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
Phase: PHASE2
Conditions: Ischemic Cardiomyopathy
Sponsor: The University of Texas Health Science Center, Houston

Official Study Title: A Phase II, Randomized, Placebo-Controlled Study of the Safety, 
Feasibility, and Efficacy of Autologous Mesenchymal Stem Cells and c-kit+ Cardiac Stem Cells, 
Alone or in Combination, Administered Transendocardially in Subjects with Ischemic Heart 
Failure 
Short Title: Combination Of meseNchymal and c-kit+ Cardiac stEm cells as Regenerative 
Therapy for Heart Failure (CONCERT-HF) 
NCT Number:  NCT02501811 
Date of Final Study Protocol (IRB approval date): Version 1.9 Approval date:12/04/2019 

CONFIDENTIAL AND PROPRIETARY 
 
    
 
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CONCERT-HF: Version 1.9 
Effective Date: November 19, 2019 
 
 
 
 
Organization:  
CARDIOVASCULAR CELL THERAPY RESEARCH NETWORK (CCTRN) 
 
Supported by: 
The National Heart, Lung, and Blood Institute (NHLBI) 
 
Network Chair:  
Robert Simari, M.D., Kansas University Medical Center 
 
Sponsor:  
 
The University of Texas Health Science Center (CCTRN Data Coordinating  
Center) 
 
 
Information Type:     Initial Protocol  
   Protocol Amendment 
 
 
 
 
Full Title: A Phase II, Randomized, Placebo-Controlled Study of the Safety, Feasibility, 
and Efficacy of Autologous Mesenchymal Stem Cells and c-kit+ Cardiac Stem Cells, 
Alone or in Combination, Administered Transendocardially in Subjects with Ischemic 
Heart Failure 
 
Short Title: Combination Of meseNchymal and c-kit+ Cardiac stEm cells as Regenerative 
Therapy for Heart Failure (CONCERT-HF) 
 
 
IND Number: 16399 
 
 
 
 
IRB NUMBER: HSC-SPH-15-0413
IRB APPROVAL DATE: 12/04/2019

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Sponsor Information Page 
 
 
Data Coordinating Center Contact Information: 
 
 
Medical and Safety 
 
Barry Davis, MD, PhD 
 
 
 
 
Linda Piller, MD, MPH 
Principal Investigator- Medical Monitor  
 
Co-Investigator- Safety Officer 
Data Coordinating Center  
 
 
 
Data Coordinating Center 
University of Texas-Health  
 
 
 
University of Texas-Health 
1200 Pressler Street #W916 
 
 
 
1200 Pressler Street #W220 
Houston, TX 77030  
 
 
 
 
Houston, TX 77030 
713-500-9515 
 
 
 
 
 
713-500-9507 
Barry.R.Davis@uth.tmc.edu 
 
 
 
Linda.B.Piller@uth.tmc.edu 
 
Lara Simpson, PhD 
 
 
 
 
 
Co-Investigator- Safety 
 
 
 
Data Coordinating Center  
 
 
 
 
University of Texas-Health  
 
 
 
 
1200 Pressler Street #W908 
 
 
 
Houston, TX 77030  
 
 
 
 
 
713-500-9503 
 
 
 
 
 
Lara.M.Simpson@uth.tmc.edu 
 
 
 
 
 
 
 
 
Project Management Team 
 
Judy Bettencourt, MPH  
 
 
 
Shelly Sayre, MPH 
Data Coordinating Center  
 
 
 
Data Coordinating Center 
University of Texas-Health  
 
 
 
University of Texas-Health 
1200 Pressler Street #W910 
 
 
 
1200 Pressler Street #W906 
Houston, TX 77030  
 
 
 
 
Houston, TX 77030 
713-500-9527 
 
 
 
 
 
713-500-9529 
Judith.L.Bettencourt@uth.tmc.edu 
 
 
Shelly.L.Sayre@uth.tmc.edu 
 
 
IRB NUMBER: HSC-SPH-15-0413
IRB APPROVAL DATE: 12/04/2019

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CCTRN Authorship Team 
 
The following individuals provided substantial input during protocol development: 
 
 
Roberto Bolli, MD 
 
 
University of Louisville 
Atul Chugh, MD 
 
 
University of Louisville 
Darcy DiFede, RN, BSN 
 
University of Miami 
Joshua Hare, MD 
 
 
University of Miami  
Alan Heldman, MD  
 
University of Miami 
Timothy Henry, MD  
 
Minneapolis Heart Institute 
Aisha Khan, PhD 
 
 
University of Miami  
Joao Lima, MD 
 
 
Johns Hopkins University 
Keith March, MD, PhD 
 
Indiana University 
Lem Moyé, MD, PhD  
 
University of Texas-Houston School of Public Health  
Carl Pepine, MD 
 
 
University of Florida 
Emerson Perin, MD, PhD  
Texas Heart Institute 
Robert Simari, MD  
 
Kansas University Medical Center 
Ivonne Schulman, MD 
 
University of Miami 
Doris Taylor, PhD 
 
 
Texas Heart Institute 
Jay Traverse, MD 
 
 
Minneapolis Heart Institute 
Rachel Vojvodic, MPH 
 
University of Texas-Houston School of Public Health 
James Willerson, MD 
 
Texas Heart Institute 
Phillip Yang, MD 
 
 
Stanford University 
 
 
 
 
 
Supported by: 
 
The National Heart, Lung, and Blood Institute (NHLBI) 
 
Ray F. Ebert, PhD 
Jerome Fleg, MD 
David Gordon, MD, PhD 
Colin Wu, PhD 
 
Grant number 5UM1HL087318 
IRB NUMBER: HSC-SPH-15-0413
IRB APPROVAL DATE: 12/04/2019

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Effective Date: November 19, 2019 
CONCERT-HF Signature Page 
 
 
I have read this protocol and any updates provided within and I agree to conduct the study as de-
scribed and in accordance with other material supplied to me.  In addition, I agree to conduct the 
study in compliance with all applicable regulations and guidelines.  
 
If changes in personnel occur during completion of this protocol, I will be responsible for identi-
fying appropriate, trained individuals to carry out the responsibilities of the protocol and will no-
tify the Data Coordinating Center promptly of these changes. 
 
 
 
 
__________________________________ 
Investigator Name (print) 
 
 
 
__________________________________  
_______________________ 
Investigator Name (signature) 
 
 
Date 
 
 
 
 
Sign and return to the Data Coordinating Center (via fax at 713-486-0981) 
IRB NUMBER: HSC-SPH-15-0413
IRB APPROVAL DATE: 12/04/2019

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Confidentiality and Non-Disclosure of Materials and Proceedings Agreement 
 
I understand and agree that information disclosed orally or in written form or discussed in any meeting 
may include confidential information that is proprietary to agencies sponsoring the proposed research 
and/or involves the privacy rights of the individuals. 
 
I agree that I will not disclose or divulge in any manner any confidential or private information provided in 
the protocol titled, “A Phase II, Randomized, Placebo-Controlled Study of the Safety, Feasibility, and Effi-
cacy of Autologous Mesenchymal Stem Cells and c-kit+ Cardiac Stem Cells, Alone or in Combination, 
Administered Transendocardially in Subjects with Ischemic Heart Failure.” Additionally, any information 
revealed during meetings in any form or manner will not be provided by me to any third party for any pur-
pose whatsoever. “Confidential or Private Information” as used in this Agreement shall not include: 
 
1. Information or knowledge in my possession prior to disclosure at CCTRN meetings; 
2. Information generally available to the public or thereafter becomes generally available to the pub-
lic through a source other than the CCTRN; 
3. Information that was rightfully obtained by me from a third party, who, I believe, is under no obli-
gation of confidentiality to CCTRN with respect to such information. 
 
Print Name:______________________________ Signature: ________________________________ 
Date:______________________ 
 
------------------------------------------------------------------------------------------------------------------------------------- 
 
Certification of Conflicts of Interest 
 
All Network members involved in the design, conduct, or analyses of this protocol must certify that they 
have read the “Cardiovascular Cell Therapy Research Network Conflict of Interest Disclosure Policy.” 
(Located on the CCTRN website: www.cctrn.org)  
(Check only one) 
 
  I have read the above referenced policy and have reviewed the proposed research.  I hereby cer-
tify that, based on the information provided to me, I do not have a conflict of interest with the pro-
posed work. 
 
  I have read the above referenced policy and have reviewed the proposed research.  I report that 
I have conflicts with the following companies/institutions/affiliations: 
 
___________________________   __________________________   _________________________ 
 
___________________________   __________________________   _________________________ 
 
My signature below indicates that, to the best of my knowledge, I have disclosed all conflicts of interest 
that I may have with this proposed research.   Furthermore, I agree to promptly notify the CCTRN if my 
financial interests, or those of my spouse or dependent children, change during the course of the trial or 
within two years after trial completion. 
 
