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UMIN ID:

Recruitment status Completed
Unique ID issued by UMIN UMIN000012134
Receipt No. R000014188
Scientific Title A multicenter, randomized, comparative trial on the effect of febuxostat in preventing cerebral and cardiorenovascular events in patients with hyperuricemia
Date of disclosure of the study information 2013/10/28
Last modified on 2018/11/27

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Basic information
Public title A multicenter, randomized, comparative trial on the effect of febuxostat in preventing cerebral and cardiorenovascular events in patients with hyperuricemia
Acronym Febuxostat for cerebral and caRdiorenovascular events prEvEntion stuDy (FREED)
Scientific Title A multicenter, randomized, comparative trial on the effect of febuxostat in preventing cerebral and cardiorenovascular events in patients with hyperuricemia
Scientific Title:Acronym Febuxostat for cerebral and caRdiorenovascular events prEvEntion stuDy (FREED)
Region
Japan

Condition
Condition hyperuricemia
Classification by specialty
Medicine in general Cardiology Endocrinology and Metabolism
Nephrology
Classification by malignancy Others
Genomic information NO

Objectives
Narrative objectives1 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.
Basic objectives2 Efficacy
Basic objectives -Others
Trial characteristics_1 Confirmatory
Trial characteristics_2 Pragmatic
Developmental phase Not applicable

Assessment
Primary outcomes Occurrence of cerebral and cardiorenovascular events and all deaths
The occurrence of cerebral and cardiorenovascular events and all deaths during the study period (enrollment to study completion or withdrawal from the study) will be assessed.
(1) Death due to cerebral or cardiorenovascular disease
(2) New or recurrent cerebrovascular disease (stroke [cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, stroke of unknown type], transient ischemic attack
(3) New or recurrent non-fatal coronary artery disease (myocardial infarction and unstable angina pectoris)
(4) Cardiac failure requiring hospitalization
(5) Arteriosclerotic disease requiring hospitalization (aortic aneurysm, aortic dissection, and arteriosclerosis obliterans)
(6) Renal impairment (development of microalbuminuria, progression to overt proteinuria, or overt proteinuria [ >= 300 mg/gCr],confirmed by two consecutive laboratory tests performed after the initiation of study treatments; doubling of serum creatinine level;and progression to ESRD)
(7) New atrial fibrillation (including paroxysmal atrial fibrillation)
(8) Deaths that are not caused by cerebral or cardiorenovascular disease
Key secondary outcomes (1) Occurrence of cerebral and cardiorenovascular events by event, by serum uric acid level, and by previous history of cerebral and cardiorenovascular disease
1) Occurrence of each cerebral and cardiorenovascular event during the study period
2) Occurrence of all cerebral and cardiorenovascular events and each cerebral and cardiorenovascular event during the study period by serum uric acid level (baseline, level reached, and change)
3) Occurrence of all cerebral and cardiorenovascular events and each cerebral and cardiorenovascular event during the study period by previous history of cerebral and cardiorenovascular disease
4) Occurrence of cerebral or cardiorenovascular events in the febuxostat group during the study period by febuxostat dose
5) Occurrence of cerebral or cardiorenovascular events in the non-febuxostat group during the study period by use of allopurinol
(2) Serum uric acid level
1) Levels of, and change in, serum uric acid level from baseline to Month 36 (or withdrawal from the study)
2) Percent achieving a serum uric acid level of 6.0 mg/dL during the study period
(3) eGFR
Levels of, and change in, eGFR from baseline to Month 36 (or withdrawal from the study)
(4) Urinary microalbumin/creatinine ratio
Levels of, and change in, urinary microalbumin/creatinine ratio from baseline to Month 36 (or withdrawal from the study)
(5) Quantification of urinary protein
Levels of, and change in, quantified urinary protein from baseline to Month 36 (or withdrawal from the study)
(6) Blood pressure
Levels of, and change in, blood pressure (systolic and diastolic) from baseline to Month 36 (or withdrawal from the study)
(7) Adverse events

