A POST-HOC ANALYSIS OF THE TIME TO ONSET OF EFFICACY AFTER INITIATION OF ESLICARBAZEPINE ACETATE AS ADJUNCTIVE THERAPY IN ADULT PATIENTS WITH REFRACTORY PARTIAL-ONSET SEIZURES
Abstract number :
1.230
Submission category :
7. Antiepileptic Drugs
Year :
2012
Submission ID :
16069
Source :
www.aesnet.org
Presentation date :
11/30/2012 12:00:00 AM
Published date :
Sep 6, 2012, 12:16 PM
Authors :
C. Elger, B. Steinhoff, J. Serratosa, C. Marchal, F. Sales, R. Sousa, T. Nunes, P. Soares-da-Silva,
Rationale: Eslicarbazepine acetate (ESL) is a novel once-daily (QD) anticonvulsant, extensively converted to eslicarbazepine after oral administration, which blocks voltage-gated sodium- and calcium-channels. This post-hoc analysis evaluated the efficacy, tolerability and time to onset of a clinically relevant reduction in seizure risk (RSR) after initiation of ESL as adjunctive therapy in adults with partial-onset seizures (POS). Methods: Data from two (BIA-2093-301 and -302) phase III multicentre, double-blind, randomized, placebo-controlled studies in adult patients with ≥4 partial-onset seizures per 4 weeks despite treatment with 1-3 AEDs was pooled and analysed. ESL QD was administered at doses of 400 mg, 800 mg and 1200 mg. The key efficacy endpoints were seizure frequency during the 12-week maintenance phase adjusted per 4 weeks (primary endpoint), relative reduction in seizure frequency, and responder rate (≥50% reduction in seizure frequency). To evaluate time to onset of a clinically relevant effect, mean cumulated seizure frequency over time (MCF) was calculated for the entire double-blind period. From the increments in MCF, the instantaneous daily seizure rate was estimated using an Epanechnikov kernel estimator (bandwidth = 28 days). Relative hazard functions over time were derived comparing each of the 3 ESL dosage groups with placebo group. Tolerability was also assessed. Results: Safety population comprised 797 patients (placebo, n=202; ESL 400 mg, n=196; ESL 800 mg, n=199; ESL 1200 mg, n=200) and intention-to treat population included 752 patients (placebo, n=198; ESL 400 mg, n=192; ESL 800 mg, n=182; ESL 1200 mg, n=180). Compared with placebo adjusted seizure frequency over the 12-week maintenance period was significantly reduced with ESL 800 mg and 1200 mg (p<0.0001 for both groups); ESL 400 mg was not significantly superior to placebo (p=0.15). Median relative reduction in seizure frequency was 13% with placebo and 34% and 38% with ESL 800 mg and 1200 mg, respectively. Responder rate was 19% with placebo and 36% and 43% with ESL 800 mg and 1200 mg, respectively. Including the titration period (up to 2 weeks), the onset of a clinically relevant effect (defined as 20% RSR compared with placebo) was observed in 28 days in ESL 1200 mg group and in 49 days in ESL 800 mg group. The 90% maximal effect was observed in 43 days in ESL 1200 mg group (24.5% RSR) and in 48 days in ESL 800 mg group (19.9% RSR) (figure 1). Treatment-emergent adverse events occurring in at least 10% of patients in any group were dizziness, somnolence, headache, diplopia and nausea (table 1). Conclusions: In this post-hoc analysis, once-daily ESL 800 mg and 1200 mg was effective as adjunctive treatment of adult patients with refractory partial-onset seizures. Including the titration period, a clinically relevant reduction in seizure risk was achieved in 28 and 48 days of therapy with once-daily ESL 1200 mg and 800 mg, respectively. Both effective dosages were well tolerated.
Antiepileptic Drugs