Print Name:______________________________ Signature: ________________________________ 
Date:______________________ 
Return signed/dated forms to the DCC via email at Shelly.L.Sayre@uth.tmc.edu or fax: 713-486-0981 
IRB NUMBER: HSC-SPH-15-0413
IRB APPROVAL DATE: 12/04/2019

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List of Abbreviations and Definition of Terms 
 
ACT 
Activated Clotting Time 
AE 
Adverse Event 
BM 
Bone Marrow 
BMA 
Bone Marrow Aspiration 
BMC 
cMRI 
Bone Marrow Mononuclear Cell 
Cardiac MRI 
CABG 
Coronary Artery Bypass Graft 
CAD 
Coronary Artery Disease 
CCMF 
Central Cell Manufacturing Facility 
CCS 
Canadian Cardiovascular Society 
CFR 
Code of Federal Regulations 
CFU-F 
Colony Forming Units – Fibroblasts 
COA 
Certificate of Analysis 
CPC 
CPL 
CPQAL 
Cardiac Progenitor Cell 
Cell Processing Lab  
Cell Processing Quality Assurance Lab 
DMSO 
Dimethyl Sulfoxide 
DEMRI 
Delayed-Enhanced Magnetic Resonance Imaging 
DSMB 
Data and Safety Monitoring Board 
EF 
Ejection Fraction 
ECG 
Electrocardiogram 
eGFR 
Glomerular Filtration Rate 
EPC 
Endothelial Progenitor Cells 
EMB 
Right Ventricle Endomyocardial Biopsy 
EMM 
Left Ventricular Electromechanical Mapping 
FACS 
Fluorescence-Activated Cell Sorting 
FBS 
Fetal Bovine Serum 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
GLP 
Granulocyte Colony Stimulating Factor 
Good Laboratory Practice 
HARP 
Harmonic Phase 
HIPAA 
Health Insurance Portability and Accountability Act 
HSA 
Human Serum Albumin 
HTLV 
Human T-cell Lymphotropic Virus 
ICD 
Implantable Cardioverter-Defibrillator 
IRB NUMBER: HSC-SPH-15-0413
IRB APPROVAL DATE: 12/04/2019

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ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Re-
quirements of Pharmaceuticals for Human Use 
ICM 
Ischemic Cardiomyopathy 
IDM 
Infectious Disease Markers 
IND 
Investigational New Drug application 
IRB 
Institutional Review Board 
IV 
Intravenous 
KDR 
VEGF Receptor-2 
LAD 
Left Anterior Descending Artery 
LAO 
Left Anterior Oblique 
LN2 
Liquid Nitrogen  
LV 
Left Ventricular 
LVAD 
Left Ventricular Assist Device  
LVEDVI 
LVESVI 
MACE 
Left Ventricular End Diastolic Volume Index 
Left Ventricular End Systolic Volume Index 
Major Adverse Cardiac Events 
MDRD 
Modification of Diet in Renal Disease formula 
MEM 
Minimum Essential Medium 
MI 
Myocardial Infarction 
MLHFQ 
Minnesota Living with Heart Failure Questionnaire 
MNC 
Mononuclear Cell 
MR 
Magnetic Resonance 
MRI 
Magnetic Resonance Imaging 
MSC 
Mesenchymal Stem Cell (human) 
NHLBI 
National Heart, Lung, and Blood Institute 
NOGA 
NOGA® XP Mapping and Navigation System 
NT-proBNP  
N-Terminal pro-Brain Natriuretic Peptide 
NYHA 
New York Heart Association 
PBS 
Phosphate Buffered Saline 
QA 
Quality Assurance 
QC 
Quality Control 
RAO 
Right Anterior Oblique 
RHC 
Right Heart Catheterization 
SAE 
Serious Adverse Event 
SDF-1 
Stromal Cell Derived Factor 1 
SOC 
Standard of Care 
SOP 
Standard Operating Procedures 
IRB NUMBER: HSC-SPH-15-0413
IRB APPROVAL DATE: 12/04/2019

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SPI  
SW 
Study Product Injection  
Stroke Work 
TTC 
Triphenyltetrazolium Chloride 
ULN 
Upper Limit of Normal 
UMMSM 
University of Miami Miller School of Medicine 
U.S. 
United States 
VEGF 
Vascular Endothelial Growth Factor 
VO2 max 
Maximal Oxygen Consumption 
WBC 
White Blood Count 
 
 
 
 
 
