Febuxostat for Cerebral and caRdiorenovascular Events prEvEntion stuDy (FREED)

• ClinicalTrials.gov Identifier: NCT01984749
• Recruitment Status: Unknown
• First Posted: November 15, 2013
• Last Update Posted: August 26, 2016
• Sponsor: Freed Study Group
• Collaborator: Teijin Pharma Limited
• Information provided by (Responsible Party): Hisao Ogawa, Freed Study Group

Tracking Information

• First Submitted Date: October 30, 2013
• First Posted Date: November 15, 2013
• Last Update Posted Date: August 26, 2016
• Study Start Date: November 2013
• Estimated Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 23, 2015)

Development of cerebral or cardiorenovascular events and all deaths [ Time Frame: Enrollment through Month 36 ]

Definition of "cerebral and cardiorenovascular events":

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

Original Primary Outcome Measures (submitted: November 7, 2013)

Development of cerebral or cardiorenovascular events [ Time Frame: Enrollment through Month 36 ]

In this study, the following are defined as "cerebral and cardiorenovascular events."

1. Death due to cerebral or cardiorenovascular disease
2. New or recurrent cerebrovascular disease (stroke [cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage], an transient ischemic attacks)
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 or progression to overt proteinuria, doubling of serum creatinine level, and progression to ESRD)
7. New atrial fibrillation (including paroxysmal atrial fibrillation)

Current Secondary Outcome Measures (submitted: December 9, 2015)

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

Original Secondary Outcome Measures (submitted: November 7, 2013)

• Occurrence of cerebral or cardiorenovascular event by event [ Time Frame: Enrollment through Month 36 ]
• Occurrence of cerebral or cardiorenovascular event by serum uric acid level [ Time Frame: Enrollment through Month 36 ]
• Occurrence of cerebral or cardiorenovascular event by prior history of cerebral or cardiorenovascular disease [ Time Frame: Enrollment through Month 36 ]
• Serum uric acid level [ Time Frame: 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 [ Time Frame: Enrollment through Week 4 ]
• Amount of change and percent change in serum uric acid level [ Time Frame: Enrollment through Week 8 ]
• Amount of change and percent change in serum uric acid level [ Time Frame: Enrollment through Week 12 ]
• Amount of change and percent change in serum uric acid level [ Time Frame: Enrollment through Month 6 ]
• Amount of change and percent change in serum uric acid level [ Time Frame: Enrollment through Month 12 ]
• Amount of change and percent change in serum uric acid level [ Time Frame: Enrollment through Month 18 ]
• Amount of change and percent change in serum uric acid level [ Time Frame: Enrollment through Month 24 ]
• Amount of change and percent change in serum uric acid level [ Time Frame: Enrollment through Month 30 ]
• Amount of change and percent change in serum uric acid level [ Time Frame: Enrollment through Month 36 (or withdrawal from the study) ]
• Percent Achieving serum uric acid level of 6.0mg/dL [ Time Frame: Enrollment to completion of study or withdrawal ]
• Estimated glomerular filtration rate (eGFR) [ Time Frame: 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 [ Time Frame: Enrollment through Week 4 ]
• Amount of change and percent change in eGFR [ Time Frame: Enrollment through Week 8 ]
• Amount of change and percent change in eGFR [ Time Frame: Enrollment through Week 12 ]
• Amount of change and percent change in eGFR [ Time Frame: Enrollment through Month 6 ]
• Amount of change and percent change in eGFR [ Time Frame: Enrollment through Month 12 ]
• Amount of change and percent change in eGFR [ Time Frame: Enrollment through Month 18 ]
• Amount of change and percent change in eGFR [ Time Frame: Enrollment through Month 24 ]
• Amount of change and percent change in eGFR [ Time Frame: Enrollment through Month 30 ]
• Amount of change and percent change in eGFR [ Time Frame: Enrollment through Month 36 (or withdrawal from the study) ]
• Urine microalbumin-creatinine ratio [ Time Frame: Enrollment, 6, 12, 24, and 36 months (or withdrawal from the study) ]
• Amount of change and percent change in urine microalbumin-creatinine ratio [ Time Frame: Enrollment through Month 6 ]
• Amount of change and percent change in urine microalbumin-creatinine ratio [ Time Frame: Enrollment through Month 12 ]
• Amount of change and percent change in urine microalbumin-creatinine ratio [ Time Frame: Enrollment through Month 24 ]
• Amount of change and percent change in urine microalbumin-creatinine ratio [ Time Frame: Enrollment through Month 36 (or withdrawal from the study) ]
• Quantification of urinary protein [ Time Frame: Enrollment, 6, 12, 24, and 36 months (or withdrawal from the study) ]
• Amount of change and percent change in quantified urinary protein [ Time Frame: Enrollment through Month 6 ]
• Amount of change and percent change in quantified urinary protein [ Time Frame: Enrollment through Month 12 ]
• Amount of change and percent change in quantified urinary protein [ Time Frame: Enrollment through Month 24 ]
• Amount of change and percent change in quantitative urinary protein [ Time Frame: Enrollment through Month 36 (or withdrawal from the study) ]
• Blood pressure (systolic/diastolic) [ Time Frame: 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) [ Time Frame: Enrollment through Month 6 ]
• Amount of change and percent change in blood pressure (systolic/diastolic) [ Time Frame: Enrollment through Month 12 ]
• Amount of change and percent change in blood pressure (systolic/diastolic) [ Time Frame: Enrollment through Month 18 ]
• Amount of change and percent change in blood pressure (systolic/diastolic) [ Time Frame: Enrollment through Month 24 ]
• Amount of change and percent change in blood pressure (systolic/diastolic) [ Time Frame: Enrollment through Month 30 ]
• Amount of change and percent change in blood pressure (systolic/diastolic) [ Time Frame: Enrollment through Month 36 (or withdrawal from the study) ]
• All deaths [ Time Frame: Enrollment through Month 36 ]
• Occurrence of adverse events [ Time Frame: Enrollment through Month 36 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hyperuricemia

Intervention

Drug: Febuxostat

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.

Study Arms

• Experimental: Febuxostat treatment group
  Once daily after breakfast (generally within 30 minutes after eating)
  Intervention: Drug: Febuxostat
• No Intervention: Non-febuxostat treatment group
  No febuxostat treatment

Publications *

• 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 randomised controlled trial. Rheumatology (Oxford). 2021 Oct 4. pii: keab739. doi: 10.1093/rheumatology/keab739. [Epub ahead of print]
• 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.
• 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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: November 7, 2013): 1000
• Original Estimated Enrollment: Same as current
• Study Completion Date: Not Provided
• Estimated Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 65 Years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan

Administrative Information

• NCT Number: NCT01984749
• Other Study ID Numbers: 0078; UMIN000012134 ( Registry Identifier: UMIN )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Hisao Ogawa, Freed Study Group
• Study Sponsor: Freed Study Group
• Collaborators: Teijin Pharma Limited

Investigators

• Study Chair: Hisao Ogawa; Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University

• PRS Account: Freed Study Group
• Verification Date: August 2016