ESETT

The trial was designed to determine the most effective second-line treatment for patients with convulsive status epilepticus that is refractory to initial benzodiazepine therapy.

The primary conclusion of the trial is that the three commonly used anticonvulsant drugs—levetiracetam, fosphenytoin, and valproate—are equally effective and have comparable safety profiles.

Furthermore, the incidence of serious adverse events, including life-threatening hypotension, cardiac arrhythmia, and the need for endotracheal intubation, did not differ significantly across the three groups.

Primary Objective: To compare the efficacy and safety of intravenous levetiracetam, fosphenytoin, and valproate in children and adults with convulsive status epilepticus that has not responded to treatment with benzodiazepines.

Trial Name: Established Status Epilepticus Treatment Trial (ESETT)

Design and Methodology:

• Type: A multicenter, randomized, blinded, adaptive comparative-effectiveness trial conducted at 57 hospital emergency departments in the United States.
• Population: The trial enrolled 384 unique patients, aged 2 years and older, who continued to have generalized convulsive seizures after receiving an adequate cumulative dose of benzodiazepines.
• Randomization: Patients were initially randomized in a 1:1:1 ratio. The trial design incorporated response-adaptive randomization, which was intended to adjust assignment probabilities to favor more effective treatments after 300 patients were enrolled.
• Blinding: The trial drugs were identical in appearance, packaging, and administration to maintain blinding for patients, clinicians, and investigators.

The authors noted several limitations that provide important context for the results:

• Early Stoppage for Futility: The trial was stopped after a planned interim analysis concluded there was only a 1% chance of identifying a superior or inferior treatment if enrollment continued.
• Clinical Outcome Assessment: The primary outcome was based on clinical observation of seizures and responsiveness, not electroencephalography (EEG). This makes it difficult to distinguish postictal sedation from ongoing non-convulsive status epilepticus in some patients who failed to meet the primary outcome.
• Inclusion of Non-Epileptic Seizures: A retrospective review by a clinical phenomenology core determined that 10% of enrolled patients had psychogenic nonepileptic seizures.
• Fosphenytoin Dosing: The 10-minute infusion constraint limited the maximum dose of fosphenytoin to 1500 mgPE, which may be a submaximal dose for patients weighing over 75 kg.
• Protocol Deviations: Due to the emergency setting, 27% of enrollments had deviations from eligibility criteria, primarily related to the timing or dosage of the initial benzodiazepine treatment. However, a per-protocol analysis yielded results consistent with the primary intention-to-treat analysis.

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1905795