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
Overview
- Phase
- Phase 3
- Intervention
- T89 capsule
- Conditions
- Chronic Stable Angina Pectoris
- Sponsor
- Tasly Pharmaceuticals, Inc.
- Enrollment
- 765
- Locations
- 1
- Primary Endpoint
- Change in symptom-limited total exercise duration (TED) at trough drug levels on standard Bruce protocol from baseline to Day 57
- Status
- Recruiting
- Last Updated
- last year
Overview
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 3-week single-blind qualifying run-in 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.
Detailed Description
After signing the consent, patients will enter the single blind qualifying run-in period for 3 weeks. All prophylactic anti-anginal medications will be withdrawn except no more than one beta blocker or one calcium channel blocker (CCB) to remain. If patients can tolerate the withdrawal of the multiple anti-anginal medications, the dose of the remained one beta blocker or one CCB will be kept unchanged until the double-blind treatment period ends. In this study period, patients will have two exercise tolerance tests (ETTs) on standard Bruce protocol, conducted one week apart. Sublingual nitroglycerin is allowed for symptomatic relief of angina attack. After screening, eligible patients will be randomly assigned to receive one of the three double-blind treatments: high dose T89 of 300 mg, bid, low dose T89 of 225 mg, bid, 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Willing to participate and sign a written informed consent
- •Males and females ≥ 18 and ≤90 years old.
- •Medical history of chronic stable angina triggered by physical effort and relieved by rest or sublingual nitroglycerin.
- •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.
- •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).
Exclusion Criteria
- •Patients with only non-cardiac chest pain or cardiac chest pain not related to angina.
- •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.
- •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.
- •Patients with history of any coronary revascularization procedure (e.g. PCI or CABG) within 2 months prior to the start of screening.
- •Patients who had unstable angina, or myocardial infarction within the recent 3 months prior to the start of screening.
- •Patients with ongoing NYHA Classes III-IV congestive heart failure.
- •Patients with angina pectoris at rest at screening.
- •Patients with rapid atrial fibrillation at screening (rest heart rate \>120/min) or any time prior to randomization from Day -
- •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.
Arms & Interventions
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.
Intervention: T89 capsule
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.
Intervention: Placebo capsule
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.
Intervention: T89 capsule
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.
Intervention: Placebo capsule
Outcomes
Primary Outcomes
Change in symptom-limited total exercise duration (TED) at trough drug levels on standard 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. Standard 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 standard Bruce protocol to Day 57 of treatment in high-dose and low-dose groups will be compared with that in placebo group.
Secondary Outcomes
- The trend of TED changes over time (Slop) from Day 1 to Day 57(Day 57 (post drug administration from randomization))
- 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].(Day 57 (post drug administration from randomization))
- Percent change in the average frequency of angina episodes (average over 14 days) from baseline [Day -14 to 1] to Week-6 visit of double-blind treatment period [Day 29 to 43](Day 43 (post drug administration from randomization))
- 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](Day 57 (post drug administration from randomization))
- Change in time to 1 mm ST depression during ETT from baseline to Day 57(Day 57 (post drug administration from randomization))
- Change in symptom-limited total exercise duration (TED) at trough drug levels on standard Bruce protocol from baseline to Day 43(Day 43(post drug administration from randomization))
- Change in time to onset of angina during ETT from baseline to Day 57(Day 57 (post drug administration from randomization))