Effect of Febuxostat Compared to Placebo on Exercise Tolerance in Participants With Chronic Stable Angina

This is a phase 2 multicenter, randomized, placebo-controlled double-blind study. This study
is comprised of a single-blind placebo run-in qualifying phase lasting approximately 3 weeks
and a double-blind treatment phase lasting 12 weeks. A safety follow-up visit is scheduled
for 2 weeks after last dose of study drug.

All participants will undergo 3 visits during a 3 week, run-in phase (Days -21 to Day 1).
During the run-in phase, all participants will receive single-blind placebo. Two exercise
treadmill tests (ETTs) will be conducted using the modified Bruce Protocol at Day -14 and at
Day -7. The results from the Day -7 ETT will be considered as Baseline.

A total of approximately 100 participants will be randomized 1:1 to receive either
febuxostat 80 mg once daily (QD) or placebo QD in a double-blind treatment for 12 weeks, and
5 more visits.

All participants will complete the Seattle Angina Questionnaire (SAQ) and EQ-5D
quality-of-life measurements at Day 1, Week 6 and Week 12/Early Termination (ET) Visit. The
investigator will also rate the overall severity of the participants angina at each visit
based on the Canadian Cardiovascular Society Grading of Angina (CCSGA).

At the Week 6 and Week 12 visits, participants will undergo an ETT.

Inclusion Criteria:

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

2. The participant or, when applicable, the participant's legally acceptable
representative, signs and dates a written, informed consent form and any required
privacy authorization prior to the initiation of any study procedures.

3. The participant has an serum urate (sUA) ≥5.0 mg/dL.

4. The participant has a history of angina, defined as:

1. Minimum of 3-month history of stable angina (at least 2 episodes of chest pain
or anginal equivalent in the past 30 days); AND

2. Receiving at least one chronic anti-ischemic medication(s), including beta
blockers, calcium channel blockers and long acting nitrates (doses must be
stable for at least 30 days prior to Screening [Day -21]); AND

3. Coronary artery disease, as defined by:

- ≥50 % stenosis of ≥1 major coronary artery confirmed by angiography; OR

- Documented prior myocardial infarction (MI) by enzymes/ECG changes; OR

- Documented myocardial imaging stress test; OR

- Prior history of coronary artery bypass graft (CABG) or percutaneous
coronary intervention (PCI) greater than 3 months prior to Screening Day
-21.

5. The participant has estimated glomerular filtration rate (eGFR) >30 mL/min by
Modification of Diet in Renal Disease (MDRD) at the Screening visit Day -21.

6. The participant has a normal/controlled blood pressure at Day 1/Randomization, as
defined by the mean of three sitting blood pressures not exceeding 140/90.

7. The participant is male or female and aged 18 to 85 years, inclusive.

8. A female participant 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. Participant is on stable (30 days) medication doses prescribed for any underlying
medical condition (ie; hypertension, angina) and will remain on stable doses
throughout the study duration.

10. Participant is able to take, in an ongoing manner, nitroglycerine for anginal
symptoms.

11. Symptom-limited exercise duration, during ETT at Day -14 and Day -7, on the modified
Bruce Protocol.

12. Exercise duration for the two ETTs at Day -14 and Day -7 did not differ by more than
20% of the longer of the two times, and did not differ by more than 60 seconds. To be
confirmed by the Core ECG Lab prior to the subject being randomized.

13. Definite electrocardiogram (ECG) signs of ischemia during the ETT at both Day -14
and Day -7 (i.e., 1 additional mm of horizontal or down-sloping ST-segment depression
beyond baseline and ≥1 mm below the isoelectric line) are present in at least one
standard ECG lead during ETT. The Day -7 ≥1 mm ST-segment depression must be verified
by the Core ECG Lab prior to participant being randomized.

Exclusion Criteria:

1. The participant has received any investigational compound within 30 days prior to
Screening Day -21.

2. The participant has received allopurinol or febuxostat in a previous clinical study
or as a therapeutic agent.

3. The participant has gout or secondary hyperuricemia (e.g., due to myeloproliferative
disorder, or organ transplant) or has experienced a gout flare.

4. The participant has a history of xanthinuria.

5. The participant 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 (e.g., spouse, parent, child, sibling) or may consent under duress.

6. The participant has a history of hypersensitivity or allergies to febuxostat or
nitroglycerine.

7. The participant has hemoglobin <10 g/L at Screening Day -21.

8. The participant has a systolic blood pressure of less than 100 mmHg.

9. The participant has a blood pressure of greater than 200/100 at any Screening or
Run-in visit.

10. The participant has a history or clinical manifestations of a significant medical
condition that might affect his/her ability to complete the study.

11. The participant has any of the following at any Screening or Run-in visit:

1. Resting ST-segment depression ≥1 mm in any lead.

2. Left bundle-branch block.

3. New York Heart Association Class III or IV heart failure.

4. Acute coronary syndrome or a coronary revascularization procedure within 3
months of Screening.

5. Wolff-Parkinson-White syndrome.

6. Pacemaker or implantable cardioverter defibrillator.

7. Arrhythmias (i.e., SVT, atrial fibrillation/flutter, VT, or rate related bundle
branch blocks).

8. Left ventricular hypertrophy with repolarization abnormalities.

12. The participant has a recent history (within the last 3 months) of myocardial
infarction, heart failure, coronary artery bypass graft, percutaneous coronary
intervention, hypertensive encephalopathy, cerebrovascular accident, or transient
ischemic attack.

13. The participant 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).

14. The participant has unstable angina that:

1. Occurs when the participant 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 (i.e., does not go away after three doses of
nitroglycerin or returns after the nitroglycerin helped at first).

15. The participant is unable to exercise sufficiently to complete ETT due to leg
claudication, arthritis, deconditioning, or associated pulmonary disease.

16. The participant has severe or critical valvular disease documented by echocardiogram,
or congenital heart disease.

17. The participant has left ventricular ejection fraction (LVEF) less than 35%, as
documented by echocardiogram or angiography.

18. The participant has clinically significant cardiac conduction defects (i.e., second-
or third-degree atrioventricular block, sick sinus syndrome or a QTc >500 msec) at
Day -21.

19. The participant has active acute myocarditis/pericarditis within the 3 months prior
to Screening Day -21.

20. The participant has hypertrophic cardiomyopathy.

21. The participant 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.

22. 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.

23. The participant is required or expected to require excluded medications digoxin and
digoxin-containing compounds.

24. If female, the participant 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.

25. The participant has participated in another clinical study within the past 30 days.

26. The participant has a history of extracorporeal external counterpulsation treatment
for chronic stable angina within 3 months prior to screening visit.