Exogenous Ketone Esters for Drug Resistant Epilepsy

Официальное название

Efficacy of Ketone Esters for Children With Drug Resistant Epilepsy

Обзор

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

Подробное описание

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.

Вмешательства

• Препарат Exogenous ketone ester
  500 mg/kg orally three times daily (with at least 4 hours between each dose) for 28 days

Первичные конечные точки

• ≥ 50% reduction in seizure frequency [Срок оценки: From 28-days observation (baseline) phase to 28-days intervention phase]

Вторичные конечные точки (11)

• Proportion of incompliance to exogenous ketone ester therapy [Срок оценки: 28-days intervention phase]
• Proportion of incompliance to anti-seizure medications (ASMs) [Срок оценки: From 28-days observation (baseline) phase to 28-days intervention phase]
• Change in seizure severity assessed by National Hospital Seizure Severity Scale (NHS3) [Срок оценки: From 28-days observation (baseline) phase to 28-days intervention phase]
• Change in seizure frequency [Срок оценки: From 28-days observation (baseline) phase to 28-days intervention phase]
• Change in frequency of status epilepticus [Срок оценки: From 28-days observation (baseline) phase to 28-days intervention phase]
• Change in occurrence of possible adverse effects [Срок оценки: From 28-days observation (baseline) phase to 28-days intervention phase]
• Change in cognitive domains [Срок оценки: From 28-days observation (baseline) phase to 28-days intervention phase]
• Change in blood βHB [Срок оценки: 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 blood glucose [Срок оценки: 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 blood pH [Срок оценки: 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 [Срок оценки: From baseline to 28 days study timepoint]

Критерии участия

Критерии включения

• Drug-resistant epilepsy
• Seizure frequency ≥ 7 per week

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Египет · 1 центр

• Department of Pediatrics at Sohag University Hospital — Sohag

Публикации

• Carson RP, Herber DL, Pan Z, Phibbs F, Key AP, Gouelle A, Ergish P, Armour EA, Patel S, Duis J. Nutritional Formulation for Patients with Angelman Syndrome: A Randomized, Double-Blind, Placebo-Controlled Study of Exogenous Ketones. J Nutr. 2021 Dec 3;151(12):3628-3636. doi: 10.1093/jn/nxab284. PMID 34510212
• Clarke K, Tchabanenko K, Pawlosky R, Carter E, Todd King M, Musa-Veloso K, Ho M, Roberts A, Robertson J, Vanitallie TB, Veech RL. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012 Aug;63(3):401-8. doi: 10.1016/j.yrtph.2012.04.008. Epub 2012 May 3. PMID 22561291
• Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, Magor-Elliott S, Hiyama S, Stirling M, Clarke K. On the Metabolism of Exogenous Ketones in Humans. Front Physiol. 2017 Oct 30;8:848. doi: 10.3389/fphys.2017.00848. eCollection 2017. PMID 29163194
• Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 2016 Aug 9;24(2):256-68. doi: 10.1016/j.cmet.2016.07.010. Epub 2016 Jul 27. PMID 27475046
• Gilbert DL, Pyzik PL, Freeman JM. The ketogenic diet: seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones. J Child Neurol. 2000 Dec;15(12):787-90. doi: 10.1177/088307380001501203. PMID 11198492
• Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshe SL, Perucca E, Wiebe S, French J. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010 Jun;51(6):1069-77. doi: 10.1111/j.1528-1167.2009.02397.x. Epub 2009 Nov 3. PMID 19889013
• Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshe SL, Nordli DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017 Apr;58(4):512-521. doi: 10.1111/epi.13709. Epub 2017 Mar 8. PMID 28276062
• Walker I, Said RR. Predictors of Ketogenic Diet Efficacy in Children Based on the Electroencephalogram (EEG). J Child Neurol. 2015 Sep;30(10):1270-4. doi: 10.1177/0883073814556888. Epub 2014 Nov 20. PMID 25414234

Идентификаторы

NCT: NCT05670847 · Soh-Med-22-12-45

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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