Rationale and design of a multicenter randomized study for evaluating vascular function under uric acid control using the xanthine oxidase inhibitor, febuxostat

The PRIZE study

On behalf of the PRIZE Study Investigators

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: Xanthine 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. Methods: The 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. Conclusions: PRIZE 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 )

Original languageEnglish
Article number87
JournalCardiovascular Diabetology
Volume15
Issue number1
DOIs
Publication statusPublished - 2016 Jun 18
Externally publishedYes

Fingerprint

Hyperuricemia
Xanthine Oxidase
Uric Acid
Carotid Intima-Media Thickness
Multicenter Studies
Blood Vessels
Ultrasonography
Oxidative Stress
Atherosclerosis
Cardiovascular Diseases
Common Carotid Artery
Random Allocation
Serum
Carotid Arteries
Pharmaceutical Preparations
Life Style
Diabetes Mellitus
Sleep
Language
Biomarkers

Keywords

  • Carotid artery
  • Febuxostat
  • Hyperuricemia
  • Intima-media thickness (IMT)
  • Randomized controlled trial
  • Xanthine oxidase inhibitor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Cardiology and Cardiovascular Medicine

Cite this

@article{a910ce4bbd744652bfc9b3f67361bf02,
title = "Rationale and design of a multicenter randomized study for evaluating vascular function under uric acid control using the xanthine oxidase inhibitor, febuxostat: The PRIZE study",
abstract = "Background: Xanthine 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. Methods: The 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. Conclusions: PRIZE 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 )",
keywords = "Carotid artery, Febuxostat, Hyperuricemia, Intima-media thickness (IMT), Randomized controlled trial, Xanthine oxidase inhibitor",
author = "{On behalf of the PRIZE Study Investigators} and Oyama, {Jun ichi} and Atsushi Tanaka and Yasunori Sato and Hirofumi Tomiyama and Masataka Sata and Tomoko Ishizu and Isao Taguchi and Takanori Kuroyanagi and Hiroki Teragawa and Nobukazu Ishizaka and Yumiko Kanzaki and Mitsuru Ohishi and Kazuo Eguchi and Yukihito Higashi and Hirotsugu Yamada and Koji Maemura and Junya Ako and Bando, {Yasuko K.} and Shinichiro Ueda and Teruo Inoue and Toyoaki Murohara and Koichi Node",
year = "2016",
month = "6",
day = "18",
doi = "10.1186/s12933-016-0409-2",
language = "English",
volume = "15",
journal = "Cardiovascular Diabetology",
issn = "1475-2840",
publisher = "BioMed Central",
number = "1",

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TY - JOUR

T1 - Rationale and design of a multicenter randomized study for evaluating vascular function under uric acid control using the xanthine oxidase inhibitor, febuxostat

T2 - The PRIZE study

AU - On behalf of the PRIZE Study Investigators

AU - Oyama, Jun ichi

AU - Tanaka, Atsushi

AU - Sato, Yasunori

AU - Tomiyama, Hirofumi

AU - Sata, Masataka

AU - Ishizu, Tomoko

AU - Taguchi, Isao

AU - Kuroyanagi, Takanori

AU - Teragawa, Hiroki

AU - Ishizaka, Nobukazu

AU - Kanzaki, Yumiko

AU - Ohishi, Mitsuru

AU - Eguchi, Kazuo

AU - Higashi, Yukihito

AU - Yamada, Hirotsugu

AU - Maemura, Koji

AU - Ako, Junya

AU - Bando, Yasuko K.

AU - Ueda, Shinichiro

AU - Inoue, Teruo

AU - Murohara, Toyoaki

AU - Node, Koichi

PY - 2016/6/18

Y1 - 2016/6/18

N2 - Background: Xanthine 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. Methods: The 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. Conclusions: PRIZE 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 )

AB - Background: Xanthine 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. Methods: The 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. Conclusions: PRIZE 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 )

KW - Carotid artery

KW - Febuxostat

KW - Hyperuricemia

KW - Intima-media thickness (IMT)

KW - Randomized controlled trial

KW - Xanthine oxidase inhibitor

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U2 - 10.1186/s12933-016-0409-2

DO - 10.1186/s12933-016-0409-2

M3 - Article

VL - 15

JO - Cardiovascular Diabetology

JF - Cardiovascular Diabetology

SN - 1475-2840

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M1 - 87

ER -