Ketogenic Emergency Treatment Of Status Epilepticus In SIREN
Benzodiazepines have been shown in randomized clinical trials (RCTs) to be safe and effective treatments for early status epilepticus. However, no RCTs have established the most effective pharmacologic treatment once status epilepticus becomes refractory. There is a critical need for prospective, randomized trials establishing safe and effective treatments for refractory status epilepticus (RSE). Ketogenic diets (high fat, low carbohydrate enteral formulas designed to induce ketone body production or ketonemia) are effective in the treatment of drug-resistant epilepsy. Our preliminary phase I/II multicenter study showed a response rate of 73% (11/15 participants) using a ketogenic formula as an adjunctive treatment for super refractory status epilepticus (SRSE). More recent studies suggest that a ketogenic formula may be feasible and even more effective f started earlier during treatment as a method of preventing SRSE.
This is a proposal for a phase II multicenter, double-blind, placebo-controlled, restricted Bayesian response adaptive randomization clinical trial designed to determine the ketogenic formula specifications needed to safely induce ketonemia (≥ 1 mmol/L blood ß-hydroxybutyrate) within 24 hours in patients with established refractory status epilepticus (requiring general anesthesia to suppress ongoing status epilepticus), as an adjunct to standard medical care.
The primary objective is to determine the most effective ketogenic enteral formula ratio needed to induce ketonemia (βHB ≥ 1 mmol/L) within 24 hours of initiation in the setting of established refractory status epilepticus, while avoiding intervention-limiting metabolic acidosis.
Secondary objectives include examining the feasibility of inducing ketonemia in the setting of established refractory status epilepticus for the purpose of conducting a future phase III efficacy study; and comparing safety and tolerability, efficacy measures including use of general anesthesia, and rate of progression to SRSE in one control and two treatment arms and to examine changes in inflammatory biomarkers and lipid species and their relation with ketonemia.
Interventions will include a standard care formula (SF), a low-dose 2:1 ratio (fat to carbohydrates and protein combined in grams) ketogenic formula (KF) and a high-dose 4:1 ratio KF.
The primary endpoint is presence or absence of ketonemia (≥ 1 mmol/L blood ß-hydroxybutyrate) within 24 hours of formula initiation without a Grade 4 intervention-limiting metabolic acidosis by 48 hours (pH < 7.3, persistent over a 6 or more consecutive hours). There are several safety, secondary efficacy, and exploratory endpoints.
210 participants will be randomized into one of three treatment arms (control arm (SF) or one of two treatment arms 2:1 (low-dose) KF or 4:1 (high-dose) KF). Participants will be 2-80 years old who have been diagnosed with refractory status epilepticus- status epilepticus with ongoing clinical and/or electrographic seizures despite administration of appropriate doses of first- and second-line treatments requiring intubation and intravenous anesthetic drugs to induce seizure suppression. Enrollment and initiation of intervention are expected to occur in the emergency departments at participating sites.