Multi-national, multi-center, randomised, double-blind, active controlled trial to compare efficacy and tolerability of cabergoline and levodopa in patients with severe restless legs syndrome

Introduction: Dopaminergic drugs are considered as the main therapeutic option for patients with a Restless Legs Syndrome (RLS). However, no clinical trial with sufficient statistical power has been conducted up to now which compared efficacy and tolerability of two active dopaminergic treatments. We report here the results on the secondary outcome measures of the first large-scale double-blind, randomized study to compare the dopamine agonist cabergoline (CAB) and levodopa/benserazide (LEV).

Methods: Patients with idiopathic RLS were treated with fixed daily doses of 2mg CAB or 200mg LEV; in the event of insufficient efficacy after six weeks, dose was increased to 3mg CAB or 300mg LEV. Treatment duration was 30 weeks. Efficacy was assessed by changes in the IRLS total score, the RLS-6 severity scales, the Clinical Global Impressions (CGI), the RLS Quality of Life scale (QoL-RLS), and the Sleep Questionnaire (SF-A).

Results: 361 of 418 screened patients (age 58±12 years, 71% females) were randomized and treated (CAB: n=178; LEV: n=183) in 51 centers of 4 European countries. Baseline IRLS total score was 25.7±6.7. Dose increase was more frequently required in LEV patients (49.4%) vs. CAB patients (24.1%, p<.001).

Improvement between final assessment and baseline (ITT population, LOCF method) was more pronounced in the CAB compared to the LEV group: IRLS: d=-16.5±10.0 vs. d=-10.0±9.7 (p<.0001), RLS-6 during the night: -5.0±3.2 vs. -3.6±3.5 (p=.0001), during the day at rest: -3.2±2.9 vs. -1.1±3.7 (p<.0001), QoL-RLS: -16.2±14.3 vs. -10.1±14.2 (p<.0001), SF-A: +0.8±0.9 vs. +0.6±1.0 (p>.10). In the CGI item „change of condition“, more patients improved „very much“ or „much“ in the CAB (80.8%) than in the LEV group (58.8%, p<.0001). In the LEV group compared to the CAB group, more patients discontinued due to augmentation (9.8% vs. 4.0%, p=.0412, log-rank test) or loss of efficacy (14.2% vs. 7.9%, p=.0290). Drug-related AEs occurred in 67.9% of the CAB group and in 50.2% of the LEV group. Most frequently, gastrointestinal AEs were reported (CAB: 54.1%, LEV: 32.4%).

Conclusions: This first large-scale active controlled study in RLS showed that both treatments were effective in relieving RLS symptoms and improving quality of life, however, cabergoline was superior to levodopa in respect to efficacy and incidence of augmentation causing discontinuation of therapy. No differences were found in changes on subjective quality of sleep.