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. 2019 Feb 22;4(1):153-163.
doi: 10.1002/epi4.12308. eCollection 2019 Mar.

Randomized trial of add-on triheptanoin vs medium chain triglycerides in adults with refractory epilepsy

Karin Borges  1 , Neha Kaul  2   3 , Jack Germaine  3 , Patrick Kwan  3   4 , Terence J O'Brien  3   4
Affiliations

Randomized trial of add-on triheptanoin vs medium chain triglycerides in adults with refractory epilepsy

Karin Borges et al. Epilepsia Open. .

Abstract

Objective: To investigate the feasibility, safety, and tolerability of add-on treatment of the triglycerides of heptanoate (triheptanoin) vs the triglycerides of octanoate and decanoate (medium chain triglycerides [MCTs]) in adults with treatment-refractory epilepsy.

Methods: After an 8-week prospective baseline period, people with drug-resistant epilepsy were randomized in a double-blind fashion to receive triheptanoin or MCTs. Treatment was titrated over 3 weeks to a maximum of 100 mL/d to be distributed over 3 meals and mixed into food, followed by 12-week maintenance before tapering. The primary aims were to assess the following: (a) safety by comparing the number of intervention-related adverse events with triheptanoin vs MCT treatment and (b) adherence, measured as a percentage of the prescribed treatment doses taken.

Results: Thirty-four people were randomized (17 to MCT and 17 to triheptanoin). There were no differences regarding (a) the number of participants completing the study (11 vs 9 participants), (b) the time until withdrawal, (c) the total number of adverse events or those potentially related to treatment, (d) median doses of oils taken (59 vs 55 mL/d, P = 0.59), or (e) change in seizure frequency (54% vs 102%, P = 0.13). Please note that people with focal unaware seizures were underrepresented in the triheptanoin treatment arm (P = 0.04). The most common adverse events were gastrointestinal disturbances (47% and 62.5% of participants). Five people taking on average 0.73 mL/kg body weight MCTs (0.64 mL/kg median) and one person taking 0.59 mL/kg triheptanoin showed >50% reduction in seizure frequency, specifically focal unaware seizures.

Significance: Add-on treatment with MCTs or triheptanoin was feasible, safe, and tolerated for 12 weeks in two-thirds of people with treatment-resistant epilepsy. Our results indicate a protective effect of MCTs on focal unaware seizures. This warrants further study.

Keywords: TCA cycle; anaplerosis; focal unaware seizure; medium chain triglyceride.

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Conflict of interest statement

The study was supported by the Epilepsy Foundation New Therapy Development Program, Parents Against Childhood Epilepsy and Uniquest Pty. Ltd. Dr. Borges filed for a patent regarding triheptanoin in epilepsy and received a license fee payment and research support from Ultragenyx Pharmaceuticals Inc. Research support was also received from Epilepsy Foundation New Therapy Development Program, Parents Against Childhood Epilepsy, Uniquest Pty. Ltd., National Health and Medical Research Council (NHMRC), Motor Neurone Disease Research Institute Australia, and funding from the Brain Foundation (Australia). Dr. Terence J O'Brien reports grants and personal fees from UCB Pharma, Eisai, and Zynerba Pharmaceuticals, outside the submitted work. He has also received research grants from the NHMRC, National Institute of Neurological Disorders and Stroke (NINDS), and the RMH Neuroscience Foundation. Dr. Kwan/his institution received speaker or consultancy fees and/or research grants from Eisai, GlaxoSmithKline, Johnson & Johnson, Pfizer, and UCB Pharma. He is supported by the Medical Research Future Fund Practitioner Fellowship. He has received research grants from the National Health and Medical Research Council of Australia, the Australian Research Council, the US National Institutes of Health, Hong Kong Research Grants Council, Innovation and Technology Fund, Health and Health Services Research Fund, and Health and Medical Research Fund. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

Figure 1
Figure 1
Schematic of the proposed biochemical effects of medium chain triglycerides (MCTs) and triheptanoin in epilepsy. Glucose is typically the main fuel for brain cells and is oxidized by the tricarboxylic acid (TCA) cycle producing most of the adenosine triphosphate (ATP) during aerobic metabolism, and lipids and amino acids, such as aspartate and glutamate. The red double lines indicate that in many epilepsy types there is evidence for impaired glucose metabolism, which is likely to result in local shortages of ATP as well as carbons to produce lipids and amino acids. This may contribute dysregulation of neuronal signaling and subsequent seizure generation. Alternative sources of carbons for the brain can be provided by C3/4 ketone bodies, which are produced when carbohydrates and calories are restricted. Another carbon source are medium chain fatty acids, such as octanoate and decanoate as well as heptanoate. Octanoate and decanoate can be provided via MCTs and heptanoate from triheptanoin, and all can directly produce acetyl‐CoA (coenzyme A). In addition, heptanoate can be metabolized by the liver to C5 ketones. Both heptanoate and C5 ketones are also metabolized to propionyl‐CoA which after carboxylation refills the C4 intermediate pool of the TCA cycle as succinyl‐CoA (anaplerosis). This is important to compensate for the loss of carbons from the TCA cycle for production of lipids and amino acids and to continue efficient TCA cycling
Figure 2
Figure 2
Diagrams specifying the trial design (A) and flow diagram indicating the number of people with refractory epilepsy from screening to study completion (B). A, Clinic visits are indicated as triangles on the weekly time line. After an 8‐week baseline period, the on‐titration period for MCTs or triheptanoin add‐on treatment was 3 weeks until maximal tolerated dose was reached and was maintained for the 12‐week maintenance phase. Thereafter, add‐on treatment was titrated off for 3 weeks and followed by a 4‐week period without add‐on treatment. B, The diagram shows the number of participants analyzed for primary and secondary outcomes and reasons for withdrawal from the study. MCT, medium chain triglyceride
Figure 3
Figure 3
A, B Seizure frequencies (number of seizures/28 d) during baseline, full‐dose treatment, and posttreatment phases are shown for people taking MCTs (A) vs triheptanoin (B). The black triangles indicate seizure frequencies from participants with treatment efficacy, as defined by >50% of reduction in seizure frequencies during the treatment phase. MCT, medium chain triglyceride
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