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

Phase 2

Completed

Conditions: Ischemic Cardiomyopathy

Interventions: Biological: c-kit+ cells
Biological: Mesenchymal Stem Cells (MSC)
Biological: Placebo (Plasmalyte A)

Registration Number: NCT02501811

Lead Sponsor: The University of Texas Health Science Center, Houston

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 125

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
c-kit+ cells	c-kit+ cells	Target dose of 5 million c-kit+ cells
Mesenchymal Stem Cells (MSC)	Mesenchymal Stem Cells (MSC)	Target dose of 150 million MSCs
Combination Cells (MSC and c-kit+ cells)	Mesenchymal Stem Cells (MSC)	Target dose of 150 million MSCs and 5 million c-kit+ cells
Placebo (Plasmalyte A)	Placebo (Plasmalyte A)	Plasmalyte A
Combination Cells (MSC and c-kit+ cells)	c-kit+ cells	Target dose of 150 million MSCs and 5 million c-kit+ cells

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)	Baseline to 6 months	Change in left ventricular ejection fraction as assessed via cardiac MRI
Change From Baseline in Global Strain (HARP MRI)	Baseline to 6 months	Change in global circumferential strain as assessed via cardiac MRI
Change From Baseline in Regional Strain (HARP MRI)	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)	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)	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	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)	Baseline to 6 months	Change in scar size percent as assessed via cardiac MRI
Change From Baseline in Scar Tissue Mass (DEMRI)	Baseline to 6 months	Change in scar tissue mass as assessed via cardiac MRI
Change From Baseline in Maximal Oxygen Consumption (Peak VO2)	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)	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	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)	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	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	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	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	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	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	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	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	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	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	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	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	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)	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	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	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.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (7): University of Louisville
🇺🇸
Louisville, Kentucky, United States
Stanford University School of Medicine (Falk Cardiovascular Research Center)
🇺🇸
Stanford, California, United States
University of Florida-Department of Medicine
🇺🇸
Gainesville, Florida, United States
University of Miami-Interdisciplinary Stem Cell Institute
🇺🇸
Miami, Florida, United States
Indiana Center for Vascular Biology and Medicine
🇺🇸
Indianapolis, Indiana, United States
Texas Heart Institute
🇺🇸
Houston, Texas, United States
Minneapolis Heart Institute Foundation
🇺🇸
Minneapolis, Minnesota, United States