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
N1 - Funding Information:
JO belongs to the research program faculty (chair course) sponsored by Fukuda Denshi. AT received research support from Astellas. YS received honorariums from Pfizer, Siemens, and Elekta; research grant from Kowa. HTo received honorarium from Omron Health Care. MS received honorariums from MSD, Takeda, Boehringer Ingelheim, Bayer, Mochida, Astellas, Mitsubishi Tanabe, Daiichi Sankyo, Novartis, AstraZeneca, and Pfizer; research grants from Ono, MSD, Bayer, Daiichi Sankyo, Boehringer Ingelheim, Novartis, Takeda, Mit‑ subishi, Tanabe, and Astellas; belongs to the research program sponsored by Boehringer Ingelheim. TIs declared no conflicts of interest. IT received honorar‑ iums from Mitsubishi Tanabe, AstraZeneca, Bristol‑Myers, Bayer, Takeda, Daiichi Sankyo, Otsuka, MSD, Shionogi, Kowa, Sumitomo Dainippon, and Goodman; research grants from Eisai, Chugai, AstraZeneca, Bristol‑Myers, Bayer, Takeda, Daiichi Sankyo, Otsuka, MSD, Boehringer Ingelheim, Teijin Pharma, Ono, Shionogi, Mitsubishi Tanabe, Kowa, Mochida, Sanwa Kagaku Kenkyusho, Sumi‑ tomo Dainippon, and Goodman. TK received honorariums from Mitsubishi Tanabe, AstraZeneca, Bristle‑Meyers, Squibb, Bayer, Takeda, Daiichi Sankyo, Otsuka, MSD, Shionogi, Kowa, Sumitomo Dainippon, and Goodman; research grants from Eisai, Chugai, AstraZeneca, Bristle‑Meyers, Squibb, Bayer, Takeda, Daiichi Sankyo, Otsuka, MSD, Boehringer Ingelheim, Teijin Pharma, Ono, Shionogi, Mitsubishi Tanabe, Kowa, Mochida, Sanwa Kagaku Kenkyusho, Sumi‑ tomo Dainippon, and Goodman. HTe received honorariums from Kowa, Bayer, Kyowa Hakko Kirin, Otsuka, Toa Eiyo, Daiichi Sankyo, and Mitsubishi Tanabe. NI received honorarium from Teijin Pharma; research grant from Teijin Pharma. YK declared no conflicts of interest. MO received honorariums MSD, Kyowa Kikaku, Pfizer, Astellas, Bayer, Toa Eiyo, Sumitomo Dainippon, Teijin Pharma, Kowa, Shionogi, Takeda, Daiichi Sankyo, and Boehringer Ingelheim; research grants from Daiichi Sankyo, Boehringer Ingelheim, Takeda, MSD, Kyowa Hakko Kirin, Kowa, Teijin Pharma, Mitsubishi Tanabe, Pfizer, Bristle‑Meyers, Sumitomo Dainippon, Mochida, Actelion, Otsuka, and Genzyme. KE received honorariums from Takeda, Sumitomo Dainippon, Mitsubishi Tanabe, Omron Healthcare, Astellas, Boehringer Ingelheim, Otsuka, Sanwa Kagaku Kenkyusho, and MSD; research grant from Nippon Shinyaku. YH received honorariums from Boehringer Ingelheim, Teijin Pharma, Mitsubishi Tanabe, AstraZeneca, Astellas, MSD, Takeda, Shionogi, Sanofi, Otsuka, Bayer, Kowa, Pfizer, Novartis, Kyowa Hakko Kirin, Toa Eiyo, Hisamitsu, M3, Kyowa Kikaku, MDS, Mochida, Asahi Kasei Medical, Sumitomo Dainippon, Torii, UNEX, Eli Lilly, House Foods, Kao, Fukuda Denshi, Daiichi Sankyo, and Sanwa Kagaku Kenkyusho; research grants from Kao, Nippon Sigmax, Nihon Kohden, Boehringer Ingelheim, Mitsubishi Tanabe, Teijin Pharma, Pfizer, Takeda, MSD, Taisho Toyama, Otsuka, Daiichi Sankyo, Sanofi, Mochida, Nippon Shinyaku, and