Tozadenant (SYN115) in patients with Parkinson's disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial
| Autor: | C. Warren Olanow, Chris Resburg, Mark F. Lew, Any Docu-Axelerad, Olexandr Kozyolkin, Emmanuelle Pourcher, Stephen Bandak, Ann C. Neale, Robert A. Hauser, Karl Kieburtz, Christopher Kenney, Uwe Meya |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Dyskinesia Drug-Induced medicine.medical_specialty Internationality Randomization Nausea Placebo law.invention Antiparkinson Agents Levodopa Efficacy Double-Blind Method Randomized controlled trial law Internal medicine medicine Humans Benzothiazoles Aged Cross-Over Studies Intention-to-treat analysis business.industry Parkinson Disease Middle Aged Crossover study Adenosine A2 Receptor Antagonists Discontinuation Surgery Female Neurology (clinical) medicine.symptom business |
| Zdroj: | The Lancet Neurology. 13:767-776 |
| ISSN: | 1474-4422 |
| Popis: | Summary Background Many patients with Parkinson's disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A 2A 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. |
| Databáze: | OpenAIRE |
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