Cardiovascular Safety of Febuxostat and Allopurinol in Participants With Gout and Cardiovascular Comorbidities (CARES)
CARES
A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the Cardiovascular Safety of Febuxostat and Allopurinol in Subjects With Gout and Cardiovascular Comorbidities
2 other identifiers
interventional
6,198
2 countries
203
Brief Summary
The purpose of this study is to see whether subjects with gout who receive febuxostat or allopurinol for up to 9 years have a higher rate of serious heart and blood vessel complications (major cardiovascular events).
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Apr 2010
Longer than P75 for phase_3
203 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
April 7, 2010
CompletedFirst Posted
Study publicly available on registry
April 9, 2010
CompletedStudy Start
First participant enrolled
April 23, 2010
CompletedPrimary Completion
Last participant's last visit for primary outcome
May 15, 2017
CompletedStudy Completion
Last participant's last visit for all outcomes
July 18, 2017
CompletedResults Posted
Study results publicly available
June 14, 2018
CompletedJune 14, 2018
June 1, 2018
7.1 years
April 7, 2010
May 11, 2018
June 12, 2018
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis)
Major adverse cardiovascular events (MACE) were defined as a composite of cardiovascular (CV) death, non-fatal myocardial infarction (MI), nonfatal stroke and unstable angina with urgent coronary revascularization; these events were adjudicated by an independent cardiovascular endpoints committee.
Up to last dose of study drug (approximately 83 months)
Percentage of Participants With Primary MACE Composite (Final Analysis)
Major adverse cardiovascular events (MACE) were defined as a composite of cardiovascular (CV) death, non-fatal myocardial infarction (MI), nonfatal stroke and unstable angina with urgent coronary revascularization; these events were adjudicated by an independent cardiovascular endpoints committee.
Up to last dose of study drug (approximately 83 months)
Secondary Outcomes (5)
Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event
Up to last dose of study drug (approximately 83 months)
Percentage of Participants With Cardiovascular (CV) Death
Up to last dose of study drug (approximately 83 months)
Percentage of Participants With Non-fatal Myocardial Infarction (MI)
Up to last dose of study drug (approximately 83 months)
Percentage of Participants With Non-fatal Stroke
Up to last dose of study drug (approximately 83 months)
Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization
Up to last dose of study drug (approximately 83 months)
Study Arms (2)
Febuxostat
EXPERIMENTALFebuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months.
Allopurinol
ACTIVE COMPARATORAllopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was \<6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance \[eCLcr\] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was \<6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but \<60 mL/min).
Interventions
Allopurinol tablets
Eligibility Criteria
You may qualify if:
- The participant or the participant's legally acceptable representative signs and dates a written, informed consent form/Health Insurance Portability and Accountability Act (HIPAA) Authorization prior to the initiation of any study procedures.
- The participant is male ≥50 years of age or female ≥55 years of age and at least 2-years post-menopausal.
- The participant has a history of major CV or cerebrovascular disease including at least one of the following:
- Myocardial infarction (MI).
- Hospitalized unstable angina.
- Cardiac or cerebrovascular revascularization procedure.
- Stroke.
- Hospitalized transient ischemic attack (TIA).
- Peripheral vascular disease (ankle brachial index ≤0.6, revascularization and/or well-documented history of claudication).
- History of diabetes mellitus with evidence of micro- or macrovascular disease (retinopathy, neuropathy, nephropathy, small vessel vascular diseases).
- The participant has a history or presence of gout defined as having one or more of the American Rheumatism Association criteria for the diagnosis of gout:
- A tophus proven to contain urate crystals by chemical or polarized light microscopic means, and/or
- Characteristic urate crystals in the joint fluid, and/or
- History of at least 6 of the following clinical, laboratory, and X-ray phenomena:
- More than 1 attack of acute arthritis.
- +15 more criteria
You may not qualify if:
- Participants who meet any of the following criteria will not qualify for entry into this study:
- The participant has secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ transplant).
- The participant has a history of xanthinuria.
- The participant has received urate-lowering therapy (i.e., febuxostat, allopurinol, probenecid, etc.) or excluded medication during the screening period (beginning with Day -7).
- The participant has a known hypersensitivity to febuxostat or allopurinol or any components of their formulation.
- The participant has active peptic ulcer disease.
- The participant has a history of cancer (other than basal cell carcinoma of the skin) within 5 years prior to the first dose of study medication.
- The participant had MI or stroke within 60 days prior to the Screening Visit.
- The participant has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values greater than 2 times the upper limit of normal (×ULN) during the Screening period.
- The participant has a significant medical condition and/or conditions that would interfere with the treatment, safety, or compliance with the protocol.
- The participant has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 5 years prior to the Screening Visit or the participant consumes \>14 alcoholic beverages per week.
- The participant has received any investigational medicinal product within the 30 days prior to the Screening Visit and throughout the study.
