title: Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies.
abstract: OBJECTIVE
  Three phase III studies (304 [ClinicalTrials.gov identifier: NCT00699972], 305 [NCT00699582], 306 [NCT00700310]) evaluated perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, as adjunctive therapy for refractory partial seizures. We report post hoc analyses of pooled study data by randomized dose.
  
  
  METHODS
  Patients with partial seizures despite receiving 1-3 antiepileptic drugs were randomized to once-daily placebo, perampanel 8 or 12 mg (studies 304, 305), or placebo, perampanel 2, 4, or 8 mg (study 306). Studies included a 6-week baseline period and double-blind treatment phase (6-week titration; 13-week maintenance). Primary end points were median change in partial seizure frequency (baseline vs. double-blind phase) and percentage of patients achieving ≥ 50% reduction in seizure frequency (baseline vs. maintenance). Here, these end points, together with secondary, exploratory, and safety end points, were assessed using pooled study data.
  
  
  RESULTS
  The pooled intent-to-treat analysis set (randomized, treated patients with any seizure data) included 1,478 patients. Median changes in partial seizure frequency were greater with perampanel than placebo (perampanel 4 mg, -23.3%; 8 mg, -28.8%; 12 mg, -27.2%; placebo, -12.8%; p < 0.01, each dose vs. placebo), as were 50% responder rates (perampanel 4 mg, 28.5%; 8 mg, 35.3%; 12 mg, 35.0%; placebo, 19.3%; p < 0.05, each dose vs. placebo). In addition, median changes in complex partial plus secondary generalized seizure frequency were also greater with perampanel than placebo (perampanel 4 mg, -31.2%; 8 mg, -35.6%; 12 mg, -28.6%; placebo, -13.9%). Perampanel was generally well tolerated. The most frequent treatment-emergent adverse events (TEAEs) were dizziness, somnolence, and headache. Most TEAEs were mild/moderate; relatively few patients experienced severe TEAEs (placebo, 5.4%; perampanel, 8.9%) or serious TEAEs (placebo, 5.0%; perampanel, 5.5%). There were no deaths and no clinically important mean changes in laboratory values, electrocardiography (ECG) findings, or vital signs.
  
  
  CONCLUSIONS
  Perampanel reduced partial seizure frequency and improved responder rates compared with placebo, with an acceptable tolerability profile.
authors.affiliation: Kork Epilepsy Center, Kehl-Kork, Germany.
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Steinhoff
authors.forename: Elinor
authors.initials: E
authors.lastname: Ben-Menachem
authors.forename: Philippe
authors.initials: P
authors.lastname: Ryvlin
authors.forename: Simon
authors.initials: S
authors.lastname: Shorvon
authors.forename: Lynn
authors.initials: L
authors.lastname: Kramer
authors.forename: Andrew
authors.initials: A
authors.lastname: Satlin
authors.forename: David
authors.initials: D
authors.lastname: Squillacote
authors.forename: Haichen
authors.initials: H
authors.lastname: Yang
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Antonio
authors.initials: A
authors.lastname: Laurenza
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011728:Pyridones / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel
keywords: Antiepileptic drugs; Epilepsy; Glutamate; Perampanel; Pooled analysis