The Transendocardial Autologous Cells (hMSC or hBMC) in Ischemic Heart Failure Trial (TAC-HFT)

Study Overview
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Brief Summary
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The technique of transplanting progenitor cells into a region of damaged myocardium, termed cellular cardiomyoplasty, is a potentially new therapeutic modality designed to replace or repair necrotic, scarred, or dysfunctional myocardium. Ideally, graft cells should be readily available, easy to culture to ensure adequate quantities for transplantation, and able to survive in host myocardium; often a hostile environment of limited blood supply and immunorejection. Whether effective cellular regenerative strategies require that administered cells differentiate into adult cardiomyocytes and couple electromechanically with the surrounding myocardium is increasingly controversial, and recent evidence suggests that this may not be required for effective cardiac repair. Most importantly, transplantation of graft cells should improve cardiac function and prevent adverse ventricular remodeling. To date, a number of candidate cells have been transplanted in experimental models, including fetal and neonatal cardiomyocytes, embryonic stem cell-derived myocytes, tissue engineered contractile grafts, skeletal myoblasts, several cell types derived from adult bone marrow, and cardiac precursors residing within the heart itself. There has been substantial clinical development in the use of whole bone marrow and skeletal myoblast preparations in studies enrolling both post-infarction patients, and patients with chronic ischemic left ventricular dysfunction and heart failure. The effects of bone-marrow derived mesenchymal stem cells (MSCs) have also been studies clinically. Currently, bone marrow or bone marrow-derived cells represent highly promising modality for cardiac repair. The totality of evidence from trials investigating autologous whole bone marrow infusions into patients following myocardial infarction supports the safety of this approach. In terms of efficacy, increases in ejection fraction are reported in the majority of the trials. Chronic ischemic left ventricular dysfunction resulting from heart disease is a common and problematic condition; definitive therapy in the form of heart transplantation is available to only a tiny minority of eligible patients. Cellular cardiomyoplasty for chronic heart failure has been studied less than for acute MI, but represents a potentially important alternative for this disease.

Official Title
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A Phase I/II, Randomized, Double-Blinded, Placebo-Controlled Study of the Safety and Efficacy of Transendocardial Injection of Autologous Human Cells (Bone Marrow or Mesenchymal) in Patients With Chronic Ischemic Left Ventricular Dysfunction and Heart Failure Secondary to Myocardial Infarction.

Conditions
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Stem Cell Transplantation, Ventricular Dysfunction, Left

