Evaluation of adjunctive perampanel in patients with refractory partial‐onset seizures: Results of randomized global phase III study 305

Abstract

SUMMARYPurpose: To assess the efficacy and safety of once-daily doses of perampanel 8 and 12 mg when added to 1-3 concomitantly administered, approved antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. Methods: Study 305 was a multicenter, double-blind, placebo-controlled trial in patients aged 12 years and older with ongoing seizures despite prior therapy with at least two AEDs, and currently receiving 1-3 AEDs. Equal randomization to once-daily oral perampanel 8 or 12 mg, or placebo was performed. Patients entered a 19-week double-blind treatment phase comprising a 6-week titration period, with weekly 2-mg dose increments, followed by a 13-week maintenance period. Primary efficacy end points were the responder rate (proportion of patients who had a ‡50% reduction in seizure frequency during treatment per 28 days relative to baseline), and the percent change in seizure frequency per 28 days relative to pre-perampanel baseline. A secondary end point was percent change in the frequency of complex partial plus secondarily generalized seizures. Adverse events (AEs) were monitored throughout the study. Key Findings: Three hundred eighty-six patients were randomized and treated with study medication. Of these, 321 patients completed the study. The 50% responder rates (intent-to-treat analysis) were 14.7%, 33.3%, and 33.9%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg, with significant improvements over placebo for both perampanel 8 mg (p = 0.002) and 12 mg (p < 0.001). The median percent change from baseline in seizure frequency per 28 days (intent-to-treat analysis) was )9.7%, )30.5%, and )17.6% for placebo, 8 mg, and 12 mg, respectively, with significant reductions compared with placebo for both 8 mg (p < 0.001) and 12 mg (p = 0.011). For complex partial seizures plus partial seizures that secondarily generalized, the median percent change in frequency was )32.7% (8 mg), )21.9 (12 mg), and )8.1% (placebo), with significant reductions for both 8 mg (p < 0.001) and 12 mg (p = 0.005). The most frequent (occurring in ‡10% of patients in any treatment group) treatment-emergent AEs were dizziness, somnolence, fatigue, and headache, with an apparent dose effect suggested for all except headache. Significance: This phase III trial demonstrated that adjunctive treatment with once-daily perampanel at 8 mg and 12 mg was effective in improving seizure control in patients 12 years and older with refractory partial-onset seizures. These study results also demonstrated that once-daily doses of 8 mg and 12 mg were safe and acceptably tolerated in this study. Perampanel demonstrated a favorable risk/benefit ratio in this population.

Review of clinical studies of perampanel in adolescent patients

“…The two other trials, studies 304 and 305, had identical methodology and assessed the higher daily doses of 8 and 12 mg (French et al. 2012, 2013). Study 307 (NCT00735397) was an open‐label extension study of patients completing the double‐blind phase of the three pivotal phase 3 trials (Krauss et al.…”

“…2012, 2013; Krauss et al. 2012), primary efficacy endpoints were median percentage change in frequency of all partial seizures per 28 days (baseline vs. double‐blind phase) and percentage of patients achieving a  ≥ 50% reduction in the frequency of all partial seizures per 28 days (50% responder rate; baseline vs. maintenance phase).…”

“…Consistent with the pivotal phase 3 trials (French et al. 2012, 2013; Krauss et al. 2012), perampanel had a favorable tolerability profile in adolescent patients with refractory partial‐onset seizures over the longer term.…”

Perampanel efficacy and safety by gender: Subanalysis of phase III randomized clinical studies in subjects with partial seizures

“…All studies were conducted in accordance with the Helsinki Declaration, European Medicines Agency requirements, and the U.S. Code of Federal Regulations, as appropriate. All subjects provided written informed consent prior to participation 4, 5, 6…”

“…During the titration period, perampanel doses were increased weekly by 2‐mg increments until the randomized dose or intolerability was reached. Subjects received ongoing treatment with stable doses of 1–3 concomitant AEDs, with only one enzyme‐inducing AED (EIAED) permitted 5, 9…”