Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression

作者：The Parkinson Study Group SURE-PD3 Investigators, Brent Bluett, Daniel M. Togasaki, Dragos Mihaila, Marian L. Evatt, Michael Rezak, Samay Jain, Michael A. Schwarzschild, Alberto Ascherio, Cindy Casaceli, Gary C. Curhan, Rebecca C. Fitzgerald, Cornelia Kamp, Codrin Lungu, Eric A. Macklin, Kenneth Marek, Dariush Mozaffarian, David Oakes, Alice Rudolph, Ira Shoulson, Aleksandar Videnović, B.L. Scott, Lisa Gauger, Jason Aldred, Melissa Bixby, Jill Ciccarello, Steven A. Gunzler, Claire Henchcliffe, Matthew Brodsky, Kellie Keith, Robert A. Hauser, Christopher G. Goetz, Mark S. LeDoux, Vanessa K. Hinson, Rajeev Kumar, Alberto J. Espay, Joohi Jimenez‐Shahed, Christine Hunter, Chadwick W. Christine, Aaron Daley, Maureen A. Leehey, Joy Antonelle de Marcaida, Joseph H. Friedman, Albert Y. Hung, Grace Bwala, Irene Litvan, David K. Simon, Tanya Simuni, Cynthia Poon, Mya C. Schiess, Kelvin L. Chou, Ariane Park, Danish Bhatti, Carolyn Peterson, Susan R. Criswell, Liana S. Rosenthal, Jennifer Durphy, Holly A. Shill, Shyamal H. Mehta, Anwar Ahmed, Andres 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 Shah, Marie Saint‐Hilaire, Raymond James, S. Elizabeth Zauber, Stephen G. Reich, David Shprecher, Rajesh Pahwa, April Langhammer, Kathrin LaFaver, Peter A. LeWitt, Patricia L. Kaminski, John L. Goudreau, Doozie Russell, David Houghton, Ashley LaRoche, Karen Thomas, Martha McGraw, Zoltan Mari, Carmen Serrano, Karen Blindauer, Marcie Rabin, Roger Kurlan, John C. Morgan, Michael J. Soileau, Melissa Ainslie, Iván Bódis-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 M. McMahon, Lindsay Pothier, Sushrut S. Waikar, Anthony E. Lang, Tiago Mestre · 发表于：JAMA · 年份：2021 · DOI：10.1001/jama.2021.10207 · 被引用次数：161 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Gout, Hyperuricemia, Uric Acid、Folate and B Vitamins Research

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, qual...