The Established Status Epilepticus Trial 2013

Abstract

Summary Benzodiazepine-refractory status epilepticus (established status epilepticus, ESE) is a relatively common emergency condition with several widely used treatments. There are no controlled, randomized, blinded clinical trials to compare the efficacy and tolerability of currently available treatments for ESE. The ESE treatment trial is designed to determine the most effective and/or the least effective treatment of ESE among patients older than 2 years by comparing three arms: fosphenytoin (fPHT) levetiracetam (LVT), and valproic acid (VPA). This is a multicenter, randomized, double-blind, Bayesian adaptive, phase III comparative effectiveness trial. Up to 795 patients will be randomized initially 1:1:1, and response-adaptive randomization will occur after 300 patients have been recruited. Randomization will be stratified by three age groups, 2–18, 19–65, and 66 and older. The primary outcome measure is cessation of clinical seizure activity and improving mental status, without serious adverse effects or further intervention at 60 min after administration of study drug. Each subject will be followed until discharge or 30 days from enrollment. This trial will include interim analyses for early success and futility. This trial will be considered a success if the probability that a treatment is the most effective is >0.975 or the probability that a treatment is the least effective is >0.975 for any treatment. Proposed total sample size is 795, which provides 90% power to identify the most effective and/or the least effective treatment when one treatment arm has a true response rate of 65% and the true response rate is 50% in the other two arms.

Preliminary results of the global audit of treatment of refractory status epilepticus

“…Preferred agents for this phase include fosphenytoin, valproic acid, phenytoin, phenobarbital, and levetiracetam. A trial comparing fosphenytoin, valproic acid, and levetiracetam for benzodiazepine-refractory SE is planned but is not yet open for recruitment [13]. If seizures continue despite firstline and second-line agents, the patient is said to be in refractory status epilepticus.…”

Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society

“…The current National Institute of Neurological Disorders and Stroke funded ESETT trial compares IV fosphenytoin, levetiracetam, and valproate in children and adults with status epilepticus who did not respond to initial benzodiazepine therapy. ESETT is designed to be a class I RCT that will identify the optimal second therapy for benzodiazepine-resistant status epilepticus (64 a Data Safety Monitoring Board (DSMB) for a UCB Pharma clinical trial of a non-epilepsy-related drug. Dr.…”

Recent advances in status epilepticus

“…There is one phase III trial in superrefractory status epilepticus (NCT02477618) currently recruiting patients[117]. Another remarkable phase III trial (NCT01960075) comparing the efficacy of levetiracetam, valproate and (fos)phenytoin in established status epilepticus (Established Status Epilepticus Trial) also started recruitment in 2015[118][119][120]. This trial uses an innovative adaptive design and its results are expected to inform clinical practice in the future.…”