Effects of long-term treatment with rotigotine transdermal system on dyskinesia in patients with early-stage Parkinson's disease.

PURPOSE: In two 6-month, double-blind, placebo-controlled studies, rotigotine transdermal system was well-tolerated and efficacious monotherapy in early-stage PD. This post hoc analysis of the long-term open-label extensions (NCT00594165; NCT00599196) of these studies assessed incidence and severity of dyskinesia in participants treated with rotigotine, with or without concomitant levodopa, for up to 6 years. METHODS: Open-label rotigotine was titrated to optimal dose (≤16 mg/24 h). Concomitant levodopa was permitted. Dyskinesia data, recorded using the Unified Parkinson's Disease Rating Scale Part IV, were pooled from the two open-label studies. RESULTS: Of 596 participants who received open-label rotigotine, 299 (50%) remained at trial closure; no patient discontinued due to dyskinesia. In the two studies, median exposure to rotigotine was 1910 days (∼5 years, 3 months), and 1564.5 days (∼4 years, 3 months). During up to 6 years of open-label rotigotine, 423/596 (71%) received levodopa. Dyskinesias were reported in 115/596 (19%) participants, 90/115 (78%) of who developed dyskinesia after levodopa was added; 25 reported dyskinesia in the absence of levodopa (includes patients who never received open-label levodopa, and those who reported dyskinesia before starting concomitant levodopa). Dyskinesia severity data were available for 107 of the 115 participants. In 56/107 (52%) participants, dyskinesia was considered 'not disabling' for all occurrences; the worst-case severity was 'mildly disabling' for 33/107 (31%), and 'moderately' or 'severely disabling' for 18/107 (17%; 3% of total participants). CONCLUSION: During treatment with rotigotine in patients with PD for up to 6 years the incidence of dyskinesia was low, and the dyskinesia was generally 'not disabling' or 'mildly disabling'.

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

BACKGROUND: Pain 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. METHODS: PD 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. RESULTS: Of 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. CONCLUSIONS: The 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 (r(2) = 0.01-0.19) at baseline, r = 0.05-0.38 (r(2) = 0.00-0.14) at EoM, and r = -0.02-0.36 (r(2) = 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.

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

BACKGROUND: Non-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. METHODS: Patients 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. RESULTS: Of 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). CONCLUSIONS: Rotigotine 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.

Novel functional imaging of changes in small airways of patients treated with extrafine beclomethasone/formoterol.

BACKGROUND: Inhaled formulations using extrafine particles of long-acting ß2-agonists and corticosteroids were developed to optimize asthma treatment. Findings that these combinations reach and treat smaller airways more effectively are predominantly based on general non-specific outcomes with little information on regional characteristics. OBJECTIVES: This study aims to assess long-term effects of extrafine beclomethasone/formoterol on small airways of asthmatic patients using novel functional imaging methods. METHODS: Twenty-four stable asthma patients were subdivided into three groups (steroid naive, n = 7; partially controlled, n = 6; well controlled, n = 11). Current treatment was switched to a fixed combination of extrafine beclomethasone/formoterol (Foster®; Chiesi Pharmaceuticals, Parma, Italy). Patients underwent lung function evaluation and thorax high-resolution computerized tomography (HRCT) scan. Local airway resistance was obtained from computational fluid dynamics (CFD). RESULTS: After 6 months, the entire population showed improvement in pre-bronchodilation imaging parameters, including small airway volume (p = 0.0007), resistance (p = 0.011), and asthma control score (p = 0.016). Changes in small airway volume correlated with changes in asthma control score (p = 0.004). Forced expiratory volume in 1 s (p = 0.044) and exhaled nitric oxide (p = 0.040) also improved. Functional imaging provided more detail and clinical relevance compared to lung function tests, especially in the well-controlled group where only functional imaging parameters showed significant improvement, while the correlation with asthma control score remained. CONCLUSIONS: Extrafine beclomethasone/formoterol results in a significant reduction of small airway obstruction, detectable by functional imaging (HRCT/CFD). Changes in imaging parameters correlated significantly with clinically relevant improvements. This indicates that functional imaging is a useful tool for sensitive assessment of changes in the respiratory system after asthma treatment.

Treatment of patients with early and advanced Parkinson's disease with rotigotine transdermal system: age-relationship to safety and tolerability.

Although dopamine agonists (DAs) are sometimes perceived as poorly tolerated by the elderly, there is little clinical evidence to support these concerns. Safety and tolerability of rotigotine have been demonstrated in four 6-month randomized placebo-controlled studies: two in early Parkinson's disease (PD) and two in advanced PD. A post hoc analysis of data from these pivotal trials was carried out to compare the adverse event (AE) profiles of younger and older patient populations. Data from early and advanced PD trials were separately pooled and evaluated using two age cut-offs (<65 vs. ≥ 65 years; <75 vs. ≥ 75 years). For most AEs, no age-related differences in incidence were observed. In the early PD pool, nausea (38% vs. 30%) and headache (15% vs. 9%) were more frequent in younger (<65 years) compared with older (≥ 65 years) patients using the 65-year age cut-off. Using the 75-year cut-off, nausea (36% vs. 21%) was more frequent in younger patients (<75 years) and dizziness (15% vs. 28%) was more frequent in older patients (≥ 75 years). In the advanced PD pool, nausea was more frequent in younger patients using the 65-year age cut-off (24% vs. 19%) and falls were more frequent in older patients using the 75-year age cut-off (8% vs. 13%). In this relatively healthy population which included only few patients aged 75 years or older, rotigotine was generally well tolerated regardless of age. Data from more representative PD populations are required to fully assess potential risks of DA therapy in elderly patients.

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.

Continuous versus on-demand pharmacotherapy of allergic rhinitis: evidence and practice.

This review aims to compare continuous with on-demand pharmacotherapy of allergic rhinitis by focusing on pharmacodynamic, pharmacokinetic, safety, effectiveness, cost and cost-effectiveness considerations. A working party of experts reviewed and discussed the literature and guidelines, and conducted a qualitative analysis of the Summary of Product Characteristics of specific medicines. With respect to medicines, the working party limited itself to antihistamines, nasal corticosteroids and leukotriene antagonists. Based on a review of the evidence from a multidisciplinary perspective, this article makes pharmacotherapeutic recommendations that are easy, functional and applicable to daily practice in primary care. The pharmacotherapeutic evidence for continuous versus on-demand treatment of allergic rhinitis was limited. Clearly, for corticosteroids, their mechanism of action in allergic rhinitis of reducing allergic inflammation requires continuous therapy at least for the duration of symptoms. For H(1)-antihistamines, some trials suggest that continuous treatment is preferable but more studies are needed to confirm this conclusion. For both H(1)-antihistamines and nasal corticosteroids safety data indicate that continuous treatment may be given without fears of adverse consequences, although a distinction can be made between the first and the second generation antihistamines. With regard to the cost and cost-effectiveness implications of continuous therapy versus on-demand therapy, more studies are necessary before definitive conclusions may be made.