 
IRB NUMBER: HSC-SPH-15-0413
IRB APPROVAL DATE: 12/04/2019

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Table of Contents 
SPONSOR INFORMATION PAGE .......................................................................................................................................... 2 
CCTRN AUTHORSHIP TEAM ................................................................................................................................................. 3 
CONCERT-HF SIGNATURE PAGE ........................................................................................................................................ 4 
CONFIDENTIALITY AND NON-DISCLOSURE OF MATERIALS AND PROCEEDINGS AGREEMENT ................. 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................................................. 6 
TABLE OF CONTENTS ............................................................................................................................................................. 9 
EXECUTIVE SUMMARY ........................................................................................................................................................ 13 
1.0 STUDY OBJECTIVES ........................................................................................................................................................ 17 
1.1 Primary Objectives .................................................................................................. 17 
1.1.1 Primary Feasibility Objective ............................................................................. 17 
1.1.2 Primary Safety Objective ................................................................................... 17 
1.1.3 Primary Efficacy Objectives ............................................................................... 17 
1.2 Relevance to the Cardiovascular Cell Therapy Research Network (CCTRN) .......... 17 
2.0 BACKGROUND .................................................................................................................................................................. 17 
2.1 Rationale ................................................................................................................. 17 
2.2 Background Preclinical Studies ............................................................................... 18 
2.3 Background Clinical Studies .................................................................................... 27 
2.3.1 Bone marrow mononuclear cells ....................................................................... 28 
2.3.2 Human Experience with Autologous and Allogeneic Human Mesenchymal Stem Cells (MSCs)
 .................................................................................................................................. 29 
2.3.3 Human experience with cardiac-derived cells .................................................... 32 
2.4 Advances in Cardiac Imaging .................................................................................. 32 
2.5 Rationale for Dual Therapy ...................................................................................... 33 
2.6 Dose Rationale ........................................................................................................ 33 
3.0 INVESTIGATIONAL PLAN .............................................................................................................................................. 34 
3.1 Research Questions ................................................................................................ 34 
3.2 Study Design ........................................................................................................... 35 
3.3 Study Treatment Assignments and Dosages ........................................................... 35 
3.4 Feasibility Assessment ............................................................................................ 36 
3.5 Safety Assessment.................................................................................................. 36 
3.6 Study Endpoints ...................................................................................................... 37 
3.6.1 Efficacy Objective .............................................................................................. 37 
3.6.2 Prospectively Declared Efficacy Endpoint Measures ......................................... 37 
3.6.2.1 Comparisons ................................................................................................................... 37 
3.6.2.2 Analyses ......................................................................................................................... 37 
3.6.2.3 Sub-study Analysis ......................................................................................................... 38 
3.6.2.4 c-kit+ cell Product Characterization Analysis ................................................................. 38 
3.7 Sample Size Computations and Assumptions ......................................................... 38 
3.7.1 Efficacy Hypotheses and Testing ...................................................................... 38 
3.7.2 Left Ventricular Ejection Fraction (LVEF) ........................................................... 40 
3.7.3 Infarct Size ........................................................................................................ 40 
3.7.4 Left Ventricular End Systolic Volume Index (LVESVI) ....................................... 41 
3.7.5 Left Ventricular End Diastolic Volume Index (LVEDVI) ...................................... 41 
3.7.6 VO2 max ............................................................................................................ 41 
3.7.7 Six Minute Walk Test (6MWT) ........................................................................... 41 
3.7.8 Minnesota Living with Heart Failure Questionnaire (MLHFQ) ............................ 41 
3.7.9 Sphericity Index ................................................................................................. 41 
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4.0 IDENTIFICATION AND ENROLLMENT OF SUBJECTS ........................................................................................... 42 
4.1 Recruitment and Screening (prior to consent) ......................................................... 42 
4.2 Consent ................................................................................................................... 43 
4.3 Inclusion Criteria ..................................................................................................... 44 
4.4 Exclusion Criteria .................................................................................................... 44 
4.5 Baseline Testing ...................................................................................................... 46 
4.6 Post-Consent Review and Randomization .............................................................. 46 
5.0 CELL PRODUCTION AND DELIVERY ......................................................................................................................... 47 
5.1 Procurement and Shipment of Bone Marrow for MSC Production ........................... 47 
5.2 Procurement and Shipment of Endomyocardial Biopsy (EMB) for c-kit+ cell Production 
47 
5.3 Receipt of harvest samples at the CCMF ................................................................ 48 
5.4 Production and Cryopreservation of MSC Product .................................................. 48 
5.5 MNCs for non-MSC Treatment Groups ................................................................... 50 
5.6 Production and Cryopreservation of c-kit+ cells ....................................................... 50 
5.7 Shipment of Cryopreserved MSC and c-kit+ cell Products ...................................... 52 
5.8 Preparation for Administration of MSC and c-kit+ cell Products ............................... 52 
5.8.1 Final Release Criteria Specifications for Autologous MSCs and c-kit+ cells ...... 52 
5.8.2 Cell Suspensions .............................................................................................. 53 
5.8.2.1 MSCs alone .................................................................................................................... 53 
5.8.2.2 c-kit+ cells alone ............................................................................................................. 53 
5.8.2.3 Combo ............................................................................................................................ 53 
5.9 Placebo Group ........................................................................................................ 53 
5.10 Positive 14-day Sterility After Injection ................................................................... 54 
5.11 Blinding and Study Teams ..................................................................................... 54 
5.12 NOGA Catheterization Procedure ......................................................................... 55 
5.13 Circumstances that may affect study product delivery ........................................... 56 
6.0 CLINICAL AND LABORATORY EVALUATIONS ....................................................................................................... 57 
6.1 Schedule of Procedures Stage 2 (Table 21b) .......................................................... 57 
6.2 Study Phases and Visits .......................................................................................... 58 
6.2.1 Baseline Phase ................................................................................................. 58 
6.2.2 BMA and RHC Procedures................................................................................ 58 
6.2.2.1 Circumstances that would halt or terminate the RHC/EMB procedure .......................... 59 
6.2.3 MRI Evaluation and Day 0 Study Product Injection (SPI) .................................. 59 
6.2.4 Day 1 Post Catheterization ................................................................................ 60 
6.2.5 Week 1 Evaluations .......................................................................................... 60 
6.2.6 Month 1 – Month 12 Visits ................................................................................. 60 
6.2.6.1 Transplants, CRT, or LVADs before Months 6 or 12 ...................................................... 60 
6.2.7 Follow-up windows ............................................................................................ 60 
6.2.8 Lost to Follow-up ............................................................................................... 61 
6.3 Procedure Details .................................................................................................... 61 
6.3.1 Medical History and Physical Exam ................................................................... 61 
6.3.2 Schedule of Laboratory Testing Stage 2 (Table 22b) ......................................... 61 
6.3.3 cMRI Procedure ................................................................................................ 62 
6.3.3.1 Performance of cMRI in subjects with implantable cardiac devices (ICD/pacemakers) 63 
6.3.4 Six-minute Walk Test (6MWT) ........................................................................... 63 
6.3.5 Questionnaires .................................................................................................. 64 
6.3.6 Electrocardiograms (ECGs) ............................................................................... 64 
6.3.7 Treadmill Testing (VO2 max) ............................................................................. 64 
6.3.8 Implantable Cardioverter Defibrillator (ICD) Interrogation .................................. 64 
6.3.9 Echocardiograms .............................................................................................. 65 
6.4 Collection of Biospecimens ..................................................................................... 65 
IRB NUMBER: HSC-SPH-15-0413
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6.4.1 Bone Marrow ..................................................................................................... 65 
6.4.2 Peripheral Blood (PB) ........................................................................................ 66 
6.4.3 MSC and/or c-kit+ cell Autografts ...................................................................... 66 
6.4.4 Explanted hearts ............................................................................................... 66 
7.0 
EVENT MONITORING AND REPORTING ................................................................................................. 66 
7.1 Definitions Related to Adverse Events ..................................................................... 66 
7.1.1 Adverse Events (AEs) ....................................................................................... 66 
7.1.2 Suspected Adverse Reaction (SARs) ................................................................ 66 
7.1.3 Serious Adverse Events (SAEs) or Serious Suspected Adverse Reaction (SSAR)66 
7.2 Role of Abnormal Test Findings and Hospitalizations in Classifying an Event ......... 67 
7.2.1 Abnormal Test Findings .................................................................................... 67 
7.2.2 Hospitalizations ................................................................................................. 67 
7.3 Reporting Responsibilities of the Investigator .......................................................... 67 
7.3.1 Severity Assessment ......................................................................................... 67 
7.3.2 Causality Assessment ....................................................................................... 68 
7.3.3 Expectedness Assessment ............................................................................... 69 
7.4 Reporting Responsibilities of the Sponsor (DCC) .................................................... 69 
7.4.1 Safety Monitoring Program and Reporting ......................................................... 69 
7.4.2 Sponsor Reporting Requirements to the EC, NHLBI and DSMB ....................... 69 
7.4.3 Sponsor Reporting Requirements to FDA ......................................................... 70 
7.5 Unanticipated Problems (UPs) ................................................................................ 70 
7.6 NHLBI DSMB Criteria .............................................................................................. 70 
7.7 Review of Open Label Lead-in (16 subjects) ........................................................... 70 
8.0 
STATISTICAL PROCEDURES ....................................................................................................................... 71 
8.1 Randomization Strategy .......................................................................................... 71 
8.1.1 Randomization in Stage 1 (open label lead-in) .................................................. 71 
8.1.2 Randomization in Stage 2 (double-blind, placebo-controlled phase) ................. 71 
8.2 Guiding Analysis Plan ............................................................................................. 72 
8.3 Delays ..................................................................................................................... 72 
8.4 Statistical Analyses ................................................................................................. 72 
8.4.1 Baseline Analyses ............................................................................................. 72 
8.4.2 Outcome Analyses ............................................................................................ 73 
8.4.2.1 Feasibility Evaluations .................................................................................................... 73 
8.4.2.2 Safety Evaluations .......................................................................................................... 73 
8.4.2.3 Prospectively Declared Endpoints .................................................................................. 73 
8.4.2.4 Variability Management .................................................................................................. 74 
8.4.2.5 Adaptive Design and Sample Size Adjustments ............................................................ 74 
8.4.2.6 Subgroup Evaluations .................................................................................................... 76 
8.4.2.7 Sub-study Evaluation ...................................................................................................... 76 
8.4.2.8 As-Treated Evaluation .................................................................................................... 76 
8.4.2.9 Dose-Response Evaluation ............................................................................................ 77 
8.4.2.10 Multiplicity Issues .......................................................................................................... 77 
8.4.3 Interim Analysis ................................................................................................. 77 
8.4.3.1 Plan for CONCERT Interim Monitoring........................................................................... 77 
9.0 
TRIAL MANAGEMENT .................................................................................................................................. 78 
9.1 Institutional Review Board (IRB) Review and Informed Consent ............................. 78 
9.1.1 Informed Consent Process ................................................................................ 78 
9.1.2 Risks Associated with the Procurement, Processing, Injection, and Assessment of the Study 
Product ...................................................................................................................... 78 
9.1.2.1 Harvest Procedures ........................................................................................................ 78 
9.1.2.2 Cell Processing Procedure ............................................................................................. 79 
IRB NUMBER: HSC-SPH-15-0413
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9.1.2.3 Cardiac Catheterization and NOGA mapping ................................................................ 79 
9.1.2.4 Study Product Injection ................................................................................................... 80 
9.1.2.5 cMRI Procedure .............................................................................................................. 80 
9.1.2.6 Radiation Risks ............................................................................................................... 81 
9.1.3 Adequacy of Protection Against Risks ............................................................... 81 
9.1.4 Potential Benefits of the Proposed Research to the Subjects and Others .......... 81 
9.1.5 Risk Benefit Analysis ......................................................................................... 81 
9.1.6 Importance of the Knowledge to be Gained ....................................................... 81 
9.1.7 Data and Safety Monitoring Board (DSMB) ....................................................... 82 
9.2 Clinical Monitoring ................................................................................................... 82 
9.2.1 Pre-Investigation Visits ...................................................................................... 82 
9.2.2 Interim site visits ................................................................................................ 82 
9.2.3 Monitor Role ...................................................................................................... 83 
9.2.4 Monitor Recording ............................................................................................. 83 
9.3 Investigator Responsibilities .................................................................................... 83 
9.3.1 Investigator Performance .................................................................................. 83 
9.3.2 Site Requirements: ............................................................................................ 84 
9.3.3 Institutional Review Board Approval .................................................................. 84 
9.3.4 Informed Consent .............................................................................................. 84 
9.3.5 Reporting Requirement of the Sites ................................................................... 84 
9.4 Sponsor Responsibilities ......................................................................................... 84 
9.4.1 Introduction ....................................................................................................... 84 
9.4.2 Routine Duties................................................................................................... 84 
9.4.3 Site Training ...................................................................................................... 84 
9.4.4 Reporting to the FDA ......................................................................................... 84 
9.5 Database ................................................................................................................. 85 
9.5.1 Framework ........................................................................................................ 85 
9.5.2 Information Security .......................................................................................... 85 
9.5.3 Follow-up .......................................................................................................... 85 
9.5.4 Laboratory Data Processing Support ................................................................. 85 
9.5.4.1 File transfers ................................................................................................................... 86 
9.5.5 Data Quality ...................................................................................................... 86 
9.5.6 Computing Infrastructure ................................................................................... 86 
9.5.7 Backup Procedure ............................................................................................. 86 
9.6 Dissemination .......................................................................................................... 86 
9.6.1 www.ClinicalTrials.gov ...................................................................................... 87 
9.6.2 NHLBI’s Data Repository (BIOLINCC) .............................................................. 87 
9.6.3 Website ............................................................................................................. 87 
9.6.4 Manuscripts and Presentations ......................................................................... 87 
9.6.5 Methodologic Developments ............................................................................. 88 
10.0 
REFERENCES ................................................................................................................................................... 89 
APPENDIX A: BONE MARROW ASPIRATION STANDARD OPERATING PROCEDURE ....................................... 98 
APPENDIX B: STANDARD OPERATING PROCEDURE FOR RIGHT HEART CATHETERIZATION WITH AND 
WITHOUT ENDOMYOCARDIAL BIOPSY (RHC/EMB) ................................................................................................. 101 
APPENDIX C: NYHA CLASSIFICATION .......................................................................................................................... 105 
APPENDIX D: CCS CLASSIFICATION .............................................................................................................................. 106 
APPENDIX E: STAGE 1- (OPEN LABEL LEAD-IN) ENROLLMENT AND ACTIVITIES ......................................... 107 
 
 
 
IRB NUMBER: HSC-SPH-15-0413
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Executive Summary 
Study Centers: Centers of the NHLBI CCTRN 
Phase of Development: Phase II 
Study Therapy: Autologous Mesenchymal Stem Cells (MSCs), c-kit+ cells , or the combination of MSCs 
plus c-kit+ cells produced from bone marrow aspirates and cardiac biopsies, respectively. 
Study Title: A Phase II, Randomized, Placebo-Controlled Study of the Safety, Feasibility, and Efficacy 
of Autologous Mesenchymal Stem Cells and c-kit+ Cardiac Stem Cells, Alone or in Combination, Admin-
istered Transendocardially in Subjects with Ischemic Heart Failure, a.k.a. Combination Of meseNchymal 
and c-kit+ Cardiac stEm cells as Regenerative Therapy for Heart Failure (CONCERT-HF) 
Objectives: To assess feasibility, safety, and efficacy of autologous MSCs and c-kit+ cells, alone or in 
combination, administered by transendocardial injection in subjects with heart failure (HF) of ischemic 
etiology. 
Subject Population: One hundred sixty (160) subjects with HF of ischemic etiology. 
Design and Investigational Plan:  This investigation will be conducted in two stages.   
 
Stage 1: An open label lead-in investigation will consist of sixteen (16) subjects randomized 1:1 to ei-
ther a standard of care (SOC) control group (i.e. subjects do not undergo harvest, mapping, or injection 
procedures) or to the combination cell therapy group (as described below in Stage 2, Group A).  All sub-
jects will be followed for 3 months to complete safety and functional assessments.  Resultant three 
month data from this phase will be reviewed by the Data and Safety Monitoring Board prior to initiation 
of Stage 2.  Those subjects randomized to the combination cell therapy group will continue to be fol-
lowed per protocol for 12 months.  Those randomized to the SOC control group will have the option to 
be evaluated for enrollment in Stage 2. 
 
