A Randomized Study of Rotigotine Dose Response on ‘Off’ Time in Advanced Parkinson's Disease

Abstract

Background: Previous phase III studies in patients with advanced Parkinson's disease (PD) not adequately controlled on levodopa demonstrated significant reduction of 'off' time with rotigotine transdermal system up to 16 mg/24 h. However, the minimal effective dose has not been established. Objective: This international, randomized, double-blind, placebo-controlled study (SP921; NCT00522379) investigated rotigotine dose response up to 8 mg/24 h. Methods: Patients with advanced idiopathic PD (≥2.5 h of daily 'off' time on stable doses of levodopa) were randomized 1:1:1:1:1 to receive rotigotine 2, 4, 6, or 8 mg/24 h or placebo, titrated over 4 weeks and maintained for 12 weeks. The primary efficacy variable was change from baseline to end of maintenance in absolute time spent 'off'. Results: 409/514 (80%) randomized patients completed maintenance. Mean (±SD) baseline daily 'off' times (h/day) were placebo: 6.4 (±2.5), rotigotine 2-8 mg/24 h: 6.4 (±2.6). Rotigotine 8 mg/24 h was the minimal dose to significantly reduce 'off' time versus placebo. LS mean (±SE) absolute change in daily 'off' time (h/day) from baseline was −2.4 (±0.28) with rotigotine 8 mg/24 h, and −1.5 (±0.26) with placebo; absolute change in 'off' time in the 8 mg/24 h group compared with placebo was −0.85 h/day (95% CI −1.59, −0.11; p = 0.024). There was an apparent dose-dependent trend. Adverse events (AEs) reported at a higher incidence in the rotigotine 8 mg/24 h group versus placebo included application site reactions, nausea, dry mouth, and dyskinesia; there was no worsening of insomnia, somnolence, orthostatic hypotension, confusional state or hallucinations, even in patients ≥75 years of age. Conclusions: The minimal statistically significant effective dose of rotigotine to reduce absolute 'off' time was 8 mg/24 h. The AE profile was similar to previous studies.

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

“…16 The efficacy of rotigotine in improving UPDRS II and III subscores has been consistently shown in large-scale studies in advanced-stage PD. [25][26][27] Thus, the relatively small numerical improvement in the UPDRS II + III total score (exploratory P value >.05) in the current study was likely due to patients being included based on the severity of their PD-associated pain rather than the severity of motor symptoms (which were reasonably well controlled in this patient population) and the activities of daily living symptoms. Rotigotine was generally well tolerated in a dose range of 4 to 16 mg/24 h, with few patients discontinuing the study as a result of AEs, and AEs were consistent with the known safety profile of rotigotine.…”

“…These results suggest that rotigotine treatment may potentially be beneficial for the treatment of fluctuation-related pain. Previous studies have demonstrated improvements in wearing-off-type motor fluctuations with rotigotine in patients with advancedstage PD inadequately controlled on levodopa, [25][26][27] and clinical experience suggests that dopaminergic therapy may provide benefits for those nonmotor symptoms that are motor fluctuation-related (ie, wearing-off symptoms such as off-period pain). 15,39 It is worth noting that an approximate 4-fold numerical difference in favor of placebo was observed in KPPS domain of "chronic pain"; however, baseline "chronic pain" scores were 2-fold higher in the placebo group than in the rotigotine group; thus, these results are difficult to interpret.…”

“…These include improvements in activities of daily living and motor symptoms (Unified Parkinson's Disease Rating Scale [UPDRS] II + III) and clinically relevant reductions in ''off'' time. [25][26][27][28][29][30] In addition, exploratory data from RECOVER, a double-blind, placebo-controlled study, suggested that rotigotine may improve pain in patients with PD. Pain in RECOVER was assessed as an exploratory outcome via an 11-point Likert pain scale measuring pain of any type.…”

Non‐oral Continuous Drug Delivery Techniques in Parkinson's Disease: For Whom, When, and How?

“…Rotigotine has repeatedly been shown to improve ADL and motor function as measured on the UPDRS part II and/or III in patients with either early or advanced PD when compared to the placebo control group 12,[27][28][29][30][31][32][33][34][35][36] Rotigotine also reduces "off" time significantly as an add-on to L-dopa in patients with mid-to advanced-stage PD. 29,34,35,37 One study showed that rotigotine doses ≤8 mg/24 hr did not reach noninferiority to ropinirole doses ≤24 mg/24 hr, but were instead similar to the efficacy of ropinirole doses ≤12 mg/24 hr. 33 This was supported by a study that showed that ≤16 mg/24 hr rotigotine was noninferior to ≤15 mg/24 hr ropinirole in its effect on UPDRS II and III and on changes in "on" and "off" duration.…”

“…34 Some studies suggested an increased occurrence of dyskinesias in patients with rotigotine compared to placebo controls. 29,34,37 The studies mainly focus on the use of rotigotine as a monotherapy in early PD and as an add-on in mid-stage to advanced PD. However, when rotigotine monotherapy no longer has the desired effect, the clinical practice is often to use rotigotine simultaneously with L-dopa also at a relatively early stage of PD.…”