Exogenous Ketone Esters for Drug Resistant Epilepsy (EKEDRE)

This study aims to investigate the efficacy of add-on exogenous ketone esters for treating children with drug-resistant epilepsy

Epilepsy is a common neurological disorder among children with significant neurobiological, cognitive, psychological, and social consequences. Seizures can usually be controlled by anti-seizure medications (ASMs) in up to two-thirds of children with epilepsy. However, this leaves a significant part of epileptic children whose seizures are not controlled by pharmacotherapy. Currently, available alternatives for drug-resistant epilepsy (DRE) include surgery, vagus nerve stimulation, and ketogenic diet (KD). KD has been classically used for treating children with DRE. However, KD requires strict dietary restriction, which may not be applicable or acceptable for many patients, and is associated with several adverse effects, commonly including gastrointestinal (e.g., constipation, nausea, vomiting), cardiovascular (e.g., dyslipidemia), renal/genitourinary (e.g., renal calculi), and growth problems. Exogenous ketone esters (EKE) could be a more convenient and superior alternative to KD for children with DRE.

Eligible children will be randomized into two equal-sized groups. Study group: will receive exogenous ketone esters plus standard of care. Control group: will receive only standard of care.

Proportion of doses of exogenous ketone esters which were not administered by patients (as recorded by parents of included children)

Proportion of doses of anti-seizure medications (ASMs) which were not administered by children (as recorded by parents of included children)

Change in attention, alertness, and memmory, each rated by parents of included children at the end of 28-days intervention phase as no change, improvement, or regression in comparison with the preceding 28-days observation phase

From baseline to 30 minutes, 1 hour, 2 hours, 4 hours, 2 days, 4 days, 7 days, 14 days, and 28 days study timepoints

From baseline to 30 minutes, 1 hour, 2 hours, 4 hours, 2 days, 4 days, 7 days, 14 days, and 28 days study timepoints

From baseline to 30 minutes, 1 hour, 2 hours, 4 hours, 2 days, 4 days, 7 days, 14 days, and 28 days study timepoints

Change in EEG score according to the scale developed by Walker & Said (2014), which includes items related to encephalopathy, interictal epileptic discharge, and seizure presence

From baseline to 30 minutes, 1 hour, 2 hours, 4 hours, 2 days, 4 days, 7 days, 14 days, and 28 days study timepoints

From baseline to 30 minutes, 1 hour, 2 hours, 4 hours, 2 days, 4 days, 7 days, 14 days, and 28 days study timepoints

From baseline to 30 minutes, 1 hour, 2 hours, 4 hours, 2 days, 4 days, 7 days, 14 days, and 28 days study timepoints

From baseline to 30 minutes, 1 hour, 2 hours, 4 hours, 2 days, 4 days, 7 days, 14 days, and 28 days study timepoints

Inclusion Criteria: Drug-resistant epilepsy Seizure frequency ≥ 7 per week Exclusion Criteria: Failure to obtain informed consent Recent intake of exogenous ketones, ketogenic diet, or any dietary restrictions/modifications Severe disease conditions, including hepatic, renal, respiratory, cardiac, gastrointestinal, endocrinal, and immune systems Hypo-/hyperglycemia Metabolic acidosis Ketosis (βHB > 2 mmol/L) GIT disorders, including gastritis/peptic ulcer, diarrhea/constipation, and irritable bowel disease Malnutrition/obesity Limitations to oral feeding (e.g., severe gastroesophageal reflux) Inborn errors of metabolism Chromosomal disorders Surgically-remediable epilepsy Allergies or any other contraindication to ketone supplements Inapplicable recording of seizures Incompliance to anti-seizure medications and/or irregular follow-up Recent propofol therapy Intake of carbonic-anhydrase inhibitors

Unidentified individual participant data (IPD) underlying study results will be available upon reasonable request

Unidentified individual participant data (IPD) underlying study results will be available upon reasonable request 6-months after publication

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