Early-morning Motor Research Articles

Apomorphine infusion for improving sleep in Parkinson's disease

Apomorphine infusion for improving sleep in Parkinson's disease

Rotigotine may improve sleep architecture in Parkinson's disease: a double-blind, randomized, placebo-controlled polysomnographic study

Background/ObjectivesGrowing evidence demonstrates that in Parkinson's Disease (PD) sleep disturbances are frequent and difficult to treat. Since the efficacy of rotigotine on sleep is corroborated by studies lacking polysomnography (PSG), this study explores the possible rotigotine-mediated impact on PSG parameters in PD patients. MethodsThis is a randomized, double-blind, placebo-controlled, parallel-group study to determine the efficacy of rotigotine vs placebo on PSG parameters in moderately advanced PD patients. An unusual protocol was utilized, since patches were maintained from 18:00 h to awakening, minimizing the possible diurnal impact on motor symptoms. All participants underwent sleep PSG recordings, subjective sleep questionnaires (Parkinson Disease Sleep Scale [PDSS], Pittsburgh Sleep Quality Index [PSQI]), and the assessment of early-morning motor disability. ResultsWe evaluated 42 PD patients (Hoehn & Yahr stages 2 and 3) with sleep impairment randomly assigned to active branch (N =21) or placebo (N = 21). Rotigotine significantly increased sleep efficiency and reduced both wakefulness after sleep onset and sleep latency compared to placebo. Moreover, the mean change in REM sleep quantity was significantly higher in the rotigotine than placebo group. The improvement of PSG parameters corresponded to the amelioration of PDSS and PSQI scores together with the improvement of patient morning motor symptoms. ConclusionsThis study demonstrated the significant effect of rotigotine on sleep quality and continuity in PD patients by promoting sleep stability and increasing REM. The effectiveness of rotigotine on sleep may be ascribed to its pharmacokinetic/pharmacodynamic profile directly on both D1 and D2 receptors.

Switch from oral pramipexole or ropinirole to rotigotine transdermal system in advanced Parkinson’s disease: an open-label study

Objective: Investigate safety, feasibility and efficacy of switching therapy in patients with advanced-stage Parkinson’s disease (PD) inadequately controlled with pramipexole (≤ 3.5 mg/day) or ropinirole (≤ 14 mg/day) to rotigotine transdermal system (≤ 14 mg/24 h; dose adjustments ≤ 16 mg/24 h permitted).Methods: PD0009 (ClinicalTrials.gov: NCT01711866) was an open-label study in patients with advanced-stage PD receiving levodopa, and experiencing sleep disturbance or early-morning motor impairment. Pramipexole/ropinirole was switched to equivalent dose rotigotine overnight or in two stages. During the 4-week treatment period rotigotine dose adjustments were permitted (up to 16 mg/24 h). Primary variable: Clinical Global Impressions (CGI) item 4: side effects (assessing safety) at end of treatment.Results: 79/87 (91%) patients completed the study; 2 (2%) withdrew due to adverse events (AEs). Most (84; 97%) had CGI item 4 score < 3 indicating switch did not interfere with functioning; three experienced drug-related AEs interfering with functioning (score = 3). 62% patients improved on Patient Global Impression of Change, assessing effectiveness. AEs occurring ≥ 5%: application site pruritus (10%), application site erythema (7%), dizziness (7%), dyskinesia (7%), erythema (6%), pruritus (6%). Unified Parkinson’s Disease Rating Scale II and III, Parkinson’s Disease Sleep Scale-2 and Pittsburgh Sleep Quality Index were unchanged. Numerical improvements in ‘off’ time, awakenings and nocturias were observed.Conclusions: Switch from pramipexole or ropinirole to rotigotine (up to 14 mg/24 h) was feasible and possibly associated with some benefit.

Rotigotine in Patients with PD and Unsatisfactory Early-morning Motor Symptom Control: a Post-hoc Analysis of Efficacy and Safety by Dose (P1.190)

Rotigotine in Patients with PD and Unsatisfactory Early-morning Motor Symptom Control: a Post-hoc Analysis of Efficacy and Safety by Dose (P1.190)

Rotigotine transdermal system and evaluation of pain in patients with Parkinson’s disease: a post hocanalysis 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.

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 Parkinson's disease (PD) and unsatisfactory early-morning motor symptom control, demonstrated significant improvements with rotigotine in early-morning motor function (Unified Parkinson's Disease Rating Scale [UPDRS] III), and nocturnal sleep disturbances (modified Parkinson's 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.

Treatment of the sleep disorders associated with Parkinson's disease.

