Exogenous Ketone Esters for Drug Resistant Epilepsy (EKEDRE)

Efficacy of Ketone Esters for Children With Drug Resistant Epilepsy

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

Study Overview

• Status: Recruiting
• Conditions: Drug Resistant Epilepsy
• Intervention / Treatment: Drug: Exogenous ketone ester

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Elsayed M Abdelkreem, MD, PhD; Phone Number: 01114232126; Email: d.elsayedmohammed@med.sohag.edu.eg

Study Locations

• Egypt
  • Sohag, Egypt, 82524
    • Recruiting
    • Department of Pediatrics at Sohag University Hospital
    • Contact: Abdelrahim A Sadek, MD, PhD; Email: abdoneurology@yahoo.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 16 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study group; Children receiving exogenous ketone esters + standard of care	Drug: Exogenous ketone ester; 500 mg/kg orally three times daily (with at least 4 hours between each dose) for 28 days
No Intervention: Control group; Children receiving only standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
≥ 50% reduction in seizure frequency	Proportion of patients achieving ≥ 50% reduction in seizure frequency	From 28-days observation (baseline) phase to 28-days intervention phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of incompliance to exogenous ketone ester therapy	Proportion of doses of exogenous ketone esters which were not administered by patients (as recorded by parents of included children)	28-days intervention phase
Proportion of incompliance to anti-seizure medications (ASMs)	Proportion of doses of anti-seizure medications (ASMs) which were not administered by children (as recorded by parents of included children)	From 28-days observation (baseline) phase to 28-days intervention phase
Change in seizure severity assessed by National Hospital Seizure Severity Scale (NHS3)	Change in seizure severity assessed by National Hospital Seizure Severity Scale (NHS3)	From 28-days observation (baseline) phase to 28-days intervention phase
Change in seizure frequency	Change in the number of seizures (as recorded by parents of included children)	From 28-days observation (baseline) phase to 28-days intervention phase
Change in frequency of status epilepticus	Change in the number of episodes of status epilepticus (evaluated from patient's medical records)	From 28-days observation (baseline) phase to 28-days intervention phase
Change in occurrence of possible adverse effects	Change in occurrence of possible adverse effects	From 28-days observation (baseline) phase to 28-days intervention phase
Change in cognitive domains	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 28-days observation (baseline) phase to 28-days intervention phase
Change in blood βHB	Change in blood level of beta-hydroxybutyrate	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	Change in blood level of glucose	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	Change in blood level of pH	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	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 28 days study timepoint

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in blood lactate level	Change in blood level of lactate	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 bicarbonate level	Change in blood level of bicarbonate	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 serum sodium level	Change in serum sodium level	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 serum potassium level	Change in serum potassium level	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 hematological counts	Change in hematological counts	From baseline to 28 days study timepoint
Change in blood triglycerides level	Change in blood triglycerides level	From baseline to 28 days study timepoint
Change in blood free fatty acids level	Change in blood free fatty acids level	From baseline to 28 days study timepoint
Change in blood cholesterol level	Change in blood cholesterol level	From baseline to 28 days study timepoint
Change in HbA1c	Change in hbA1c	From baseline to 28 days study timepoint
Change in blood alanine transaminase level	Change in blood level of alanine transaminase enzyme (ALT)	From baseline to 28 days study timepoint
Change in serum creatinine level	Change in serum level of creatinine	From baseline to 28 days study timepoint

Collaborators and Investigators

• Sponsor: Sohag University
• Investigators: Study Chair: Abdelrahim A Sadek, MD, PhD, Sohag University

Publications and helpful links

General Publications

• 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. Erratum In: Epilepsia. 2010 Sep;51(9):1922.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2023
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: December 18, 2022
• First Submitted That Met QC Criteria: December 31, 2022
• First Posted (Actual): January 4, 2023

Study Record Updates

• Last Update Posted (Estimated): November 27, 2024
• Last Update Submitted That Met QC Criteria: November 26, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Children; Drug resistant epilepsy; Exogenous ketone esters
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Drug Resistant Epilepsy; Epilepsy
• Other Study ID Numbers: Soh-Med-22-12-45

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Unidentified individual participant data (IPD) underlying study results will be available upon reasonable request
• IPD Sharing Time Frame: Unidentified individual participant data (IPD) underlying study results will be available upon reasonable request 6-months after publication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No