Abstract
Objective
Alprazolam administered via the Staccato® breath-actuated device is delivered into deep lung for rapid systemic exposure and is a potential therapy for rapid epileptic seizure termination (REST). We conducted an inpatient study (ENGAGE-E-001 [NCT03478982]) in patients with stereotypic seizure episodes with prolonged or repetitive seizures to determine whether Staccato® alprazolam rapidly terminates seizures in a small observed population after administration under direct supervision.
Methods
Adult patients with established diagnosis of focal and/or generalized epilepsy with a documented history of seizure episodes with a predictable pattern were enrolled. They were randomized 1:1:1 to double-blind treatment of a single seizure event with one dose of Staccato® alprazolam 1.0 mg or 2.0 mg, or Staccato® placebo in an inpatient unit. The primary endpoint of the study was the proportion of responders in each treatment group achieving seizure activity cessation within 2 mins after administration of study drug and no recurrence of seizure activity within 2 hours.
Results
A total of 273 patients were screened, and 116 randomized patients received treatment with study drug in the double-blind part. The proportion of treated patients who were responders was 65.8% for each of Staccato® alprazolam 1.0 mg (n=38; P=.0392) and 2.0 mg (n=38; P=.0392), compared with 42.5% for Staccato® placebo (n=40). Staccato® alprazolam was well tolerated when administered as a single dose of 1.0 or 2.0 mg: cough and somnolence were the most common adverse events (AEs) (both 14.5%), followed by dysgeusia (13.2%). AEs were mostly mild or moderate in intensity with no treatment-related serious AEs.
Significance
Both 1.0 mg and 2.0 mg doses of Staccato® alprazolam demonstrated efficacy in rapidly terminating seizures in an inpatient setting and were well tolerated. The next step is a Phase 3 confirmatory study to demonstrate efficacy and safety of Staccato® alprazolam for rapid cessation of seizures in an outpatient setting.
OCT