Administration of Allogeneic-MSC in Patients With Non-Ischemic Dilated Cardiomyopathy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and effectiveness of an experimental drug called human allogeneic mesenchymal stem cell therapy.

Official Title
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A Phase IIB Randomized, Placebo-Controlled, Multicenter Study of the Comparative Efficacy and Safety of Administration of Allogeneic-MSC Versus Placebo in Patients With Non- Ischemic Dilated Cardiomyopathy

Conditions
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Non-ischemic Dilated Cardiomyopathy

Intervention / Treatment
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* Biological: allogeneic human mesenchymal stem cells (hMSCs)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Men and women aged 18 to 80 years (inclusive) at the time of signing the informed consent form. Diagnosis of NIDCM with left ventricular ejection fraction ≤45%. Appropriate guideline-directed optimal medical therapy for non-ischemic cardiomyopathy. At a minimum, subjects must be on beta blockers and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) or Angiotensin Receptor Neprilysin Inhibitors (ARNI) or have appropriate medical indication precluding use of one or both of these agents. Subjects must be on a stable regimen for at least 30 days prior to the procedure. Dose titration is allowed. Be a candidate for cardiac catheterization* Be willing to undergo DNA test. Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: Be eligible for or require standard-of-care surgical or percutaneous intervention for the treatment of non-ischemic dilated cardiomyopathy Clinical manifestation of coronary artery disease (CAD) (e.g., chest pain and concomitant clinical findings such as electrocardiogram changes suggestive of coronary ischemia, myocardial infarction) or evidence of endocardial or transmural scar on cardiac MRI suggestive of undiagnosed CAD or history of percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). Be indicated for or require coronary artery revascularization Documented presence of epicardial stenosis of 70% or greater in one or more major epicardial coronary arteries Valvular heart disease including 1) aortic valve prosthesis, mechanical mitral valve, and mitral valve clip; 2) severe aortic valve insufficiency/regurgitation within 12 months of consent* Aortic stenosis with valve area ≤ 1.5cm2* Cardiomyopathy due to acute Post-partum (within 6 months), Non-compaction*, or Hypertrophic* cardiomyopathy Cardiomyopathy due to known toxin (e.g amyloid) Note: anthracycline induced cardiomyopathy will be allowed QTc interval > 550 ms on baseline electrocardiogram (ECG) (note: QTc interval is the interval between the start of the Q wave and the end of the T wave in the heart's electrical cycle) Automated Implantable Cardioverter Defibrillator (AICD) appropriate firing or anti tachycardia pacing for ventricular tachycardia or ventricular fibrillation within 30 days prior to consent Have an estimated baseline glomerular filtration rate below the clinical site's institutional cutoff A hematologic abnormality during baseline testing as evidenced by hemoglobin < 9 g/dl; hematocrit < 30%; absolute neutrophil count < 2,000 or total WBC count more than 2 times upper limit of normal; or platelet values < 100,000/ul Have liver dysfunction, as evidenced by enzymes Aspartate Transaminase Enzyme (AST) and Alanine Aminotransferase Enzyme (ALT) greater than three times the ULN Have a bleeding diathesis or coagulopathy (International Normalised Ratio (INR) > 1.5), cannot be withdrawn from anticoagulation therapy, or will refuse blood transfusions Be a solid organ transplant recipient. This does not include prior cell based therapy (>12 months prior to enrollment), bone, skin, ligament, tendon or corneal grafting. Have a history of organ or cell transplant rejection Have a clinical history of malignancy within the past 12 months (i.e., subjects with prior malignancy must be disease free for 12 months), except curatively treated basal cell or squamous cell carcinoma or cervical carcinoma Drug and/or alcohol abuse or dependence within the past 9 months Be serum positive for HIV, hepatitis B surface antigen, or viremic hepatitis C Documented presence of a known Left Ventricular (LV) thrombus, aortic dissection, or aortic aneurysm. (Refer to Guidance to the PI section with regards to LV thrombus, below)* Blood glucose levels (HbA1c) >10% Severe radiographic contrast allergy Known history of anaphylactic reaction to penicillin or streptomycin Hypersensitivity to dimethyl sulfoxide (DMSO) Non-cardiac condition with life expectancy < 1 year Acute stroke or transient ischemic attack within 3 months of enrollment Be pregnant, nursing, or of childbearing potential while not practicing effective contraceptive methods Pacemaker-dependence with an Implantable Cardioverter Defibrillator (ICD) (Note: pacemaker-dependent candidates without an ICD are not excluded) Presence of a pacemaker and/or 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 A cardiac resynchronization therapy (CRT) device implanted less than 3 months prior to consent Other MRI contraindications (e.g. subject body habitus incompatible with MRI) Need for advanced heart failure therapy (e.g. IV inotropes) Be currently participating (or participated within the previous 30 days) in an investigational therapeutic or device trial Any other condition that in the judgment of the Investigator would be a contraindication to enrollment or follow-up (*) Applies to subjects receiving product via transendocardial administration only

