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
Top Cited Papers
Open Access
- 16 October 2015
- Vol. 56 (12), 1890-1898
- https://doi.org/10.1111/epi.13212
Abstract
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. 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. 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%). Adjunctive BRV 100 and 200 mg/day was efficacious in reducing POS in adults without concomitant levetiracetam use and was well tolerated.Keywords
Funding Information
- Eisai
- GlaxoSmithKline
This publication has 19 references indexed in Scilit:
- Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial‐onset seizures: A phase IIb, randomized, controlled trialEpilepsia, 2012
- Patterns of treatment response in newly diagnosed epilepsyNeurology, 2012
- Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: Relationship to anti-convulsant propertiesEuropean Journal of Pharmacology, 2011
- Modern antiepileptic drug development has failed to deliver: Ways out of the current dilemmaEpilepsia, 2011
- Adjunctive brivaracetam for refractory partial-onset seizuresNeurology, 2010
- Estimation of the burden of active and life‐time epilepsy: A meta‐analytic approachEpilepsia, 2010
- Anti‐convulsive and anti‐epileptic properties of brivaracetam (ucb 34714), a high‐affinity ligand for the synaptic vesicle protein, SV2ABritish Journal of Pharmacology, 2008
- SV2A protein is a broad-spectrum anticonvulsant target: Functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsyNeuropharmacology, 2007
- Discovery of 4-Substituted Pyrrolidone Butanamides as New Agents with Significant Antiepileptic ActivityJournal of Medicinal Chemistry, 2003
- Early Identification of Refractory EpilepsyNew England Journal of Medicine, 2000