Search

Objective The aim of this study was to evaluate long-term safety, efficacy, and quality of life (QOL) of ≤ 400-mg/day USL255, Qudexy® XR (topiramate) extended-release capsules, as adjunctive therapy for partial-onset seizures (POS) in adults. Methods Patients who completed the 11-week double-blind treatment phase of the phase 3 PREVAIL study were eligible to enroll in this 1-year open-label extension (OLE) study (PREVAIL OLE). The primary objective was to evaluate the safety and tolerability of USL255 (including treatment-emergent adverse events [TEAEs]). The secondary objective was to assess seizure frequency in patients (e.g., median percent reduction from baseline in weekly POS frequency, responder rate [proportion of patients with ≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction from baseline in POS frequency], and seizure-free intervals [proportion of patients who were seizure-free for 4, 12, 24, 36, or 48 weeks]). Exploratory clinical-status endpoints included the Global Impression of Change (CGI-C) and Quality of Life in Epilepsy—Problems (QOLIE-31-P) questionnaires. Post hoc analyses evaluated neurocognitive TEAE incidences during the first 11 and entire 55 weeks of treatment and efficacy by patient age and drug-resistant status. Results Of the 217 patients who completed PREVAIL (USL255, n = 103; placebo, n = 114), 210 (97%) enrolled in PREVAIL OLE and were included in the ITT population. Across the entire 55-week treatment period, USL255 was generally safe and well tolerated, with low individual neurocognitive TEAE incidences. Seizure reduction was sustained across the year-long study and observed in patient subgroups, including those with highly drug-resistant seizures and those ≥ 50 years of age. Improvements in CGI-C and QOLIE-31-P were also observed. Significance The results of PREVAIL OLE are consistent with those from PREVAIL and demonstrate that adjunctive treatment with up to 400 mg/day of USL255 may be a safe and effective treatment option for a variety of adult patients with refractory POS. more...

Objective To evaluate the efficacy and safety of USL255, Qudexy™ XR (topiramate) extended-release capsules, as an adjunctive treatment for refractory partial-onset seizures (POS) in adults taking one to three concomitant antiepileptic drugs. Methods In this global phase III study (PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once-daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life (QOLIE-31-P) and clinical global impression of change (CGI-C), were evaluated. Results Across the entire 11-week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life. Significance The PREVAIL phase III clinical study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects. more...

Objective The objectives of these two studies were to determine if beads from extended-release topiramate capsules sprinkled onto soft food are bioequivalent to the intact capsule and if beads from the capsule can be passed through enteral gastrostomy (G-) and jejunostomy (J-) feeding tubes. Methods Bioequivalence of 200-mg USL255 (Qudexy® XR [topiramate] extended-release capsules) sprinkled onto soft food (applesauce) versus the intact capsule was evaluated in a phase 1, randomized, single-dose, crossover study (N = 36). Pharmacokinetic evaluations included area under the curve (AUC), maximum plasma concentration (Cmax), time to Cmax (Tmax), and terminal elimination half-life (t1/2). If 90% confidence intervals (CI) of the ratio of geometric least-squares means were between 0.80 and 1.25, AUC and Cmax were considered bioequivalent. In separate in vitro experiments, 100-mg USL255 beads were passed through feeding tubes using gentle syringe pressure to develop a clog-free bead-delivery method. Multiple tube sizes (14- to 18-French [Fr] tubes), dilutions (5 mg/15 mL–25 mg/15 mL), and diluents (deionized water, apple juice, Ketocal, sparkling water) were tested. Results Area under the curve and Cmax for USL255 beads sprinkled onto applesauce were bioequivalent to the intact capsule (GLSM [90% CI]: AUC0–t 1.01 [0.97–1.04], AUC0–∞ 1.02 [0.98–1.05]; Cmax 1.09 [1.03–1.14]). Median Tmax was 4 h earlier for USL255 sprinkled versus the intact capsule (10 vs 14 h; p = 0.0018), and t1/2 was similar (84 vs 82 h, respectively). In 14-Fr G-tubes, USL255 beads diluted in Ketocal minimized bead clogging versus deionized water. Recovery of USL255 beads diluted in deionized water was nearly 100% in 16-Fr G-, 18-Fr G-, and 18-Fr J-tubes. Significance For patients with difficulty swallowing pills, USL255 sprinkled onto applesauce offers a useful once-daily option for taking topiramate. USL255 beads were also successfully delivered in vitro through ≥ 14-Fr G- or J-tubes, with tube clogging minimized by portioning the dose and using glidant diluents for smaller tubes. more...

Results from a previously conducted global phase III study (PREVAIL; NCT01142193) demonstrate the safety and efficacy of once-daily USL255, Qudexy™ XR (topiramate) extended-release capsules, as adjunctive treatment of drug-resistant partial-onset seizures (POSs). In this study, we report a post hoc analysis of PREVAIL data according to patient level of treatment resistance (based upon the number of concomitant antiepileptic drugs [AEDs] and lifetime AEDs) at baseline, with patients defined as either having "highly" drug-resistant seizures (≥ 2 concurrent AEDs and ≥ 4 lifetime AEDs) or having "less" drug-resistant seizures (1 concurrent AED or more...

Objective For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (t 1/2eff ) may be a more clinically relevant parameter than elimination half-life (t 1/2z ). Using topiramate as a real-life example, the objective was to compare these half-life values for immediate- and extended-release topiramate (TPM-IR and USL255, respectively) to understand how drug pharmacokinetics may impact drug dosing recommendations. Methods The t 1/2z and t 1/2eff for USL255 and TPM-IR were compared using data from a phase I study (N=36) of 200mg USL255 administered once daily (QD) or TPM-IR twice daily (BID); effect of sampling duration on t 1/2z was investigated. To further explore the relationship between half-life and dosing, steady-state PK was simulated for USL255 and TPM-IR. Results As previously reported, mean t 1/2z was similar between USL255 (80.2h) and TPM-IR (82.8h); TPM-IR t 1/2z was ∼4 times longer than reported in the Topamax label (21h). In contrast, USL255 displayed a 1.5 fold longer t 1/2eff (55.7 vs 37.1h for TPM-IR). When t 1/2z was calculated from 48 to 336h, values ranged from 28.8 to 82.8h. Simulated steady-state PK profiles of USL255 QD exhibited reduced plasma fluctuations during a dosing interval vs TPM-IR QD or BID. Significance As expected for the same moiety, t 1/2z of USL255 and TPM-IR were similar; however, the longer t 1/2eff for USL255 better approximates differences in recommend dosing (QD USL255 vs BID TPM-IR). Further, sampling duration impacted t 1/2z , diminishing its predictive value for determining dose regimens; sampling-time differences may also explain t 1/2z discrepancy between TPM-IR here versus Topamax label. As expected, steady-state simulations confirm that although TPM-IR has a long t 1/2z , taking TPM-IR QD would lead to large plasma fluctuations. These data demonstrate that t 1/2z may be less clinically meaningful than t 1/2eff, and using t 1/2z for some drugs may lead to erroneous conclusions regarding dosing regimens. more...