Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Effect of Urate-Elevating Inosine on Early Parkinson Disease ProgressionThe SURE-PD3 Randomized Clinical Trial

Educational Objective
To learn whether treatment with inosine, a metabolic precursor of urate, slows the clinical progression of Parkinson disease.
1 Credit CME
Key Points

Question  Does treatment with oral inosine for up to 2 years slow progression of Parkinson disease?

Findings  In this randomized clinical trial that included 298 participants with early Parkinson disease, the rate of clinical disease progression as measured by the Movement Disorder Society Unified Parkinson Disease Rating Scale (parts I-III) total score prior to initiation of dopaminergic medication was 11.1 points per year in the inosine group and 9.9 points per year in the placebo group, a difference that was not statistically significant.

Meaning  Urate-elevating inosine treatment was not clinically beneficial in early Parkinson disease.

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

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding Author: Michael A. Schwarzschild, MD, PhD, Department of Neurology, Massachusetts General Hospital, Mass General Institute for Neurodegenerative Disease, 114 16th St, Boston, MA 02129 (michaels@helix.mgh.harvard.edu).

Accepted for Publication: June 5, 2021.

Authors/Parkinson Study Group SURE-PD3 Investigators: Michael A. Schwarzschild, MD, PhD; Alberto Ascherio, MD, DrPH; Cindy Casaceli, MBA; Gary C. Curhan, MD, ScD; Rebecca Fitzgerald, JD; Cornelia Kamp, MBA; Codrin Lungu, MD; Eric A. Macklin, PhD; Kenneth Marek, MD; Dariush Mozaffarian, MD, DrPH; David Oakes, PhD; Alice Rudolph, PhD; Ira Shoulson, MD; Aleksandar Videnovic, MD; Burton Scott, MD, PhD; Lisa Gauger; Jason Aldred, MD; Melissa Bixby, MS; Jill Ciccarello, BA; Steven A. Gunzler, MD; Claire Henchcliffe, MD, DPhil; Matthew Brodsky, MD; Kellie Keith, BA; Robert A. Hauser, MD, MBA; Christopher Goetz, MD; Mark S. LeDoux, MD, PhD; Vanessa Hinson, MD, PhD; Rajeev Kumar, MD; Alberto J. Espay, MD; Joohi Jimenez-Shahed, MD; Christine Hunter, BSN; Chadwick Christine, MD; Aaron Daley, MA; Maureen Leehey, MD; J. Antonelle de Marcaida, MD; Joseph Harold Friedman, MD; Albert Hung, MD, PhD; Grace Bwala, MBBS, MPH; Irene Litvan, MD; David K. Simon, MD, PhD; Tanya Simuni, MD; Cynthia Poon, PhD; Mya C. Schiess, MD; Kelvin Chou, MD; Ariane Park, MD, MPH; Danish Bhatti, MBBS; Carolyn Peterson, BSN; Susan R. Criswell, MD, MSCl; Liana Rosenthal, MD, PhD; Jennifer Durphy, MD; Holly A. Shill, MD; Shyamal H. Mehta, MD, PhD; Anwar Ahmed, MD; Andres F. Deik, MD, MSEd; John Y. Fang, MD; Natividad Stover, MD; Lin Zhang, MD; Richard B. Dewey Jr, MD; Ashley Gerald, MA; James T. Boyd, MD; Emily Houston, BS; Valerie Suski, DO; Sherri Mosovsky, MPH; Leslie Cloud, MD, MSc; Binit B. Shah, MD; Marie Saint-Hilaire, MD; Raymond James, BS; Sarah Elizabeth Zauber, MD; Stephen Reich, MD; David Shprecher, DO, MSci; Rajesh Pahwa, MD; April Langhammer, BA; Kathrin LaFaver, MD; Peter A. LeWitt, MD; Patricia Kaminski, MSN; John Goudreau, DO, PhD; Doozie Russell, BS; David J. Houghton, MD; Ashley Laroche, BS; Karen Thomas, DO; Martha McGraw, MD; Zoltan Mari, MD, PhD; Carmen Serrano, MD; Karen Blindauer, MD; Marcie Rabin, MD; Roger Kurlan, MD; John C. Morgan, MD, PhD; Michael Soileau, MD; Melissa Ainslie; Ivan Bodis-Wollner, MD, DSc; Ruth B. Schneider, MD; Cheryl Waters, MD; Amber Servi Ratel, BA; Christopher A. Beck, PhD; Patrick Bolger, RPh, MBA; Katherine F. Callahan, BS; Grace F. Crotty, MD, BAO, MBBCH; David Klements, MS; Melissa Kostrzebski, MS; Gearoid Michael McMahon, MB, BCh; Lindsay Pothier, BA; Sushrut S. Waikar, MD, MPH; Anthony Lang, MD; Tiago Mestre, MD, MSc.

Affiliations of Authors/Parkinson Study Group SURE-PD3 Investigators: Mass General Institute for Neurodegenerative Disease, Boston, Massachusetts (Schwarzschild); Massachusetts General Hospital, Boston (Schwarzschild, Macklin, Videnovic, Hung, Bwala, Callahan, Crotty, Klements, Pothier); Harvard School of Public Health, Boston, Massachusetts (Ascherio); University of Rochester, Rochester, New York (Casaceli, Kamp, Oakes, Rudolph, Schneider, Bolger, Kostrzebski); Brigham and Women’s Hospital, Boston, Massachusetts (Curhan, McMahon); Parkinson’s Foundation Research Advocates, Parkinson’s Foundation, New York, New York (Fitzgerald); Division of Clinical Research, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland (Lungu); Harvard Medical School, Boston, Massachusetts (Macklin); Institute for Neurodegenerative Disorders, New Haven, Connecticut (Marek); Tufts School of Medicine and Division of Cardiology, Tufts Medical Center, Boston, Massachusetts (Mozaffarian); Friedman School of Nutrition Science and Policy, Boston, Massachusetts (Mozaffarian); Department of Neurology, University of Rochester Medical Center, Rochester, New York (Shoulson); Duke University, Durham, North Carolina (Scott); Duke Medical Center, Durham, North Carolina (Gauger); Inland Northwest Research, Spokane, Washington (Aldred, Bixby, Ciccarello); Selkirk Neurology, Spokane, Washington (Aldred); University Hospitals Cleveland Medical Center, Cleveland, Ohio (Gunzler); University of California, Irvine (Henchcliffe); Weill Cornell Medical College, New York, New York (Henchcliffe); Oregon Health & Science University, Portland (Brodsky, Keith); University of South Florida, Tampa (Hauser); Rush University Medical Center, Chicago, Illinois (Goetz); Veracity Neuroscience LLC, Memphis, Tennessee (LeDoux); Medical University of South Carolina, Charleston (Hinson); Rocky Mountain Movement Disorders Center, Englewood, Colorado (Kumar); University of Cincinnati, Cincinnati, Ohio (Espay); Icahn School of Medicine at Mount Sinai, New York, New York (Jimenez-Shahed); Baylor College of Medicine, Houston, Texas (Hunter); University of California, San Francisco (Christine, Daley); University of Colorado, Denver (Leehey); Ayer Neuroscience Institute, Hartford HealthCare, Hartford, Connecticut (de Marcaida); Butler Hospital, Providence, Rhode Island (Friedman); University of California, San Diego (Litvan); Beth Israel Deaconess Medical Center, Boston, Massachusetts (Simon); Northwestern University Feinberg School of Medicine, Chicago, Illinois (Simuni, Poon, LaFaver); The University of Texas Health Science Center, Houston McGovern Medical School, Houston (Schiess); University of Michigan, Ann Arbor (Chou); The Ohio State University Wexner Medical Center, Columbus (Park); University of Nebraska Medical Center, Omaha (Bhatti, Peterson); Washington University School of Medicine in St Louis, St Louis, Missouri (Criswell); Johns Hopkins School of Medicine, Baltimore, Maryland (Rosenthal); Albany Medical College, Albany, New York (Durphy); Banner Sun Health Research Institute, Sun City, Arizona (Shill, Shprecher); University of Arizona School of Medicine–Phoenix (Shill, Shprecher); Mayo Clinic Arizona, Scottsdale (Mehta); Cleveland Clinic, Cleveland, Ohio (Ahmed); University of Pennsylvania, Philadelphia (Deik); Vanderbilt University Medical Center, Nashville, Tennessee (Fang); The University of Alabama at Birmingham (Stover); UC Davis, Davis, California (Zhang); University of Texas Southwestern Medical Center, Dallas (Dewey Jr, Gerald); University of Vermont, Burlington (Boyd); University of Vermont Medical Center, Burlington (Houston); University of Pittsburgh, Pittsburgh, Pennsylvania (Suski, Mosovsky); VCU Parkinson’s & Movement Disorders Center, Richmond, Virginia (Cloud); University of Virginia, Charlottesville (Shah); Boston University School of Medicine, Boston, Massachusetts (Saint-Hilaire, Waikar); Boston Medical Center, Boston, Massachusetts (James, Waikar); Indiana University, Bloomington (Zauber); University of Maryland School of Medicine, Baltimore (Reich); University of Kansas Medical Center, Kansas City (Pahwa, Langhammer); Henry Ford Hospital–West Bloomfield, West Bloomfield Township, Michigan (LeWitt, Kaminski); Michigan State University, East Lansing (Goudreau, Russell); Ochsner Medical Center, Jefferson, Louisiana (Houghton); Ochsner Health System, Jefferson, Louisiana (Laroche); Sentara Neurology Specialists, Norfolk, Virginia (Thomas); Center for Movement Disorders and Neurodegenerative Disease, Northwestern Medicine/Central DuPage Hospital, Winfield, Illinois (McGraw); Cleveland Clinic–Las Vegas, Las Vegas, Nevada (Mari); University of Puerto Rico, San Juan (Serrano); Medical College of Wisconsin, Milwaukee (Blindauer); Atlantic Neuroscience Institute, Summit, New Jersey (Rabin, Kurlan); Augusta University, Augusta, Georgia (Morgan); Texas Movement Disorder Specialists, Georgetown (Soileau); Scott & White Healthcare/Texas A&M University, Temple (Soileau); Baylor Scott & White Health, Temple, Texas (Ainslie); State University of New York Downstate Medical Center, Brooklyn (Bodis-Wollner); Columbia University, New York, New York (Waters, Ratel); University of Rochester Medical Center, Rochester, New York (Beck); University of Toronto, Toronto, Ontario, Canada (Lang); Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, Toronto, Ontario, Canada (Lang); University of Ottawa, Ottawa, Ontario, Canada (Mestre).