Stage 2: A phase II, double-blind, placebo-controlled trial will consist of one hundred forty-four (144) 
subjects who meet all inclusion/exclusion criteria.  All subjects will be randomized 1:1:1:1 to one of four 
treatment strategies:   
1. Group A (36 subjects) – Combination of autologous MSCs and c-kit+ cells (“Combo”): Target 
dose is a mixture of 150 x 106 (150 million) MSCs plus 5 x 106 (5 million) c-kit+ cells deliv-
ered in 15 injections each of 0.4 ml volume 
2. Group B (36 subjects) – Autologous MSCs: Target dose is 150 x 106 (150 million) MSCs de-
livered in 15 injections each of 0.4 ml 
3. Group C (36 subjects) – Autologous c-kit+ cells: Target dose is 5 x 106 (5 million) c-kit+ cells 
delivered in 15 injections each of 0.4 ml 
4. Group D (36 subjects) – Placebo: 15 injections each of 0.4 ml cell-free PlasmaLyte-A me-
dium 
• 
Within 60 days of signing informed consent, all subjects will have iliac crest bone marrow aspira-
tion and right heart catheterization, including transvenous right ventricle endomyocardial biopsy 
only for groups A and C. 
• 
A central cell manufacturing facility will manufacture the target doses of MSCs and c-kit+ cells. 
• 
After cell manufacturing, cells or placebo will be administered via the NOGA® XP Mapping and 
Navigation System (NOGA). 
• 
Subjects will return to the cardiac catheterization laboratory to receive study product –approxi-
mately 14 weeks after harvest procedures. 
• 
Injections will be administered transendocardially during left ventricular catheterization (NOGA) 
and will be targeted to the border zone and the adjacent scarred tissue.  
• 
Following cell or placebo injections, subjects will be followed at day 1, week 1, and months 1, 3, 
6, and 12 to complete safety and efficacy assessments. 
Eligibility Criteria:   
Inclusion Criteria 
     To participate, a subject MUST: 
1. Be ≥ 21 and <80 years of age 
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2. Have documented coronary artery disease (CAD) with evidence of myocardial injury, LV dys-
function, 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% reduc-
tion 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 HF 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 
     To participate, a subject MUST NOT HAVE: 
1. Indication for standard-of-care surgery (including valve surgery, placement of left-ventricular as-
sist device, or imminent heart transplantation), coronary artery bypass grafting (CABG), and/or 
percutaneous coronary intervention (PCI) for the treatment of ischemic and/or valvular heart dis-
ease. 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 with-
out delay. Indication for imminent heart transplantation is defined as a high likelihood of trans-
plant 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 valvular 
(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 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 contra-
indicated 
7. Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without an ICD 
are not excluded)  
8. A cardiac resynchronization therapy (CRT) device implanted < 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 (See guidance in section 6.3.3) 
13. Evidence of active myocarditis 
14. Baseline VO2 max greater than 75% of age and gender based predictive values (see Section 
6.3.7) 
15. Baseline eGFR <35 ml/min/1.73m2    
16. Blood glucose levels (HbA1c) >10%    
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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 ULN 
19. Coagulopathy (INR ≥ 1.3) not due to a reversible cause (e.g., warfarin and/or Factor Xa inhibi-
tors) (see Sections 6.2.2 and 6.2.3 re: study procedures and anticoagulation therapy). Subjects 
who cannot be withdrawn from anticoagulation will be excluded. 
20. HIV and/or active HBV or 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 de-
finitively treated 
25. Condition that limits lifespan to < 1 year 
26. History of drug abuse (use of 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  
Hypotheses: 
Feasibility: MSCs and c-kit+ cells, both alone and in combination, can be manufactured and deliv-
ered to subjects with ischemic cardiomyopathy 
 
Safety: MSCs and c-kit+ cells, alone or in combination are well-tolerated by subjects with ischemic 
cardiomyopathy 
 
 Efficacy: 
• 
Combo improves LV function and functional status when compared with placebo from baseline 
to 6 months and baseline through 12 months 
• 
MSCs alone improve LV function and functional status when compared with placebo from base-
line to 6 months and baseline through 12 months 
• 
c-kit+ cells alone improve LV function and functional status when compared with placebo from 
baseline to 6 months and baseline through 12 months 
• 
Combo improves LV function and functional status when compared with MSCs from baseline to 
6 months and baseline through 12 months 
• 
Combo improves LV function and functional status when compared with c-kit+ cells from base-
line to 6 months and baseline through 12 months 
• 
MSCs or c-kit+ cells improve LV function and functional status when compared with each other 
from baseline to 6 months and baseline through 12 months 
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Feasibility Measures:  
The number and percent of subjects who have: 
• 
Events between randomization and study product injection (SPI) that precludes the subject from 
getting SPI 
• 
Failed bone marrow aspiration procedure 
• 
Failed endomyocardial biopsy procedure 
• 
Failed release criteria (including minimum number of cells) for receiving the MSC product 
• 
Failed release criteria (including minimum number of cells) for receiving the c-kit+ cell product 
• 
Less than 15 injections during the SPI procedure 
• 
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 
Safety Measures:  
The following safety data will be collected and analyzed by therapy group between baseline and a) 6 
months and b) 12 months: 
Major adverse cardiac events (MACE)1 including: death, hospitalization for worsening HF, and/or exac-
erbation of HF (non-hospitalization) 
• 
Other significant clinical events including: non-fatal stroke, non-fatal myocardial infarction, coro-
nary artery revascularization, ventricular tachycardia/fibrillation, and/or pericardial tamponade 
• 
All adverse events that are at least grade 2 in severity  
Prospectively Declared Endpoint Measures: 
Each of the following domains and measures has the same priority for the efficacy analyses to assess 
improvement in LV function and functional status: 
• 
Myocardial evaluations by cMRI over time: 
− 
Function: 
 
Change in LVEF 
 
Change in global and regional strain (HARP MRI) 
− 
Structure: 
 
Change in LVEDVI 
 
Change in LVESVI  
 
Change in LV Sphericity Index 
− 
Morphology:  
 
Change in infarct/scar volume (DEMRI) 
• 
Functional capacity over time: 
− Change in VO2 max (treadmill) 
− 
Change in exercise tolerance (6MWT)  
− 
Change in MLHF Questionnaire (subject reported) 
• 
Clinical outcomes over time: 
− 
MACE 
− 
Cumulative days alive and out of hospital for HF 
• 
Biomarkers over time: 
− 
Change in NT-proBNP  
Duration of Study Follow-Up: Following discharge from the hospital, subjects will be assessed at 
week 1, and months 1, 3, 6 and 12. 
 
 
 
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1.0 STUDY OBJECTIVES 
 
1.1 Primary Objectives 
The purpose of this study is to assess feasibility, safety, and efficacy of autologous bone mar-
row-derived mesenchymal stem cells (MSCs) and c-kit+ cells, alone or in combination, adminis-
tered by transendocardial injection in subjects with heart failure (HF) of ischemic etiology.  
 
1.1.1 Primary Feasibility Objective 
To assess whether MSCs and c-kit+ cells, alone or in combination, can be manufactured and 
delivered to subjects with ischemic cardiomyopathy (ICM). 
 
1.1.2 Primary Safety Objective 
To assess the relative safety of c-kit+ cells and MSCs, delivered alone or in combination, when 
compared with placebo. 
 
1.1.3 Primary Efficacy Objectives 
• To assess whether the combination of autologous MSCs and c-kit+ cells (hereinafter re-
ferred to as “Combo”) improves left ventricular (LV) function and functional status when 
compared with placebo from baseline to 6 months and baseline through 12 months. 
• To assess whether MSCs alone improve LV function and functional status when com-
pared with placebo from baseline to 6 months and baseline through 12 months. 
• To assess whether c-kit+ cells alone improve LV function and functional status when 
compared with placebo from baseline to 6 months and baseline through 12 months. 
• To assess whether Combo improves LV function and functional status when compared 
with MSCs from baseline to 6 months and baseline through 12 months. 
• To assess whether Combo improves LV function and functional status when compared 
with c-kit+ cells from baseline to 6 months and baseline through 12 months. 
• To assess whether MSCs or c-kit+ cells improve LV function and functional status when 
compared with each other from baseline to 6 months and baseline through 12 months. 
 
1.2 Relevance to the Cardiovascular Cell Therapy Research Network (CCTRN) 
This study is consistent with the overall mission of the CCTRN, which is to investigate the safety 
and effectiveness of stem cell therapy in subjects with cardiovascular disease.  It is also con-
sistent with the goal of accelerating research in the use of cell-based therapies for the manage-
ment of cardiovascular disease.  This study will collect important clinical and mechanistic infor-
mation on the safety, feasibility and impact of administering adult stem cells, including a com-
bined cell product, in subjects with HF of ischemic etiology, a population with limited treatment 
options. 
 
2.0 BACKGROUND 
 
2.1 Rationale 
The field of stem cell-based cardiac repair has advanced rapidly since publication of the first 
adult human stem cell clinical trials in 2002-032,3.  At present, several categories of adult stem 
cells (possibly enhanced by concomitant strategies aimed at improved migration or survival) 
hold great promise to restore function in diseased hearts. CONCERT-HF will compare MSCs 
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alone, c-kit+ cells alone, and Combo as therapy for ischemic cardiomyopathy (ICM). MSCs have 
been chosen because of: 1) their efficacy in small and large animal models; 2) their safety and 
efficacy in clinical trials4-8; and 3) they offer the substantial advantage of already having approval 
from the FDA for investigational use in humans.  c-kit+ cells have been shown to be safe and 
efficacious in preclinical models including large animal models9-23.  In addition, recent data from 
animal models and mechanistic studies suggest that the combination of MSCs and c-kit+ cells 
has greater therapeutic efficacy than either cell type alone17-19,23,24.  CONCERT-HF will assess 
the feasibility, safety, and clinical efficacy of combining c-kit+ cells with MSCs compared with 
each of placebo, MSCs alone, and c-kit+ cells alone in subjects with ICM. 
 
