Elsevier

The Lancet Neurology

Volume 10, Issue 8, August 2011, Pages 710-720
The Lancet Neurology

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Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study

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Summary

Background

Safety and efficacy of non-ergot dopamine agonists for the treatment of idiopathic restless legs syndrome have been shown in short-term trials. We did a prospective open-label extension of a 6-week, double-blind randomised trial to assess the safety, tolerability, and efficacy of rotigotine transdermal patch for up to 5 years in patients with restless legs syndrome.

Methods

Patients (aged 18–75 years) with moderate-to-severe idiopathic restless legs syndrome were treated with once-daily rotigotine transdermal patch in 33 centres in Austria, Germany, and Spain between July 31, 2003, and April 15, 2009. The dose was titrated in weekly increments (up to 4 weeks) from 0·5 mg/24 h to a maximum of 4 mg/24 h, and was followed by up to 5 years of maintenance at the optimum dose. Primary safety outcomes included occurrence of adverse events and dropouts. Efficacy assessments were secondary and included the International Restless Legs Syndrome study group severity rating scale (IRLS). Augmentation of symptoms was assessed by means of standard diagnostic criteria and was confirmed by an international expert panel. All patients who received at least one dose of study drug were included in assessments. This study is registered with ClinicalTrials.gov, number NCT00498186.

Findings

295 patients entered the open-label study, of whom 126 (43%) completed 5 years of follow-up. 169 (57%) patients discontinued treatment, 89 (30%) because of adverse events and 31 (11%) because of lack of efficacy. 70 patients (24%) discontinued during year 1 of maintenance. The most common adverse events were application site reactions, which occurred in 37% (106/290) of patients in year 1, 17% (38/220) of patients in year 2, 14% (27/191) of patients in year 3, and in less than 6% of patients during year 4 (8/159) and year 5 (8/147). 56 patients (19%) discontinued because of application site reactions. Mean rotigotine dose was 2·43 mg/24 h (SD 1·21) after initial titration and 3·09 mg/24 h (1·07) at the end of maintenance. Of 89 patients who discontinued because of adverse events, 28 (31%) were on 4 mg/24 h rotigotine. Mean IRLS score of patients entering the open-label study was 27·8 (SD 5·9) at baseline of the double-blind trial. In patients who completed the maintenance period, mean IRLS score was reduced from a baseline score of 27·7 (SD 6·0) by a mean of 18·7 points (SD 9·5) to a score of 9·0 (SD 9·2) at the end of maintenance. 39% (48/123) of patients who completed the trial were classified as symptom free according to the IRLS. Clinically significant augmentation was recorded in 39 patients (13%), of whom 15 (5%) were receiving a dose of rotigotine within the range approved by the European Medicines Agency (EMA; 1–3 mg/24 h) and 24 (8%) were receiving 4 mg/24 h rotigotine.

Interpretation

Rotigotine transdermal patch is generally well tolerated after 1 year and provides sustained efficacy for patients with moderate-to-severe restless legs syndrome at a stable dose for up to 5 years. Thus, rotigotine transdermal patch is an appropriate long-term treatment option for moderate-to-severe restless legs syndrome, a disorder that often requires lifelong treatment.

Funding

UCB BioSciences, on behalf of Schwarz Pharma, Ireland.

Introduction

Idiopathic restless legs syndrome is a common, chronic neurological disorder that often requires long-term therapy,1 particularly if symptoms are severe, frequent, and impair daily activities and quality of life.2, 3 The disease has a circadian pattern, with symptoms worsening in the evening and at night.4 Patients with restless legs syndrome have an urge to move their legs or arms during periods of rest and inactivity, which is frequently accompanied by unpleasant sensations in these limbs. These sensations are uncomfortable for the patient, and can include paraesthesia, itching, or pain. Sleep disruption is a major complaint and can result in chronic loss of sleep. Daytime symptoms are sometimes masked because movement, especially walking, provides almost immediate relief. As disease severity increases, additional daytime symptoms develop and daytime functioning can become impaired.4

Dopamine agonists are the first-line treatment for moderate-to-severe restless legs syndrome.5 However, their efficacy has been investigated only in short-term double-blind trials (12 weeks,6, 7, 8, 9 or 6 months10, 11, 12) and in open-label trials of up to 1 year in duration.13, 14, 15 Rotigotine is a non-ergot dopamine agonist that has been shown to be well tolerated and efficacious in patients with restless legs syndrome in placebo-controlled trials of up to 6 months.10, 12 Additionally, findings of a polysomnographic study showed benefits on sleep.16 Rotigotine is administered via a transdermal patch; continuous 24-h transdermal drug delivery maintains stable concentrations in plasma.17 The patch is replaced once daily in the morning. This treatment schedule might be particularly advantageous for patients who have daytime symptoms or fluctuations in the time of symptom onset.

To investigate the long-term safety, tolerability, and efficacy of rotigotine transdermal patch in patients with moderate-to-severe restless legs syndrome, we did a prospective 5-year open-label extension of a 6-week randomised trial.18 Findings of interim analyses suggest that rotigotine transdermal patch provides sustained relief from symptoms of restless legs syndrome with a good safety and tolerability profile at 1 year19 and 2 years20 of follow-up.

Additionally, we did a retrospective systematic analysis of study data to investigate the 5-year incidence of augmentation of restless legs syndrome with rotigotine therapy. Augmentation is defined as an increase in the severity of symptoms beyond baseline levels, and represents the main complication of long-term dopaminergic treatment.21 Previous studies have indicated that the incidence of augmentation with rotigotine is low during 6 months22 and 1 year23 of treatment.

Section snippets

Patients

Patients completing the 6-week treatment period in a phase 2b, randomised, double-blind, placebo-controlled, dose-finding trial (SP709, NCT00243217)18 were given the opportunity to enter a single-arm open-label extension study (SP710) after tapering of randomly assigned study treatment. The extension study was done between July 31, 2003, and April 15, 2009, in 33 hospital outpatient units, university centres, sleep centres, or private neurology clinics in three European countries (Austria,

Results

Of 310 patients who completed the double-blind trial, 295 entered the open-label extension study (figure 1). Five patients (2%) discontinued during the open-label titration period and 70 (24%) discontinued during the first year of follow-up. In total, 169 patients (57%) discontinued treatment before the end of maintenance, 31 (11%) because of lack of efficacy and 89 (30%) because of adverse events. 126 patients (43%) completed the maintenance period.

Patients had a long history of restless legs

Discussion

The findings of our study show that rotigotine transdermal patch is generally well tolerated with a good safety profile for up to 5 years of treatment (panel). Application site reactions were the main tolerability issue and mostly occurred during the first year of maintenance. Efficacy was sustained for up to 5 years at a level consistent with that attained in the initial 6-week double-blind study.18 Few patients required a dose increase, although the most frequently applied dose in 44% of

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