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(Abst. 2.417), 2014

Authors: Pavel Klein, Jimmy Schiemann, Michael Sperling, John Whitesides, Wei Liang and Tracy Stalvey
Content: Rationale: To evaluate the efficacy and safety of brivaracetam (BRV) at fixed doses of 100 and 200 mg, with no up-titration compared to placebo (PBO), as adjunctive treatment in adult epilepsy patients with partial onset seizures (POS) not fully controlled despite current treatment with one or two concomitant anti-epileptic drugs (AEDs). Methods: This randomized, double-blind, PBO-controlled, multicenter, phase 3 study (NCT01261325) enrolled adults (≥16-80 years) with refractory POS whether or not secondarily generalized. Patients completed an 8-week prospective Baseline Period, followed by a 12-week Treatment Period. Patients taking levetiracetam (LEV), either as concomitant AED or within 90 days prior to Visit 1 were excluded. Patients were randomized to PBO, BRV 100mg or BRV 200mg (1:1:1). Upon completion of the treatment period, patients were eligible for conversion to a long-term follow-up study. Efficacy was assessed using seizure diaries. Safety was assessed with adverse events, laboratory tests, vital signs, ECGs, psychiatric status, and physical and neurological examinations. The primary efficacy outcomes were percent reduction over PBO in 28-day adjusted POS frequency (USA); and 50% responder rate based on percent reduction in POS frequency from Baseline to the Treatment Period (EU). Results: 764 of 768 randomized patients were included in the safety population (mean age 39.5±12.9 years; 51.8% female). 760 randomized patients were included in the intent-to-treat (ITT) population (mean duration of epilepsy 22.8 years). 696 (90.6%) randomized patients completed the study. Study discontinuation rates were low: 6.5% in the PBO group, 11.4% in the BRV 100 mg group, and 10.4% in the BRV 200 mg group. For the ITT population, 81.1% of patients had a history of taking ≥2 previous AEDs, with 33.8% reporting 2-4 previous AEDs and 47.2% reporting ≥5 previous AEDs. Both primary efficacy outcomes were clinically relevant and statistically significant (p<0.001) for both BRV dose groups (Table 1). Percent reduction over PBO in 28-day adjusted POS frequency was 22.8% for BRV 100 mg and 23.2% for BRV 200 mg. Responder rate was 21.6% for PBO, 38.9% for BRV 100 mg and 37.8% for BRV 200 mg. Twenty-three patients on BRV (13, 5.2% on 100 mg; 10, 4.0% on 200 mg) were seizure free for all seizure types during the Treatment Period compared with two patients (0.8%) in the PBO group. Efficacy was seen in both LEV naïve patients and patients previously exposed to LEV. Treatment-emergent AEs (TEAEs) occurred in 173 (68.4%) and 167 (66.8%) patients in the BRV 100 mg and 200 mg groups, respectively, and 155 (59.4%) patients in the PBO group. The most frequent TEAEs were somnolence, dizziness and fatigue (Table 2). Conclusions: BRV at 100 mg and 200 mg showed statistically significant reductions in POS frequency for both USA and EU primary efficacy endpoints. BRV doses of 100 mg and 200 mg were generally well tolerated when administered as adjunctive therapy in adult epilepsy patients with POS.