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

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.

Conflict of interest statement

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.

Figures

Figure 1.. Participant Flow in the SURE-PD3 Trial

DaT indicates dopamine transporter; eGFR, estimated glomerular filtration rate. aWith stratification by clinical site. bThese participants had completed participation but stopped study drug early prior to early study closure. cAmong these participants, 18 experienced treatment-emergent adverse events, including 11 who had a kidney stone. dAmong these participants, 9 experienced treatment-emergent adverse events, including 1 who had a kidney stone. eAmong these participants, 10 experienced treatment-emergent adverse events, including 2 who had a kidney stone. fAmong these participants, 2 experienced treatment-emergent adverse events (none had a kidney stone).

Figure 2.. Time Courses of Biochemical, Clinical, and Radiographic Outcomes in the SURE-PD3 Trial

Serum urate (panel A), Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) (parts I-III) total score (the primary outcome, which comprises both clinician- and patient-reported outcomes and both motor and nonmotor features) (panel B), need for dopaminergic therapy (panel C), and radiographic striatal dopamine transporter (DaT) ligand binding (panel D) are compared between participants randomized to inosine vs placebo. Model estimates are plotted with 95% confidence intervals from analysis of the as-randomized sample or as-treated sample, stratified by treatment assignment to inosine or placebo. Estimates for serum urate (panel A) were adjusted for sex. Estimates in panels B and D are adjusted for sex, monoamine oxidase B inhibitor use at baseline, modified Schwab and England Activities of Daily Living Scale scores at baseline, and each respective outcome measure at baseline. The number of participants contributing to each data point is shown by treatment group under each graph in panels A, B, and D; the number at risk of need for dopaminergic therapy is shown in panel C. The safety visit, which followed study drug discontinuation by 3 months, was intended to occur at month 27, following 3-month washout, but could occur earlier (eg, in participants whose planned 24-month follow-up was shortened due to early termination of the study). Vertical tick marks on the curves of panel C indicate times when individual participants were censored for this time-to-event analysis. The indicated timing of the striatal DaT specific binding ratio estimate at 21 months reflects the mean time after baseline at which follow-up DaTscan imaging occurred, but all such imaging was performed at least 2 weeks into the 3-month washout. The y-axis scales in panels A and D focus on relatively narrow ranges to maximize comparison between groups.