This is a phase I/IIa study to investigate the safety, tolerability, and preliminary effectiveness of HeXell-2020 in patients with stable coronary artery disease (CAD). HeXell-2020 is an investigational drug product consisting of allogenic umbilical cord mesenchymal stem cells (UCMSCs) as the drug substance. All enrolled and eligible subjects will receive HeXell-2020 treatment.
Coronary artery disease (CAD) is the most common form of heart disease and a leading cause of mortality worldwide. It is a manifestation of myocardial ischemia, a condition resulting from insufficient blood flow to the myocardial tissue. CAD occurs when the coronary arteries become progressively narrowed and stiffened due to atherosclerosis-the accumulation of cholesterol, lipids, and plaque along the inner arterial walls. Narrowed blood vessels and increased shear stress may contribute to plaque destabilization, vessel outward remodeling, as well as increased pro-inflammatory cytokines production, leading to advanced atherosclerosis. As the disease advances, this narrowing impairs coronary blood flow, causing permanent heart damage. Over time, CAD can progressively weaken the heart muscle, contributing to heart failure. Mesenchymal stem cells (MSC) become a potential therapeutic tool for treating cardiovascular diseases due to their capabilities in tissue repair, anti-oxidation, immune-modulation and anti-inflammatory. Intravenous infusion of HeXell-2020, the allogenic umbilical cord MSC, in an atherosclerotic rat model improved blood glucose tolerance, LDL cholesterol levels, and the severity of aortic arch stenosis. Additionally, results further demonstrated significant improvement in atherosclerotic lesions caused by fat deposition at the aortic arch and descending aorta after the treatment. Although the mode of actions of MSCs in CADs have not been fully elucidated, these nonclinical results, together with the established immunomodulatory and anti-inflammatory effects of MSCs, are supportive for the rationale of HeXell-2020 in treating patients with CAD. This study is composed of two phases, Phase I and Phase IIa. In Phase I, two cohorts were designed following traditional 3+3 scheme to define recommended phae 2 dose (RP2D). In Phase IIa, 22 evaluable subjects are estimated. Safety and efficacy will be evaluated through follow-up visit over one year.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
39
Phase I Cohort 1: HeXell-2020 with a total of 3 doses, 9x10\^7 cells/dose. Phase I Cohort 2: HeXell-2020 with a total of 6 doses, 9x10\^7 cells/dose. Phase IIa: RP2D from phase I.
Incidence of TEAE, SAE and SUSAR over the study
To evaluate the number of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), suspected and unexpected serious adverse reactions (SUSARs) over the study period,
Time frame: Within the first year after cell transplantaion
To determine the recommended phase II dose (RP2D) in Phase I study
To determination RP2D, number and proportion of subjects having experienced DLTs will be presented and the RP2D should be determined on the indicated dose at which ≤ 1 patient experiences DLT out of 6 patients who have been DLT evaluated.
Time frame: Within the first year after cell transplantaion
Change in myocardial perfusion defect severity under the rest acquisition and pharmacological stress of dipyridamole in Phase IIa study
Measured by SPECT with thallium-201 from baseline. The SRS, SSS and SDS are three variables used to measure cardiac perfusion and ischemia.
Time frame: Before first dosing and at 12 months post cell transplantaion
Time to the first occurrence of major adverse cardiovascular events (MACEs)
Including AMI, stroke, cardiovascular mortality, and hospitalization for unstable angina or revascularization procedures, from the date of the first treatment will be analyzed by Kaplan-Meier method.
Time frame: From the date of the first treatment until the first occurrence of MACE, death, or study cut-off point, unless the subject has withdrawn consent for all contacts or is loss of follow-up, whichever came first, assessed up to 24 months.
Change in the evaluation result of CCTA from baseline
The stenosis percent of the different coronary segments, using the 17-segment model.
Time frame: Before first dosing and at 3, 6 months post cell transplantation
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Change from baseline in echocardiographic measures.
Ventricular remodeling: including LVEF in percentage, global longitudinal strain (GLS) in percentage.
Time frame: Before first dosing and at 3, 6, 12 months post cell transplantation
Change in functional class of angina by using CCS angina classification from baseline.
Change in functional class of angina by using CCS angina classification will be summarized descriptively by visit
Time frame: Before first dosing, and 1, 3, 6 , 12 months post cell transplantation
Change in the 6-minute walk test (6-MWT) from baseline.
The 6-MWT measures the distance walked on level ground in 6 minutes.
Time frame: Before first dosing and 6, 12 months post cell transplantation
Change in serum levels of amino-terminal pro-brain natriuretic peptide (NT pro-BNP) and high sensitivity cardiac troponin (hs-cTn) from baseline.
Change in serum levels of NT pro-BNP and hs-cTn from baseline will be summarized descriptively.
Time frame: Before first dosing, and 1, 3, 6 , 12 months post cell transplantation
Change in quality of life using the Seattle Angina Questionnaire (SAQ) from baseline.
The SAQ, a 19-item self-administered questionnaire measuring 5 dimensions of CAD: physical limitation, anginal stability, anginal frequency, treatment satisfaction and disease perception will be used to assess the functional change of CAD in HeXell-2020 administered patients.
Time frame: Before first dosing, and 1, 3, 6 , 12 months post cell transplantation
Change from baseline in echocardiographic measures.
Myocardial performance \[including isovolumic relaxation time (IVRT), isovolumic contraction time (IVCT), LV ejection time (ET), and myocardial performance index (MPI or Tei Index)\]\[MPI= (IVCT+IVRT)/ET\]
Time frame: Before first dosing and at 3, 6, 12 months post cell transplantation
Change in the evaluation result of CCTA from baseline
Severity of stenosis assessed by 2022 Coronary Artery Disease Reporting and Data System (CAD-RADSTM 2.0), ranging from CAD-RADS 0 for absence of any plaque or stenosis to CAD-RADS 5 for the presence of at least 1 totally occluded coronary artery.
Time frame: Before first dosing and at 3, 6 months post cell transplantation
Change in the evaluation result of CCTA from baseline
Coronary artery calcium score (CACS, as per Agatston method, J Am Coll Cardiol. 1990;15:827-32), higher scores mean a worse outcome.
Time frame: Before first dosing and at 3, 6 months post cell transplantation
Change from baseline in echocardiographic measures.
Ventricular remodeling: LV end-diastolic volume (EDV) in mL, and end-systolic volume (ESV) in mL, stroke volume (SV in ), calculated by EDV - ESV ( mL)
Time frame: Before first dosing and at 3, 6, 12 months post cell transplantation.
Change from baseline in echocardiographic measures.
Ventricular remodeling: LV internal diameter in diastole and systole (LVIDd and LVIDs in mm), interventricular septum diameter (IVSD in mm), posterior wall thickness (PWT in mm), anteroseptal wall thickness (ASWT in mm)
Time frame: Before first dosing and at 3, 6, 12 months post cell transplantation.