Search

Objective To investigate the pharmacokinetics (PK) of rotigotine transdermal system in adolescents with moderate-to-severe idiopathic restless legs syndrome (RLS). Methods This multicenter, open-label, dose-escalation study enrolled patients ≥13 to SS /f; L) of unconjugated rotigotine for each dose step, calculated for the PK per-protocol set (PKPPS). Other PK, safety, and efficacy variables (International RLS Study Group Rating Scale [IRLS]; Clinical Global Impressions Item 1 [CGI-1]) were assessed. Results Of 24 patients who received rotigotine, 23 completed all dose steps and 17 formed the PKPPS. Least-squares mean (95% confidence interval) CL/f and V SS /f values were broadly similar across all dose steps (CL/f: 0.5 mg/24 h: 676.86 [408.50–1121.51]; 1 mg/24 h: 671.72 [459.11–982.80]; 2 mg/24 h: 937.56 [658.50–1334.89]; 3 mg/24 h: 1088.77 [723.47–1638.53]; V SS /f: 5403.16 [2850.67–10,241.17]; 6220.79 [3842.05–10,072.28]; 7114.01 [4547.88–11,128.07]; 6037.92 [3598.36–10,131.41]). Among 23 patients with efficacy data, mean IRLS and CGI-1 scores improved at each dosage level. Adverse events reported by ≥3 patients were nausea (seven) and application site reactions (four). Conclusions Key PK properties of rotigotine in adolescent patients with moderate-to-severe idiopathic RLS were comparable to those previously observed in adults. Rotigotine improved RLS symptoms and was well tolerated. ClinicalTrials.gov: NCT01495793.

Aim The aim of this study is to assess the effect of switching to rotigotine transdermal patch on severity of restless legs syndrome (RLS) in patients who experienced acute augmentation with previous oral dopaminergics. Methods In this 13-month observational study, adults with moderate-to-severe RLS and augmentation were switched to rotigotine per the physician's independent decision. Assessments included Clinical Global Impression severity score (CGI-1); (primary), treatment regimen for switching (secondary), RLS-6, International RLS Study Group Rating Scale (IRLS), and augmentation severity rating scale (ASRS). Results A total of 99 patients received rotigotine, of whom 46 completed observational period, and 43 were assessed for effectiveness. A total of 5 patients switched to rotigotine after a >1-day drug holiday, 23 switched overnight, 9 had an overlapping switch, and 6 received ongoing oral dopaminergics with rotigotine for ≥28 days. Of the 99 patients, 57 took concomitant RLS medications (excluding switching medications) on at least 1 day. At the final visit, median change in CGI-1 (Hodges–Lehman estimate [95% CI]) was −2.0 (–2.5, −1.50); 37 of the 43 patients improved by ≥1 CGI-1 category, and 16 of 43 were responders (≥50% improvement). RLS-6 and IRLS scores also improved. Patients had median ASRS of 0 at the final visit indicating "no worsening/occurrence of augmentation." ASRS item 1 showed a shift in mean time of symptom onset (24-h clock) from 12:38 (baseline) to 18:25 (final visit). Most common reasons for withdrawal of rotigotine were adverse events (26 patients) and lack of efficacy (14 patients). Conclusions Switching from oral therapies to rotigotine was effective in improving RLS symptoms in 37 of the 43 patients (from the original population of 99 patients) who remained in the study over 13 months. Clinical trial registration ClinicalTrials.gov NCT01386944.