- The participant's estimated creatinine clearance (CLcr) is \<30 mL/min, where CLcr is calculated using the Cockcroft and Gault formula based on ideal body weight (IBW),
- The participant is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
- The participant is required to take excluded medications
- +1 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Takedalead
Study Sites (203)
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Decatur, Georgia, United States
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Dunwoody, Georgia, United States
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Marietta, Georgia, United States
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Norcross, Georgia, United States
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Roswell, Georgia, United States
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Suwanee, Georgia, United States
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Waycross, Georgia, United States
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Honolulu, Hawaii, United States
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Boise, Idaho, United States
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Coeur d'Alene, Idaho, United States
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Nampa, Idaho, United States
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Addison, Illinois, United States
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Arlington Heights, Illinois, United States
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Evanston, Illinois, United States
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Evergreen Park, Illinois, United States
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Flossmoor, Illinois, United States
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Melrose Park, Illinois, United States
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Morton, Illinois, United States
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Naperville, Illinois, United States
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Quincy, Illinois, United States
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Rockford, Illinois, United States
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Bloomington, Indiana, United States
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Brownsburg, Indiana, United States
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Lafayette, Indiana, United States
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Valparaiso, Indiana, United States
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Iowa City, Iowa, United States
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Lenexa, Kansas, United States
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Overland Park, Kansas, United States
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Topeka, Kansas, United States
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Wichita, Kansas, United States
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Elizabethtown, Kentucky, United States
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Lexington, Kentucky, United States
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Owensboro, Kentucky, United States
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Paducah, Kentucky, United States
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Mer Rouge, Louisiana, United States
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Monroe, Louisiana, United States
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Shreveport, Louisiana, United States
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Biddeford, Maine, United States
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Rockport, Maine, United States
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Baltimore, Maryland, United States
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Cumberland, Maryland, United States
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Hagerstown, Maryland, United States
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Lutherville, Maryland, United States
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Wheaton, Maryland, United States
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Brockton, Massachusetts, United States
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Fall River, Massachusetts, United States
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Hyannis, Massachusetts, United States
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Worcester, Massachusetts, United States
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Ann Arbor, Michigan, United States
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Bingham Farms, Michigan, United States
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Chelsea, Michigan, United States
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Detroit, Michigan, United States
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Flint, Michigan, United States
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Kalamazoo, Michigan, United States
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Lansing, Michigan, United States
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Chaska, Minnesota, United States
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Duluth, Minnesota, United States
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Edina, Minnesota, United States
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Saint Paul, Minnesota, United States
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Jackson, Mississippi, United States
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Olive Branch, Mississippi, United States
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Port Gibson, Mississippi, United States
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Clarkson Valley, Missouri, United States
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Hazelwood, Missouri, United States
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Kansas City, Missouri, United States
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Saint Charles, Missouri, United States
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St Louis, Missouri, United States
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Washington, Missouri, United States
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Billings, Montana, United States
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Butte, Montana, United States
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Bellevue, Nebraska, United States
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Grand Island, Nebraska, United States
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Lincoln, Nebraska, United States
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Omaha, Nebraska, United States
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Henderson, Nevada, United States
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Las Vegas, Nevada, United States
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Reno, Nevada, United States
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Brick, New Jersey, United States
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Edison, New Jersey, United States
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Oradell, New Jersey, United States
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Albuquerque, New Mexico, United States
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Las Vegas, New Mexico, United States
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Endwell, New York, United States
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Freeport, New York, United States
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Glens Falls, New York, United States
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Mineola, New York, United States
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New Windsor, New York, United States
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New York, New York, United States
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Rochester, New York, United States
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West Seneca, New York, United States
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Westfield, New York, United States
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Asheboro, North Carolina, United States
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Cary, North Carolina, United States
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Charlotte, North Carolina, United States
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Columbia, North Carolina, United States
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Greensboro, North Carolina, United States
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Huntersville, North Carolina, United States
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Lenoir, North Carolina, United States
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Monroe, North Carolina, United States
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Raleigh, North Carolina, United States
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Salisbury, North Carolina, United States
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Shelby, North Carolina, United States
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Wilmington, North Carolina, United States
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Winston-Salem, North Carolina, United States
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Fargo, North Dakota, United States
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Akron, Ohio, United States
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Centerville, Ohio, United States
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Cincinnati, Ohio, United States
