Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.
Level 2 - randomized trial
Multicenter phase 3 randomized, double-blind, placebo-controlled trial
PubMed 34519802 · doi:10.1001/jama.2021.10207
What was done
A multicenter, double-blind, phase 3 randomized controlled trial (SURE-PD3) evaluated whether elevating serum urate with oral inosine slows early Parkinson disease (PD) progression across 58 US sites. Researchers randomized 298 patients with early PD not yet requiring dopaminergic medication, confirmed striatal dopamine transporter deficiency, and baseline serum urate below 5.8 mg/dL to receive either titrated inosine (targeting serum urate of 7.1–8.0 mg/dL; n=149) or matching placebo (n=149) for up to 2 years. The primary outcome was the rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS parts I–III, score range 0–236) prior to starting dopaminergic therapy. Secondary outcomes included dopamine transporter binding loss and adverse event rates.
What was found
The trial was terminated early for futility after 273 participants (92%) completed the study. Inosine successfully elevated serum urate by 2.03 mg/dL (a 44% increase from a baseline of 4.6 mg/dL) compared to a 0.01 mg/dL change with placebo (difference: 2.02 mg/dL [95% CI, 1.85–2.19]; P < .001). However, clinical progression did not differ significantly: the MDS-UPDRS score increased by 11.1 points/year (95% CI, 9.7–12.6) with inosine versus 9.9 points/year (95% CI, 8.4–11.3) with placebo (difference: 1.26 points/year [95% CI, -0.59 to 3.11]; P = .18). Secondary efficacy outcomes, including striatal dopamine transporter binding loss, showed no significant differences. The inosine group had fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but a higher rate of kidney stones (7.0 vs 1.4 per 100 patient-years).
Why it matters
Despite strong epidemiological and preclinical rationale suggesting that urate elevation could provide neuroprotection, these findings demonstrate that inosine does not slow early Parkinson disease progression and carries an increased risk of urolithiasis.
Limits
The study was terminated early for futility based on prespecified interim criteria, resulting in a shortened observation window for some participants. Enrollment was restricted to patients with baseline serum urate below the population median (<5.8 mg/dL) and early-stage PD prior to dopaminergic therapy, so findings may not generalize to patients with higher baseline urate or advanced disease.
Cited by
- supports A study published in JAMA evaluating inosine to raise uric acid in Parkinson's disease patients showed that inosine was ineffective at improving scores on the UPDRS rating scale.