2.2 Background Preclinical Studies 
MSCs: A well-developed porcine model of anterior myocardial infarction (MI) has characterized 
the impact of cellular cardiomyoplasty on cardiac structure and function using hemodynamic, im-
aging, and histological analyses.  Two distinct sets of studies have been conducted, represent-
ing the early treatment of acute MI, as well as the treatment of chronic ICM (see Table 1).  
 
Published work demonstrates that autologous and allogeneic MSC transplantation in post-MI 
pigs improved cardiac function with histological evidence of robust engraftment at 8 weeks and 
differentiation to a myocyte-like phenotype25,26.  Studies of MSC engraftment in rodent and 
swine models of MI have shown that the administration of MSCs produces: 1) functional benefit 
in post-MI recovery of ventricular function, 2) evidence of neoangiogenesis at the infarct, 3) de-
crease in collagen deposition in the region of scar, and 4) some evidence of cells expressing 
contractile and sarcomeric proteins but lacking true sarcomeric functional organization, although 
these cells are quantitatively insufficient to account for the functional improvement25,27.   
 
HF is characterized by mechanoenergetic uncoupling: decreased efficiency of work per unit oxy-
gen consumption.  In placebo-treated animals, stroke work (SW) decreased substantially during 
the 8 weeks following MI, with a paradoxical increase in myocardial oxygen consumption result-
ing in decreased ratio of SW/VO2 max28.  However, investigators observed that after a period of 
follow-up, MSC-injected animals demonstrated improved myocardial efficiency principally due to 
increasing SW (from 374.4±59.3 to 654.4±129.9 mmHg/mm at 8 weeks) and decreasing VO2 
max (from10.3±2 to 3.7±1.8 Joules/beat), both toward normal. Thus, MSC therapy exerts favora-
ble effects on the damaged heart that extend to improvements in cellular energy metabolism.   
 
In addition to the studies outlined above using models of acute MI in the pig, a model of chronic 
MI in the Gottingen mini-swine has also been developed 29-31.  Both autologous and allogeneic 
MSCs have been used, with surgical and catheter delivery strategies, and sufficient experience 
has been developed to translate the therapy from the laboratory bench to clinical trials4-8,32.  To-
gether the results indicate that bone marrow-derived MSCs stimulate cardiac recovery by en-
grafting, forming new blood vessels that increase tissue perfusion in hypoperfused areas, form-
ing new cardiac myocytes, and importantly interacting with endogenous precursor cells (i.e., car-
diac stem cells) to also contribute to new cardiac myocyte formation6,24,29,33.  
 
 
 
 
 
 
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Table 1 
Preclinical Studies: Autologous and Allogeneic Mesenchymal Stem Cells (MSCs) Administered Via 
Intramyocardial Injection 
Study 
Model 
N 
Cell  
Delivery 
Cell Source 
& Type 
Cell Doses 
(x 106) 
Safety  
Results 
Efficacy  
Results 
Shake25 
 
14-
Day 
Post-
MI Pig 
14 
Surgical 
(needle) 
IM Injec-
tion 
Autologous, 
porcine 
MSCs 
60.0 
• No ectopic tis-
sue formation 
• No MSC differ-
entiation to non-
cardiac tissue 
• No significant in-
flammatory infil-
trates at site of 
MSC implanta-
tion 
• MSC engraft-
ment 
• ↑regional con-
tractile func-
tion 
Cattaneo34 
1-Day 
Post-
MI Pig 
13 
Surgical 
(needle) 
IM Injec-
tion 
Allogeneic, 
porcine 
MSCs 
200.0 
• No ectopic tis-
sue formation 
• No significant in-
flammatory re-
sponse 
• MSC engraft-
ment 
• ↑EF and 
global wall 
motion score 
Amado28 
3-Day 
Post-
MI Pig 
14 
PIM 
(catheter) 
Injection 
Allogeneic, 
porcine 
MSCs 
200.0 
• No deaths; no 
malignant ar-
rhythmias 
• No evidence of 
cardiac perfora-
tion during injec-
tion 
• MSC engraft-
ment 
• ↓infarct scar 
• Improved sys-
tolic and dias-
tolic function 
Amado35 
3-Day 
Post-
MI Pig 
22 
PIM 
(catheter) 
Injection 
Allogeneic, 
porcine 
MSCs 
200.0 
• No difference in 
deaths between 
treated/placebo 
• MSC engraft-
ment 
• ↑Viable myo-
cardium 
• ↓infarct scar 
Schuleri30 
90-
Day 
Post-
MI Pig 
9 
Surgical 
(needle) 
IM injec-
tion 
Autologous, 
porcine 
MSCs 
20.0 (Low) 
200.0 (High) 
• No difference in 
deaths between 
groups 
• No evidence of 
post-injection ar-
rhythmias 
• No ectopic tis-
sue formation 
• ↓infarct scar at 
High Dose 
• ↑EF 
Quevedo29 
90-
Day 
Post-
MI Pig 
6 
PIM 
(catheter) 
Injection 
Allogeneic, 
porcine 
MSCs 
200.0 
  
• MSC engraft-
ment & differ-
entiation 
• ↓infarct scar 
• ↑global LV 
function and 
EF 
Hatzistergos24 
3-Day 
Post-
MI Pig 
12 
PIM       
(catheter 
injection) 
Allogeneic 
porcine 
MSCs & 
concentrated 
condition 
medium 
75 
100 &  
10 x concen-
trated condi-
tion medium 
  
• MSC engraft-
ment & differ-
entiation 
• ↑EF 
  
  
  
  
  
  
  
  
EF: Ejection Fraction; IM: intramyocardial; MSC: Mesenchymal Stem Cell; PIM: percutaneous intramyocar-
dial; VT: ventricular tachycardia 
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Finally, a review of the available preclinical work demonstrates no ectopic tissue formation, sig-
nificant inflammatory responses, nor arrhythmias or deaths attributed to either allogeneic or au-
tologous MSC therapy. Thus, preclinical work demonstrates that MSC injection can produce a 
wide range of benefits, including improved regional and global ventricular function, reduced my-
ocyte apoptosis, and improved tissue perfusion26. 
 
c-kit+ cells: Cardiac stem cells have stimulated great interest as a potential therapy for patients 
with heart disease.  In the past 15 years, the ability of rodent and porcine c-kit+ cells to alleviate 
LV dysfunction and remodeling has been repeatedly demonstrated by several independent la-
boratories in various preclinical animal models of acute MI10. A number of preclinical studies 
have also demonstrated their efficacy in subacute or chronic HF, and are summarized below 
(See Table 2).  
 
Wysoczynski et al.11 performed a study in a mouse model of left anterior descending coronary 
artery (LAD) ligation, in which echo-guided administration of 1 million c-kitpos cardiac cells into 
the LV cavity at 2 days after MI significantly improved cardiac function and increased vascular 
density compared with vehicle treatment. The endothelial phenotype of the cells, coupled with 
the finding of increased vascular density, suggested a potential pro-vasculogenic action of c-kit+ 
cells. 
 
In a study by Li et al.2  mice underwent a 60-min LAD occlusion followed by reperfusion; at 2 
days after reperfusion they received either 4 intramyocardial injections of 1 x 105 c-kit+ cells in 
the peri-infarct region or an intracoronary infusion (cells were infused into the aortic root during 
aortic clamping) of 4 x 105 c-kit+ cells.  At 39 days after treatment, mice that received c-kit+ cells 
via either route exhibited significantly improved regional function in the infarcted region, im-
proved global LV systolic and diastolic function, and decreased LV dilation. This study showed 
that intracoronary c-kit+ cell infusion is at least as effective as intramyocardial injection in limit-
ing LV remodeling and improving both regional and global LV function. 
 
Given the promising results of the mouse study by Li et al.12, Hong et al.13 developed a highly 
sensitive and accurate method to quantify the absolute number of male mouse c-kit+ cells in fe-
male recipients after transplantation. Using the same murine model of a 60-min LAD occlusion 
followed by reperfusion, 100,000 male c-kit+ cells were infused intracoronarily. Only 12.7% of 
the male c-kit+ cells present in the heart immediately (5 min) after infusion were still present at 
24 h, and their number declined rapidly thereafter. By 35 days after infusion, only ∼ 1,000 male 
c-kit+ cells were found in the heart. Despite the low retention and rapid disappearance of c-kit+ 
cells from the recipient heart, intracoronary delivery of c-kit+ cells significantly improved LV 
function at 35 days, as assessed by Millar catheter. These results suggest that direct differentia-
tion of c-kit+ cells cannot account for the beneficial effects of c-kit+ cells on LV function, and that 
paracrine effects must be the major mechanism. 
 
To assess the utility of repeated treatments, Bolli and colleagues performed a study of multiple 
administrations of c-kit+ cells in a rat model of ICM36.  Rats with a 30-day-old MI and LV dys-
function received one or three c-kit+ cell infusions (12 million cells each) into the LV cavity, 35 
days apart. Compared with vehicle-treated rats, the single-dose group exhibited improved LV 
function after the 1st infusion (consisting of c-kit+ cells) but not after the 2nd and 3rd infusions 
(consisting of vehicle). In contrast, in the multiple-dose group regional and global LV function im-
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proved by a similar degree after each c-kit+ cell infusion, resulting in cumulative effects. The sin-
gle- and multiple-dose groups exhibited less scar and less collagen in the risk and noninfarcted 
regions. This study demonstrates that a single infusion of c-kit+ cells alleviates LV dysfunction in 
a model of chronic ICM, and that repeated c-kit+ cell infusions are even more effective than a 
single administration. 
 
