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Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial

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Summary

Introduction

Uric acid is an antioxidant with neuroprotective effects in experimental models of stroke. We assessed whether uric acid therapy would improve functional outcomes at 90 days in patients with acute ischaemic stroke.

Methods

URICO-ICTUS was a randomised, double-blind, placebo-controlled, phase 2b/3 trial that recruited patients with acute ischaemic stroke admitted to ten Spanish stroke centres. Patients were included if they were aged 18 years or older, had received alteplase within 4·5 h of symptom onset, and had an eligible National Institutes of Health Stroke Scale (NIHSS) score (>6 and ≤25) and premorbid (assessed by anamnesis) modified Rankin Scale (mRS) score (≤2). Patients were randomly allocated (1:1) to receive uric acid 1000 mg or placebo (both infused intravenously in 90 min during the infusion of alteplase), stratified by centre and baseline stroke severity. The primary outcome was the proportion of patients with excellent outcome (ie, an mRS score of 0–1, or 2 if premorbid score was 2) at 90 days, analysed in the target population (all randomly assigned patients who had been correctly diagnosed with ischaemic stroke and had begun study medication). The study is registered with ClinicalTrials.gov, number NCT00860366.

Findings

Between July 1, 2011, and April 30, 2013, we randomly assigned 421 patients, of whom 411 (98%) were included in the target population (211 received uric acid and 200 received placebo). 83 (39%) patients who received uric acid and 66 (33%) patients who received placebo had an excellent outcome (adjusted risk ratio 1·23 [95% CI 0·96–1·56]; p=0·099). No clinically relevant or statistically significant differences were reported between groups with respect to death (28 [13%] patients who received uric acid vs 31 [16%] who received placebo), symptomatic intracerebral haemorrhage (nine [4%] vs six [3%]), and gouty arthritis (one [<1%] vs four [2%]). 516 adverse events occurred in the uric acid group and 532 in the placebo group, of which 61 (12%) and 67 (13%), respectively, were serious adverse events (p=0·703).

Interpretation

The addition of uric acid to thrombolytic therapy did not increase the proportion of patients who achieved excellent outcome after stroke compared with placebo, but it did not lead to any safety concerns.

Funding

Institute of Health Carlos III of the Spanish Ministry of Health and Fundación Doctor Melchor Colet.

Introduction

Intravenous alteplase (recombinant tissue plasminogen activator) administered within 4·5 h after onset of symptoms is the only approved treatment for ischaemic stroke in Europe,1, 2 but many patients continue to have substantial disability after receiving the therapy.3 Thus, new methods to enhance the general efficacy of intravenous thrombolysis are imperative in patients with acute stroke.

The human brain has few endogenous antioxidant resources compared with other organs, which makes it more susceptible to oxidative stress.4 Uric acid is an endogenous antioxidant derived from the metabolism of purines, and human beings and apes have higher concentrations than do other mammals because they have two distinct loss-of-function mutations in the gene encoding uricase.5, 6 Descriptive studies show that higher concentrations of uric acid in serum are beneficial in patients with acute stroke7 and are associated with better outcome after thrombolytic treatment.8 However, uric acid concentrations in serum decline rapidly after the onset of stroke symptoms,9 and this reduction is more pronounced in patients who have arterial recanalisation.10

Exogenous administration of uric acid was reported to be neuroprotective in several models of transient focal brain ischaemia in rats,11, 12 and its coadministration with alteplase had synergistic effects, improving functional outcome in rats.12 A pilot randomised controlled trial9 showed that the coadministration of uric acid and alteplase was safe in patients with acute stroke, and provided surrogate evidence that uric acid restricted the increment of oxidative stress biomarkers.13 These findings lend support to the scrutiny of the coadministration of uric acid and thrombolytic therapy in patients with acute stroke.14 The URICO-ICTUS trial was set up to assess whether combined treatment with uric acid and alteplase improves clinical outcomes at 90 days in patients with acute ischaemic stroke.

Section snippets

Study design and participants

URICO-ICTUS was an investigator-initiated, multicentre, randomised, double-blind, placebo-controlled, phase 2b/3 study undertaken in ten Spanish stroke centres that gave alteplase to more than 50 patients per year. The details of the study design have been published previously,15 and are further described in the protocol. The trial was approved by local institutional review boards, and written informed consent was obtained from the patients or from legally acceptable surrogates.

Participants

Results

Patients were enrolled in the study from July 1, 2011, to April 30, 2013. Of 1129 patients who received thrombolytic therapy and were screened during the trial, 421 (37%) underwent randomisation and 411 (36%) were included in the target population (211 received uric acid and 200 received placebo). Six patients with stroke mimics and four patients who did not start the experimental medication were not included in the target population (figure 1). Assessment of the main characteristics of the

Discussion

URICO-ICTUS was a moderately sized trial of uric acid therapy for acute ischaemic stroke that did not show a significant between-group difference in the proportion of patients who achieved an excellent outcome at 90 days. However, the addition of uric acid to thrombolytic therapy resulted in a non-significant 6·3% absolute effect size on the primary outcome measure compared with placebo—a treatment effect within the range of absolute effect sizes (2–8%) that the Stroke Therapy Academic Industry

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