title: Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier NCT00627640.
authors.affiliation: Department of Clinical Neurosciences, University College London Institute of Neurology, London, United Kingdom.
authors.forename: Anthony H V
authors.initials: AH
authors.lastname: Schapira
authors.affiliation: Department of Medicine, Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fox
authors.affiliation: Department of Neurology, University of South Florida College of Medicine, Tampa.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hauser
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, Texas.
authors.forename: Joseph
authors.initials: J
authors.lastname: Jankovic
authors.affiliation: Parkinson-Klinik, Wolfach, Germany.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Jost
authors.affiliation: Biotie Therapies Inc, San Francisco, California.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kenney
authors.affiliation: Servicio de Neurología, Sant Pau Hospital, Universidad Autonoma de Barcelona, Universitat Oberta de Catalunya, Barcelona, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Kulisevsky
authors.affiliation: Department of Neurology, University of Kansas Medical Center, Kansas City.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Pahwa
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.affiliation: APC, St Moritz, Switzerland.
authors.forename: Ravi
authors.initials: R
authors.lastname: Anand
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001596:Benzylamines / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007391:International Cooperation; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D017063:Outcome Assessment, Health Care; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology*; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000978:Antiparkinson Agents; D001596:Benzylamines; D007980:Levodopa; C092797:safinamide; D000409:Alanine