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 |
| --- | --- |
| Placebo Comparator: Genotype A administered with placebo Group<br>Participants whose blood genotyping resulted with Genotype A (absence of any variant/ presence of benign variant) and randomized to the placebo group will receive the placebo intervention. | Other: Placebo<br>* Placebo will be administered as injections of plasmalyte A supplemented with 1% of 25% human serum albumin (HSA). 0.5 ml/ injection x 10 injections or an intravenous placebo infusion of Cell-free PlasmaLyte-A medium supplemented with 1% of 25% human serum albumin (HSA)<br>|
| Experimental: Genotype A administered with hMSC Group<br>Participants whose blood genotyping resulted with Genotype A (absence of any variant/ presence of benign variant) and randomized to the treatment group will receive the hMSC intervention. | Biological: allogeneic human mesenchymal stem cells (hMSCs)<br>* allo-hMSCs, 16-20 million cells/ml delivered at a dose of 0.5 ml/ injection x 10 injections for a total of 80-100 million allo-hMSCs or a single administration of intravenous allogeneic hMSCs (100 million).<br>|
| Placebo Comparator: Genotype B administered with placebo Group<br>Participants whose blood genotyping resulted with Genotype B (variants of uncertain significance) and randomized to the placebo group will receive the placebo intervention. | Other: Placebo<br>* Placebo will be administered as injections of plasmalyte A supplemented with 1% of 25% human serum albumin (HSA). 0.5 ml/ injection x 10 injections or an intravenous placebo infusion of Cell-free PlasmaLyte-A medium supplemented with 1% of 25% human serum albumin (HSA)<br>|
| Experimental: Genotype B administered with hMSC Group<br>Participants whose blood genotyping resulted with Genotype B (variants of uncertain significance) and randomized to the treatment group will receive the hMSC intervention. | Biological: allogeneic human mesenchymal stem cells (hMSCs)<br>* allo-hMSCs, 16-20 million cells/ml delivered at a dose of 0.5 ml/ injection x 10 injections for a total of 80-100 million allo-hMSCs or a single administration of intravenous allogeneic hMSCs (100 million).<br>|
| Placebo Comparator: Genotype C administered with placebo Group<br>Participants whose blood genotyping resulted with Genotype C (pathogenic or likely pathogenic variants) and randomized to the placebo group will receive the placebo intervention. | Other: Placebo<br>* Placebo will be administered as injections of plasmalyte A supplemented with 1% of 25% human serum albumin (HSA). 0.5 ml/ injection x 10 injections or an intravenous placebo infusion of Cell-free PlasmaLyte-A medium supplemented with 1% of 25% human serum albumin (HSA)<br>|
| Experimental: Genotype C administered with hMSC Group<br>Participants whose blood genotyping resulted with Genotype C (pathogenic or likely pathogenic variants) and randomized to the treatment group will receive the hMSC intervention. | Biological: allogeneic human mesenchymal stem cells (hMSCs)<br>* allo-hMSCs, 16-20 million cells/ml delivered at a dose of 0.5 ml/ injection x 10 injections for a total of 80-100 million allo-hMSCs or a single administration of intravenous allogeneic hMSCs (100 million).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in LVEF | Change in Left Ventricular Ejection Fraction (LVEF) as assessed via cardiac Magnetic Resonance Imaging (MRI) | Baseline, 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in global ventricular strain | Change in global ventricular strain as assessed via cardiac Harmonic Phase (HARP) MRI | Baseline, 12 months | 
| Change in left regional strain | Change in regional ventricular strain as assessed via cardiac HARP MRI | Baseline, 12 months | 
| Left ventricular function concordance | The left ventricular function concordance will be measured as the Number of individuals who experienced an increase in left ventricular ejection fraction (LVEF) and a simultaneous decrease in both left ventricular end systolic volume index (LVESVI) and left ventricular end diastolic volume index (LVEDVI) | 12 months | 
| Change in LVEDVI | Change in left ventricular end diastolic index (LVEDVI) as assessed via cardiac MRI | Baseline, 12 months | 
| Change in LVESVI | Change in left ventricular end systolic index (LVESVI) as assessed via cardiac MRI | Baseline, 12 months | 
| Change in Maximal oxygen consumption (peak VO2) | Change in maximal oxygen consumption (peak VO2) as assessed via treadmill | Baseline, 12 months | 
| Change in Exercise tolerance | Change in exercise tolerance as assessed as the distance covered via the six-minute walk test | Baseline, 12 months | 
| Change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) Score | Minnesota Living with Heart Failure Questionnaire (MLHFQ) is a 21-item questionnaire with a total score ranging from 0 to 105 with lower scores indicative of better outcome. | Baseline, 12 months | 
| Change in New York Heart Association (NYHA) Class | NYHA Classifications of heart failure are as follows: Class I (no limitations); Class II (mild symptoms); Class III (marked limitations); Class IV (Severe limitations) | Baseline, 12 months | 
| Percent change in flow mediated diameter | Change in endothelial function will be reported as the percent change in flow mediated diameter assessed via flow mediated dilation (FMD). | Baseline, 12 months | 
| Change in EPC-CFU | Change in endothelial function will be reported as the change in Endothelial Progenitor Cell Colony Forming Unit (EPC-CFU) assessed via blood sample assay | Baseline, 12 months | 
| Change in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) | Change in NT-proBNP as assessed via blooddraw | Baseline, 12 months | 
| Change in cytokines | Change in NT-proBNP as assessed via blooddraw | Baseline, 12 months | 
| Incidence of MACE | Safety will be reported as the incidence of Major Adverse Cardiac Events (MACE) assessed by treating physician | 12 months | 
| Incidence of TE-SAEs | Safety will be reported as the incidence of Treatment Emergent Serious Adverse Events (TE-SAEs) assessed by treating physician | Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic mesenchymal stem cells, Bone marrow-derived mesenchymal stem cells