Abstracts

Rationale: Introduction: Many patients with epilepsy experience acute repetitive seizures (ARS) which can evolve into status epilepticus if not treated promptly. An intra-muscular auto-injector of diazepam has been developed that can be administered by a patient's family or caregiver to treat ARS (Fig 1). Rationale: To evaluate the efficacy and safety of a diazepam auto-injector administered by family or caregivers, for the management of patients with epilepsy who require intermittent treatment to control episodes of ARS. Methods: In a Phase 3, randomized, double-blind, parallel, placebo-controlled, multicenter study, with an optional open-label continuation, patients were randomized to either placebo or diazepam auto-injector. Patients were stratified according to age group (2-5, 6-11, ≥12 yrs), and assigned dose (5 mg, 10 mg, 15 mg, or 20 mg) based on age and weight range. The primary endpoint was time to next seizure or rescue from 15 min to 12 h post-dose. Secondary endpoints included frequency of rescue events, numbers of seizures experienced post-dose, caregiver and physician treatment assessments, and safety. Results: Patients (n=234) were randomized to receive placebo or diazepam auto-injector, of whom 81/110 patients in the placebo and 82/124 patients in the diazepam auto-injector were included in the intent to treat group. Baseline characteristics were similar for the placebo and diazepam auto-injector groups. The time to next seizure or rescue showed statistically significant favorable results for diazepam over placebo auto-injector group (Fig 2). The 25th percentile for time to the next seizure was 1.18 hrs for placebo and 2.70 hrs for the diazepam auto-injector groups. Median time to event was inestimable for diazepam due to low number of events in the diazepam auto-injector group. Hazard ratio (diazepam vs. placebo, adjusted for age group) and 95% CI for an endpoint was 0.55 (0.34 to 0.88, p=0.012). Rescue medication post-dose occurred in 30% (24/81) placebo vs. 17% (14/82) diazepam auto-injector group (p=0.066). A statistically significant reduction in the number of seizures for diazepam compared to placebo auto-injector group during the 12-h post-dose period was observed (median 1.0 seizures placebo, 0.0 seizures diazepam, p=0.010). Treatment-emergent adverse events were reported in 43% (34/79) of placebo and 42% (34/81) diazepam auto-injector patients. The most common AEs were injection site pain, 14% placebo / 17% diazepam auto-injector group and injection site hemorrhage, 6% placebo/ 5% diazepam auto-injector group. Conclusions: The diazepam auto-injector was significantly more effective than placebo at delaying the time to next seizure or rescue. Secondary efficacy endpoints were supportive of this primary result. Family or caregiver administered diazepam auto-injector was an effective and well tolerated treatment with AEs similar to placebo.