A randomized, double-blind, placebo-controlled, crossover study of XP13512/GSK1838262 in the treatment of patients with primary restless legs syndrome

Abstract

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.

Figure 1

Subject disposition. All randomized subjects were included in the safety population. Four subjects (2 taking XP13512 and 2 taking placebo) were withdrawn from the study and excluded from the modified intent-to-treat (MITT) population.

Figure 2

Least squares mean ± SEM change from baseline International Restless Legs Syndrome Study Group rating scale (IRLS) total score at Day 7 (secondary endpoint) and Day 14 (primary endpoint) of treatment with XP13512 1800 mg/day (n = 34) and placebo (n = 34). ***P < 0.0001, ^† adjusted P < 0.0060 (nominal P < 0.0001) vs placebo, comparison across total distribution.

Figure 3

Maximum restless legs syndrome (RLS) severity over 24 hours (6 periods of 4 hours each) on Day 14 in subjects treated with XP13512 1800 mg/day (n = 34) and placebo (n = 34).

Figure 4

Individual and mean changes from baseline in the following parameters: periodic leg movements (PLM), periodic leg movements during sleep, not associated with an arousal (PLMS), periodic leg movements during sleep causing an arousal (PLMSA), and periodic leg movement during sleep causing an awakening (PLMSW). Scores were obtained on Day 14 in subjects treated with XP13512 1800 mg (n = 34) and placebo (n = 34).

Figure 5

Sleep architecture in subjects treated with XP13512 1800 mg (n = 34) and placebo (n = 34) as measured by polysomnography at baseline and on Day 14. ^†Adjusted P < 0.0054 (nominal P < 0.0001), ^‡Adjusted P = 0.0092 (nominal P = 0.0002) vs baseline; analysis of variance. REM refers to rapid eye movement.

Figure 6

Mean ± SEM leg discomfort (visual analog scale [VAS]) recorded in 5-minute intervals, 2 hours before lights out, by subjects treated with XP13512 1800 mg/day (n = 34) and placebo (n = 34) during administration of the suggested immobilization test at baseline and on Day 14. ^†Adjusted P = 0.0468 (nominal P = 0.0012) vs placebo, comparison across total distribution.