Exogenous Ketone Esters for Drug Resistant Epilepsy

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

Detailed Description
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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.

Official Title
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Efficacy of Ketone Esters for Children With Drug Resistant Epilepsy

Conditions
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Drug Resistant Epilepsy

Intervention / Treatment
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* Drug: Exogenous ketone ester


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug resistant epilepsy, Exogenous ketone esters, Children