The study 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.: RRL100013 Title: A 12-Week, Double-Blind, -Controlled, Twice-Daily Dosing Study to Assess the Efficacy and Safety of in Patients Suffering from Restless Legs Syndrome (RLS) Requiring Extended Treatment Coverage Rationale: The approved dosage regimen for ropinirole in the treatment of RLS is a flexible titration regimen (0.25-4 mg) with once daily dosing, 1-3 hours prior to bedtime. Because many subjects with RLS experience evening and night-time symptoms, once daily dosing may be adequate to cover the majority of symptoms. However, some subjects experience an earlier onset of symptoms in late afternoon and early evening. For these subjects with earlier onset of symptoms, or with more severe symptoms, a twice daily regimen with dosing in the early evening and again in the late evening or bedtime may demonstrate improved efficacy. In addition, these subjects may also benefit from increased doses up to a total of 6 mg/day. This study was conducted to test efficacy and safety of ropinirole, administered twice daily, in these subjects. Phase: IIIb Study Period: 24 October 2004-15 July 2005. Study Design: Multicenter, double-blind, randomized, parallel group study. Centres: 47 centers in the United States. Indication: Primary (idiopathic) Restless Legs Syndrome. Treatment: Twelve-week randomized (1:1) flexible dose treatment phase with either oral ropinirole IR (0.5 mg total/day to 6 mg total/day) or matching placebo, using a twice daily dosing regimen (early evening and bedtime dose). Objectives: Primary: To compare the efficacy and safety of ropinirole and placebo using a twice daily dosing regimen in subjects with RLS requiring extended treatment coverage. Primary Outcome/Efficacy Variable: The primary endpoint was mean change from baseline in the International Restless Legs Syndrome Rating Scale (IRLS Rating Scale) total score at Week 12 last observation carried forward (LOCF). Secondary Outcome/Efficacy Variable(s): Key Secondary Efficacy Variables, within the Primary Inferential Set Proportion of subjects with a score of much improved (2) or very much improved (1) (i.e., responders) on the CGI-I scale at Week 12 LOCF. Change from baseline in the IRLS Rating Scale total score at Day 3 observed case (OC). Proportion of responders on the CGI-I scale at Day 3 OC. Proportion of subjects scoring much (2) or very much (1) improved on the PGI scale on Days 1 through 7 LOCF. Secondary Efficacy Variables: Change from baseline in the Sleep Disturbance, Sleep Quantity, Sleep Adequacy and Daytime Somnolence domains, and the Sleep Problems Index II, of the Medical Outcomes Study (MOS) Sleep Scale at Week 12 LOCF. Change from baseline in the domains of the RLS Quality of Life (QoL) Questionnaire at Week 12 LOCF. Change from baseline in the Profile of Mood States (POMS) scale at Week 12 LOCF. Change from baseline in the Hospital Anxiety and Depression Scale (HADS) at Week 12 LOCF. Time to response, where response was defined as a score of much improved (2) or very much improved (1) on the CGI-I scale. Proportion of subjects reporting that they were satisfied or very satisfied on the Patient Satisfaction Question at Week 12 or early withdrawal. Change from baseline in the number of periodic limb movements (PLMs) as measured by actigraphy at Week 12. Change from baseline in the number of periodic limb movements per hour (PLM Index; PLMI) as measured by actigraphy at Week 12. Change from baseline in the global score of the Pittsburgh Sleep Quality Index at Week 12 LOCF. Proportion of subjects with a global score >5 on the Pittsburgh Sleep Quality Index at Week 12 LOCF. Statistical Methods: A hierarchical hypothesis testing approach was applied to the analysis of endpoints in the primary inferential set to maintain the overall Type I error rate. If at any stage in the hierarchy there was insufficient evidence to reject a null hypothesis (i.e., p>0.05), no further hypothesis testing was reported. The primary null 1
