Elsevier

Sleep Medicine

Volume 14, Issue 11, November 2013, Pages 1085-1091
Sleep Medicine

Original Article
Efficacy and safety of rotigotine in Japanese patients with restless legs syndrome: a phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group study

https://doi.org/10.1016/j.sleep.2013.07.007Get rights and content

Abstract

Objective

We aimed to ascertain the efficacy and safety of transdermal rotigotine (2 and 3 mg/24 h) in Japanese patients with restless legs syndrome (RLS).

Methods

In our double-blind placebo-controlled study, 284 Japanese patients with idiopathic RLS were randomly assigned to receive rotigotine 2 mg/24 h or 3 mg/24 h, or placebo, for 13 weeks. The primary endpoint was the change in International Restless Legs Syndrome Study Group rating scale (IRLS) total score.

Results

The placebo-subtracted decreases in IRLS total score for rotigotine 2 mg/24 h and 3 mg/24 h were −2.8 ± 1.3 and −3.1 ± 1.3, respectively, which were significant (P < 0.05). The interaction between baseline Pittsburgh Sleep Quality Index (PSQI) and treatment group for the change in IRLS total score was significant, indicating greater improvements in IRLS total score in patients with severe insomnia. Overall, 80.0%, 86.2%, and 51.6% of patients in the rotigotine 2 mg/24 h, 3 mg/24 h, and placebo groups, respectively, experienced adverse events (AEs) including application site reactions in 42.1%, 50.0%, and 7.4% of patients, respectively. None of the AEs were severe.

Conclusions

Our results showed that rotigotine was effective without major safety concerns at doses of up to 3 mg/24 h in Japanese patients with RLS.

Introduction

Restless legs syndrome (RLS) is a sensorimotor disorder associated with abnormal sensations, particularly in the legs [1], [2]. Patients often have a strong desire to move the affected extremities and these sensations are either completely or partially relieved by voluntary movements such as walking. These symptoms are aggravated at rest during the night and often lead to insomnia [3]. Serious RLS can result in daytime sleepiness or malaise associated with nocturnal sleep deprivation, resulting in deteriorated quality of life, depression, and anxiety disorders [4], [5], [6]. RLS is also known to be a risk factor for the development of cardiovascular disease [7], [8]. Several epidemiologic surveys have been conducted using the International Restless Legs Syndrome Study Group (IRLSSG) and the National Institutes of Health (NIH) criteria [9] and revealed that the morbidity of RLS ranges from 5% to 10% in Western countries [4], [10], [11] and from 2% to 4% in Japan [12], [13].

The four essential criteria for RLS established by the IRLSSG/NIH [9] are as follows: (1) an urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs; (2) an urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting; (3) an urge to move or unpleasant sensations are partially or totally relieved by movements, such as walking or stretching, at least as long as the activity continues; and (4) an urge to move or unpleasant sensations that become clearly worse in the evening or at night than during the day or only occur during these periods.

For pharmacotherapy, dopamine receptor agonists are regarded as the first-line treatment of moderate to severe RLS [14], [15], [16], [17]. Rotigotine is a non-ergot-derived dopamine agonist for all dopamine receptors (D1–D5), with highest affinity for the D3 dopamine receptor [18], [19]. When formulated as a patch, stable plasma concentrations of the drug can be maintained over a 24-h period by continuous delivery [20], allowing control of RLS symptoms during both the daytime and the nighttime [21], [22]. To date several clinical trials have been conducted in the United States and Europe to confirm the superiority of the treatment response with rotigotine to that with placebo [21], [22]. However, such studies have not yet been conducted in Asian patients. Moreover, the effects of rotigotine on subjective insomnia associated with RLS have not been confirmed. For these reasons, we investigated the efficacy of rotigotine (2 mg/24 h and 3 mg/24 h) on RLS symptoms, the RLS-associated subjective sleep disturbances using an authorized sleep disturbance questionnaire, and the safety of rotigotine (2 mg/24h and 3 mg/24 h) in Japanese patients with idiopathic RLS.

Section snippets

Patients

Our phase 3, multicenter (44 institutions in Japan), randomized, double-blind, placebo-controlled, parallel-group study of Japanese patients with idiopathic RLS was conducted between February 2010 and December 2010. Patients who fulfilled the following inclusion criteria were enrolled: (1) ages 20 to <80 years at the time of providing informed consent, (2) diagnosis of RLS fulfilling all four items of the IRLSSG/NIH criteria, (3) responsive to prior dopaminergic therapy or no prior treatment for

Patient characteristics

Of the 480 enrolled patients, 196 were withdrawn before randomization. Therefore, 284 were randomized with 95, 94, and 95 patients assigned to the rotigotine 2 mg/24 h, 3 mg/24 h, and the placebo groups, respectively (Fig. 1). All of these patients were included in the FAS and SAS. Down-titration was performed in five patients (5%) in the rotigotine 2 mg/24 h group and 10 patients (11%) in the 3 mg/24 h group. Treatment was discontinued in 31 patients (14, 8, and 9 patients in the rotigotine 2 mg/24 h, 3 

Discussion

Our study was conducted to confirm the superiority of rotigotine at doses of 2 mg/24 h and 3 mg/24 h to placebo; both doses were found to be superior to placebo in the improvement in IRLS total score from baseline to the EOT. Notably a larger proportion of patients experienced a ⩾50% improvement in IRLS total score in both rotigotine groups compared with the placebo group. The mean changes in IRLS total scores in our study were −14.3 and −14.6 for the rotigotine 2 mg/24 h and the 3 mg/24 h groups,

Conflict of interest

The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.07.007.

. ICMJE Form for Disclosure of Potential Conflicts of Interest form.

Acknowledgments

Our study was financially supported by Otsuka Pharmaceutical Co, Ltd., Japan. The authors wish to thank Nicholas D. Smith, PhD and Daniel McGowan, PhD for providing medical writing services.

Members of the Rotigotine Trial Group: Masako Kousaka, Osamu Kanno, Takashi Kanbayashi, Yasuyuki Kaneko, Souichi Katayama, Taku Hatano, Miho Murata, Tohru Nakajima, Takurou Endo, Kayo Shibui, Kenichi Hayashida, Kouji Tada, Masazumi Komagamine, Hideo Muraoka, Kazuhira Miki, Mitsuo Sasaki, Haruhito Tanaka,

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