Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304

Abstract

Objective: To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, when added to concomitant antiepileptic drugs (AEDs) in the treatment of drug-resistant partial-onset seizures.

Methods: This was a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00699972). Patients (≥12 years, with ongoing seizures despite 1-3 AEDs) were randomized (1:1:1) to once-daily perampanel 8 mg, 12 mg, or placebo. Following baseline (6 weeks), patients entered a 19-week double-blind phase: 6-week titration (2 mg/week increments to target dose) followed by a 13-week maintenance period. Percent change in seizure frequency was the primary endpoint; 50% responder rate was the primary endpoint for EU registration.

Results: Of 388 patients randomized and treated, 387 provided seizure frequency data. Using this intent-to-treat population over the double-blind phase, the median percent change in seizure frequency was -21.0%, -26.3%, and -34.5% for placebo and perampanel 8 and 12 mg, respectively (p = 0.0261 and p = 0.0158 for 8 and 12 mg vs placebo, respectively). Fifty percent responder rates during the maintenance period were 26.4%, 37.6%, and 36.1%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg; these differences were not statistically significant for 8 mg (p = 0.0760) or 12 mg (p = 0.0914). Sixty-eight (17.5%) patients discontinued, including 40 (10.3%) for adverse events. Most frequent treatment-emergent adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia.

Conclusions: This trial demonstrated that once-daily, adjunctive perampanel at doses of 8 or 12 mg improved seizure control in patients with uncontrolled partial-onset seizures. Doses of perampanel 8 and 12 mg were safe, and tolerability was acceptable.

Classification of evidence: This study provides Class I evidence that once-daily 8 and 12 mg doses of adjunctive perampanel are effective in patients with uncontrolled partial-onset seizures.

Figures

Figure 1. Patient flow

a Patients who signed informed consent forms. b Includes 3 patients who were screen failures and were inappropriately randomized to a treatment group. c One patient was treated for 1 day and did not complete a seizure diary that day. Admin = administrative; INC/EXC = inclusion/exclusion; ITT = intent-to-treat.

Figure 2. Median percentage change and responder rates

(A) Median percentage change in seizure frequency per 28 days (ITT population). (B) Responder rates (percentage of patients achieving a ≥50% reduction in seizure frequency, ITT population). *vs placebo. ITT = intent-to-treat; NS = not significant.