hypothesis was that there was no difference between ropinirole and placebo for the change from baseline in IRLS Rating Scale Total Score for the Week 12 LOCF endpoint in the intention-to-treat (ITT) population. A two-sided hypothesis test was conducted at the 5% significance level. All other comparisons of ropinirole versus placebo in the primary inferential set, which included four secondary endpoints, were made in the ITT population at the 5% level of significance. The statistical model on which the primary inference was based, for the primary endpoint of change from baseline in IRLS Rating Scale score at Week 12 LOCF, included terms for baseline total IRLS Rating Scale score and treatment group, regardless of their significance. The results were presented as the point estimate and 95% confidence interval (CI) for the difference between ropinirole and placebo. Continuous secondary efficacy variables were analyzed by analysis of covariance fitting terms for baseline and treatment group. Dichotomous secondary efficacy variables were analyzed using logistic regression fitting term for treatment group. The time to response was analyzed based on the Kaplan-Meier method. Safety endpoints were summarized using descriptive statistics. 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. An actigraphy subgroup analysis was conducted for the actigraphy subgroup which included ITT subjects with an average PLMI over 3 nights at baseline of 10 or greater in at least one leg. A HADS subgroup analysis was conducted for the HADS-Anxiety and HADS-Depression subgroups, which included ITT subjects with a baseline score of 8 or greater on the respective HADS domain. Study Population: Key inclusion criteria included: Subjects 18 years and <80 years of age diagnosed with RLS using IRLSSG diagnostic criteria. A history of a minimum of 15 nights of RLS symptoms during the previous month. Discontinuation of any medications to treat RLS or sleep. If the subject was receiving medication for the treatment of RLS or sleep prior to the baseline visit, the medication was discontinued for 5 half-lives or 10 consecutive nights prior to baseline, whichever was the longer period. During the washout and screening phase, RLS symptoms must have been present for at least 4 of the 7 nights immediately prior to baseline. Total score 20 on the International Restless Legs Syndrome (IRLS) Rating Scale and total score 15 on the Insomnia Severity Index at baseline. Experiencing RLS symptom onset no earlier than 5pm, and prior to the onset of bedtime. Key exclusion criteria included: Subjects who suffered from a primary sleep disorder other than RLS that may have significantly affected the symptoms of RLS. Subjects with signs of secondary RLS. Subjects suffering from movement disorders (i.e. Parkinson s disease, dyskinesias or dystonias). Subjects with augmentation and/or end-of-dose rebound symptoms at baseline. Subjects who had exhibited intolerance to ropinirole or any other dopamine agonist. 2
