Abstracts

Rationale: Clobazam (CLB) is approved in the US for treatment of Lennox Gastaut Syndrome. The purpose of this study is to evaluate efficacy and safety of CLB add-on treatment in adults with refractory focal epilepsy. Methods: This is a single center open-label prospective study.After a prospective baseline of 26 weeks CLB was added.In patients in whom seizure diaries had been kept prospectively prior to screening visit,retrospective baseline was accepted.Patients were titrated up to seizure freedom, side effects or 40 mg/day,whichever came first.Titration rate was not forced.Starting dose was 10 mg/day,followed by default weekly 10 mg/day dose increments.Maintenance treatment lasted 22 weeks, for targeted whole treatment period of 26 weeks.At the end of 26 weeks’ treatment, patients could enter study extension for further 26 weeks,for 1year total treatment.Primary efficacy outcome measure was seizure count/28 days.Primary efficacy outcomes were 100% and =75% seizure reduction for the whole treatment period.Secondary efficacy outcomes included 100% and =75% seizure reduction for the maintenance treatment and mean % seizure reduction, =90% and =50% seizure reduction during whole treatment-,maintenance 6 and 12-month extension treatment periods.Safety outcome measures were TEAEs,treatment discontinuation due to TEAEs and SAEs.Intent-to-treat analysis was used. Results: The study is ongoing.30 patients have enrolled (16M, mean age 40.6 years, mean epilepsy duration 28.8 years,mean  number of prior AEDS 7, mean number of concomitant AEDs 2). All 30 patients have completed the 26 weeks’ treatment. 26/30 patients have completed the 12 months treatment.13 patients (43.3%) stopped treatment early,2 for social reasons,6/30 (20%) for lack of efficacy,5/30 (16.7%) due to TEAEs.9/30 (30%) patients did not reach the target dose of 40 mg/day because of TEAEs.5/30 (16.7%) patient exceeded that dose (50-60 mg/day) to maximize efficacy.At six months,7/30 (23.3%) patients were seizure free during the whole treatment period, 8/30 (26.6%) during maintenance treatment.=90-, =75%- and =50%- seizure frequency reduction for the whole treatment period occurred in 8/30 (26.7%),13/30 (43.3%) and 18/30 (60%) patients.Mean seizure frequency/28 days declined from baseline 9.81 by 61% and 54.4% to 5.99 and 5.34 during whole treatment- and maintenance treatment periods (both p=0.001,Wilcoxon test). TEAEs occurred in 28/30 (93.3%) patients, resulting in treatment discontinuation in 5/30 (16.7%) patients and in dose-reduction in 13/30 (43.3%).Most TEAEs were mild to moderate in severity and resolved with dose reduction.Commonest TEAEs were somnolence/fatigue (63.3% of all patients),dizziness/ataxia (56.6%),irritability/anger (33.3%), depression (16.6%), memory decline (16.6%),  blurred vision (13.3%) and weight gain (40%).  Conclusions: Adjunctive clobazam treatment may be effective in adults with refractory focal epilepsy.A significant proportion of previously refractory patients may achieve 75-100% seizure reduction. Side effects are common,but abate with flexible dose adjustment in most patients.  Funding: Lundbeck Pharmaceutical Company