Abstracts

Rationale: Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand, which also displays inhibitory activity at neuronal voltage-dependent sodium channels. In Phase IIb studies, adjunctive BRV (5-150 mg/day) demonstrated a favorable safety and tolerability profile in patients with partial-onset seizures. The primary objective of this Phase III trial was to further assess the safety and tolerability of BRV at individualized tailored doses (20-150 mg/day) in patients with refractory partial or primary generalized epilepsy. Methods: This was a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose trial (N01254). Adults (16-70 years) who experienced at least 4 partial-onset seizures whether or not secondarily generalized or at least 4 days with primary generalized seizures during the 4-week prospective baseline period despite treatment with 1-3 AEDs were randomized (3:1) to BRV or placebo. BRV was initiated at a dose of 20 mg/day and could be increased at the investigator's discretion as medically indicated up to 150 mg/day (20, 50, 100 and 150 mg/day, bid) during the 8-week dose-finding period. This was followed by an 8-week stable-dose period. Tolerability and safety assessments included treatment-emergent adverse events (TEAEs), laboratory tests, ECGs, vital signs, physical and neurological examinations. Results: Of 480 (359 BRV, 121 placebo) randomized subjects (mean age 35.9 years; 52% male) 431 (89.8%) were diagnosed as having partial-onset seizures and 49 (10.2%) primary generalized seizures. 17.1%, 45.4% and 37.3% patients were on 1, 2 and ≥3 concomitant AEDs. Most patients on BRV entered the stable-dose period at higher dose levels (48.2% on BRV150, 23.4% on BRV100, 15.6% on BRV50, 5.8% on BRV20). The retention rate on BRV was high with 90.0% patients completing the study compared with 91.7% on placebo. A similar proportion of BRV and placebo-treated patients reported at least 1 TEAE (66.6% vs 66.1%). The overall incidence of TEAEs was higher during the dose-finding period (BRV 56.0%; placebo 55.4%) than during the maintenance period (BRV 36.8%; placebo 40.9%). Only 6.4% of BRV-treated patients discontinued study medication because of TEAEs, similar to placebo (5.8%). The majority of TEAEs were mild to moderate, most frequently headache (BRV 14.8%; placebo 19.8%; Table 1). A greater proportion of patients on BRV than on placebo (difference >3%) reported somnolence (BRV 11.1%; placebo 4.1%), dizziness (BRV 8.9%; placebo 5.8%) and fatigue (BRV 7.8; placebo 4.1%). Serious TEAEs were reported by 5.6% BRV and 7.4% placebo-treated patients. No clinically significant changes in vital signs, ECGs or laboratory findings were observed. Conclusions: When given at individualized tailored doses mimicking clinical practice, BRV (20-150 mg/day) demonstrated a favorable safety and tolerability profile as add-on therapy in adults with refractory partial or primary generalized epilepsy. UCB sponsored (NCT00504881)