Study No Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable(s):

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1 Studies listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: SKF /190 Title: A 12 Week, Double-Blind, Placebo-Controlled, Parallel Group Study to Assess the Efficacy and Safety of in Patients Suffering from Restless Legs Syndrome (RLS). Rationale: RLS is a neurological disorder characterised by uncomfortable sensations (dysthesias or paresthesias) in the legs and less frequently in the arms. These sensations are often described as creeping, crawling, burning or pulling sensations and are accompanied by an urge to move the limbs. The urge to move and uncomfortable sensations occur primarily during periods of rest or inactivity, are generally relieved at least temporarily by movement and are worse in the evening or night. is a non-ergot dopamine agonist. There was evidence from clinical studies cited in the literature for the role of ropinirole in the treatment of RLS. Thus on the basis of this evidence there was reason to believe that ropinirole could be beneficial in this disease area. Thus, the aim of this placebo-controlled, parallel group, flexible dose study was to evaluate the efficacy and safety of ropinirole in the treatment of RLS. Phase: III Study Period: 8 November August 2002 Study Design: This was a multicentre, randomized, double-blind, placebo-controlled, parallel group study evaluating the efficacy and tolerability of ropinirole in comparison to placebo () in the treatment of subjects suffering from RLS. Centres: 43 centres in Austria, Belgium, France, Germany, Italy, Netherlands, Norway, Spain, Sweden and the United Kingdom. Indication: Idiopathic Restless Legs Syndrome Treatment: Subjects were randomized (1:1) to receive oral ropinirole (flexible dose, ranging from 0.25mg/day to 4mg/day once daily) or matched for 12 weeks. Objectives: The primary objective of this pivotal phase III study was to compare the efficacy of ropinirole and in the treatment of subjects with RLS. Primary Outcome/Efficacy Variable(s): The primary efficacy variable was the mean change from baseline in the Week 12 Last Observation Carried Forward (LOCF) endpoint of the International Restless Legs Syndrome Study Group Rating (IRLS) Scale total score. Secondary Outcome/Efficacy Variable(s): Key secondary efficacy variables within the Primary Inferential set were: The proportion of subjects with a score of much improved (2) or very much improved (1) on the Clinical Global Impression Improvement of illness (CGI-I) Scale at Week 12 LOCF endpoint The mean change in the IRLS Scale Total score at Week 1 observed case (OC) endpoint The proportion of subjects with a score of much improved (2) or very much improved (1) on the CGI-I Scale at Week 1 LOCF endpoint. The secondary efficacy variables were as follows: Time to first response, where response is defined as a decrease of 6 points or more relative to the subject s score at baseline on the IRLS Scale total score. Time to score of much improved (2) or very much improved (1) on the CGI-I Scale. Mean change from baseline in the Sleep Disturbance, Sleep Quantity, Sleep Adequacy and Somnolence domains of the Medical Outcomes Study (MOS) Sleep Scale at endpoint. Mean change from baseline in the parameters of the Work Productivity and Activity Impairment (WPAI) Questionnaire at endpoint (percentage of work time missed due to RLS, percentage of impairment while working due to RLS, percentage of overall work impairment due to RLS, and percentage of activity impairment due to RLS). Mean change from baseline in the overall life impact score of the RLS Quality of Life Questionnaire at endpoint. Mean change from baseline in the domains of the Short Form 36 (SF-36) Health Survey at endpoint. Statistical Methods: Hierarchical testing was utilized. A primary inferential set of hypotheses was defined and the hypotheses were tested in the order given, only proceeding to the next one if all previous hypotheses were rejected for the Intent-to-Treat (ITT) population, as follows: (i) Primary endpoint null hypothesis: no difference between ropinirole and in the change from baseline in the IRLS Scale total score at Week 12 LOCF; (ii) Secondary endpoint 1 null hypothesis: no difference between ropinirole and in the proportion of subjects with a score of much improved or final 10 Feb 05 1

