Clinical trial NCT01984749: Febuxostat for Cerebral and caRdiorenovascular Events prEvEntion stuDy
Official title: A Multicenter, Randomized, Comparative Trial on the Effect of Febuxostat in Preventing Cerebral and Cardiorenovascular Events in Patients With Hyperuricemia
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Hyperuricemia
Lead sponsor: Freed Study Group
Sponsor class: OTHER
Collaborators: name: Teijin Pharma Limited
First posted: 2013-11-15
Enrollment: 1000
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to demonstrate the effect of febuxostat in preventing cerebral and cardiorenovascular events in elderly patients with hyperuricemia who are at risk for cerebral and cardiorenovascular disease.


Eligibility criteria: Inclusion Criteria:

* (1) Patients 65 years of age or older at enrollment who are able to visit
* (2) Patients with hyperuricemia, who have a serum uric acid level \>7.0 mg/dL and \<= 9.0 mg/dL (7.0 mg/dL \< serum uric acid level \<= 9.0 mg/dL) within 2 months prior to enrollment
* (3) Patients at risk for any of the cerebral or cardiorenovascular diseases in i) through iv) below (i) Previous or current history of hypertension (ii) Previous or current history of type 2 diabetes mellitus (iii) Renal disorders (30 mL/min/1.73 m2 \<= eGFR \< 60 mL/min/1.73 m2 within 3 months prior to enrollment) (iv) Previous history of cerebral or cardiorenovascular disease for more than 3 months prior to enrollment (stroke \[cerebral hemorrhage, cerebral infarction, or subarachnoid hemorrhage\], coronary artery disease, vascular disease, or cardiac failure)
* (4) Patients who personally give written informed consent to participate in this study

Exclusion Criteria:

* (1) Patients with gouty tophus, or patients with subjective symptoms of gouty arthritis within 1 year prior to enrollment
* (2) Patients with a previous history of hypersensitivity to febuxostat or allopurinol
* (3) Patients with malignant tumors
* (4) Patients with serious kidney disease, Acute kidney disease, nephrotic syndrome, dialysis patients, kidney transplant patients, eGFR \< 30 mL/min/1.73 m2 , etc.
* (5) Patients with a previous history of acute coronary syndrome or stroke within 3 months prior to enrollment (cerebral hemorrhage, cerebral infarction, or subarachnoid hemorrhage)
* (6) Patients with a \>= 50% increase in serum creatinine within 3 months prior to enrollment
* (7) Patients with severe hypertension characterized by systolic blood pressure \>= 180 mmHg or diastolic blood pressure \>= 110 mmHg within 3 months prior to enrollment
* (8) Patients with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 2 or more times the upper limit of normal within 3 months prior to enrollment
* (9) Patients on any of the following medications at enrollment Mercaptopurine hydrate, azathioprine, vidarabine, or didanosine
* (10) Patients who receive any of the following medications for the treatment of hyperuricemia within 1 month prior to enrollment Allopurinol, benzbromarone, probenecid, bucolome, topiroxostat, or febuxostat
* (11) Patients who start, modify the dose of, or discontinue any of the following medications within 1 month prior to enrollment Losartan, irbesartan, fenofibrate, thiazide diuretics, or loop diuretics
* (12) Patients on hormone replacement therapy with estrogen (estrogenic hormone products)
* (13) Patients who have participated in other clinical research (including trials) within 6 months prior to enrollment (non-interventional observational research not excluded)
