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Original Investigation
Clinical Trial
February 2017

Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor FluctuationsA Randomized Clinical Trial

Author Affiliations
  • 1Department of Clinical Neurosciences, University College London Institute of Neurology, London, United Kingdom
  • 2Department of Medicine, Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
  • 3Department of Neurology, University of South Florida College of Medicine, Tampa
  • 4Department of Neurology, Baylor College of Medicine, Houston, Texas
  • 5Parkinson-Klinik, Wolfach, Germany
  • 6Biotie Therapies Inc, San Francisco, California
  • 7Servicio de Neurología, Sant Pau Hospital, Universidad Autonoma de Barcelona, Universitat Oberta de Catalunya, Barcelona, Spain
  • 8Department of Neurology, University of Kansas Medical Center, Kansas City
  • 9Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
  • 10APC, St Moritz, Switzerland
JAMA Neurol. 2017;74(2):216-224. doi:10.1001/jamaneurol.2016.4467
Key Points

Question  Is safinamide a beneficial treatment for motor fluctuations in patients using oral levodopa for the treatment of Parkinson disease?

Findings  In this 24-week, randomized clinical trial, 549 patients had more than 1.5 hours per day of “off” time despite pharmacotherapy optimized to minimize motor fluctuations. Safinamide taken once daily significantly increased daily “on” time without troublesome dyskinesia by a mean 1.42 hours vs 0.57 hour for placebo.

Meaning  The study supports the use of safinamide as an effective adjunct to levodopa for fluctuating Parkinson disease.

Abstract

Importance  Although levodopa remains the most effective oral pharmacotherapy for Parkinson disease (PD), its use is often limited by wearing off effect and dyskinesias. Management of such complications continues to be a significant challenge.

Objective  To investigate the efficacy and safety of safinamide (an oral aminoamide derivative with dopaminergic and nondopaminergic actions) in levodopa-treated patients with motor fluctuations.

Design, Setting, and Participants  From March 5, 2009, through February 23, 2012, patients from academic PD care centers were randomized (1:1 ratio) to receive double-blind adjunctive safinamide or placebo for 24 weeks. All patients had idiopathic PD with “off” time (time when medication effect has worn off and parkinsonian features, including bradykinesia and rigidity, return) of greater than 1.5 hours per day (excluding morning akinesia). Their pharmacotherapy included oral levodopa plus benserazide or carbidopa in a regimen that had been stable for 4 weeks or longer. During screening, each patient’s regimen was optimized to minimize motor fluctuations. Study eligibility required that after 4 weeks of optimized treatment, the patients still have more than 1.5 hours per day of off time. Adverse events caused the premature study discontinuation of 12 individuals (4.4%) in the safinamide group and 10 individuals (3.6%) in the placebo group.

Interventions  Patients took safinamide or placebo as 1 tablet daily with breakfast. If no tolerability issues arose by day 14, the starting dose, 50 mg, was increased to 100 mg.

Main Outcomes and Measures  The prespecified primary outcome was each treatment group’s mean change from baseline to week 24 (or last “on” treatment value) in daily “on” time (relief of parkinsonian motor features) without troublesome dyskinesia, as assessed from diary data.

Results  At 119 centers, 549 patients were randomized (mean [SD] age, 61.9 [9.0] years; 334 male [60.8%] and 371 white [67.6%]): 274 to safinamide and 275 to placebo. Among them, 245 (89.4%) receiving safinamide and 241 (87.6%) receiving placebo completed the study. Mean (SD) change in daily on time without troublesome dyskinesia was +1.42 (2.80) hours for safinamide, from a baseline of 9.30 (2.41) hours, vs +0.57 (2.47) hours for placebo, from a baseline of 9.06 (2.50) hours (least-squares mean difference, 0.96 hour; 95% CI, 0.56-1.37 hours; P < .001, analysis of covariance). The most frequently reported adverse event was dyskinesia (in 40 [14.6%] vs 15 [5.5%] and as a severe event in 5 [1.8%] vs 1 [0.4%]).

Conclusions and Relevance  The outcomes of this trial support safinamide as an effective adjunct to levodopa in patients with PD and motor fluctuations to improve on time without troublesome dyskinesia and reduce wearing off.

Trial Registration  clinicaltrials.gov Identifier NCT00627640

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