UMIN-CTR Clinical Trial

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

hyperuricemia

Classification by specialty

Medicine in general	Cardiology	Endocrinology and Metabolism
Nephrology

Classification by malignancy

Others

Genomic information

NO

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

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

Study type

Interventional

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

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

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

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

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

Institute

FREED Study Group

Institute

Department

Personal name

Organization

TEIJIN PHARMA LIMITED

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Address

Tel

Email

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2013

Year

10

Month

28

Day

URL releasing protocol

Publication of results

Published

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

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 related information

Registered date

2013

Year

10

Month

28

Day

Last modified on

2018

Year

11

Month

27

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014188