The safety and tolerability of rotigotine transdermal system over a 6-year period in patients with early-stage Parkinson’s disease

Abstract

This open-label extension (SP716; NCT00599196) of a 6-month, double-blind, randomized study (SP513) investigated the safety and tolerability of rotigotine transdermal system over up to ~6 years in patients with Parkinson's disease (PD; early-stage PD at double-blind enrollment). Eligible patients completing the 6-month study received optimal dose open-label rotigotine (≤ 16 mg/24 h) for up to ~6 years. Adjunctive levodopa was permitted. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Analysis of adjunctive levodopa use, dyskinesias [unified Parkinson's disease rating scale (UPDRS) IV], and efficacy (UPDRS II + III total score) were also assessed. Of 381 patients enrolled in the open-label extension, 52 % were still in the study at time of closure; 24 % withdrew because of AEs and 6 % because of lack of efficacy. Patients received rotigotine for a median duration of 1,564.5 days (~4 years, 3 months; range 5-2, 145 days). 69 % of patients started supplemental levodopa; median time to levodopa was 485 days (~1 year, 4 months). Most common AEs (% per patient-year) were somnolence (18 %), application site reactions (12 %), nausea (9 %), peripheral edema (7 %), and fall (7 %). AEs indicative of impulsive-compulsive behavior were recorded in 25 (7 %) patients. Dyskinesias were experienced by 65 (17 %) patients; the majority [47 of 65 (72 %)] reported first dyskinesia after starting levodopa. Mean UPDRS II + III total scores remained below double-blind baseline for 4 years (assessment of all patients). In conclusion, rotigotine was generally well tolerated for up to ~6 years in patients with early-stage PD. The AEs reported were in line with previous studies of rotigotine transdermal system, with typical dopaminergic side effects and application site reactions seen.

Impact of 6-month earlier versus postponed initiation of rotigotine on long-term outcome:post hocanalysis of patients with early Parkinson’s disease with mild symptom severity

“…However, as the proportion of patients who received levodopa was similar in each treatment group (i.e., 'Rotigotine--Rotigotine' 74% vs 'Placebo--Rotigotine' 73%), this does not appear to explain the longer sustained efficacy observed in the group of patients who received rotigotine treatment 6 months earlier. Finally, as approximately half of the patients in the open-label studies did not have the opportunity to complete the full 6 years of study participation [18,19], this prevents a comprehensive longitudinal analysis of the entire study cohort. In studies comparing the long-term outcome of an active treatment group versus a group receiving initial placebo treatment, the 'lessebo-effect' (the negative expectation related to receiving a placebo) in the latter group should be considered [24].…”

“…Patients were maintained at their optimal dose until rotigotine became commercially available or the sponsor closed the trial, whichever came first. Maintenance visits were scheduled at the end of the first month of open-label maintenance and at 3-month intervals thereafter [18,19].…”

“…The SP702 and SP716 studies were longterm, single-arm, open-label extensions of the SP512 and SP513 studies. Continuous transdermal delivery of rotigotine was well tolerated for up to 6 years, and demonstrated sustained efficacy (UPDRS II + III below double-blind baseline) for~2 years in the SP702 study [18] and 4 years in the SP716 study [19]. Moreover, the incidence of dyskinesia was low in these long-term studies of rotigotine [20].…”

“…In addition, the following other anti-Parkinson medications were allowed after 1 month of open-label rotigotine maintenance: monoamine oxidase B inhibitors, anticholinergic agents, N-Methyl-D-aspartate receptor-antagonists (e.g., amantadine), entacapone and modafinil. Complete inclusion and exclusion criteria are published [15][16][17][18][19].…”

Safety and Tolerability of Transdermal Rotigotine in a Clinical Practice Cohort for 2 Years

“…Multiple data of clinical trials indicate that rotigotine remains well tolerated over treatment periods of up to 6 years [4]- [7]. The objective of this study was to characterize the safety and tolerability of transdermal rotigotine in patients with PD being treated during routine management in a clinical hospital for up to 2 years.…”