Intranasal midazolam vs mouth-dissolving clobazam in terminating seizures: A randomized controlled trial

Acute seizure crises, such as prolonged seizures and impending status epilepticus, need prompt out-of-hospital treatment with benzodiazepines. However, efficacious and easily administered rescue medications are grossly underutilized and form an unmet need in management paradigms. The aim of the current study was to compare the efficacy of mouth-dissolving clobazam with intranasal midazolam in terminating seizures in the epilepsy monitoring unit (EMU).

A single-center, prospective, randomized, open blinded end point (PROBE) trial was conducted over a period of 1.5 years. Patients with drug-resistant epilepsy (DRE) having clobazam as one of the polytherapy agents were enrolled prospectively into the study. They were randomized to receive either intranasal midazolam or mouth-dissolving clobazam if they had prolonged seizures lasting more than 2 min. Time to clinical and electrographic termination of seizures was the primary outcome. Adverse effects or injury, treatment failure, seizure recurrence, and treatment satisfaction were secondary outcomes.

Ninety-five patients were enrolled in the study: 47 in the intranasal midazolam group, and 48 in mouth dissolving clobazam group. The Cox proportional hazards model suggested hazard ratio [HR]: .39 (.15-1.02) (p = .05), for clinical termination of seizures, and HR: .56 (.23-1.37) (p = .22), for electrographic termination of seizures. The log-rank test suggested no statistically significant difference between two curves with respect to time of termination of clinical (p = .17) and electrographic (p = .39) seizures. There were no significant adverse effects, and treatment failure or seizure recurrence was noted in either arm. Treatment satisfaction did not significantly differ between the two arms.

There was no statistically significant difference between intranasal midazolam and mouth-dissolving clobazam for termination of clinical and electrographic seizures. We propose that mouth-dissolving clobazam merits further research as a reasonably efficacious, convenient, and cost-effective alternative to intranasal midazolam for acute termination of pre-hospital seizures.