Erwin Surmann

Rotigotine Effects on Early Morning Motor Function and Sleep in Parkinson's Disease: A Double-Blind, Randomized, pLacebo-Controlled Study (RECOVER)

In a multinational, double‐blind, placebo‐controlled trial (NCT00474058), 287 subjects with Parkinsons disease (PD) and unsatisfactory early‐morning motor symptom control were randomized 2:1 to receive rotigotine (2–16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose maintenance for 4 weeks. Early‐morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinsons Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinsons Disease Sleep Scale (PDSS‐2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by −7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by −3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS‐2 total score had decreased by −5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by −1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: −3.55 [95% confidence interval (CI) −5.37, −1.73]; P = 0.0002) and PDSS‐2 (treatment difference: −4.26 [95% CI −6.08, −2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty‐four‐hour transdermal delivery of rotigotine to PD patients with early‐morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances.

Long-term safety and tolerability of rotigotine transdermal system in patients with early-stage idiopathic Parkinson’s disease: A prospective, open-label extension study

PURPOSE This prospective, open-label extension (SP702; NCT00594165) of a 6-month double-blind, randomized study investigated the long-term safety and tolerability of rotigotine transdermal system in early Parkinsons disease (PD). METHODS Patients with early-stage idiopathic PD received transdermal rotigotine for up to 6 years at optimal dose (up to 16 mg/24h). Adjunctive levodopa was allowed. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Other outcomes included time to levodopa, incidence of dyskinesias, and efficacy using the Unified Parkinsons Disease Rating Scale (UPDRS) II+III total score. RESULTS Of 217 patients entering the open-label study, 47% were still in the study upon closure; 24% withdrew because of AEs and 6% because of lack of efficacy. The median exposure to rotigotine was 1910 days (≈ 5 years, 3 months; range 1-2188 days). Most common AEs were somnolence (23% per patient-year), falls (17%), peripheral edema (14%), nausea (12%), and application site reactions (ASRs; 12%). 3% withdrew because of ASRs. 26% patients did not initiate levodopa; of those who did, fewer than half started levodopa in the first year. Dyskinesias were reported by 25% patients; the majority (83%) reported their first episode after initiating levodopa. Mean UPDRS II+III total scores remained below double-blind baseline for up to 2 years of open-label treatment. CONCLUSION This is the longest interventional study of rotigotine conducted to date. Transdermal rotigotine was generally well tolerated for up to 6 years; AEs reported were similar to those observed in shorter studies and led to discontinuation in only 24% patients.

Rotigotine transdermal system and evaluation of pain in patients with Parkinson’s disease: a post hoc analysis of the RECOVER study

BackgroundPain is a troublesome non-motor symptom of Parkinson’s disease (PD). The RECOVER (Randomized Evaluation of the 24-hour Coverage: Efficacy of Rotigotine; Clintrials.gov: NCT00474058) study demonstrated significant improvements in early-morning motor function (UPDRS III) and sleep disturbances (PDSS-2) with rotigotine transdermal system. Improvements were also reported on a Likert pain scale (measuring any type of pain). This post hoc analysis of RECOVER further evaluates the effect of rotigotine on pain, and whether improvements in pain may be attributable to benefits in motor function or sleep disturbance.MethodsPD patients with unsatisfactory early-morning motor impairment were randomized to optimal-dose (up to 16 mg/24 h) rotigotine or placebo, maintained for 4 weeks. Pain was assessed in the early-morning using an 11-point Likert pain scale (rated average severity of pain (of any type) over the preceding 12 hours from 0 [no pain] to 10 [worst pain ever experienced]). Post hoc analyses for patients reporting ‘any’ pain (pain score ≥1) at baseline, and subgroups reporting ‘mild’ (score 1–3), and ‘moderate-to-severe’ pain (score ≥4) were performed. Likert pain scale change from baseline in rotigotine-treated patients was further analyzed based on a UPDRS III/PDSS-2 responder analysis (a responder defined as showing a ≥30% reduction in early morning UPDRS III total score or PDSS-2 total score). As post hoc analyses, all p values presented are exploratory.ResultsOf 267 patients with Likert pain data (178 rotigotine, 89 placebo), 187 (70%) reported ‘any’ pain; of these 87 (33%) reported ‘mild’, and 100 (37%) ‘moderate-to-severe’ pain. Change from baseline pain scores decreased with rotigotine compared with placebo in patients with ‘any’ pain (-0.88 [95% CI: -1.56, -0.19], p = 0.013), and in the subgroup with ‘moderate-to-severe’ pain (-1.38 [-2.44, -0.31], p = 0.012). UPDRS III or PDSS-2 responders showed greater improvement in pain than non-responders.ConclusionsThe results from this post hoc analysis of the RECOVER study suggest that pain was improved in patients with PD treated with rotigotine; this may be partly attributable to benefits in motor function and sleep disturbances. Prospective studies are warranted to investigate this potential benefit and the clinical relevance of these findings.

