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PurposeBrivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand in clinical development for the treatment of epilepsy. This phase III study (N01252; NCT00490035) evaluated the efficacy and safety/tolerability of BRV (20, 50, and 100mg/day) compared with placebo (PBO) in patients aged 16-70years with uncontrolled focal seizures with/without secondary generalization, despite treatment with one to two concomitant antiepileptic drugs at a stable and optimal dosage. MethodsThis was a double-blind, randomized, placebo-controlled trial conducted across Europe and India. Eligible patients had two or more focal seizures/month for 3months 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, 100mg/day or PBO with no up-titration for 12weeks, 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, 20mg/day), and thus required BRV to demonstrate superiority over PBO at 50mg/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 (TEAEs). Key FindingsOf 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 100mg/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 100mg/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 100mg/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 100mg/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 100mg/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 100mg/day, respectively, compared with 0/100 on PBO. The incidence of TEAEs was higher for BRV 20 (56/99, 56.6%), 50 (62/99, 62.6%), and 100mg/day (63/100, 63.0%) than PBO (53/100, 53.0%); most TEAEs were mild or moderate in severity. The most frequently reported TEAEs in the BRV groups were headache, somnolence, dizziness, and fatigue. SignificanceIn this study of adjunctive BRV (20-100mg/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50mg/day dose was not statistically significant. However, BRV 100mg/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 100mg/day. BRV 20-100mg/day was well tolerated without up-titration, with a high completion rate.
- 出版日期2014-1
