Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: Results from a double‐blind, randomized, placebo‐controlled trial

Summary Purpose Brivaracetam ( BRV ) is a novel high‐affinity synaptic vesicle protein 2 A ligand in clinical development for the treatment of epilepsy. This phase III study ( N 01252; NCT 00490035) evaluated the efficacy and safety/tolerability of BRV (20, 50, and 100 mg/day) compared with placebo ( PBO ) in patients aged 16–70 years with uncontrolled focal seizures with/without secondary generalization, despite treatment with one to two concomitant antiepileptic drugs at a stable and optimal dosage. Methods This was a double‐blind, randomized, placebo‐controlled trial conducted across E urope and I ndia. Eligible patients had two or more focal seizures/month for 3 months prior to screening and eight or more focal seizures during the 8‐week prospective baseline. Concomitant use of levetiracetam was limited to 20% of randomized patients. Patients were randomized (1:1:1:1) to BRV 20, 50, 100 mg/day or PBO with no up‐titration for 12 weeks, followed by down‐titration or entry into a long‐term follow‐up study. The primary efficacy end point was percent reduction over PBO in baseline‐adjusted focal seizure frequency/week over the 12‐week treatment period. Comparison of BRV with PBO was sequential to control for multiplicity (50, 100, 20 mg/day), and thus required BRV to demonstrate superiority over PBO at 50 mg/day to meet the primary efficacy end point. Secondary efficacy variables were median percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate, and seizure freedom (all seizure types). Safety assessments included treatment‐emergent adverse events ( TEAE s). Key Findings Of 399 randomized patients, 398 were included in the intent‐to‐treat ( ITT ) and safety populations. Overall, 367 (92.2%) of 398 patients completed the study ( BRV : 93.9%, 88.9%, and 94.0% for 20, 50, and 100 mg/day, respectively; PBO : 92.0%) and 345 (86.7%) of 398 patients continued into long‐term follow‐up studies ( BRV : 87.9%, 82.8%, and 88.0% for 20, 50, and 100 mg/day, respectively; PBO : 88.0%). The study did not meet its primary efficacy end point based on the predefined sequential testing strategy. Indeed, percent reduction over PBO in baseline‐adjusted focal seizure frequency/week (primary efficacy analysis) was 6.8% (p = 0.239), 6.5% (p = 0.261), and 11.7% (p = 0.037) for BRV 20, 50, and 100 mg/day, respectively. Median percent reduction from baseline in focal seizure frequency/week was 30.0% (p = 0.019), 26.8% (p = 0.092), and 32.5% (p = 0.004) for BRV 20, 50, and 100 mg/day, respectively, compared with 17.0% for PBO . Responder rates (≥50%) were 27.3% (p = 0.339), 27.3% (p = 0.372), and 36.0% (p = 0.023) for BRV 20, 50, and 100 mg/day, respectively, compared with 20.0% for PBO . Complete seizure freedom was reported by 2/99, 0/99, and 4/100 patients on BRV 20, 50, and 100 mg/day, respectively, compared with 0/100 on PBO . The incidence of TEAE s was higher for BRV 20 (56/99, 56.6%), 50 (62/99, 62.6%), and 100 mg/day (63/100, 63.0%) than PBO (53/100, 53.0%); most TEAE s were mild or moderate in severity. The most frequently reported TEAE s in the BRV groups were headache, somnolence, dizziness, and fatigue. Significance In this study of adjunctive BRV (20–100 mg/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50 mg/day dose was not statistically significant. However, BRV 100 mg/day reduced baseline‐adjusted focal seizure frequency/week by 11.7% over PBO , achieving statistical significance (p = 0.037). Secondary efficacy analyses (percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate) provided supportive evidence for the efficacy of BRV 100 mg/day. BRV 20–100 mg/day was well tolerated without up‐titration, with a high completion rate.