Author Contributions: Drs Schwarzschild and Macklin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Schwarzschild, Ascherio, Casaceli, Curhan, Fitzgerald, Kamp, Macklin, Marek, Oakes, Rudolph, Shoulson, Kostrzebski, Pothier, Bhatti, Kurlan, Simuni, Stover.

Acquisition, analysis, or interpretation of data: Schwarzschild, Ascherio, Casaceli, Curhan, Fitzgerald, Kamp, Lungu, Macklin, Marek, Mozaffarian, Rudolph, Videnovic, Beck, Bolger, Callahan, Crotty, Klements, Kostrzebski, McMahon, Waikar, Lang, Mestre, Ahmed, Aldred, Blindauer, Boyd, Brodsky, Chou, Christine, Cloud, Criswell, de Marcaida, Deik, Dewey, Durphy, Espay, Fang, Friedman, Goetz, Goudreau, Gunzler, Hauser, Henchcliffe, Hinson, Houghton, Hung, Jimenez-Shahed, Kumar, Kurlan, LaFaver, LeDoux, Leehey, LeWitt, Litvan, Mari, McGraw, Mehta, Morgan, Pahwa, Park, Rabin, Reich, Rosenthal, Saint-Hilaire, Schiess, Schneider, Scott, Serrano, Shah, Shill, Shprecher, Simon, Soileau, Stover, Suski, Thomas, Waters, Zauber, Zhang, Ainslie, Bixby Sanchez, Bwala, Ciccarello, Daley, Gauger, Gerald, Houston, Hunter, James, Kaminski, Keith, Langhammer, Laroche, Mosovsky, Peterson, Ratel, Russell, Bodis-Wollner, Poon.

Drafting of the manuscript: Schwarzschild, Casaceli, Fitzgerald, Macklin, Marek, Callahan, Crotty, Goudreau, Simuni, Thomas, Ciccarello.

Critical revision of the manuscript for important intellectual content: Schwarzschild, Ascherio, Curhan, Fitzgerald, Kamp, Lungu, Mozaffarian, Oakes, Rudolph, Shoulson, Videnovic, Beck, Bolger, Callahan, Crotty, Klements, Kostrzebski, McMahon, Pothier, Waikar, Lang, Mestre, Ahmed, Aldred, Bhatti, Blindauer, Boyd, Brodsky, Chou, Christine, Cloud, Criswell, de Marcaida, Deik, Dewey, Durphy, Espay, Fang, Friedman, Goetz, Goudreau, Gunzler, Hauser, Henchcliffe, Hinson, Houghton, Hung, Jimenez-Shahed, Kumar, Kurlan, LaFaver, LeDoux, Leehey, LeWitt, Litvan, Mari, McGraw, Mehta, Morgan, Pahwa, Park, Rabin, Reich, Rosenthal, Saint-Hilaire, Schiess, Schneider, Scott, Serrano, Shah, Shill, Shprecher, Simon, Simuni, Soileau, Stover, Suski, Waters, Zauber, Zhang, Ainslie, Bixby Sanchez, Bwala, Daley, Gauger, Gerald, Houston, Hunter, James, Kaminski, Keith, Langhammer, Laroche, Mosovsky, Peterson, Ratel, Russell, Bodis-Wollner, Poon.

