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(Abst. 1.318), 2014

ESLICARBAZEPINE ACETATE MONOTHERAPY IN ADULTS WITH PARTIAL-ONSET SEIZURES: A POOLED ANALYSIS OF TWO RANDOMIZED DOUBLE-BLIND STUDIES WITH USE OF A HISTORICAL CONTROL
Authors: Ladislav Pazdera, Jacqueline French, Michael Sperling, Mercedes Jacobson, Hailong Cheng and David Blum
Content: Rationale: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED), approved in the US and EU as adjunctive treatment of partial-onset seizures (POS). ESL is not approved as monotherapy. We present the pooled analysis of two identical studies using a historical control ‘withdrawal to monotherapy' design (French et al. Epilepsia 2010;51:1936-43). Conducting two independent studies made it possible to reduce the total sample size, increase the statistical power of the analysis, and conduct one trial exclusively in North America (NA). Methods: The two randomized double-blind studies were performed in NA (study 045) and NA/Europe (study 046). Patients aged ≥16 yrs, using 1-2 AEDs, with ≥4 POS in the 8 wks before screening, and no 4-wk seizure-free period, were randomized (2:1) to ESL 1600/1200mg QD (2-wk titration; 6-wk conversion [other AEDs withdrawn]; 10-wk monotherapy). The primary endpoint was exit rate (the proportion of patients meeting ≥1 of 5 exit criteria [worsening seizure control] by wk 16). ESL was considered effective if the upper 95% confidence limit (UCL) of the Kaplan-Meier-estimated exit rate was <65.3% (single study) or <72.2% (two studies). Results: Overall, 365 patients began titration (1600mg, n=242; 1200mg, n=123). Median age was 38 yrs; 52.1% were female. Compared with non-US patients, US patients weighed more, had a greater duration of epilepsy, and had higher maximum 2- and 28-day seizure rates at baseline. The pooled efficacy population (patients who began conversion) comprised 332 patients (1600mg, n=218; 1200mg, n=114). Estimated exit rates (95% CI) with ESL 1600 and 1200mg respectively were: study 045, 28.7% (21.2-38.1%) and 44.4% (32.5-58.3%); study 046, 12.8% (7.5-21.5%) and 15.6% (8.1-28.7%); pooled 045/046, 20.6% (15.6-26.8%) and 30.8% (23.0-40.5%; Figure 1). The UCLs were less than the 65.3% threshold for all treatment groups; both doses of ESL monotherapy were superior to historical controls. Exit rates in the pooled population were higher in US vs non-US patients: ESL 1600mg, US 25.0%, non-US 13.1%; ESL 1200mg, US 42.9%, non-US 10.2%. UCLs for all groups were ˂65.3%. Higher exit rates occurred in patients with: epilepsy duration ≥20 yrs; baseline use of 2 AEDs; rescue medication use. Except for phenytoin, no baseline AED significantly affected exit rate. Headache was the only treatment-emergent adverse event (TEAE) observed in ≥5% of patients during monotherapy (8.5%; Table 1). Minor differences in TEAE profile were observed by baseline AED. From baseline to study end, QOLIE-31 scores improved by 5.7 (ESL 1600mg) and 3.3 points (1200mg; clinically meaningful change: ≥5 points; Borghs et al. Epilepsy Behav 2012;23:230−4). There were no notable changes in MADRS scores. Conclusions: Exit rates with ESL (1600mg and 1200mg) were superior to historical controls; differences between US and non-US patients may be due to differences in placebo response, or to more severe epilepsy in US patients. ESL was well tolerated as monotherapy.
Figure 1