* (14) Patients otherwise judged by the principal or sub-investigator to be unsuitable for the study

Primary outcomes:
measure: Development of cerebral or cardiorenovascular events and all deaths
timeFrame: Enrollment through Month 36
Secondary outcomes:
measure: Occurrence of cerebral or cardiorenovascular event by event
timeFrame: Enrollment through Month 36
measure: Occurrence of cerebral or cardiorenovascular event by serum uric acid level
timeFrame: Enrollment through Month 36
measure: Occurrence of cerebral or cardiorenovascular event by prior history of cerebral or cardiorenovascular disease
timeFrame: Enrollment through Month 36
measure: Serum uric acid level
timeFrame: At screening, at enrollment, at 4, 8, and 12 weeks and 6, 12, 18, 24, 30, and 36 months (or at withdrawal from the study)
measure: Change in serum uric acid level
timeFrame: Enrollment through Week 4
measure: Amount of change and percent change in serum uric acid level
timeFrame: Enrollment through Week 8
measure: Amount of change and percent change in serum uric acid level
timeFrame: Enrollment through Week 12
measure: Amount of change and percent change in serum uric acid level
timeFrame: Enrollment through Month 6
measure: Amount of change and percent change in serum uric acid level
timeFrame: Enrollment through Month 12
measure: Amount of change and percent change in serum uric acid level
timeFrame: Enrollment through Month 18
measure: Amount of change and percent change in serum uric acid level
timeFrame: Enrollment through Month 24
measure: Amount of change and percent change in serum uric acid level
timeFrame: Enrollment through Month 30
measure: Amount of change and percent change in serum uric acid level
timeFrame: Enrollment through Month 36 (or withdrawal from the study)
measure: Percent Achieving serum uric acid level of 6.0mg/dL
timeFrame: Enrollment to completion of study or withdrawal
measure: Estimated glomerular filtration rate (eGFR)
timeFrame: Enrollment, 4, 8, and 12 weeks and 6, 12, 18, 24, 30, and 36 months (or withdrawal from the study)
measure: Amount of change and percent change in eGFR
timeFrame: Enrollment through Week 4
measure: Amount of change and percent change in eGFR
timeFrame: Enrollment through Week 8
measure: Amount of change and percent change in eGFR
timeFrame: Enrollment through Week 12
measure: Amount of change and percent change in eGFR
timeFrame: Enrollment through Month 6
measure: Amount of change and percent change in eGFR
timeFrame: Enrollment through Month 12
measure: Amount of change and percent change in eGFR
timeFrame: Enrollment through Month 18
measure: Amount of change and percent change in eGFR
timeFrame: Enrollment through Month 24
measure: Amount of change and percent change in eGFR
timeFrame: Enrollment through Month 30
measure: Amount of change and percent change in eGFR
timeFrame: Enrollment through Month 36 (or withdrawal from the study)
measure: Urine microalbumin-creatinine ratio
timeFrame: Enrollment, 6, 12, 24, and 36 months (or withdrawal from the study)
measure: Amount of change and percent change in urine microalbumin-creatinine ratio
timeFrame: Enrollment through Month 6
measure: Amount of change and percent change in urine microalbumin-creatinine ratio
timeFrame: Enrollment through Month 12
measure: Amount of change and percent change in urine microalbumin-creatinine ratio
timeFrame: Enrollment through Month 24
measure: Amount of change and percent change in urine microalbumin-creatinine ratio
