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

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

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.

Study Overview

• Status: Completed
• Conditions: Ischemic Cardiomyopathy
• Intervention / Treatment: Biological: Mesenchymal Stem Cells (MSC); Biological: c-kit+ cells; Biological: Placebo (Plasmalyte A)

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.

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine (Falk Cardiovascular Research Center)
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida-Department of Medicine
    • Miami, Florida, United States, 33101
      • University of Miami-Interdisciplinary Stem Cell Institute
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana Center for Vascular Biology and Medicine
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Minneapolis Heart Institute Foundation
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Heart Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 79 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Be ≥ 21 and <80 years of age
2. Have documented coronary artery disease (CAD) with evidence of myocardial injury, LV dysfunction, and clinical evidence of HF
3. Have a "detectable" area of myocardial injury defined as ≥ 5% LV involvement (infarct volume) and any subendocardial involvement by cMRI
4. Have an EF ≤ 40% by cMRI
5. 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.
6. Be a candidate for cardiac catheterization
7. Have NYHA class I, II, or III heart failure symptoms
8. 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:

1. 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
2. Valvular heart disease including 1) mechanical or bioprosthetic heart valve; or 2) severe (any valve) insufficiency/regurgitation within 12 months of consent
3. Aortic stenosis with valve area ≤ 1.5 cm2
4. History of ischemic or hemorrhagic stroke within 90 days of consent
5. History of a left ventricular remodeling surgical procedure utilizing prosthetic material

6. 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
7. Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without an ICD are not excluded)
8. A cardiac resynchronization therapy (CRT) device implanted less than 3 months prior to consent
9. Other MRI contraindications (e.g. patient body habitus incompatible with MRI)
10. An appropriate ICD firing or anti-tachycardia pacing (ATP) for ventricular fibrillation or ventricular tachycardia within 30 days of consent
11. 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
12. Presence of LV thrombus
13. Evidence of active myocarditis
14. Baseline maximal oxygen consumption (VO2 max) greater than 75% of age and gender based predictive values
15. Baseline eGFR <35 ml/min/1.73m2
16. Blood glucose levels (HbA1c) >10%
17. Hematologic abnormality evidenced by hematocrit < 25%, white blood cell < 2,500/ul or platelet count < 100,000/ul
18. Liver dysfunction evidenced by enzymes (AST and ALT) ˃ 3 times the upper limit of normal (ULN)
19. 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.
20. HIV and/or active hepatitis B virus (HBV) or hepatitis C virus (HCV)
21. Allergy to radiographic contrast material that cannot adequately be managed by premedication
22. Known history of anaphylactic reaction to penicillin or streptomycin
23. Received gene or cell-based therapy from any source within the previous 12 months
24. 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
25. Condition that limits lifespan to < 1 year
26. 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
27. Participation in an investigational therapeutic or device trial within 30 days of consent
28. Cognitive or language barriers that prohibit obtaining informed consent or any study elements
29. Pregnancy or lactation or plans to become pregnant in the next 12 months
30. Any other condition that, in the judgment of the Investigator or Sponsor, would impair enrollment, study product administration, or follow-up

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mesenchymal Stem Cells (MSC); Target dose of 150 million MSCs	Biological: Mesenchymal Stem Cells (MSC); 15 transendocardial injections of 0.4ml MSCs administered to the left ventricle via NOGA Myostar injection catheter (single procedure)
Experimental: c-kit+ cells; Target dose of 5 million c-kit+ cells	Biological: c-kit+ cells; 15 transendocardial injections of 0.4ml c-kit+ cells administered to the left ventricle via NOGA Myostar injection catheter (single procedure)
Experimental: Combination Cells (MSC and c-kit+ cells); Target dose of 150 million MSCs and 5 million c-kit+ cells	Biological: Mesenchymal Stem Cells (MSC); 15 transendocardial injections of 0.4ml MSCs administered to the left ventricle via NOGA Myostar injection catheter (single procedure); Biological: c-kit+ cells; 15 transendocardial injections of 0.4ml c-kit+ cells administered to the left ventricle via NOGA Myostar injection catheter (single procedure)
Placebo Comparator: Placebo (Plasmalyte A); Plasmalyte A	Biological: Placebo (Plasmalyte A); 15 transendocardial injections of 0.4ml placebo administered to the left ventricle via NOGA Myostar injection catheter (single procedure); Other Names: Plasmalyte A

