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Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: Results of a phase III , double‐blind, randomized, placebo‐controlled, flexible‐dose trial
Author(s) -
Kwan Patrick,
Trinka Eugen,
Paesschen Wim,
Rektor Ivan,
Johnson Martin E.,
Lu Sarah
Publication year - 2014
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12391
Subject(s) - tolerability , discontinuation , epilepsy , medicine , adverse effect , placebo , adjunctive treatment , randomized controlled trial , anesthesia , somnolence , pediatrics , psychiatry , alternative medicine , pathology
Summary Purpose To evaluate the safety and tolerability of adjunctive brivaracetam ( BRV ), a high‐affinity synaptic vesicle protein 2 A ( SV 2 A ) ligand, in adults with uncontrolled epilepsy. Efficacy was also assessed in patients with focal seizures as a secondary objective, and explored by descriptive analysis in patients with generalized seizures. Methods This was a phase III , randomized, double‐blind, placebo ( PBO )‐controlled flexible dose trial ( N 01254/ NCT 00504881) in adults (16–70 years) with uncontrolled epilepsy (up to 20% could be patients with generalized epilepsy). After a prospective 4‐week baseline, patients were randomized (3:1) to b.i.d. BRV or PBO , initiated at 20 mg/day and increased, as needed, to 150 mg/day during an 8‐week dose‐finding period. This was followed by an 8‐week stable‐dose maintenance period. The treatment period comprised the dose‐finding period plus the maintenance period (16 weeks). Key Findings A total of 480 patients were randomized ( BRV 359, PBO 121); of these, 431 had focal epilepsy and 49 had generalized epilepsy. Ninety percent BRV ‐ and 91.7% PBO ‐treated patients completed the study. Similar proportions of patients ( BRV 66.0%, PBO 65.3%) reported adverse events ( AE s) during the treatment period. AE s led to treatment discontinuation in 6.1% and 5.0% of BRV ‐ and PBO ‐treated patients, respectively. The incidence of AE s declined from the dose‐finding ( BRV 56.0%, PBO 55.4%) to the maintenance ( BRV 36.8%, PBO 40.9%) period. The most frequent AE s during the treatment period were headache ( BRV 14.2% vs. PBO 19.8%), somnolence ( BRV 11.1% vs. PBO 4.1%), and dizziness ( BRV 8.6% vs. PBO 5.8%). The incidence of psychiatric AE s was similar for BRV and PBO ( BRV 12.3%, PBO 11.6%). In patients with focal seizures, the baseline‐adjusted percent reduction in seizure frequency/week in the BRV group (n = 323) over PBO (n = 108) was 7.3% (p = 0.125) during the treatment period. The median percent reduction in baseline‐adjusted seizure frequency/week was 26.9% BRV versus 18.9% PBO (p = 0.070), and the ≥50% responder rate was 30.3% BRV versus 16.7% PBO (p = 0.006). In patients with generalized seizures only, the number of seizure days/week decreased from 1.42 at baseline to 0.63 during the treatment period in BRV ‐treated patients (n = 36), and from 1.47 at baseline to 1.26 during the treatment period in PBO ‐treated patients (n = 13). The median percent reduction from baseline in generalized seizure days/week was 42.6% versus 20.7%, and the ≥50% responder rate was 44.4% versus 15.4% in BRV ‐treated and PBO ‐treated patients, respectively. Significance Adjunctive BRV given at individualized tailored doses (20–150 mg/day) was well tolerated in adults with uncontrolled epilepsy, and our results provided support for further evaluation of efficacy in reducing focal and generalized seizures.