Objective A new and unique methodology was developed to evaluate the association between periodic limb movements (PLMs) and nocturnal blood pressure (BP) excursions in patients with restless legs syndrome (RLS). Methods All data were collected at baseline of the ENCORE (Effects of Neupro on Cardiovascular Observations in Patients with Restless Legs Syndrome) study, a placebo-controlled polysomnographic study of rotigotine in patients with idiopathic RLS. Continuous beat-by-beat BP and heart rate assessments were performed during a full night of polysomnography. All BP elevations occurring with and without PLMs were systematically identified and analyzed. Results Patients ( n = 89) had a mean total of 508.9 ± 405.7 PLMs, 788.4 ± 261.9 systolic BP elevations, and 349.7 ± 242.9 diastolic BP elevations during the night. Higher time-adjusted frequencies of systolic BP elevations [mean difference (95% confidence interval, CI): 543.0 (487.2, I); p 0.0001] and diastolic BP elevations (205.8 (169.3, I); p 0.0001) were observed with PLMs than without PLMs. A peak in the frequency of PLM onset coincided with BP elevation onset. Conclusion Our methodology allowed the first evaluation of the total number of nocturnal PLM-associated BP elevations occurring in patients with RLS. Our data clearly indicate an interdependence between BP elevations and PLMs, and they have clinical relevance as BP variability is a potential cardiovascular risk factor.

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.

Objective We aimed to assess effectiveness and tolerability of rotigotine in patients with moderate to severe idiopathic restless legs syndrome (RLS) under daily practice conditions in Germany. Methods In this 3-month noninterventional study, effectiveness was assessed using RLS-6 (primary variables were symptom severity when falling asleep [item 2] and during the night [item 3]). Data were collected at baseline and at the end of treatment. Safety assessments included adverse events (AEs). Results Six hundred and eighty-four patients were treated with rotigotine and 418 (61%) completed the study. The full analysis set (FAS) comprised 564 patients (106 de novo; 458 pretreated [454 had complete rotigotine dosing data]). Mean rotigotine dose of longest duration was 2.4 ± 1.4 mg/24 h. Rotigotine improved all RLS-6 items (mean change from baseline [item 2], −2.4 ± 3.6; [item 3], −2.7 ± 3.4), with the most pronounced improvement observed in daytime symptoms while at rest (item 4, −2.9 ± 3.2). AEs were typical of dopaminergic treatment and transdermal administration. De novo patients generally started rotigotine on 1 mg/24 h (85% [90/106]) and pretreated patients on 1 (50% [227/454]) or 2 mg/24 h (40% [183/454]). Most patients who were pretreated with levodopa (57%), pramipexole (84%), or ropinirole (78%) monotherapy discontinued these medications on initiation of rotigotine. Conclusions Rotigotine was effective and well-tolerated when used in routine clinical practice.

Background Restless legs syndrome (RLS) has been associated with insomnia, decreased quality of life, and increased morbidity and mortality in end-stage renal disease. This randomized controlled trial investigated effects of rotigotine in patients with RLS and end-stage renal disease. Study Design Double-blind placebo-controlled study. Setting & Participants Adults with moderate to severe RLS (International RLS Study Group Rating Scale [IRLS] ≥ 15) and Periodic Limb Movement Index (PLMI) ≥ 15 who were receiving thrice-weekly hemodialysis enrolled from sites in the United States and Europe. Intervention Following randomization and titration (≤21 + 3 days) to optimal-dose rotigotine (1-3mg/24 h) or placebo, patients entered a 2-week maintenance period. Polysomnography was performed at baseline and the end of maintenance. Outcomes & Measurements Primary efficacy outcome: reduction in PLMI, assessed by ratio of PLMI at end of maintenance to baseline. Secondary/other outcomes ( P values exploratory) included mean changes from baseline in PLMI, IRLS, and Clinical Global Impression item 1 (CGI-1 [severity of illness]) score. Results 30 patients were randomly assigned (rotigotine, 20; placebo, 10); 25 (15; 10) completed the study with evaluable data. Mean (SD) PLMI ratio (end of maintenance to baseline) was 0.7±0.4 for rotigotine and 1.3±0.7 for placebo (analysis of covariance treatment ratio, 0.44; 95% CI, 0.22 to 0.88; P =0.02). Numerical improvements were observed with rotigotine versus placebo in IRLS and CGI-1 (least squares mean treatment differences of −6.08 [95% CI, −12.18 to 0.02; P =0.05] and −0.81 [95% CI, −1.94 to 0.33; P =0.2]). 10 of 15 rotigotine and 2 of 10 placebo patients were CGI-1 responders (≥50% improvement). Hemodialysis did not affect unconjugated rotigotine concentrations. The most common adverse events (≥2 patients) were nausea (rotigotine, 4 [20%]; placebo, 0); vomiting (3 [15%]; 0); diarrhea (1 [5%]; 2 [20%]); headache (2 [10%]; 0); dyspnea (2 [10%]; 0); and hypertension (2 [10%]; 0). Limitations Small sample size and short duration. Conclusions Rotigotine improved periodic limb movements and RLS symptoms in the short term among ESRD patients requiring hemodialysis in a small-scale study. No dose adjustments are necessary for hemodialysis patients.

