title: Efficacy and safety of perampanel in patients with drug-resistant partial seizures after conversion from double-blind placebo to open-label perampanel.
abstract: OBJECTIVE
  To evaluate the efficacy and safety of perampanel in patients with drug-resistant partial seizures after the conversion from double-blind placebo in three phase III studies to open-label perampanel, and to assess the impact of perampanel titration rates through a comparison of weekly vs biweekly dose increases.
  
  
  METHODS
  Patients who completed the three multinational, double-blind, placebo-controlled, phase III core studies (studies 304, 305, or 306) were eligible to enroll in the extension study (study 307). Patients completing the double-blind treatment (6-week titration, 13-week maintenance) with placebo (DB-PBO) or perampanel (DB-PER) began the extension study with a 16-week blinded conversion period, during which DB-PBO patients were switched to perampanel. Doses were titrated in 2-mg increments (biweekly) to an individualized maximum tolerated dose of perampanel (up to 12 mg/day). Patients then entered a planned, open-label treatment period.
  
  
  RESULTS
  Perampanel treatment during the extension study reduced total seizure frequency/28 days relative to the double-blind prerandomization baseline regardless of prior perampanel or placebo treatment in the core studies. In the DB-PBO patients, median percent reductions in seizure frequency at the end of the double-blind period, at the end of the conversion period, and at Weeks 40-52 in the open-label maintenance period were 18.6%, 44.3%, and 55.0%, respectively. Seizure control was also improved in the DB-PER patients during the extension period compared to the end of the double-blind period. Responder rates were similar between the 2 patient groups at the end of the conversion period. Perampanel was well tolerated, with the most common treatment-emergent adverse events being dizziness, somnolence, weight increase, irritability, fatigue, and headache. For those patients randomized to the 12 mg group (DB-PER 12 mg), 78.4% reached the daily dose of 10 or 12 mg by the end of the 6-week titration period of the double-blind phase. By the end of the 16-week conversion period of the extension study, 64.0% of DB-PBO patients reached the daily dose of 10 or 12 mg. Seizure frequency reduction was greater after the first 13-week maintenance period of the extension study in the DB-PBO group compared to patients assigned to DB-PER 12mg during the 13-week maintenance period of the double-blind study.
  
  
  CONCLUSIONS
  Patients who received placebo in the phase III core DB studies and transitioned to perampanel in the open-label extension study (DB-PBO) achieved seizure control at the end of the conversion period similar to that of patients who had been previously exposed to perampanel (DB-PER) as well as comparable safety outcomes. Patients who received perampanel during the core studies and continued with treatment during the extension study (DB-PER) also showed sustained improvements in seizure control with long-term exposure to perampanel.
authors.affiliation: Boston University School of Medicine, Boston, MA, USA. Electronic address: Georgia.Montouris@bmc.org.
authors.forename: Georgia
authors.initials: G
authors.lastname: Montouris
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Woodcliff Lake, NJ, USA. Electronic address: Haichen_Yang@eisai.com.
authors.forename: Haichen
authors.initials: H
authors.lastname: Yang
authors.affiliation: Eisai Medical and Scientific Affairs, Woodcliff Lake, NJ, USA. Electronic address: betsy_williams@eisai.com.
authors.forename: Betsy
authors.initials: B
authors.lastname: Williams
authors.affiliation: Eisai Medical and Scientific Affairs, Woodcliff Lake, NJ, USA. Electronic address: Xiaozheng_Zhou@eisai.com.
authors.forename: Sharon
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Woodcliff Lake, NJ, USA. Electronic address: Antonio_Laurenza@eisai.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Laurenza
authors.affiliation: Eisai Medical and Scientific Affairs, Woodcliff Lake, NJ, USA. Electronic address: randi_fain@eisai.com.
authors.forename: Randi
authors.initials: R
authors.lastname: Fain
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D004311:Double-Blind Method; D000069279:Drug Resistant Epilepsy / Q000188:drug therapy*; D023381:Endpoint Determination; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009570:Nitriles; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D012640:Seizures / Q000517:prevention & control; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel
keywords: Epilepsy; Long-term; Open-label; Partial seizures; Perampanel; Titration