Statistical analysis: Casaceli, Macklin, Marek, Oakes, Beck, Simuni.

Obtained funding: Schwarzschild, Casaceli, Curhan, Oakes, Shoulson.

Administrative, technical, or material support: Schwarzschild, Casaceli, Fitzgerald, Kamp, Lungu, Mozaffarian, Oakes, Rudolph, Videnovic, Bolger, Callahan, Crotty, Klements, Kostrzebski, Pothier, Waikar, Ahmed, Aldred, Cloud, Criswell, Dewey, Goetz, Goudreau, Kurlan, LeDoux, LeWitt, McGraw, Park, Rabin, Shah, Ainslie, Bixby Sanchez, Bwala, Gerald, Houston, James, Keith, Langhammer, Mosovsky, Peterson, Ratel, Russell.

Supervision: Schwarzschild, Ascherio, Curhan, Lungu, Macklin, Shoulson, Videnovic, Klements, Durphy, LeDoux, Leehey, Litvan, Mehta, Serrano, Stover, Kaminski.

Conflict of Interest Disclosures: In keeping with the conflict of interest policy of the Parkinson Study Group, the authors have attested that they have no conflicts of interest with any company determined to be involved in the study (Tuoxin Group, Euticals, and University of Iowa Pharmaceuticals). Dr Curhan reported receipt of grants from the National Institutes of Health (NIH); receipt of personal fees from Allena, Dicerna, and AstraZeneca; being a part-time employee for OM1; and receipt of royalties from UpToDate. Dr Lungu reported receipt of compensation from Elsevier for editorial work. Dr Macklin reported receipt of personal fees from Novartis, Shire Human Genetic Therapies, Biogen, Enterin, Stoparkinson Healthcare Systems, Cerevance Cortexyme, Intrance, Inventram, and Partner Therapeutics and grants to his institution from Acorda Therapeutics, Amylyx Pharmaceuticals, GlaxoSmithKline, and Mitsubishi Tanabe Pharmaceuticals of America. Dr Marek reported receipt of personal fees from GE Healthcare, Takeda, Invicro, the Michael J Fox Foundation, Roche, UCB, Neuron23, Hemacure, Inhibikase, Alkahest, BioHaven, and Sanofi. Dr Mozaffarian reported receipt of grants from the NIH, the Gates Foundation, and the Rockefeller Foundation; receipt of personal fees from GOED, Danone, Motif FoodWorks, Barilla, Amarin, Acasti Pharma, the Cleveland Clinic Foundation, and America’s Test Kitchen; scientific advisory board membership for Beren Therapeutics, Brightseed, Calibrate, DayTwo, Elysium Health, Filtricine, Foodome, HumanCo, January Inc, and Tiny Organics; and royalties from UpToDate. Dr Videnovic reported receipt of personal fees from Alexion Pharmaceuticals, Axovant Pharmaceuticals, Jazz Pharmaceuticals, and Biogen. Dr Beck reported receipt of grants from Boston Scientific, the American Orthopaedic Foot & Ankle Society, the US Food and Drug Administration, Auspex Pharmaceuticals, Abeona Therapeutics, and PCORI and personal fees from the American Academy of Neurology, Neurocrine Biosciences, and Azevan Pharmaceuticals. Dr Lang reported personal fees from AbbVie, AFFiRis Biogen, Denali, Janssen, Lundbeck, Maplight, Roche, Sun Pharma, and Sunovion. Dr Mestre reported personal fees from AbbVie, CHDI Foundation/Management, Sunovion, Valeo Pharma, nQ Medical, Merz, Medtronic, Biogen, and Roche and grants from uOBMRI, Parkinson Canada, the Michael J. Fox Foundation for Parkinson’s Research, the Canadian Institutes of Health Research, the Ontario Research Fund, Brain Canada, the LesLois Foundation, and the PSI Foundation. Dr Aldred reported receipt of honoraria for consulting or speaker’s bureau participation from Abbott, AbbVie, Acorda, Adamas, Allergan, Biogen, Boston Scientific, Medtronic, Neurocrine, Sunovion, Teva, and US WorldMeds; Dr Aldred is also retained as an expert. Dr Bhatti reported receipt of personal fees for speaking or advisory group membership from Adamas, Accadia, Barret Hodgson, PharmEvo, Amneal, and Accorda. Dr Boyd reported receipt of personal fees from Neuroderm and Neurocrine. Dr Criswell reported being site principal investigator for clinical trials with AbbVie, Impax, and the NIH. Dr de Marcaida reported receipt of speakers bureau personal fees from Acorda Therapeutics, AbbVie, and US WorldMeds. Dr Dewey reported receipt of personal fees from Amneal, Acorda, Supernus, Eva, Adamas, and US WorldMeds. Dr Espay reported receipt of personal fees as a scientific advisory consultant and/or honoraria for speaking services from