Objective To assess the risk of augmentation under treatment with the transdermally delivered dopamine agonist rotigotine for restless legs syndrome (RLS). Methods Experts in RLS augmentation retrospectively reviewed data from two double-blind, placebo-controlled 6-month trials (745 rotigotine and 214 placebo subjects, NCT00136045 and NCT00135993) and from two open-label 1-year trials (620 rotigotine subjects, NCT00498108 and NCT00263068). All study visits were systematically evaluated applying the Max Planck Institute (MPI) criteria for the diagnosis of both augmentation and clinically relevant augmentation. Results MPI criteria for augmentation were met on at least one visit by 8.2% of all subjects in the double-blind trials with 12 subjects meeting the criteria for clinically relevant augmentation: 11 under rotigotine (1.5%) and one under placebo treatment. In the open-label trials, 9.7% of all subjects met the MPI criteria for augmentation and 2.9% met the criteria for clinically relevant augmentation. None of the patients treated with rotigotine for up to 1.5 years (double-blind plus open-label trial) discontinued prematurely owing to augmentation. Neither could dose-dependency or a time pattern for clinically relevant augmentation episodes be detected. Conclusions Our analyses suggest that the risk for clinically relevant augmentation for the duration of up to 18 months of rotigotine treatment is low.

This 12 week double-blind, placebo-controlled study (ClinicalTrials.gov: NCT01569464) was conducted to evaluate the effects of rotigotine transdermal patch on daytime symptoms in patients with idiopathic restless legs syndrome (RLS).Adult patients with moderate-to-severe RLS were randomized to rotigotine (optimal dose: 1-3 mg/24 h) or placebo. A modified four-assessment version (4:00 pm, 6:00 pm, 8:00 pm, and 10:00 pm) of the Multiple Suggested Immobilization Test (m-SIT) was performed at baseline and end of 4 week maintenance (EoM). Primary study outcomes were change from baseline to EoM in International Restless Legs Syndrome Rating Scale (IRLS) and in average of means for the m-SIT Discomfort Scale (m-SIT-DS) (combined average of mean values from each of the individual assessments). Secondary outcomes included average of means of Periodic Limb Movement during Wakefulness Index (PLMWI; PLM/hour) for the combination of m-SIT.A total of 150 patients were randomized and 137 (rotigotine: 92/101 [91.1%]; placebo: 45/49 [91.8%]) completed maintenance. All 150 randomized patients were assessed for efficacy. At EoM, mean change in IRLS was -14.9 ± 9.3 with rotigotine vs. -12.7 ± 7.6 with placebo (ANCOVA, LS mean treatment difference [95% CI]: -0.27 [-2.96, 2.42]; p = 0.8451). Changes in average of means of m-SIT-DS values of each individual SIT were comparable with rotigotine (-2.68 ± 2.31) vs. placebo (-2.62 ± 2.61) (ANCOVA, LS mean treatment difference [95% CI]: 0.07 [-0.61, 0.75]; p = 0.8336) and comparable reductions in PLMWI were observed in both treatment groups (8.34 [-8.50, 25.17]; p = 0.3290). Rotigotine was generally well tolerated. Application site reactions (rotigotine: 20 patients [19.8%]; placebo: 4 [8.2%]) and nausea (16 [15.8%]; 3 [6.1%]) were the most common AEs.Rotigotine was beneficial in improving overall RLS symptom severity (assessed by IRLS) and RLS symptom severity at various times of the day (m-SIT-DS); however, superiority to placebo was not established.