Sleep disorders are common in patients with Parkinson's disease (PD), and preliminary work has suggested viable treatment options for many of these disorders. For rapid eye movement sleep behavior disorder, melatonin and clonazepam are most commonly used, while rivastigmine might be a useful option in patients whose behaviors are refractory to the former. Optimal treatments for insomnia in PD have yet to be determined, but preliminary evidence suggests that cognitive-behavioral therapy, light therapy, eszopiclone, donepezil, and melatonin might be beneficial. Use of the wake-promoting agent modafinil results in significant improvement in subjective measures of excessive daytime sleepiness, but not of fatigue. Optimal treatment of restless legs syndrome and obstructive sleep apnea in PD are not yet established, although a trial of continuous positive airway pressure for sleep apnea was recently completed in PD patients. In those patients with early morning motor dysfunction and disrupted sleep, the rotigotine patch provides significant benefit.

Rotigotine and specific non-motor symptoms of Parkinson's disease: Post hoc analysis of RECOVER

BackgroundNon-motor symptoms of Parkinson's disease (PD) represent major causes of morbidity. RECOVER, a randomized controlled trial of rotigotine transdermal system, was the first prospective controlled trial to use the Non-Motor Symptoms Scale (NMSS) as an exploratory outcome for assessment of treatment effects on non-motor symptoms in PD. Rotigotine improved NMSS total score compared with placebo, and the “Sleep/fatigue” and “Mood/apathy” domains. This post hoc analysis further characterizes the effects of rotigotine on sleep/fatigue and mood/apathy. MethodsPatients with PD and unsatisfactory early-morning motor impairment were randomized to transdermal patches of rotigotine (2–16 mg/24 h) or placebo. Treatment was titrated to optimal dose over 1–8 weeks, maintained for 4 weeks. The NMSS was assessed at baseline and end of treatment. Post hoc analyses are presented for individual items of the “Sleep/fatigue” and “Mood/apathy” domains. The interpretation of p-values is considered exploratory in nature. ResultsOf 287 patients randomized, NMSS data were available for 267 patients (178 rotigotine, 89 placebo). Within the “Sleep/fatigue” domain there was a significant difference, in favor of rotigotine, in change from baseline score in 1 of 5 items: “fatigue (tiredness) or lack of energy” (ANCOVA, p < 0.0001). Within the “Mood/apathy” domain, there were significant differences in favor of rotigotine in 4 of 7 items: “lost interest in surroundings” (p < 0.0001), “lost interest in doing things” (p < 0.0001), “seems sad or depressed” (p < 0.01), and “difficulty experiencing pleasure” (p < 0.05). ConclusionsRotigotine transdermal system may improve non-motor symptoms such as fatigue, symptoms of depression, anhedonia, and apathy in patients with PD; further prospective controlled studies are required to confirm this post hoc analysis.

Rotigotine transdermal system for the management of motor function and sleep disturbances in Parkinson’s disease: Results from a 1-year, open-label extension of the RECOVER study

In RECOVER, a multinational, double-blind, placebo-controlled trial, continuous 24-h transdermal delivery of rotigotine resulted in significant improvements in early-morning motor function and nocturnal sleep disturbances in subjects with idiopathic Parkinson’s disease (PD). On completion of RECOVER, subjects were eligible to enter a 1-year, open-label extension in which they received rotigotine (2–16mg/24h) for a 10-month maintenance period. Safety and tolerability were assessed by monitoring adverse events, changes in vital signs, physical and neurological findings, ECGs, and clinical laboratory values. The primary efficacy measure was the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (Motor Examination) with the modified Parkinson’s Disease Sleep Scale (PDSS-2) as a co-primary measure. Of 84 subjects from RECOVER who enrolled, 79% completed 1year of open-label treatment. Rotigotine was well tolerated; the most common adverse events (AEs; open-label phase) were application site reactions (ASRs; 24%); somnolence and hallucinations (13% each); nausea and fall (12% each); and dizziness and dyskinesia (11% each). Most were mild or moderate in intensity and had resolved at the end of the trial. Twelve subjects (14%) discontinued due to AEs, most commonly ASRs (5 subjects) and peripheral edema (2 subjects). At end of maintenance, the mean UPDRS Part III score was improved by 5.8 (±9.4) points relative to open-label baseline and 10.9 (±10.7) points relative to double-blind baseline and the mean PDSS-2 score by 5.8 (±7.8) points relative to double-blind baseline. Hence, the beneficial effects of rotigotine transdermal system on motor function and sleep disturbances were sustained for up to 1year.