AbbVie, Neuroderm, Neurocrine, Amneal, Acadia, Acorda, Kyowa Kirin, Sunovion, Lundbeck, and US WorldMeds. Dr Goetz reported receipt of grants/research funding by his institution from the NIH, the Department of Defense, and the Michael J. Fox Foundation for Parkinson’s Research; receipt of a faculty stipend from the International Parkinson and Movement Disorder Society; guest professorship honorarium from the University of Chicago and Illinois State Neurological Society; editor stipend from Elsevier; royalties from Elsevier and Wolters Kluwer; and salary from Rush University Medical Center. Dr Goudreau reported industry-sponsored research for Intec Pharma, Biotie Therapies, Global Kinetics, Pharma 2B, Voyager Therapeutics, Impax Pharmaceutical, Sunovion Pharmaceutical, and Acadia Pharmaceutical and speaker bureau participation for Adamas Pharmaceutical and Teva. Dr Gunzler reported receipt of grants from the NIH, Amneal, and Biogen. Dr Hauser reported receipt of personal fees from Acadia, Acorda, Adamas, Affiris, Amneal, Apopharma, Axovant, Cadent, Cerevel, Curium, Denali, Enterin, Hoffman-LaRoche, Impax, Impel, Inhibikase, Jazz, Kashiv, Kyowa Kirin, Lundbeck, Neurocrine, Neuroderm, Orion, Pharmather, Regenera, Revance, Seelos, Sunovion, Supernus, Teva, Tolmar, US WorldMeds, Cerespir, Axial Therapeutics, and Cerevance. Dr Henchcliffe reported personal fees from US WorldMeds, Adamas, Mitsubishi Tanabe Pharma, Prevail Therapeutics, InSightec, and Zywie. Dr Jimenez-Shahed reported receipt of personal fees from St Jude Medical, Amneal, and Impel and grants from Impax. Dr LaFaver reported receipt of advisory board fees from Acorda. Dr Litvan reported personal fees from Lundbeck and grants from Roche, AbbVie, Biogen, EIP-Pharma, and Biohaven. Dr McGraw reported receipt of personal fees from Adamas, Acorda, Acadia, Anneal, Lundbeck, and Teva. Dr Morgan reported receipt of personal fees from Sunovion, Kyowa Kirin, Acadia, Biogen, and Amneal and grants from Cerevel, Takeda, Pharma2B, Neuraly, Aptinyx, Prilenia, and the Parkinson Foundation. Dr Rabin reported speakers bureau participation for Allergan, Merz, and Teva. Dr Reich reported receipt of grants from the National Institute of Neurological Disorders and Stroke (NINDS); personal fees from Best Doctors, Enterin, and UpToDate; and royalties from Oxford University Press and Springer. Dr Saint-Hilaire reported receipt of grants from the NIH and PSG. Dr Schiess reported consultancy for Medtronic. Dr Schneider reported receipt of grants from Acadia Pharmaceuticals, Biohaven, the Michael J. Fox Foundation for Parkinson’s Research, the Parkinson Study Group, the Canadian Institute of Health Research, Teva, Pfizer, the CHDI Foundation, and NINDS. Dr Serrano reported receipt of grants from Eli Lilly. Dr Shill reported receipt of grants from Impax Laboratories, Biogen, US WorldMeds, Sunovion, and Intec Pharma and personal fees from Acorda Therapeutics, Kyowa Kirin, Acadia Pharmaceuticals, and Mitsubishi Tanabe. Dr Shprecher reported being employed by Banner Health; receipt of research support from the Arizona Alzheimer’s Consortium, AbbVie, Acadia, Aptinyx, Axovant, Biogen, Eisai, Eli Lilly, Enterin, Neurocrine, the Michael J Fox Foundation, the NIH, Nuvelution, Theravance, and Teva; consultant fees from Amneal, Emalex, Forensis, and Neurocrine; and speaker honoraria from Acorda, Amneal, Neurocrine, Sunovion, Teva, and US WorldMeds/Supernus. Dr Simon reported receipt of personal fees from Biogen and Bial Biotech and grants from Voyager Therapeutics and Neuraly. Dr Simuni reported receipt of grants from Biogen, Roche, Neuroderm, Sanofi, Sun Pharma, Amneal, Prevail, and UCB and personal fees from Acadia, Denali, GE, Neuroderm, Sanofi, Sinopia, Sunovion, Roche, Takeda, and Voyager. Dr Soileau reported receipt of personal fees from AbbVie, Medtronic, Abbott, Teva, Sunovion, Amneal, Neurocrine, Acorda, and Merz. Dr Waters reported receipt of grants from Sanofi and Biogen and personal fees from Kyowa, Amneal, Neurocrine, Adamas, and Sunovion. Dr Zauber reported receipt of personal fees from AbbVie and grants from the Parkinson’s Foundation. Mrs Peterson reported receipt of grants from the University of Nebraska Medical Center. No other disclosures were reported.

