Please select the eligibility criteria that correspond to the clinical trial below.
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
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).


Options:
A: Inclusion Criteria:

* Subject is able to understand the study procedures, the risks involved and willing to provide written informed consent before the first study related activity.
* Subject meets the diagnosis of gout as per the American Rheumatism Association Criteria for the Classification of Acute Arthritis of Primary Gout.
* Subject has been taking allopurinol as the sole urate-lowering therapy indicated for the treatment of gout for at least 8 weeks prior to the Screening Visit at a stable, medically appropriate dose, as determined by the investigator, of at least 300 mg per day (at least 200 mg for subjects with moderate renal impairment).
* Subject must be able to take gout flare prophylaxis with colchicine or an NSAID (including Cox-2 selective NSAID) ±PPI.
* Subject has an sUA level ≥ 6.5 mg/dL at the Screening Visit and ≥ 6.0 mg/dL at Day -7 Visit.
* Subject has reported at least 2 gout flares in the prior 12 months.
* Body mass index (BMI) \< 45 kg/m2

Exclusion Criteria:

* Subject with known hypersensitivity or allergy to allopurinol.
* Subject who is taking any other approved urate-lowering medication that is indicated for the treatment of gout other than allopurinol within 8 weeks of the Screening Visit.
* Subject who is pregnant or breastfeeding.
* Subject who consumes more than 14 drinks of alcohol per week (eg, 1 drink = 5 oz \[150 mL\] of wine, 12 oz \[360 mL\] of beer, or 1.5 oz \[45 mL\] of hard liquor).
* Subject with a history or suspicion of drug abuse within the past 5 years.
* Subject that requires or may require systemic immunosuppressive or immunomodulatory treatment.
* Subject with known or suspected human immunodeficiency virus (HIV) infection.
* Subject with a positive test for active hepatitis B or hepatitis C infection.
* Subject with a history of malignancy within the previous 5 years with the exception of non-melanoma skin cancer that has been treated with no evidence of recurrence, treated cervical dysplasia or treated in situ Grade 1 cervical cancer.
* Subject within the last 12 months with: unstable angina, New York Heart Association class III or IV heart failure, myocardial infarction, stroke, or deep venous thrombosis; or subjects currently receiving anticoagulants.
* Subject with uncontrolled hypertension.
* Subject with an estimated creatinine clearance \< 30 mL/min.
* Subject with active peptic ulcer disease requiring treatment.
* Subject with a history of xanthinuria, active liver disease, or hepatic dysfunction.
* Subject receiving chronic treatment with more than 325 mg of salicylates per day.
* Subject taking valpromide, progabide, or valproic acid.
* Subject who has received an investigational therapy within 8 weeks or 5 half-lives (whichever is longer) prior to the Screening Visit.
* Subject with any other medical or psychological condition, which might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements, or to complete the study.
B: Inclusion Criteria:

* Subject is able to understand the study procedures, the risks involved and willing to provide written informed consent before the first study related activity.
* Subject meets the diagnosis of gout as per the American Rheumatism Association Criteria for the Classification of Acute Arthritis of Primary Gout.
* Subject has been taking allopurinol as the sole urate-lowering therapy indicated for the treatment of gout for at least 8 weeks prior to the Screening Visit at a stable, medically appropriate dose, as determined by the investigator, of at least 300 mg per day (at least 200 mg for subjects with moderate renal impairment).
* Subject must be able to take gout flare prophylaxis with colchicine or an Nonsteroidal anti-inflammatory drug (NSAID) (including Cox-2 selective NSAID) ± PPI.
* Subject has an sUA level ≥ 6.5 mg/dL at the Screening Visit and ≥ 6.0 mg/dL at Day -7 Visit.
* Subject has reported at least 2 gout flares in the prior 12 months.
* Body mass index (BMI) \< 45 kg/m2

Exclusion Criteria:

* Subject with known hypersensitivity or allergy to allopurinol.
* Subject who is taking any other approved urate-lowering medication that is indicated for the treatment of gout other than allopurinol within 8 weeks of the Screening Visit.
* Subject who is pregnant or breastfeeding.
* Subject who consumes more than 14 drinks of alcohol per week (eg, 1 drink = 5 oz \[150 mL\] of wine, 12 oz \[360 mL\] of beer, or 1.5 oz \[45 mL\] of hard liquor).
* Subject with a history or suspicion of drug abuse within the past 5 years.
* Subject that requires or may require systemic immunosuppressive or immunomodulatory treatment.
* Subject with known or suspected human immunodeficiency virus (HIV) infection.
* Subject with a positive test for active hepatitis B or hepatitis C infection.
* Subject with a history of malignancy within the previous 5 years with the exception of non-melanoma skin cancer that has been treated with no evidence of recurrence, treated cervical dysplasia or treated in situ Grade 1 cervical cancer.
* Subject within the last 12 months with: unstable angina, New York Heart Association class III or IV heart failure, myocardial infarction, stroke, or deep venous thrombosis; or subjects currently receiving anticoagulants.
* Subject with uncontrolled hypertension.
* Subject with an estimated creatinine clearance \< 30 mL/min.
* Subject with active peptic ulcer disease requiring treatment.
* Subject with a history of xanthinuria, active liver disease, or hepatic dysfunction.
* Subject receiving chronic treatment with more than 325 mg of salicylates per day.
* Subject taking valpromide, progabide, or valproic acid.
* Subject who has received an investigational therapy within 8 weeks or 5 half-lives (whichever is longer) prior to the Screening Visit.
* Subject with any other medical or psychological condition, which might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements, or to complete the study.
C: 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.
D: Inclusion Criteria:

* Age 18 years
* History of gout - crystal proven or historical as defined by ACR criteria listed above
* Serum urate level \> 6.8 mg/dl

Exclusion Criteria:

* Stage 4 or 5 Chronic Kidney Disease (CKD) - defined as eGFR \< 30 ml/min/1.73 m2
* Women less than 50 years of age
* Patients with a history of prior solid organ / hematopoietic transplantation
* Previous allergy or intolerance to allopurinol or febuxostat
* Patients who are not candidates for any of the recommended prophylactic medications (colchicine, naprosyn or glucocorticoids)
* Patients who in the opinion of the investigator have a high genetic risk for allopurinol hypersensitivity syndrome (AHS\*) unless they have been found to be negative for HLA B5801.
* Previous history of failure to reach target uric acid levels despite therapy with allopurinol at dose \> 300 mg/day
* Prior febuxostat use
* Patients with malignancies that are currently active with exception of non-melanoma skin cancer
* Patients with serum uric acid levels \>15 mg/dl
* Patients with myelodysplasia and hemoglobin of \< 8.5 mg/dL
* Patients with chronic liver disease with more than one of the following:

  * INR \> 1.7, not on Warfarin therapy
  * Bilirubin 2 mg/dL
  * Serum albumin \< 3.5 mg/dL
  * Ascites
  * Encephalopathy
* Current use of azathioprine, mercaptopurine, didanosine, cyclophosphamide, probenecid, lesinurad or pegloticase
* Enrollment in another randomized interventional clinical trial
* Any severe medical condition that, in the enrolleer's opinion, is likely to compromise the participant's ability to complete the trial

Answer: C