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjects With Events Between Randomization and Study Product Injection (SPI) That Preclude the Receipt of Product	Number and percent of subjects with events between randomization and study product injection (SPI) that preclude the subject from receiving product. Reasons include those who did not undergo harvest (n=6; death, subject withdraw, subject changed mind) and those who did not undergo SPI (n=9; death, LVAD placement, episodes of ventricular tachycardia, and cancelled procedures)	Randomization to SPI, an average of 14 weeks
Subjects Who Have a Failed Bone Marrow Aspiration Procedure	Number and percent of subjects who do not successfully undergo bone marrow aspiration	During bone marrow aspiration procedure
Subjects Who Have a Failed Endomyocardial Biopsy Procedure	Number and percent of subjects who do not successfully undergo endomyocardial biopsy procedure. Note only participants who were assigned to MSC+CPC or to CPC groups had endomyocardial biopsy procedures attempted.	During endomyocardial biopsy procedure
Subject MSC Products Which Failed Release Criteria	Number and percent of subjects who have MSC products which failed release criteria	Harvest to Study Product Injection Procedure
Subject CPC Products Which Failed Release Criteria	Number and percent of subjects who have CPC products which failed release criteria	Harvest to Study Project Injection procedure
Subjects Who Receive Less Than 15 Injections During SPI	Number and percent of subjects who received less than 15 injections during SPI	During SPI procedure
Subjects Who Have at Least One Cardiac MRI Endpoint Measure That is Uninterpretable	Number and percent of subjects who have at least one cardiac MRI endpoint measure that is uninterpretable due to issues related to the device, including, but not limited to, inability to undergo the procedure	Baseline to 12 months

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center, Houston
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Hare JM, Bolli R, Cooke JP, Gordon DJ, Henry TD, Perin EC, March KL, Murphy MP, Pepine CJ, Simari RD, Skarlatos SI, Traverse JH, Willerson JT, Szady AD, Taylor DA, Vojvodic RW, Yang PC, Moye LA; Cardiovascular Cell Therapy Research Network. Phase II clinical research design in cardiology: learning the right lessons too well: observations and recommendations from the Cardiovascular Cell Therapy Research Network (CCTRN). Circulation. 2013 Apr 16;127(15):1630-5. doi: 10.1161/CIRCULATIONAHA.112.000779. No abstract available.
• Nazarian S, Halperin HR. How to perform magnetic resonance imaging on patients with implantable cardiac arrhythmia devices. Heart Rhythm. 2009 Jan;6(1):138-43. doi: 10.1016/j.hrthm.2008.10.021. Epub 2008 Oct 22. No abstract available.
• Bolli R, Hare JM, March KL, Pepine CJ, Willerson JT, Perin EC, Yang PC, Henry TD, Traverse JH, Mitrani RD, Khan A, Hernandez-Schulman I, Taylor DA, DiFede DL, Lima JAC, Chugh A, Loughran J, Vojvodic RW, Sayre SL, Bettencourt J, Cohen M, Moye L, Ebert RF, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit+ Cardiac Stem Cells As Regenerative Therapy for Heart Failure). Circ Res. 2018 Jun 8;122(12):1703-1715. doi: 10.1161/CIRCRESAHA.118.312978. Epub 2018 Apr 27.
• Kato Y, Kizer JR, Ostovaneh MR, Lazar J, Peng Q, van der Geest RJ, Lima JAC, Ambale-Venkatesh B. Extracellular volume-guided late gadolinium enhancement analysis for non-ischemic cardiomyopathy: The Women's Interagency HIV Study. BMC Med Imaging. 2021 Jul 27;21(1):116. doi: 10.1186/s12880-021-00649-6.

Helpful Links

• Information on stem cells from the National Institutes of Health
• Cardiovascular Cell Therapy Research Network
• National Heart, Lung, and Blood Institute

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): June 25, 2020
• Study Completion (Actual): July 22, 2020

Study Registration Dates

• First Submitted: July 15, 2015
• First Submitted That Met QC Criteria: July 15, 2015
• First Posted (Estimate): July 17, 2015

Study Record Updates

• Last Update Posted (Actual): April 26, 2021
• Last Update Submitted That Met QC Criteria: March 29, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Heart Failure; Ischemia; Mesenchymal Stem Cells; Functional status; LV dysfunction; LV function; Autologous Stem Cells; c-kit+ Cells; Combination Cell Therapy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Cardiomyopathies; Pharmaceutical Solutions; Ophthalmic Solutions; Plasma-lyte 148
• Other Study ID Numbers: HSC-SPH-15-0413; 5UM1HL087318 (U.S. NIH Grant/Contract)