2 very much improved on the CGI-I Scale at Week 12 LOCF; (iii) Secondary endpoint 2 null hypothesis: no difference between ropinirole and in the change from baseline in the IRLS Scale total score at Week 1 Observed Case (OC); (iv) Secondary endpoint 3 null hypothesis: no difference between ropinirole and in the proportion of subjects with a score of much improved or very much improved on the CGI-I Scale at Week 1 LOCF. The variables in the primary inferential set, and the order of testing, were defined prior to the unblinding of the study. For continuous efficacy variables, the change from baseline to study endpoint was analyzed using parametric analysis of covariance, with results presented as the adjusted mean change for each treatment group, the difference in means between groups, associated 95% confidence interval (CI) and p-value. For dichotomous efficacy variables, logistic regression models were fitted to the binary endpoints, with results presented as the adjusted odds ratio, associated 95% CI and p-value. Time to event data were analyzed using Cox s regression model, with results presented as the hazard ratio, 95% CI and p-value. Kaplan-Meier survival curves and survival estimates of the time to event data were also presented. The statistical model on which the inference for the primary efficacy variable was based included prespecified terms for country, baseline IRLS Scale total score and treatment group, regardless of significance. The Safety population consisted of all randomized subjects who received at least one dose of study medication. The ITT population consisted of all randomized subjects who received at least one dose of study medication and who had at least one post-baseline efficacy assessment available. Study Population. Males or females aged years, with RLS diagnosed using the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria with a history of a minimum of 15 nights of RLS symptoms during the previous month and a total score 15 on the IRLS Scale at baseline. If the subject was receiving medication for the treatment of RLS, the investigator was to use best clinical judgement to assess whether that subject would have suffered from a minimum of 15 nights with RLS symptoms if they had not been taking any medication. Subjects with signs of secondary RLS were excluded. Number of Subjects: Planned, N Randomized, N Safety Population, n ITT Population, n Completed, n (%) 112 (76.7) 109 (79.0) Total Number Subjects Withdrawn, nn (%) 34 (23.3) 29 (21.0) Withdrawn due to Adverse Events n (%) 16 (11.0) 6 (4.3) Withdrawn due to Lack of Efficacy n (%) 4 (2.7) 11 (8.0) Withdrawn for other reasons n (%) 14 (9.6) 12 (8.7) Demographics ITT Population: N Females: Males 88:58 91:47 Mean Age, years (SD) 54.0 (11.13) 56.2 (11.20) White, n (%) 144 (98.6) 137 (99.3) Primary Efficacy Results: IRLS Scale Total Score at Week 12 LOCF Mean Score at Baseline (SD) 24.4 (5.75) 25.2 (5.63) (0.72) -8.0 (0.74) Adjusted treatment difference % Confidence Interval -5.0, -1.0 p value Secondary Outcome Variable(s): CGI-I Score at Week 12 LOCF Subjects Very much improved (1) Or Much improved (2) n (%) 78/146 (53.4) 56/137 (40.9) Adjusted Odds Ratio % Confidence Interval 1.0, 2.7 IRLS Scale Total Score at Week 1 OC Placebo Baseline n (0.59) -5.1 (0.62) Adjusted Treatment Difference % Confidence Interval -4.7, -1.4 final 10 Feb 05 2

3 CGI-I Score at Week 1 LOCF Subjects Very much improved (1) or Much improved (2) n (%) 50/146 (34.2) 18/137 (13.1) Adjusted Odds Ratio % Confidence Interval 2.0, 6.9 Time to First Response - IRLS Score decrease of 6 pts relative to baseline Median (days) 7 12 Hazard Ratio % Confidence Interval 1.18, 1.95 Time to score Much Improved (2) or Very Much Improved (1) on CGI-I Median (days) Hazard Ratio % Confidence Interval 1.39, 2.42 MOS Study Sleep Scale Change From Baseline in Domains to Week 12 LOCF Sleep Disturbance (0-100 points) (1.97) (2.02) Adjusted Treatment Difference % Confidence Interval -13.2, -2.2 Sleep Quantity (Hours) Baseline n (0.12) 0.3 (0.13) Adjusted Treatment Difference % Confidence Interval 0.0, 0.7 Sleep Adequacy (0-100 points) 19.3 (2.39) 8.4 (2.45) Adjusted Treatment Difference % Confidence Interval 4.2, 17.6 Somnolence (0-100 points) -9.8 (1.55)) -4.8 (1.60) Adjusted Treatment Difference % Confidence Interval -9.4,-0.6 WPAI Change from Baseline in Domains to Week 12 LOCF % Work Time Missed Due to RLS Baseline n (1.16) -1.6 (1.22) Adjusted Treatment Difference % Confidence Intervals -1.3, 5.3 % Impairment While Working Due to RLS Baseline n (2.07) -6.1 (2.07) Adjusted Treatment Difference -2.5 final 10 Feb 05 3

