Evaluation of the Anti-Anginal Efficacy of T89 and Glyceryl Trinitrate in Patients with Stable Angina Pectoris: A Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2024-512313-41-00
- Protocol
- T89-08-ORESA
- Sponsor
- Tasly Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to confirm the **anti-anginal effect** of T89 in patients with chronic stable angina pectoris. This is clinically relevant as stable angina pectoris is a common manifestation of coronary artery disease, and effective management is crucial to improve patient outcomes and quality of life. The study aims to provide evidence on the efficacy of T89 in reducing anginal episodes, which could potentially offer a new therapeutic option for patients.
Secondary objectives include evaluating the long-term safety of T89 in patients with chronic stable angina pectoris. Assessing the safety profile over an extended period is essential to ensure that the benefits of T89 outweigh any potential risks, thereby supporting its use in clinical practice for the management of stable angina pectoris.
Participants
The clinical trial involves a total of **79 participants** diagnosed with **stable angina pectoris**. The study population comprises both male and female subjects, aged between 18 and 90 years. Participants were selected based on their medical history of chronic stable angina, which is triggered by physical effort and relieved by rest or sublingual nitroglycerin. The trial does not include a vulnerable population. Participants are required to have a documented history of coronary artery disease, with conditions such as previous myocardial infarction or clinically significant coronary stenosis. Lifestyle considerations include the stability of current doses of antiplatelet drugs, statins, ACE inhibitors, and other relevant medications for at least two weeks prior to screening. Participants must be able to comply with study procedures and restrictions, including the use of highly effective birth control methods for those of child-bearing potential. The trial aims to confirm the anti-anginal effect of T89 in patients with chronic stable angina pectoris.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, three-arm parallel-group, multi-center Phase III study. The primary objective is to confirm the anti-anginal effect of T89 in patients with **stable angina pectoris**. The trial will involve a total duration of approximately 52 weeks, with participant involvement expected to last up to 57 days during the double-blind treatment period. The study will commence with a single-blind qualifying run-in period, followed by the double-blind treatment phase, and conclude with an extended open-label study period to evaluate the long-term safety of T89.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific inclusion criteria, such as age, medical history, and current medication regimen. The screening visit will occur 21 days prior to randomization. Eligible participants will then proceed to the randomization visit on Day 1, where they will be assigned to one of the three study arms: T89, placebo, or an active comparator. Follow-up visits will be conducted at regular intervals to monitor efficacy and safety endpoints, including changes in symptom-limited total exercise duration and the frequency of angina episodes. The end-of-study visit will occur on Day 57, marking the completion of the double-blind treatment phase.
Participants are expected to adhere to the study protocol, including the use of highly effective birth control methods for women of childbearing potential and compliance with all study procedures and restrictions. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or the occurrence of significant adverse events. The primary efficacy endpoint is the change in symptom-limited total exercise duration at trough drug levels from baseline to Day 57, while safety endpoints include the frequency and severity of adverse events and notable laboratory abnormalities. Secondary endpoints will assess trends in exercise duration and changes in angina episode frequency over time.
Treatment
The clinical trial involves the administration of **T89**, an experimental medication developed by TASLY PHARMACEUTICALS INC. T89 is provided in the form of a **capsule** and is intended for **oral** administration. The maximum daily dose of T89 is 600 mg, with a total maximum dose of 218,400 mg over a treatment period of up to 52 weeks. The active substance in T89 is derived from a specified substance group, and the formulation is not designed for pediatric use. Participant compliance with the dosing regimen will be monitored throughout the study.
The study also includes a **placebo** group, where participants receive T89 placebo capsules. These capsules contain brown-coated dripping pills and are also administered **orally**. The placebo is designed to match the appearance of the T89 capsules to maintain the double-blind nature of the trial. The maximum daily dose for the placebo is 2160 mg, with a total maximum dose of 166,320 mg over a treatment period of 11 weeks.
