Sleep Medicine 14 (2013) 1375–1380

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Original Article

Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire Richard Allen a,⇑, Wolfgang Oertel b, Arthur Walters c, Heike Benes d, Erwin Schollmayer e, Frank Grieger e, Kimberly Moran f, Ralf Kohnen g,h a

Johns Hopkins University, Baltimore, MD, USA Department of Neurology, Philipps-Universität, Marburg, Germany c Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN, USA d } r Medizinische Forschung und Schlafmedizin, Schwerin, Germany Somni Bene Institut fu e UCB Pharma, Monheim am Rhein, Germany f UCB Pharma, Smyrna, GA, USA g Research Pharmaceutical Services Inc., Fort Washington, PA, USA h University of Erlangen-Nuremberg, Nuremberg, Germany b

a r t i c l e

i n f o

Article history: Received 22 February 2013 Received in revised form 16 July 2013 Accepted 19 September 2013 Available online 18 October 2013 Keywords: CGI IRLS RLS-6 RLS-QoL Restless legs syndrome Willis-Ekbom disease

a b s t r a c t Background: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL. Methods: Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n = 458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed. Results: There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM. Conclusion: Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials. Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction Restless legs syndrome (RLS) is a sensory motor disorder characterized by an urge to move the limbs, often accompanied by unpleasant or uncomfortable sensations [1]. Symptoms are engendered by rest, relieved by movement, and worsen during the evening and at night [2]. Patients with moderate to severe RLS also experience chronic or episodic daytime symptoms that become more pronounced the more severe the RLS [1]. Due to

⇑ Corresponding author. Tel.: +1 410 550 1044; fax: +1 410 550 3364. E-mail address: [email protected] (R. Allen). 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.09.008

the subjective nature of RLS symptoms, assessment scales are particularly important for the clinical evaluation of the disease [3]. Clinical trials in patients with RLS generally include several different scales as outcome measures. The need for each assessment should be carefully considered, taking into account the potential value of the data and the added burden placed on trial participants. The International Restless Legs Syndrome Study Group rating scale (IRLS) is a validated disease-specific instrument for measuring RLS severity [4,5]. Although the IRLS is considered to be the gold standard for evaluating outcome in clinical trials [3,6], the clinical utility of this relatively new and disease-specific scale may be underrecognized. The SP790 study (ClinicalTrials.gov, NCT00136045) was a 6-month double-blind trial of rotigotine

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transdermal system in patients with moderate to severe idiopathic RLS [7]. Patients who were treated with rotigotine for up to 6 months achieved significantly greater improvements from baseline in IRLS sum score and Clinical Global Impression item 1 (CGI1) (severity of illness) score than patients who received placebo [7]. Our post hoc analysis used the SP790 data to assess associations between the IRLS and CGI-1, the IRLS and RLS-6, and the IRLS and RLS-quality of life questionnaire (RLS-QoL). The CGI-1 offers a generic means for the treating physician to assess a patient’s disease severity. The descriptive titles of the RLS-6 domains (symptom severity at various time points during the day, daytime tiredness, and sleep satisfaction) may provide a narrative context for the numeric values of the IRLS. Associations between the IRLS and RLS-QoL may indicate whether IRLS scores relate to meaningful benefits from the patient’s perspective of the impact of RLS symptoms on sleep, activities of daily living, mood, and social interactions. Our study provides a frame of reference for what a change in IRLS score means from a clinical perspective. Our results may aid in guiding the choice of subjective assessment scales for RLS trials and in determining whether multiple scales are needed. 2. Methods 2.1. SP790 study design The SP790 study was a phase 3, double-blinded, randomized, placebo-controlled trial of rotigotine transdermal system in patients with moderate to severe idiopathic RLS [7]. Eligibility criteria included a diagnosis of idiopathic RLS as confirmed by the standardized diagnostic interview [8], an initial response to previous dopaminergic treatment or no previous dopaminergic treatment, an IRLS sum score of P15 at baseline (i.e., at least ‘‘moderate’’ severity), and a CGI-1 score of P4 points (i.e., at least ‘‘marked’’ severity). Following a 3-week titration, patients received their randomized fixed dose of rotigotine (1, 2, or 3 mg/24 h) or placebo for a 6-month maintenance period. Primary efficacy variables were the absolute change from baseline to end of maintenance (EoM) (last observation carried forward approach) in IRLS sum score and CGI-1 score; secondary efficacy variables included change from baseline in RLS-6 and RLS-QoL. The CGI was completed by an experienced clinician who was not permitted to perform any other assessments at the study visit and who was blinded to the patient-reported outcome measures. Detailed methods have been previously reported [7]. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice and was approved by the relevant institutional review boards or ethics committees. Written informed consent was obtained from all patients prior to participation. 2.2. Scale association analyses The 10-item patient-rated IRLS was based on the diagnostic criteria for RLS as defined by the International Restless Legs Syndrome Study Group [9]. The questions assess the severity and frequency of RLS symptoms and their impact on sleep, mood, and daily life. Each item is graded from 0 to 4, giving a maximum total score of 40, which represents very severe RLS. The IRLS can also be divided into distinct subscales for symptom intensity and symptom impact [4,10]. The CGI [11] represents a more direct clinical assessment of generic disease severity; it is completed by the clinician based on consultation with the patient. The scale was originally developed for the assessment of psychiatric disorders and is made up of four separate items: Severity of illness (CGI-1), Global rating of change of condition (CGI-2), Therapeutic effect (CGI-3),