timeFrame: Enrollment through Month 36 (or withdrawal from the study)
measure: Quantification of urinary protein
timeFrame: Enrollment, 6, 12, 24, and 36 months (or withdrawal from the study)
measure: Amount of change and percent change in quantified urinary protein
timeFrame: Enrollment through Month 6
measure: Amount of change and percent change in quantified urinary protein
timeFrame: Enrollment through Month 12
measure: Amount of change and percent change in quantified urinary protein
timeFrame: Enrollment through Month 24
measure: Amount of change and percent change in quantitative urinary protein
timeFrame: Enrollment through Month 36 (or withdrawal from the study)
measure: Blood pressure (systolic/diastolic)
timeFrame: Enrollment, 6, 12, 18, 24, 30, and 36 months (or withdrawal from the study)
measure: Amount of change and percent change in blood pressure (systolic/diastolic)
timeFrame: Enrollment through Month 6
measure: Amount of change and percent change in blood pressure (systolic/diastolic)
timeFrame: Enrollment through Month 12
measure: Amount of change and percent change in blood pressure (systolic/diastolic)
timeFrame: Enrollment through Month 18
measure: Amount of change and percent change in blood pressure (systolic/diastolic)
timeFrame: Enrollment through Month 24
measure: Amount of change and percent change in blood pressure (systolic/diastolic)
timeFrame: Enrollment through Month 30
measure: Amount of change and percent change in blood pressure (systolic/diastolic)
timeFrame: Enrollment through Month 36 (or withdrawal from the study)
measure: Occurrence of adverse events
timeFrame: Enrollment through Month 36
measure: Occurrence of cerebral or cardiorenovascular events in the febuxostat group during the study period by febuxostat dose
timeFrame: Enrollment through Month 36
measure: Occurrence of cerebral or cardiorenovascular events in the non-febuxostat group during the study period by use of allopurinol
timeFrame: Enrollment through Month 36
Other outcomes:
Locations:
city: Nagoya
country: Japan
facility: Hiramitsu Heart Clinic
state: Aichi
city: Nagoya
country: Japan
facility: Ogawa-naika Clinic
state: Aichi
city: Nagoya
country: Japan
facility: Shakaiiryohoｊin Koｊunkai Daido Hospital
state: Aichi
city: Yurihonjo
country: Japan
facility: Honjo Daiichi Hospital
state: Akita
city: Matsudo
country: Japan
facility: Iriyouhoujin Siyadan Yanagisawakai Yanagisawaiin
state: Chiba
city: Iyo-gun
country: Japan
facility: Matsuno Medical Clinic
state: Ehime
city: Matsuyama
country: Japan
facility: Ishite Matsumoto Naika Junkanki Clinic
state: Ehime
city: Niihama
country: Japan
facility: Ehime Medical CO-OP Izumigawa Clinic
state: Ehime
city: Buzen
country: Japan
facility: Hanaoka IC Clinic
state: Fukuoka
city: Chikushino
country: Japan
facility: Otonari Clinic
state: Fukuoka
city: Kitakyushu
country: Japan
facility: Medical Cooperation Toseikai Goto Clinic
state: Fukuoka
city: Onga-gun
country: Japan
facility: ONGA NAKAMA Medical Association ONGA Hospital
state: Fukuoka
city: Koriyama
country: Japan
facility: Southern Tohoku Research Institute For Neuroscience Southern Tohoku Medical Clinic
state: Fukushima
city: Ibi
country: Japan
facility: Noda Clinic
state: Gifu
city: Ogaki
country: Japan
facility: Sunomata Clinic
state: Gifu
city: Isesaki
country: Japan
facility: Tsurugaya Hospital
state: Gunma
city: Shibukawa
country: Japan
facility: Nakano Clinic
state: Gunma
city: Takasaki
country: Japan
facility: Iryouhoujinn Makikai Makibyouinn
state: Gunma
city: Miyoshi
country: Japan
