Abstracts

Rationale: Brivaracetam (BRV), a novel high-affinity SV2A ligand with inhibitory activity on neuronal voltage-dependent sodium channels, has demonstrated efficacy against partial-onset seizures in phase 2 clinical trials. Data from preclinical studies suggest BRV may have a broad spectrum of clinical activity. To explore its tolerability and efficacy against generalized seizures (GS), we analyzed a sub-population of a phase 3 clinical trial, focusing on patients with GS only and diagnosis of generalized epilepsy (GE). Methods: The prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose trial (N01254/NCT00504881) randomized (BRV:Placebo 3:1) adults (16-70 years) experiencing uncontrolled focal seizures or GS, despite treatment with 1-3 AEDs. The proportion of patients with GS was limited to 20%. Patients with GE had to experience ?2 GS days/month for 3 months prior to screening and ?4 GS days during the 4-week prospective Baseline. The Treatment Period comprised an 8-week Dose-finding and 8-week Maintenance. BRV was initiated at 20 mg/day and increased stepwise (50, 100 and 150 mg/day, bid) at the investigator s discretion. Results: Of 480 patients randomized to treatment, 49 (10.2%) presented with GE (36 BRV; 13 placebo; mean age:30 years; 53% male). Syndrome classification was idiopathic in 27/49 (55%), cryptogenic in 14/49 (29%), symptomatic in 4/49 (8%) and unknown in 4/49 (8%) patients. Patients were on 1 (29%), 2 (41%) or ?3 (29%) concomitant AEDs, the most common of which were lamotrigine (33%), carbamazepine (29%) and valproate (25%). During Baseline, patients experienced tonic-clonic (59%), absence (37%), tonic (14%), myoclonic (10%), clonic (6%) and atonic (4%) seizures. 34/36 (94.4%) BRV and 13/13 (100%) placebo patients completed the Treatment Period, during which similar proportions (72.2% and 76.9%, respectively) reported ?1 treatment emergent adverse event (TEAE); the majority of which were mild to moderate. The most frequently reported TEAEs (?10% patients; either group) were headache (BRV 7/36, 19.4%; placebo 4/13, 30.8%), somnolence (BRV 4/36, 11.1%; placebo 0/13, 0%) and mouth injury (BRV 0/36, 0%; placebo 2/13, 15.4%). Only one patient on BRV (1/36, 2.8%) discontinued treatment because of TEAE. The median baseline GS days/week was similar in both groups (BRV 1.42; placebo 1.47). Exploratory efficacy analysis showed that during the Treatment Period the median GS days/week decreased to 0.63 on BRV and remained relatively stable on placebo (1.26). The median percentage reduction from baseline and 50% responder rate in GS days/week were higher on BRV (42.6% and 44.4%, respectively) compared with placebo (20.7% and 15.4%, respectively). 3 (8.3%) patients on BRV were seizure free during the entire Treatment Period compared with none on placebo. Conclusions: The results of this exploratory analysis provide preliminary data suggesting potential efficacy and good tolerability of adjunctive BRV in adults with GE. UCB-sponsored