Allogeneic iPSC-derived Cardiomyocyte Therapy in Patients With Worsening Ischemic Heart Failure

Study Overview
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Brief Summary
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This study is designed to evaluate the safety and efficacy of allogeneic induced pluripotent cell derived cardiomyocytes (iPSC-CMs) in treating patients with worsening ischemic heart failure undergoing coronary artery bypass graft surgery. After screening, iPSC-CMs will be administrated intramyocardially in consented and eligible patients undergoing open-chest CABG surgery and the estimated population size for the study will be 32 patients.

Official Title
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Epicardial Injection of Allogeneic Human Pluripotent Stem Cell-derived Cardiomyocytes to Treat Severe Chronic Heart Failure

Conditions
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Ischemic Heart Failure, Chronic Heart Failure

Intervention / Treatment
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* Biological: Human (allogeneic) iPS-cell-derived cardiomyocyte


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 35-75 (including 35 and 75). Signed the Informed Consent Form (ICF). Have chronic left ventricular dysfunction. Have NYHA Class III-IV cardiac function even after improved medication for the treatment of advanced chronic heart failure. Have indications for Coronary Artery Bypass Grafting. LVEF < 40% as determined by echocardiogram (data collected up to 6 months prior to inclusion evaluation are valid; data collected within 1 month since a myocardial infarction are invalid). Weakening or absence of segmental regional wall motion as determined by standard imaging Exclusion Criteria: PRA ≥ 20% or DSA-positive Patient received ICD transplantation, CRT or similar treatment. Patients with valvular heart disease or received heart valvular disease Patients received treatment of percutaneous transluminal coronary intervention (PCI) Patients with atrial fibrillation Patients previously suffered sustained ventricular tachycardia or sudden cardiac death. Baseline glomerular filtration rate <30ml/min/1.73m2. Liver dysfunction, as evidenced by enzymes (AST and ALT) greater than three times the ULN. Hematological abnormality: A hematocrit <25% as determined by HCT, white blood cell<2500/ul or platelet values <100000/ul without another explanation. Known, serious radiographic contrast allergy, penicillin allergy, streptomycin allergy. Coagulopathy (INR>1.3) not due to a reversible cause. Contra-indication to performance of a MRI scan. Recipients of organ transplant. Clinical history of malignancy within 5 years (patients with prior malignancy must be disease free for 5 years). Non-cardiac condition that limits lifespan <1 year. On chronic therapy with immunosuppressant medication, such as glucocorticoid and TNFα antagonist. Patients allergy to or cannot use immunosuppressant. Serum positive for HIV, HBV, HCV, TP. Currently enrolled other investigational therapeutic or device study. Patients who are pregnant or breast feeding. Other conditions that researchers consider not suitable to participate in this study.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose level 1<br>100 million iPSC-CMs administration | Biological: Human (allogeneic) iPS-cell-derived cardiomyocyte<br>* 10-20 epicardial injections (0.25 mL each) of iPSC-CMs will be delivered in the border zone of the infarcted myocardium<br>|
| Experimental: Dose level 2<br>200 million iPSC-CMs administration | Biological: Human (allogeneic) iPS-cell-derived cardiomyocyte<br>* 10-20 epicardial injections (0.25 mL each) of iPSC-CMs will be delivered in the border zone of the infarcted myocardium<br>|
| Experimental: Dose level 3<br>400 million iPSC-CMs administration | Biological: Human (allogeneic) iPS-cell-derived cardiomyocyte<br>* 10-20 epicardial injections (0.25 mL each) of iPSC-CMs will be delivered in the border zone of the infarcted myocardium<br>|
| No Intervention: Control<br>Participants will received CABG surgery only | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety in terms of the incidence and severity of adverse events | Number of participants with death, fatal myocardial infarction, stroke, ventricular tachycardia sustained for >15 seconds and newly formed tumor | within 1 month post CABG surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Adverse events that require medical intervention | 1 6 months post CABG surgery | 
| Cardiac assessment | 24-hour Holter Monitoring post the CABG surgery | 1 6 months post CABG surgery | 
| Incidence of newly formed tumor | Evaluation by chest, abdominal and pelvic CT scan and PET-CT scan | 1 12 months post CABG surgery | 
| Immunogenic assessments | Donor specific antibody (DSA), serum anti-human leukocyte antigens (anti-HLA) antibody/panel-reactive antibody (PRA) serology monitoring | 1 month, 3 months and 6 months post CABG surgery | 
| Changes in left ventricle function evaluation by echocardiogram (ECHO) or cardiac MRI | Changes in cardiac function will be assessed by left ventricular end-systolic volume (LVESV, mL) changes from baseline to 12 months post surgery | from baseline to 12 months at 3, 6, and 12 months post CABG surgery | 
| Changes in 6-minute walk test (6MWT) |  | from baseline to 12 months at 1, 3, 6, and 12 months post CABG surgery | 
| Changes in NYHA functional classification |  | from baseline to 12 months at 1, 3, 6, and 12 months post CABG surgery | 
| Changes in quality of life (QoL) | Quality of life changes as measured by Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores | from baseline to 12 months at 1, 3, 6, and 12 months post CABG surgery | 
| Incidence of hospitalization for worsening heart failure |  | 1 12 months post CABG surgery |