Abstracts

Rationale: Eslicarbazepine acetate (ESL) is an antiepileptic that is converted to eslicarbazepine after oral administration. ESL was approved in 2009 by the European Medicines Agency as adjunctive therapy in adults with partial-onset seizures (POS), with or without secondary generalization. ESL is not approved in the US. This phase III study evaluated the safety and efficacy of ESL QD as adjunctive therapy for adult patients with refractory POS.Methods: Patients aged 16 yrs with 4 POS/4-wk, receiving 1 2 anti-epileptic drugs (AEDs), entered an 8-wk baseline (BL) phase followed by 1:1:1 randomization to placebo (PBO), ESL 800mg or ESL 1200mg, all QD. On randomization, patients entered a 2-wk, double-blind titration phase followed by a 12-wk double-blind, fixed-dose maintenance phase and, for patients not entering an open-label extension, a 2-wk tapering-off phase. The primary endpoint was standardized seizure frequency (SSF) per 28-days during the maintenance phase. Safety endpoints included adverse events (AEs), clinical laboratory results, vital sign, body weight and electrocardiogram (ECG) readings. Safety analyses included incidence of treatment-emergent AEs (TEAEs), serious AEs (SAEs) and TEAEs leading to death.Results: Of the 653 patients randomized, 650 received 1 dose of the study drug (safety population) of which 640 had 1 post-baseline seizure frequency assessment (intention-to-treat population). Demographics were similar across treatment groups: mean age, 38 39 yrs; ~50% male; 63 64% Caucasian; mean weight 72 74kg. Percentages of patients completing the double-blind phase were 84% (PBO), 80% (ESL 800mg), and 67% (ESL 1200mg). The least squares mean SSFs during the 12-wk maintenance phase were: PBO=7.88, ESL 800mg=6.54 (p=0.058 vs placebo), and 1200mg=6.00 (p=0.004). Overall responder rates ( 50% reduction in SSF) were 23.1% (PBO), 30.5% (ESL 800mg), and 42.6% (ESL 1200mg). Percentages of patients who experienced 1 TEAE in each group were 55.8% (PBO), 67.1% (ESL 800mg), and 77.6% (ESL 1200mg). The most common TEAEs occurring in 5% of patients in both ESL groups were dizziness, somnolence, nausea, headache, and diplopia with a trend towards increasing TEAEs with increasing ESL dose (Table 1). More patients reported SAEs in the PBO (3.1%) and ESL 800mg (6.5%) groups than the ESL 1200mg group (1.4%). Two deaths occurred during the double-blind portion of the study; 1 in the PBO group (acute respiratory failure); 1 in the ESL 800mg group during the titration phase (found dead in bed). There was 1 fatality during BL. Vital signs, body weight, and ECG parameters were not substantially different across visits for the PBO and ESL groups. Conclusions: ESL 800mg and 1200mg QD were generally well tolerated in patients with refractory POS. The incidence of TEAEs was higher in the ESL than PBO group and increased in a dose-dependent manner.