Abstract
BackgroundXanthine oxidase inhibitors are anti-hyperuricemic drugs that decrease serum uric acid levels by inhibiting its synthesis. Xanthine oxidase is also recognized as a pivotal enzyme in the production of oxidative stress. Excess oxidative stress induces endothelial dysfunction and inflammatory reactions in vascular systems, leading to atherosclerosis. Many experimental studies have suggested that xanthine oxidase inhibitors have anti-atherosclerotic effects by decreasing in vitro and in vivo oxidative stress. However, there is only limited evidence on the clinical implications of xanthine oxidase inhibitors on atherosclerotic cardiovascular disease in patients with hyperuricemia. We designed the PRIZE study to evaluate the effects of febuxostat on a surrogate marker of cardiovascular disease risk, ultrasonography-based intima-media thickness of the carotid artery in patients with hyperuricemia.MethodsThe study is a multicenter, prospective, randomized, open-label and blinded-endpoint evaluation (PROBE) design. A total of 500 patients with asymptomatic hyperuricemia (uric acid >7.0 mg/dL) and carotid intima-media thickness ≥1.1 mm will be randomized centrally to receive either febuxostat (10–60 mg/day) or non-pharmacological treatment. Randomization is carried out using the dynamic allocation method stratified according to age (<65, ≥65 year), gender, presence or absence of diabetes mellitus, serum uric acid (<8.0, ≥8.0 mg/dL), and carotid intima-media thickness (<1.3, ≥1.3 mm). In addition to administering the study drug, we will also direct lifestyle modification in all participants, including advice on control of body weight, sleep, exercise and healthy diet. Carotid intima-media thickness will be evaluated using ultrasonography performed by skilled technicians at a central laboratory. Follow-up will be continued for 24 months. The primary endpoint is percentage change in mean intima-media thickness of the common carotid artery 24 months after baseline, measured by carotid ultrasound imaging.ConclusionsPRIZE will be the first study to provide important data on the effects of febuxostat on atherosclerosis in patients with asymptomatic hyperuricemia.Trial Registration Unique trial Number, UMIN000012911 (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000015081&language=E)Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0409-2) contains supplementary material, which is available to authorized users.
Highlights
MethodsThe study is a multicenter, prospective, randomized, open-label and blinded-endpoint evaluation (PROBE) design
Xanthine oxidase inhibitors are anti-hyperuricemic drugs that decrease serum uric acid levels by inhib‐ iting its synthesis
Evidence from clinical studies has suggested that hyperuricemia is associated with the characteristics of the metabolic syndrome (MetS), including obesity, hypertension (HT), hyperlipidemia (HL), diabetes mellitus (DM) [3,4,5,6,7], and cardiovascular disease (CVD) [8,9,10,11]
Summary
Study overview and design The PRIZE study is a multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) clinical trial that is being carried out in Japan. Statistical considerations Sample size and power calculation We assumed the percentage changes in average carotid IMT in the control and febuxostat groups 24 months after randomization in the study would be as follows:. The effect of febuxostat was set conservatively at +1.0 ± 6.0 % based on data on pitavastatin from a previous study that showed an annual rate of change in carotid IMT of −0.8 % [37] Based on these assumptions of a 1.6 % group difference in the primary endpoint at 24 months and a SD of 6.0 % for individual differences to achieve 90 % power for a two-sided, two-sample t test at the 0.05 significance level, a sample size of 250 patients in each group is required. At present (31 March, 2016), a total of 456 patients have been recruited into the study
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