(Abst. 1.222 ), 2013
TIME TO ONSET OF EFFICACY AND SUSTAINED TREATMENT EFFECTS OF USL255: RESULTS FROM THE PHASE 3 PREVAIL CLINICAL TRIAL
Authors: B. Lawson, S. S. Chung, A. M. Clark, M. B. Halvorsen, I. Blatt
USL255 is a once-daily extended-release topiramate formulation developed for the treatment of epilepsy. USL255 requires up-titration over a number of weeks to achieve an optimal maintenance dose. During this up-titration, however, it may be possible to observe clinical efficacy. The phase 3 PREVAIL clinical trial (NCT01142193) demonstrated the efficacy, safety, and tolerability of USL255 as an adjunctive treatment for refractory partial-onset seizures (POS). The data presented here specifically evaluate the onset and maintenance of USL255 efficacy across the entire 11-week double-blind treatment period (titration and maintenance phases).
Adult subjects with POS (N=249) on 1-3 concomitant antiepileptic drugs, 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. Time to efficacy onset and maintenance of treatment effects were assessed during the titration and maintenance phases separately. Prospective efficacy endpoints included the median percent reduction from baseline in weekly POS frequency as well as the 50% responder rate (defined as the proportion of subjects with ≥50% reduction in weekly POS frequency). Further, a post-hoc analysis evaluated the median percent reduction in POS frequency for each individual week across the 11 weeks of treatment.
All 249 subjects randomized to treatment (n=124 USL255; n=125 placebo) were included in these analyses. During the 3-week titration phase, USL255-treated subjects demonstrated a significantly greater median percent reduction from baseline in weekly POS frequency as compared with placebo-treated subjects (33.9% vs 8.6%, P<.001). This significant treatment effect was sustained during the 8-week maintenance phase (45.7% vs 22.1%, P=.001). When evaluated weekly, POS frequency was significantly reduced as early as Week 1 (P<.05) in USL255-treated subjects compared with placebo. This improvement in seizure frequency was observed at every subsequent week. In addition, a significantly higher proportion of subjects receiving USL255 compared with placebo were considered treatment responders during both the titration (33.9% vs 17.6%, P=.007) and maintenance (44.2% vs 30.8%, P=.048) phases.
USL255 was efficacious as early as the first week of treatment (50 mg/d). Significant seizure reduction was sustained throughout the remaining weeks of the titration phase and overall during the 8-week maintenance phase. In addition, by as early as 3 weeks following treatment initiation, >30% of USL255 subjects were considered treatment responders. Together, these data demonstrate that USL255, a once-daily extended-release formulation of topiramate, is an efficacious adjunctive treatment for POS, and the early onset of efficacy offers a significant benefit to patients with epilepsy. Supported by Upsher-Smith Laboratories, Inc.
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