BACKGROUND:As with studies of other dopamine agonists, previously reported studies of ropinirole in restless legs syndrome (RLS) recruited patients with baseline International Restless Legs Scale (IRLS) total scores ≥ 15. The reported pooled analyses of clinical trials data suggest benefits of ropinirole in patients with IRLS total scores ≥ 24, but the effects of ropinirole have not been prospectively evaluated in this patient population. OBJECTIVE:The goal of this study was to evaluate the efficacy and tolerability of ropinirole in patients with RLS and baseline IRLS total scores ≥ 24. This study was conducted in part to fulfill a postlicensing commitment between the maker of ropinirole and the European Union's Committee for Medicinal Products for Human Use. METHODS:The protocol for this study comprised a randomized, double-blind, placebo-controlled, parallel-group, 26-week phase during which adults with baseline IRLS total scores ≥ 24 received a ropinirole dose from 0.25 to 4 mg (n = 197) or placebo (n = 207) followed by a 40-week, open-label phase during which all patients (n = 269) received ropinirole. The primary efficacy end point was the change from baseline in the IRLS total score at week 12. Tolerability measures included the incidence of adverse events, augmentation, and early morning rebound. Due to the possibility of a treatment-by-center group interaction (P = 0.04) in the IRLS analysis, further efficacy exploratory analyses were performed to assess the impact of the interaction on the overall assessment of efficacy. RESULTS:Demographic characteristics were comparable between groups (mean [SD] age: placebo, 56.1 [11.38] years; ropinirole, 56.5 [11.92] years; 63% female in both groups). All of the patients in the ropinirole group were white; 99% of the placebo group was white. Ropinirole was significantly better than placebo for change from baseline in the IRLS total score during both short- and long-term treatment, with mean treatment differences of -2.1 (P = 0.039) and -2.5 (P = 0.023) for weeks 12 and 26, respectively. A statistically significant treatment by center group interaction was observed (P = 0.040) for the change from baseline in IRLS total score, indicating variation of treatment effects among center groups; however, all center groups showed an improvement from baseline at both week 12 and week 26 for the ropinirole immediate-release group and the placebo group. The incidences of augmentation and early morning rebound were ≤ 4% for ropinirole. The adverse event profile of ropinirole was consistent with that reported in previous clinical trials. CONCLUSIONS:In this subset of patients with RLS and a baseline IRLS total score ≥ 24, ropinirole was effective and well tolerated compared with placebo. The incidence of augmentation and early morning rebound in this study was low.