Astellas. HY received honorariums from MSD, Takeda, Sumitomo Dainippon, Actelion, Pfizer, GlaxoSmithKline, Novartis, Nippon Shinyaku, Bayer, Toshiba Medical Systems, and GE Healthcare; research grants from Ono and MSD. KM received hono‑ rariums from MSD, Ono, Sanwa Kagaku Kenkyusho, Kowa, Takeda, Mitsubishi Tanabe, Novartis, Boehringer Ingelheim, Kyowa Hakko Kirin, and Teijin Pharma; research grants from Boehringer Ingelheim, MSD, Mitsubishi Tanabe, Takeda, Sanwa Kagaku Kenkyusho, Novartis, and Kowa. JA received honorariums from Actelion, Sanofi, Mitsubishi Tanabe, Takeda, Mochida, Shionogi, Kaneka, AstraZeneca, Astellas, Volcano, Terumo, Eisai, Bristle‑Meyers, St. Jude Medical, Kyowa Hakko Kirin, Pfizer, Ono, Abbott Vascular Japan, Toa Eiyo, JIMRO, Kissei, Sumitomo Dainippon, Boehringer Ingelheim, and Daiichi Sankyo; research grants from Kissei, Astellas, Mediphysics, Ono, Bristle‑Meyers, Pfizer, Boehringer Ingelheim, Kyowa Hakko Kirin, Bayer, Daiichi Sankyo, Eisai, Teijin Pharma, Kowa, Mochida, Abbott Vascular Japan, Asahi Intec, AstraZeneca, Sumitomo Dainippon, Otsuka, Mitsubishi Tanabe, Takeda, and Japan Lifeline. YKB received honorarium from MSD, Takeda, Daiichi‑Sankyo, AstraZeneca, Mitsubishi Tanabe, Denso, and Boehringer Ingelheim; research grants from Daiichi Sankyo, AstraZeneca, Mitsubishi Tanabe, Novartis, Denso, MSD, and Takeda. SU received honorariums from MSD, Mitsubishi Tanabe, Pfizer, Boehringer Ingelheim, Bayer, Sumitomo Dainippon, AstraZeneca, and Astellas; research grants from Bayer, Kowa, Bristle‑Meyers, MSD, Pfizer, Takeda, and Astellas. TIn received honorariums from Daiichi Sankyo, Otsuka, Bayer, MSD, Takeda, Shionogi, Astellas, Pfizer, Boehringer Ingelheim, Mochida, AstraZeneca, Kowa, Teijin Pharma, Medtronic, Abbott Vascular Japan, and Fukuda Denshi; research grants from Bayer, Nippon Shinyaku, Abbott Vascular Japan, Daiichi Sankyo, Otsuka, Bayer, MSD, Takeda, Shionogi, Astellas, Pfizer, Boehringer Ingelheim, Mochida, AstraZeneca, Kowa, and Teijin Pharma. TM received honorariums from Bayer, Daiichi Sankyo, Sumitomo Dainippon, Kowa, MSD, Mitsubishi Tan‑ abe, Boehringer Ingelheim, Pfizer, Takeda, Sanofi, and Astellas; research grants from Astellas, Daiichi Sankyo, Sumitomo Dainippon, Kowa, MSD, Mitsubishi Tanabe, Boehringer Ingelheim, Novartis, Otsuka, Pfizer, Sanofi, Takeda, and Teijin Pharma. KN received honorariums from Boehringer Ingelheim, Daiichi Sankyo, Astellas, Merck, Takeda, Mitsubishi Tanabe, and Sanofi; research grants from Sanwa Kagaku Kenkyusho, Astellas, Takeda, Boehringer Ingelheim, and Mitsubishi Tanabe.
Publisher Copyright:
© 2016 The Author(s).
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
UR - http://www.scopus.com/inward/record.url?scp=84975229374&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84975229374&partnerID=8YFLogxK
U2 - 10.1186/s12933-016-0409-2
DO - 10.1186/s12933-016-0409-2
M3 - Article
C2 - 27317093
AN - SCOPUS:84975229374
VL - 15
JO - Cardiovascular Diabetology
JF - Cardiovascular Diabetology
SN - 1475-2840
IS - 1
M1 - 87
ER -