Intervention / Treatment
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* Biological: Autologous human mesenchymal cells (hMSCs)
* Biological: Autologous human bone marrow cells (hBMCs)
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of chronic ischemic left ventricular dysfunction secondary to MI. Be a candidate for cardiac catheterization. Been treated with appropriate maximal medical therapy for heart failure or post-infarction left ventricular dysfunction. Ejection fraction less than or equal to 50%. Able to perform a metabolic stress test. Exclusion Criteria: Baseline glomerular filtration rate < 45 ml/min/1.73m2. Presence of a mechanical aortic valve or heart constrictive device. Documented presence of aortic stenosis (aortic stenosis graded as ≥+2 equivalent to an orifice area of 1.5cm2 or less). Documented presence of moderate to severe aortic insufficiency (echocardiographic assessment of aortic insufficiency graded as ≥+2). Evidence of a life-threatening arrhythmia (nonsustained ventricular tachycardia ≥ 20 consecutive beats or complete heart block) or QTc interval > 550 ms on screening ECG. In addition; patients with sustained or a short run of ventricular tachycardia on ECG or 48 hour Ambulatory ECG during the screening period will be removed from the protocol. Documented unstable angina. AICD firing in the past 60 days prior to the procedure. Contra-indication to performance of a magnetic resonance imaging scan. Be eligible for or require coronary artery revascularization. Have a hematologic abnormality as evidenced by hematocrit < 25%, white blood cell < 2,500/ul or platelet values < 100,000/ul without another explanation. Have liver dysfunction, as evidenced by enzymes (ALT and AST) greater than three times the ULN. Have a coagulopathy condition = (INR > 1.3) not due to a reversible cause. Known, serious radiographic contrast allergy. Known allergies to penicillin or streptomycin. Organ transplant recipient. Clinical history of malignancy within 5 years (i.e., patients with prior malignancy must be disease free for 5 years), except curatively-treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma. Non-cardiac condition that limits lifespan to < 1 year. On chronic therapy with immunosuppressant medication. Serum positive for HIV, hepatitis BsAg, or non-viremic hepatitis C. Female patient who is pregnant, nursing, or of child-bearing potential and not using effective birth control.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 90 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Participants will receive an injection of 100 million or 200 million autologous human mesenchymal stem cells (hMSCs). | Biological: Autologous human mesenchymal cells (hMSCs)<br>* Participants will receive 40 million cells/mL delivered in either a dose of 0.25 mL per injection for a total of 1 x 108 (100 million) hMSCs x 10 injections or a dose of 0.5 mL per injection for a total of 2 x 108 (200 million) x 10 injections. The injections will be administered transendocardially during cardiac catheterization using the Biocardia Helical Infusion Catheter.<br>|
| Experimental: 2<br>Participants will receive an injection of 100 million or 200 million autologous human bone marrow cells (hBMCs). | Biological: Autologous human bone marrow cells (hBMCs)<br>* Participants will receive 40 million cells/mL delivered in either a dose of 0.25 mL per injection for a total of 1 x 108 (100 million) hBMCs x 10 injections or a dose of 0.5 mL per injection for a total of 2 x 108 (200 million) x 10 injections. The injections will be administered transendocardially during cardiac catheterization using the Biocardia Helical Infusion Catheter.<br>|
| Placebo Comparator: 3<br>Participants will receive a placebo injection of phosphate-buffered saline (PBS) and 1% human serum albumin (HAS). | Biological: Placebo<br>* Participants will receive 0.5 mL injections of phosphate-buffered saline (PBS) and 1% human serum albumin (HAS) x 10 injections. The injections will be administered transendocardially during cardiac catheterization using the Biocardia Helical Infusion Catheter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of TE-SAE Define as Composite of Death, Non-fatal MI, Stroke, Hospitalization for Worsening Heart Failure, Cardiac Perforation, Pericardial Tamponade, Ventricular Arrhythmias >15 Sec. or With Hemodynamic Compromise or Atrial Fibrillation |  | one month post-catheterization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serial Troponin Values (Every 12 Hours for the First 48 Hours Post-catheterization). |  | Measured every 12 hours for the first 48 hours post-catheterization | 
| Serial Creatine Kinase Values (Every 12 Hours for the First 48 Hours Post-catheterization). |  | Measured every 12 hours for the first 48 hours post-catheterization | 
| Incidence of the Major Adverse Cardiac Events (MACE) Endpoint, Defined as the Composite Incidence of (1) Death, (2) Hospitalization for Heart Failure, or (3) Non-fatal Recurrent MI. |  | 12 months post-catheterization | 
| Ectopic Tissue Formation. |  | 12 months post-catheterization | 
| Number of Deaths |  | 12-months post-catheterization | 
| Change From Baseline in Distance Walked in Six-minutes (Six-minute Walk Test). | Data provided are with respect to the change from baseline at 12-months post-catheterization. | 12 months post-catheterization | 
| Change From Baseline in the Minnesota Living With Heart Failure (MLHF) Questionnaire Total Score. | Data provided are with respect to the change from baseline at 12-months post-catheterization. The Minnesota living with heart failure questionnaire uses a 6-point, zero to five, Likert scale. The total score is the sum of the 21 responses. The total score is considered the best measure of how heart failure and treatments impact a patients quality of life. The max score is 105, minimum score is 0. A lower score is considered a better quality of life. | 12 months post-catheterization | 
| Percent Change From Baseline in Scar Mass as a Fraction of Left Ventricle Mass by Cardiac MRI or CT. | Data provided are with respect to the change from baseline at 12-months post-catheterization. | 12 Months post-catheterization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Ischemic Left Ventricular Dysfunction