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. A pooled analysis of data from 3 randomized, double-blind, placebo-controlled phase III studies (BIA-2093-301, -302 and -304) was conducted to investigate the efficacy of ESL QD as adjunctive therapy for POS.Methods: The studies enrolled patients aged 16 yrs (only study 3; BIA-2093-304) or 18 yrs who had 4 POS/month and were receiving 1 3 anti-epileptic drug (AED) prior to screening. After an 8-wk baseline (BL) phase, patients were randomized equally to placebo (PBO), ESL 400mg (2 studies only), 800mg, or 1200mg all administered QD. A 2-wk titration phase was followed by a 12-wk fixed-dose maintenance phase. The primary endpoint for all 3 studies was the standardized seizure frequency (SSF) per 4-wks during the maintenance phase. Secondary endpoints included relative change in seizure frequency from BL and responder rates (% patients with 50% or 75% seizure reduction). Efficacy analyses were based on the modified intent-to-treat (mITT) population, defined as all randomized patients with 1 dose of study medication and 1 post-BL seizure frequency assessment.Results: The pooled mITT population comprised 1410 patients. Demographics were similar across all treatment groups: mean age 38 yrs (range 16 75 yrs), 49.9% male, and 80.0% Caucasian. Overall, 71.5% of patients were receiving 2 AEDs. In placebo- and all ESL-treated patients, respectively, mean duration of epilepsy was 21.6 and 21.5 yrs; mean SSF at BL was 14.8 and 15.2 seizures/4-wks. Completion rates for the double-blind phase were 86.8% (PBO), 88.9% (ESL 400mg), 81.9% (ESL 800mg), and 70.6% (ESL 1200mg). Least squares (LS) mean SSFs during maintenance exhibited a dose response and were lower in the ESL groups than PBO in all studies, with statistically significant improvements for 800mg and 1200mg doses in the pooled analysis: PBO=7.7, ESL 400mg=7.3 (p=0.8136), ESL 800mg=6.1 (p=0.0001), and ESL 1200mg=5.7 (p<0.0001). These results were consistent regardless of alternate imputation, region, seizure type, duration of epilepsy, and concomitant medications. The median change in SSF was -16.7% (PBO), -22.6% (ESL 400mg), -31.2% (ESL 800mg), and -33.3% (ESL 1200mg). The 50% (Figure 1) and 75% responder rates, respectively, were 20.9% and 8.4% (PBO), 22.2% and 4.3% (ESL 400mg), 32.3% and 14.4% (ESL 800mg), and 40.9% and 15.6% (ESL 1200mg). Analysis by 4-wk intervals revealed no decrease in efficacy during maintenance. Safety and tolerability results are reported separately.Conclusions: Data from 3 controlled phase III studies demonstrate that ESL 800mg and 1200mg QD are effective as adjunctive therapy for the treatment of adult patients with refractory POS.