Abstracts

Rationale: USL255, a once-daily extended-release topiramate formulation, recently demonstrated efficacy and favorable tolerability as an adjunctive treatment for refractory partial-onset seizures (POS) in a randomized, double-blind, phase 3 clinical trial (PREVAIL; NCT01142193). The long-term effects of USL255 in this population are currently being evaluated in a 1-year open-label extension (OLE) study. Presented here are the interim safety and exposure data, as of 25 January 2013, following the completion of the PREVAIL trial by all subjects.Methods: In this 1-year, global, phase 3, OLE study, the long-term safety and efficacy of USL255 as adjunctive therapy in patients with refractory POS are undergoing evaluation. Only subjects who completed the 11-week double-blind treatment phase from PREVAIL were eligible to enroll. Subjects opting to participate in the OLE study underwent a 3-week blinded conversion phase, where PREVAIL subjects randomized to placebo treatment were titrated to 200 mg/d USL255 by 50 mg/d each week, and those randomized to USL255 were titrated with matching placebo. This conversion phase was followed by a 52-week open-label treatment phase, where dose adjustments (up or down titrated by 50 mg/d weekly) were permitted after 8 weeks, as deemed necessary by the investigator, until an optimal dose was achieved (up to 400 mg/d). At the end of the open-label phase, subjects are then tapered off study drug by 50 mg/d each week over a minimum of 3 weeks. Safety and tolerability assessments include adverse event (AE) monitoring, laboratory evaluations, vital sign measurements, and physical examinations. Additional analyses include evaluation of POS frequency, Clinical Global Impression of Change (CGI-C) scores, and Quality of Life in Epilepsy Problems (QOLIE-31-P) Survey. Results: Although the PREVAIL OLE study is ongoing, presented here are interim exposure and safety results. Of the 217 subjects who completed the PREVAIL trial, 210 (96.8%) elected to continue into the OLE study. As of 25 January 2013, 32 subjects (15.2%) had completed the year-long OLE study. A total of 17 subjects (8.1%) had discontinued due to AEs. Of the 15 serious adverse events (SAEs) experienced by 11 subjects, only 1 event of cholelithiasis that resolved with sequelae was deemed by the investigator as possibly related to USL255; all other events were deemed unrelated. These included 2 SAEs that resolved with sequelae (fibula fracture and tibia fracture) and 1 death resulting from ischemic stroke. The 11 remaining SAEs unrelated to treatment resolved without sequelae.Conclusions: While the PREVAIL OLE study is ongoing, interim exposure and safety data suggest that USL255, at dosages up to 400 mg/d, is generally well tolerated as an adjunctive treatment for refractory partial-onset seizures. Supported by Upsher-Smith Laboratories, Inc.