title: Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01155466 and NCT01227265.
authors.affiliation: Parkinson's Disease and Movement Disorders Center, University of South Florida, National Parkinson Foundation Center of Excellence, Tampa.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hauser
authors.affiliation: Institute of Neurology, L'Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Stocchi
authors.affiliation: Clinical Investigation Center, Institut National de la Santé et de la Récherche Médicale, Toulouse University, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rascol
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Huyck
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Rachel
authors.initials: R
authors.lastname: Capece
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Tony W
authors.initials: TW
authors.lastname: Ho
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Peter
authors.initials: P
authors.lastname: Sklar
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lines
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: David
authors.initials: D
authors.lastname: Michelson
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: David
authors.initials: D
authors.lastname: Hewitt
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007391:International Cooperation; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology; D011743:Pyrimidines / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000978:Antiparkinson Agents; D011743:Pyrimidines; D014230:Triazoles; D007980:Levodopa; C539997:2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine