Robert A Hauser1, C Warren Olanow2, Karl D Kieburtz3, Emmanuelle Pourcher4, Any Docu-Axelerad5, Mark Lew6, Olexandr Kozyolkin7, Ann Neale8, Chris Resburg8, Uwe Meya8, Christopher Kenney8, Stephen Bandak8. 1. 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. 2. Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA. 3. University of Rochester School of Medicine, Rochester, NY, USA. 4. Clinique Sainte-Anne Mémoire et Mouvement, Faculty of Medicine, Laval University, Quebec, QC, Canada. 5. Department of General Medicine, Ovidius University of Constanta, Constanta, Romania. 6. Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 7. Department of General Neurology, Zaporizhzhya State Medical University, Zaporizhzhya, Ukraine. 8. Biotie Therapies, South San Francisco, CA, USA.
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. FINDINGS: 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). INTERPRETATION: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. FUNDING: Biotie Therapies.
RCT Entities:
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. FINDINGS: 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). INTERPRETATION: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. FUNDING: Biotie Therapies.
Authors: Eero Rissanen; Jouni Tuisku; Pauliina Luoto; Eveliina Arponen; Jarkko Johansson; Vesa Oikonen; Riitta Parkkola; Laura Airas; Juha O Rinne Journal: J Cereb Blood Flow Metab Date: 2014-11-05 Impact factor: 6.200
Authors: Paul A Beavis; Melissa A Henderson; Lauren Giuffrida; Jane K Mills; Kevin Sek; Ryan S Cross; Alexander J Davenport; Liza B John; Sherly Mardiana; Clare Y Slaney; Ricky W Johnstone; Joseph A Trapani; John Stagg; Sherene Loi; Lev Kats; David Gyorki; Michael H Kershaw; Phillip K Darcy Journal: J Clin Invest Date: 2017-02-06 Impact factor: 14.808