Effects of Eslicarbazepine Acetate (Esl, Bia 2-093) on Cognitive Function in Children With Partial Onset Seizures

Effects of Eslicarbazepine Acetate (Esl, Bia 2-093) on Cognitive Function in Children With Partial Onset Seizures: an add-on, Double-blind, Randomised, Placebo-controlled, Parallel Group, Multicentre Clinical Trial

To evaluate the effects of eslicarbazepine acetate on cognition in comparison with placebo as adjunctive therapy in children aged 6 to 16 years old with refractory partial-onset seizures.

This will be a 2-part multicentre study in approximately 117 patients. Part I of the study will consist of a 4-week prospective observational baseline period, a 12-week double-blind period (4-week up-titration and 8-week maintenance), and a tapering-off period.

After the screening visit (V1), patients will enter the baseline period. At the end of the baseline period (V2), eligible patients will be randomised in a ratio of 2:1 to receive double-blind treatment with Eslicarbazepine acetate or Placebo in addition to concomitant therapy with 1 or 2 Anti-Epileptic Drugs (AEDs). Concomitant AED therapy will be kept stable during the whole study.

Initial dose of the study treatment will be 10 mg/kg/day. After 2-weeks on 10 mg/kg/day, the dose will be up-titrated to 20 mg/kg/day (maximum 1200 mg/day). After 2 weeks on 20 mg/kg/day, dose will be up-titrated to 30 mg/kg/day (maximum 1200 mg/day) and patients will receive this dose for 8 weeks. If intolerable adverse events (AEs) occur, the patient can be down-titrated to the previous dose (only 1 down-titration step will be allowed) or discontinued. After the 8-week maintenance period, the study treatment will be tapered off in 10 mg/kg/day 2 week steps. However, if a patient experiences an increase in seizure frequency (e.g. more than 100% increase vs. baseline) during tapering-off, the patient can proceed directly to the open-label part of the study (Part II).

After completion of the last 2-week 10 mg/kg/day step, patients will have the option to enter a 1 year open-label treatment (Part II) with Eslicarbazepine acetate (up to 30 mg/kg/day, maximum 1200 mg/day), or will have a 4 week observational follow-up period.

Inclusion Criteria:

At visit 1 (screening), patient must be/have:

• written informed consent by parent or legal guardian and, where applicable, the patient;
• age 6 to 16 years, inclusive;
• a documented diagnosis of epilepsy for at least 12 months prior to screening;
• at least 2 partial onset seizures during the 4 weeks prior to screening despite treatment with 1 to 2 AEDs in a stable dose regimen;
• an Intelligence Quotient (IQ) of at least 70;
• current treatment with 1 to 2 AEDs (except oxcarbazepine, benzodiazepines other than clobazam and vagus nerve stimulation (VNS));
• excepting epilepsy, patient is judged to be in general good health based on medical history, physical examination and clinical laboratory tests;
• in the opinion of the investigator, able to complete the Cognitive Drug Research (CDR) test battery;
• in case of a girl of childbearing potential, patient presents a serum B-human chorionic gonadotropin (B hCG) test consistent with a non gravid state and agrees to remain abstinent or use reliable contraception (if used, hormonal contraception must be combined with a barrier method) starting at screening and continuing until at least the post-study visit (PSV).

At visit 2 (randomisation), patient must be/have:

• at least 2 partial-onset seizures during the 4 week baseline period prior to randomisation (documented in a diary);
• in case of a girl of childbearing potential, patient presents a urine B-hCG test consistent with a non-gravid state;
• stable dose regimen of concomitant AEDs during the 4 week baseline period;
• diaries satisfactorily completed by the patient or his/her caregiver during the baseline period;
• satisfactory compliance with the study requirements during the baseline period.

Exclusion Criteria:

At visit 1 (screening), patients must not be/have:

• only simple partial seizures with no motor symptomatology;
• primarily generalised seizures;
• known rapidly progressive neurological disorders (progressive brain disease, epilepsy secondary to progressive cerebral lesion);
• occurrence of seizures too close to count accurately;
• history of status epilepticus or cluster seizures (i.e., 3 or more seizures within 30 minutes) within the 3 months prior to screening; seizures of non-epileptic origin;
• Lennox-Gastaut syndrome;
• West syndrome;
• major psychiatric disorders;
• seizures of psychogenic origin within the last 2 years;
• history of schizophrenia or suicide attempt;
• history of attention deficit disorder or other diseases adversely affecting cognitive abilities;
• currently treated with oxcarbazepine, benzodiazepines other than clobazam (on a routine or chronic basis) and/or VNS;
• known hypersensitivity to carboxamide derivatives (oxcarbazepine or carbamazepine);
• uncontrolled cardiac, renal, hepatic, endocrine, gastrointestinal, metabolic, haematological or oncology disorder;
• second or third degree atrioventricular blockade;
• relevant clinical laboratory abnormalities;
• estimated creatinine clearance (CLCR) <60 mL/min;
• pregnancy or nursing;
• treatment with eslicarbazepine acetate in any previous study;
• participation in other drug clinical trial within the last 2 months;
• not ensured capability to perform the trial;
• any other condition or circumstance that, in the opinion of the investigator, may compromise the patient's ability to comply with the study protocol.

At visit 2 (randomisation), patients must not be / have:

• any condition or circumstance that, in the opinion of the investigator, may compromise the patient's ability to comply with the study protocol.