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.
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 ).
Department of Cardiovascular Medicine, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
Jun-Ichi
J
Oyama
Department of Cardiovascular Medicine, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
Atsushi
A
Tanaka
Department of Clinical Research, Chiba University Graduate School of Medicine, Chiba, Japan.
Yasunori
Y
Sato
Department of Cardiology, Tokyo Medical University, Tokyo, Japan.
Hirofumi
H
Tomiyama
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Masataka
M
Sata
Department of Clinical Laboratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Tomoko
T
Ishizu
Department of Cardiology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan.
Isao
I
Taguchi
Department of Cardiology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan.
Takanori
T
Kuroyanagi
Department of Cardiovascular Medicine, Hiroshima General Hospital of West Japan Railway Company, Hiroshima, Japan.
Hiroki
H
Teragawa
Internal Medicine (III), Department of Cardiology, Osaka Medical College, Takatsuki, Japan.
Nobukazu
N
Ishizaka
Internal Medicine (III), Department of Cardiology, Osaka Medical College, Takatsuki, Japan.
Yumiko
Y
Kanzaki
Department of Cardiovascular Medicine and Hypertension, Kagoshima University, Kagoshima, Japan.
Mitsuru
M
Ohishi
Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan.
Kazuo
K
Eguchi
Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Yukihito
Y
Higashi
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Hirotsugu
H
Yamada
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Koji
K
Maemura
Department of Cardiovascular Medicine, Kitasato University, Sagamihara, Japan.
Junya
J
Ako
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yasuko K
YK
Bando
Department of Clinical Pharmacology & Therapeutics, University of the Ryukyus, Nishihara, Japan.
Shinichiro
S
Ueda
Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan.
Teruo
T
Inoue
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Toyoaki
T
Murohara
Department of Cardiovascular Medicine, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga, 849-8501, Japan. node@cc.saga-u.ac.jp.
Koichi
K
Node
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000188:drug therapy*; D017536:Carotid Artery, Common / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D000069465:Febuxostat / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D033461:Hyperuricemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D014527:Uric Acid / Q000097:blood*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D055815:Young Adult
D004791:Enzyme Inhibitors; D000069465:Febuxostat; D014527:Uric Acid; D014969:Xanthine Oxidase
Carotid artery; Febuxostat; Hyperuricemia; Intima-media thickness (IMT); Randomized controlled trial; Xanthine oxidase inhibitor