Conclusion: Although the clinical efficacy of adjunctive ESL was shown to be superior to placebo, the addition of ESL to carbamazepine, phenytoin and barbiturates may require monitoring of patients’ clinical progress and possible dose adjustment. The concomitant administration of other AEDs did not affect the ESL exposure-response relationship. Supported by BIAL – Portela & Ca. SA. p341 TO WHAT EXTENT CAN ESLICARBAZEPINE ACE- TATE INFLUENCE THE PLASMA LEVELS OF COM- BINED ANTIEPILEPTIC DRUGS? AN EVALUATION BASED ON THREE DOUBLE-BLIND PHASE III CLINI- CAL STUDIES Bialer M 1 , Falc¼o A 2,3 , Costa R 4 , Lopes N 4 , Nunes T 4 , Soares-da-Silva P 4,5 1 The Hebrew University of Jerusalem, Jerusalem, Israel, 2 Health Consulting, Cantanhede, Portugal, 3 University of Coimbra, Coimbra, Portugal, 4 BIAL – Portela & Ca. SA, S. Mamede do Coronado, Portugal, 5 University of Porto, Porto, Portugal Purpose: Eslicarbazepine acetate (ESL) is a novel once-daily voltage- gated sodium channel blocker approved in Europe for use in adults as adjunctive therapy for refractory partial-onset seizures (POS) with or without secondary generalization. The variability of the population phar- macokinetics (PK) and systemic plasma exposure to concomitant antiepi- leptic drugs (AEDs) in treating patients with refractory POS were analyzed to determine the potential influence of ESL on the metabolism and PK of concomitant AEDs. Method: Plasma concentrations of eslicarbazepine (main active metab- olite of ESL) and other concomitant AEDs were obtained from 641 patients receiving ESL. Data were analyzed using nonlinear mixed-effect modelling (NONMEM) methods. Plasma exposure PK parameters were calculated from individual parameters estimates derived from the model. A population PK model of trough (C min,ss ) eslicarbazepine plasma con- centrations at steady-state was fitted. Results: ESL did not affect the clearance of clobazam, gabapentin, phenytoin, phenobarbital, levetiracetam and valproate. ESL slightly increased the oral clearance (CL/F) of carbamazepine, lamotrigine and topiramate up to 14%, 12% and 16%, respectively. Interindividual vari- ability of CL/F for carbamazepine, clobazam, gabapentin, phenytoin, phenobarbital, topiramate and valproic acid was 24%, 77%, 48%, 72%, 42%, 39% and 64%, respectively. Conclusion: In this integrated data analysis, it appears as though the magnitude of pharmacokinetic effect of ESL on the clearance of concom- itant AEDs may not be clinically relevant and therefore may not justify the need for dose adjustment. Supported by BIAL – Portela & Ca. SA. p342 METHODS USED TO EVALUATE COGNITIVE EFFECTS OF ESLICARBAZEPINE ACETATE ADD-ON THERAPY IN EPILEPTIC CHILDREN OF AGE 6–16: THE DESIGN OF A PLACEBO-CONTROLLED CLINI- CAL TRIAL Capovilla G 1 , Pinto R 2 , Moreira J 2 , Mota F 2 , Nunes T 2 , Soares-da-Silva P 2,3 1 Ospedale Carlo Poma, Mantova, Italy, 2 BIAL – Portela & Ca. SA, S. Mamede do Coronado, Portugal, 3 University of Porto, Porto, Portugal Purpose: Eslicarbazepine acetate (ESL) is a novel once-daily voltage- gated sodium channel blocker approved in Europe for use in adults as adjunctive therapy for refractory partial-onset seizures with or without secondary generalization. Epilepsy is associated with significant cogni- tive comorbidity, correlated to both the underlying disease and antiepi- leptic drugs (AEDs). The study aimed to evaluate the effect of ESL as add-on therapy on the cognitive function in children and adolescents with partial-onset seizures, treated with 1–2 AEDs and experiencing ‡2 seizures/4-weeks. Method: After a 4-week baseline-period, 117 subjects will be rando- mized in 2:1 ratio to ESL (10–30 mg/kg/day) or placebo once-daily. Potential effects on attention, memory and information processing/psy- chomotor speed will be assessed by the UBC System, a computerized neurocognitive test battery validated in clinical studies in epileptic chil- dren. The primary end point is the change in the composite Power of Attention, over a 12-week double-blind maintenance period. Patients’ global cognitive skills, social competence, quality of life, and seizure fre- quency will also be evaluated. Safety will be assessed by records of adverse events, clinical laboratory tests, physical and neurological exam- inations and measurement of growth and development. A 1-year open- label will follow the double-blind period. Results: The study is expected to be completed by the end of 2012 and the results will be available thereafter. Conclusion: The use of a validated cognitive-battery in a noninferiority study with a placebo control is an appropriate study-design to assess cog- nitive effects of ESL while accounting for developmental changes and disease progression in children and adolescents. Supported by BIAL – Portela & Ca. SA. p343 THE DESIGN OF A DOUBLE-DUMMY, ACTIVE- CONTROLLED, MULTINATIONAL PHASE-III NONIN- FERIORITY TRIAL IN 900 PATIENTS WITH PARTIAL- ONSET SEIZURES: ESLICARBAZEPINE ACETATE VERSUS CONTROLLED-RELEASE CARBAMAZEPINE IN MONOTHERAPY Trinka E 1 , Pinto R 2 , Moreira J 2 , Mota F 2 , Nunes T 2 , Soares- da-Silva P 2,3 1 Paracelsus Medical University of Salzburg, Salzburg, Austria, 2 BIAL – Portela & Ca. SA, S. Mamede do Coronado, Portugal, 3 University of Porto, Porto, Portugal Purpose: Given the demonstration of efficacy and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy in partial-onset seizures (POS) in clinical studies, ESL may be an alternative as a first- line agent in monotherapy. This phase-III, randomized, double-blind, active-controlled, noninferiority study aims to demonstrate the efficacy and safety of ESL once-daily as monotherapy treatment for newly diagnosed adults with POS in comparison to controlled-release carbamazepine (CBZ-CR) twice-daily. Method: Patients (‡18 year) with ‡2 unprovoked seizures in the past year and ‡1 in the last 3-months will be randomized in a 1:1 ratio to receive ESL 800 mg once-daily or CBZ-CR 200 mg twice-daily during a 26-week evaluation-period. In case of seizure occurrence during the eval- uation-period, subjects are titrated to dose-levels B (1200 mg once-daily/ 400 mg twice-daily) and C (1600 mg once-daily/600 mg twice-daily). To assess maintenance of the effect over 1-year, a 26-week maintenance- period will follow. Exit criteria include seizures at dose-level C at evalua- tion period or at any dose-level in the maintenance-period. The primary end point is seizure freedom in the 26-week evaluation-period at the last received dose level. The sample size was calculated to achieve a ‡ 90% power to establish noninferiority, using a -12% margin. Secondary end points include tolerability, QOLIE-31, sedation and clinical laboratory assessments. Results: The study is expected to be completed by the end of 2013. Conclusion: The use of a noninferiority design implies the predefini- tion of a clinically relevant margin and adequate power to detect 109 Abstracts Epilepsia, 52(Suppl. 6):23–263, 2011 doi: 10.1111/j.1528-1167.2011.03207.x