Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures

Abstract

Objective: To evaluate the efficacy and safety of adjunctive cenobamate 200 mg/d in patients with uncontrolled focal (partial-onset) seizures despite treatment with 1 to 3 antiepileptic drugs.

Methods: In this multicenter, double-blind, placebo-controlled study, adults 18 to 65 years of age with focal seizures were randomized 1:1 (cenobamate:placebo) after an 8-week baseline period. The 12-week double-blind treatment period consisted of a 6-week titration phase and a 6-week maintenance phase. The primary outcome was percent change in seizure frequency (from baseline) per 28 days during double-blind treatment.

Results: Two hundred twenty-two patients were randomized; 113 received cenobamate and 109 received placebo; and 90.3% and 90.8% of patients, respectively, completed double-blind treatment. Median baseline seizure frequency was 6.5 in 28 days (range 0-237). Compared to placebo, cenobamate conferred a greater median percent seizure reduction (55.6% vs 21.5%; p < 0.0001) The responder rate (≥50% reduction in seizure frequency) was 50.4% for cenobamate and 22.2% for placebo (p < 0.0001). Focal seizures with motor component, impaired awareness, and focal to bilateral tonic-clonic seizures were significantly reduced with cenobamate vs placebo. During maintenance, 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure-free. Treatment-emergent adverse events reported in >10% in either group (cenobamate vs placebo) were somnolence (22.1% vs 11.9%), dizziness (22.1% vs 16.5%), headache (12.4% vs 12.8%), nausea (11.5% vs 4.6%), and fatigue (10.6% vs 6.4%).

Conclusion: Adjunctive treatment with cenobamate 200 mg/d significantly improved seizure control in adults with uncontrolled focal seizures and was well tolerated.

Clinicaltrialsgov identifier: NCT01397968.

Classification of evidence: This study provides Class I evidence that, for patients with uncontrolled focal seizures, adjunctive cenobamate reduces seizures.

Figure 1. Patient disposition

ITT = intention-to-treat.

Figure 2. Median percent reduction in seizure frequency from baseline and ≥50% responder rates (ITT population)

(A) Median percent reduction in seizure frequency normalized to 28-day rate. (B) Responder rates during the double-blind period. Responder defined as ≥50 reduction in seizure frequency. ITT = intention-to-treat.

Figure 3. Median percent reduction for focal seizure types (ITT population)

ITT = intention-to-treat. Seizure frequency normalized to 28-day rate.

Figure 4. Post hoc responder rates during the maintenance phase

(A) Responder rates during the 6-week maintenance phase (intention-to-treat population who took ≥1 dose of study drug during the maintenance phase n = 208). (B) Responder rates during the 6-week maintenance phase (completer population n = 201). Responder defined as ≥75%, 90%, or 100% reduction in seizure frequency during the maintenance phase. CI = confidence interval; OR = odds ratio.

Figure 5. Median percent reduction from baseline in seizure frequency per 28 days over sequential 4-week intervals (completer population)

*p = 0.001, **p < 0.001 vs placebo.