4 95% Confidence Interval -8.2, 3.2 % Overall Work Impairment Due to RLS Baseline n (2.36) -7.0 (2.47) Adjusted Treatment Difference % Confidence Interval -5.9, 7.4 % Activity Impairment Due to RLS Baseline n Adjusted Change from (1.76) -9.3 (1.80) Adjusted Treatment Difference % Confidence Intervals -7.4, 2.4 RLS Quality of Life Overall Life Impact Baseline, n (1.44) 12.6 (1.47) Baseline to Week 12 LOCF Adjusted Treatment Difference % Confidence Interval 0.4, 8.4 SF-36 Health Survey Change From Baseline in Domains to Week 12 LOCF (Part 1) Physical Functioning Baseline, n (1.31) 4.1 (1.34) Adjusted Treatment difference % Confidence Interval -5.7, 1.6 Bodily Pain Baseline, n (1.84) 8.5 (1.89) Adjusted Treatment difference % Confidence Interval -9.0, 1.3 Role - Physical Baseline, n (3.04) 5.0 (3.11) Adjusted Treatment difference % Confidence Interval -4.3, 12.8 Role - Emotional Baseline, n (2.92) 10.9 (3.01) Adjusted Treatment difference % Confidence Interval -4.1, 12.3 SF-36 Health Survey Change From Baseline in Domains to Week 12 LOCF (Part 2) Mental Health Baseline, n (1.28) 4.7 (1.30) Adjusted Treatment difference % Confidence Interval -3.4, 3.7 Social Functioning final 10 Feb 05 4

5 Baseline, n (1.72) 8.0 (1.76) Adjusted Treatment difference % Confidence Interval -6.1, 3.6 Vitality Baseline, n (1.47) 6.2 (1.51) Adjusted Treatment difference % Confidence Interval -2.1, 6.2 General Health Baseline, n (1.23) 1.6 (1.26) Adjusted Treatment difference % Confidence Interval -3.8, 3.1 Safety Results: All AEs occurring after administration of the first dose of study medication and on or before the final visit were to be reported on the AE form in the Case Report Form (CRF). All AEs had to be recorded irrespective of whether they were considered drug related..an on- therapy adverse event (AE) was defined as an AE with onset on or after the start date after the medication but not later than the last date of the study medication. An on therapy serious adverse event (SAE) was defined as a SAE with onset on or after the start date of study medication and up to 30 days after the last dose of medication. Most Frequent Adverse Events On-Therapy Subjects with any AE(s), n(%) 120 (82.2) 103 (74.6) Nausea 55 (37.7) 9 (6.5) Headache 29 (19.9) 23 (16.7) Vomiting 19 (13.0) 2 (1.4) Abdominal Pain 18 (12.3) 12 (8.7) Somnolence 18 (12.3) 10 (7.2) Upper Respiratory Tract Infection 14 (9.6) 15 (10.9) Dizziness 12 (8.2) 7 (5.1) Insomnia 10 (6.8) 12 (8.7) Fatigue 9 (6.2) 8 (5.8) Arthralgia 8 (5.5) 5 (3.6) Dyspepsia 7 (4.8) 5 (3.6) Mouth Dry 5 (3.4) 7 (5.1) Pharyngitis 2 (1.4) 5 (3.6) Hyperkinesia 1 (0.7) 5 (3.6) Depression 1 (0.7) 5 (3.6) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with Any SAEs, n (%) includes both fatal and non-fatal events 3 (2.1) 6 (4.3) n (%) [related] n (%) [related] Fever 0 2 (1.4) [0] Injury 1 (0.7) [0] 0 Syncope 0 1 (0.7) [0] Abdominal Pain 0 1 (0.7) [0] Gastrointestinal Disorder NOS 1 (0.7) [0] 0 Menstrual Disorder 1 (0.7) [0] 0 final 10 Feb 05 5

6 Pharyngitis 0 1 (0.7) [0] Urinary Tract Infection 0 1 (0.7) [0] Injury 0 1 (0.7) [0] Cholelithiasis 0 1 (0.7) [0] Endocarditis 0 1 (0.7) [0] Subjects with fatal SAEs, n (%) 0 0 Conclusion: See publication below. Publications: Trenkwalder C, Garcia-Borreguero D, Montagna P, Lainey E, de Weerd A W, Tidswell P, Saletu-Zyhlarz G, Telstad W, Ferini-Strambi L, on behalf of the TREAT RLS 1 Study Group. in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry 2004; 75: Date Updated: 01-Mar-2005 final 10 Feb 05 6