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Cardiovascular DiseasePhase 3CARESNCT01101035

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

A Phase 3 study testing Febuxostat and Allopurinol in people with Cardiovascular Disease, run by Takeda at 203 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 50 years and older
Conditions the study is for
Cardiovascular Disease
What is being tested?
Febuxostat and Allopurinol
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
6,198 participants
Where
203 sitesin 2 countries
Study dates
23 Apr 2010to 18 Jul 2017
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 50 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

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

Who cannot join

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

Trial locations and contacts

203 sites in 2 countries.

203 sites in 2 countries

United States202 sites

  • Study site

    Addison, Illinois

  • Study site

    Akron, Ohio

  • Study site

    Albuquerque, New Mexico

  • Study site

    Alexandria, Virginia

  • Study site

    Altoona, Pennsylvania

  • Study site

    Anderson, South Carolina

  • Study site

    Ann Arbor, Michigan

  • Study site

    Arlington, Virginia

  • Study site

    Arlington Heights, Illinois

  • Study site

    Asheboro, North Carolina

  • Study site

    Ashland, Oregon

  • Study site

    Athens, Tennessee

  • Study site

    Baltimore, Maryland

  • Study site

    Bellaire, Texas

  • Study site

    Bellevue, Nebraska

  • Study site

    Bend, Oregon

  • Study site

    Bensalem, Pennsylvania

  • Study site

    Bethlehem, Pennsylvania

  • Study site

    Biddeford, Maine

  • Study site

    Billings, Montana

  • Study site

    Bingham Farms, Michigan

  • Study site

    Bloomington, Indiana

  • Study site

    Boise, Idaho

  • Study site

    Bountiful, Utah

  • Study site

    Brick, New Jersey

  • Study site

    Brockton, Massachusetts

  • Study site

    Brownsburg, Indiana

  • Study site

    Burke, Virginia

  • Study site

    Butte, Montana

  • Study site

    Carrollton, Texas

  • Study site

    Cary, North Carolina

  • Study site

    Centerville, Ohio

  • Study site

    Charleston, South Carolina

  • Study site

    Charlotte, North Carolina

  • Study site

    Chaska, Minnesota

  • Study site

    Chattanooga, Tennessee

  • Study site

    Chelsea, Michigan

  • Study site

    Cincinnati, Ohio

  • Study site

    Clarksburg, West Virginia

  • Study site

    Clarkson Valley, Missouri

  • Study site

    Clarksville, Tennessee

  • Study site

    Coeur d'Alene, Idaho

  • Study site

    Collierville, Tennessee

  • Study site

    Columbia, North Carolina

  • Study site

    Columbia, South Carolina

  • Study site

    Columbus, Ohio

  • Study site

    Cumberland, Maryland

  • Study site

    Cumberland, Rhode Island

  • Study site

    Dallas, Texas

  • Study site

    Danville, Virginia

  • Study site

    Dayton, Ohio

  • Study site

    Decatur, Georgia

  • Study site

    Delaware, Ohio

  • Study site

    Detroit, Michigan

  • Study site

    Downingtown, Pennsylvania

  • Study site

    Draper, Utah

  • Study site

    Duluth, Minnesota

  • Study site

    Duncansville, Pennsylvania

  • Study site

    Dunwoody, Georgia

  • Study site

    East Providence, Rhode Island

  • Study site

    Edina, Minnesota

  • Study site

    Edison, New Jersey

  • Study site

    El Paso, Texas

  • Study site

    Elizabethtown, Kentucky

  • Study site

    Endwell, New York

  • Study site

    Ephrata, Pennsylvania

  • Study site

    Eugene, Oregon

  • Study site

    Evanston, Illinois

  • Study site

    Evergreen Park, Illinois

  • Study site

    Fall River, Massachusetts

  • Study site

    Fargo, North Dakota

  • Study site

    Fayetteville, Tennessee

  • Study site

    Flint, Michigan

  • Study site

    Flossmoor, Illinois

  • Study site

    Fort Worth, Texas

  • Study site

    Franklin, Ohio

  • Study site

    Freeport, New York

  • Study site

    Glens Falls, New York

  • Study site

    Grand Island, Nebraska

  • Study site

    Grapevine, Texas

  • Study site

    Green Bay, Wisconsin

  • Study site

    Greensboro, North Carolina

  • Study site

    Greenville, South Carolina

  • Study site

    Greenwood, South Carolina

  • Study site

    Greer, South Carolina

