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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Study group | Experimental | Children receiving exogenous ketone esters + standard of care |
|
| Control group | No Intervention | Children receiving only standard of care |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Exogenous ketone ester | Drug | 500 mg/kg orally three times daily (with at least 4 hours between each dose) for 28 days |
|
| 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 |
| 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) |
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Elsayed M Abdelkreem, MD, PhD | Contact | 01114232126 | d.elsayedmohammed@med.sohag.edu.eg |
| Name | Affiliation | Role |
|---|---|---|
| Abdelrahim A Sadek, MD, PhD | Sohag University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Pediatrics at Sohag University Hospital | Recruiting | Sohag | 82524 | Egypt |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34510212 | Background | 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. | |
| 22561291 | Background |
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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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| ID | Term |
|---|---|
| D000069279 | Drug Resistant Epilepsy |
| ID | Term |
|---|---|
| D004827 | Epilepsy |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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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.
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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 |
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 |
| 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. |
| 29163194 | Background | 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. |
| 27475046 | Background | 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. |
| 11198492 | Background | 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. |
| 19889013 | Background | 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. |
| 28276062 | Background | 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. |
| 25414234 | Background | 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. |