and Side effects (CGI-4). CGI-1 and CGI-2 are graded from 1 to 7, whereas a 4-point rating is used for CGI-3 and CGI-4. The validated RLS-6 scale is used to assess the severity of RLS symptoms during various time periods (at bedtime, during the night, when resting during the day, and when active), as well as sleep satisfaction and daytime sleepiness [12]. The scale consists of six separate items which are each highly descriptive of either RLS symptoms or the impact of RLS symptoms. Items are graded from 0 to 10. The effects of RLS on quality of life can be assessed using the RLS-QoL, which was developed by Kohnen et al. [13]. This validated 12-item questionnaire asks about the impact of RLS symptoms on sleep, activities of daily living, mood, and social interactions [13]. Each question is graded into one of six severity categories with answers ranging from ‘‘absent’’ (0 points) to ‘‘very strong’’ (5 points), giving a maximum total score of 60, which indicates severely impaired quality of life. Post hoc scale association analyses were performed using data for the overall safety set (all rotigotine- and placebo-treated patients combined). Scale associations were analyzed as categorical and continuous variables. For the categorical analyses, IRLS categories were defined as 0–10 (mild), 11–20 (moderate), 21–30 (severe), and 31–40 (very severe) [5]. Association analyses were performed as the IRLS category vs the mean and median score for comparator scale, and as the IRLS score vs comparator scale scores (continuous analysis). Association analyses were performed at baseline and EoM (last observation carried forward). In addition, scale associations for change from baseline to EoM in IRLS scores vs comparator scale scores were analyzed. For continuous assessments, the magnitude of the relationship between IRLS scores and CGI, RLS-6, and RLSQoL scores was analyzed using Pearson product moment correlation coefficients.

3. Results 3.1. Baseline characteristics and patient disposition Detailed demographics for each of the SP790 treatment groups have been reported previously [7]. Our analysis included data from all 458 randomized patients, of which 341 received rotigotine and 117 received placebo. Most patients had severe or very severe RLS symptoms at baseline as indicated by their IRLS scores (mean IRLS sum score, 28.1; range, 15–40). In total, 313 patients completed the study. Baseline characteristics are shown in Table 1. 3.2. IRLS scale association analyses 3.2.1. IRLS and CGI-1 All 458 randomized patients had IRLS and CGI-1 data at baseline, and 436 patients had these data at EoM. At both time points, increasing IRLS severity category corresponded with increasing mean and median CGI-1 score (Fig. 1). When assessed as continuous variables, IRLS and CGI-1 were well correlated at baseline (r = 0.615) and EoM (r = 0.843), and for the change from baseline to EoM (r = 0.793) (Table 2). 3.2.2. IRLS and RLS-6 The IRLS and RLS-6 data were available for all patients at baseline, and for 436 patients at EoM. For all RLS-6 items, increasing IRLS severity category showed a correspondence with increasing mean and median RLS-6 score (Fig. 2). Continuous analyses showed correlations between IRLS and RLS-6 item scores at baseline and EoM, as well as correlations for changes from baseline to EoM (Table 2).

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R. Allen et al. / Sleep Medicine 14 (2013) 1375–1380 Table 1 Baseline demographics. Safety set (n = 458) Age, mean y ± SD (range) Age