(Abst. 1.221 ), 2013
USL255, A ONCE-DAILY, EXTENDED-RELEASE TOPIRAMATE, IS EFFICACIOUS AS AN ADJUNCTIVE THERAPY FOR REFRACTORY PARTIAL-ONSET SEIZURES: RESULTS FROM THE RANDOMIZED PHASE 3 PREVAIL CLINICAL TRIAL
Authors: S. S. Chung, T. A. Fakhoury, B. Anders, D. Laine, S. Arnold, M. B. Halvorsen
Despite the addition of new antiepileptic drugs (AEDs) over the past 20 years, approximately 30% of patients with epilepsy continue to experience recurrent seizures. Additionally, the current literature suggests that noncompliance with medication regimens, whether due to side effects or multiple daily dosing, may contribute to a loss of seizure control. While immediate-release topiramate (TPM-IR) is efficacious in the treatment of epilepsy, the recommended dosing of TPM-IR is twice daily. As such, patients can experience large plasma concentration fluctuations throughout the day, which may increase the risk of breakthrough seizures and peak-dose toxicity. USL255, a once-daily extended-release topiramate formulation, is pharmacokinetically equivalent to TPM-IR but reduces topiramate plasma fluctuations. Efficacy and safety of USL255, as an adjunctive treatment for refractory partial-onset seizures (POS), was evaluated in subjects with epilepsy taking 1-3 concomitant AEDs (PREVAIL phase 3 clinical trial, NCT01142193).
Adult subjects with POS (N=249), reporting ≥8 seizures with a ≤21-day seizure-free period during an 8-week baseline phase, were randomized (1:1) to receive once-daily USL255 or placebo. Subjects were up-titrated by 50 mg/d each week over 3 weeks and maintained at 200 mg/d for 8 weeks with USL255 or matching placebo. Primary and secondary efficacy endpoints included median percent reduction in weekly POS frequency, 50% responder rate (defined as the proportion of subjects with ≥50% reduction in weekly POS frequency), and seizure freedom.
All 249 subjects randomized to treatment (n=124 USL255; n=125 placebo) were included in the intent-to-treat population. The median frequency of weekly POS during baseline was similar between USL255 and placebo groups (2.29 vs 2.66 seizures/wk, respectively). After 11 weeks of treatment (3-week titration plus 8-week maintenance), USL255 was associated with a significantly greater median percent reduction in seizure frequency compared with placebo (39.5% vs 21.6%, P<.001). The 50% responder rate during the 11 weeks of treatment was also significantly greater with USL255 compared with placebo (37.9% vs 23.2%, P=.013). Further, treatment with USL255 resulted in a significant improvement in time to seizure freedom (P=.004), and a significantly higher percentage of subjects achieved seizure freedom for at least 21 days prior to the last dose of study drug (P=.006) as compared with placebo.
The PREVAIL phase 3 clinical trial demonstrated that USL255, extended-release topiramate, was efficacious as an adjunctive treatment in subjects with refractory POS, and significantly increased the seizure freedom rate. The PREVAIL study supports that USL255 may provide significant benefits to patients with refractory partial epilepsy. Supported by Upsher-Smith Laboratories, Inc.
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