Phase I trial of oral triheptanoin add-on treatment for children with medically refractory epilepsy
To determine to which extent children 3-18yrs with medically refractory epilepsy given treatment with triheptanoin oil will experience fewer seizures and fewer side effects.
University of Queensland
50 participants
Mar 14, 2014
Interventional
Conditions
Summary
We established that triheptanoin (triglyceride of heptanoate), a stable, edible tasteless oil that has been used in the clinic in patients with metabolic disorders, is an anticonvulsant in four mouse seizure models. This Phase I clinical trial aims to establish the feasibility, safety and tolerability of triheptanoin as add-on treatment in children with treatment-resistant epilepsy, and obtain indications for its efficacy against medically refractory seizures. We propose to initiate a pilot phase I clinical trial of 50 children (3-18 yr of age) with treatment-resistant epilepsy at the Royal and Mater Children’s Hospitals in Brisbane. Eligible patients without contraindications to triheptanoin will count seizures during a baseline period of two months. Subjects with more than two seizures per fortnight will be enrolled and receive slowly increasing doses of triheptanoin (max 35% of caloric intake) during meals until the maximum tolerable dose is reached. All patients will be counselled and monitored by a dietitian before, during and after the treatment to ensure that they receive adequate nutrition. This treatment would be ideal for patients with epilepsy in the developed and developing world, because: 1) triheptanoin does not require refrigeration and is straightforward to add to meals and 2) it is not expected to change metabolism of other drugs and require “drug monitoring” nor to have significant side effects.
Eligibility
Inclusion Criteria3
- Male or female subjects (3-18 years old) with epilepsy who have experienced at least two motor seizures per fortnight over two months prior to enrolment despite treatment with at least one antiepileptic drug (AED) at clinically appropriate doses; (*Eligible seizure types are: complex partial seizures (focal dyscognitive seizures), secondary generalised seizures, simple partial seizures with motor features, primary generalised seizures, tonic seizures, atonic seizures);
- There has been no change in anti-epileptic drugs over the four weeks prior to enrolment;
- Females of childbearing potential must have a negative serum Beta subunit of human chorionic gonadotropin (Beta hCG) at Visit 1 and a negative urine pregnancy test prior to randomization at Visit 2. Female subjects of childbearing potential must also agree to be abstinent or to use at least 1 medically acceptable method of contraception. If the subject is on a hormonal type of contraceptive, they must agree to use an additional second approved method of contraception.
Exclusion Criteria6
- History of major psychiatric morbidity (such as psychiatric illness requiring hospitalisation or history of psychosis or major depression) in patients;
- Patients and/or parents with history of substance abuse;
- A history of having had psychogenic non-epileptic seizures;
- Patients who have seizure clusters or other reasons that make counting of numbers of seizures inaccurate;
- Females who are breast feeding;
- Patients with propionic academia or methylmalonic acidemia or with disorders affecting medium and short chain fatty acid oxidation. This includes medium-chain acyl-CoA dehydrogenase deficiency - MCAD, short-chain acyl-CoA dehydrogenase deficiency - SCAD, short-chain-3 hydroxyacyl-CoA dehydrogenase deficiency –SCHAD and HMG CoA (3-hydroxy-3-methyl-glutaryl-CoA) synthase deficiency
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Interventions
Intervention: Triheptanoin (triglyceride of heptanoate), a stable, edible tasteless oil that has been used in patients with metabolic disorders. After an 8 week baseline period counting seizures, subjects with > 2 seizures per fortnight will be enrolled and treated with up to 35% of caloric input triheptanoin (max 100 ml oil/day). The oil will be added to a normal diet, starting at 5ml dosed 3 times per day, titrated up over 6weeks and full dose given for a period of 12 weeks. For example, patients eating 2000 Kcal per day, will start with 3 x 5ml triheptanoin daily for the 1st week, followed by 3 x 10 ml in the 2nd, 3 x 15 ml in the 3rd, 3 x 20 ml in the 4th week, and 3 x 25 ml in the 5th week and 3 x 27.5 ml as the final maximal dose (35% of caloric intake, 87.5 ml/day). The full dose will be 35% of caloric intake if tolerated. During the full time of the study seizures, adverse events, side effects, weight and quality of life will be recorded. To improve adherence the participants will have regular contact with a dietitian face-to-face and via phone. Participants/carers will fill in a food diary and treatment diary to monitor compliance and return the used and unused bottles of oil.
Locations(1)
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ACTRN12614000187640