To address the question as to whether the beneficial effects of 3 repeated c-kit+ cell doses can 
be recapitulated by 1 large dose containing the same total number of cells, a study37 was per-
formed in the same model (rats with a 30-day-old MI). Rats received via infusion into the LV 
cavity either a single large dose of 36×106 c-kit+ cells followed by 2 doses of vehicle or 3 equal 
doses of 12×106 c-kit+ cells 35 days apart. Infusion of a single, large dose of c-kit+ cells im-
proved LV function, but there was no further improvement after the 2 doses of vehicle. In con-
trast, the 3 doses of c-kit+ cells caused a progressive improvement in LV function, the cumula-
tive magnitude of which was greater than achieved with a single dose. This study confirms that 
a single administration of c-kit+ cells improves LV function in a rat model of ICM and shows that 
dividing this single dose into 3 smaller doses is even more effective. 
 
In a rat model of isoproterenol (ISO)-induced cardiomyopathy14, intravenous administration of 5 
x 105 clonogenic c-kit+ cells at 28 days after ISO injection significantly improved LV fractional 
shortening and dP/dt max and reduced LV end-diastolic pressure and diameter at 28 days after 
treatment compared with vehicle-treated and cardiac fibroblast-treated rats. These beneficial ef-
fects of c-kit+ cells were maintained at 56 days after cell treatment. 
 
To develop a safe and efficient delivery method for c-kit+ cell therapy, the efficacy of retrograde 
coronary vein (RCV) infusion of c-kit+ cells was studied15. Rats with ICM received an RCV infu-
sion of c-kit+ cells at 21 days after MI. RCV-treated rats showed a significant improvement in 
cardiac function and exhibited an increase in capillary density, a decrease in total heart colla-
gen, and a reduction in both infarct size and cardiomyocyte hypertrophy when compared with 
vehicle-treated rats. 
 
To enhance the cardiogenic potential of c-kit+ cells, c-kit+ cells were treated with mocetinostat 
(MOCE), a specific class I HDAC inhibitor, and were retrogradely infused into the coronary vein 
of rats at 3 weeks after MI16.  Transplantation of either control or MOCE/c-kit+ cells resulted in 
an improvement in cardiac function and retardation of LV remodeling, as evidenced by cardio-
myocyte hypertrophy reduction. Compared with control cells, infusion of MOCE/c-kit+ cells re-
sulted in a further reduction in LV end-diastolic pressure and myocardial collagen. 
 
In a study by Bao et al.17 in a rat model of ICM, 4 intramyocardial injections of 1 x 106 c-kit+ 
cells, 1 x 106 BM-MSCs, or 5 x 105 c-kit+ cells + 5 x 105 BM-MSCs into the infarct border zone 
were performed at 28 days after MI. c-kit+ cells and/or BM-MSCs improved cardiac function af-
ter MI and reduced infarct size despite the fact that in vivo cell tracking experiments showed 
minimal persistence of donor cells in the myocardium after transplantation. c-kit+ cells also en-
hanced the expression of pro-angiogenic factors and boosted post-MI angiogenesis in the myo-
cardium in a paracrine manner.  This study showed that transplantation of c-kit+ cells + BM-
MSCs was superior to transplantation of either c-kit+ cells or BM-MSCs alone in promoting post-
MI angiogenesis and improving cardiac function after MI. 
 
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Since these studies in rodents yielded promising results, the effects of c-kit+ cells were as-
sessed in porcine models of ICM. In a study by Williams et al.23 in an immunosuppressed swine 
model of ICM, human c-kit+ cells/MSCs (1 million cells/200 million cells), human c-kit+ cells 
alone (1 million cells), human MSCs alone (200 million cells), or placebo (phosphate-buffered 
saline) were injected into the infarct border zone at 14 days after MI.  Swine in all 3 cell therapy 
groups showed significantly reduced infarct size and improved LV ejection fraction at 6 weeks 
after treatment compared with placebo. The infarct size reduction was 2-fold greater with combi-
nation therapy versus either cell therapy alone. A substantial improvement in left ventricular 
chamber compliance (end-diastolic pressure-volume relationship) and contractility (preload re-
cruitable stroke work and dP/dtmax) were also observed in combination-treated swine. This study 
demonstrated that c-kit+ cells improve LV function in a porcine model of ICM, and that the com-
bination of c-kit+ cells and MSCs is superior to either cell alone. 
 
A subsequent study by Karantalis et al.18 demonstrated that the combination of autologous 
MSCs and c-kit+ cells produces greater improvement in cardiac performance than MSCs alone 
in a nonimmunosuppressed swine model of ICM. In this study, Gottingen mini-pigs underwent 
myocardial ischemia/reperfusion to produce an MI, and cardiac tissue and bone marrow were 
obtained for isolation of autologous c-kit+ cells and BM-MSCs. Autologous MSCs alone (200 x 
106 MSCs) or in combination with c-kit+ cells (1 x 106 c-kit+ cells) were injected transendocardi-
ally at 3 months after MI. At 3 months after treatment, both groups of cell-treated animals exhib-
ited significantly reduced scar size, increased viable tissue, and improved wall motion relative to 
placebo. Significant improvement in ejection fraction, stroke volume, cardiac output, and dias-
tolic strain was only seen in the combination-treated animals. This study is notable because it 
used autologous cells (thus mimicking CONCERT-HF); it demonstrates that the addition of c-
kit+ cells to MSCs significantly improves the beneficial effects of MSCs.  
 
In view of the finding that the combination of autologous MSCs and c-kit+ cells provides additive 
beneficial effects in ICM, Natsumeda et al.19 further studied whether a combination of allogeneic 
stem cells promotes cardiac repair. Cardiac tissue and bone marrow were obtained from male 
Yorkshire swine for isolation of c-kit+ cells and MSCs. Nonimmunosuppressed female Göttingen 
pigs were subjected to MI and received transendocardial injections of either allo-MSCs + allo-c-
kit+ cells (200 million MSCs/1 million c-kit+ cells), 200 million allo-MSCs, 1 million allo-c-kit+ 
cells, or placebo at 3 months post MI. All three treatments improved LV function but the combi-
nation exerted the greatest effect, improving the end-systolic pressure-volume relation. Only 
combination therapy, but not MSCs or c-kit+ cells, prevented ongoing negative LV remodeling 
by offsetting increases in chamber volumes. Both combination therapy and allo-MSCs reduced 
scar size and resulted in less immunotolerant regulatory T cells and low-grade inflammatory in-
filtrates in the myocardium. This study confirms that c-kit+ cells are effective in ICM but the com-
bination of c-kit+ cells over MSCs is superior. 
 
Kulandavelu et al.21 studied whether overexpression of Pim1 in c-kit+ cells enhances their cardi-
oreparative properties. Immunosuppressed Yorkshire pigs with ICM received intramyocardial 
injection of 1 x 106 human c-kit+ cells or human c-kit+ cells overexpressing Pim1 at 2 weeks af-
ter MI. At 8 weeks after treatment, both human c-kit+ cells reduced MI size compared with pla-
cebo, but Pim1+ cells produced greater decrease in scar compared with human c-kit+ cells. 
Pim1+ human c-kit+ cells also produced a greater increase in regional contractility in both infarct 
and border zones. Both c-kit+ cell types significantly increased LV ejection fraction at 4 weeks. 
 
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Kamata et al.20 studied the beneficial effects of transplanting a sheet of c-kit+ cells in a porcine 
model of ICM. Immunosuppressed swine were subjected to MI induced by ameroid constrictor; 
a cell sheet with 1 x 108 human c-kit+ cells with or without 2.5 x 106 cells human EPCs was 
placed on the epicardium of the ischemic area at 4 weeks post ischemia. At 2 months after 
sheet transplantation, the epicardial radial strain (RS) in the ischemic area was similarly in-
creased after treatment with c-kit+ cell-derived cell sheets alone or in combination with EPCs. 
The endocardial RS in the ischemic area was greatest after combined treatment compared with 
c-kit+ cells only. The authors concluded that transplantation of c-kit+ cell sheets induced signifi-
cant functional recovery of the ischemic epicardium, and that concomitant EPC transplantation 
elicited transmural improvement in function in this porcine model of chronic ischemic injury.  
 
In addition to the above-mentioned studies of ICM, Taghavi et al.22 tested c-kit+ cell therapy in a 
cat model of ISO-induced cardiomyopathy. Approximately 1 × 106 autologous c-kit+ cells or 
MSCs were delivered by intracoronary injection at 10 days of ISO infusion. At 28 days after 
treatment, fractional shortening was found to improve with either c-kit+ cells and MSCs com-
pared with vehicle. This study suggests that both c-kit+ cell and MSC therapy improves cardiac 
function and attenuates pathological remodeling.  
 
