Abstracts

Rationale: In the US, phenytoin (PHT) is widely used for rapid initiation of therapy for new-onset epilepsy, particularly in emergency rooms. A comparative study was designed to evaluate the efficacy, tolerability and safety of rapid initiation of topiramate (TPM) 100 mg/day vs oral loading with PHT 1,000 mg/day in patients (pts) with new-onset epilepsy in the early post-initiation period. Methods: This was a multicenter, randomized, double-blind, parallel-group, double-dummy trial (Protocol CAPSS-272) consisting of a screening phase of up to 7 days and a 4-wk double-blind phase. Eligible pts were 12-65 y old, had 1-20 unprovoked complex partial (CP) or generalized tonic-clonic (GTC) seizures (sz) in the past 3 mos, were candidates for rapid initiation of anti-epileptic drug (AED) monotherapy, and had a diagnosis of new-onset epilepsy or epilepsy relapse after stopping AED therapy in the past. Pts were randomized (1:1) to oral PHT (target initiation dose of 1,000 mg on Day 1 followed by maintenance dose of 300 mg/day) or TPM (target initiation and maintenance dose of 100 mg/day). The primary efficacy variable, time to first sz over a 28-day period, was analyzed using a Cox proportional hazard model with treatment as a main effect. A non-inferiority hypothesis on hazard ratio (HR: TPM/PHT) was tested; TPM to be considered non-inferior to PHT if the upper 95% CI of HR was <2.275. Post-hoc analysis of time to discontinuation was performed using the Kaplan-Meier method and a log-rank test. Results: 261 pts were randomized, 133 to TPM, 128 to PHT; the safety population was composed of 259 pts and the ITT population of 254. Overall, 217 pts (83.1%) completed the double-blind phase (116/133 [87.2%] TPM; 101/128 [78.9%] PHT). The most common reason for discontinuation (9.2%) was adverse events (AEs): 8/133 (6.0%) TPM pts and 16/128 (12.5%) PHT pts. Analysis of the primary efficacy variable did not establish non-inferiority of TPM to PHT (HR=2.0, 95% CI, 0.98 to 4.12, P=0.366) in time to first seizure. Since the 95% CI included 1, superiority of PHT also was not established. CP or GTC sz were experienced by 18.8% of TPM and 11.1% of PHT pts. Overall retention rate was significantly higher in the TPM group compared with the PHT group (89.4% vs 80.3%, P=0.047). The most common treatment-related AEs were dizziness (13.6% TPM, 19.7% PHT), paresthesia (9.8% TPM, 0.8% PHT) and somnolence (6.8% TPM, 8.7% PHT). Approximately twice as many PHT pts (13.4%) discontinued study medication due to AEs compared with TPM pts (6.8%). Cognitive AEs led to withdrawal in 2 TPM pts and 0 PHT pts. Rash/macropapular rash or pruritus led to withdrawal in 0 TPM pts and 12 PHT pts. Conclusions: Although non-inferiority of TPM compared with PHT was not established, rapid initiation of TPM resulted in a higher overall retention rate and lower dropout rate due to AEs, suggesting that TPM 100 mg/day can be considered a reasonable alternative to oral PHT loading for pts with new-onset epilepsy requiring rapid AED initiation.