Glucose Transporter Type 1 Deficiency SyndromePhase 2Glut1C7NCT02000960
Pilot Study of Triheptanoin in Patients With Glucose Transporter 1 Deficiency Syndrome
A Phase 2 study testing Triheptanoin in people with Glucose Transporter Type 1 Deficiency Syndrome, run by University of British Columbia at 1 site in Canada.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 1 year to 18 years
- Conditions the study is for
- Glucose Transporter Type 1 Deficiency Syndrome
- What is being tested?
- Triheptanoin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 1 siteCanada
- Study dates
- Apr 2014to Oct 2016
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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.
- Being tested
- Triheptanoin
- Keywords
- Glut1 DS
- Medical subject headings
- Glut1 Deficiency Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TriheptanoinDrug
Also called C7 oil
Triheptanoin (C7 oil) is a triglyceride of the anaplerotic odd-chain fatty acid heptonate.
| Study group | Role | What they receive |
|---|---|---|
| Triheptanoin | Experimental | 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. Receives: Drug: Triheptanoin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Seizure Control
Complete seizure control (measured using seizure log book completed by the parents; defined by absence of clinical seizures and normalization of the EEG)
Measured: 8 months
Secondary outcomes (3)
Biochemical markers
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
Measured: 8 months
Neurodevelopmental function
This will be measured by a psychologist using age-appropriate measurement scales from the NIH Toolbox (http://www.nihtoolbox.org).
Measured: 8 months
Movement Disorder
assessed by neurological exam, Movement Disorder Childhood Rating Scale1 and tests from NIH Toolbox
Measured: 8 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2013 (estimated)
- Study startApr 2014
- Primary completionFeb 2016
- Study completionOct 2016 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Glucose Transporter Type 1 Deficiency SyndromeStudies of the same condition, open and under way.
- More trials run by University of British ColumbiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of British Columbia
- Sponsor type
- University, hospital or other
- Collaborators
- Ultragenyx Pharmaceutical Inc
- Responsible party
- Sponsor
- Investigators
- Sylvia Stockler, Principal investigator, The University of British Columbia/BC Children's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02000960
- Sponsor's protocol ID
- H13-03330
- Other IDs
- VGTPH001
- Acronym
- Glut1C7
- Status last verified
- May 2016
- First submitted
- 27 Nov 2013
- Last updated
- 1 Jun 2016
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 1 Jun 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02000960
- Acronym / sponsor ID
- Glut1C7 / H13-03330
- Keywords
- Glut1 DS
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 3 participants (estimated)
- Lead sponsor
- University of British ColumbiaUniversity, hospital or other
- Collaborators
- Ultragenyx Pharmaceutical Inc
- Study start
- Apr 2014
- Primary completion
- Feb 2016 (actual)
- Study completion
- Oct 2016 (estimated)
- First posted
- 4 Dec 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Triheptanoin | Experimental | Drug: TriheptanoinAll 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. |
Who may qualify
- Ages
- 1 year to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (4 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TriheptanoinAlso: C7 oilTriheptanoin (C7 oil) is a triglyceride of the anaplerotic odd-chain fatty acid heptonate. | Drug | Triheptanoin |
Primary outcome
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)
3 secondary outcomes
Biochemical markers
Time frame: 8 months
Neurodevelopmental function
Time frame: 8 months
Movement Disorder
Time frame: 8 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jun 2016.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sylvia Stockler principal investigator
The University of British Columbia/BC Children's Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Triheptanoin in people with Glucose Transporter Type 1 Deficiency Syndrome, run by University of British Columbia at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 1 Jun 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Seizure Control (time frame: 8 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jun 2016.