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Outcome Research to Confirm the Anti-anginal Effect of T89 in Patients With Stable Angina

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03789552
Recruitment Status : Recruiting
First Posted : December 28, 2018
Last Update Posted : August 26, 2019
Sponsor:
Information provided by (Responsible Party):
Tasly Pharmaceuticals, Inc.

Brief Summary:
This is a multi-center, double-blind, randomized, placebo-controlled, parallel-group phase 3 clinical study to confirm the safety and efficacy of T89 in patients with stable angina pectoris, with an extended open-label period to evaluate the long-term safety of T89.This study includes three main periods: the first study period is a 4-week single-blind qualifying period to screen eligible stable angina patients by exercise tolerance test (ETT). The second study period is a 8-week double-blind treatment period to evaluate the efficacy and safety of T89 in patients with stable angina by ETT. And the last study period is a 44-week open-label period to observe long-term use safety of T89.

Condition or disease Intervention/treatment Phase
Chronic Stable Angina Pectoris Drug: T89 capsule Drug: Placebo capsule Phase 3

Detailed Description:

After the signing the consent, patients will enter the Single Blind Qualifying Period for 4 weeks. All prophylactic anti-anginal medications will be withdrawn to allow only one beta blocker or one calcium channel blocker (CCB) to remain. If the patients can tolerate the withdrawal of the multiple anti-anginal medications, the dose of the one beta blocker or one CCB will be reduced to half of the pre-screening starting dose. Patients will have two qualifying exercise tolerance tests (ETTs), using modified Bruce protocol, conducted one week apart. Sublingual nitroglycerin is allowed for symptomatic relief.

Eligible patients will be randomly assigned to receive one of the three double-blind treatments: high dose T89, low dose T89 or placebo, in a 1:1:1 ratio. Each patient will be instructed to administer assigned treatment twice daily for 8 weeks. ETTs will be performed at the end of week 6 and 8 of treatment, or end of treatment (EOT) if study patient discontinues study prematurely.

Seattle Angina Questionnaire (SAQ) will be used to record patients' quality of life. Clinical evaluations and adverse event monitoring will be assessed throughout the study. Laboratory tests will be performed at screening and the designated visits.

Once the treatment period is completed, patients will enter the extended open label safety assessment period for a further 44 weeks. During this period, all patients will receive T89 at a daily dose of 600 mg, and they can resume their original anti-anginal medications as needed.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 765 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group Phase 3 Study to Confirm the Safety and Efficacy of T89 in Patients With Stable Angina Pectoris, With an Extended Open-label Period to Evaluate the Long-term Safety
Actual Study Start Date : August 1, 2019
Estimated Primary Completion Date : April 1, 2022
Estimated Study Completion Date : September 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Angina

Arm Intervention/treatment
Experimental: T89 low-dose group

T89 capsule is a botanical drug containing 75mg active substance which is the water extract of Danshen and Sanqi. Placebo capsule does not contain any amount of active substance.

Subjects in this group will use three T89 capsules and one Placebo capsule each time by oral administration twice daily for 8 weeks.

Drug: T89 capsule
T89 capsules (75mg)

Drug: Placebo capsule
Placebo capsules (0mg)

Experimental: T89 high-dose group

T89 capsule is a botanical drug containing 75mg active substance which is the water extract of Danshen and Sanqi.

Subjects in this group will use four T89 capsules each time by oral administration twice daily for 8 weeks.

Drug: T89 capsule
T89 capsules (75mg)

Placebo Comparator: Placebo group
Placebo capsule does not contain any amount of active substance. Subjects in this group will use four Placebo capsules each time by oral administration twice daily for 8 weeks.
Drug: Placebo capsule
Placebo capsules (0mg)




Primary Outcome Measures :
  1. Change in symptom-limited total exercise duration (TED) at trough drug levels on modified Bruce Protocol from baseline to Day 57 [ Time Frame: Day 57 (post drug administration from randomization) ]
    Exercise, a common physiological stress, can elicit cardiovascular abnormalities that are not present at rest, and it can be used to determine the adequacy of cardiac function. Clinical exercise tolerance test (ETT) is an established non-invasive procedure that provides diagnostic and prognostic information for the evaluation of several pathologies, the most common of which is coronary heart disease. Total exercise duration (TED) is the time from starting ETT to terminating ETT, usually presented by minutes and seconds. Modified Bruce protocol, one of the protocols used for the conduction of an ETT as a pre-defined speed and gradient in different time interval, will be applied in this study. The TED at each ETT will be collected and recorded as primary parameter, and the change from baseline of symptom-limited TED at trough drug levels on modified Bruce Protocol to Day 57 of treatment in high-dose and low-dose groups will be compared with that in placebo group.


