study as MCAD and PCC are required for triheptanoin metabolism.
  • A known allergy or sensitivity to any component of triheptanoin.
  • The participant is using valproate for controlling his/her seizures. They are eligible for the study, if they had not taken valproate within 3 weeks prior to baseline visit and willing to not take it for the entire study duration. Valproate is an AED that partially inhibits the TCA cycle via alpha-ketoglutarate dehydrogenase, and should not be administered to subjects taking triheptanoin.
  • Participant has any condition or situation which, in the investigator's opinion, places the patient at significant risk of adverse events, or may interfere significantly with their participation and compliance in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Triheptanoin
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.
Drug: Triheptanoin
Triheptanoin (C7 oil) is a triglyceride of the anaplerotic odd-chain fatty acid heptonate.
Other Names:
  • C7 oil

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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)
8 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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.

Markers:

Urine:

TCA compounds: Succinate, fumarate, alphaketoglutarate Anaplerotic precursors: Propionate Ketone bodies: Betahydroxybutyrate, acetoacetate

Blood:

Aminoacids: Glutamate, gluatamine, alanine Acylcarnitine/propionylcarnitine Beta hydroxypentanoate, beta ketopentanoate;

CSF:

Aminoacids: Glutamate, gluatamine, alanine
8 months
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).
8 months
Movement Disorder
Time Frame: 8 months
assessed by neurological exam, Movement Disorder Childhood Rating Scale1 and tests from NIH Toolbox
8 months

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Seizure Frequency
Time Frame: 8 months
Median percent reduction in frequency of seizures from baseline from seizure log book.
8 months
Clinical Global Impression-Improvement Scale
Time Frame: 8 months
Treatment response measured by Clinical Global Impression-Improvement Scale
8 months
Patient specific outcomes of interest
Time Frame: 8 months
Patient specific outcomes of interest measured by Goal Attainment Scale
8 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of British Columbia

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Ultragenyx Pharmaceutical Inc

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Sylvia Stockler, The University of British Columbia/BC Children's Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2014

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 1, 2016

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 1, 2016

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 27, 2013

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 27, 2013

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 4, 2013

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 1, 2016

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 30, 2016

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • H13-03330
  • VGTPH001 (Other Identifier: Ultragenyx Pharmaceutical Inc.)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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