 
 
 
 
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TABLE 2 
 
Studies of c-kit+ cells in experimental settings of chronic ischemic cardiomyopathy 
Authors 
Model 
Treatment 
Delivery 
Outcomes 
Summary 
Wysoczyn-
ski11 
Mice/Sub-
acute MI 
c-kit+ cells  
12 Slow adhering 
10 rapidly adher-
ing 
15 vehicle 
1 x 106 
Intra LV admin 
2 days post-MI 
35 days post treatment 
  LVEF 
  Infarcted wall thickness 
   Histologic exam  
SA group: significant  
↑ LVEF 
↑ infarcted wall thickness 
↓ scar over vehicle 
Li12 
Mice/Sub-
acute MI 
c-kit+ vs. vehicle 
8 IC c-kit+ 
9 IC vehicle 
10 IM c-kit+ 
12 IM vehicle 
4 x 105 for IC 
1 x 105 for IM 
IC admin 
IM admin 
2 days post-MI 
 
39 days post treatment 
LVEF 
LVFS 
LV volume 
LV diameter 
Infarcted wall thickness 
Infarcted wall thickening frac-
tion 
 Hemodynamics   
 Histologic exam 
Both c-kit+ groups: significant  
↑ LVEF 
↑ LVFS 
↑ infarcted wall thickness 
↑ infarcted wall thickening fraction 
↓ LV volume 
↓ LV diameter 
↑dP/dt max&min 
↑ elastance 
↑ viable myocardium over vehicle 
Hong13 
Mice/Sub-
acute MI 
c-kit+ vs. vehicle 
7 c-kit+ 
9 vehicle 
IM1 x 105  
IC administration 
2 days post-MI 
 
 
35 days post treatment 
Hemodynamics   
Histological cell characterization  
c-kit+ group: significant  
↑ LVEF 
↑ Elastance 
↓ LVEDP over vehicle 
Tokita36 
Rats/ICM 
(old MI) 
c-kit+ vs. vehicle 
16 c-kit+ x 1 dose 
18 c-kit+15 x 3 
doses 
16 vehicle  
112 x 106 
Intra LV admin 
30 days post-MI and 35 
days post-1st and 35 days 
post 2nd dose 
5 days post each treatment 
LVEF 
Infarcted LV wall thickening 
fraction 
Hemodynamics   
Histologic exam  
1 and 3 doses c-kit+ groups: significant  
↑ LVEF 
↑ infarcted wall thickening fraction 
↑ dP/dt max&min 
↑ elastance 
↓ LVEDP 
↓ scar and collagen over vehicle 
Tang37 
Rats/ICM 
(old MI) 
c-kit+ vs. vehicle 
16 c-kit+ x 1 dose 
18 c-kit+ x 3 doses 
16 vehicle  
36 x 106 x 1 or 12 x 106 x 
3 
Intra LV admin 
30 days post-MI and 35 
days post-1st and 35 days 
post 2nd dose 
35 days post each treatment 
LVEF 
LV volume  
Infarcted LV wall thickening 
fraction 
Hemodynamics   
Histologic exam 
 
 
I1 high and 3 repeated doses c-kit+ 
groups: significant  
↑ LVEF 
↓ LVESV 
↑ Elastance 
↓ scar over vehicle 
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Authors 
Model 
Treatment 
Delivery 
Outcomes 
Summary 
Ellison14 
Rats/ 
ISO-in-
duced CM 
 
 
c-kit+ vs.  cardiac 
fibroblasts and vehi-
cle 
4 c-kit+ 
4 cFibro 
4 vehicle 
15-245 x 105 c-kit+ 
IV admin 
28 days post-ISO 
628 days post treatment 
GLVFS 
Hemodynamics 
c-kit+ group: significant  
↑ LVFS 
↑ dP/dt max 
↓ LVEDP 
↓ LVID over cFibro or vehicle   
Zakharova15 
Rats/ICM 
(old MI) 
c-kit+ cells vs. vehi-
cle 
9 c-kit+ cells 
9 vehicle 
 
 
RCV infusion at 21 days 
post-MI 
21 days post treatment 
Hemodynamics 
Histological exam 
 
c-kit+ cells group: significant  
↑ LVEF 
↑ dP/dt max&min 
↑ SW 
↑ CO 
↓ LVEDP 
↓ Tau 
↓ infarct size 
↓ fibrosis over vehicle   
Zakharova16 
Rats/ICM 
(old MI) 
c-kit+ cells, HDACI-
c-kit+ cells vs. vehi-
cle 
8 c-kit+ cells 
8 HDACI-c-kit+ 
cells 
8 vehicle 
 
RCV infusion at 21 days 
post-MI 
21 days post treatment 
Hemodynamics 
Histological exam 
 
c-kit+ cells (and more so HDACI-c-kit+ 
cells) significant:  
↑ LVEF 
↑ dP/dt max 
↑ CO 
↓ LVEDP 
↓ infarct size  
↓ fibrosis over vehicle   
Bao17 
Rats/ICM 
(old MI) 
CPCs vs. vehicle 
6 c-kit+ 
6 vehicle 
1 x 106 
IM admin 
4 weeks post-MI 
28 days post treatment  
LVEF  
Fractional shortening  
Histological exam 
c-kit+ group: significant  
↑ LVEF, ↑ fractional shortening, ↓ infarct 
size, ↓ fibrosis over vehicle   
Williams23 
Pigs/ICM  
(old MI) 
hc-kit+ or hc-
kit++hMSCs vs. pla-
cebo 
5 c-kit+ 
5 c-kit++MSCs 
5 vehicle 
1 x 106 c-kit+ 
1 x 106 c-kit+ + 2 x 108 
MSCs 
Intramyocardial 
14 days post-MI 
 
4 weeks post treatment 
LVEF 
LV volume 
PV loops 
Histologic exam 
c-kit+ and c-kit++MSC groups: signifi-
cant ↑ LVEF, ↑ SV&CO, 
↑ dP/dt min, ↓ tau, & ↓ scar over placebo  
 
Karantalis18 
Pigs/ICM  
(old MI) 
c-kit++MSCs vs. 
placebo 
8 c-kit+ +MSCs 
6 placebo 
1 x 106 c-kit+ + 2 x 108 
MSCs 
Transendocardial 
3 months post-MI 
3 months post treatment 
LVEF 
LV volume 
Diastolic performance 
Histologic exam 
c-kit++MSC group: significant  
↑ LVEF 
↑ SV&CO 
↑ endothelial function 
↓ scar over placebo 
 
 
 
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Authors 
Model 
Treatment 
Delivery 
Outcomes 
Summary 
Kulandavelu21 
Pigs/ICM  
(old MI) 
hc-kit+, 
Pim+ hc-kit+ vs. pla-
cebo 
10 c-kit+ 
9 Pim+ c-kit+ 
10 placebo 
1 x 106 c-kit+ or Pim+ c-
kit+ 
Epicardium 
2 weeks post-MI 
4 or 8 weeks post-treatment 
LVEF 
LV volume 
PV loops 
Histologic exam 
c-kit+ and Pim+ c-kit+ groups: significant 
↑LVEF, ↑ SV&SW, ↓scar over placebo at 
4 weeks post-treatment 
Pim+ c-kit+ group extended significant 
↑LVEF, ↑ SW, ↑ cardiac efficiency, ↓scar 
over placebo at 8 weeks post-treatment 
Natsumeda19 
Pigs/ICM  
(old MI) 
Allo-c-kit+ 
+allo-MSCs vs. pla-
cebo 
7 c-kit+ +MSCs 
6 placebo 
1 x 106 c-kit++2 x 108 
MSCs 
Transendocardial injec-
tion  
3 months post-MI 
3 months post treatment 
Hemodynamics 
LV volume 
Morphometric exam 
 
c-kit++MSC group: significant  
↑ ESPVR 
↓ LV EDV 
↓ LV ESV 
↓ scar over placebo   
Kamata20 
Pigs/ICM  
(old MI) 
c-kit+ vs. sham 
6 c-kit+ 
6 sham 
1 x 108 c-kit+ sheet 
Epicardium  
21 days post ischemia 
8 weeks post c-kit+ sheet 
LVEF 
LV volume 
PV loops 
dP/dt 
LVEDP 
LV strain analysis 
Perfusion score 
Histologic exam  
c-kit+ group: significant  
↑ LVEF 
↓ EDV & ESV 
↑ dP/dt max & dP/dt min 
↑ Elastance 
↑ dP/dt 
↓ LVEDP 
↑ LV wall motion 
↑ Perfusion score 
↓ fibrosis 
Taghavi22 
Cats/ISO-
induced 
CM 
c-kit+ vs. no treat-
ment (sham) 
7 c-kit+ 
5 sham 
1 x 106  
IC administration 
28 days post ISO 
38 days post treatment 
LVEF 
Fractional shortening 
LV volume 
Transmitral E/A ratio 
LV dP/dt 
Contractility index 
Relaxation index 
Myocardial collagen content 
c-kit+ group: significant  
↑fractional shortening,  
↑E/A ratio,  
↑max LV dP/dt,  
↑Contractility index;  
↓Relaxation index (Tau),  
↓collagen deposition when compared to 
sham group 
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In summary, the foregoing preclinical data demonstrate that delivery of c-kit+ cells is associated 
with improved LV function in various animal models (mice, rats, pigs, cats) of subacute MI, old 
MI, or ISO-induced cardiomyopathy.  Among these, the studies in large (porcine) animal models 
of chronic ICM18-21,23 have greater clinical relevance for the CONCERT-HF trial. 
 
Combined MSCs and c-kit+ cells: Based on findings that MSCs induce proliferation of c-kit+ 
cells24, an investigation was carried out to determine if the combination of both cell types pro-
duced a greater reduction in MI size and improvement in LV function than each cell type alone23. 
Yorkshire swine underwent balloon occlusion of the LAD coronary artery followed by reperfu-
sion, and were immunosuppressed after MI with cyclosporine and methylprednisolone. Intra-
myocardial injection of either combination human c-kit+ cells/human MSCs (1M/200M, n=5), hu-
man c-kit+ cells alone (1M, n=5), human MSCs alone (200M, n=5), or placebo (PBS, n=5) was 
administered to the infarct border zones at 14 days post-MI.  Each cell therapy group reduced 
MI size relative to placebo (p<0.05), and the MI size reduction was two-fold greater in combina-
tion vs. either cell therapy alone (p<0.05). Significant improvement in LV chamber compliance 
(end-diastolic pressure volume relationship, p<0.01) and contractility (preload recruitable SW 
and dP/dtmax, p<0.05) was also observed in combination treated swine. LV ejection fraction 
(LVEF) was restored to baseline in all the cell therapy groups, while pigs receiving placebo had 
persistently depressed LV function (p<0.05). The engraftment of stem cells was seven-fold 
greater in the combination group vs. either cell type alone (p<0.001). In summary, combining 
human MSCs and human c-kit+ cells as a cell therapeutic enhanced MI size reduction and re-
stored diastolic and systolic function toward normal after MI.  
 
