Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures

Background: Zonisamide is a sulfonamide antiepilepsy drug with sodium and c alcium channel-blocking actions. Experience in Japan and a previous Europea n double-blind study have demonstrated its efficacy against partial-onset s eizures. Methods: A randomized, double-blind, placebo-controlled trial enro lling 203 patients was conducted at 20 United States sites to assess zonisa mide efficacy and dose response as adjunctive therapy for refractory partia l-onset seizures. Zonisamide dosages were elevated by 100 mg/d each week. T he study design allowed parallel comparisons with placebo for three dosages and a final crossover to 400 mg/d of zonisamide for all patients. The prim ary efficacy comparison was change in seizure frequency From a 4-week place bo baseline to weeks 8 through 12 on blinded therapy. Results: At 400 mg/d, zonisamide reduced the median frequency of all seizures by 40.5% from base line, compared with a 9% reduction (p = 0.0009) with placebo treatment, and produced a greater than or equal to 50% seizure reduction (responder rate) in 42% of patients. A dosage of 100 mg/d produced a 20.5% reduction in med ian seizure frequency (p = 0.038 compared with placebo) and a dosage of 200 mg/d produced a 24.7% reduction in median seizure frequency (p = 0.004 com pared with placebo). Dropouts from adverse events (10%) did not differ from placebo (8.2%, NS). The only adverse event differing significantly from pl acebo was weight loss, though somnolence, anorexia, and ataxia were slightl y more common with zonisamide treatment. Serum zonisamide concentrations ro se with increasing dose. Conclusion: Zonisamide is effective and well toler ated as an adjunctive agent for refractory partial-onset seizures. The mini mal effective dosage was 100 mg/d, but 400 mg/d was the most effective dosa ge.