Cardiovascular Safety of Febuxostat and Allopurinol in Participants With Gout and Cardiovascular Comorbidities (CARES)

NCT ID: NCT01101035

Last Updated: 2018-06-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 6198 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-23
• Study Completion Date: 2017-07-18

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).

Detailed Description

The drug tested in this study was called Febuxostat (TMX-67). Febuxostat compared with allopurinol was evaluated for the cardiovascular (CV) safety in people with gout and significant CV comorbidities.

The study enrolled 6198 patients. Participants with a diagnosis of gout were enrolled in a 1:1 ratio to receive either:

• Febuxostat
• Allopurinol

Participants received febuxostat 40 mg or 80 mg for the study depending on their serum uric acid levels were either <6.0 mg/dL or ≥6.0 mg/dL during specified visits. Allopurinol 200 mg to 400 mg (for moderate renal impairment),or 300 mg to 600 mg (for normal and mild renal impairment), increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL was received.

This multi-center trial was conducted in Canada, Mexico and United States. The overall time to participate in this study was approximately 7 years (84 months). Participants made multiple visits to the clinic and were also contacted through the telephone.

Conditions

Cardiovascular Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Febuxostat

Febuxostat 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.

Group Type: EXPERIMENTAL

Febuxostat

Intervention Type: DRUG

Febuxostat tablets

Allopurinol

Allopurinol 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).

Group Type: ACTIVE_COMPARATOR

Allopurinol

Intervention Type: DRUG

Allopurinol tablets

Interventions

Febuxostat

Febuxostat tablets

Intervention Type: DRUG

Allopurinol

Allopurinol tablets

Intervention Type: DRUG

Other Intervention Names

Uloric; TMX-67; Zyloprim; Allohexal; Allosig; Milurit; Alloril; Progout; Zyloric; Puricos; Zyrik 300; Aluron

Eligibility Criteria

Inclusion Criteria

1. 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.

2. The participant is male ≥50 years of age or female ≥55 years of age and at least 2-years post-menopausal.

3. 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).

4. 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.
• Maximum inflammation developed within 1 day.
• Monoarticular arthritis.
• Redness observed over joints.
• First metatarsophalangeal joint painful or swollen.
• Unilateral first metatarsophalangeal joint attack.
• Unilateral tarsal joint attack.
• Tophus (proven or suspected).
• Hyperuricemia.
• Asymmetric swelling within a joint on x-ray.
• Subcortical cysts without erosions on x-ray.
• Joint fluid culture negative for organisms during attack.

5. The participants must have either:

• a serum urate or serum uric acid (sUA) level ≥7.0 mg/dL (≥416 μmol/L) at the Day -7 Visit OR
• a sUA level ≥6.0 mg/dL (≥354 μmol/L) at the Day -7 Visit AND inadequately controlled gout (≥1 flare in the 12 months prior to screening and/or the presence of tophi).

6. The participant is capable of understanding and complying with protocol requirements

Exclusion Criteria

Participants who meet any of the following criteria will not qualify for entry into this study:

1. The participant has secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ transplant).

2. The participant has a history of xanthinuria.

3. The participant has received urate-lowering therapy (i.e., febuxostat, allopurinol, probenecid, etc.) or excluded medication during the screening period (beginning with Day -7).

4. The participant has a known hypersensitivity to febuxostat or allopurinol or any components of their formulation.

5. The participant has active peptic ulcer disease.

6. 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.

7. The participant had MI or stroke within 60 days prior to the Screening Visit.

8. 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.

9. The participant has a significant medical condition and/or conditions that would interfere with the treatment, safety, or compliance with the protocol.

10. 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.

11. The participant has received any investigational medicinal product within the 30 days prior to the Screening Visit and throughout the study.

12. 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),

13. 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.