  • Study site

    Hagerstown, Maryland

  • Study site

    Harleysville, Pennsylvania

  • Study site

    Hazelwood, Missouri

  • Study site

    Henderson, Nevada

  • Study site

    Honolulu, Hawaii

  • Study site

    Houston, Texas

  • Study site

    Huntersville, North Carolina

  • Study site

    Hyannis, Massachusetts

  • Study site

    Iowa City, Iowa

  • Study site

    Irving, Texas

  • Study site

    Jackson, Mississippi

  • Study site

    Jackson, Tennessee

  • Study site

    Kalamazoo, Michigan

  • Study site

    Kansas City, Missouri

  • Study site

    Kettering, Ohio

  • Study site

    Kingsport, Tennessee

  • Study site

    Lafayette, Indiana

  • Study site

    Lansdale, Pennsylvania

  • Study site

    Lansing, Michigan

  • Study site

    Las Vegas, Nevada

  • Study site

    Las Vegas, New Mexico

  • Study site

    Lenexa, Kansas

  • Study site

    Lenoir, North Carolina

  • Study site

    Lexington, Kentucky

  • Study site

    Lincoln, Nebraska

  • Study site

    Lutherville, Maryland

  • Study site

    Lyndhurst, Ohio

  • Study site

    Marietta, Georgia

  • Study site

    Marion, Ohio

  • Study site

    McKinney, Texas

  • Study site

    McLean, Virginia

  • Study site

    McMurray, Pennsylvania

  • Study site

    Melrose Park, Illinois

  • Study site

    Memphis, Tennessee

  • Study site

    Mentor, Ohio

  • Study site

    Mer Rouge, Louisiana

  • Study site

    Middleburg Heights, Ohio

  • Study site

    Milwaukee, Wisconsin

  • Study site

    Mineola, New York

  • Study site

    Monroe, Louisiana

  • Study site

    Monroe, North Carolina

  • Study site

    Morton, Illinois

  • Study site

    Myrtle Beach, South Carolina

  • Study site

    Nampa, Idaho

  • Study site

    Naperville, Illinois

  • Study site

    New Berlin, Wisconsin

  • Study site

    New Braunfels, Texas

  • Study site

    New Tazewell, Tennessee

  • Study site

    New Windsor, New York

  • Study site

    New York, New York

  • Study site

    Norcross, Georgia

  • Study site

    Norfolk, Virginia

  • Study site

    Odessa, Texas

  • Study site

    Oklahoma City, Oklahoma

  • Study site

    Olive Branch, Mississippi

  • Study site

    Omaha, Nebraska

  • Study site

    Oradell, New Jersey

  • Study site

    Orangeburg, South Carolina

  • Study site

    Oregon, Wisconsin

  • Study site

    Overland Park, Kansas

  • Study site

    Owensboro, Kentucky

  • Study site

    Paducah, Kentucky

  • Study site

    Pearland, Texas

  • Study site

    Pelzer, South Carolina

  • Study site

    Philadelphia, Pennsylvania

  • Study site

    Plano, Texas

  • Study site

    Port Gibson, Mississippi

  • Study site

    Port Orchard, Washington

  • Study site

    Portland, Oregon

  • Study site

    Providence, Rhode Island

  • Study site

    Quakertown, Pennsylvania

  • Study site

    Quincy, Illinois

  • Study site

    Raleigh, North Carolina

  • Study site

    Reno, Nevada

  • Study site

    Richardson, Texas

  • Study site

    Richmond, Virginia

  • Study site

    Rochester, New York

  • Study site

    Rockford, Illinois

  • Study site

    Rockport, Maine

  • Study site

    Roswell, Georgia

  • Study site

    Saint Charles, Missouri

  • Study site

    Saint Paul, Minnesota

  • Study site

    Salem, Virginia

  • Study site

    Salisbury, North Carolina

  • Study site

    Salt Lake City, Utah

  • Study site

    San Antonio, Texas

  • Study site

    Shelby, North Carolina

  • Study site

    Shreveport, Louisiana

  • Study site

    Simpsonville, South Carolina

  • Study site

    Southlake, Texas

  • Study site

    Spartanburg, South Carolina

  • Study site

    St Louis, Missouri

  • Study site

    Sugar Land, Texas

  • Study site

    Suwanee, Georgia

  • Study site

    Tacoma, Washington

  • Study site

    Toledo, Ohio

  • Study site

    Tomball, Texas

  • Study site

    Topeka, Kansas

  • Study site

    Tulsa, Oklahoma

  • Study site

    Valparaiso, Indiana

  • Study site

    Verona, Wisconsin

  • Study site

    Virginia Beach, Virginia

  • Study site

    Waco, Texas

  • Study site

    Washington, Missouri

  • Study site

    Waukesha, Wisconsin

  • Study site

    Waycross, Georgia

  • Study site

    West Jordan, Utah

  • Study site

    West Seneca, New York

  • Study site