Number of Subjects: Planned, N 180 180 Randomised, N 187 176 Safety Population, n (%) 186 (99) 176 (100) ITT Population, n (%) 184 (98) 175 (99) HADS Anxiety Subgroup, n (%) 80 (43) 69 (39) HADS Depression Subgroup, n (%) 79 (42) 68 (39) Actigraphy Subgroup, n (%) 88 (47) 86 (49) Completed, n (%) 160 (86) 150 (85) Total Number Subjects Withdrawn, n (%) 27 (14) 26 (15) Withdrawn due to Adverse Events n (%) 6 (3) 8 (5) Withdrawn due to Lack of Efficacy n (%) 3 (2) 0 Withdrawn for other reasons n (%) 18 (10) 18 (10) Demographics N (Safety) 186 176 Females : Males 108 : 78 109 : 67 Mean Age, years (SD) 50.4 (13.07) 51.4 (13.80) African American/ Black, n (%) 2 (1) 6 (3) American Indian/ Alaska Native, n (%) 6 (3) 5 (3) Asian/ Mixed Asian, n (%) 1 (<1) 0 White/ Mixed White, n (%) 173 (93) 163 (93) Not Recorded, n (%) 4 (2) 2 (1) Primary Efficacy Results: Adjusted Analysis of Change from Baseline for IRLS Rating Scale Total Score at Week 12 LOCF: ITT population IRLS Rating Scale Total Score (0-40 Scale) N=184 N=175 Score at Baseline n=184 n=175 Mean (SD) 26.0 (4.25) 26.0 (4.70) Score at Week 12 LOCF n=184 n=175 Mean (SD) 14.6 (9.67) 10.5 (9.51) Adjusted Change from Baseline to Week 12 LOCF n=184 n=175 Adjusted Mean (SE) -11.44 (0.70) -15.55 (0.72) Adjusted Treatment Difference at Week 12 LOCF Mean (95% CI) -4.11 (-6.08, -2.14) P-Value <0.001 Secondary Efficacy Results: Secondary Efficacy Variables within the Primary Inferential Set (in order of testing): 3
Adjusted Analysis of the Proportion of Responders on the CGI-I Scale at Week 12 LOCF: ITT Population Adjusted Odds Ratio 95% CI Subjects with Score of Much or Very Much Improved on CGI-I Week 12 LOCF 50% (92/184) 71% (124/175) 2.43 (1.57, 3.76) Adjusted Analysis of Change from Baseline for IRLS Rating Scale Total Score at Day 3 OC: ITT Population IRLS Rating Scale Total Score (0-40 Scale) N=184 N=175 Score at Baseline n=184 n=175 Mean (SD) 26.0 (4.25) 26.0 (4.70) Score at Day 3 OC n=171 n=160 Mean (SD) 21.0 (7.31) 18.2 (8.73) Adjusted Change from Baseline to Day 3 OC n=171 n=160 Adjusted Mean (SE) -5.08 (0.57) -7.91 (0.59) Adjusted Treatment Difference at Day 3 OC Mean (95% CI) -2.83 (-4.45, -1.21) Adjusted Analysis of the Proportion of Responders on the CGI-I Scale at Day 3 OC: ITT Population Adjusted Odds Ratio 95% CI Subjects with Score of Much or Very Much Improved on CGI-I Day 3 OC 15% (26/169) 32% (51/159) 2.60 (1.52, 4.43) Adjusted Analysis of the Proportion of Responders on the PGI Scale on Day 1 through Day 7 LOCF: ITT Population Adjusted Odds Ratio 95% CI Subjects with Score of Much or Very Much Improved on PGI Scale Day 1 OC 14% (26/180) 25% (43/171) 1.99 (1.16, 3.42) Day 2 LOCF 14% (26/181) 31% (53/171) 2.68 (1.58, 4.53) Day 3 LOCF 17% (31/182) 30% (52/171) 2.13 (1.28, 3.53) Day 4 LOCF 15% (28/183) 35% (61/173) 3.01 (1.81, 5.02) Day 5 LOCF 20% (37/183) 33% (57/173) 1.94 (1.20, 3.13) Day 6 LOCF 20% (36/183) 35% (60/173) 2.17 (1.34, 3.51) Day 7 LOCF 25% (46/183) 37% (64/173) 1.75 (1.11, 2.76) 4
Secondary Efficacy Variables: Adjusted Analysis of Change from Baseline for Continuous Secondary Efficacy Variables: ITT Population (unless otherwise indicated) Adjusted Mean (SE) Change from Baseline N=184 N=175 Adjusted Difference 95% CI MOS Sleep Scale - Sleep Disturbance Domain (0-100 Scale) Week 12 LOCF -20.27 (2.00) -29.73 (2.05) -9.46 (-15.11, -3.82) MOS Sleep Scale - Sleep Quantity Domain (Hours) Week 12 LOCF 0.49 (0.09) 0.49 (0.09) -0.01 (-0.26, 0.24) MOS Sleep Scale - Sleep Adequacy Domain (0-100 Scale) Week 12 LOCF 13.11 (2.06) 17.70 (2.11) 4.59 (-1.22, 10.4) MOS Sleep Scale - Daytime Somnolence Domain (0-100 Scale) Week 12 LOCF -14.29 (1.52) -19.26 (1.55) -4.97 (-9.24, -0.69) MOS Sleep Scale - Sleep Problems II Index (0-100 Scale) Week 12 LOCF -16.56 (1.60) -22.60 (1.64) -6.04 (-10.56, -1.52) RLS QoL Questionnaire - Overall Life Impact Score (0-100 Scale) Week 12 LOCF 17.89 (1.39) 25.78 (1.42) 7.89 (3.97, 11.81) POMS - Total Mood Disturbance (-32-200 Scale) Week 12 LOCF -20.20 (2.03) -26.46 (2.08) -6.25 (-11.97, -0.54) POMS - Tension-Anxiety Domain (0-36 Scale) Week 