title: A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures.
abstract: OBJECTIVE
  Brivaracetam (BRV), a selective and high-affinity synaptic vesicle protein 2A ligand, is in development as adjunctive treatment for partial-onset (focal) seizures (POS). This phase 3 study (N01358; NCT01261325) aimed to confirm the efficacy and safety/tolerability of BRV in adults (≥ 16-80 years) with POS.
  
  
  METHODS
  This randomized, double-blind, placebo-controlled, multicenter study enrolled patients with uncontrolled POS despite ongoing treatment with 1-2 antiepileptic drugs. Patients exposed to levetiracetam ≤ 90 days before visit 1 were excluded. Patients entered an 8-week prospective baseline period, followed by a 12-week treatment period when they were randomized 1:1:1 to placebo (PBO), BRV 100 mg/day, or BRV 200 mg/day, started without up-titration. The co-primary efficacy outcomes were percent reduction over placebo in 28-day adjusted POS frequency, and ≥ 50% responder rate based on percent reduction in POS frequency from baseline to the treatment period.
  
  
  RESULTS
  Seven hundred sixty-eight patients were randomized; 760 were included in the efficacy analysis: 259, 252, and 249 in PBO, BRV 100 mg/day, and BRV 200 mg/day groups, respectively. Percent reduction over PBO in 28-day adjusted seizure frequency (95% confidence interval [CI]) was 22.8% for BRV 100 mg/day (13.3-31.2%; p < 0.001) and 23.2% for BRV 200 mg/day (13.8-31.6%; p < 0.001). The ≥ 50% responder rate (odds ratio vs. PBO; 95% CI) was 21.6% for PBO, 38.9% for BRV 100 mg/day (2.39; 1.6-3.6; p < 0.001), and 37.8% for BRV 200 mg/day (2.19; 1.5-3.3; p < 0.001). Treatment-emergent adverse events (TEAEs) occurred in 155 (59.4%) of 261 PBO patients versus 340 (67.6%) of 503 BRV-treated patients (safety population). Discontinuation rates due to TEAEs were 3.8%, 8.3%, and 6.8% for PBO, BRV 100 mg/day, and BRV 200 mg/day, respectively. Most frequent TEAEs (PBO versus BRV) were somnolence (7.7% vs. 18.1%), dizziness (5.0% vs. 12.3%), and fatigue (3.8% vs. 9.5%).
  
  
  CONCLUSIONS
  Adjunctive BRV 100 and 200 mg/day was efficacious in reducing POS in adults without concomitant levetiracetam use and was well tolerated.
authors.affiliation: Mid-Atlantic Epilepsy and Sleep Center, Bethesda, Maryland, U.S.A.
authors.forename: Pavel
authors.initials: P
authors.lastname: Klein
authors.affiliation: UCB Pharma, Raleigh, North Carolina, U.S.A.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Schiemann
authors.affiliation: Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sperling
authors.affiliation: UCB Pharma, Raleigh, North Carolina, U.S.A.
authors.forename: John
authors.initials: J
authors.lastname: Whitesides
authors.affiliation: UCB Pharma, Raleigh, North Carolina, U.S.A.
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.affiliation: UCB Pharma, Raleigh, North Carolina, U.S.A.
authors.forename: Tracy
authors.initials: T
authors.lastname: Stalvey
authors.affiliation: Bethel Epilepsy Centre, Mara Hospital, Bielefeld, Germany.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0001-8666-1640
authors.initials: C
authors.lastname: Brandt
authors.affiliation: University of Melbourne and Royal Melbourne Hospital, Parkville, Victoria, Australia.|Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kwan
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D011760:Pyrrolidinones / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D011760:Pyrrolidinones; C482793:brivaracetam
keywords: Brivaracetam; Efficacy; Focal epilepsy; Partial-onset seizures; Phase 3; Safety/tolerability