Rotigotine Transdermal System Improves Neuropsychiatric Features (Apathy, Anhedonia, Anxiety, and Depression) and Fatigue in Patients with Parkinson's Disease: A Post-Hoc Analysis of Five Double-Blind Placebo-Controlled Studies (P06.088)

Objective: To investigate the effect of rotigotine on neuropsychiatric features and fatigue in patients with Parkinson9s disease (PD). Background Neuropsychiatric features (including apathy, anhedonia, anxiety, and depression) and fatigue are frequently reported for patients with PD and are key determinants of health-related quality of life. Design/Methods: Post-hoc analysis of 5 placebo-controlled studies of rotigotine in patients with early-PD (SP512, SP513), advanced-PD (SP650 [PREFER], SP515 [CLEOPATRA-PD, NCT00244387]), and PD with unsatisfactory control of early-morning motor symptoms (SP889 [RECOVER, NCT00474058]). Individual items assessing apathy, anhedonia, anxiety, anxiety/depression, depression, and fatigue were identified from scales used in these studies (NMSS, BDI-II, PDQ-39, EQ-5D, and PDQ-8). As a post-hoc analysis, all p-values are exploratory. Results: Improvements were observed with rotigotine versus placebo in items assessing feelings of depression (a total of 3 items were assessed: CLEOPATRA-PD [1 item] and RECOVER [2 items]; least square [LS] mean treatment differences p Conclusions: This exploratory post-hoc analysis suggests that neuropsychiatric features (including apathy, anhedonia, anxiety, and depression) and fatigue in PD may be improved with transdermal rotigotine. The effect of rotigotine on these prevalent non-motor symptoms warrants further investigation in prospective studies. Supported by: UCB Pharma. Disclosure: Dr. Hauser has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals, Inc., Teva Neuroscience, Impax Pharmaceuticals, UCB, Inc., GE Healthcare, Ipsen, Novartis, Parkinson Study Group, Solvay S.A., Quintiles, Biogen Idec, Bial, Lundbeck Research USA, Inc., Chelsea Therapeutics, Impax, Santhera Pharmaceuticals, Serono, Synosia Therapeutics, Schering-Plough Corporation, Shire Pharmaceuticals Group, XenoPort, Inc., Medivation, Inc., Addex, Adamas Pharmaceuticals, and Noven Pharmaceuticals as a speaker, consultant and/or member of an advisory board.Dr. Hauser has received research support from PICO-Tesla, Schwartz Biosciences, Genzyme Corporation, Acadia, Solvay S.A., Impax, TEVA Neuroscience, Serono, Schering-Plough Corporation, Novartis, Ipsen, XenoPort Pharmaceuticals, Chelsea Therapeutics, Allergan, Inc., Molecular Biometrics, The Michael J. Fox Foundation for Parkinson9s Research, and the National Parkinson Foundation. Dr. Nausieda has nothing to disclose. Dr. Surmann has received personal compensation for activities with UCB Pharma. Dr. Moran has received personal compensation for activities with UCB Pharma as an employee. Dr. Moran holds stock and/or stock options in UCB Pharma. Dr. Barone has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GE Healthcare, Merck Serono, Novartis, UCB Pharma, and Lundbeck Research USA, Inc as a speaker and/or participant on an advisory board. Dr. Barone has received research support from Boehringer Ingelheim Pharmaceuticals, Inc., Merck Serono, Novartis, UCB Pharma, Lundbeck Research USA, Inc., and Solvay S.A.

Spotlight on Rotigotine Transdermal Patch in Parkinsonʼs Disease†

Rotigotine transdermal patch (Neupro(®)) [referred to here as rotigotine] is a non-ergolinic dopamine agonist that is available in the EU as monotherapy for the treatment of early Parkinson's disease and as combination therapy with levodopa throughout the course of the disease. Daily application of the rotigotine patch provided predictable release and absorption of rotigotine, with steady-state rotigotine concentrations reached within 1-2 days. In early Parkinson's disease, compared with placebo, rotigotine monotherapy produced significantly greater improvements in the Unified Parkinson's Disease Rating Scale summed motor and activities of daily living (ADL) scores (primary endpoint), as well as significantly higher response rates. In advanced Parkinson's disease, rotigotine in combination with levodopa reduced 'off' time (primary endpoint) and improved motor functioning and ADL significantly more than levodopa plus placebo. In patients with inadequate early morning motor control despite antiparkinsonian treatment, rotigotine improved morning motor functioning and reduced sleep disturbances, night-time motor symptoms, depressive symptoms, pain and functioning, and quality of life to a significantly greater extent than placebo. The efficacy of rotigotine relative to other treatments requires further evaluation, as there were inconsistent results in noninferiority analyses that compared rotigotine to other dopamine agonists. Rotigotine was generally well tolerated across the trials, with the most common treatment-emergent adverse events being application-site reactions, gastrointestinal disturbances, somnolence and headache. No unexpected adverse effects were observed in extension studies of up to 6 years. Thus, rotigotine offers a novel approach to the treatment of Parkinson's disease and, given its ease of administration, efficacy in reducing disabling motor and non-motor symptoms, and acceptable tolerability profile, it has the potential to be an attractive treatment option for this highly debilitating disease.

