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Original Investigation | Clinical Trial

Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease Two Randomized Clinical Trials and Lessons Learned

Robert A. Hauser, MD1; Fabrizio Stocchi, MD2; Olivier Rascol, MD3; Susan B. Huyck, DrPH4; Rachel Capece, BS4; Tony W. Ho, MD4; Peter Sklar, MD4; Christopher Lines, PhD4; David Michelson, MD4; David Hewitt, MD4
[+] Author Affiliations
1Parkinson’s Disease and Movement Disorders Center, University of South Florida, National Parkinson Foundation Center of Excellence, Tampa
2Institute of Neurology, L’Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Rome, Italy
3Clinical Investigation Center, Institut National de la Santé et de la Récherche Médicale, Toulouse University, Toulouse, France
4Merck & Co, Inc, Kenilworth, New Jersey
JAMA Neurol. 2015;72(12):1491-1500. doi:10.1001/jamaneurol.2015.2268.
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Importance  Preladenant is an adenosine 2A receptor antagonist that reduced “off” time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials.

Objective  To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations.

Design, Setting, and Participants  Two 12-week, phase 3, randomized, placebo-controlled, double-blind trials performed from July 15, 2010, to April 16, 2013. The setting included neurology clinics, clinical research centers, and hospitals in the Americas, the European Union, Eastern Europe, India, and South Africa. Participants included patients with moderate to severe PD taking levodopa who were experiencing motor fluctuations.

Interventions  In trial 1, a total of 778 eligible patients were randomized to the addition of preladenant (2 mg, 5 mg, or 10 mg twice daily), placebo, or rasagiline mesylate (1 mg/d) in a 1:1:1:1:1 ratio. In trial 2, a total of 476 eligible patients were randomized to the addition of preladenant (2 mg or 5 mg twice daily) or placebo in a 1:1:1 ratio.

Main Outcomes and Measures  The primary outcome measure was change in off time from baseline to week 12.

Results  In trial 1, neither preladenant nor rasagiline was superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were −0.10 hour (95% CI, −0.69 to 0.46 hour) for preladenant 2 mg twice daily, −0.20 hour (95% CI, −0.75 to 0.41 hour) for preladenant 5 mg twice daily, −0.00 hour (95% CI, −0.62 to 0.53 hour) for preladenant 10 mg twice daily, and −0.30 hour (95% CI, −0.90 to 0.26 hour) for rasagiline mesylate 1 mg/d. In trial 2, preladenant was not superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were −0.20 hour (95% CI, −0.72 to 0.35 hour) for preladenant 2 mg twice daily and −0.30 hour (95% CI, −0.86 to 0.21 hour) for preladenant 5 mg twice daily. Preladenant was well tolerated, with the most common adverse event that showed an increase over placebo in both trials being constipation (6%-8% for preladenant vs 1%-3% for placebo).

Conclusions and Relevance  In these phase 3 trials, preladenant did not significantly reduce off time compared with placebo. That the active control rasagiline also failed to demonstrate a significant reduction in off time suggests that issues of study design or conduct may have affected these trials.

Trial Registration  clinicaltrials.gov Identifier: NCT01155466 and NCT01227265

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Figure 1.
Participant Flow in Trial 1 and Trial 2

PRL indicates preladenant; PBO, placebo; and RAS, rasagiline.

aFewer than the number treated because patients with no post baseline data were excluded from the efficacy analyses.

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Figure 2.
Post Hoc Analysis of Change in Off Time by Enrollment Half in Trial 1

Shown is the estimated mean (SE) change from baseline in mean off time (hours per day) over time by enrollment half in trial 1 for the first 50% and the second 50%. CFB indicates change from baseline.

aP < .05 vs placebo.

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Submit a Comment
Off time must be normalized for time in dyskinesia
Posted on December 15, 2015
David L. Keller, MD
disabled with Parkinson disease
Conflict of Interest: None Declared
As a disabled physician with Parkinson disease (PD) and motor fluctuations, I know how to reduce \"off time\": take more carbidopa/levodopa. The problem, of course, is that, after the point of diminishing returns, each extra minute out of the \"off\" state is purchased with more than one minute in an equally disabling state of dyskinesia. My goal is to be neither \"off\" nor wracked with dyskinesias. Any study which seeks to reduce off time must report the concomitant effect on dyskinesias. If the new medication being tested allows a reduction in dopaminergic medication to maintain or decrease the off time (or demands a decrease in dopaminergic medication to avoid worsening dyskinesias) then those adjustments to the patients' baseline PD meds must be reported.
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