title: Tozadenant (SYN115) in patients with Parkinson's disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial.
abstract: BACKGROUND
  Many patients with Parkinson's disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A2A receptor antagonist that improves motor function in animal models of Parkinson's disease. We aimed to assess the safety and efficacy of tozadenant as an adjunct to levodopa in patients with Parkinson's disease who have motor fluctuations on levodopa.
  
  
  METHODS
  We did an international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of tozadenant in levodopa-treated patients with Parkinson's disease who had motor fluctuations (at least 2·5 h off-time per day). Eligible patients were randomly assigned via a computer-generated randomisation schedule to receive tozadenant 60, 120, 180, or 240 mg or matching placebo twice daily for 12 weeks. All study management, site personnel, and patients were masked to treatment assignment. The primary outcome was change from baseline to week 12 in hours per day spent in the off-state (assessed from Parkinson's disease diaries completed by patients). This study is registered at ClinicalTrials.gov, number NCT01283594.
  
  
  RESULTS
  Of 420 randomised patients (mean age 63·3 [SD 8·3] years; mean duration of Parkinson's disease 8·7 [4·7] years), 403 provided post-baseline diary data and 337 completed study treatment. Compared with placebo, mean daily off-time was significantly reduced in the combined tozadenant 120 mg twice-daily and 180 mg twice-daily group (-1·1 h, 95% CI -1·8 to -0·5; p=0·0006), the tozadenant 120 mg twice-daily group (-1·1 h, -1·8 to -0·4; p=0.0039), and the tozadenant 180 mg twice-daily group (-1·2 h, -1·9 to -0·4; p=0·0039). The most common adverse events in these groups were dyskinesia (seven [8%] of 84 patients in the placebo group, 13 [16%] of 82 in the 120 mg twice-daily group, and 17 [20%] of 85 in the 180 mg twice-daily group), nausea (three [4%], 9 [11%], and ten [12%]), and dizziness (one [1%], four [5%], and 11 [13%]). Tozadenant 60 mg twice daily was not associated with a significant reduction in off-time, and tozadenant 240 mg twice daily was associated with an increased rate of discontinuation because of adverse events (17 [20%] of 84 patients).
  
  
  CONCLUSIONS
  Tozadenant at 120 or 180 mg twice daily was generally well tolerated and was effective at reducing off-time. Further investigation of tozadenant treatment in phase 3 trials is warranted.
  
  
  BACKGROUND
  Biotie Therapies.
authors.affiliation: University of South Florida Parkinson's Disease and Movement Disorders Center, National Parkinson Foundation Center of Excellence, Tampa, FL, USA. Electronic address: rhauser@health.usf.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hauser
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: C Warren
authors.initials: CW
authors.lastname: Olanow
authors.affiliation: University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: Karl D
authors.initials: KD
authors.lastname: Kieburtz
authors.affiliation: Clinique Sainte-Anne Mémoire et Mouvement, Faculty of Medicine, Laval University, Quebec, QC, Canada.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Pourcher
authors.affiliation: Department of General Medicine, Ovidius University of Constanta, Constanta, Romania.
authors.forename: Any
authors.initials: A
authors.lastname: Docu-Axelerad
authors.affiliation: Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lew
authors.affiliation: Department of General Neurology, Zaporizhzhya State Medical University, Zaporizhzhya, Ukraine.
authors.forename: Olexandr
authors.initials: O
authors.lastname: Kozyolkin
authors.affiliation: Biotie Therapies, South San Francisco, CA, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Neale
authors.affiliation: Biotie Therapies, South San Francisco, CA, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Resburg
authors.affiliation: Biotie Therapies, South San Francisco, CA, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Meya
authors.affiliation: Biotie Therapies, South San Francisco, CA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kenney
authors.affiliation: Biotie Therapies, South San Francisco, CA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Bandak
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000009:adverse effects*; D000368:Aged; D000978:Antiparkinson Agents / Q000009:adverse effects*; D052160:Benzothiazoles / Q000009:adverse effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004409:Dyskinesia, Drug-Induced / Q000175:diagnosis* / Q000453:epidemiology; D005260:Female; D006801:Humans; D038622:Internationality; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000175:diagnosis* / Q000188:drug therapy* / Q000453:epidemiology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D052160:Benzothiazoles; D007980:Levodopa; C000593256:tozadenant