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Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures

From the University of Pennsylvania (R.J.P.), Philadelphia; Shire Pharmaceuticals (A.P.), Westchester, PA; Robert Wood Johnson University Hospital (R.S.), New Brunswick, NJ; Emory University (V.N.), Atlanta, GA; and Valeant Research and Development (W.M.A.), Costa Mesa, CA.

Address correspondence and reprint requests to Dr. Roger J. Porter, 461 Timber Lane, Devon, PA 19333; e-mail: rjportermd{at}aol.com

Objective: To evaluate the efficacy and safety of retigabine 600, 900, and 1,200 mg/day administered three times daily as adjunctive therapy in patients with partial-onset seizures.

Methods: A multicenter, randomized, double-blind, placebo-controlled trial was performed. After an 8-week baseline phase, patients were randomized to a 16-week double-blind treatment period (8-week forced titration and 8-week maintenance) followed by either tapering or entry into an open-label extension study. Primary efficacy was the percentage change from baseline in monthly seizure frequency and compared across treatment arms. Secondary efficacy comparisons included the proportion of patients experiencing 50% reduction in seizure frequency (responder rate), emergence of new seizure types, and physician assessment of global clinical improvement. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluations. Efficacy analyses were performed on the intent-to-treat population.

Results: Of the 399 randomized patients, 279 (69.9%) completed the double-blind treatment period. The median percent change in monthly total partial seizure frequency from baseline was –23% for 600 mg/day, –29% for 900 mg/day, and –35% for 1,200 mg/day vs –13% for placebo (p < 0.001 for overall difference across all treatment arms). Responder rates for retigabine were 23% for 600 mg/day, 32% for 900 mg/day (p = 0.021), and 33% for 1,200 mg/day (p = 0.016), vs 16% for placebo. The most common treatment-emergent AEs were somnolence, dizziness, confusion, speech disorder, vertigo, tremor, amnesia, abnormal thinking, abnormal gait, paresthesia, and diplopia.

Conclusion: Adjunctive therapy with retigabine is well tolerated and reduces the frequency of partial-onset seizures in a dose-dependent manner.

*Principal investigators of the 205 Study Group are listed in the appendix.

Financed by Wyeth Research, Radnor, PA, and ASTA Medica AG (predecessor of VIATRIS GmbH), Frankfurt, Germany.

Disclosure: This study was sponsored and conducted by Wyeth Pharmaceuticals. Dr. Porter and Dr. Partiot were full-time Wyeth employees at the time this study was performed and currently have either consultantship with industry, including Wyeth and Valeant (Dr. Porter, <$10,000 per year each), or work full time for the industry (Dr. Partiot, Shire Pharmaceuticals). Dr. Sachdeo has performed clinical trials for Wyeth and other pharmaceutical companies. His consultation with Wyeth was >$10,000. Dr. Nohria is a consultant to the industry, including Wyeth and Valeant; his consultation was >$10,000. Dr. Alves was a full-time employee of Valeant Pharmaceuticals, the current owner of retigabine.

Received May 12, 2006. Accepted in final form December 7, 2006.

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