14. The participant is required to take excluded medications

15. The participant has a known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Takeda

Locations

Verona, Wisconsin, United States

Waukesha, Wisconsin, United States

Weston, Wisconsin, United States

Jalisco, Mexico City, Mexico

Decatur, Georgia, United States

Dunwoody, Georgia, United States

Marietta, Georgia, United States

Norcross, Georgia, United States

Roswell, Georgia, United States

Suwanee, Georgia, United States

Waycross, Georgia, United States

Honolulu, Hawaii, United States

Boise, Idaho, United States

Coeur d'Alene, Idaho, United States

Nampa, Idaho, United States

Addison, Illinois, United States

Arlington Heights, Illinois, United States

Evanston, Illinois, United States

Evergreen Park, Illinois, United States

Flossmoor, Illinois, United States

Melrose Park, Illinois, United States

Morton, Illinois, United States

Naperville, Illinois, United States

Quincy, Illinois, United States

Rockford, Illinois, United States

Bloomington, Indiana, United States

Brownsburg, Indiana, United States

Lafayette, Indiana, United States

Valparaiso, Indiana, United States

Iowa City, Iowa, United States

Lenexa, Kansas, United States

Overland Park, Kansas, United States

Topeka, Kansas, United States

Wichita, Kansas, United States

Elizabethtown, Kentucky, United States

Lexington, Kentucky, United States

Owensboro, Kentucky, United States

Paducah, Kentucky, United States

Mer Rouge, Louisiana, United States

Monroe, Louisiana, United States

Shreveport, Louisiana, United States

Biddeford, Maine, United States

Rockport, Maine, United States

Baltimore, Maryland, United States

Cumberland, Maryland, United States

Hagerstown, Maryland, United States

Lutherville, Maryland, United States

Wheaton, Maryland, United States

Brockton, Massachusetts, United States

Fall River, Massachusetts, United States

Hyannis, Massachusetts, United States

Worcester, Massachusetts, United States

Ann Arbor, Michigan, United States

Bingham Farms, Michigan, United States

Chelsea, Michigan, United States

Detroit, Michigan, United States

Flint, Michigan, United States

Kalamazoo, Michigan, United States

Lansing, Michigan, United States

Chaska, Minnesota, United States

Duluth, Minnesota, United States

Edina, Minnesota, United States

Saint Paul, Minnesota, United States

Jackson, Mississippi, United States

Olive Branch, Mississippi, United States

Port Gibson, Mississippi, United States

Clarkson Valley, Missouri, United States

Hazelwood, Missouri, United States

Kansas City, Missouri, United States

Saint Charles, Missouri, United States

St Louis, Missouri, United States

Washington, Missouri, United States

Billings, Montana, United States

Butte, Montana, United States

Bellevue, Nebraska, United States

Grand Island, Nebraska, United States

Lincoln, Nebraska, United States

Omaha, Nebraska, United States

Henderson, Nevada, United States

Las Vegas, Nevada, United States

Reno, Nevada, United States

Brick, New Jersey, United States

Edison, New Jersey, United States

Oradell, New Jersey, United States

Albuquerque, New Mexico, United States

Las Vegas, New Mexico, United States

Endwell, New York, United States

Freeport, New York, United States

Glens Falls, New York, United States

Mineola, New York, United States

New Windsor, New York, United States

New York, New York, United States

Rochester, New York, United States

West Seneca, New York, United States

Westfield, New York, United States

Asheboro, North Carolina, United States

Cary, North Carolina, United States

Charlotte, North Carolina, United States

Columbia, North Carolina, United States

Greensboro, North Carolina, United States

Huntersville, North Carolina, United States

Lenoir, North Carolina, United States

Monroe, North Carolina, United States

Raleigh, North Carolina, United States

Salisbury, North Carolina, United States

Shelby, North Carolina, United States

Wilmington, North Carolina, United States

Winston-Salem, North Carolina, United States

Fargo, North Dakota, United States

Akron, Ohio, United States

Centerville, Ohio, United States

