Effect Of Urate-Elevating Inosine On Early Parkinson Disease Progression: The Sure-Pd3 Randomized Clinical Trial

Key PointsQuestionDoes treatment with oral inosine for up to 2 years slow progression of Parkinson disease? FindingsIn 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. MeaningUrate-elevating inosine treatment was not clinically beneficial in early Parkinson disease.ImportanceUrate 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. ObjectiveTo determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and SettingRandomized, 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. InterventionsInosine, 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 MeasuresThe 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. ResultsBased 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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT02642393This randomized clinical trial assesses whether sustained urate-elevating treatment with the urate precursor inosine, compared with placebo, slows rate of clinical disease progression among patients with early Parkinson disease.