A large practical monotherapy trial for the treatment of new-onset epilepsy in adults shows once-daily zonisamide to be generally as effective and safe as controlled-release, twice-daily carbamazepine.

Few new antiepileptic drugs (AEDs) are studied for efficacy as monotherapy, and most such studies involve medically intractable epilepsy. Therefore, despite numerous new-generation AEDs, little guidance is available for choice in newly diagnosed epilepsy patients. Now, researchers have designed a manufacturer-funded, randomized, double-blind, international trial to test the noninferiority of zonisamide (ZNS) to carbamazepine (CBZ) in adults with newly diagnosed epilepsy. The 583 patients enrolled had only generalized tonic–clonic seizures and no evidence of idiopathic generalized epilepsy, new-onset epilepsy (with at least two seizures in the previous year and at least one seizure in the preceding 3 months), and no prior treatment with an AED for >2 weeks. The study was powered such that it met strict noninferiority criteria. The primary endpoint was the proportion of patients achieving 6-month seizure freedom. Secondary endpoints were the proportion achieving 12-month seizure freedom and times to 6- and 12-month seizure freedom. Safety and tolerability were examined by measuring the incidence of treatment-related adverse events, withdrawal, and laboratory abnormalities.

Of the 456 patients who completed the protocol, 79% and 68% taking ZNS achieved 6-month and 12-month seizure freedom, compared with 84% and 75% taking CBZ — fulfilling the strict noninferiority criteria. Intention-to-treat results supported the results of the per-protocol analysis. The times to both 6- and 12-month endpoints were the same in both arms. Few patients in either group withdrew because of treatment-related adverse events — primarily rash, dizziness, fatigue, and memory impairment. Two cases of severe rash occurred in the CBZ arm. One case of mild purpura occurred in the ZNS arm. None of the other eight reported severe adverse events had a clear association with treatment. No clinically significant laboratory abnormalities occurred in either arm.

Comment: This remarkable clinical trial addresses an important clinical question: Whether a newer-generation AED may be used as first-line monotherapy in newly diagnosed epilepsy. Moreover, the trial was designed to reflect typical clinical practice, given the population involved and the use of flexible dosing regimens for a meaningful treatment duration. Both treatment arms were well balanced, including frequency of seizures pretreatment, a strong predictor of prognosis. Because ZNS has few drug interactions and is formulated for once-daily dosing, the finding that ZNS is generally as effective as CBZ may actually change clinical practice.

Source: Journal Watch Neurology