Secondary Outcome Measures :
  1. Percent change in the average frequency of angina episodes (average over 14 days) from baseline [Day -14 to 1] to end of double-blind treatment period [Day 43 to 57] as recorded on the WCM device. [ Time Frame: Day 57 (post drug administration from randomization) ]
    A Wearable Cardiac Monitor (WCM) is a device similar to a Holter but quite smaller in size. This is a FDA-approved device used for recording the ECG up to for 7 days when patients may suffer from transient symptoms such as palpitations, dizziness, anxiety, fatigue, syncope, pre-syncope, light-headedness, shortness of breath. The WCM device is safe and easy for patients to use even when they are taking a short shower. Angina episodes during the past 7 days will be collected from this device and recorded by site staff at due visit until Day 57. And percent change in the average frequency of angina episodes (average over 14 days) from baseline [Day -14 to 1] to end of double-blind treatment period [Day 43 to 57] in high-dose and low-dose groups will be compared with that in placebo group.

  2. Percent change in the average on-demand consumption of short-acting nitroglycerin (average over 14 days) from baseline [Day -14 to 1] to end of double-blind treatment period [Day 43 to 57]. [ Time Frame: Day 57 (post drug administration from randomization) ]
    The amount of used short-acting nitroglycerin since last visit will be counted and recorded at each visit (except for the first visit), and percent change in the average on-demand consumption of short-acting nitroglycerin (average over 14 days) from baseline [Day -14 to 1] to end of double-blind treatment period [Day 43 to 57] in high-dose and low-dose groups will be compared with that in placebo group.

  3. The trend of TED changes over time (Slop) from Day 1 to Day 57 double-blind treatment period. [ Time Frame: Day 57 (post drug administration from randomization) ]
    The trend of TED changes from Day 1 to Day 57 double-blind treatment period will be compared among high dose group, low dose group and placebo group.

  4. Change in symptom-limited total exercise duration (TED) at trough drug levels on modified Bruce Protocol from baseline to Day 43 [ Time Frame: Day 43(post drug administration from randomization) ]
    The TED at each ETT will be collected and recorded as primary parameter, and change in symptom-limited total exercise duration (TED) at trough drug levels on modified Bruce Protocol from baseline to Day 43 in high-dose and low-dose groups will be compared with that in placebo group.

  5. Change in time to onset of angina during ETT from baseline to Day 57 [ Time Frame: Day 57 (post drug administration from randomization) ]
    Commonly, exercise will make heart pump harder and faster, and further cause in patients with stable angina as a result of myocardial ischemia. The time from the beginning of ETT to onset of angina during ETT will be collected and recorded at each ETT, and change in time to onset of angina during ETT from baseline to Day 57 in high-dose and low-dose groups will be compared with that in placebo group.

  6. Change in time to 1 mm ST depression during ETT from baseline to Day 57 [ Time Frame: Day 57 (post drug administration from randomization) ]
    Commonly, exercise will make heart pump harder and faster, and further cause angina event during ETT as a result of myocardial ischemia, sometimes accompanied by horizontal or down-slopping ST segment depression in electrocardiograph (ECG) in some patients with stable angina. The time from the beginning of ETT to onset of at least of 1 millimeter (mm) horizontal or down-slopping ST segment depression during ETT will be collected and recorded at each ETT, and the change in time to onset of at least of 1 mm horizontal or down-slopping ST segment depression during ETT from baseline to Day 57 of treatment in high-dose and low-dose groups will be compared with that in placebo group.


Other Outcome Measures:
  1. Frequency and severity of adverse events and serious adverse events [ Time Frame: Day 57 (post drug administration from randomization) ]
    A safety endpoint to compare frequency and severity of adverse events and frequency and severity of serious adverse events among high dose, low dose and placebo group.

  2. Notable laboratory abnormalities which are treatment-emergent [ Time Frame: Day 57 (post drug administration from randomization) ]
    A safety endpoint to compare the rate of notable laboratory abnormalities among high dose, low dose and placebo group.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   20 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Willing to participate and sign a written informed consent
  2. Males and females between the ages of 20 and 80 years.
  3. Documented history of stable, exertional angina pectoris which is relieved by rest or sublingual nitroglycerin during the 12 weeks prior to the start of screening.
  4. The study doctor will get agreement from the health care provider who is responsible for subject's cardiac care (if this is not the study doctor) that the subject's participation will not pose an undue safety risk.
  5. Patients must be on only one beta blocker or one calcium channel blocker for at least 28 days prior to randomization and must be able to remain on the same medication at a reduced and stable dose (half of the prescreening dose), from day -21 until the completion of the double-blind period (either one beta blocker or one calcium channel blocker (amlodipine, diltiazem, verapamil or nicardipine is acceptable).

    *Only NITROSTAT®, provided by sponsor, is allowed to be used for symptomatic relief of angina for all eligible patients during the qualifying and treatment periods to ensure an accurate calculation of consumption.

  6. Documented history of coronary artery disease with one or more of the following conditions:

    6.1) History of myocardial infarction more than 12 months prior to the start of screening; 6.2) Documentation of clinically significant coronary stenosis ≥ 50% in any vessel detected by most recent coronary angiography (or coronary CT angiography) within 6 months prior to the start of screening; 6.3) Patients with documented ischemic heart disease determined by stress myocardial imaging examination (including nuclear stress test, cardiac stress MRI and echocardiography stress test) within 6 months prior to start of screening.

