Medline ® Abstracts for References 5,38,39

Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is a common disorder, occurring at least twice a week and causing at least moderate distress in 1.5% to 2.7% of the population. It is important for primary care physicians to be familiar with this disorder and its management. Much has changed in its management since our previous algorithm was published in 2004, including the availability of several new drugs. This revised algorithm was written by members of the Medical Advisory Board of the Willis-Ekbom Disease Syndrome Foundation based on scientific evidence and expert opinion. It considers the management of RLS/WED under intermittent RLS/WED, chronic persistent RLS/WED, and refractory RLS/WED. Nonpharmacological approaches, including mental alerting activities, avoiding substances or medications that may exacerbate RLS, and the role of iron supplementation, are outlined. Chronic persistent RLS/WED should be treated with either a nonergot dopamine agonist or a calcium channelα-2-δligand. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS/WED and describe management approaches, including combination therapy and the use of high-potency opioids.

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.

STUDY OBJECTIVE: To evaluate the efficacy and tolerability of XP13512/ GSK1838262, an investigational nondopaminergic agent for the treatment of moderate-to-severe primary restless legs syndrome (RLS).

DESIGN: Randomized, double-blind, placebo-controlled, crossover trial.

SETTING: Nine US clinical sites.

PATIENTS: Thirty-eight treatment-naive subjects with RLS (mean +/- SD age 50.1 +/- 13.2 years).

INTERVENTIONS: XP13512 1800 mg/day followed by placebo or placebo followed by XP13512 1800 mg/day for 14 days, with a 7-day washout between treatment periods.

MEASUREMENTS AND RESULTS: The primary endpoint was mean change from baseline International RLS Study Group rating scale (IRLS) total score on Day 14, analyzed using analysis of variance with sequence, period, and treatment as fixed effects and subjects within sequence as a random effect. XP13512 significantly reduced IRLS total score on Day 14 compared with placebo (mean +/- SD: XP13512 -12.1 +/-6.5, placebo -1.9 +/- 6.3; P<0.0001). Polysomnographic data showed that XP13512 significantly improved sleep architecture on Day 14 compared with placebo (mean +/- SD change from baseline sleep time [minutes]: stage 1: XP13512 -9.8 +/- 23.9, placebo 0.4 +/-23.2; adjusted P<0.0054, nominal P<0.0001; stage 3/4 (slow-wave sleep): XP13512 22.8 +/- 40.8, placebo 1.4 +/- 34.3; adjusted P=0.0092, nominal P=0.0002). The most frequently reported adverse events were somnolence (XP13512 30.6%, placebo 2.8%) and dizziness (XP13512 27.8%, placebo 5.6%).

CONCLUSIONS: XP13512 1800 mg/day significantly reduced RLS symptoms, improved sleep, and was generally well tolerated in subjects with moderate-to-severe primary RLS across 14 days of treatment.