    Westfield, New York

  • Study site

    Weston, Wisconsin

  • Study site

    Wheaton, Maryland

  • Study site

    Wichita, Kansas

  • Study site

    Willoughby Hills, Ohio

  • Study site

    Wilmington, North Carolina

  • Study site

    Winston-Salem, North Carolina

  • Study site

    Worcester, Massachusetts

  • Study site

    Wyomissing, Pennsylvania

Other trials in United States

Mexico1 site

  • Study site

    Jalisco, Mexico City

Other trials in Mexico

About this study

Official title: A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the Cardiovascular Safety of Febuxostat and Allopurinol in Subjects With Gout and Cardiovascular Comorbidities

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).

Read the 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.

Being tested
Febuxostat, Allopurinol
Keywords
Cardiovascular Outcomes, Heart Attack, Stroke, Drug Therapy, Physiology, Hyperuricemia, Uric Acid
Medical subject headings
Cardiovascular Diseases, Myocardial Infarction, Stroke, Hyperuricemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • FebuxostatDrug

    Also called Uloric, TMX-67

    Febuxostat tablets

  • AllopurinolDrug

    Also called Zyloprim, Allohexal, Allosig, Milurit

    Allopurinol tablets

Study groups in NCT01101035
Study groupRoleWhat they receive
FebuxostatExperimentalFebuxostat 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.
Receives: Drug: Febuxostat
AllopurinolActive 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).
Receives: Drug: Allopurinol

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to last dose of study drug (approximately 83 months)

  2. 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.

    Measured: Up to last dose of study drug (approximately 83 months)

Secondary outcomes (5)

  1. Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event

    APTC events were defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke; these events were adjudicated by an independent cardiovascular endpoints committee.

    Measured: Up to last dose of study drug (approximately 83 months)

  2. Percentage of Participants With Cardiovascular (CV) Death

    Events were adjudicated by an independent cardiovascular endpoints committee as CV death.

    Measured: Up to last dose of study drug (approximately 83 months)

  3. Percentage of Participants With Non-fatal Myocardial Infarction (MI)

    Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal MI.

    Measured: Up to last dose of study drug (approximately 83 months)

  4. Percentage of Participants With Non-fatal Stroke

    Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal stroke.

    Measured: Up to last dose of study drug (approximately 83 months)

  5. Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization

    Events were adjudicated by an independent cardiovascular endpoints committee as unstable angina with urgent coronary revascularization.

    Measured: Up to last dose of study drug (approximately 83 months)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Apr 2010 (estimated)
  2. Study start23 Apr 2010
  3. Primary completion15 May 2017
  4. Study completion18 Jul 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
6,198 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01101035
Sponsor's protocol ID
TMX-67_301
Other IDs
U1111-1114-4194
Acronym
CARES
Status last verified
Jun 2018
First submitted
7 Apr 2010
Last updated
14 Jun 2018
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 22795277

  • 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.

    PubMed 29527974

  • 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.

    PubMed 35536764

  • 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.

    PubMed 21849262

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Febuxostat and Allopurinol in people with Cardiovascular Disease, run by Takeda at 203 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 30 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 203 sites in United States, Mexico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 14 Jun 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis) (time frame: Up to last dose of study drug (approximately 83 months)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01101035, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jun 2018.

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