Cardiovascular Safety of Febuxostat and Allopurinol in Participants With Gout and Cardiovascular Comorbidities (CARES)
Condition: Cardiovascular Disease
MeSH terms: Cardiovascular Diseases
Intervention: Febuxostat; Allopurinol
Intervention description: Febuxostat tablets; Allopurinol tablets
Intervention MeSH terms: Allopurinol; Febuxostat
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 6198.0
Sex: All
Minimum age: 50 Years
Healthy volunteers: No
Keywords: Cardiovascular Outcomes; Heart Attack; Stroke; Drug Therapy; Physiology; Hyperuricemia; Uric Acid

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).
    

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.