A randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of adjunctive cenobamate in Asian patients with focal seizures

Abstract

Objectives: This randomized, double-blind, placebo-controlled study (NCT04557085), conducted in China, Japan, and the Republic of Korea, evaluated the efficacy and safety of adjunctive cenobamate in patients with uncontrolled focal seizures. Methods: Adults 18-70 years of age with >= 8 seizures (focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic) during an 8-week baseline, despite treatment with 1-3 antiseizure medications (ASMs), were randomized 1:1:1:1 to placebo or cenobamate 100, 200, or 400 mg/day. The study included an 18-week titration phase and a 6-week maintenance phase. The primary efficacy analysis was a hierarchical step-down comparison of the percent change from baseline in 28-day seizure frequency vs placebo during the maintenance phase for cenobamate 200, then 400, and then 100 mg/day. Results: Among 519 patients randomized, 446 received >= 1 dose of study drug and had >= 1 efficacy measure during the maintenance phase (placebo, n = 117; 100 mg/day, n = 113; 200 mg/day, n = 113; and 400 mg/day, n = 103). Median percent change in seizure frequency during the maintenance phase was -25.9% for placebo vs -42.6%, -78.3%, and -100% for cenobamate 100, 200, and 400 mg/day, respectively (all p&apos;s < .001). During the 12-week period encompassing the last 6 weeks of titration and the 6-week maintenance phase (secondary outcome), the median percent change in seizure frequency was -20.1% for placebo vs -42.6%, -77.1%, and -89.2% for cenobamate 100, 200, and 400 mg/day, respectively. Seizure-free rates during the maintenance phase were 2.6% of patients for placebo vs 12.4%, 30.1%, and 52.4% for cenobamate 100, 200, and 400 mg/day, respectively, and during the 12-week period were 0.8% for placebo vs 8.5%, 19.7%, and 30.6% for the cenobamate groups. The most common treatment-emergent adverse events in cenobamate patients (>= 20%) were dose-related dizziness and somnolence. Significance: Cenobamate 100, 200, and 400 mg/day reduced focal seizures in Asian patients in a dose-related fashion and was generally well tolerated.