Authors

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. Gunzler
Claire 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, Henry Ford Health SystemFollow
Patricia Kaminski, Henry Ford Health SystemFollow
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

Document Type

Article

Publication Date

9-14-2021

Publication Title

JAMA : the journal of the American Medical Association

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.

Comments

Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Medical Subject Headings

Aged; Biomarkers; Disease Progression; Dopamine Plasma Membrane Transport Proteins; Double-Blind Method; Female; Humans; Inosine; Kidney Calculi; Male; Middle Aged; Parkinson Disease; Severity of Illness Index; Treatment Failure; Uric Acid

PubMed ID

34519802

Volume

326

Issue

10

First Page

926

Last Page

939

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