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.