The TRansendocardial Stem Cell Injection Delivery Effects on Neomyogenesis STudy (The TRIDENT Study)

Study Overview
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Brief Summary
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Thirty (30) patients with chronic ischemic left ventricular dysfunction secondary to MI scheduled to undergo cardiac catheterization will be enrolled in the study. This is a phase II study intended to gain additional safety and efficacy assessments among two dose levels previously studied in a phase I setting.

Detailed Description
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Thirty (30) patients with chronic ischemic left ventricular dysfunction secondary to MI scheduled to undergo cardiac catheterization will be enrolled in the study.This is a phase II study intended to gain additional safety and efficacy assessments among two dose levels previously studied in a phase I setting. In this study, a 20 million total hMSC dose and a 100 million total hMSC dose will be randomly allocated administered via the Biocardia Helical infusion system in a blinded manner. 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, which is 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 grafts9, 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 studied clinically. Currently, bone marrow or bone marrow-derived cells represent a 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 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 II, Randomized, Blinded, Study of the Safety and Efficacy of Transendocardial Injection of Allogeneic Human Mesenchymal Stem Cells (hMSCs) (20 Million or 100 Million Total MSCs) in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction.

Conditions
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Chronic Ischemic Left Ventricular Dysfunction, Myocardial Infarction

Intervention / Treatment
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* Biological: Allogeneic hMSCs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to participate in this study, a patient MUST: Be ≥ 21 and < 90 years of age. Provide written informed consent. Have a diagnosis of chronic ischemic left ventricular dysfunction secondary to myocardial infarction (MI) as defined by previous myocardial infarction documented by an imaging study demonstrating coronary artery disease with corresponding areas of akinesis, dyskinesis, or severe hypokinesis. Been treated with appropriate maximal medical therapy for heart failure or post-infarction left ventricular dysfunction. For beta-blockade, the patient must have been on a stable dose of a clinically appropriate beta-blocker for 3 months. For angiotensin-converting enzyme inhibition, the patient must have been on a stable dose of a clinically appropriate agent for 1 month. Be a candidate for cardiac catheterization within 5 to 10 weeks of screening as determined by doctors. Have an ejection fraction of less than or equal to 50% by gated blood pool scan, two-dimensional echocardiogram, CT, or left ventriculogram within the prior six months and not in the setting of a recent ischemic event. Exclusion Criteria: In order to participate in this study, a patient MUST NOT: Have a baseline glomerular filtration rate ≤ 35 ml/min/1.73m2. Have a known, serious radiographic contrast allergy. Have a Mechanical aortic valve or heart constrictive device. Have a documented presence of aortic stenosis (aortic stenosis graded as 1.5cm2 or less). Have a documented presence of moderate to severe aortic insufficiency (echocardiographic assessment of aortic insufficiency graded as ≥+2). Require coronary artery revascularization. Patients who require or undergo revascularization procedures should undergo these procedures a minimum of 3 months in advance of treatment in this study. In addition, patients who develop a need for revascularization following enrollment will be submitted for this therapy without delay. Have evidence of a life-threatening arrhythmia in the absence of a defibrillator (non-sustained ventricular tachycardia ≥ 20 consecutive beats or complete second or third degree heart block in the absence of a functioning pacemaker) or Corrected for heart rate (QTc) interval > 550 ms on screening ECG Automatic Implantable Cardioverter Defibrillator (AICD) firing in the past 60 days prior to enrollment. Have a hematologic abnormality as evidenced by hematocrit < 25%, white blood cell < 2,500/µl or platelet values < 100,000/µl without another explanation. Have liver dysfunction, as evidenced by enzymes (AST and ALT) greater than three times the upper limit of normal (ULN). Have a coagulopathy = (INR > 1.3) not due to a reversible cause (i.e., Coumadin). Patients on Coumadin will be withdrawn 5 days before the procedure and confirmed to have an INR < 1.3. Patients who cannot be withdrawn from Coumadin will be excluded from enrollment Have known allergies to penicillin or streptomycin. Hypersensitivity to Dimethyl Sulfoxide (DMSO). Be an organ transplant recipient. Have a history of organ or cell transplant rejection Have a 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, melanoma in situ or cervical carcinoma. Have a non-cardiac condition that limits lifespan to < 1 year. Have a history of drug or alcohol abuse within the past 24 months. Be on chronic therapy with immunosuppressant medication, such as corticosteroids or TNFα antagonists. Be serum positive for HIV, hepatitis BsAg or viremic hepatitis C. Be currently participating (or participated within the previous 30 days) in an investigational therapeutic or device trial. Be a female who is pregnant, nursing, or of childbearing potential while not practicing effective contraceptive methods. Female patients must undergo a blood or urine pregnancy test at screening and within 36 hours prior to injection.