Funding/Support: This study was funded by the NIH/NINDS via grants U01NS090259 to Massachusetts General Hospital as the study’s clinical coordinating center (principal investigator, Dr Schwarzschild) and U01NS089666 to the University of Rochester as the study’s data coordinating center (principal investigator, Dr Oakes), with additional support from the Michael J. Fox Foundation for Parkinson’s Research via grants 11942 and 14489 (including funding for blood and imaging biomarker substudies) and GE Healthcare (all DaTscan doses).

Role of the Funder/Sponsor: Neither the funding organizations (NINDS and the Michael J. Fox Foundation for Parkinson’s Research) nor GE Healthcare had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication, with the exception that a NINDS scientific program director served on the study steering committee.

Group Information: The nonauthor collaborators of the Parkinson Study Group SURE-PD3 Investigators are listed in Supplement 4. The Parkinson Study Group SURE-PD3 Investigators authoring the article are as follows: Steering committee: Michael A. Schwarzschild, MD, PhD (chair); Alberto Ascherio, MD, DrPH (cochair); Cindy Casaceli, MBA; Gary C. Curhan, MD, ScD; Rebecca Fitzgerald, JD; Cornelia Kamp, MBA; Codrin Lungu, MD; Eric A. Macklin, PhD; Kenneth Marek, MD; Dariush Mozaffarian, MD, DrPH; David Oakes, PhD; Alice Rudolph, PhD; Ira Shoulson, MD; Aleksandar Videnovic, MD. Clinical site investigators and coordinators (in descending order of their site’s number of enrolled participants): Burton Scott, MD, PhD; Lisa Gauger; Jason Aldred, MD; Melissa Bixby, MS; Jill Ciccarello; Steven A. Gunzler, MD; Claire Henchcliffe, MD, DPhil; Matthew Brodsky, MD; Kellie Keith; Robert A. Hauser, MD, MBA; Christopher Goetz, MD; Mark S. LeDoux, MD, PhD; Vanessa Hinson, MD, PhD; Rajeev Kumar, MD; Alberto J. Espay, MD; Joohi Jimenez-Shahed, MD; Christine Hunter; Chadwick Christine, MD; Aaron Daley, MA; Maureen Leehey, MD; J. Antonelle de Marcaida, MD; Joseph Harold Friedman, MD; Albert Hung, MD, PhD; Grace Bwala, MBBS, MPH; Irene Litvan, MD; David K. Simon, MD, PhD; Tanya Simuni, MD; Cynthia Poon, PhD; Mya C. Schiess, MD; Kelvin Chou, MD; Ariane Park, MD, MPH; Danish Bhatti, MBBS; Carolyn Peterson; Susan R. Criswell, MD, MSCl; Liana Rosenthal, MD, PhD; Jennifer Durphy, MD; Holly A. Shill, MD; Shyamal H. Mehta, MD, PhD; Anwar Ahmed, MD; Andres F. Deik, MD, MSEd; John Y. Fang, MD; Natividad Stover, MD; Lin Zhang, MD; Richard B. Dewey Jr, MD; Ashley Gerald, MA; James T. Boyd, MD; Emily Houston; Valerie Suski, DO; Sherri Mosovsky, MPH; Leslie Cloud, MD, MSc; Binit B. Shah, MD; Marie Saint-Hilaire, MD; Raymond James; Sarah Elizabeth Zauber, MD; Stephen Reich, MD; David Shprecher, DO, MSci; Rajesh Pahwa, MD; April Langhammer; Kathrin LaFaver, MD; Peter A. LeWitt, MD; Patricia Kaminski, MSN; John Goudreau, DO, PhD; Doozie Russell; David J. Houghton, MD; Ashley Laroche; Karen Thomas, DO; Martha McGraw, MD; Zoltan Mari, MD, PhD; Carmen Serrano, MD; Karen Blindauer, MD; Marcie Rabin, MD; Roger Kurlan, MD; John C. Morgan, MD, PhD; Michael Soileau, MD; Melissa Ainslie; Ivan Bodis-Wollner, MD, DSc; Ruth B. Schneider, MD; Cheryl Waters, MD; Amber Servi Ratel. Coordination centers and other non–clinical site investigators: Christopher A. Beck, PhD; Patrick Bolger, RPh, MBA; Katherine F. Callahan; Grace F. Crotty, MD, BAO, MBBCH; David Klements, MS; Melissa Kostrzebski; Gearoid Michael McMahon, MB, BCh; Lindsay Pothier; Sushrut S. Waikar, MD, MPH; Anthony Lang, MD; Tiago Mestre, MD, MSc.

