Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease.

Abstract

OBJECTIVE:

To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy.

METHODS:

This was a randomized, 26-week, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving l-dopa or dopamine agonists. Patients with a Unified Parkinson's Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo. The primary endpoint was the change from baseline at week 26 in the sum of UPDRS parts 2 (activities of daily living) and 3 scores (UPDRS2+3).

RESULTS:

The number of patients treated was 1,007. Neither preladenant nor rasagiline was superior to placebo after 26 weeks. The differences vs placebo (95% confidence interval) in UPDRS2+3 scores (with a negative difference indicating improvement vs placebo) were preladenant 2 mg = 2.60 (0.86, 4.30), preladenant 5 mg = 1.30 (-0.41, 2.94), preladenant 10 mg = 0.40 (-1.29, 2.11), and rasagiline 1 mg = 0.30 (-1.35, 2.03). Post hoc analyses did not identify a single causal factor that could explain the finding of a failed trial. Preladenant was generally well-tolerated with few patients discontinuing due to adverse events (preladenant 7%, rasagiline 3%, placebo 4%).

CONCLUSIONS:

No evidence supporting the efficacy of preladenant as monotherapy was observed in this phase 3 trial. The lack of efficacy of the active control rasagiline makes it difficult to interpret the results.

CLINICAL TRIAL REGISTRATION:

Clinicaltrials.gov: NCT01155479.

CLASSIFICATION OF EVIDENCE:

This study provides Class I evidence that for patients with early PD, preladenant is not effective as monotherapy at the doses studied (2, 5, 10 mg).

• Authors: Fabrizio Stocchi, Olivier Rascol, Robert A Hauser, Susan Huyck, Anjela Tzontcheva, Rachel Capece, Tony W Ho, Peter Sklar, Christopher Lines, David Michelson, David J Hewitt, Preladenant Early Parkinson Disease Study Group
• Journal: Neurology (Neurology) Vol. 88 Issue 23 Pg. 2198-2206 (Jun 06 2017) ISSN: 1526-632X [Electronic] United States
• PMID: 28490648 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: © 2017 American Academy of Neurology.

Chemical References

• Adenosine A2 Receptor Antagonists
• Antiparkinson Agents
• Indans
• Pyrimidines
• Triazoles
• rasagiline
• 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

Topics

• Activities of Daily Living
• Adenosine A2 Receptor Antagonists (therapeutic use)
• Antiparkinson Agents (adverse effects, therapeutic use)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• Indans (adverse effects, therapeutic use)
• Internationality
• Male
• Middle Aged
• Motor Activity (drug effects)
• Parkinson Disease (drug therapy)
• Pyrimidines (adverse effects, therapeutic use)
• Severity of Illness Index
• Treatment Failure
• Triazoles (adverse effects, therapeutic use)