The purpose of this study is to assess the effect of febuxostat on coronary artery flow in patients with coronary artery disease.

The drug being tested in this study is called febuxostat. Febuxostat is being tested to treat people who have angina. This study will look at the heart and blood flow of people who take febuxostat.

The study will enroll approximately 30 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups (or sequences)-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

• Sequence 1: 6 weeks febuxostat followed by 6 weeks of placebo.
• Sequence 2: 6 week placebo followed by 6 weeks of febuxostat

All participants will be asked to take one capsule at the same time each day throughout the study. All participants will be asked to record any time they have angina symptoms during the study.

This single-center trial will be conducted in the United States. The overall time to participate in this study is 16 weeks. Participants will make 7 visits to the clinic including a final visit 4 weeks after last dose of study drug for a follow-up assessment.

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.

2. The participant signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

3. Has a serum urate ≥4.0 mg/dL.

4. Has a history of coronary artery disease, defined as:

   1. ≥50 % stenosis of ≥1 major coronary artery confirmed by angiography; OR
   2. Documented prior myocardial infarction (MI) by enzymes/electrocardiogram (ECG) changes; OR
   3. Documented prior exercise or pharmacologic stress/echo myocardial imaging study positive for ischemia.

5. Has estimated glomerular filtration rate (eGFR) ≥30 mL/min by Modification of Diet in Renal Disease (MDRD) at the screening visit.

6. Has a change in coronary artery flow from rest to isometric handgrip exercise of less than + 10 mL/min.

7. Is male or female and aged 18 to 85 years, inclusive.

8. A female of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study.

9. Is on stable (30 days prior to Screening Day-21) medication doses prescribed for any underlying medical condition (ie, hypertension, angina) and is expected to remain on stable doses throughout the study duration.

10. Is able to take nitroglycerin for anginal symptoms during study procedures.

Exclusion Criteria:

1. Has received any investigational compound within 30 days prior to Screening.

2. Has received allopurinol or febuxostat in a previous clinical study or as a therapeutic agent with-in 6 months of randomization.

3. Has gout or secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ transplant) or has experienced a gout flare.

4. Has a history of xanthinuria.

5. Has known contraindication to magnetic resonance imaging (MRI) scanning

6. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

7. Has a history of hypersensitivity or allergies to febuxostat or nitroglycerin.

8. Has hemoglobin <10 g/L at Screening.

9. Has a history or clinical manifestations of a significant medical condition that might affect his/her ability to complete the study.

10. Has any of the following during Screening:

    1. New York Heart Association Class III or IV heart failure.
    2. Acute coronary syndrome or a coronary revascularization procedure within 2 months of Screening.
    3. Wolff-Parkinson-White syndrome.
    4. Pacemaker or implantable cardioverter defibrillator.
    5. Arrhythmias (ie, supraventricular tachycardia (SVT), atrial fibrillation/flutter, or ventricular tachycardia (VT) during Screening).

11. Has a recent history (within the last 2 months prior to Screening) of acute coronary syndrome or a coronary revascularization procedure, MI, heart failure, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.

12. Has a contraindication for using nitrates (severe anemia, increased intracranial pressure, and those with a known sensitivity or hypersensitivity to nitroglycerin or its ingredients, or other nitrates or nitrites; concomitant use either regularly and/or intermittently, with phosphodiesterase type 5 (PDE5) inhibitors).

13. Has unstable angina that:

    1. Occurs when the patient is at rest.
    2. Is prolonged, usually greater than 20 minutes.
    3. Occurs with increasing in intensity, duration, and/or frequency.
    4. Responds poorly to nitroglycerin (ie, does not go away after three doses of nitroglycerin or returns after the nitroglycerin helped at first).

14. Is unable to exercise sufficiently to complete exercise treadmill test (ETT) due to leg claudication, arthritis, deconditioning, or associated pulmonary disease.

15. Has severe or critical valvular disease documented by echocardiogram, or congenital heart disease.

16. The subject has left ventricular ejection fraction (LVEF) less than 35%, as documented by echocardiogram, left ventriculogram, or gated blood pool scan..

17. The subject has clinically significant cardiac conduction defects (ie, second- or third-degree atrioventricular block, or sick sinus syndrome) at Screening

18. Has hypertrophic cardiomyopathy.

19. Has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level of greater than 2.0 times the upper limit of normal, has active liver disease, or jaundice.

20. 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.

21. Is required or expected to require excluded medications including digoxin or digoxin-containing compounds.

22. If female, is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.

23. Has participated in another clinical trial within the past 30 days.

All participants

First dose of study drug to up to 30 days after the last dose of study drug (Up to 16 Weeks)

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.