Data Sharing Statement: See Supplement 5.

Additional Contributions: The University of Rochester’s Clinical Materials Service Unit coordinated the supply chain for the investigational product, including the labeling and distribution to clinical sites. The contributions made by the study participants and their families are deeply appreciated, as are the expertise and guidance of the data and safety monitoring board (which was convened and compensated by the NIH directly): Caroline M. Tanner, MD, PhD (chair; University of San Francisco), Inmaculada Aban, PhD (University of Alabama at Birmingham), Karen Anderson, MD (Georgetown University), David Goldfarb, MD (New York University), Joel Grace, PhD (Parkinson’s Disease Foundation), Leslie McClure, PhD (Drexel University), and G. Webster Ross, MD (University of Hawaii). Contributions made by all site staff, including clinical coordinators Lisa Richardson of Sentara Clinical Research and Marie Mejaki, BA, of the Medical College of Wisconsin (who were not compensated outside of their usual salary), are greatly appreciated.

References
1.
Wu  XW , Muzny  DM , Lee  CC , Caskey  CT .  Two independent mutational events in the loss of urate oxidase during hominoid evolution.   J Mol Evol. 1992;34(1):78-84. doi:10.1007/BF00163854PubMedGoogle ScholarCrossref
2.
Crotty  GF , Ascherio  A , Schwarzschild  MA .  Targeting urate to reduce oxidative stress in Parkinson disease.   Exp Neurol. 2017;298(pt B):210-224.Google Scholar
3.
Benzie  IFSJ , Strain  JJ .  The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay.   Anal Biochem. 1996;239(1):70-76. doi:10.1006/abio.1996.0292PubMedGoogle ScholarCrossref
4.
Guerreiro  S , Ponceau  A , Toulorge  D ,  et al.  Protection of midbrain dopaminergic neurons by the end-product of purine metabolism uric acid: potentiation by low-level depolarization.   J Neurochem. 2009;109(4):1118-1128. doi:10.1111/j.1471-4159.2009.06040.xPubMedGoogle ScholarCrossref
5.
Chen  X , Burdett  TC , Desjardins  CA ,  et al.  Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration.   Proc Natl Acad Sci U S A. 2013;110(1):300-305. doi:10.1073/pnas.1217296110PubMedGoogle ScholarCrossref
6.
Davis  JWGA , Grandinetti  A , Waslien  CI , Ross  GW , White  LR , Morens  DM .  Observations on serum uric acid levels and the risk of idiopathic Parkinson’s disease.   Am J Epidemiol. 1996;144(5):480-484. doi:10.1093/oxfordjournals.aje.a008954PubMedGoogle ScholarCrossref
7.
de Lau  LMKP , Koudstaal  PJ , Hofman  A , Breteler  MM .  Serum uric acid levels and the risk of Parkinson disease.   Ann Neurol. 2005;58(5):797-800. doi:10.1002/ana.20663PubMedGoogle ScholarCrossref
8.
Weisskopf  MG , O’Reilly  E , Chen  H , Schwarzschild  MA , Ascherio  A .  Plasma urate and risk of Parkinson’s disease.   Am J Epidemiol. 2007;166(5):561-567. doi:10.1093/aje/kwm127PubMedGoogle ScholarCrossref
9.
Schwarzschild  MASS , Schwid  SR , Marek  K ,  et al; Parkinson Study Group PRECEPT Investigators.  Serum urate as a predictor of clinical and radiographic progression in Parkinson disease.   Arch Neurol. 2008;65(6):716-723. doi:10.1001/archneur.2008.65.6.nct70003PubMedGoogle ScholarCrossref
10.
Ascherio  A , LeWitt  PA , Xu  K ,  et al; Parkinson Study Group DATATOP Investigators.  Urate as a predictor of the rate of clinical decline in Parkinson disease.   Arch Neurol. 2009;66(12):1460-1468. doi:10.1001/archneurol.2009.247PubMedGoogle ScholarCrossref
11.
Moccia  M , Picillo  M , Erro  R ,  et al.  Presence and progression of non-motor symptoms in relation to uric acid in de novo Parkinson’s disease.   Eur J Neurol. 2015;22(1):93-98. doi:10.1111/ene.12533PubMedGoogle ScholarCrossref
12.
