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Title: Transdermal Rotigotine Appears as Safe and Effective as Pramipexole: Presented at EFNS

"Transdermal Rotigotine Appears as Safe and Effective as Pramipexole: Presented at EFNS"

By Chris Berrie BRUSSELS, BELGIUM -- August 27, 2007 -- A transdermal patch system with rotigotine, a nonergoline D3>2>1 dopamine receptor agonist, appears safe and shows efficacy comparable with pramipexole and significantly better than placebo for patients with advanced Parkinson's disease (PD), say researchers. The abdominal patch application, recently licensed in Europe for use in early and late PD, has been shown to provide maintained mean plasma rotigotine concentrations. These findings were presented on August 26th here at the 11th Congress of the European Federation of Neurological Societies (EFNS). The aim of the CLEOPATRA-PD (Clinical Efficacy of Pramipexole and Transdermal Rotigotine in Advanced Parkinson's Disease) trial was to determine efficacy and safety of transdermal rotigotine in comparison with placebo and pramipexole treatments in patients with advanced PD. Niall Quinn, MD, Member of the Study Design Committee and Emeritus Professor of Clinical Neurology, Institute of Neurology, Queen Square, London, United Kingdom, presented the findings of the international, multicentre, randomised, double-blind, double-dummy, 3-arm parallel group, phase 3 trial. Study subjects were aged 30 years or older and had levodopa-treated (300 mg/day; 3x/day; 28 days prebaseline) idiopathic PD for more than 3 years, as per the UK Brain Bank criteria, with Hoehn and Yahr stages 2 to 4 for both the "on" and "off" states. An average of 2.5 hours per day or more "off" was required, with a Mini Mental State Examination (MMSE) score of 25 or higher, and stable treatment dosing. "The dose of L-dopa could be varied according to requirements," Dr. Quinn added. Those with atypical PD and and/or who used various classes of pharmaceuticals (eg, patients on budipine and tolcapone were not allowed), or had other disease conditions were excluded. Because a transdermal patch was used, subjects with a history of significant skin hypersensitivity or recent unresolved contact dermatitis were also excluded, as were those with known intolerance or hypersensitivity to pramipexole. The 506 subjects were randomised to placebo (n = 101), pramipexole (n = 201), or rotigotine (n = 204). "The doses were titrated up to the subjects' optimum dose, with rotigotine increased up to 16 mg/24 hours as necessary [mean dose, 13 mg/day], and pramipexole increased up to the maximum permitted of 4.5 mg/day [mean dose, 3.1 mg/day]," explained Dr. Quinn. This occurred over 7 weeks and was followed by a 16-week maintenance phase, a 6-day deescalation, and a 4-week follow-up. The mean patient baseline demographics for all groups (placebo, pramipexole, rotigotine) were essentially the same for age, respectively, (65.0, 63.2, 64.3 years), MMSE (28.4, 28.7, 28.6), time since diagnosis (8.5, 8.4, 8.9 years), daily levodopa (814, 813, 795 mg), Unified Parkinson's Disease Rating Scale (UPDRS) part 3 (26.8, 26.4, 26.3), and daily absolute off time (6.6, 6.0, 6.2 hours). The subjects' anti-Parkinson's medications from baseline through treatment were similar for (respectively): anticholinergics (10%, 6%, 12%), standard L-dopa and derivatives (94%, 96%, 95%), slow-release L-dopa derivatives (22%, 27%, 22%), entacapone (12%, 23%, 28%), amantadine (21%, 18%, 17%), and selegiline (15%, 14%, 20%). The primary efficacy measure was mean absolute decrease (hours/day) in "off" time, as compared with baseline, with equivalent significant improvements over placebo (0.88) maintained for pramipexole (-2.8; [P <.0001) and rotigotine (-2.5; P <.0001).

Similarly, the mean daily absolute time spent "'on' without troublesome dyskinesis" (hours/day) was increased over placebo (1.5) for both pramipexole (3.0; P <.0003) and rotigotine (3.1; P <.0003). These improvements were also paralleled by the frequency of 30% responders: 35.0% versus 67.0% versus 59%, respectively (P <.0001 vs placebo for both). Dr. Quinn noted, "In this case, rotigotine just failed to reach noninferiority with pramipexole."

The frequencies of adverse events were similar across the three treatments. Those most common for pramipexole were dyskinesia (15%), nausea (13%), somnolence (12%), and dizziness (10%); and for rotigotine, nausea (17%), dyskinesia (12%), somnolence (12%), and application-site erythema/pruritus (9%). Dr. Quinn noted that when related to trial discontinuation, site reactions with rotigotine accounted for only 3% (n = 6) of withdrawals with rotigotine, with symptomatic orthostatic hypotension and hallucinations/confusion showing greater withdrawal tendencies with pramipexole (5%, 4%, respectively) over rotigotine (0.5%, 0%, respectively).

Dr. Quinn added, "In terms of the other secondary endpoints, both of the active drugs decreased to a significant degree the number of 'off' periods/day, decreased the proportion of events where there was an 'on status without troublesome dyskinesia on waking,' and showed significant improvements on UPDRS 2 and 3; and the overall rate of adverse events reported for pramipexole and rotigotine was comparable."

This study was recently published as: Poewe WH, Rascol O, Quinn N et al, for the SP 515 Investigators. Lancet Neurology. 2007;6:513-520. An honorarium was provided to Dr. Quinn by Schwarz Pharma.

[Presentation title: CLEOPATRA-PD: Clinical Efficacy of Pramipexole and Transdermal Rotigotine in Advanced Parkinson's Disease. Abstract SC107.]

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