This randomized, double-blinded, placebo-controlled trial (NCT00135993) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome (RLS) over a 6-month maintenance period. A total of 505 eligible participants with moderate to severe RLS (IRLS sum score >or= 15) were randomly assigned to five groups to receive either placebo or rotigotine (0.5, 1, 2, or 3 mg/24 hr) delivered by once-daily transdermal patch (fixed-dose regimen). The two co-primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions (CGI-1) score. On both primary measures, 2 and 3 mg/24 hr rotigotine was superior to placebo (P < 0.001). Adjusted treatment differences to placebo for the IRLS sum score were -4.5 (95% CI: -6.9, -2.2) for 2 mg/24 hr rotigotine, -5.2 (95% CI: -7.5, -2.9) for 3 mg/24 hr rotigotine, and for CGI item 1 -0.65 (95% CI: -1.0, -0.3) and -0.9 (95% CI: -1.3, -0.5) for the 2 and 3 mg/24 hr doses, respectively. Skin reactions (27%) and known dopaminergic side effects such as nausea (18.1%) and headache (11.6%) were mostly mild or moderate in rotigotine subjects. Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms. Treatment efficacy was maintained throughout the 6-month double-blind period.

Long-term efficacy and tolerability data are not yet available for patch formulations of dopamine agonists in restless legs syndrome.Efficacy and safety of rotigotine (0.5-4mg/24h), formulated as a once-daily transdermal system (patch), were investigated in an open extension (SP710) of a preceding 6-week placebo-controlled trial (SP709, 341 randomized patients) in patients with idiopathic restless legs syndrome. For efficacy assessment the international RLS severity scale (IRLS), the RLS-6 scales, the clinical global impressions (CGI) and the QoL-RLS questionnaire were administered. In addition, long-term tolerability and safety were assessed.Of 310 patients who finished the controlled trial, 295 (mean age 58+/-10 years, 66% females) with a mean IRLS score of 27.8+/-5.9 at baseline of SP709 were included. We report results after one year of this ongoing long-term trial. Two hundred twenty patients (retention rate=74.6%) completed the 12-month follow-up period. The mean daily dose was 2.8+/-1.2mg/24h with 4mg/24h (40.6%) being the most frequently applied dose; 14.8% were sufficiently treated with 0.5 or 1.0mg/24h. The IRLS total score improved by ?17.4+/-9.9 points between baseline and end of Year 1 (p0.001). The other measures of severity, sleep satisfaction and quality of life supported the efficacy of rotigotine (p0.001 for pre-post-comparisons of all efficacy variables). The tolerability was described as "good" or "very good" by 80.3% of all patients. The most common adverse events were application site reactions (40.0%), which led to withdrawal in 13.2%. Further relatively frequent adverse events were nausea (9.5%) and fatigue (6.4%). Two drug-related serious adverse events, nausea and syncope, required hospitalization. Symptoms of augmentation were not reported by the patients.Rotigotine provided a stable, clinically relevant improvement in all efficacy measures throughout one year of maintenance therapy. The transdermal patch was safe and generally well tolerated by the majority of patients. Comparable to any transdermal therapy, application site reactions were the main treatment complication.

In a pilot placebo-controlled study, low dosages of 0.5-2mg/24h rotigotine showed a dose-dependent beneficial effect in restless legs syndrome (RLS) patients.Efficacy and safety of the dopamine agonist rotigotine, formulated as a once-daily transdermal system (patch), was investigated for five fixed dosages and compared to placebo in patients with idiopathic RLS in a double-blind, randomized, parallel-group, multicenter, six-week dose-finding trial. Primary efficacy measure was the total score of the International RLS Severity Scale (IRLS); in addition, the RLS-6 scales and the Clinical Global Impressions (CGI) were administered.Of 371 enrolled patients, 341 patients (mean age 58+/-10years, 67% females) were randomized. The IRLS total score improved between baseline and end of the six-week treatment period by -10.6 (0.5mg/24h rotigotine; patch area 2.5cm2), -15.1 (1mg/24h; 5cm2), -15.7 (2mg/24h; 10cm2), -17.5 (3mg/24h; 15cm2), and -14.8 (4mg/24h, 20cm2) as compared to placebo (-9.2). The hierarchical statistical test procedure demonstrated superiority of rotigotine over placebo for 4mg/24h, 3mg/24h, 2mg/24h, and 1mg/24h, with p-values of 0.0013,0.0001, 0.0003, and 0.0004, respectively. Only the 0.5mg/24h dose was not different compared to placebo (p=0.2338). The CGI and the RLS-6 severity items supported the efficacy of the rotigotine doses beyond 0.5mg/24h. The most frequent side effects were application site reactions and nausea and tended to be more frequent with higher doses.This dose-finding trial identified the range for a maintenance dose of rotigotine from 1mg/24h to 3mg/24h. The lowest dose was ineffective and, with the highest dose, no additional benefit was observed.

