Phase III Trial of Dantonic® (T89) Capsule to Prevent and Treat Stable Angina

Study Overview
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Brief Summary
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This phase III study is designed as a double blind, randomized, multi-nation, multi-center, placebo controlled clinical research, which aims to evaluate the safety and efficacy of Dantonic® (T89) in patients with chronic stable angina pectoris.

Detailed Description
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Dantonic® (T89) is a botanical drug consists of extracts of Danshen (Radix Salviae Miltiorrhizae) and Sanqi (Radix Notoginseng) with borneol in a capsule form. The drug is currently approved in 26 countries outside the USA for the treatment and prevention of chronic stable angina pectoris and other cardiovascular disease related conditions. This pivotal confirmative Phase III clinical trial is to confirm the efficacy and safety of the drug at 150mg and 225mg doses in the prevention and treatment of angina pectoris in patients with Chronic Stable Angina. The contribution of the main herb Danshen to, and the difference of various production batches in, the overall efficacy and safety profiles will also be explored. Patients will take a morning and an evening dose orally (every 12 hours) for 6 weeks while stop taking any long-acting nitroglycerin, ranolazine, and/or multiple beta-blockers or beta blocker(s) with calcium channel blocker during the trial. Single beta-blocker and/or on-demand short acting nitroglycerin to relief angina pectoris is allowed during the trial. After physical exams and if eligible to participation, patients will stop taking other drugs, and undergo two baseline screen Exercise Treadmill Tests (ETT) on Standard Bruce Protocol in the clinic one week before and right before starting the drug treatment. Patients will perform three more ETTs before the morning dose at the end of week 2, 4 and 6 after receiving the drug treatment. The primary efficiency endpoint is the change of symptom-limited Total Exercise Duration of the ETT at the end of the 4th week of treatment from the average of the two screening baselines compared with that of placebo treatment.

Official Title
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Phase III Confirmatory Trial to Confirm the Anti-anginal Effect of Dantonic® (T89) in Patients With Chronic Stable Angina

Conditions
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Angina Pectoris

Intervention / Treatment
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* Drug: T89 high dose
* Drug: T89 Low dose
* Drug: Sanqi+Bingpian
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent. Males and females between the ages of 20 and 80 years. Females of childbearing potential must have a negative pregnancy test, not be breast feeding and established on a method of contraception that in the investigator's opinion is acceptable. Females must agree to remain on their established method of contraception through their participation in the study and for 14 days following the last dose of study drug. Evidence of coronary artery disease that consists of a well-documented medical history (over 3 months prior to the enrolment) of myocardial infarction or significant coronary artery disease with noninvasive or angiographic confirmation. Symptoms that support the diagnosis of chronic angina and/or a history of an abnormal exercise response limited by angina and/or electrocardiograph (ECG) changes. Moderate angina pectoris (Class II or III, Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System). Patient whose symptom-limited Total Exercise Duration (TED) is between 3 to 7 minutes in Exercise Tolerance Test (ETT) on Standard Bruce Protocol, and symptom-limited TED on two screen examinations (Day -7 and 0) in which the shorter is within 85% of the longer . Patient has been on one beta-blocker or on one calcium-channel blocker for at least 14 days prior to dosing of study medication and can remain on this treatment throughout the study as background anti-anginal treatment. Short-acting nitroglycerin for on-demand use is allowed for all eligible patients. Understand and be willing, able and likely to comply with all study procedures and restrictions and comprehends the verbal rating scales and diary cards. Exclusion Criteria: With contraindication to, unable to, or with other co-morbidities that may prevent or interfere with the ability to perform treadmill ETT (including, but not limited to: pulmonary hypertension, functionally limiting COPD (chronic obstructive pulmonary disease), history of pulmonary tuberculosis, prior hospitalization for acute exacerbation of chronic lung disease, home oxygen use, chronic oral steroid therapy that can limit exercise capacity, functionally limiting peripheral artery disease, etc.). Presence of electrocardiographic or other abnormalities/factors that could interfere with exercise electrocardiograph interpretation or may lead to a false positive stress test (e.g., pre-exercise horizontal or down-sloping ST segment depression in any standard lead, cardiac glycoside therapy, Lown-Ganong-Levine Syndrome, Wolff-Parkinson-White syndrome (WPW), left bundle branch block, left ventricular hypertrophy with repolarization abnormality, implanted pacemaker, etc.). Clinically significant arrhythmias or atrioventricular conduction block greater than first degree, decompensated heart failure, atrial fibrillation, hypertrophic cardiomyopathy. Acute coronary syndrome (acute myocardial infarction or unstable angina) in the prior 2 months or coronary revascularization within the prior 6 months or planned coronary revascularization during the study period. Congenital cardiac defects, ongoing history of decompensated congestive heart failure, severe valvular disease, severe uncontrolled hypertension (seated systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg), severe anemia, suspected or known dissecting aortic aneurysm, acute myocarditis or pericarditis, thrombophlebitis or pulmonary embolism. History of bleeding diathesis, cerebral hemorrhage, or seizure disorders that required anticonvulsant medication. Patients requiring the use of long-acting nitroglycerin, ranolazine, and/or multiple anti-anginal drugs. Aspirin and/or statins started less than 14 days prior to the signing of informed consent. Pregnancy or lactation. Clinical trials/experimental medication 1) Participation in any other clinical trial or receipt of an investigational drug within 30 days prior to the initial visit. 2) Previous participation in the studies of T89. 11. Substance abuse. Patients with a recent history (within the last 2 years) of alcoholism or known drug dependence. 12. Is a family member or relative of the study site staff. 13. Any other conditions that, in the opinion of the investigator, are likely to prevent compliance with the study protocol or pose a safety concern if the subject participates in the study.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T89 high dose<br>T89 225mg bid | Drug: T89 high dose<br>* 225mg bid<br>* Other names: Salvtonic®;|
| Experimental: T89 low dose<br>T89 150mg bid | Drug: T89 Low dose<br>* 150mg bid<br>* Other names: Compound Danshen Dripping Pill;|
| Experimental: Sanqi+Bingpian<br>225mg bid | Drug: Sanqi+Bingpian<br>* 225 mg bid<br>|
| Placebo Comparator: Placebo<br>225mg bid | Drug: Placebo<br>* 225mg bid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change of symptom-limited TED from baseline compared to placebo at the end of week 4. | The change of symptom-limited Total Exercise Duration (TED) at trough drug levels at the end of the 4th week of treatment from screen baseline on Standard Bruce Protocol compared with placebo. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change of symptom-limited TED at trough drug levels at the end of the 2nd and 6th weeks | The change of symptom-limited TED at trough drug levels at the end of the 2nd and 6th weeks of treatment from screen baseline on Standard Bruce Protocol compared with placebo; | 2nd weeks and 6th weeks | 
| Frequency of weekly angina episodes | Frequency of weekly angina episodes | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Angina Pectoris Treatment Prevention