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.

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.