Objective: This double-blind, placebo-controlled, interventional trial was conducted to investigate the effects of rotigotine patch on periodic limb movement (PLM)–associated nocturnal systolic blood pressure (SBP) elevations. Methods: Patients with moderate to severe restless legs syndrome (RLS) were randomized to rotigotine (optimal dose [1–3 mg/24 h]) or placebo. Continuous beat-to-beat blood pressure (BP) assessments were performed during polysomnography at baseline and at the end of 4-week maintenance. Primary outcome was change in number of PLM-associated SBP elevations (defined as slope of linear regression ≥2.5 mm Hg/beat-to-beat interval over 5 consecutive heartbeats [≥10 mm Hg]). Additional outcomes were total SBP elevations, PLM-associated and total diastolic BP (DBP) elevations, periodic limb movements index (PLMI), and PLM in sleep arousal index (PLMSAI). Results: Of 81 randomized patients, 66 (37 rotigotine, 29 placebo) were included in efficacy assessments. PLM-associated SBP elevations were significantly reduced with rotigotine vs placebo (least squares mean treatment difference [95% confidence interval (CI)] −160.34 [−213.23 to −107.45]; p < 0.0001). Rotigotine-treated patients also had greater reduction vs placebo in total SBP elevations (−161.13 [−264.47 to −57.79]; p = 0.0028), PLM-associated elevations (−88.45 [−126.12 to −50.78]; p < 0.0001), and total DBP elevations (−93.81 [−168.45 to −19.16]; p = 0.0146), PLMI (−32.77 [−44.73 to −20.80]; p < 0.0001), and PLMSAI (−7.10 [−11.93 to −2.26]; p = 0.0047). Adverse events included nausea (rotigotine 23%; placebo 8%), headache (18% each), nasopharyngitis (18%; 8%), and fatigue (13%; 15%). Conclusions: Further investigation is required to determine whether reductions in nocturnal BP elevations observed with rotigotine might modify cardiovascular risk. Classification of evidence: This study provides Class I evidence that for patients with moderate to severe RLS, rotigotine at optimal dose (1–3 mg/24 h) reduced PLM-associated nocturnal SBP elevations.

Efficacy and safety of the dopamine agonist rotigotine (RTG) was investigated in patients with moderate to severe idiopathic restless legs syndrome (RLS), including daytime symptoms. Three fixed doses of rotigotine (1.125 mg, 2.25 mg, and 4.5 mg) and placebo were applied by patches (size, 2.5 cm2 per 1.125 mg) in a double-blind, randomized, parallel-group, multicenter, 1-week, proof-of-principle trial. The primary efficacy measure was the total score on the International Restless Legs Syndrome Scale (IRLS). Additionally, the RLS-6 scale, the Clinical Global Impressions (CGI), and a sleep diary were used. Of 68 enrolled patients, 63 (mean age, 58+/-; 9 years; 64% women) were randomly assigned. RLS severity improved related to dose by 10.5 (1.125 mg RTG/die; P = 0.41), 12.3 (2.25 mg RTG/die; P = 0.18), and 15.7 points (4.5 mg RTG/die; P < 0.01) on the IRLS compared to placebo (8 points). According to the RLS-6 scales, daytime symptoms significantly improved with all rotigotine doses. The CGI items supported the favorable efficacy of the 4.5-mg dose. Skin tolerability of the patches and systemic side effects were similar between rotigotine and placebo. This pilot study suggests that continuous delivery of rotigotine by means of a patch may provide an effective and well-tolerated treatment of RLS symptoms both during night and day.