facility: Shigenobu Clinic
state: Hiroshima
city: Asahikawa
country: Japan
facility: Keiyukai Yoshida Hospital
state: Hokkaido
city: Asahikawa
country: Japan
facility: Matsui Naika Clinic
state: Hokkaido
city: Asahikawa
country: Japan
facility: Omiya Clinic
state: Hokkaido
city: Sapporo
country: Japan
facility: Miyanomori Memorial Hospital
state: Hokkaido
city: Sapporo
country: Japan
facility: Okamoto Naika Clinic
state: Hokkaido
city: Sapporo
country: Japan
facility: River Side Clinic
state: Hokkaido
city: Amagasaki
country: Japan
facility: Katsuya Iin
state: Hyogo
city: Himeji
country: Japan
facility: Kousei Hospital
state: Hyogo
city: Himeji
country: Japan
facility: Nakatani Hospital
state: Hyogo
city: Kakogawa
country: Japan
facility: Harima Clinic
state: Hyogo
city: Kobe
country: Japan
facility: Kusunose Surgery Clinic
state: Hyogo
city: Hitachinaka
country: Japan
facility: Yamaki Medical Clinic
state: Ibaraki
city: Hakui
country: Japan
facility: Shika Clinic
state: Ishikawa
city: Hakusan
country: Japan
facility: Yanagi Medical Clinic
state: Ishikawa
city: Kahoku
country: Japan
facility: Kakuda Iin
state: Ishikawa
city: Kanazawa
country: Japan
facility: Dr Hayakawa's Family Clinic
state: Ishikawa
city: Kanazawa
country: Japan
facility: Wakasa Medical Clinic
state: Ishikawa
city: Nonoichi
country: Japan
facility: Okyozuka Clinic
state: Ishikawa
city: Takamatsu
country: Japan
facility: Matsuoka Clinic
state: Kagawa
city: Ashigarakami
country: Japan
facility: Ori Clinic
state: Kanagawa
city: Kamakura
country: Japan
facility: Iroden Clinic
state: Kanagawa
city: Kamakura
country: Japan
facility: Nagasu Clinic
state: Kanagawa
city: Kamakura
country: Japan
facility: Shohei Clinic
state: Kanagawa
city: Kawasaki
country: Japan
facility: Kamegaya Clinic
state: Kanagawa
city: Odawara
country: Japan
facility: Kobayashi Hospital
state: Kanagawa
city: Sagamihara
country: Japan
facility: Hakuai Iin
state: Kanagawa
city: Sagamihara
country: Japan
facility: Yamamoto Clinic
state: Kanagawa
city: Yokohama
country: Japan
facility: International Goodwill Hospital
state: Kanagawa
city: Yokohama
country: Japan
facility: Kikuchi Clinic
state: Kanagawa
city: Yokohama
country: Japan
facility: Shimokurata Heart Clinic
state: Kanagawa
city: Yokohama
country: Japan
facility: Tani Clinic Internal Medicine, Allergology & Rheumatology
state: Kanagawa
city: Yokohama
country: Japan
facility: Tsurumi Chuo Clinic
state: Kanagawa
city: Yokohama
country: Japan
facility: Yamagami Naika
state: Kanagawa
city: Yokohama
country: Japan
facility: Yokohama City University Medical Center
state: Kanagawa
city: Yokohama
country: Japan
facility: Yokohama Sotetsu bldg Clinic of Internal Medicine
state: Kanagawa
city: Aso
country: Japan
facility: Toihata Naika
state: Kumamoto
city: Koshi
country: Japan
facility: Omori Iin
state: Kumamoto
city: Tamana
country: Japan
facility: Kan Kaimeido Clinic
state: Kumamoto
city: Tamana
country: Japan
facility: Matsuo Clinic
state: Kumamoto
city: Yatsushiro
country: Japan
facility: Miyagi clinic cardiovascular medicine
state: Kumamoto
city: Tsu
country: Japan
facility: Iwasaki Hospital
state: Mie
city: Nichinan
country: Japan
facility: Eto Clinic
state: Miyazaki
city: Nichinan
country: Japan
facility: Kawano Clinic
state: Miyazaki
city: Nobeoka
country: Japan
facility: Miyata Naika Iin
state: Miyazaki
city: Kashihara
country: Japan
facility: Nara Medical University Hospital
state: Nara
city: Sakurai
country: Japan
facility: Ote Clinic of Internal
state: Nara
city: Joetsu
country: Japan