Sleeman  I , Lawson  RA , Yarnall  AJ ,  et al.  Urate and homocysteine: predicting motor and cognitive changes in newly diagnosed Parkinson’s disease.   J Parkinsons Dis. 2019;9(2):351-359. doi:10.3233/JPD-181535PubMedGoogle ScholarCrossref
13.
Schwarzschild  MA , Ascherio  A , Beal  MF ,  et al; Parkinson Study Group SURE-PD Investigators.  Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.   JAMA Neurol. 2014;71(2):141-150. doi:10.1001/jamaneurol.2013.5528PubMedGoogle Scholar
14.
Bhattacharyya  S , Bakshi  R , Logan  R , Ascherio  A , Macklin  EA , Schwarzschild  MA .  Oral inosine persistently elevates plasma antioxidant capacity in Parkinson’s disease.   Mov Disord. 2016;31(3):417-421. doi:10.1002/mds.26483PubMedGoogle ScholarCrossref
15.
Grinnon  ST , Miller  K , Marler  JR ,  et al.  National Institute of Neurological Disorders and Stroke Common Data Element Project—approach and methods.   Clin Trials. 2012;9(3):322-329. doi:10.1177/1740774512438980PubMedGoogle ScholarCrossref
16.
Hauser  RA , Auinger  P ; Parkinson Study Group.  Determination of minimal clinically important change in early and advanced Parkinson’s disease.   Mov Disord. 2011;26(5):813-818. doi:10.1002/mds.23638PubMedGoogle ScholarCrossref
17.
Poewe  W , Seppi  K , Marini  K , Mahlknecht  P .  New hopes for disease modification in Parkinson’s disease.   Neuropharmacology. 2020;171:108085. doi:10.1016/j.neuropharm.2020.108085PubMedGoogle Scholar
18.
Romero  K , Conrado  D , Burton  J ,  et al; Critical Path for Parkinson’s Consortium; Parkinson’s Progression Markers Initiative.  Molecular neuroimaging of the dopamine transporter as a patient enrichment biomarker for clinical trials for early Parkinson’s disease.   Clin Transl Sci. 2019;12(3):240-246. doi:10.1111/cts.12619PubMedGoogle ScholarCrossref
19.
Stephenson  D , Hill  D , Cedarbaum  JM ,  et al; Critical Path for Parkinson’s Consortium.  The qualification of an enrichment biomarker for clinical trials targeting early stages of Parkinson’s disease.   J Parkinsons Dis. 2019;9(4):825. doi:10.3233/JPD-199003PubMedGoogle ScholarCrossref
20.
Kobylecki  CJ , Nordestgaard  BG , Afzal  S .  Plasma urate and risk of Parkinson’s disease: a mendelian randomization study.   Ann Neurol. 2018;84(2):178-190. doi:10.1002/ana.25292PubMedGoogle ScholarCrossref
21.
Kia  DA , Noyce  AJ , White  J ,  et al; IPDGC Collaborators.  Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson’s disease.   Ann Neurol. 2018;84(2):191-199. doi:10.1002/ana.25294PubMedGoogle ScholarCrossref
22.
Simon  KC , Eberly  S , Gao  X ,  et al; Parkinson Study Group.  Mendelian randomization of serum urate and Parkinson disease progression.   Ann Neurol. 2014;76(6):862-868. doi:10.1002/ana.24281PubMedGoogle ScholarCrossref
23.
Yamamoto  T , Moriwaki  Y , Cheng  J ,  et al.  Effect of inosine on the plasma concentration of uridine and purine bases.   Metabolism. 2002;51(4):438-442. doi:10.1053/meta.2002.31322PubMedGoogle ScholarCrossref
24.
Nazeri  A , Roostaei  T , Sadaghiani  S ,  et al.  Genome-wide variant by serum urate interaction in Parkinson’s disease.   Ann Neurol. 2015;78(5):731-741. doi:10.1002/ana.24504PubMedGoogle ScholarCrossref
25.
Bandres-Ciga  S , Saez-Atienzar  S , Kim  JJ ,  et al; American Genome Center; International Parkinson Disease Genomics Consortium.  Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease.   Acta Neuropathol. 2020;140(3):341-358. doi:10.1007/s00401-020-02181-3PubMedGoogle ScholarCrossref
26.
Schwarzschild  MA , Macklin  EA , Bakshi  R ,  et al; Parkinson Study Group SURE-PD Investigators.  Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial.   Neurology. 2019;93(14):e1328-e1338. doi:10.1212/WNL.0000000000008194PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close