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

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ClinicalTrials.gov Identifier: NCT01101035
Recruitment Status : Completed
First Posted : April 9, 2010
Results First Posted : June 14, 2018
Last Update Posted : June 14, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda

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).

Condition or disease Intervention/treatment Phase
Cardiovascular Disease Drug: Febuxostat Drug: Allopurinol Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6198 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : April 23, 2010
Actual Primary Completion Date : May 15, 2017
Actual Study Completion Date : July 18, 2017

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Gout
MedlinePlus related topics: Gout

Arm Intervention/treatment
Experimental: 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.
Drug: Febuxostat
Febuxostat tablets
Other Names:
  • Uloric
  • TMX-67

Active Comparator: 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).
Drug: Allopurinol
Allopurinol tablets
Other Names:
  • Zyloprim
  • Allohexal
  • Allosig
  • Milurit
  • Alloril
  • Progout
  • Zyloric
  • Puricos
  • Zyrik 300
  • Aluron




Primary Outcome Measures :
  1. 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) ]
    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.

  2. Percentage of Participants With Primary MACE Composite (Final Analysis) [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    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.


Secondary Outcome Measures :
  1. Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    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.

  2. Percentage of Participants With Cardiovascular (CV) Death [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    Events were adjudicated by an independent cardiovascular endpoints committee as CV death.

  3. Percentage of Participants With Non-fatal Myocardial Infarction (MI) [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal MI.

  4. Percentage of Participants With Non-fatal Stroke [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal stroke.

  5. Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    Events were adjudicated by an independent cardiovascular endpoints committee as unstable angina with urgent coronary revascularization.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01101035


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Locations
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United States, Georgia
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
United States, Hawaii
Honolulu, Hawaii, United States
United States, Idaho
Boise, Idaho, United States
Coeur d'Alene, Idaho, United States
Nampa, Idaho, United States
United States, Illinois
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
United States, Indiana
Bloomington, Indiana, United States
Brownsburg, Indiana, United States
Lafayette, Indiana, United States
Valparaiso, Indiana, United States
United States, Iowa
Iowa City, Iowa, United States
United States, Kansas
Lenexa, Kansas, United States
Overland Park, Kansas, United States
Topeka, Kansas, United States
Wichita, Kansas, United States
United States, Kentucky
Elizabethtown, Kentucky, United States
Lexington, Kentucky, United States
Owensboro, Kentucky, United States
Paducah, Kentucky, United States
United States, Louisiana
Mer Rouge, Louisiana, United States
Monroe, Louisiana, United States
Shreveport, Louisiana, United States
United States, Maine
Biddeford, Maine, United States
Rockport, Maine, United States
United States, Maryland
Baltimore, Maryland, United States
Cumberland, Maryland, United States
Hagerstown, Maryland, United States
Lutherville, Maryland, United States
Wheaton, Maryland, United States
United States, Massachusetts
Brockton, Massachusetts, United States
Fall River, Massachusetts, United States
Hyannis, Massachusetts, United States
Worcester, Massachusetts, United States
United States, Michigan
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
United States, Minnesota
Chaska, Minnesota, United States
Duluth, Minnesota, United States
Edina, Minnesota, United States
Saint Paul, Minnesota, United States
United States, Mississippi
Jackson, Mississippi, United States
Olive Branch, Mississippi, United States
Port Gibson, Mississippi, United States
United States, Missouri
Clarkson Valley, Missouri, United States
Hazelwood, Missouri, United States
Kansas City, Missouri, United States
Saint Charles, Missouri, United States
Saint Louis, Missouri, United States
Washington, Missouri, United States
United States, Montana
Billings, Montana, United States
Butte, Montana, United States
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Bellevue, Nebraska, United States
Grand Island, Nebraska, United States
Lincoln, Nebraska, United States
Omaha, Nebraska, United States
United States, Nevada
Henderson, Nevada, United States
Las Vegas, Nevada, United States
Reno, Nevada, United States
United States, New Jersey
Brick, New Jersey, United States
Edison, New Jersey, United States
Oradell, New Jersey, United States
United States, New Mexico
Albuquerque, New Mexico, United States
Las Vegas, New Mexico, United States
United States, New York
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
United States, North Carolina
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
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Wilmington, North Carolina, United States
Winston-Salem, North Carolina, United States
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Fargo, North Dakota, United States
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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
United States, Oklahoma
Oklahoma City, Oklahoma, United States
Tulsa, Oklahoma, United States
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Ashland, Oregon, United States
Bend, Oregon, United States
Eugene, Oregon, United States
Portland, Oregon, United States
United States, Pennsylvania
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
United States, Rhode Island
Cumberland, Rhode Island, United States
East Providence, Rhode Island, United States
Providence, Rhode Island, United States
United States, South Carolina
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
United States, Tennessee
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
United States, Texas
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
United States, Utah
Bountiful, Utah, United States
Draper, Utah, United States
Salt Lake City, Utah, United States
West Jordan, Utah, United States
United States, Virginia
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
United States, Washington
Port Orchard, Washington, United States
Tacoma, Washington, United States
United States, West Virginia
Clarksburg, West Virginia, United States
United States, Wisconsin
Green Bay, Wisconsin, United States
Milwaukee, Wisconsin, United States
New Berlin, Wisconsin, United States
Oregon, Wisconsin, United States
Verona, Wisconsin, United States
Waukesha, Wisconsin, United States
Weston, Wisconsin, United States
Mexico
Jalisco, Distrito Federal, Mexico
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Medical Director Takeda
  Study Documents (Full-Text)

Documents provided by Takeda:
Study Protocol  [PDF] August 27, 2013
Statistical Analysis Plan  [PDF] February 22, 2017


Additional Information:
Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01101035     History of Changes
Other Study ID Numbers: TMX-67_301
U1111-1114-4194 ( Registry Identifier: WHO )
First Posted: April 9, 2010    Key Record Dates
Results First Posted: June 14, 2018
Last Update Posted: June 14, 2018
Last Verified: June 2018
Keywords provided by Takeda:
Cardiovascular Outcomes
Heart Attack
Stroke
Drug Therapy
Physiology
Hyperuricemia
Uric Acid
Additional relevant MeSH terms:
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Gout Suppressants
Cardiovascular Diseases
Allopurinol
Febuxostat
Uric Acid
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Antirheumatic Agents
Free Radical Scavengers
Antioxidants
Protective Agents
Physiological Effects of Drugs