Base
Study type Interventional

Study design
Basic design Parallel
Randomization Randomized
Randomization unit Individual
Blinding Open -but assessor(s) are blinded
Control Active
Stratification NO
Dynamic allocation YES
Institution consideration Institution is considered as adjustment factor in dynamic allocation.
Blocking NO
Concealment Central registration

Intervention
No. of arms 2
Purpose of intervention Treatment
Type of intervention
Medicine
Interventions/Control_1 Febuxostat treatment group: Febuxostat will be taken orally for 36 months after enrollment (approximately 3 years).
Febuxostat will be taken once daily after breakfast (generally within 30 minutes after eating) but can be taken around the time of breakfast even if no food has been eaten. When the dose is to be increased, the principal or sub-investigator will carry out any required examinations and tests as needed.
(1) The starting dose of the investigational product (febuxostat) will be 10 mg/day.
(2) The dose will be increased to 20 mg/day at Week 4.
(3) The aim is to increase the dose to 40 mg/day at Week 8.

Investigational product (febuxostat) treatment criteria
Serum uric acid level is not below 2.0 mg/dL.
(1) If the serum uric acid level falls to <= 2.0 mg/dL during febuxostat up-titration, the dose will not be increased.
(2) If the serum uric acid level falls to <= 2.0 mg/dL during treatment with febuxostat, the dose will be decreased one level (20 mg).
Interventions/Control_2 Non-febuxostat treatment group: The administration of allopurinol 100 mg will be investigated as a response for increases in serum uric acid level for 36 months after enrollment (approximately 3 years).
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit
65 years-old <=
Age-upper limit

Not applicable
Gender Male and Female
Key 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 1) through 4) below
1) Previous or current history of hypertension
2) Previous or current history of type 2 diabetes mellitus
3) Renal disorders (30 mL/min/1.73 m2 <= eGFR < 60 mL/min/1.73 m2 within 3 months prior to enrollment)
4) 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
Key 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 AST or 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
Target sample size 1000

Research contact person
Name of lead principal investigator
1st name
Middle name
Last name Sunao Kojima
Organization Kumamoto University Graduate School of Life Sciences, part heart failure advanced medical joint research course
Division name Associate Professor
Zip code
Address 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan
TEL 096-373-5175
Email Kojimas@kumamoto-u.ac.jp

Public contact
Name of contact person
1st name
Middle name
Last name FREED Study Support Center
Organization FREED Study Support Center
Division name FREED Study Support Center
Zip code
Address 2-12-8 Shinjyuku , Shinjyuku-ku , Tokyo , 160-0022 , Japan
TEL 0120-604-654
Homepage URL http://www.freed.jp.net/
Email freed@sa-tt.co.jp

Sponsor
Institute FREED Study Group
Institute
Department

Funding Source
Organization TEIJIN PHARMA LIMITED
Organization
Division
Category of Funding Organization Profit organization
Nationality of Funding Organization

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization
Address
Tel
Email

Secondary IDs
Secondary IDs NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions

Other administrative information
Date of disclosure of the study information
2013 Year 10 Month 28 Day

Related information
URL releasing protocol
Publication of results Published

Result
URL related to results and publications
Number of participants that the trial has enrolled
Results
Uric acid level lowering by febuxostat provides clinical benefit for prevention of cerebral, cardiovascular, and renal events in elderly patients with hyperuricemia. 
Febuxostat may be expected to prevent the development and progression of chronic kidney disease.
However, excessive lowering treatment by febuxostat may be avoided.
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status Completed
Date of protocol fixation
2013 Year 09 Month 17 Day
Date of IRB
Anticipated trial start date
2013 Year 11 Month 01 Day
Last follow-up date
2017 Year 10 Month 31 Day
Date of closure to data entry
2018 Year 03 Month 30 Day
Date trial data considered complete
2018 Year 03 Month 31 Day
Date analysis concluded

Other
Other related information

Management information
Registered date
2013 Year 10 Month 28 Day
Last modified on
2018 Year 11 Month 27 Day


Link to view the page
URL(English) https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014188

Research Plan
Registered date File name

Research case data specifications
Registered date File name

Research case data
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