Elsevier

The Lancet Neurology

Volume 7, Issue 7, July 2008, Pages 595-604
The Lancet Neurology

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Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S1474-4422(08)70112-1Get rights and content

Summary

Background

Continuous administration of a dopamine agonist could be used to treat patients with restless legs syndrome. Our aim was to investigate the efficacy of transdermal rotigotine in the treatment of idiopathic restless legs syndrome.

Methods

In this randomised, double-blind, placebo-controlled trial, 458 patients with moderate-to-severe idiopathic restless legs syndrome (average baseline International Restless Legs Syndrome Study Group severity rating scale [IRLS] sum score of 28·1) were randomly assigned to receive transdermal rotigotine 1 mg over 24 h (n=115), 2 mg over 24 h (n=112), or 3 mg over 24 h (n=114), or to receive placebo (n=117). Study medication was delivered via patches, applied once a day for 6 months. Randomisation was done with a computer-generated randomisation list, stratified by centre. Primary efficacy outcomes were absolute change from baseline to end of maintenance in IRLS sum score and in the clinical global impressions (CGI) item 1 score, assessed by analysis of covariance in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00136045.

Findings

Efficacy analyses were done on 112 patients in the 1 mg group, 109 in the 2 mg group, 112 in the 3 mg group, and 114 in the placebo group. Mean change in IRLS sum score from baseline at the end of the maintenance phase was −13·7 (SE 0·9) in the 1 mg group, −16·2 (0·9) in the 2 mg group, −16·8 (0·9) in the 3 mg group, and −8·6 (0·9) in the placebo group (p<0·0001 for treatment difference vs placebo with each dose). Mean change in CGI item 1 score from baseline at the end of the maintenance phase was −2·09 (0·14) in the 1 mg group, −2·41 (0·14) in the 2 mg group, −2·55 (0·14) in the 3 mg group, and −1·34 (0·14) in the placebo group (p<0·0001 for treatment difference vs placebo with each dose). Skin reactions, mostly mild or moderate, were seen in 145 (43%) of 341 patients who received rotigotine and in two (2%) of 117 who received placebo. Ten patients had serious adverse event that were deemed to be related to rotigotine: elevation of liver enzymes (one patient), worsening of tinnitus (one patient), non-response to anticoagulation (one patient), electrocardiogram changes (one patient), and application-site reactions (six patients). No admissions to hospital were needed for the application-site reactions, and they all resolved within a short time of patch removal without any other therapeutic intervention. The rate of typical dopaminergic side-effects in patients who received rotigotine was low; no signs of augmentation were noted.

Interpretation

24 h transdermal delivery of low-dose rotigotine could be used to relieve the night-time and daytime symptoms of restless legs syndrome.

Funding

Schwarz Biosciences.

Introduction

A recent genome-wide association study1 found a significant association of common genetic variants in three genomic regions with the risk for restless legs syndrome; one of these genomic regions was also found to be associated with periodic limb movements in patients with restless legs syndrome2 who have a substantially decreased quality of life compared with the general population.3, 4 These new findings suggest that restless legs syndrome might be regarded as a type of inborn error of the excitability of various structures, and accordingly needs to be treated as a general neurological disorder, rather than just a sleep disorder. Dopaminergic drugs but not hypnotics are currently the first-line treatment for this condition.5, 6

Previous treatment concepts have focused on the nocturnal aspects of restless legs syndrome, with single dopaminergic doses at bedtime to alleviate problems during the night. One possible treatment strategy, which also includes coverage of daytime symptoms, is via stable plasma concentrations of dopamimetics—ie, by administration of divided doses of an oral dopaminergic agent, or a transdermal patch with rotigotine, a non-ergot agonist of D3, D2, and D1 dopamine receptors. Rotigotine has already proven effective in the treatment of early and advanced Parkinson's disease7, 8 and has been approved for treatment of the signs and symptoms of early Parkinson's disease in the USA and for treatment of all stages of Parkinson's disease in Europe. A 1-week proof-of-concept trial9 and a 6-week dose-finding trial in patients with restless legs syndrome10 showed efficacy of the treatment and established the likely therapeutic window as rotigotine 1–3 mg every 24 h.10 Stable drug concentrations over 24 h might, in addition, be a favourable strategy to avoid augmentation, the main complication of long-term dopaminergic treatment.11, 12, 13 The primary objective of this trial was to investigate the efficacy of rotigotine in the treatment of idiopathic restless legs syndrome. We aimed to test whether transdermal administration of rotigotine for 24 h per day at the lowest levels of effctiveness can provide benefit to patients with restless legs syndrome during both day and night, and to investigate the safety of this transdermal system.

Section snippets

Patients

This double-blind, randomised, placebo-controlled, four-arm trial was done at 49 centres in eight European countries (Austria, Finland, Germany, Italy, Netherlands, Spain, Sweden, UK). Enrolment started in May, 2005; the trial was completed in August, 2006.

Patients aged 18–75 years with a diagnosis of idiopathic restless legs syndrome based on the four cardinal clinical features according to the International Restless Legs Syndrome Study Group (IRLSSG)14 who were either de-novo patients

Results

458 patients were randomly assigned to treatment (figure 2). The trial was completed by 313 (68%) patients; more patients in the placebo group than patients in each of the three rotigotine groups discontinued prematurely. In the rotigotine groups, withdrawal was highest in the 3 mg group. Lack of efficacy was the main reason for withdrawal in the placebo group, whereas adverse events were more frequent in the rotigotine groups (figure 2 and webtable 1). 447 (98%) patients were included in the

Discussion

The results of this 6-month trial indicate that transdermal delivery of low doses of rotigotine for 24 h per day are more effective than placebo in relieving the symptoms of restless legs syndrome in patients who are moderately to severely affected. This trial, together with a pilot study9 and dose-finding trial,10 suggest that, despite differences in treatment duration and other design features, there exists a clear therapeutic window in terms of dose of rotigotine to treat restless legs

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