  7. 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.
  8. 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 -28, quantitative serum human chorionic gonadotropin (β-hCG test)) and randomization visit (Day 1, urine pregnancy test).
  9. Patients are able to tolerate the withdrawal of multiple background anti-anginal medications and remain on half of the prescreening dose of the remaining one beta blocker or one calcium channel blocker for at least 14 days prior to the first qualifying ETT on Day -7.
  10. Patients must experience at least three angina episodes recorded by WCM device from day -14 to day 1. (Patients are allowed to use short acting nitroglycerin for relief of angina.)
  11. Patients must have two qualifying ETTs on modified Bruce protocol one week apart (Day -7 and Day 1) with both exercise duration fall between 3 and 9 min during each qualifying ETT. Qualifying ETTs must meet the positive ETT criteria and the difference in exercise duration between the two ETTs must not exceed 15% of the longer test. In patients with permitted baseline ST-segment depression at rest (<1 mm), qualifying ST-segment depression will be defined as additional ST-segment depression ≥1 mm below the resting value.

Exclusion Criteria:

  1. Patients who experienced less than three anginal episodes during Day -14 to Day 1 in the Single Blind Qualifying Period evidenced by WCM device.
  2. Patients with only non-cardiac chest pain or cardiac chest pain not related to angina.
  3. 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, severe kidney failure (glomerular filtration rate (GFR) < 30 cc/min), physical disability or other intercurrent illness such as acute respiratory infection/illness that may interfere with the ability to perform ETT.
  4. 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, or atrial fibrillation. etc.).

    *Left ventricular hypertrophy (LVH) without repolarization abnormalities is not considered an exclusion criterion.

  5. Patients with history of unstable angina or any coronary revascularization procedure (e.g. percutaneous coronary intervention(PCI) or CABG) within 2 months prior to the start of screening.
  6. Patients who had myocardial infarction within 12 months prior to the start of screening.
  7. Patients with history of heart failure (NYHA Classes II-IV) and/or left ventricular ejection fraction (LVEF) ≤40%.
  8. Ongoing myocarditis, pericarditis, thrombophlebitis or pulmonary embolism or who have recovered from these conditions < 1 month prior to screening. Patients who just are on anticoagulant prophylaxis for a pulmonary embolism or thrombophlebitis are not subject to the one-month restriction.
  9. Prior history of atrial fibrillation.
  10. Uncontrolled hypertension characterized by seated systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg, within 2 months prior to Single Blind Qualifying Period. Known congenital cardiac defects, significant valvular disease, aortic aneurysm, hypertrophic cardiomyopathy.
  11. Hgb<10 g/dL, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x upper limit of normal (ULN), and hemoglobin A1C (HgA1C) > 8.5%, in any of the single blind qualifying lab tests.
  12. History of bleeding diathesis or cerebral hemorrhage.
  13. Patients on ivabradine or calcium channel blockers other than, amlodipine, verapamil, nicardipine or diltiazem are excluded. Patients on more than one anti-anginal agent (except for sublingual nitroglycerin) are excluded.
  14. Patients who need digoxin, digitalis, or other herbal products containing Danshen (Radix Salviae Miltiorrhizae, RSM), Sanqi (Radix Notoginseng, RN) or Ginkgo biloba during the screening and/or qualifying period.
  15. Patients on antiplatelet drugs (except for aspirin), statins, angiotensin converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), warfarin or other direct acting oral anticoagulants (DOACs) started less than 14 days prior to the start of screening.
  16. Clinical trials/experimental medication 16.1). Participation in any other clinical trial or receipt of an investigational drug or device within 30 days prior to the start of screening.

    16.2). Previous participation in the studies of T89.

  17. Female patients with known, suspected or planned pregnancy, or lactation.
  18. Substance abuse. Patients with a recent history (within the last 2 years) of alcoholism, marijuana, or known drug dependence.
  19. Any family member or relative of the study site staff is ineligible.
  20. Any other 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. The Fridericia's method corrected QT interval (QTcF) > 450 ms in male and > 470 ms in female patients that are taking any medication that are known to prolong the QTc interval at screening or any time prior to randomization from day -28;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03789552


Contacts
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Contact: Henry H Sun, PhD, MD 301-978-3905 HSun@taslyUS.com

Locations
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United States, Florida
Southwest Florida Research LLC Recruiting
Naples, Florida, United States, 34102
Contact: James V Talano, PhD         
Sponsors and Collaborators
Tasly Pharmaceuticals, Inc.
Investigators
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Study Chair: Henry H Sun, PhD, MD Tasly Pharmaceuticals, Inc.

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Responsible Party: Tasly Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03789552    
Other Study ID Numbers: T89-08-ORESA
First Posted: December 28, 2018    Key Record Dates
Last Update Posted: August 26, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Tasly Pharmaceuticals, Inc.:
angina pectoris
Additional relevant MeSH terms:
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Angina Pectoris
Angina, Stable
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Chest Pain
Pain
Neurologic Manifestations
Signs and Symptoms