Rotigotine Transdermal Patch

A transdermal patch formulation of the non-ergolinic dopamine agonist rotigotine (Neupro®) is indicated as monotherapy for the treatment of early Parkinson's disease and as combination therapy with levodopa throughout the course of the disease. Daily application of the rotigotine transdermal patch (referred to here as rotigotine) provided predictable release and absorption of rotigotine, with steady-state rotigotine concentrations reached within 1-2 days. In six large, well designed clinical trials, rotigotine was an efficacious treatment for Parkinson's disease. In early Parkinson's disease, rotigotine initiated without levodopa produced significantly greater improvements than placebo in the Unified Parkinson's Disease Rating Scale (UPDRS) summed motor and activities of daily living (ADL) scores, as well as significantly higher response rates. In a comparison with oral ropinirole, rotigotine did not meet a prespecified response-rate noninferiority criterion, although this may reflect the dosages used, which may not have been directly comparable. In advanced Parkinson's disease, rotigotine in combination with levodopa reduced 'off' time and improved motor functioning and ADL significantly more than levodopa plus placebo. Rotigotine was noninferior to oral pramipexole in reducing 'off' time, although it did not meet a response-rate noninferiority criterion. A recent trial focused on both motor and non-motor endpoints in patients with inadequate early morning motor control despite antiparkinsonian treatment (most received levodopa). Rotigotine improved morning motor functioning and reduced sleep disturbances, night-time motor symptoms, depressive symptoms, pain and functioning, and quality of life to a significantly greater extent than placebo. Rotigotine was generally well tolerated across the trials and in longer-term extension studies, with the most common treatment-emergent adverse events being application-site reactions, gastrointestinal disturbances, somnolence and headache. Application-site reactions were generally mild to moderate in severity; where reported, up to 3% of patients had severe skin reactions. Thus, rotigotine offers a novel approach to the treatment of Parkinson's disease and, given its ease of administration, efficacy in reducing disabling motor and non-motor symptoms, and acceptable tolerability profile, it has the potential to be an attractive treatment option for this highly debilitating disease.

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 Parkinson's 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 Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's 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. © 2010 Movement Disorder Society

Rotigotine transdermal system for control of early morning motor impairment and sleep disturbances in patients with Parkinson’s disease

This open-label study (NCT00243945) investigated the efficacy of rotigotine transdermal system in 54 Parkinson's disease (PD) patients with unsatisfactory control of early morning motor impairment and sleep disturbances. Rotigotine dose was up titrated for 8weeks and maintained for 4weeks. Mean rotigotine dose at end of maintenance was 11.83mg/24h (SD 3.86). Patients had two overnight hospital stays at baseline and end of treatment during which early morning motor performance was assessed, prior to first morning dose of regular oral antiparkinsonian medication. Rotigotine improved mean Unified Parkinson's Disease Rating Scale (UPDRS) part III score by -9.3 points, mean Timed Up and Go test duration by -1.4s and mean morning finger tapping by 26.5taps/min; 46% of patients were considered responders (≥30% improvement of UPDRS III). Mean Nocturnal Akinesia, Dystonia and Cramps Sum Score was reduced by 61%; mean number of nocturias decreased by 32%. Rotigotine also improved sleep quality. These results suggest a role for rotigotine in treatment of nocturnal and early morning motor disabilities in PD patients.

P2.170 Effect of rotigotine on control of early morning motor function and sleep quality in subjects with idiopathic Parkinson's disease

P2.170 Effect of rotigotine on control of early morning motor function and sleep quality in subjects with idiopathic Parkinson's disease

P2.152 Changes in early-morning motor status following adjunctive treatment of advanced Parkinson's disease with rotigotine transdermal system: two large, placebo-controlled trials

P2.152 Changes in early-morning motor status following adjunctive treatment of advanced Parkinson's disease with rotigotine transdermal system: two large, placebo-controlled trials