Purpose: Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand currently being investigated for the treatment of epilepsy. The purpose of this phase III study was to evaluate the efficacy and safety/tolerability of adjunctive BRV in adults with uncontrolled partial-onset (focal) seizures.
Methods: This was a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose trial (N01253; NCT00464269). Adults aged 16-70 years with well-characterized partial epilepsy not fully controlled despite treatment with one or two antiepileptic drugs (AEDs) were enrolled. Patients who experienced eight or more partial-onset seizures, whether or not secondarily generalized, during the 8-week prospective baseline period were randomized (1:1:1:1) to receive twice-daily placebo (PBO) or BRV (5, 20, or 50 mg/day) without titration. The primary efficacy endpoint was percent reduction over PBO in baseline-adjusted partial-onset seizure frequency/week during the 12-week treatment period. Comparison of BRV with PBO was sequential (50, 20 mg/day, then 5 mg/day). Secondary endpoints included ≥50% responder rate and median percent reduction from baseline in partial-onset seizure frequency/week. Post hoc analyses included the primary efficacy endpoint evaluated over 28 days and exploratory subanalyses of efficacy by seizure subtype. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs), laboratory tests, electrocardiography, vital signs, and physical and neurologic examinations.
Key findings: Of 400 patients randomized, 396 were included in the intent-to-treat (ITT) population (PBO n = 98, BRV 5 mg/day n = 97, BRV 20 mg/day n = 100, BRV 50 mg/day n = 101) and 392 comprised the modified ITT (mITT) population. A total of 361 (91.2%) of 396 patients completed the study. Most patients (78.3%) were receiving two concomitant AEDs. Percent reduction in partial-onset seizure frequency/week over PBO was -0.9% (p = 0.885) for BRV 5 mg/day, 4.1% (p = 0.492) for BRV 20 mg/day, and 12.8% (p = 0.025) for BRV 50 mg/day (mITT population). Statistical significance was also achieved for the percent reduction over PBO in baseline-adjusted partial-onset seizure frequency/28 days for BRV 50 mg/day (22.0%; p = 0.004) but not for the other BRV dose groups. In the BRV 50 mg/day group, statistical significance was also seen for the ≥50% responder rate (BRV 32.7% vs. PBO 16.7%; p = 0.008) and median percent reduction from baseline in partial-onset seizure frequency/week (BRV 30.5% vs. PBO 17.8%; p = 0.003). In the exploratory subanalysis by seizure subtype, median percent reduction from baseline in seizure frequency/week and ≥50% responder rate were numerically greater than PBO in the BRV 20 and 50 mg/day groups for simple partial, complex partial, and secondarily generalized seizures. BRV was generally well tolerated, with the majority of TEAEs being mild-to-moderate in intensity. Of the TEAEs reported by ≥5% patients, those with a frequency >3% higher than PBO for any dose of BRV compared with PBO were somnolence, dizziness, fatigue, influenza, insomnia, nasopharyngitis, vomiting, diarrhea, urinary tract infection, and nausea.
Significance: Adjunctive BRV at a daily dose of 50 mg was associated with statistically significant reductions in seizure frequency compared with PBO. All doses of BRV showed good tolerability throughout the study.
Keywords: Brivaracetam; Efficacy; Partial epilepsy; Phase III; Safety/tolerability.
Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.