A Randomized Controlled Exploratory Pilot Study to Evaluate the Effect of Rotigotine Transdermal Patch on Parkinson's Disease-Associated Chronic Pain

Pain is a troublesome nonmotor symptom of Parkinsons disease (PD). This double‐blind exploratory pilot study (NCT01744496) was the first to specifically investigate the effect of a dopamine agonist on PD‐associated pain as primary outcome. Patients with advanced PD (ie, receiving levodopa) and at least moderate PD‐associated chronic pain (≥3 months, ≥4 points on 11‐point Likert pain scale) were randomized to rotigotine (optimal/maximum dose ≤16 mg/24h) or placebo and maintained for 12 weeks. Primary efficacy variable was change in pain severity (Likert pain scale) from baseline to end of maintenance. Secondary variables included percentage of responders (≥2‐point Likert pain scale reduction), Kings PD Pain Scale (KPPS) domains, and PD Questionnaire (PDQ‐8). Statistical analyses were exploratory. Of 68 randomized patients, 60 (rotigotine, 30; placebo, 30) were evaluable for efficacy. A numerical improvement in pain was observed in favor of rotigotine (Likert pain scale: least‐squares mean [95%CI] treatment difference, −0.76 [−1.87 to 0.34]; P = .172), and proportion of responders was 18/30 (60%) rotigotine vs 14/30 (47%) placebo. An ∼2‐fold numerical improvement in KPPS domain “fluctuation‐related pain” was observed with rotigotine vs placebo. Rotigotine improved PDQ‐8 vs placebo (−8.01 [−15.56 to −0.46]; P = .038). These results suggest rotigotine may improve PD‐associated pain; a large‐scale confirmatory study is needed.

Effect of rotigotine on sleep and quality of life in Parkinson's disease patients: post hoc analysis of RECOVER patients who were symptomatic at baseline

Objective: The aim of this research is to characterize further the potential motor and non-motor benefits of rotigotine reported in the double-blind, placebo-controlled RECOVER trial primary publication, by performing a post hoc exploratory analysis of patient status (symptom improvement/worsening). Methods: Full RECOVER trial methodological details have already been reported. The post hoc analyses presented here are done on individual items of the PDSS-2 and PDQ-8 for all patients and two subgroups (baseline symptomatic and highly symptomatic patients). Results: Ten PDSS-2 and five PDQ-8 items show significant mean treatment difference versus placebo. In the overall population, items that most favor rotigotine in percentage of patients with improvement are ‘limb pain causes waking’ and ‘uncomfortable in bed due to immobility’ for PDSS-2; for PDQ-8, rotigotine is most favored in ‘difficulty dressing’, ‘felt depressed’ and ‘difficulty getting around in public’. Among symptomatic and highly symptomatic patients, the PDSS-2 items that most favor rotigotine are both indicators of pain. On the PDQ-8, the two items most favored in symptomatic patients are ‘difficulty dressing’ and ‘embarrassed in public due to PD’, and in the highly symptomatic subgroup ‘difficulty dressing’ and ‘difficulty getting around in public’. Conclusion: Though this trial was not powered for statistical subgroup analysis, these post hoc results indicate that treatment with rotigotine may benefit patients with sleep, pain, mood and quality-of-life issues.

Associations between severity of motor function and nonmotor symptoms in Parkinson's disease: a post hoc analysis of the RECOVER Study.

Background: RECOVER (NCT00474058), a double-blind, placebo-controlled trial in patients with Parkinsons disease (PD) and unsatisfactory early-morning motor symptom control, demonstrated significant improvements with rotigotine in early-morning motor function (Unified Parkinsons Disease Rating Scale [UPDRS] III), and nocturnal sleep disturbances (modified Parkinsons Disease Sleep Scale [PDSS-2]), and improvements in nonmotor symptoms (NMS; Non-Motor Symptom Scale [NMSS]). Methods: Post hoc analyses investigated the correlation between motor symptom and NMS severity in PD by evaluating associations between UPDRS III and both NMSS and PDSS-2 scores. Categories were defined for UPDRS III, NMSS, and PDSS-2 total scores; analyses were conducted for the full analysis set (n = 267). Results: There was a trend toward increasing PDSS-2 and NMSS total and domain scores with increasing UPDRS III category at baseline and end of maintenance (EoM). Pearson correlation coefficients between UPDRS III and both NMSS and PDSS-2 total and domain scores were r = 0.12-0.44 (r2 = 0.01-0.19) at baseline, r = 0.05-0.38 (r2 = 0.00-0.14) at EoM, and r = -0.02-0.36 (r2 = 0.00-0.13) for change from baseline to EoM. Conclusion: There was only a small correlation between severity of early-morning motor symptoms and overall burden of NMS and nocturnal sleep disturbances in RECOVER, suggesting that motor symptoms and NMS originate, at least partly, from distinct pathophysiological pathways.