Epilepsia, 45(6):610–617, 2004 Blackwell Publishing, Inc. C  2004 International League Against Epilepsy Randomized, Controlled Clinical Trial of Zonisamide as Adjunctive Treatment for Refractory Partial Seizures ∗ J. Chris Sackellares, †R. Eugene Ramsay, ∗ B. Joseph Wilder, ‡Thomas R. Browne III, and §M. Kent Shellenberger ∗ University of Florida and Malcolm Randall VA Medical Center, Gainesville, and †University of Miami and Miami VA Medical Center, Miami, Florida; ‡Boston University, Boston, Massachusetts; and §Elan Pharmaceuticals, South San Francisco, California, U.S.A. Summary: Purpose: This study was designed to evaluate effi- cacy and safety of zonisamide (ZNS) as adjunctive treatment for patients with refractory partial seizures. Methods: This randomized, double-blind, placebo-controlled study was conducted at four epilepsy treatment centers. It in- cluded a baseline phase (8 to 12 weeks) and a double-blind treatment phase (12 weeks). Initially, patients randomized to ZNS treatment were given a 7-mg/kg/d dosage. When investi- gators found that adverse effects could be reduced by gradu- ally introducing ZNS, patients were allowed to begin treatment at lower doses (100 mg or ∼1.5 mg/kg/d) titrated over several weeks to a maximum of 400 to 600 mg/d. Primary and sec- ondary efficacy measures were the median percentage reduction from baseline in seizure frequency and the proportion of patients achieving a ≥50% reduction from baseline (responder rate). Pa- tient and physician global assessments also served as indicators of efficacy. Safety was assessed primarily by treatment-emergent adverse events. Results: ZNS-treated patients had a 28.9% reduction in seizure frequency, which differed significantly from the 4.7% increase in placebo-treated patients. The responder rate for ZNS-treated pa- tients was 26.9%, compared with 16.2% for placebo-treated pa- tients. At study’s end, 66.2% of ZNS-treated patients and 12.3% of placebo-treated patients considered their condition improved; similarly, physicians assessed 63.6% of ZNS-treated patients and 10.8% of placebo-treated patients as improved. The most fre- quently reported adverse events with ZNS treatment included somnolence, irritability, dizziness, nausea, and fatigue. Conclusions: As adjunctive treatment, ZNS was gener- ally well tolerated and significantly improved seizure con- trol among patients with refractory partial seizures. Key Words: Zonisamide—Antiepilepsy drug—Epilepsy—Partial- onset seizures—Randomized controlled trial. Zonisamide (ZNS, 1,2-benzisoxazole-3-methane- sulfonamide) is a relatively new antiepileptic drug (AED) with multiple mechanisms of action, including blockage of voltage-sensitive sodium channels (1) and voltage-dependent T-type calcium channels (2), blockage of potassium-evoked glutamate response (3), reduction of glutamate-mediated synaptic excitation (4), facilitation of dopaminergic (5) and serotonergic (6) neurotransmission, scavenging of hydroxyl and nitric oxide radicals (7,8), increasing γ -aminobutyric acid (GABA) release from the hippocampus (9,10), and weak inhibition of carbonic anhydrase (11). Such mechanisms suggest that ZNS is a broad-spectrum treatment for epilepsy. Early pilot and open-label studies conducted in the United States char- acterized ZNS as effective (12,13). Studies conducted in Accepted January 14, 2004. Address correspondence and reprint requests to Dr. J.C. Sackellares at Department of Neuroscience, University of Florida Health Science Center, P.O. Box 100244, Gainesville, FL 32610-0244, U.S.A. E-mail: sackellares@epilepsy.health.ufl.edu Europe and Japan have confirmed the safety and efficacy of ZNS at dosages of 400 to 500 mg, administered once or twice daily (14,15). In addition, these studies have shown ZNS to be effective at the recommended starting dosage (100 mg/d). The second of two placebo-controlled clinical trials in the United States has shown that ZNS is both effective and well tolerated as an adjunctive treatment for refractory partial seizures (16). This report presents data from the first of two placebo- controlled trials conducted in the United States. The study was a randomized, multicenter, double-blind trial exam- ining the efficacy, safety, and tolerability of ZNS as an ad- junctive treatment for refractory partial seizures at dosages of 400 to 600 mg/d. METHODS Study design This was a randomized, double-blind, placebo- controlled, parallel-group, multicenter study. Epilepsy 610