Preexisting renal impairment is an all-encompassing risk factor for radiocontrast-associated nephrotoxicity. Renal impairment appears to be associated with the inadequate production of renal prostaglandins at the critical time of radiocontrast administration and for a variable time period afterward. We prospectively studied 130 patients with chronic renal insufficiency (serum creatinine > or =1.5 mg/dL) who were undergoing radiocontrast administration. Using a double-blind, randomized, prospective technique, patients were assigned to either placebo or one of three prostaglandin E1 (PGE1) treatment groups (10, 20, or 40 ng/kg/min). Infusion was started 60 +/- 30 minutes before the administration of radiocontrast and was continued for a total of 6 hours. In the placebo group, radiocontrast administration resulted in a mean increase (+/- SD) in serum creatinine of 0.72 +/- 1.15 mg/dL at 48 hours. This increase was less in each of the PGE1 treatment groups after 48 hours, with a significant difference between placebo and the 20 ng/kg/min PGE1 group (P = 0.01). Using baseline adjusted means, analysis of covariance with baseline serum creatinine as the covariable demonstrated significant differences between the placebo and 20 ng/kg/min PGE1 group (P = 0.03) and between the placebo and 10 ng/kg/min PGE1 group P = 0.047). In a subgroup analysis of the diabetic patients, the increase in serum creatinine was less pronounced in the three PGE1 groups versus the placebo group, and the 20 ng/kg/min PGE1 group had the most favorable outcome. The parenteral administration of PGE1 immediately before radiocontrast exposure and continued for a period of 5 to 5.5 hours significantly reduced the elevation of serum creatinine poststudy. The most effective of the three PGE1 dosing regimens was 20 ng/kg/min.

This post-hoc analysis of a prospective open-label study investigated patients with restless legs syndrome (RLS) taking approved dosages (1, 2 or 3 mg/24 h) of rotigotine transdermal patch for up to 5 years.Following 6 weeks' double-blind treatment, patients with moderate-to-severe RLS received open-label rotigotine titrated to optimal dosage.Safety was assessed by adverse events (AEs) and efficacy was assessed by the International Restless Legs Syndrome Study Group Rating Scale (IRLS).Of 295 patients who entered the open-label study, 198 (67%) began the maintenance period taking rotigotine dosages of 1 - 3 mg/24 h, or increased their dosage from 0.5 mg in the first 3 months of the maintenance period. Of the 198 patients, 45 patients (23%) completed 5 years of follow-up within this dosage range, 79 patients (40%) had their dosage adjusted outside this range during follow-up and 74 patients (37%) withdrew (including 49 [25%] due to AEs and 6 [3%)] for lack of efficacy). Application site reactions were the most common AEs (102 of 198 patients [52%]), with an incidence of 35% (69 of 198) in year 1, 19% (19 of 102) in year 2, and 4 - 6% during each of years 3 - 5. Mean IRLS total score decreased from 27.1 ± 6.0 at double-blind baseline to 6.5 ± 6.5 at the beginning of maintenance, and to 7.4 ± 8.4 after 5 years' treatment on 1 - 3 mg/24 h (n = 45); 21 patients (47%) were classified as symptom-free (IRLS = 0).Consistent with the results for the overall population, rotigotine transdermal patch at approved dosages of 1 - 3 mg/24 h was generally well tolerated after the first year, with sustained efficacy in patients who completed 5 years of treatment at dosages of 1 - 3 mg/24 h.

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.

