Clinical trial NCT01101035: Cardiovascular Safety of Febuxostat and Allopurinol in Participants With Gout and Cardiovascular Comorbidities (CARES)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cardiovascular Disease
Keywords: Cardiovascular Outcomes
Heart Attack
Stroke
Drug Therapy
Physiology
Hyperuricemia
Uric Acid
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2010-04-09
Enrollment: 6198
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis)
timeFrame: Up to last dose of study drug (approximately 83 months)
measure: Percentage of Participants With Primary MACE Composite (Final Analysis)
timeFrame: Up to last dose of study drug (approximately 83 months)
Secondary outcomes:
measure: Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event
timeFrame: Up to last dose of study drug (approximately 83 months)
measure: Percentage of Participants With Cardiovascular (CV) Death
timeFrame: Up to last dose of study drug (approximately 83 months)
measure: Percentage of Participants With Non-fatal Myocardial Infarction (MI)
timeFrame: Up to last dose of study drug (approximately 83 months)
measure: Percentage of Participants With Non-fatal Stroke
timeFrame: Up to last dose of study drug (approximately 83 months)
measure: Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization
timeFrame: Up to last dose of study drug (approximately 83 months)
Other outcomes:
Locations:
city: Decatur
country: United States
state: Georgia
city: Dunwoody
country: United States
state: Georgia
city: Marietta
country: United States
state: Georgia
city: Norcross
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state: Georgia
city: Roswell
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state: Georgia
city: Suwanee
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state: Georgia
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state: Hawaii
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city: Coeur d'Alene
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state: Illinois
city: Arlington Heights
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city: Monroe
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city: Shreveport
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state: Maine
city: Rockport
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city: Baltimore
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city: Cumberland
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city: Fall River
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city: Worcester
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city: Ann Arbor
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country: United States
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city: Lincoln
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city: Edison
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city: Las Vegas
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city: Freeport
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city: Mineola
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city: New Windsor
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state: North Carolina
city: Cary
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city: Charlotte
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city: Columbia
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city: Greensboro
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city: Lenoir
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city: Monroe
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city: Raleigh
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city: Salisbury
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city: Kettering
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city: Lyndhurst
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city: Marion
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city: Mentor
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city: Middleburg Heights
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city: Toledo
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city: Willoughby Hills
country: United States
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city: Oklahoma City
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city: Philadelphia
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city: Cumberland
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city: East Providence
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city: Anderson
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city: Charleston
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city: Myrtle Beach
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city: Orangeburg
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city: Pelzer
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city: Simpsonville
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city: Athens
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city: Chattanooga
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city: Clarksville
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country: United States
state: Tennessee
city: Fayetteville
country: United States
state: Tennessee
city: Jackson
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state: Tennessee
city: Kingsport
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state: Tennessee
city: Memphis
country: United States
state: Tennessee
city: New Tazewell
country: United States
state: Tennessee
city: Bellaire
country: United States
state: Texas
city: Carrollton
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: El Paso
country: United States
state: Texas
city: Fort Worth
country: United States
state: Texas
city: Grapevine
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Irving
country: United States
state: Texas
city: McKinney
country: United States
state: Texas
city: New Braunfels
country: United States
state: Texas
city: Odessa
country: United States
state: Texas
city: Pearland
country: United States
state: Texas
city: Plano
country: United States
state: Texas
city: Richardson
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Southlake
country: United States
state: Texas
city: Sugar Land
country: United States
state: Texas
city: Tomball
country: United States
state: Texas
city: Waco
country: United States
state: Texas
city: Bountiful
country: United States
state: Utah
city: Draper
country: United States
state: Utah
city: Salt Lake City
country: United States
state: Utah
city: West Jordan
country: United States
state: Utah
city: Alexandria
country: United States
state: Virginia
city: Arlington
country: United States
state: Virginia
city: Burke
country: United States
state: Virginia
city: Danville
country: United States
state: Virginia
city: McLean
country: United States
state: Virginia
city: Norfolk
country: United States
state: Virginia
city: Richmond
country: United States
state: Virginia
city: Salem
country: United States
state: Virginia
city: Virginia Beach
country: United States
state: Virginia
city: Port Orchard
country: United States
state: Washington
city: Tacoma
country: United States
state: Washington
city: Clarksburg
country: United States
state: West Virginia
city: Green Bay
country: United States
state: Wisconsin
city: Milwaukee
country: United States
state: Wisconsin
city: New Berlin
country: United States
state: Wisconsin
city: Oregon
country: United States
state: Wisconsin
city: Verona
country: United States
state: Wisconsin
city: Waukesha
country: United States
state: Wisconsin
city: Weston
country: United States
state: Wisconsin
city: Jalisco
country: Mexico
state: Distrito Federal
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.