facility: Uchiyama Clinic
state: Niigata
city: Nakagami
country: Japan
facility: Hospital, University of the Ryukyus
state: Okinawa
city: Fujiidera
country: Japan
facility: Nishimura Clinic
state: Osaka
city: Higashiosaka
country: Japan
facility: Ikeda Clinic
state: Osaka
city: Izumi
country: Japan
facility: Kanazawa Clinic
state: Osaka
city: Sakai
country: Japan
facility: Hayashi Medical Clinic
state: Osaka
city: Yao
country: Japan
facility: Matsuo Clinic
state: Osaka
city: Ageo
country: Japan
facility: Enomoto Clinic
state: Saitama
city: Kawagoe
country: Japan
facility: Saitama Medical Center
state: Saitama
city: Kawaguchi
country: Japan
facility: Iryohojin Hogi sinryojyo
state: Saitama
city: Kawaguchi
country: Japan
facility: Okuaki Clinic
state: Saitama
city: Kawaguchi
country: Japan
facility: Tokutake Iin
state: Saitama
city: Kumagaya
country: Japan
facility: Medical Corporation Shibuya Clinic
state: Saitama
city: Awa
country: Japan
facility: Ota Clinic
state: Tokushima
city: Kaifu-gun
country: Japan
facility: Minami National Health Insurance Hospital Of Minami Town
state: Tokushima
city: Komatsushima
country: Japan
facility: Sekishinkan Hospital
state: Tokushima
city: Myozai-gun
country: Japan
facility: Tanaka Clinic
state: Tokushima
city: Adachi-ku
country: Japan
facility: Harada Clinic
state: Tokyo
city: Adachi-ku
country: Japan
facility: Johoku Clinic
state: Tokyo
city: Bunkyo-ku
country: Japan
facility: Moritani Clinic
state: Tokyo
city: Edogawa-ku
country: Japan
facility: Nishimura Memorial Hospital
state: Tokyo
city: Katsushika-ku
country: Japan
facility: Hosoda-Clinic
state: Tokyo
city: Kita-ku
country: Japan
facility: Okuda clinic
state: Tokyo
city: Mitaka
country: Japan
facility: Tenjinmae Clinic
state: Tokyo
city: Nakano-ku
country: Japan
facility: Daiba Shinryojo
state: Tokyo
city: Nerima-ku
country: Japan
facility: Kurumatani Clinic
state: Tokyo
city: Nerima-ku
country: Japan
facility: Oono Iin
state: Tokyo
city: Nerima-ku
country: Japan
facility: Sugawara Clinic
state: Tokyo
city: Nishitokyo
country: Japan
facility: Baba Iin
state: Tokyo
city: Ota-ku
country: Japan
facility: Miyahara Clinic
state: Tokyo
city: Shinagawa-ku
country: Japan
facility: Taguchi Clinic
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Tokyo Women's Medical University Hospital
state: Tokyo
city: Suginami-ku
country: Japan
facility: Kobayashi Clinic
state: Tokyo
city: Tachikawa
country: Japan
facility: Tominaga Clinic
state: Tokyo
city: Toshima-ku
country: Japan
facility: Kirino Clinic
state: Tokyo
city: Toshima-ku
country: Japan
facility: Yamada Clinic
state: Tokyo
city: Shimonoseki
country: Japan
facility: Ayame Medical Clinic
state: Yamaguchi
city: Shimonoseki
country: Japan
facility: Matuda Clinic
state: Yamaguchi
city: Otsuki city
country: Japan
facility: Kuroda Iin
state: Yamanashi pref.
city: Fukuoka
country: Japan
facility: Saku Hospital
city: Fukuoka
country: Japan
facility: Tohaya Iin
city: Gifu
country: Japan
facility: Iryohojin Shadan Seijinkai Kawade Iin
city: Gifu
country: Japan
facility: Kawai Naika Clinic
city: Gifu
country: Japan
facility: Miwa Clinic: Gastroenterology Hepatology
city: Gifu
country: Japan
facility: Sagou Clinic
city: Gifu
country: Japan
facility: Sasaki Clinic
city: Gifu
country: Japan
facility: Takai Clinic
city: Gifu
country: Japan
facility: Takeda Clinic
city: Gifu
country: Japan
facility: Totani Medical Clinic
city: Kochi
country: Japan
facility: Shimamoto Hospital
city: Kumamoto
country: Japan
facility: Honjo Internal Medicine Hospital