Cincinnati, Ohio, United States

Columbus, Ohio, United States

Dayton, Ohio, United States

Delaware, Ohio, United States

Franklin, Ohio, United States

Kettering, Ohio, United States

Lyndhurst, Ohio, United States

Marion, Ohio, United States

Mentor, Ohio, United States

Middleburg Heights, Ohio, United States

Toledo, Ohio, United States

Willoughby Hills, Ohio, United States

Oklahoma City, Oklahoma, United States

Tulsa, Oklahoma, United States

Ashland, Oregon, United States

Bend, Oregon, United States

Eugene, Oregon, United States

Portland, Oregon, United States

Altoona, Pennsylvania, United States

Bensalem, Pennsylvania, United States

Bethlehem, Pennsylvania, United States

Downingtown, Pennsylvania, United States

Duncansville, Pennsylvania, United States

Ephrata, Pennsylvania, United States

Harleysville, Pennsylvania, United States

Lansdale, Pennsylvania, United States

McMurray, Pennsylvania, United States

Philadelphia, Pennsylvania, United States

Quakertown, Pennsylvania, United States

Wyomissing, Pennsylvania, United States

Cumberland, Rhode Island, United States

East Providence, Rhode Island, United States

Providence, Rhode Island, United States

Anderson, South Carolina, United States

Charleston, South Carolina, United States

Columbia, South Carolina, United States

Greenville, South Carolina, United States

Greenwood, South Carolina, United States

Greer, South Carolina, United States

Myrtle Beach, South Carolina, United States

Orangeburg, South Carolina, United States

Pelzer, South Carolina, United States

Simpsonville, South Carolina, United States

Spartanburg, South Carolina, United States

Athens, Tennessee, United States

Chattanooga, Tennessee, United States

Clarksville, Tennessee, United States

Collierville, Tennessee, United States

Fayetteville, Tennessee, United States

Jackson, Tennessee, United States

Kingsport, Tennessee, United States

Memphis, Tennessee, United States

New Tazewell, Tennessee, United States

Bellaire, Texas, United States

Carrollton, Texas, United States

Dallas, Texas, United States

El Paso, Texas, United States

Fort Worth, Texas, United States

Grapevine, Texas, United States

Houston, Texas, United States

Irving, Texas, United States

McKinney, Texas, United States

New Braunfels, Texas, United States

Odessa, Texas, United States

Pearland, Texas, United States

Plano, Texas, United States

Richardson, Texas, United States

San Antonio, Texas, United States

Southlake, Texas, United States

Sugar Land, Texas, United States

Tomball, Texas, United States

Waco, Texas, United States

Bountiful, Utah, United States

Draper, Utah, United States

Salt Lake City, Utah, United States

West Jordan, Utah, United States

Alexandria, Virginia, United States

Arlington, Virginia, United States

Burke, Virginia, United States

Danville, Virginia, United States

McLean, Virginia, United States

Norfolk, Virginia, United States

Richmond, Virginia, United States

Salem, Virginia, United States

Virginia Beach, Virginia, United States

Port Orchard, Washington, United States

Tacoma, Washington, United States

Clarksburg, West Virginia, United States

Green Bay, Wisconsin, United States

Milwaukee, Wisconsin, United States

New Berlin, Wisconsin, United States

Oregon, Wisconsin, United States

Countries

United States; Mexico

References

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.

Reference Type: RESULT

PMID: 22795277 (View on PubMed)

White 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.

Reference Type: RESULT

PMID: 29527974 (View on PubMed)

Saag 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.

Reference Type: DERIVED

PMID: 35536764 (View on PubMed)

Fravel 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.

Reference Type: DERIVED

PMID: 21849262 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://general.takedapharm.com/content/file.aspx?applicationcode=6C7C39D8-5D09-453B-BF30-696A4AB88E62&fileTypeCode=ULORICPI

Uloric Package Insert

Other Identifiers

U1111-1114-4194

Identifier Type: REGISTRY

Identifier Source: secondary_id

TMX-67_301

Identifier Type: -

Identifier Source: org_study_id