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Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial.
JAMA Neurol 2017; 74(2):216-224JN

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.

Authors+Show Affiliations

Department of Clinical Neurosciences, University College London Institute of Neurology, London, United Kingdom.Department of Medicine, Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.Department of Neurology, University of South Florida College of Medicine, Tampa.Department of Neurology, Baylor College of Medicine, Houston, Texas.Parkinson-Klinik, Wolfach, Germany.Biotie Therapies Inc, San Francisco, California.Servicio de Neurología, Sant Pau Hospital, Universidad Autonoma de Barcelona, Universitat Oberta de Catalunya, Barcelona, Spain.Department of Neurology, University of Kansas Medical Center, Kansas City.Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.APC, St Moritz, Switzerland.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

27942720

Citation

Schapira, Anthony H V., et al. "Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: a Randomized Clinical Trial." JAMA Neurology, vol. 74, no. 2, 2017, pp. 216-224.
Schapira AH, Fox SH, Hauser RA, et al. Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol. 2017;74(2):216-224.
Schapira, A. H., Fox, S. H., Hauser, R. A., Jankovic, J., Jost, W. H., Kenney, C., ... Anand, R. (2017). Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurology, 74(2), pp. 216-224. doi:10.1001/jamaneurol.2016.4467.
Schapira AH, et al. Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: a Randomized Clinical Trial. JAMA Neurol. 2017 Feb 1;74(2):216-224. PubMed PMID: 27942720.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. AU - Schapira,Anthony H V, AU - Fox,Susan H, AU - Hauser,Robert A, AU - Jankovic,Joseph, AU - Jost,Wolfgang H, AU - Kenney,Christopher, AU - Kulisevsky,Jaime, AU - Pahwa,Rajesh, AU - Poewe,Werner, AU - Anand,Ravi, PY - 2016/12/13/pubmed PY - 2017/5/27/medline PY - 2016/12/13/entrez SP - 216 EP - 224 JF - JAMA neurology JO - JAMA Neurol VL - 74 IS - 2 N2 - 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. SN - 2168-6157 UR - https://www.unboundmedicine.com/medline/citation/27942720/Assessment_of_Safety_and_Efficacy_of_Safinamide_as_a_Levodopa_Adjunct_in_Patients_With_Parkinson_Disease_and_Motor_Fluctuations:_A_Randomized_Clinical_Trial_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2016.4467 DB - PRIME DP - Unbound Medicine ER -