Abstract
ObjectiveTo investigate feasibility, safety, and tolerability of long‐term (48 weeks) add‐on treatment with triheptanoin (UX007), the triglyceride of heptanoate, in adults with drug‐resistant epilepsy.MethodsThis extension study was offered to adult participants with drug‐resistant epilepsy who completed a 12‐week randomized controlled trial of add‐on medium‐chain triglycerides (MCT) vs triheptanoin. Participants were asked to titrate triheptanoin to their maximum tolerated dose over 3 weeks, followed by 48‐week maintenance before tapering or treatment extension. The primary aims were to assess retention and safety of the triheptanoin treatment, and secondary aims to assess the tolerated doses and changes in seizure frequency.ResultsEleven adults were enrolled and ten people were analyzed (because one patient was diagnosed as having nonepileptic seizures while on the study). Two adults finished the study and extended their treatment. Eight participants withdrew from the study, due to lack of efficacy (n = 3), unknown reasons (n = 2), belief of weight gain (n = 1), wanting to try a different treatment (n = 1), and a colonoscopy (n = 1). Diarrhea in two people and bloating in one person were deemed possibly related to treatment, but other adverse events were not. The duration of maintenance treatment dose was 27‐513 days (median 247 days, range 27‐513 days), and 0.49 ‐1.1 mL/kg triheptanoin was taken per day (0.77 ± 0.19 mL/kg, mean ± standard deviation, 40‐100 mL/d). Two participants experienced >90% and three people >50% reduction in seizure frequency, and all had focal seizures. The median seizure reduction was 48% (average 38%).SignificanceOur results indicate antiseizure effects of triheptanoin on focal seizures in 5 out of 10 adults. However, only two people finished and extended the 48‐week add‐on treatment phase, despite lack of safety or tolerability issues.More studies focused on improved treatment formulations, the potential of lower dosages, and efficacy are needed. Trial registration number: ACTRN12615000406505.
Highlights
Reduced glucose metabolism could lead to local energy deficiency and is likely to contribute to seizure generation.[6]
The decreases in brain levels of glutamate, glutamine, and malate found in people with epilepsy and rodent chronic epilepsy models indicate that the tricarboxylic acid (TCA) cycle is deficient of intermediates containing 4 or 5 carbons.[7,8,9,10,11]
In a previous randomized controlled trial (RCT),[28] we investigated safety and tolerability of triheptanoin vs medium-chain triglycerides (MCT, which contain triglycerides with octanoate and decanoate) as add-on treatments in adults with drug-resistant epilepsy
Summary
Heightened excitability of the brain and reduced glucose metabolism in epileptogenic areas are hallmarks of epilepsy in people and animal models.[1,2,3,4,5] Reduced glucose metabolism could lead to local energy deficiency and is likely to contribute to seizure generation.[6]. Patients who had completed the study were invited to take part in this long-term open-label extension trial of triheptanoin at maximal tolerated dose to assess retention and safety of the triheptanoin treatment, and secondary aims to assess the tolerated doses and changes in
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