Combination of Mesenchymal and C-kit+ Cardiac Stem Cells as Regenerative Therapy for Heart Failure

Study Overview
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Brief Summary
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This is a phase II, randomized, placebo-controlled clinical trial designed to assess feasibility, safety, and effect of autologous bone marrow-derived mesenchymal stem cells (MSCs) and c-kit+ cells both alone and in combination (Combo), compared to placebo (cell-free Plasmalyte-A medium) as well as each other, administered by transendocardial injection in subjects with ischemic cardiomyopathy.

Detailed Description
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This is a randomized, placebo-controlled clinical trial designed to evaluate the feasibility, safety, and effect of Combo, MSCs alone, and c-kit+ cells alone compared with placebo as well as each other in subjects with heart failure of ischemic etiology. Following a successful lead-in phase, a total of one hundred forty-four (144) subjects will be randomized (1:1:1:1) to receive Combo, MSCs, c-kit+ cells, or placebo. After randomization, baseline imaging, relevant harvest procedures, and study product injection, subjects will be followed up at 1 day, 1 week, 1 month, 3 months, 6 months and 12 months post study product injection. All subjects will receive study product injection (cells or placebo) using the NOGA® XP Mapping and Navigation System. Subjects will have delayed-enhanced magnetic resonance imaging (DEMRI) scans to assess scar size and LV function and structure at baseline and at 6 and 12 months post study product administration. All endpoints will be assessed at the 6 and 12 month visits which will occur 180 ±30 days and 365 ±30 days respectively from the day of study product injection (Day 0). For the purpose of the endpoint analysis and safety evaluations, the Investigators will utilize an intention-to-treat study population, however an as treated analysis will also be conducted.

Official Title
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A Phase II, Randomized, Placebo-Controlled Study of the Safety, Feasibility, & Efficacy of Autologous Mesenchymal Stem Cells & C-kit+ Cardiac Stem Cells, Alone or in Combination, Administered Transendocardially in Subjects With Ischemic HF

Conditions
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Ischemic Cardiomyopathy

Intervention / Treatment
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* Biological: Mesenchymal Stem Cells (MSC)
* Biological: c-kit+ cells
* Biological: Placebo (Plasmalyte A)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be ≥ 21 and <80 years of age Have documented coronary artery disease (CAD) with evidence of myocardial injury, LV dysfunction, and clinical evidence of HF Have a detectable area of myocardial injury defined as ≥ 5% LV involvement (infarct volume) and any subendocardial involvement by cMRI Have an EF ≤ 40% by cMRI Be receiving guideline-driven medical therapy for heart failure at stable and tolerated doses for ≥ 1 month prior to consent. For beta-blockade stable is defined as no greater than a 50% reduction in dose or no more than a 100% increase in dose. Be a candidate for cardiac catheterization Have NYHA class I, II, or III heart failure symptoms If a female of childbearing potential, be willing to use one form of birth control for the duration of the study, and undergo a pregnancy test at baseline and within 36 hours prior to injection Exclusion Criteria: Indication for standard-of-care surgery (including valve surgery, placement of left-ventricular assist device, or imminent heart transplantation), coronary artery bypass grafting (CABG) procedure, and/or percutaneous coronary intervention (PCI) for the treatment of ischemic and/or valvular heart disease. Subjects who require or undergo PCI should undergo these procedures a minimum of 3 months in advance of randomization. Subjects who require or undergo CABG should undergo these procedures a minimum of 4 months in advance of randomization. In addition, subjects who develop a need for revascularization following enrollment should undergo revascularization without delay. Indication for imminent heart transplantation is defined as a high likelihood of transplant prior to collection of the 12 month study endpoint. Candidates cannot be UNOS status 1A or 1B, and they must have documented low probability of being transplanted Valvular heart disease including 1) mechanical or bioprosthetic heart valve; or 2) severe (any valve) insufficiency/regurgitation within 12 months of consent Aortic stenosis with valve area ≤ 1.5 cm2 History of ischemic or hemorrhagic stroke within 90 days of consent History of a left ventricular remodeling surgical procedure utilizing prosthetic material Presence of a pacemaker and/or implantable cardioverter-defibrillator (ICD) generator with any of the following limitations/conditions: manufactured before the year 2000 leads implanted < 6 weeks prior to consent non-transvenous epicardial, or abandoned leads subcutaneous ICDs leadless pacemakers any other condition that, in the judgment of device-trained staff, would deem an MRI contraindicated Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without an ICD are not excluded) A cardiac resynchronization therapy (CRT) device implanted less than 3 months prior to consent Other MRI contraindications (e.g. patient body habitus incompatible with MRI) An appropriate ICD firing or anti-tachycardia pacing (ATP) for ventricular fibrillation or ventricular tachycardia within 30 days of consent Ventricular tachycardia ≥ 20 consecutive beats without an ICD within 3 months of consent, or symptomatic Mobitz II or higher degree atrioventricular block without a functioning pacemaker within 3 months of consent Presence of LV thrombus Evidence of active myocarditis Baseline maximal oxygen consumption (VO2 max) greater than 75% of age and gender based predictive values Baseline eGFR <35 ml/min/1.73m2 Blood glucose levels (HbA1c) >10% Hematologic abnormality evidenced by hematocrit < 25%, white blood cell < 2,500/ul or platelet count < 100,000/ul Liver dysfunction evidenced by enzymes (AST and ALT) ˃ 3 times the upper limit of normal (ULN) Coagulopathy (INR ≥ 1.3) not due to a reversible cause (e.g., warfarin and/or Factor Xa inhibitors). Subjects who cannot be withdrawn from anticoagulation will be excluded. HIV and/or active hepatitis B virus (HBV) or hepatitis C virus (HCV) Allergy to radiographic contrast material that cannot adequately be managed by premedication Known history of anaphylactic reaction to penicillin or streptomycin Received gene or cell-based therapy from any source within the previous 12 months History of malignancy within 5 years (i.e., subjects with prior malignancy must be disease free for 5 years), excluding basal cell carcinoma and cervical carcinoma in situ which have been definitively treated Condition that limits lifespan to < 1 year History of drug abuse (illegal street drugs except marijuana, or prescription medications not being used appropriately for a pre-existing medical condition) or alcohol abuse (≥ 5 drinks/day for ˃ 3 months), or documented medical, occupational, or legal problems arising from the use of alcohol or drugs within the past 24 months Participation in an investigational therapeutic or device trial within 30 days of consent Cognitive or language barriers that prohibit obtaining informed consent or any study elements Pregnancy or lactation or plans to become pregnant in the next 12 months Any other condition that, in the judgment of the Investigator or Sponsor, would impair enrollment, study product administration, or follow-up

