The Influence of Febuxostat on Coronary Artery Endothelial Dysfunction in Participants With Chronic Stable Angina

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.