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
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Ischemic Cardiomyopathy
- Sponsor
- The University of Texas Health Science Center, Houston
- Enrollment
- 125
- Locations
- 7
- Primary Endpoint
- Change From Baseline in Left Ventricular Ejection Fraction (LVEF)
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
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
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.
Investigators
Barry R Davis
Professor of Biostatistics
The University of Texas Health Science Center, Houston
Eligibility Criteria
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
Outcomes
Primary Outcomes
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)
Time Frame: Baseline to 6 months
Change in left ventricular ejection fraction as assessed via cardiac MRI
Change From Baseline in Global Strain (HARP MRI)
Time Frame: Baseline to 6 months
Change in global circumferential strain as assessed via cardiac MRI
Change From Baseline in Regional Strain (HARP MRI)
Time Frame: Baseline to 6 months
Change in regional longitudinal strain as assessed via cardiac MRI
Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)
Time Frame: Baseline to 6 months
Change in left ventricular end diastolic volume index as measured via cardiac MRI
Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)
Time Frame: Baseline to 6 months
Change in left ventricular end systolic volume index as assessed via cardiac MRI
Change From Baseline in Left Ventricular Sphericity Index
Time Frame: Baseline to 6 months
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.
Change From Baseline in Scar Size Percent (DEMRI)
Time Frame: Baseline to 6 months
Change in scar size percent as assessed via cardiac MRI
Change From Baseline in Scar Tissue Mass (DEMRI)
Time Frame: Baseline to 6 months
Change in scar tissue mass as assessed via cardiac MRI
Change From Baseline in Maximal Oxygen Consumption (Peak VO2)
Time Frame: Baseline to 6 months
Change in maximal oxygen consumption (peak V02) as assessed via treadmill
Change From Baseline in Exercise Tolerance (Six Minute Walk Test)
Time Frame: Baseline to 6 months
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.
Change From Baseline in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score
Time Frame: Baseline to 6 months
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.
Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)
Time Frame: Baseline to 6 months
Change in N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) as measured via laboratory blood draw
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
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.
Change From Baseline in Global Strain (HARP MRI)-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
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.
Change From Baseline in Regional Strain (HARP MRI)-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
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.
Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
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.
Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI)-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, 12 months)
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.
Change From Baseline in Left Ventricular Sphericity Index-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
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.
Change From Baseline in Scar Size Percent (DEMRI)-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
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.
Change From Baseline in Scar Tissue Mass (DEMRI)-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
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.
Change From Baseline in Maximal Oxygen Consumption (Peak VO2)-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
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.
Change From Baseline in Exercise Tolerance (Six Minute Walk Test)-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
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.
Change From Baseline in Minnesota Living With Heart Failure Questionnaire (MLHFQ) Score-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
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.
Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)-Trajectory
Time Frame: Assessed as a trajectory (baseline, 6 months, and 12 months)
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.
Participants With Major Adverse Cardiac Events (MACE)
Time Frame: Baseline to End of 12 Month Visit Window, an average of 395 days following study product injection
Number of participants with adjudicated events including death, hospitalization for worsening heart failure, and/or other exacerbation of heart failure (non-hospitalization).
Participants Experiencing Other Significant Clinical Events
Time Frame: Baseline to End of 12 Month Visit Window, an average of 395 days following study product injection
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
Cumulative Days Alive and Out of Hospital for Heart Failure
Time Frame: Baseline to End of 12 Month Visit Window, an average of 395 days following study product injection
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.