Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies

Abstract

Objective: To assess the efficacy, safety, and tolerability of adjunctive brivaracetam (BRV), a selective, high-affinity ligand for SV2A, for treatment of partial-onset (focal) seizures (POS) in adults.

Methods: Data were pooled from patients (aged 16-80 years) with POS uncontrolled by 1 to 2 antiepileptic drugs receiving BRV 50, 100, or 200 mg/d or placebo, without titration, in 3 phase III studies of BRV (NCT00490035, NCT00464269, and NCT01261325, ClinicalTrials.gov, funded by UCB Pharma). The studies had an 8-week baseline and a 12-week treatment period. Patients receiving concomitant levetiracetam were excluded from the efficacy pool.

Results: In the efficacy population (n = 1,160), reduction over placebo (95% confidence interval) in baseline-adjusted POS frequency/28 days was 19.5% (8.0%-29.6%) for 50 mg/d (p = 0.0015), 24.4% (16.8%-31.2%) for 100 mg/d (p < 0.00001), and 24.0% (15.3%-31.8%) for 200 mg/d (p < 0.00001). The ≥50% responder rate was 34.2% (50 mg/d, p = 0.0015), 39.5% (100 mg/d, p < 0.00001), and 37.8% (200 mg/d, p = 0.00003) vs 20.3% for placebo (p < 0.01). Across the safety population groups (n = 1,262), 90.0% to 93.9% completed the studies. Treatment-emergent adverse events (TEAEs) were reported by 68.0% BRV overall (n = 803) and 62.1% placebo (n = 459). Serious TEAEs were reported by 3.0% (BRV) and 2.8% (placebo); 3 patients receiving BRV and one patient receiving placebo died. TEAEs in ≥5% patients taking BRV (vs placebo) were somnolence (15.2% vs 8.5%), dizziness (11.2% vs 7.2%), headache (9.6% vs 10.2%), and fatigue (8.7% vs 3.7%).

Conclusions: Adjunctive BRV was effective and generally well tolerated in adults with POS.

Classification of evidence: This analysis provides Class I evidence that adjunctive BRV is effective in reducing POS frequency in adults with epilepsy and uncontrolled seizures.

Figure 1. Study designs and patient disposition

(A) Designs of phase III fixed-dose studies N01253, N01252, and N01358. Concomitant levetiracetam was limited to ≤20% of patients in studies N01252 and N01253 and was not permitted in study N01358. (B) Patient disposition (safety population). ^aPatients taking BRV 5 or 20 mg/d were excluded from the pooled analysis. BRV = brivaracetam; LTFU = long-term follow-up; PBO = placebo.

Figure 2. Primary efficacy outcomes

(A) Percent reduction over placebo in baseline-adjusted POS frequency/28 days. (B) ≥50% responder rate. BRV = brivaracetam; POS = partial-onset seizure.

Figure 3. Secondary efficacy outcomes

(A) Median percent reduction in POS frequency from baseline. (B) Seizure freedom. (C) Categorized percent reduction in POS frequency per 28 days. BRV = brivaracetam; POS = partial-onset seizure.