Efficacy and augmentation during 6 months of double-blind pramipexole for restless legs syndrome

Background: Pramipexole is an effective treatment for restless legs syndrome (RLS), but no controlled studies have lasted > 12 weeks. Methods: RLS patients (N = 331) with pretreatment serum ferritin > 30 ng/mL were randomly assigned to take double-blind optimized pramipexole (0.125-0.75 mg/d) or placebo for 26 weeks. The primary efficacy endpoint was change in International RLS Study Group Rating Scale (IRLS) score. Other endpoints assessed global change, symptoms, and QoL. Patients maintained symptom diaries. Cases meeting predefined criteria for suspected augmentation were reviewed by a blinded expert panel, which used a predefined algorithm. Results: Among 321 patients providing post-baseline data, of whom 234 completed 26 weeks, pramipexole was more effective than placebo by multiple endpoints, including an adjusted mean IRLS score change of -13.7 vs. -11.1 (p = 0.0077) and an IRLS responder rate (>= 50% score reduction) of 58.6% vs. 42.8% (p = 0.0044). Efficacy showed considerable country-to-country variability. Six-Month incidence of confirmed augmentation was 9.2% for pramipexole and 6.0% for placebo. The rate increased with treatment duration for pramipexole but not placebo. Treatment-related adverse events (AEs) were more likely for pramipexole than for placebo, but discontinuation due to AEs was less likely. Conclusions: During a 6-month period, pramipexole was effective, safe, and generally well tolerated. Because risk of augmentation may have increased over 6 months, it should be studied in longer trials. Beginning or mild augmentation is difficult to distinguish from natural RLS fluctuation, at least in a non-iron-deficient population. (C) 2011 Elsevier B.V. All rights reserved..