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Original Investigation | Clinical Trial

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.2013.5528.
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Importance  Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).

Objective  To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial.

Design, Setting, and Participants  The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled.

Interventions  Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month.

Main Outcomes and Measures  The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid.

Results  Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability.

Conclusions and Relevance  Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD.

Trial Registration  clinicaltrials.gov Identifier: NCT00833690

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Figure 1.
Consolidated Standards of Reporting Trials Flow Diagram for the Safety of Urate Elevation in PD (SURE-PD) Trial

aA majority of these 80 participants (89%) were determined ineligible based on screening serum urate values greater than the population median, a criterion that was expected to exclude approximately half of all consenting individuals.bThe participant who withdrew did so after discontinuation of the study drug, which was because of declining to receive alkalinization treatment for acidic urine.

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Figure 2.
Tolerability of Inosine and Its Effects on Serum and Cerebrospinal Fluid (CSF) Urate Levels

A, Tolerability of the study drug from baseline to drug discontinuation displayed as Kaplan-Meier survival curves over the maximum 2-year period for participants taking placebo or inosine dosed to mildly or moderately raise serum urate. Tick marks indicate censored events (see the Methods section). B, Estimated time course of serum urate levels across study visits with the study drug initiated at the baseline (BL) visit and continued for as long as 24 months (V12) until 1 month before the final (safety) visit (SV). Means and 95% confidence intervals from a mixed model are displayed. For visits V1 to V12, serum was collected after morning study drug intake, except for the “trough” sample at week 12 (V05). The shaded range of serum urate concentrations represents exclusionary values at the screening visits (SC1 and SC2). C, The CSF urate concentrations and ranges (bars, with boxes and dots representing the interquartile and median values, respectively) after 12 weeks of receiving the study drug. P < .001 for the mild and moderate inosine groups compared with placebo. D, Correlation between CSF and serum urate levels at the 12-week visit for individuals identified by their treatment groups and sex. F indicates female and M, male.

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Figure 3.
Secondary Analyses of Clinical Outcomes in the Safety of Urate Elevation in PD (SURE-PD) Trial

A, Kaplan-Meier curves showing time to disability warranting dopaminergic therapy for up to 2 years of follow-up for each of the 3 treatment groups. B, Futility analysis of the change in total Unified Parkinson's Disease Rating Scale (UPDRS) scores over 12 months or until need for dopaminergic therapy, based on National Institutes of Health Exploratory Trials in PD (NET-PD) methods.24,25 Much or most of the 95% confidence interval for the mild or moderate inosine treatment groups, respectively, falls below the futility boundary (FB), defined as 70% of the placebo group’s mean rate of change. C, The 24-month change of total UDPRS score estimated from a mixed-model analysis of variance (ANOVA) allowing unstructured profiles over time suggests a trend of decreasing rate with increasing inosine dose. D, A weaker trend is observed when using a complementary random-slopes model incorporating sex-specific effects and assuming linearity in change over time. E, Rates of mood change during the study as assessed by differences in Geriatric Depression Scale short form (GDS-S) scores over an average of 18 months’ follow-up. Receiving either dose of inosine, the rate appears slower (comparison-wise P < .001) compared with placebo.

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