Exogenous Ketone Esters for Refractory Status Epileptics

Status Epilepticus Clinical Trial

— EKERSE  

Official title:

Efficacy of Exogenous Ketone Esters for Children With Refractory Convulsive Status Epileptics

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05674552
• Other study ID #: Soh-Med-22-12-46
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: January 10, 2023
• Est. completion date: July 1, 2024

Study information

• Verified date: February 2024
• Source: Sohag University
• Contact: Elsayed M Abdelkreem, MD, PhD
• Phone: 01114232126
• Email: d.elsayedmohammed[@]med.sohag.edu.eg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study aims to investigate the efficacy of add-on exogenous ketone esters for the treatment of children with refractory generalized convulsive status epilepticus

Description:

Generalized convulsive status epilepticus (GCSE) is a common neurological emergency in children with significant morbidity and mortality. Benzodiazepines (Bzs) are the initial anti-seizure medications (ASMs) for children with GCSE, but nearly a third of cases are not controlled by (Bzs). Moreover, about 40% of cases not responding to BZs are not controlled by second-line ASMs. Ketogenic diet (KD) has been classically used for treating children with drug resistant epilepsy. Recently, KD has been used for refractory and super refractory status epilepticus. However, KD takes time to achieve ketosis and may be practically challenging in emergency situations and critically ill patients. Exogenous ketone esters (EKE) could be a more convenient and rapid way to achieve ketosis in acute settings.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: July 1, 2024
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 10 Years

Eligibility

Inclusion Criteria:

• Refractory Generalized convulsive status epilepticus.

Exclusion Criteria:

• Failure to obtain informed consent.
• Recent intake of exogenous ketones, ketogenic diet, or any dietary restrictions/modifications.
• Hemodynamic or cardio-respiratory instability.
• Traumatic brain injury.
• Hypo-/hyperglycemia.
• Metabolic acidosis.
• Ketosis (ßHB > 2 mmol/L).
• Associated severe disease condition, including hepatic, renal, respiratory, cardiac, gastrointestinal, endocrinal, and immune systems.
• Malnutrition/obesity.
• Limitations to nasogastric tube feeding.
• Inborn errors of metabolism.
• Allergies or any other contraindication to exogenous ketone esters.
• Current or recent (within the last 24 hours) propofol therapy.
• Intake of carbonic-anhydrase inhibitors.

Related Conditions & MeSH terms

• Status Epilepticus

Intervention

Drug:
• Exogenous ketone ester
500 mg/kg over 5 min administered by nasogastric tube, followed after 1 hr by repeated hourly doses of 125 mg/kg for 8 hrs.

Locations

Country	Name	City	State
Egypt	Department of Pediatrics at Sohag University Hospital	Sohag

Sponsors (1)

Lead Sponsor	Collaborator
Sohag University

Country where clinical trial is conducted

Egypt, 

References & Publications (10)

Arya R, Peariso K, Gainza-Lein M, Harvey J, Bergin A, Brenton JN, Burrows BT, Glauser T, Goodkin HP, Lai YC, Mikati MA, Fernandez IS, Tchapyjnikov D, Wilfong AA, Williams K, Loddenkemper T; pediatric Status Epilepticus Research Group (pSERG). Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus. Epilepsy Res. 2018 Aug;144:1-6. doi: 10.1016/j.eplepsyres.2018.04.012. Epub 2018 Apr 27. — View Citation

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. — View Citation

Chomtho S, Uaariyapanichkul J, Chomtho K. Outcomes of parenteral vs enteral ketogenic diet in pediatric super-refractory status epilepticus. Seizure. 2022 Mar;96:79-85. doi: 10.1016/j.seizure.2022.01.019. Epub 2022 Feb 5. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Schoeler NE, Simpson Z, Zhou R, Pujar S, Eltze C, Cross JH. Dietary Management of Children With Super-Refractory Status Epilepticus: A Systematic Review and Experience in a Single UK Tertiary Centre. Front Neurol. 2021 Mar 12;12:643105. doi: 10.3389/fneur.2021.643105. eCollection 2021. — View Citation

Si J, Wang Y, Xu J, Wang J. Antiepileptic effects of exogenous beta-hydroxybutyrate on kainic acid-induced epilepsy. Exp Ther Med. 2020 Dec;20(6):177. doi: 10.3892/etm.2020.9307. Epub 2020 Oct 9. — View Citation

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. — View Citation

Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S, Shorvon S, Lowenstein DH. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015 Oct;56(10):1515-23. doi: 10.1111/epi.13121. Epub 2015 Sep 4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in blood bicarbonates level	Change in blood bicarbonates level	From baseline to 30 minutes, 1 hour, 2 hours, 5 hours, 9 hours, and 12 hours study timepoints
Other	Change in blood lactate level	Change in blood lactate level	From baseline to 30 minutes, 1 hour, 2 hours, 5 hours, 9 hours, and 12 hours study timepoints
Other	Change in hemoglobin level	Change in hemoglobin level	From baseline to 1 hour and 12 hours study timepoints
Other	Change in leukocyte count	Change in leukocyte count	From baseline to 1 hour and 12 hours study timepoints
Other	Change in platelets count	Change in platelets count	From baseline to 1 hour and 12 hours study timepoints
Other	Change in serum sodium level	Change in serum sodium level	From baseline to 1 hour and 12 hours study timepoints
Other	Change in serum potassium level	Change in serum potassium level	From baseline to 1 hour and 12 hours study timepoints
Other	Change in CRP level	Change in CRP level	From baseline to 1 hour and 12 hours study timepoints
Other	Change in lipid profile	Change in lipid profile	From baseline to 1 hour and 12 hours study timepoints
Other	Change in blood alanine transaminase level	Change in blood alanine transaminase (ALT) level	From baseline to 1 hour and 12 hours study timepoints
Other	Change in serum creatinine level	Change in serum creatinine level	From baseline to 1 hour and 12 hours study timepoints
Primary	Proportion of patients achieving electroclinical cessation of seizures	Proportions of patients who achieve cessation of BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG])	60 minutes
Secondary	Proportion of patients achieving electroclinical cessation of seizures	Proportions of patients who achieve cessation of BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG])	12 hours
Secondary	Time to electroclinical cessation of seizures	Time to cessation of BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG])	24 hours
Secondary	Proportion of patients achieving electroclinical seizure freedom	Proportion of patients achieving freedom from BOTH clinical seizures (as observed clinically) AND electrical seizures (evaluated by electroencephalography [EEG])	24 hours
Secondary	Proportion of patients with super-refractory status epilepticus	Proportion of patients with persistent seizures for 24 hours or more after initiation of 3rd line medications (anesthetics) or recurrence of seizure during withdrawal of the anesthetics	24 hours
Secondary	Proportion of patients with adverse gastrointestinal effects	Proportion of patients with adverse gastrointestinal effects (vomiting, diarrhea, abdominal pain) evaluated by direct observation and patient-reporting	24 hours
Secondary	Change in blood beta-hydroxybutyrate level	Change in blood level of beta-hydroxybutyrate	From baseline to 30 minutes, 1 hour, 2 hours, 5 hours, 9 hours, and 12 hours study timepoints
Secondary	Change in blood glucose level	Change in blood level of glucose	From baseline to 30 minutes, 1 hour, 2 hours, 5 hours, 9 hours, and 12 hours study timepoints
Secondary	Change in blood pH	Change in blood pH	From baseline to 30 minutes, 1 hour, 2 hours, 5 hours, 9 hours, and 12 hours study timepoints