Inclusion Criteria:
1. Willing to participate and sign a written informed consent
2. Males and females ≥ 18 and ≤90 years old.
3. Medical history of chronic stable angina triggered by physical effort and relieved by rest or sublingual nitroglycerin.
4. Patients who agree and in the opinion of the investigator are able to withdraw all non-beta blocker and all non-calcium channel blocker anti-anginal medications. For those subjects who are on beta blockers and/or calcium channel blockers, they are able to keep only one beta blocker or one calcium channel blocker (acceptable calcium channel blocker: amlodipine, diltiazem, verapamil or nicardipine), but not both, and subjects agree and are expected to be able to remain on this treatment regimen from Day -21 until the completion of the double-blind period in the opinion of the investigator.
4.1) For patients who have to modify their anti-anginal treatment regimen to meet the above qualification criteria, health care provider who is responsible for the patient's cardiac care (if this is not the study doctor) must provide a form of agreement (verbal conversation, phone call, in writing or shown as referral) to the PI before the treatment modification.
4.2) For patients who are not on beta blocker or calcium channel blocker or other antianginal medications, there is no requirement to start on antianginal medication.
\*nitroglycerin tablets, only those provided by sponsor, are allowed to be used for on-demand symptomatic relief of angina during the qualifying and treatment periods to ensure an accurate calculation of consumption.
5. Documented history of coronary artery disease with one or more of the following conditions:
5.1) History of previous myocardial infarction (previous MI that occurred and was diagnosed at least 3 months prior to start of screening).
5.2) Ischemic heart disease determined by stress myocardial imaging examination (including nuclear stress test, cardiac stress MRI and echocardiography stress test).
5.3) Clinically significant coronary stenosis ≥50% in any vessel detected by coronary angiography (or coronary CT angiography).
6. Understand and be willing, able and likely to comply with all study procedures and restrictions and comprehends the Seattle Angina Questionnaire rating scales and diary cards.
7. Women of child bearing potential: Female patients of child-bearing potential or male patients with partners of child-bearing potential must use appropriate birth control from the start of screening, until 3 months after the last dose of study medication. Female patients of child bearing potential must have negative pregnancy tests at screening visit \[Day -21, quantitative serum human chorionic gonadotropin (β-hCG test)\] and randomization visit (Day 1, urine pregnancy test).
8. Patient must experience two or more angina episodes from Day-14 to Day 1, as the baseline frequency of angina. At least two of the angina episodes must be recorded by WCM (Other written forms of recording/reporting angina episodes may be acceptable only in situations and times that recording by WCM is impractical. In addition, patients are allowed to use short acting nitroglycerin for relief of angina).
9. To be qualified, patients must have two qualifying ETTs on standard Bruce protocol on Day- 7 and Day 1. The qualifying ETTs are:
1. ETTs must meet the positive ETT criteria;
2. Total exercise duration (TED) of the positive ETT is between 3-12 minutes of exercise;
3. The difference in TED between the two ETTs must not exceed 15% of the longer one.
* For the qualifying ETTs, in patients with permitted baseline ST-segment depression at rest (\<1 mm at 80 msec after the J point), qualifying ST-segment depression during ETT will be defined as additional ST-segment depression ≥1 mm (at 80 msec after the J point) below the resting value.
Exclusion Criteria:
1. Patients with only non-cardiac chest pain or cardiac chest pain not related to angina.
2. Patients with contraindication to, unable to, or with other co-morbidities that may prevent or interfere with the ability to perform ETT, in the opinion of investigator, including but not limited to: hospitalization for acute exacerbation of chronic lung disease within 4 weeks prior to the start of screening, current home oxygen use, needs for cardiac glycoside therapy, functionally limiting peripheral arterial disease, physical disability or other intercurrent illness such as acute respiratory infection/illness that, in the opinion of the Investigator or Sub-investigator, may interfere with the ability to perform ETT.
3. Patients with presence of electrographic or other abnormalities/factors that could interfere with exercise ECG interpretation or may lead to a false positive stress test (including but not limited to, Lown-Ganong-Levine Syndrome (LGL), Wolff-Parkinson-White Syndrome (WPW), left bundle branch block, ≥1 mm ST segment depression at rest, pacemaker rhythm etc.).
\*Left ventricular hypertrophy (LVH) without repolarization abnormalities is not considered an exclusion criterion.
4. Patients with history of any coronary revascularization procedure (e.g. PCI or CABG) within 2 months prior to the start of screening.
5. Patients who had unstable angina, or myocardial infarction within the recent 3 months prior to the start of screening.
6. Patients with ongoing NYHA Classes III-IV congestive heart failure.
7. Patients with angina pectoris at rest at screening.
8. Patients with rapid atrial fibrillation at screening (rest heart rate \>120/min) or any time prior to randomization from Day -21.
9. Patients with ongoing myocarditis, pericarditis, thrombophlebitis or pulmonary embolism or who have recovered from these conditions \<1 month prior to screening. Note: Patients who are on anticoagulant prophylaxis just for a pulmonary embolism or thrombophlebitis will not be subject to the one-month restriction.
10. Patient with uncontrolled hypertension characterized by seated systolic blood pressure \>180mm Hg or diastolic blood pressure \>100mm Hg, within 2 months prior to, or during, the Single Blind Qualifying Period. Or patients with severe congenital cardiac defects, severe valvular disease, suspected or known dissecting aortic aneurysm and hypertrophic cardiomyopathy should be excluded.
11. Patients with hemoglobin (HGB) \<10 g/dL, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2×upper limit of normal (ULN), hemoglobin A1C (HbA1C) \>10%, or glomerular filtration rate (GFR) \<30cc/min, in any of the single blind qualifying lab tests.
12. Patient with history of bleeding diathesis or cerebral hemorrhage or seizure disorder that need anticonvulsant.
13. Patients who have to be on ranolazine, ivabradine or calcium channel blockers other than, amlodipine, verapamil, nicardipine or diltiazem, and patients who have to be on more than one beta blockers and/or calcium channel blockers, or other anti-anginal agent other than only sublingual nitroglycerin for on-demand angina relief.
14. Patients who have to be on digoxin, digitalis, or other herbal products containing Danshen (Radix Salviae Miltiorrhizae, RSM), Sanqi (Radix Notoginseng, RN) or Ginkgo biloba during the single-blind screening and/or double-blind treatment period.
15. Patients on antiplatelet drugs (except aspirin or clopidogrel), statins, ACE inhibitor, angiotensin II receptor blocker (ARB), warfarin or other direct acting oral anticoagulants (DOACs) need to be stable at current dose for at least 2 weeks prior to the start of screening.
16. Clinical trials/experimental medication: participation in any other clinical trial or receipt of an investigational drug or device within 30 days prior to the start of screening.
17. Female patients with known, suspected or planned pregnancy, or lactation.
18. Patients with a recent (within the last 2 years) history of substance abuse (alcohol, marijuana, or known drug dependence). Or patients who have a positive urine substance screening test at the Day -21 initial visit.
19. Any family member or relative of the study site staff, sponsor or CRO.
20. Patients with any other severe or serious condition that, in the opinion of the investigator is likely to prevent compliance with the study protocol or pose a safety concern if the patient participates in the study.
21. Patients whose QTcF (Fridericia's method corrected QT interval) is \>460 ms in male and \>470 ms in female during supine 12-lead ECG at rest at screening or any time prior to randomization from Day -21. And patients who are currently taking any medication that are known to prolong the QTcF interval at screening or any time prior to randomization from Day -21.