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: Group 1: 20 million Allogeneic hMSCs<br>Fifteen (15) patients to be treated with Allo-hMSCs: 4 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 0.2x 10^8 (20 million) Allo-hMSCs. | Biological: Allogeneic hMSCs<br>* Allogeneic Adult Human Mesenchymal Stem Cells (MSCs) delivered via injection<br>* Other names: Allogeneic Adult Human Mesenchymal Stem Cells (MSCs);|
| Experimental: Group 2: 100 million Allogeneic hMSCs<br>Fifteen (15) patients to be treated with Allo-hMSCs: 20 million cells/ml delivered in a dose of 0.5 ml per injection x 10 injections for a total of 1x 10^8 (100 million) Allo-hMSCs. | Biological: Allogeneic hMSCs<br>* Allogeneic Adult Human Mesenchymal Stem Cells (MSCs) delivered via injection<br>* Other names: Allogeneic Adult Human Mesenchymal Stem Cells (MSCs);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Serious Adverse Events (SAE). | Incidence (at one month post-catheterization) of any treatment-emergent serious adverse events, defined as the composite of: death, non-fatal MI, stroke, hospitalization for worsening heart failure, cardiac perforation, pericardial tamponade, sustained ventricular arrhythmias (characterized by ventricular arrhythmias lasting longer than 15 seconds or with hemodynamic compromise). | One month post-catheterization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infarct Scar Size (ISS) | Determined by delayed contrast enhanced Computed Tomography (CT) Scan | Baseline, 12 months | 
| Number of Participant With Reported Tissue Perfusion | Tissue perfusion measured by CT. | 6 months, 12 months | 
| Peak Oxygen Consumption (VO2) | Peak VO2 assessed via treadmill determination. | Baseline, 6 months, 12 months | 
| Six-minute Walk Test. | A test that measures how far a patient can walk in 6 minutes. | Baseline, 3 months, 6 months, 12 months | 
| Changed in New York Heart Association (NYHA) Functional Classification Based on Patient's Self Reported Activity Level. | Changed in NYHA Functional Classification will be evaluated. Worsened: Documented increase in limitation in physical activity. Improved: Documented decrease in limitation in physical activity. Unchanged: No documented change in limitation in physical activity. | Baseline to 3 months, Baseline to 6 months, Baseline to 12 months | 
| Number of Incidents of Major Adverse Cardiac Events (MACE). | Incidence of the Major Adverse Cardiac Events (MACE) endpoint, defined as the composite incidence of (1) death, (2) hospitalization for worsening heart failure, or (3) non-fatal recurrent MI. | 1 month, 6 months, 12 months post injection. | 
| Number of Participants With Treatment Emergent Adverse Event (AE) | Incidence of Treatment Emergent Adverse Event defined as any untoward medical occurrence in a patient or clinical investigation subject temporally associated with the use of the study product. | 6 months, 12 months | 
| Minnesota Living With Heart Failure (MLHF) Questionnaire Scores | Minnesota Living with Heart Failure (MLHF) Questionnaire has a total score from 0 to 105. A higher score indicates that participant's heart failure is preventing them from living their life. | Baseline, 3 months, 6 months, 12 months | 
| Echocardiographic-derived Measures of Left Ventricular Function | Left ventricular end diastolic wall thickness as determined by echocardiogram. | 6 months, 12 months | 
| Difference Between Regional Left Ventricular Function (at the Site of Allogeneic Cell Injections) | As determined by Computed Tomography Scan | Baseline, 12 Months | 
| Difference Between the Regional Left Ventricular Wall Thickening | As determined by Computed Tomography Scan | Baseline, Month 12 | 
| Difference Between Left Ventricular End Diastolic Wall Thickness | As determined by Computed Tomography Scan | Baseline, 12 Months | 
| Difference Between the Left Ventricular Ejection Fraction (LVEF) | Change in 1-year LVEF by CT as compared to baseline. | Baseline, 12 months | 
| Difference in LVEF | As assessed via ECHO | Baseline, 6 months, 12 months | 
| Difference in Left Ventricular Volume | Difference in left ventricular end diastolic and end systolic volume will be assessed via ECHO | Baseline, 6 months, 12 months | 
| Difference in Left Ventricular Volume | Difference in left ventricular end diastolic and end systolic volume will be assessed via CT | Baseline, 12 months | 
| Difference in Left Ventricular Regional Myocardial Perfusion | As measured via myocardial mass by CT | Baseline, 12 months | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Reads. | The number of participants with abnormal ECG readings via 24 hour ambulatory ECG recordings as assessed per treating physician discretion. | 12 months | 
| Number of Clinically Significant of Abnormal Lab Values. | Clinical significance of abnormal lab values will be assessed by treating physician | 12 months | 
| Serial Troponin I | Serial Troponin I values in ng/mL over time. | 12 hours, 24 hours post cardiac catheterization | 
| Number of Participants With Abnormal ECHO Reading | The number of participants with abnormal reading post-cardiac catheterization. As assessed per treating physician discretion. | 6 hours post cardiac catheterization | 
| Creatinine Kinase Muscle/Brain (CK-MB) | CK-MB values in ng/mL over time. | 12 hours, 24 hours post cardiac catheterization | 

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