Adjunctive perampanel for refractory partial-onset seizures

Abstract

Objective: To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive ␣-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 (Ն12 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 Ϫ21.0%, Ϫ26.3%, and Ϫ34.5% for placebo and perampanel 8 and 12 mg, respectively (p ϭ 0.0261 and p ϭ 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 ϭ 0.0760) or 12 mg (p ϭ 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. Neurology ® 2012;79:589-596 GLOSSARY AE ϭ adverse event; AED ϭ antiepileptic drug; AMPA ϭ ␣-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; ANCOVA ϭ analysis of covariance; CGIC ϭ Clinical Global Impression of Change; CI ϭ confidence interval; EU ϭ European Union; ITT ϭ intent-to-treat; PGIC ϭ Patient Global Impression of Change; QOLIE-31-P ϭ Quality of Life in Epilepsy questionnaire; SAE ϭ serious adverse event; TEAE ϭ treatment-emergent adverse event.Perampanel is an orally active, noncompetitive ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist under development for the treatment of epilepsy. AMPA receptors, a class of ionotropic glutamate receptors, are localized at excitatory synapses in the CNS where they serve as the principal mediators of fast excitatory postsynaptic neurotransmission and are critical to the generation and spread of epileptic activity.

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…”

Not all that glitters is gold: A guide to the critical interpretation of drug trials in epilepsy

“…As a rule, changes in seizure frequency or responder rates in adjunctive therapy are calculated by applying the last‐observation‐carried‐forward (LOCF) analysis 23. In this type of analysis, when patients withdraw prematurely from the trial as a result of adverse events or other reasons, efficacy estimates are calculated by using the seizure outcomes recorded up to the time of exit.…”