12 LOCF -3.86 (0.40) -5.00 (0.41) -1.15 (-2.27, -0.02) POMS - Anger-Hostility Domain (0-48 Scale) Week 12 LOCF -3.00 (0.40) -3.95 (0.41) -0.95 (-2.06, 0.17) POMS - Fatigue-Inertia Domain (0-28 Scale) Week 12 LOCF -4.39 (0.42) -5.57 (0.43) -1.18 (-2.36, 0.00) POMS - Depression-Dejection Domain (0-60 Scale) Week 12 LOCF -3.93 (0.48) -4.49 (0.49) -0.56 (-1.92, 0.80) POMS - Vigor-Activity Domain (0-32 Scale) Week 12 LOCF 2.73 (0.42) 4.22 (0.43) 1.50 (0.32, 2.67) POMS - Confusion-Bewilderment Domain (0-28 Scale) Week 12 LOCF -2.37 (0.27) -3.16 (0.28) -0.79 (-1.56, -0.02) HADS - Anxiety Subscale (0-21 Scale) (HADS Anxiety Subgroup) Week 12 LOCF -2.98 (0.41) -3.90 (0.44) -0.92 (-2.10, 0.26) HADS - Depression Subscale (0-21 Scale) (HADS Depression Subgroup) Week 12 LOCF -3.02 (0.40) -4.06 (0.43) -1.04 (-2.19, 0.11) Actigraphy - Number of PLMs (total throughout night) (Actigraphy Subgroup) Week 12 OC -59.22 (11.87) -164.69 (12.31) -105.47 (-139.29, -71.64) Actigraphy - PLMI (PLM/h of time down during the night) (Actigraphy Subgroup) Week 12 OC -5.86 (1.61) -20.03 (1.67) -14.17 (-18.75, -9.58) Pittsburgh Sleep Quality Index - Global Score (0-21 Scale) Week 12 LOCF -3.26 (0.30) -4.41 (0.30) -1.14 (-1.98, -0.30) 5
Adjusted Analysis for Dichotomous Secondary Efficacy Variables: ITT Population Adjusted Odds Ratio 95% CI Subjects Satisfied or Very Satisfied on the Patient Satisfaction Question Week 12 OC 50% (87/174) 74% (124/168) 2.82 (1.79, 4.44) Subjects with Global Score >5 ( Poor Sleepers ) on the Pittsburgh Sleep Quality Index Week 12 LOCF 73% (133/183) 64% (63/112) 0.67 (0.43, 1.05) Kaplan-Meier Analysis for Time-to-Event Secondary Efficacy Variable: ITT Population Time to First Score of Much Improved or Very Much Improved on CGI-I Scale Subjects in analysis 184 175 Subjects with response (%) 137 (76%) 153 (90%) Median time 21 days 14 days Safety Results: All adverse events (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). An on-therapy AE was defined as an event with onset on or after the start date of study medication and up to 1 day after the last dose of 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. N=186 N=176 Most Frequent Adverse Events On-Therapy n (%) n (%) Subjects with any AE(s), n (%) 119 (64) 138 (78) Most Frequent 10 Adverse Events in Each Group, n (%) Nausea 28 (15) 59 (34) Headache 33 (18) 42 (24) Somnolence 11 (6) 34 (19) Vomiting 6 (3) 18 (10) Dizziness 20 (11) 16 (9) Fatigue 12 (6) 16 (9) Nasopharyngitis 10 (5) 10 (6) Insomnia 5 (3) 10 (6) Upper respiratory tract infection 12 (6) 8 (5) Dyspepsia 2 (1) 7 (4) Diarrhoea 7 (4) 4 (2) Serious Adverse Events (SAEs) - On-Therapy n (%) [n considered by the investigator to be related to study medication] N=186 N=176 n (%) [related] n (%) [related] Subjects with any SAE(s) 3 (2) [0] 2 (1) [0] Subjects with non-fatal SAE(s) 3 (2) [0] 2 (1) [0] Hip fracture 1 (<1) [0] 0 Radius fracture 1 (<1) [0] 0 Ulna fracture 1 (<1) [0] 0 Non-cardiac chest pain 1 (<1) [0] 0 Hypertension 1 (<1) [0] 0 Cerebrovascular accident 0 1 (<1) [0] Pulmonary embolism 0 1 (<1) [0] Subjects with fatal SAE(s) 0 0 6
Conclusions:, up to 6 mg/day administered in divided doses, demonstrated statistically superior efficacy compared to placebo for the treatment of RLS. Adverse events were reported in 119 (64%) subjects in the placebo group, and 138 (78%) subjects in the ropinirole group. Headache and nausea were the most frequently reported adverse events in both groups. Non-fatal serious adverse events were reported in 3 (2%) subjects in the placebo group, and 2 (1%) subjects in the ropinirole group. No fatal serious adverse events were reported in either group. Publications: No publication Date Updated: 15-Mar-2006 7