(Abst. 1.219 ), 2013
SAFETY AND TOLERABILITY OF USL255 IN SUBJECTS WITH REFRACTORY PARTIAL-ONSET SEIZURES: RESULTS FROM THE RANDOMIZED, PHASE 3 PREVAIL CLINICAL TRIAL
Authors: R. E. Hogan, S. Arnold, T. A. Fakhoury, B. Anders, D. Laine, W. M. Todd, B. Lawson
Immediate-release topiramate (TPM-IR) is an efficacious prophylactic treatment for the management of epilepsy. However, twice-daily dosing can lead to reduced compliance and large fluctuations in drug plasma concentrations, which can contribute to adverse events. Upsher-Smith Laboratories, Inc. has developed USL255, a once-daily extended-release topiramate formulation, for the treatment of epilepsy. The PREVAIL phase 3 clinical trial (NCT01142193) evaluated the efficacy and safety of USL255 in subjects with refractory partial-onset seizure (POS) taking 1-3 concomitant AEDs. The data presented here focus on the safety, tolerability, and treatment compliance of USL255.
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 (PBO). 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 PBO. Subjects unable to tolerate 200 mg/d were discontinued from the study. Safety and tolerability were evaluated through adverse event monitoring, vital sign measurements, and clinical laboratory evaluations. Treatment compliance, based on medication count, was also evaluated.
All 249 subjects randomized to treatment (n=124 USL255; n=125 PBO) were included in these analyses. At the end of the 11-week treatment period, mean medication compliance rates for the USL255 and PBO groups were 99% and 100%, respectively. Study completion rates were 83% and 91%, respectively, with fewer than 10% of subjects in either treatment group discontinuing due to adverse events. The overall incidence of treatment-emergent adverse events (TEAEs) was 66% (USL255) and 50% (PBO) (P=.015), with the majority reported as mild-to-moderate in intensity. A higher proportion of subjects reported TEAE onset during the 3-week titration phase than during the first or last 4 weeks of the maintenance phase. Somnolence, dizziness, paraesthesia, and weight decrease were the most commonly reported treatment-related TEAEs. The proportion of subjects reporting a neurocognitive or psychiatric TEAE (eg, memory impairment, psychomotor retardation) was less than 3% in both treatment groups, with the exception of disturbance in attention (2.4% [USL255]; 3.2% [PBO]). No deaths were reported, and while 2 (1.6%) subjects in both treatment groups had serious TEAEs, none were considered treatment related. Shifts in serum bicarbonate and chloride, parameters known to be affected by topiramate use, occurred in 15% and 5% of USL255-treated patients, respectively. No abnormal trends in other safety evaluations, including ECG, were observed.
USL255 demonstrated high treatment compliance with favorable safety and tolerability in subjects with refractory POS. The low incidence of neurocognitive adverse events, combined with the overall favorable safety profile, suggests USL255 may provide a significant benefit to patients with epilepsy. Supported by Upsher-Smith Laboratories, Inc.
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