Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial

Michael A. Schwarzschild, Alberto Ascherio, Cindy Casaceli, Gary C. Curhan, Rebecca Fitzgerald, Cornelia Kamp, Codrin Lungu, Eric A. Macklin, Kenneth Marek, Dariush Mozaffarian, David Oakes, Alice Rudolph, Ira Shoulson, Aleksandar Videnovic, Burton Scott, Lisa Gauger, Jason Aldred, Melissa Bixby, Jill Ciccarello, Steven A. GunzlerClaire Henchcliffe, Matthew Brodsky, Kellie Keith, Robert A. Hauser, Christopher Goetz, Mark S. Ledoux, Vanessa Hinson, Rajeev Kumar, Alberto J. Espay, Joohi Jimenez-Shahed, Christine Hunter, Chadwick Christine, Aaron Daley, Maureen Leehey, J. Antonelle De Marcaida, Joseph Harold Friedman, Albert Hung, Grace Bwala, Irene Litvan, David K. Simon, Tanya Simuni, Cynthia Poon, Mya C. Schiess, Kelvin Chou, Ariane Park, Danish Bhatti, Carolyn Peterson, Susan R. Criswell, Liana Rosenthal, Jennifer Durphy, Holly A. Shill, Shyamal H. Mehta, Anwar Ahmed, Andres F. Deik, John Y. Fang, Natividad Stover, Lin Zhang, Richard B. Dewey, Ashley Gerald, James T. Boyd, Emily Houston, Valerie Suski, Sherri Mosovsky, Leslie Cloud, Binit B. Shah, Marie Saint-Hilaire, Raymond James, Sarah Elizabeth Zauber, Stephen Reich, David Shprecher, Rajesh Pahwa, April Langhammer, Kathrin Lafaver, Peter A. Lewitt, Patricia Kaminski, John Goudreau, Doozie Russell, David J. Houghton, Ashley Laroche, Karen Thomas, Martha McGraw, Zoltan Mari, Carmen Serrano, Karen Blindauer, Marcie Rabin, Roger Kurlan, John C. Morgan, Michael Soileau, Melissa Ainslie, Ivan Bodis-Wollner, Ruth B. Schneider, Cheryl Waters, Amber Servi Ratel, Christopher A. Beck, Patrick Bolger, Katherine F. Callahan, Grace F. Crotty, David Klements, Melissa Kostrzebski, Gearoid Michael McMahon, Lindsay Pothier, Sushrut S. Waikar, Anthony Lang, Tiago Mestre

Research output: Contribution to journalArticlepeer-review

Abstract

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P =.18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Original languageEnglish (US)
Pages (from-to)926-939
Number of pages14
JournalJAMA - Journal of the American Medical Association
Volume326
Issue number10
DOIs
StatePublished - Sep 14 2021

ASJC Scopus subject areas

  • Medicine(all)

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