Background Rotigotine is a unique dopamine agonist with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites. This study reports the 2-year follow-up safety and efficacy data of an ongoing open-label multicenter extension study (NCT00498186) of transdermal rotigotine in patients with moderate to severe restless legs syndrome (RLS). Methods Patients received a once-daily patch application of an individually optimized dose of rotigotine between 0.5 mg/24 h to 4 mg/24 h. Safety assessments included adverse events (AEs) and efficacy was measured by the International RLS Study Group Severity Rating Scale (IRLS), RLS-6 scales and Clinical Global Impression (CGI). Quality of life (QoL) was measured by QoL-RLS. Results Of 310 patients who completed a 6-week placebo-controlled trial (SP709), 295 (mean age 58 ± 10 years, 66% females) were included in the open-label trial SP710. 64.7% (190/295 patients) completed the 2-year follow-up; 29 patients discontinued during the second year. Mean daily rotigotine dose after 2 years was 2.93 ± 1.14 mg/24 h with a 2.9% dose increase from year 1. Rotigotine was generally well tolerated. The rate of typical dopaminergic side effects, nausea and fatigue, was low (0.9% and 2.3%, respectively) during the second year; application site reactions were frequent but lower than in year 1 (16.4% vs. 34.5%). The IRLS total score improved from baseline of SP709 (27.8 ± 5.9) by 17.2 ± 9.2 in year 2 completers. Similar improvements were observed in RLS-6 scales, CGI scores and QoL-RLS. The responder rate in the CGI change item 2 ("much" and "very much" improved) was 95% after year 2. Conclusions Transdermal rotigotine is an efficacious and well-tolerated long-term treatment option for patients with moderate to severe RLS with a high retention rate during 2 years of therapy. Trial registration NCT00498186

This randomized, double-blinded, placebo-controlled trial (NCT00135993) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome (RLS) over a 6-month maintenance period. A total of 505 eligible participants with moderate to severe RLS (IRLS sum scoreor= 15) were randomly assigned to five groups to receive either placebo or rotigotine (0.5, 1, 2, or 3 mg/24 hr) delivered by once-daily transdermal patch (fixed-dose regimen). The two co-primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions (CGI-1) score. On both primary measures, 2 and 3 mg/24 hr rotigotine was superior to placebo (P0.001). Adjusted treatment differences to placebo for the IRLS sum score were -4.5 (95% CI: -6.9, -2.2) for 2 mg/24 hr rotigotine, -5.2 (95% CI: -7.5, -2.9) for 3 mg/24 hr rotigotine, and for CGI item 1 -0.65 (95% CI: -1.0, -0.3) and -0.9 (95% CI: -1.3, -0.5) for the 2 and 3 mg/24 hr doses, respectively. Skin reactions (27%) and known dopaminergic side effects such as nausea (18.1%) and headache (11.6%) were mostly mild or moderate in rotigotine subjects. Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms. Treatment efficacy was maintained throughout the 6-month double-blind period.

Introduction Rotigotine transdermal system reduces periodic leg movements (PLM) during sleep in patients with restless legs syndrome (RLS). Episodic nocturnal blood pressure (BP) excursions coincide with PLM, possibly increasing the risk of hypertension and cardiovascular disease. We examined the effect of rotigotine on PLM-associated and total nocturnal systolic BP (NSBP) elevations in patients with moderate-to-severe RLS (IRLS ⩾ 15). Materials and methods This double-blind, placebo-controlled study (SP0977 ENCORE [NCT01455012]) randomized patients (1:1) to optimal dose rotigotine (1–3 mg/24 h) or placebo. Continuous beat-by-beat BP and heart rate assessments were performed at baseline and end of 4-week maintenance (EoM). Primary outcome was change from baseline to EoM in PLM-associated NSBP elevations (defined: a slope of linear regression ⩾2.5 over 5 consecutive heartbeats [equivalent to ⩾10 mmHg]). Change in total NSBP elevations and PLM index (PLMI) were also assessed. Efficacy data are reported for the full analysis set (FAS). Results 81 patients (mean ± SD age: 57.2 ± 10.5 years; 63% female) were randomized (rotigotine: 40; placebo: 41); 66 (rotigotine: 37; placebo: 29) comprised the FAS. Mean (±SD) baseline PLMI was similar between rotigotine (72.9 ± 55.6) and placebo (69.9 ± 47.9). Reductions from baseline (∼300 elevations) in PLM-associated NSBP elevations were greater with rotigotine vs. placebo (LS mean [95% CI]: −239.95 [−275.34, −204.56] vs −79.61 [119.25, −39.97]; treatment difference: −160.34 [−213.23, −107.45]; p p = 0.0028). Greater decreases from baseline to EoM in PLMI were observed for rotigotine (−49.4 [−57.4, −41.4]) vs. placebo (−16.6 [−25.6, −7.7]) (−32.8 [−44.7, −20.8]; p Conclusion Rotigotine reduced PLM-associated and total NSBP elevations in patients with RLS. Further investigation is required to determine whether decreases in PLMI-related and total nocturnal BP translate into reductions in cardiovascular risk in patients with RLS. Acknowledgement This study was supported by UCB Pharma, Monheim am Rhein, Germany.

