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

Inclusion Criteria

• 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.
• 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

Exclusion Criteria

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 f