Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307

Abstract

Objective: To evaluate safety, tolerability, seizure frequency, and regional variations in treatment responses with the AMPA antagonist, perampanel, in a large extension study during up to 3 years of treatment.

Methods: Patients ≥ 12 years old with partial-onset seizures despite treatment with 1-3 antiepileptic drugs at baseline completed a perampanel phase III trial and entered extension study 307 (NCT00735397). Patients were titrated to 12 mg/day (or their individual maximum tolerated dose) during the blinded conversion period, followed by open-label maintenance. Exposure, safety (adverse events [AEs], vital signs, weight, electrocardiography [ECG], laboratory values) and seizure outcomes were analyzed; key measures were assessed by geographic regions.

Results: Among 1,216 patients, median exposure was 1.5 years (range 1 week to 3.3 years), with >300 patients treated for >2 years. Treatment retention was 58.5% at cutoff. AEs reported in ≥ 10% of patients were dizziness, somnolence, headache, fatigue, irritability, and weight increase. Only dizziness and irritability caused discontinuation in >1% of patients (3.9% and 1.3%, respectively). The only serious AEs reported in >1% of patients were epilepsy-related (convulsion, 3.0%; status epilepticus, 1.1%). No clinically relevant changes in vital signs, ECG or laboratory parameters were seen. After titration/conversion, responder rate and median percentage change from baseline in seizure frequency were stable: 46% for both measures at 9 months (in 980 patients with ≥ 9 months' exposure) and 58% and 60%, respectively, at 2 years (in the 337 patients with 2 years' exposure). Median percentage reduction in frequency of secondarily generalized (SG) seizures ranged from 77% at 9 months (N = 422) to 90% at 2 years (N = 141). Among the 694 patients with maintenance data ≥ 1 year, 5.3% were seizure-free for the entire year.

Significance: No new safety signals emerged during up to 3 years of perampanel exposure in 39 countries. Seizure responses remained stable, with marked reductions, particularly in SG seizures.

Keywords: AMPA receptor; Antagonist; Antiepilepsy drugs; Epilepsy; Seizure freedom.

Figure 1

Kaplan–Meier curve of retention, by previous treatment group in the core studies. Survival probability (patients ongoing as a proportion of the patients at risk [patients at risk determined by study entry and data cutoff]) assessed by previous treatment group. Study time is shown in weeks on the x-axis; exposure to perampanel began at week 0 for patients randomized to perampanel treatment in the core studies, and from week 19 for patients randomized to placebo in the core studies. Patients who did not enter the extension are censored at the end of the 19-week core study (vertical lines), and patients who were ongoing at time of cutoff are also censored (vertical lines, at the corresponding exposure duration they had reached). PER, perampanel; PBO, placebo.

Figure 2

Reasons for discontinuations during perampanel treatment duration. Discontinuations during extension study conversion period (weeks 1–16) and in 13-week periods during maintenance are shown for the safety group (N = 1,216; all patients who received at least one dose of perampanel in the extension and had at least one post-dose safety assessment in the extension). Other includes “lost to follow-up,” “missing,” and “admin/other.” AEs, adverse events.

Figure 3

Seizure outcomes for each 13-week period from first exposure to perampanel, by treatment duration cohort. Perampanel treatment duration starts from first perampanel exposure, either in the core study or extension, except for patients with a gap in perampanel exposure of >14 days between the core study and the extension, for whom duration is based on the extension study. (A) Responder rate (percentage of patients with ≥50% reduction in seizure frequency/28 days from pre-perampanel baseline); (B) median percentage change in seizure frequency from pre-perampanel baseline; and (C) median percentage change in SG seizure frequency from pre-perampanel baseline in patients with SG seizures during baseline. Analysis carried out in all patients who received at least one dose of perampanel in the extension and had valid seizure data during perampanel treatment (either core study or extension). SG, secondarily generalized.

Figure 4

Responder rate during perampanel treatment duration, overall and by region. Responder rate (percentage of patients with ≥50% reduction in seizure frequency/28 days from pre-perampanel baseline), by 13-week exposure periods. Perampanel treatment duration starts from first perampanel exposure, either in the core study or extension, except for patients with a gap in perampanel exposure of >14 days between the core study and the extension, for whom duration is based on the extension study. Analysis carried out in all patients who received at least one dose of perampanel in the extension and had valid seizure data during perampanel treatment (either core study or extension). EMEA, Europe, Middle East, and Africa.