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

• Published in: Epilepsia (Copenhagen) 2014-01, Vol.55 (1), p.47-56
• Main Authors: Ryvlin, Philippe, Werhahn, Konrad J., Blaszczyk, Barbara, Johnson, Martin E., Lu, Sarah
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Anticonvulsants - administration & dosage; Anticonvulsants - therapeutic use; Antiepileptic agents; Brivaracetam; Double-Blind Method; Drug Therapy, Combination; Efficacy; Epilepsies, Partial - drug therapy; Epilepsy; Female; Focal epilepsy; Humans; Male; Middle Aged; Phase III; Pyrrolidinones - administration & dosage; Pyrrolidinones - therapeutic use; Safety/tolerability; Treatment Outcome; Young Adult
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.12432

Summary Purpose Brivaracetam (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 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 Europe and India. 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 (TEAEs). 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 10