Comparison of Zonisamide and Carbamazepine Monotherapy in Adults with Newly Diagnosed Partial Epilepsy: Results of a Phase III, Randomized, Double-Blind, Non-Inferiority Trial (IN5-1.005)

Abstract

Objective: To compare efficacy and safety of once-daily zonisamide (ZNS) and twice-daily controlled-release carbamazepine (CBZ) monotherapy in adults with newly diagnosed partial epilepsy. Background ZNS is a benzisoxazole derivative, chemically unrelated to other antiepileptic drugs (AEDs), which displays multiple mechanisms of action. It is currently licensed (USA, Europe) for adjunctive treatment of partial seizures in adults. Design/Methods: Phase III, international, randomized, double-blind, non-inferiority trial, in which 583 untreated adults (18–75 years) with newly diagnosed partial epilepsy received ZNS or CBZ monotherapy. Following initiation (ZNS 100 mg/day; CBZ 200 mg/day) and up-titration (to 300 and 600 mg/day, respectively), patients entered a 26–78-week flexible-dosing period (200–500 and 400–1200 mg/day, respectively, according to response/tolerability). Once seizure-free for 26 weeks, patients entered a 26-week maintenance phase. Primary endpoint was proportion of patients achieving seizure freedom for ≥26 weeks. Safety/tolerability evaluation included assessment of treatment-emergent adverse events (TEAEs). Results: Overall, 161/282 (57.1%) patients randomized to ZNS and 192/301 (63.8%) patients randomized to CBZ completed the trial. 26-week seizure freedom rates were 79.4% (177/223) for ZNS vs. 83.7% (195/233) for CBZ (Per Protocol Population). Adjusted absolute treatment difference was -4.5% (95% confidence interval [CI]: -12.2, 3.1). The lower CI limit narrowly exceeded the protocol-specified -12% margin, but the lower CI limit of relative difference (-14.7%) was within the ILAE-recommended margin (-20%). In most patients seizure freedom was achieved at the lowest target dose level (ZNS 300 mg, 87.0%; CBZ 600 mg, 88.7%). Incidence of TEAEs was similar for ZNS (60.5%) vs. CBZ (61.7%), as was incidence of serious TEAEs (5.3% vs. 5.7%) and TEAEs leading to withdrawal (11.0% vs. 11.7%). Conclusions: In a trial using flexible dosing to reproduce clinical practice, both ZNS and CBZ demonstrated high seizure-freedom rates and were well-tolerated in newly diagnosed partial epilepsy patients. Supported by: Eisai. Disclosure: Dr. Baulac has received personal compensation for activities with Eisai Inc., USB Pharma, Pfizer Inc, Medtronics and Novartis as a speaker and/or participant on an advisory board. Dr. Brodie has received personal compensation for activities with Pfizer Inc, UCB Pharma, Eisai Inc., GlaxoSmithKline, Inc., Sanofi-Aventis Pharmaceuticals, Inc., and Lundbeck Research USA, Inc. Dr. Brodie has received research support from Eisai Inc. Dr. Segieth has received personal compensation for activities with Eisai Ltd as an employee. Dr. Giorgi has received personal compensation for activities with Eisai Ltd as an employee.