city: Kumamoto
country: Japan
facility: Jinnouchi Clinic Diabetes Care Center
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Kumamoto
country: Japan
facility: Maki Cardiovascular Clinic
city: Kumamoto
country: Japan
facility: Otsuka Hospital
city: Kumamoto
country: Japan
facility: Suizenji Touya Hospital
city: Kumamoto
country: Japan
facility: TERAO Hospital
city: Kyoto
country: Japan
facility: Isoda Internal Medical Clinic
city: Kyoto
country: Japan
facility: Koseikai Clinic
city: Kyoto
country: Japan
facility: Takenaka Clinic
city: Miyazaki
country: Japan
facility: Yokota Naika
city: Niigata
country: Japan
facility: Maeda Medical Clinic
city: Osaka
country: Japan
facility: Akioka Clinic
city: Osaka
country: Japan
facility: Kinugawa Cardiology Clinic
city: Osaka
country: Japan
facility: Kondo Clinic
city: Osaka
country: Japan
facility: Kubota Clinic
city: Osaka
country: Japan
facility: Matsushita Medical Clinic
city: Osaka
country: Japan
facility: Nanko Clinic
city: Osaka
country: Japan
facility: Seo Heart Clinic
city: Osaka
country: Japan
facility: Watanabe Iin
city: Shizuoka
country: Japan
facility: Harada Medical Clinic
city: Shizuoka
country: Japan
facility: Shizuoka Municipal Hospital
city: Shizuoka
country: Japan
facility: Waki Riichiro Clinic
city: Tokushima
country: Japan
facility: Itsumo Smile Clinic
city: Yamagata
country: Japan
facility: Shimasaki Clinic
Study officials:
affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
name: Hisao Ogawa
role: STUDY_CHAIR
References:
citation: Kojima S, Uchiyama K, Yokota N, Tokutake E, Wakasa Y, Hiramitsu S, Waki M, Jinnouchi H, Kakuda H, Hayashi T, Kawai N, Sugawara M, Mori H, Tsujita K, Matsui K, Hisatome I, Ohya Y, Kimura K, Saito Y, Ogawa H; Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED) investigators. C-reactive Protein Levels and Cardiovascular Outcomes After Febuxostat Treatment in Patients with Asymptomatic Hyperuricemia: Post-hoc Analysis of a Randomized Controlled Study. Cardiovasc Drugs Ther. 2023 Oct;37(5):965-974. doi: 10.1007/s10557-022-07347-7. Epub 2022 Jun 1.
citation: Kojima S, Uchiyama K, Yokota N, Tokutake E, Wakasa Y, Hiramitsu S, Waki M, Jinnouchi H, Kakuda H, Hayashi T, Kawai N, Sugawara M, Mori H, Tsujita K, Matsui K, Hisatome I, Ohya Y, Kimura K, Saito Y, Ogawa H; Febuxostat for Cerebral and Cardiorenovascular Events Prevention Study (FREED) investigators. Optimal uric acid levels by febuxostat treatment and cerebral, cardiorenovascular risks: post hoc analysis of a randomized controlled trial. Rheumatology (Oxford). 2022 May 30;61(6):2346-2359. doi: 10.1093/rheumatology/keab739.
citation: Kojima S, Matsui K, Hiramitsu S, Hisatome I, Waki M, Uchiyama K, Yokota N, Tokutake E, Wakasa Y, Jinnouchi H, Kakuda H, Hayashi T, Kawai N, Mori H, Sugawara M, Ohya Y, Kimura K, Saito Y, Ogawa H. Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy. Eur Heart J. 2019 Jun 7;40(22):1778-1786. doi: 10.1093/eurheartj/ehz119.
citation: Kojima S, Matsui K, Ogawa H, Jinnouchi H, Hiramitsu S, Hayashi T, Yokota N, Kawai N, Tokutake E, Uchiyama K, Sugawara M, Kakuda H, Wakasa Y, Mori H, Hisatome I, Waki M, Ohya Y, Kimura K, Saito Y; Febuxostat for Cerebral and Cardiorenovascular Events Prevention Study (FREED) investigators. Rationale, design, and baseline characteristics of a study to evaluate the effect of febuxostat in preventing cerebral, cardiovascular, and renal events in patients with hyperuricemia. J Cardiol. 2017 Jan;69(1):169-175. doi: 10.1016/j.jjcc.2016.02.015. Epub 2016 Apr 20.