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Columbus, Ohio, United States
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Dayton, Ohio, United States
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Delaware, Ohio, United States
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Franklin, Ohio, United States
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Kettering, Ohio, United States
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Lyndhurst, Ohio, United States
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Marion, Ohio, United States
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Mentor, Ohio, United States
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Middleburg Heights, Ohio, United States
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Toledo, Ohio, United States
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Willoughby Hills, Ohio, United States
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Oklahoma City, Oklahoma, United States
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Tulsa, Oklahoma, United States
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Ashland, Oregon, United States
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Bend, Oregon, United States
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Eugene, Oregon, United States
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Portland, Oregon, United States
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Altoona, Pennsylvania, United States
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Bensalem, Pennsylvania, United States
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Bethlehem, Pennsylvania, United States
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Downingtown, Pennsylvania, United States
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Duncansville, Pennsylvania, United States
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Ephrata, Pennsylvania, United States
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Harleysville, Pennsylvania, United States
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Lansdale, Pennsylvania, United States
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McMurray, Pennsylvania, United States
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Philadelphia, Pennsylvania, United States
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Quakertown, Pennsylvania, United States
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Wyomissing, Pennsylvania, United States
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Cumberland, Rhode Island, United States
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East Providence, Rhode Island, United States
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Providence, Rhode Island, United States
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Anderson, South Carolina, United States
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Charleston, South Carolina, United States
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Columbia, South Carolina, United States
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Greenville, South Carolina, United States
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Greenwood, South Carolina, United States
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Greer, South Carolina, United States
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Myrtle Beach, South Carolina, United States
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Orangeburg, South Carolina, United States
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Pelzer, South Carolina, United States
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Simpsonville, South Carolina, United States
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Spartanburg, South Carolina, United States
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Athens, Tennessee, United States
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Chattanooga, Tennessee, United States
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Clarksville, Tennessee, United States
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Collierville, Tennessee, United States
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Fayetteville, Tennessee, United States
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Jackson, Tennessee, United States
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Kingsport, Tennessee, United States
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Memphis, Tennessee, United States
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New Tazewell, Tennessee, United States
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Bellaire, Texas, United States
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Carrollton, Texas, United States
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Dallas, Texas, United States
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El Paso, Texas, United States
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Fort Worth, Texas, United States
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Grapevine, Texas, United States
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Houston, Texas, United States
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Irving, Texas, United States
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McKinney, Texas, United States
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New Braunfels, Texas, United States
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Odessa, Texas, United States
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Pearland, Texas, United States
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Plano, Texas, United States
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Richardson, Texas, United States
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San Antonio, Texas, United States
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Southlake, Texas, United States
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Sugar Land, Texas, United States
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Tomball, Texas, United States
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Waco, Texas, United States
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Bountiful, Utah, United States
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Draper, Utah, United States
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Salt Lake City, Utah, United States
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West Jordan, Utah, United States
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Alexandria, Virginia, United States
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Arlington, Virginia, United States
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Burke, Virginia, United States
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Danville, Virginia, United States
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McLean, Virginia, United States
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Norfolk, Virginia, United States
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Richmond, Virginia, United States
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Salem, Virginia, United States
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Virginia Beach, Virginia, United States
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Port Orchard, Washington, United States
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Tacoma, Washington, United States
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Clarksburg, West Virginia, United States
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Green Bay, Wisconsin, United States
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Milwaukee, Wisconsin, United States
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New Berlin, Wisconsin, United States
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Oregon, Wisconsin, United States
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Verona, Wisconsin, United States
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Waukesha, Wisconsin, United States
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Weston, Wisconsin, United States
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Jalisco, Mexico City, Mexico
Related Publications (4)
White WB, Chohan S, Dabholkar A, Hunt B, Jackson R. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities. Am Heart J. 2012 Jul;164(1):14-20. doi: 10.1016/j.ahj.2012.04.011. Epub 2012 Jun 13.
PMID: 22795277RESULTWhite WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, Hunt B, Castillo M, Gunawardhana L; CARES Investigators. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018 Mar 29;378(13):1200-1210. doi: 10.1056/NEJMoa1710895. Epub 2018 Mar 12.
PMID: 29527974RESULTSaag KG, Becker MA, White WB, Whelton A, Borer JS, Gorelick PB, Hunt B, Castillo M, Gunawardhana L; CARES Investigators. Evaluation of the Relationship Between Serum Urate Levels, Clinical Manifestations of Gout, and Death From Cardiovascular Causes in Patients Receiving Febuxostat or Allopurinol in an Outcomes Trial. Arthritis Rheumatol. 2022 Sep;74(9):1593-1601. doi: 10.1002/art.42160. Epub 2022 Aug 5.
PMID: 35536764DERIVEDFravel MA, Ernst ME. Management of gout in the older adult. Am J Geriatr Pharmacother. 2011 Oct;9(5):271-85. doi: 10.1016/j.amjopharm.2011.07.004. Epub 2011 Aug 17.
PMID: 21849262DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Medical Director
- Organization
- Takeda
Study Officials
- STUDY DIRECTOR
Medical Director
Takeda
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
April 7, 2010
First Posted
April 9, 2010
Study Start
April 23, 2010
Primary Completion
May 15, 2017
Study Completion
July 18, 2017
Last Updated
June 14, 2018
Results First Posted
June 14, 2018
Record last verified: 2018-06