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

NCT02501811 | Completed Phase 2 Results DMC

• 2 other identifiers: HSC-SPH-15-04135UM1HL087318
• Study Type: interventional
• Target: 125
• Locations: 1 country
• Sites: 7

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.

Conditions

Ischemic Cardiomyopathy

Keywords

Heart Failure; Ischemia; Autologous Stem Cells; LV dysfunction; Mesenchymal Stem Cells; c-kit+ Cells; Combination Cell Therapy; LV function; Functional status

Outcome Measures

Primary Outcomes (27)

• 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 Outcomes (7)

• Subjects With Events Between Randomization and Study Product Injection (SPI) That Preclude the Receipt of Product

  Randomization to SPI, an average of 14 weeks

• Subjects Who Have a Failed Bone Marrow Aspiration Procedure

  During bone marrow aspiration procedure

• Subjects Who Have a Failed Endomyocardial Biopsy Procedure

  During endomyocardial biopsy procedure

Study Arms (4)

Mesenchymal Stem Cells (MSC)

EXPERIMENTAL

Target dose of 150 million MSCs

Biological: Mesenchymal Stem Cells (MSC)

c-kit+ cells

EXPERIMENTAL

Target dose of 5 million c-kit+ cells

Biological: c-kit+ cells

Combination Cells (MSC and c-kit+ cells)

EXPERIMENTAL

Target dose of 150 million MSCs and 5 million c-kit+ cells

Biological: Mesenchymal Stem Cells (MSC); Biological: c-kit+ cells

Placebo (Plasmalyte A)

PLACEBO COMPARATOR

Plasmalyte A

Biological: Placebo (Plasmalyte A)

Interventions

Mesenchymal Stem Cells (MSC) BIOLOGICAL

15 transendocardial injections of 0.4ml MSCs administered to the left ventricle via NOGA Myostar injection catheter (single procedure)

Combination Cells (MSC and c-kit+ cells); Mesenchymal Stem Cells (MSC)

c-kit+ cells BIOLOGICAL

15 transendocardial injections of 0.4ml c-kit+ cells administered to the left ventricle via NOGA Myostar injection catheter (single procedure)

Combination Cells (MSC and c-kit+ cells); c-kit+ cells

Placebo (Plasmalyte A) BIOLOGICAL

15 transendocardial injections of 0.4ml placebo administered to the left ventricle via NOGA Myostar injection catheter (single procedure)

Also known as: Plasmalyte A

Placebo (Plasmalyte A)

Eligibility Criteria

• Age: 21 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

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

Study Sites (7)

Stanford University School of Medicine (Falk Cardiovascular Research Center)

Stanford, California, 94305, United States

Location

University of Florida-Department of Medicine

Gainesville, Florida, 32610, United States

Location

University of Miami-Interdisciplinary Stem Cell Institute

Miami, Florida, 33101, United States

Location

Indiana Center for Vascular Biology and Medicine

Indianapolis, Indiana, 46202, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

Minneapolis Heart Institute Foundation

Minneapolis, Minnesota, 55407, United States

Location

Texas Heart Institute

Houston, Texas, 77030, United States

Location

Related Publications (4)

• 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.

  PMID: 23588961 BACKGROUND

• 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.

  PMID: 19121814 BACKGROUND

• 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.

  PMID: 29703749 BACKGROUND

• 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.

  PMID: 34315432 DERIVED

Related Links

• Cardiovascular Cell Therapy Research Network
• National Heart, Lung, and Blood Institute

MeSH Terms

Conditions

Heart Failure; Ischemia; Ventricular Dysfunction, Left

Interventions

Plasmalyte A

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Ventricular Dysfunction

Limitations and Caveats

Relatively small group sizes overall. Relatively long interval between harvest visit and study product injection (approx. 14wks) resulting in patient attrition. Failure of cells to grow from tissue of some patients, resulting in some patients crossing over into other treatment groups.

Results Point of Contact

• Title: Shelly Sayre, M.P.H. Project Manager
• Organization: University of Texas-Houston School of Public Health

Shelly.L.Sayre@uth.tmc.edu

713-500-9529

Study Officials

• Robert Simari, MD

  CCTRN Steering Committee Chair

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Biostatistics

Study Record Dates

• First Submitted: July 15, 2015
• First Posted: July 17, 2015
• Study Start: October 1, 2015
• Primary Completion: June 25, 2020
• Study Completion: July 22, 2020
• Last Updated: April 26, 2021
• Results First Posted: April 26, 2021

Record last verified: 2021-03

Locations

US (7)