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Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS

From the Stanford University Center of Excellence for Sleep Disorders (C.A.K.), Stanford, CA; Sleep Medicine Associates of Texas (P.M.B.), Dallas, TX; Quest Research Institute (A.L.E.), Bingham Farms, MI; and XenoPort, Inc. (D.M.C., R.W.B.), Santa Clara, CA.

Address correspondence and reprint requests to Dr. Clete A. Kushida, Stanford University Center of Excellence for Sleep Disorders, 401 Quarry Road, Suite 3301, Stanford, CA 94305-5730 clete{at}stanford.edu

Objective: To assess the efficacy and tolerability of the nondopaminergic agent XP13512/GSK1838262 in adults with moderate to severe primary restless legs syndrome (RLS).

Methods: Patient Improvements in Vital Outcomes following Treatment in Restless Legs Syndrome I was a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of XP13512 1,200 mg or placebo taken once daily at 5:00 pm with food. Coprimary endpoints were mean change from baseline International Restless Legs Scale (IRLS) total score and proportion of investigator-rated responders (very much improved or much improved on the Clinical Global Impression–Improvement scale) at week 12 (last observation carried forward). Tolerability was assessed using adverse events, vital signs, and clinical laboratory parameters.

Results: A total of 222 patients were randomized (XP13512 = 114, placebo = 108) and 192 patients (XP13512 = 100, placebo = 92) completed the study. At week 12, the mean change from baseline IRLS total score was greater with XP13512 (–13.2) compared with placebo (–8.8). Analysis of covariance, adjusted for baseline score and pooled site, demonstrated a mean treatment difference of –4.0 (95% confidence interval [CI], –6.2 to –1.9; p = 0.0003). More patients treated with XP13512 (76.1%) were responders compared with placebo (38.9%; adjusted OR 5.1; 95% CI, 2.8 to 9.2; p < 0.0001). Significant treatment effects for both coprimary measures were identified at week 1, the earliest time point measured. The most commonly reported adverse events were somnolence (XP13512 27%, placebo 7%) and dizziness (XP13512 20%, placebo 5%), which were mild to moderate in intensity and generally remitted.

Conclusions: XP13512 1,200 mg, taken once daily, significantly improved restless legs syndrome (RLS) symptoms compared with placebo and was generally well tolerated in adults with moderate to severe primary RLS.

Abbreviations: AE = adverse event; ANCOVA = analysis of covariance; CGI-I = Clinical Global Impression–Improvement; CI = confidence interval; ESS = Epworth Sleepiness Scale; IRLS = International Restless Legs Scale; LOCF = last observation carried forward; LS = least squares; MITT = modified intent-to-treat population; MOS = Medical Outcomes Study; NNT = numbers needed to treat; OR = odds ratio; PghSD = Pittsburgh Sleep Diary; PSQ = post-sleep questionnaire; RLS = restless legs syndrome; RLSQoL = RLS Quality of Life; SAE = serious adverse events; SOS = Sudden Onset of Sleep questionnaire; TST = total sleep time; WASO = wake time after sleep onset.

Supplemental data at www.neurology.org

Disclosure: Author disclosures are provided at the end of the article.

Received June 11, 2008. Accepted in final form October 24, 2008.