Efficacy and safety of the dopamine agonist rotigotine (RTG) was investigated in patients with moderate to severe idiopathic restless legs syndrome (RLS), including daytime symptoms. Three fixed doses of rotigotine (1.125 mg, 2.25 mg, and 4.5 mg) and placebo were applied by patches (size, 2.5 cm2 per 1.125 mg) in a double-blind, randomized, parallel-group, multicenter, 1-week, proof-of-principle trial. The primary efficacy measure was the total score on the International Restless Legs Syndrome Scale (IRLS). Additionally, the RLS-6 scale, the Clinical Global Impressions (CGI), and a sleep diary were used. Of 68 enrolled patients, 63 (mean age, 58+/-; 9 years; 64% women) were randomly assigned. RLS severity improved related to dose by 10.5 (1.125 mg RTG/die; P = 0.41), 12.3 (2.25 mg RTG/die; P = 0.18), and 15.7 points (4.5 mg RTG/die; P0.01) on the IRLS compared to placebo (8 points). According to the RLS-6 scales, daytime symptoms significantly improved with all rotigotine doses. The CGI items supported the favorable efficacy of the 4.5-mg dose. Skin tolerability of the patches and systemic side effects were similar between rotigotine and placebo. This pilot study suggests that continuous delivery of rotigotine by means of a patch may provide an effective and well-tolerated treatment of RLS symptoms both during night and day.

Background Immobilisation, blood loss, sleep deficiency, and (concomitant) medications during perioperative periods might lead to acute exacerbation of symptoms in patients with the restless legs syndrome (RLS). Continuous transdermal delivery of the dopamine agonist rotigotine provides stable plasma levels over 24 h and may provide RLS patients with a feasible treatment option for perioperative situations. To assess the feasibility of use of rotigotine transdermal patch for the perioperative management of moderate to severe RLS, long-term data of an open-label extension of a rotigotine dose-finding study were retrospectively reviewed. Methods The data of all 295 patients who had entered the 5-year study were screened independently by two reviewers for the occurrence of surgical interventions during the study period. The following data were included in this post-hoc analysis: patient age, sex, surgical intervention and outcome, duration of hospital stay, rotigotine maintenance dose at the time of surgery, rotigotine dose adjustment, and continuation/discontinuation of rotigotine treatment. All parameters were analysed descriptively. No pre-specified efficacy assessments (e.g. IRLS scores) were available for the perioperative period. Results During the study period, 61 surgical interventions were reported for 52 patients (median age, 63 years; 67% female); the majority of patients (85%) had one surgical intervention. The mean rotigotine maintenance dose at time of surgery was 3.1 ± 1.1 mg/24 h. For most interventions (95%), rotigotine dosing regimens were maintained during the perioperative period. Administration was temporarily suspended in one patient and permanently discontinued in another two. The majority (96%) of the patients undergoing surgery remained in the study following the perioperative period and 30 of these patients (61%) completed the 5-year study. Conclusions Although the data were obtained from a study which was not designed to assess rotigotine use in the perioperative setting, this post-hoc analysis suggests that treatment with rotigotine transdermal patch can be maintained during the perioperative period in the majority of patients and may allow for uninterrupted alleviation of RLS symptoms. Trial Registration The 5-year rotigotine extension study is registered with ClinicalTrials.gov, identifier NCT00498186.