Caroline Cassels

May 01, 2012

May 1, 2012 (New Orleans, Louisiana) — A transdermal patch that delivers 8 mg of the dopamine-receptor agonist rotigotine (Neupro, UCB) in a once-daily, single application is the lowest effective dose for reducing absolute "off time" in patients with advanced Parkinson's disease (PD), a phase 3 study shows.

Presented here at the American Academy of Neurology (AAN) 64th Annual Meeting, the multicenter, double-blind placebo-controlled trial showed that PD patients receiving the 8-mg dose had a reduction in absolute off time of 2.36 hours vs 1.5 hours for patients receiving placebo — a difference that was statistically significant (P = .024).

"We are moving to a new age in the treatment of Parkinson's disease. For so many years, patients were dependent on taking medication multiple, multiple times per day. Now, as we move into a stage when we are able to give patients medication once daily, it is really going to be a major breakthrough," principal investigator Lawrence Elmer, MD, PhD, medical director of the Center for Neurological Disorders, University of Toledo, in Ohio, told Medscape Medical News.

Dr, Lawrence Elmer

"Controlling Parkinson's disease is not like controlling hypertension because patients don't know when their blood pressure is high, but they know very distinctly when their Parkinson's symptoms are uncontrolled," he added.

New Product

Approved by the US Food and Drug Administration (FDA) in early April for the treatment of PD and restless legs syndrome and reported by Medscape Medical News at that time, the transdermal delivery system is designed to maintain stable blood plasma levels for 24 hours with a single daily application.

This recent approval of the rotigotine patch follows a 2008 FDA recall of the product. Reported by Medscape Medical News at that time, the patch was recalled because of drug crystallization that potentially hampered absorption.

The FDA sent the manufacturer back to the drawing board, calling for a new formulation, and this new patch is the resulting product.

Previous phase 3 studies in patients with advanced PD that was not adequately controlled with levodopa have shown that adjunctive therapy with the patch in doses of up to 16 mg/day and either 8 or 12 mg/day significantly decreases absolute off time compared with placebo. Dr. Elmer noted that a minimally effective dose for the patch with respect to off time has not been established.

"The aim of this study was to answer this question," he said.

International Trial

The international trial included 514 patients from the United States, India, and Latin America. Patients were randomly assigned to receive 1 of 4 doses of rotigotine or placebo delivered transdermally.

All study participants had advanced PD that was not adequately controlled with optimal-dose levodopa, experiencing an average off time of at least 2.5 hours per day.

Patients were randomly assigned to receive placebo (n = 108), or rotigotine 2 mg/24 h (n = 101), 4 mg/24 h (n = 107), 6 mg/24 h (n = 104), or 8 mg/24 h (n = 94).

Treatment was titrated to the randomized dose during a period of 1 to 4 weeks and was maintained at that dose for 12 weeks, the investigators report.

The study's primary outcome was the change in the absolute time spent "off" from baseline to end of maintenance (EoM). Self-report home diaries were used to track off time; on time with troublesome dyskinesia; or on time without troublesome dyskinesia.

Secondary outcome measures included the following:

  • Change in the relative time spent "off" from baseline to EoM;

  • Change in absolute time spent "on" from baseline to EoM;

  • Change in Unified Parkinson's Disease Rating Scale (UPDRS) parts II (activities of daily living) and III (motor) from baseline to EoM.

The majority of patients had achieved their assigned rotigotine dose at the start of maintenance. A total of 406 participants completed the study.

Large Placebo Effect

Rotigotine significantly reduced absolute daily off time in the 8 mg/24 h group vs placebo, with an apparent dose-dependent trend.

"The placebo effect was slightly higher than what we usually see, making it more difficult to see a statistically significant differentiation between placebo and the 2-, 4-, and 6-mg doses. However, there was a clear dose-response trend in the right direction for the lower doses. The only dose that reached statistical significance was the 8 mg," said Dr. Elmer.

Secondary outcomes, including changes in relative off time, absolute on time, and UPDRS scores, also suggested dose-dependent improvements, said Dr. Elmer.

The tolerability of rotigotine was generally good, he reported. The most common adverse events included application site reactions, nausea, and dyskinesias.

The remainder of its safety profile was similar to that seen in previous studies of rotigotine in patients with advanced PD, he added. However, he said, it was notable that the incidence of somnolence and orthostatic hypotension across all doses of rotigotine were equivalent to, or lower than, placebo.

On the basis of these findings, said Dr. Elmer, clinicians who opt to treat advanced PD with the rotigotine patch should employ a "go low, go slow" approach and take time to titrate to the 8 mg/day dose.

"The key take-home from this study is that the threshold of clinical benefit for advance Parkinson's is about 8 mg, and neurologists and other clinicians should work up to that target.

"Just like other dopamine agonists, the most common side effect of rotigotine is GI [gastrointestinal] upset, and even though the patch is absorbed slowly, it is still good to titrate up.

"Personally, I usually go slower [than the trial protocol suggests] to ensure that side effects are minimized and patients' chances of continuing with the drug is maximized. If patients stop the medication because they have a bad reaction, they could potentially deprive themselves of a very effective medication that can provide years of benefit."

Dr. Elmer said he would like to see more studies exploring the efficacy of higher doses of the rotigotine patch.

Potential Concerns

Commenting on the study for Medscape Medical News, Lisa Shulman, MD, professor of neurology at the University of Maryland School of Medicine, in Baltimore, said it was "surprising" that only the 8-mg dose resulted in a significant improvement in daily off time.

"The authors suggest that an unusually large placebo effect may underlie these results," said Dr. Shulman.

She noted that among the available dopamine agonists, rotigotine is the only transdermal preparation available, and some patients, she said, "prefer the convenience of this."

"Reviewing the baseline features of the patient sample," said Dr. Shulman, "it is unusual to see that the average number of hours of off time per day was over 6 hours (very high), while the average UPDRS motor score was about 25 (moderate), and the average levodopa dose was about 630 mg/day (moderate). This combination raises concern that these patients may not have been optimized on their medications prior to enrollment, as the inclusion criteria requires."

Dr. Elmer reports that he has received personal compensation for activities with Lundbeck Research USA, Inc, Teva Neuroscience, UCB Pharma, GlaxoSmithKline, Inc, and Novartis. Dr. Elmer has received research support from GlaxoSmithKline, Inc. Dr. Shulman has disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 64th Annual Meeting. Emerging Science Session 002, presented April 25, 2012.