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 79 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: Mesenchymal Stem Cells (MSC)<br>Target dose of 150 million MSCs | Biological: Mesenchymal Stem Cells (MSC)<br>* 15 transendocardial injections of 0.4ml MSCs administered to the left ventricle via NOGA Myostar injection catheter (single procedure)<br>|
| Experimental: c-kit+ cells<br>Target dose of 5 million c-kit+ cells | Biological: c-kit+ cells<br>* 15 transendocardial injections of 0.4ml c-kit+ cells administered to the left ventricle via NOGA Myostar injection catheter (single procedure)<br>|
| Experimental: Combination Cells (MSC and c-kit+ cells)<br>Target dose of 150 million MSCs and 5 million c-kit+ cells | Biological: Mesenchymal Stem Cells (MSC)<br>* 15 transendocardial injections of 0.4ml MSCs administered to the left ventricle via NOGA Myostar injection catheter (single procedure)<br>Biological: c-kit+ cells<br>* 15 transendocardial injections of 0.4ml c-kit+ cells administered to the left ventricle via NOGA Myostar injection catheter (single procedure)<br>|
| Placebo Comparator: Placebo (Plasmalyte A)<br>Plasmalyte A | Biological: Placebo (Plasmalyte A)<br>* 15 transendocardial injections of 0.4ml placebo administered to the left ventricle via NOGA Myostar injection catheter (single procedure)<br>* Other names: Plasmalyte A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | Change in left ventricular ejection fraction as assessed via cardiac MRI | Baseline to 6 months | 
| Change From Baseline in Global Strain (HARP MRI) | Change in global circumferential strain as assessed via cardiac MRI | Baseline to 6 months | 
| Change From Baseline in Regional Strain (HARP MRI) | Change in regional longitudinal strain as assessed via cardiac MRI | Baseline to 6 months | 
| Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) | Change in left ventricular end diastolic volume index as measured via cardiac MRI | Baseline to 6 months | 
| Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI) | Change in left ventricular end systolic volume index as assessed via cardiac MRI | Baseline to 6 months | 
| Change From Baseline in Left Ventricular Sphericity Index | Change in left ventricular sphericity as assessed via cardiac MRI. Sphericity index is the ratio of the long and short axis measurements of the left ventricle. | Baseline to 6 months | 
| Change From Baseline in Scar Size Percent (DEMRI) | Change in scar size percent as assessed via cardiac MRI | Baseline to 6 months | 
| Change From Baseline in Scar Tissue Mass (DEMRI) | Change in scar tissue mass as assessed via cardiac MRI | Baseline to 6 months | 
| Change From Baseline in Maximal Oxygen Consumption (Peak VO2) | Change in maximal oxygen consumption (peak V02) as assessed via treadmill | Baseline to 6 months | 
| Change From Baseline in Exercise Tolerance (Six Minute Walk Test) | Change in distance walked (in meters) as measured by the 6 minute walk test. Two walk tests were completed at each endpoint visit (separated by 30 minutes). The average distance of the two walk tests was used for analysis. | Baseline to 6 months | 
| Change From Baseline in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score | Change in the quality of life summary score as measured by the Minnesota Living with Heart Failure Questionnaire. Minimum and maximum scores for the scale are 0 and 105 respectively. Lower scores indicative of better outcomes. | Baseline to 6 months | 
| Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) | Change in N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) as measured via laboratory blood draw | Baseline to 6 months | 
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF)-Trajectory | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The second set of results reflects an overall model with all patients and the results represent the change per 6 months irrespective of treatment arm. | Assessed as a trajectory (baseline, 6 months, and 12 months) | 
| Change From Baseline in Global Strain (HARP MRI)-Trajectory | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The second set of results reflects an overall model with all patients and the results represent the change per 6 months irrespective of treatment arm. | Assessed as a trajectory (baseline, 6 months, and 12 months) | 
| Change From Baseline in Regional Strain (HARP MRI)-Trajectory | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The second set of results reflects an overall model with all patients and the results represent the change per 6 months irrespective of treatment arm. | Assessed as a trajectory (baseline, 6 months, and 12 months) | 
| Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)-Trajectory | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The second set of results reflects an overall model with all patients and the results represent the change per 6 months irrespective of treatment arm. | Assessed as a trajectory (baseline, 6 months, and 12 months) | 
| Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)-Trajectory | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The second set of results reflects an overall model with all patients and the results represent the change per 6 months irrespective of treatment arm. | Assessed as a trajectory (baseline, 6 months, 12 months) | 
| Change From Baseline in Left Ventricular Sphericity Index-Trajectory | Sphericity index is the ratio of the long and short axis measurements of the left ventricle. The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The second set of results reflects an overall model with all patients and the results represent the change per 6 months irrespective of treatment arm. | Assessed as a trajectory (baseline, 6 months, and 12 months) | 
| Change From Baseline in Scar Size Percent (DEMRI)-Trajectory | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The second set of results reflects an overall model with all patients and the results represent the change per 6 months irrespective of treatment arm. | Assessed as a trajectory (baseline, 6 months, and 12 months) | 
| Change From Baseline in Scar Tissue Mass (DEMRI)-Trajectory | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The second set of results reflects an overall model with all patients and the results represent the change per 6 months irrespective of treatment arm. | Assessed as a trajectory (baseline, 6 months, and 12 months) | 
| Change From Baseline in Maximal Oxygen Consumption (Peak VO2)-Trajectory | The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The second set of results reflects an overall model with all patients and the results represent the change per 6 months irrespective of treatment arm. | Assessed as a trajectory (baseline, 6 months, and 12 months) | 
| Change From Baseline in Exercise Tolerance (Six Minute Walk Test)-Trajectory | Two walk tests were completed at each endpoint visit (separated by 30 minutes). The average distance of the two walk tests was used for analysis. The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The second set of results reflects an overall model with all patients and the results represent the change per 6 months irrespective of treatment arm. | Assessed as a trajectory (baseline, 6 months, and 12 months) | 
| Change From Baseline in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score-Trajectory | Minimum and maximum scores for the scale are 0 and 105 respectively. Lower scores indicative of better outcomes. The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The 2nd and 3rd set of results represent differences for varying slopes from the interaction model. | Assessed as a trajectory (baseline, 6 months, and 12 months) | 
| Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)-Trajectory | Log transformation used. The change in this measure over time is assessed using a repeated measures linear regression model of trajectory (change over time). The first set of results reflects the model within each arm and represents change per 6 months within that treatment arm. The second set of results reflects an overall model with all patients and the results represent the change per 6 months irrespective of treatment arm. | Assessed as a trajectory (baseline, 6 months, and 12 months) | 
| Participants With Major Adverse Cardiac Events (MACE) | Number of participants with adjudicated events including death, hospitalization for worsening heart failure, and/or other exacerbation of heart failure (non-hospitalization). | Baseline to End of 12 Month Visit Window, an average of 395 days following study product injection | 
| Participants Experiencing Other Significant Clinical Events | Number of participants experiencing other significant adjudicated clinical events including: non-fatal stroke, non-fatal MI, coronary artery revascularization, ventricular tachycardia/fibrillation, and pericardial tamponade | Baseline to End of 12 Month Visit Window, an average of 395 days following study product injection | 
| Cumulative Days Alive and Out of Hospital for Heart Failure | Days alive and out of hospital during the study evaluation period. Subjects were allotted a visit window extending 30 days past their anticipated 12-month visit. Some participants had extended 12-month visit windows due to the COVID-19 pandemic. | Baseline to End of 12 Month Visit Window, an average of 395 days following study product injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Ischemia, Autologous Stem Cells, LV dysfunction, Mesenchymal Stem Cells, c-kit+ Cells, Combination Cell Therapy, LV function, Functional status