Febuxostat for Cerebral and caRdiorenovascular Events prEvEntion stuDy

Study Overview
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Brief Summary
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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.

Official Title
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A Multicenter, Randomized, Comparative Trial on the Effect of Febuxostat in Preventing Cerebral and Cardiorenovascular Events in Patients With Hyperuricemia

Conditions
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Hyperuricemia

Intervention / Treatment
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* Drug: Febuxostat


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Febuxostat treatment group<br>Once daily after breakfast (generally within 30 minutes after eating) | Drug: Febuxostat<br>* 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. The starting dose of the investigational product (febuxostat) will be 10 mg/day. The dose will be increased to 20 mg/day at Week 4. The aim is to increase the dose to 40 mg/day at Week 8.<br>|
| No Intervention: Non-febuxostat treatment group<br>No febuxostat treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Development of cerebral or cardiorenovascular events and all deaths | Definition of cerebral and cardiorenovascular events: Death due to cerebral or cardiorenovascular disease New or recurrent cerebrovascular disease (stroke [cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, stroke of unknown type], transient ischemic attack New or recurrent non-fatal coronary artery disease (myocardial infarction and unstable angina pectoris) Cardiac failure requiring hospitalization Arteriosclerotic disease requiring hospitalization (aortic aneurysm, aortic dissection, and arteriosclerosis obliterans) 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) New atrial fibrillation (including paroxysmal atrial fibrillation) Deaths that are not caused by cerebral or cardiorenovascular disease | Enrollment through Month 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of cerebral or cardiorenovascular event by event |  | Enrollment through Month 36 | 
| Occurrence of cerebral or cardiorenovascular event by serum uric acid level |  | Enrollment through Month 36 | 
| Occurrence of cerebral or cardiorenovascular event by prior history of cerebral or cardiorenovascular disease |  | Enrollment through Month 36 | 
| Serum uric acid level |  | 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) | 
| Change in serum uric acid level |  | Enrollment through Week 4 | 
| Amount of change and percent change in serum uric acid level |  | Enrollment through Week 8 | 
| Amount of change and percent change in serum uric acid level |  | Enrollment through Week 12 | 
| Amount of change and percent change in serum uric acid level |  | Enrollment through Month 6 | 
| Amount of change and percent change in serum uric acid level |  | Enrollment through Month 12 | 
| Amount of change and percent change in serum uric acid level |  | Enrollment through Month 18 | 
| Amount of change and percent change in serum uric acid level |  | Enrollment through Month 24 | 
| Amount of change and percent change in serum uric acid level |  | Enrollment through Month 30 | 
| Amount of change and percent change in serum uric acid level |  | Enrollment through Month 36 (or withdrawal from the study) | 
| Percent Achieving serum uric acid level of 6.0mg/dL |  | Enrollment to completion of study or withdrawal | 
| Estimated glomerular filtration rate (eGFR) |  | Enrollment, 4, 8, and 12 weeks and 6, 12, 18, 24, 30, and 36 months (or withdrawal from the study) | 
| Amount of change and percent change in eGFR |  | Enrollment through Week 4 | 
| Amount of change and percent change in eGFR |  | Enrollment through Week 8 | 
| Amount of change and percent change in eGFR |  | Enrollment through Week 12 | 
| Amount of change and percent change in eGFR |  | Enrollment through Month 6 | 
| Amount of change and percent change in eGFR |  | Enrollment through Month 12 | 
| Amount of change and percent change in eGFR |  | Enrollment through Month 18 | 
| Amount of change and percent change in eGFR |  | Enrollment through Month 24 | 
| Amount of change and percent change in eGFR |  | Enrollment through Month 30 | 
| Amount of change and percent change in eGFR |  | Enrollment through Month 36 (or withdrawal from the study) | 
| Urine microalbumin-creatinine ratio |  | Enrollment, 6, 12, 24, and 36 months (or withdrawal from the study) | 
| Amount of change and percent change in urine microalbumin-creatinine ratio |  | Enrollment through Month 6 | 
| Amount of change and percent change in urine microalbumin-creatinine ratio |  | Enrollment through Month 12 | 
| Amount of change and percent change in urine microalbumin-creatinine ratio |  | Enrollment through Month 24 | 
| Amount of change and percent change in urine microalbumin-creatinine ratio |  | Enrollment through Month 36 (or withdrawal from the study) | 
| Quantification of urinary protein |  | Enrollment, 6, 12, 24, and 36 months (or withdrawal from the study) | 
| Amount of change and percent change in quantified urinary protein |  | Enrollment through Month 6 | 
| Amount of change and percent change in quantified urinary protein |  | Enrollment through Month 12 | 
| Amount of change and percent change in quantified urinary protein |  | Enrollment through Month 24 | 
| Amount of change and percent change in quantitative urinary protein |  | Enrollment through Month 36 (or withdrawal from the study) | 
| Blood pressure (systolic/diastolic) |  | Enrollment, 6, 12, 18, 24, 30, and 36 months (or withdrawal from the study) | 
| Amount of change and percent change in blood pressure (systolic/diastolic) |  | Enrollment through Month 6 | 
| Amount of change and percent change in blood pressure (systolic/diastolic) |  | Enrollment through Month 12 | 
| Amount of change and percent change in blood pressure (systolic/diastolic) |  | Enrollment through Month 18 | 
| Amount of change and percent change in blood pressure (systolic/diastolic) |  | Enrollment through Month 24 | 
| Amount of change and percent change in blood pressure (systolic/diastolic) |  | Enrollment through Month 30 | 
| Amount of change and percent change in blood pressure (systolic/diastolic) |  | Enrollment through Month 36 (or withdrawal from the study) | 
| Occurrence of adverse events |  | Enrollment through Month 36 | 
| Occurrence of cerebral or cardiorenovascular events in the febuxostat group during the study period by febuxostat dose |  | Enrollment through Month 36 | 
| Occurrence of cerebral or cardiorenovascular events in the non-febuxostat group during the study period by use of allopurinol |  | Enrollment through Month 36 |