Additionally, **Nitroglycerin Orifarm** is used as a comparator treatment in the trial. This medication is provided in the form of a **sublingual tablet** and contains **glyceryl trinitrate** as the active substance. The maximum daily dose of Nitroglycerin Orifarm is 1.5 mg, with a total maximum dose of 115.5 mg over an 11-week period. The sublingual route of administration is employed to ensure rapid absorption and onset of action. This comparator is included to evaluate the anti-anginal effect of T89 in patients with stable angina.
Efficacy
The efficacy of the investigational product T89 in the treatment of chronic stable angina pectoris will be assessed through a series of predefined endpoints. The primary efficacy endpoint is the change in symptom-limited total exercise duration (TED) at trough drug levels on the standard Bruce protocol from baseline to Day 57. This measurement will be conducted using exercise tolerance tests (ETTs) to evaluate the patient's exercise capacity and endurance.
Secondary efficacy endpoints include the trend of TED changes over time from Day 1 to Day 57, the percent change in the average frequency of angina episodes from baseline to the end of the double-blind treatment period, and the percent change in the average on-demand consumption of short-acting **nitroglycerin**. Additionally, changes in time to the onset of angina and time to the onset of 1 mm ST depression during ETT from baseline to Day 57 will be assessed. These parameters will be collected and analyzed at specified time points throughout the study to determine the therapeutic effect of T89.
Inclusion and Exclusion 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 with grade II and III stable angina based on Canadian Cardiovascular Society angina grading.
- 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 one beta blocker or one calcium channel blocker can keep their medication. And patients 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. 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. 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.
- Documented history of coronary artery disease with one or more of the following conditions: History of previous myocardial infarction (previous MI that occurred and was diagnosed at least 3 months prior to start of screening). Ischemic heart disease determined by stress myocardial imaging examination (including nuclear stress test, cardiac stress MRI and echocardiography stress test). Clinically significant coronary stenosis ≥50% in any vessel detected by coronary angiography (or coronary CT angiography).
- 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.
- Women of child bearing potential: Female patients of child-bearing potential or male patients with partners of child-bearing potential must use highly effective birth control methods from the start of screening, until 3 months after the last dose of study medication (for details please refer to Appendix III). 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).
- 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.
- To be qualified, patients must have two qualifying ETTs on standard Bruce protocol on Day- 7 and Day 1. The qualifying ETTs are: ETTs must meet the positive ETT criteria (refer to ETT explanation section 1.6 and 3.2.4); Total exercise duration (TED) of the positive ETT is between 3-12 minutes of exercise; The difference in TED between the two ETTs must not exceed 15% of the longer one.
- 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.
Exclusion Criteria
- Patients with only non-cardiac chest pain or cardiac chest pain not related to angina.
- 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.
- 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.
- Patient with history of bleeding diathesis or cerebral hemorrhage or seizure disorder that need anticonvulsant.
- Patients who have to be on ranolazine, ivabradine and patients who have to be on both beta blocker and calcium channel blocker, more than one beta blockers or calcium channel blockers, or other anti-anginal agent other than only sublingual nitroglycerin for on-demand angina relief.
- 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.
- 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.
- Female patients with known, suspected or planned pregnancy, or lactation.
- 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.
- Any family member or relative of the study site staff, sponsor or CRO.
- 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 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.
- 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.
- 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.).
- 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 -21.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Yet Recruiting | 24 Nov 2024 | 200 |
 Poland | Not Yet Recruiting | 24 Nov 2024 | 200 |
 Romania | Not Yet Recruiting | 24 Nov 2024 | 145 |
 Slovakia | Not Yet Recruiting | 24 Nov 2024 | 145 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
T89 Placebo; capsules contain brown coated dripping pills. | Placebo | N/A | ORAL | 2160 | 11 | N/A |
Nitroglycerin Orifarm 0,5 mg tabletes lietošanai zem mēles | Other | TABLETES LIETOŠANAI ZEM MĒLES | SUBLINGUAL USE | 1.5 | 11 | PRD9532127 |