Epilepsia, zyxwvutsrqponm 41( zyxwvutsrqponmlk 10): zyxwvutsrqpo 1276 zyxwvutsrqponm 1283, 2000 Lippincon Williams & Wilkins, Inc., Baltimore zyxwvutsrqp 0 International League Against Epilepsy Clinical Research Efficacy and Tolerability of Levetiracetam 3000 mg/d in Patients with Refractory Partial Seizures: A Multicenter, Double-Blind, Responder-Selected Study Evaluating Monotherapy “Elinor Ben-Menachem zyxwvu and “frsula Falter for the European Levetiracetam Study Group *Department zyxwvutsr of Clinical Neuroscience, Saklgrenska, University Hospital, Goteborg, Sweden: and tUCB Phamza, Brussels, Belgium Summary: Purpose: To evaluate the efficacy and tolerability of levetiracetam (LEV) monotherapy in selected patients with refractory partial seizures. Methods: In this multicenter, double-blind, placebo- controlled, parallel-group, responder-selected study, patients were randomized (2: 1 ratio) to receive oral LEV 1500 mg twice daily or placebo during a 12-week add-on phase. Treatment responders (patients with a reduction in partial seizure fre- quency of 50% or more compared with baseline) entered a monotherapy phase that included a maximum 12-week down- titration period and 12 weeks of rnonotherapy at 1500 mg twice daily. In both phases, responder rate, seizure frequency, and adverse events were analyzed. Results: A total of 286 patients (placebo, n = 105; LEV, n = 181) entered the add-on phase, and 86 patients (placebo, n = 17; LEV, n = 69) were eligible for the monotherapy phase. Thirty-six of 181 patients (19.9%) who received LEV com- pleted the entire study compared with only 10 of 105 patients (9.5%) in the placebo group (p = 0.029). The odds of com- pleting the study on LEV were 2.36 times (95% confidence interval, 1.08,5.57) higher than on placebo. The responder rate during the add-on phase was significantly higher in the LEV group compared with the placebo group (42.1% vs. 16.7%, respectively; p < 0.001). In the LEV monotherapy group, the median percent reduction in partial seizure frequency compared with baseline was 73.8% (p = 0.037), with a responder rate of 59.2%. Nine patients (18.4%) remained seizure-free on LEV monotherapy. Conclusions: Conversion to LEV monotherapy (I500 rng twice daily) is effective and well tolerated in patients with refractory partial seizures who responded to 3000 mg/d LEV as add-on therapy. Key Words: Antiepileptic drugs-Partial sei- zures-Monotherapy-Levetiracetan-Epilepsy . Levetiracetam (LEV) [ (S)-a-ethyl-2-oxo- 1 - pyrrolidine acetamide] is a novel antiepileptic drug (AED). Findings from preclinical and phase II studies have established that LEV is a broad-spectrum antiepi- leptic agent with a wide margin of safety (1-3). In phase zyxwv III trials, LEV at dosages between 1000 and 3000 mg/d has been found to be effective and well tolerated as add- on therapy in patients with partial seizures (4). LEV has a favorable pharmacokinetic profile with excellent oral Accepted May 25, 2000. Address correspondence and reprint requests to Dr. Elinor Ben-Menachem at Department of Clinical Neuroscience, Section of Neurology, Sahlgren University Hospital, 413 45 Goteborg, Sweden. E-mail: ebm@neuro.gu.se absorption, minimal protein binding, lack of hepatic me- tabolism, and renal excretion. Although the half-life in adults is 6 to 8 hours, twice-daily dosing is possible (5). Drug interactions are unlikely. LEV can be initiated at a therapeutic dosage, which allows for quick evaluation of efficacy. Because of these features, LEV was thought to be ideal for use as a single agent. Therefore, this study was conducted in an early stage of development to de- termine the “proof of principle” that conversion to LEV monotherapy could be effective in patients with partial seizures. A stepwise approach was taken, starting with add-on trials, then the add-on trial with conversion to monotherapy, reported here, to be followed by testing of efficacy in newly diagnosed patients. 1276