Effect of Febuxostat Compared to Placebo on Exercise Tolerance in Participants With Chronic Stable Angina
Condition: Angina
MeSH terms: Angina Pectoris; Angina, Stable
Intervention: Febuxostat; Placebo
Intervention description: Febuxostat tablets; Febuxostat placebo-matching tablets
Intervention MeSH terms: Febuxostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Drug Therapy

Summary:

      The purpose of this study is to evaluate the effect of febuxostat, once daily (QD), compared
      to placebo as an add on to stable anti-anginal therapy, on the total exercise time of
      participants with Chronic Stable Angina.
    

Eligibility criteria:

        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/electrocardiogram
                       (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 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.