The superiority of the c-kit+ cell + MSC combination over either cell alone was further demon-
strated by two subsequent studies in porcine models of chronic ICM18,21 and in a rat model of 
chronic ICM17, as detailed above. Taken together, these studies17-19,23 illustrate potentially im-
portant biological interactions between c-kit+ cells and MSCs that enhance cell therapeutic re-
sponses and support the conduct of human clinical trials. 
 
Although the above study demonstrated the benefits of combining 1 million c-kit+ cells and 200 
million MSCs, the dose of c-kit+ cells was relatively small and it is possible that greater efficacy 
could be achieved by increasing it.  In this regard, evidence for the safety of intracoronary infu-
sion of higher doses of c-kit+ cells has been provided by a recent study in pigs38.  Fourteen nor-
mal pigs (i.e., pigs not subjected to myocardial infarction) received an intracoronary infusion 
(into the LAD, using a catheter without balloon inflation) of 20 x 106 human c-kit+ cells (n=9) or 
placebo (n=5, PlasmaLyte A solution). There was no significant difference between treated and 
control groups attributable to the cell product with respect to any of the tests of cardiac, renal, or 
liver injury. Furthermore, echocardiographic analyses did not reveal decline in myocardial func-
tion or change in cardiac dimensions.  
 
2.3 Background Clinical Studies 
Transplanting progenitor cells into a region of damaged myocardium, termed cellular cardiomyo-
plasty39, is a potentially new therapeutic modality designed to repair necrotic, scarred, or dys-
functional myocardium40-42.  Ideally, graft cells should be readily available, easy to culture to en-
sure adequate quantities for transplantation, and able to survive in host myocardium that can be 
a hostile environment of limited blood supply and hostile immune reaction.  Although it was origi-
nally thought that effective cellular regenerative strategies require that the administered cells dif-
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ferentiate into adult cardiomyocytes and couple electromechanically with the surrounding myo-
cardium, recent evidence indicates that is not required for effective cardiac repair.  More im-
portantly, transplantation of graft cells should improve cardiac function and prevent adverse ven-
tricular remodeling.   
 
To date, a number of candidate cells have been transplanted in experimental models, including 
fetal and neonatal cardiomyocytes43, pluripotent stem cell-derived cardiomyocytes44,45, tissue 
engineered contractile grafts46, skeletal myoblasts47, several cell types derived from adult bone 
marrow48-53, and cardiac progenitors residing within the heart itself.  There has been substantial 
clinical development in use of whole bone marrow and skeletal myoblast preparations in studies 
enrolling both post-infarction patients, and patients with chronic ischemic left ventricular (LV) 
dysfunction and HF.  
 
 
2.3.1 Bone marrow mononuclear cells 
Evidence from trials investigating delivery of bone marrow or bone marrow-derived cells repre-
sents a highly promising modality for cardiac repair and suggests that cellular cardiomyoplasty 
is a safe and effective strategy to improve cardiac function in patients with acute MI or chronic 
ICM54,55.  The clinical experience with the administration of cells using the IC route, peripheral IV 
injection, and transendocardial injection also provides substantial evidence of clinical safety at 
the cell doses administered.  Although CONCERT-HF will not use these cells, a review of these 
studies (Table 3) is relevant since the mode of delivery for many of them (i.e., catheter-based IM 
injection) is the same as that proposed for CONCERT-HF. 
 
 
For example, the FOCUS-CCTRN trial56 (First Mononuclear Cells injected in the United States 
conducted by the CCTRN) employed transendocardial injections to assess the safety and effec-
tiveness of bone marrow mononuclear cells in patients with chronic HF and ongoing myocardial 
ischemia.  This phase II randomized double-blind, placebo-controlled trial recruited 92 patients 
who were symptomatic (New York Heart Association classification II-III or Canadian Cardiovas-
cular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfu-
sion defect by single-photon emission tomography (SPECT), and coronary artery disease not 
amenable to revascularization received maximal medical therapy. Cells were delivered by direct 
IM injection, and patients were followed for six months by clinic visit and for five years by tele-
phone. No deaths, serious arrhythmias, or other serious adverse events were attributed to cell 
therapy, and the DSMB never placed the study on hold due to a safety signal. 
 
This and other studies in Table 3 provide substantial evidence of: 1) clinical safety with the ad-
ministration of cells by transendocardial injection; 2) clinical safety at the cell doses adminis-
tered; and 3) preliminary support the potential for clinical efficacy. 
 
 
 
 
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TABLE 3 
CLINICAL STUDIES: AUTOLOGOUS BONE MARROW-DERIVED MONONUCLEAR CELLS (BMCs) 
Study 
N 
Cell Delivery         
Method 
Cell Source    
& Type 
Cell Dose    
(x 106) 
Safety 
Efficacy 
Results 
Results 
Stamm57 
6 
Direct IM injection 
during CABG surgery 
Autologous, 
AC133+ BMCs 
1.2 - 3.4 
No arrhythmias; 
no neoplasia 
↑ global contrac-
tility (EF) 
Tse58 
8 
Catheter-based IM in-
jection 
Autologous 
BMCs 
2.6 - 21.2 
No arrhythmias 
↑ wall motion & 
thickening 
Fuchs59 
10 
Catheter-based IM in-
jection 
Autologous 
BMCs 
32.6 + 27.5 
No arrhythmias 
or other SAEs 
↓ angina score;    
↓ ischemia 
Perin3 
14 
Catheter-based IM in-
jection 
Autologous 
CD34+ BMCs 
25.5 + 6.3 
No arrhythmias at 
6-mo. F/U 
↑ global contrac-
tility (EF); ↓ ESV 
Beeres60 
25 
Catheter-based IM in-
jection 
Autologous 
BMCs 
84.1 + 28.7 
No arrhythmias 
or pericardial ef-
fusion 
↑ global contrac-
tility (EF); ↓ ESV 
Briguori61 
10 
Catheter-based IM in-
jection 
Autologous 
CD34+ BMCs 
4.6 + 1.5 
No arrhythmias 
or AMI 
↑ quality of life;    
↑ perfusion 
de La 
Fuente62 
10 
Catheter-based IM in-
jection 
Autologous 
CD34+ BMCs 
86 + 3 
No arrhythmias at 
12-mo. F/U 
↑ global contrac-
tility (EF) 
Mocini63 
36 
Direct IM injection 
during CABG surgery 
Autologous 
CD34+ BMCs 
292 + 232 
No SAEs 
↑ global contrac-
tility (EF) 
Hendrikx64 
20 
Direct IM injection 
during CABG surgery 
Autologous 
BMCs 
60.1 + 31.1 
Possible induci-
ble VT 
↑ global contrac-
tility (EF) 
Stamm65 
55 
Direct IM injection 
during CABG surgery 
Autologous, 
CD133+ BMCs 
3.85 - 103.0 
No arrhythmias 
↑ global contrac-
tility (EF) 
Li66 
6 
Direct IM injection 
during CABG surgery 
Autologous 
BMCs 
50 – 100 
No arrhythmias; 
no neoplasia 
Not assessed 
Perin56 
92 
Catheter-based IM in-
jection 
Autologous 
BMCs 
100 
No arrhythmias; 
no neoplasia 
small ↑ EF     
(exploratory) 
Traverse67  
87 
IC infusion 
Autologous 
BMCs 
150 
No arrhythmias; 
no neoplasia 
No effect on LV 
function 
Traverse68 
120 
IC Infusion 
Autologous 
BMCs 
150 
No arrhythmias; 
no neoplasia 
No effect on LV 
function 
AMI: acute myocardial infarction; IM: intramyocardial; CABG: coronary artery bypass graft; BMC: bone marrow-
derived mononuclear cells; EF: Ejection Fraction; ESV: end systolic volume; F/U: follow-up; SAE: serious adverse 
event; VT: ventricular tachycardia; IC: intracoronary 
2.3.2 Human Experience with Autologous and Allogeneic Human Mesenchymal Stem 
Cells (MSCs) 
MSCs are a particularly promising bone marrow-derived cell for cardiac regenerative therapy 
because of their availability, immunomodulatory properties, and track-record of safety and effi-
cacy5,8,32,42.  Although there is no agreed upon cell surface marker that characterizes MSCs, 
they appear related to c-kit+ cells as they pass through a stage of cardiac differentiation in 
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which they express this cell surface marker.  C-kit is a tyrosine kinase receptor for stem cell fac-
tor69.   
 
Administration of autologous or allogeneic human MSCs to cardiovascular patients has been 
performed in several clinical studies to date. In the post-MI setting, previous studies have ad-
ministered MSCs via the intracoronary route (IC) and via peripheral intravenous (IV) injection. 
 
 
Chen et al.70 randomly assigned 69 patients to receive intracoronary (IC) infusions of autologous 
MSCs (average cell dose: 5.4 x 1010) or placebo (saline) 18 days after the onset of acute MI 
symptoms.  At the three-month follow-up visit, LVEF was significantly improved in the MSC-
treated group (from 49% ± 9% at baseline to 67% ± 11%) compared to the placebo group (from 
48% ± 10% at baseline to 53% ± 18%; p<0.01 for the between-group comparison).  This im-
proved EF was sustained at six months post-infusion.  In addition, significant reductions in per-
fusion defect, LV End Diastolic Volume (LVEDV) and LV End Systolic Volume (LVESV) were 
reported in the MSC-treated group.  No adverse events were reported in this study. 
 
 
A multi-center, randomized, double-blinded, placebo-controlled study was performed in 53 pa-
tients who were treated 3-10 days post-MI4. Patients were administered with one of three cell-
dose levels of allogeneic MSCs (0.5, 1.6 and 5.0 cells/kg; corresponding to 3.5 x 107, 1.1 x 108, 
and 3.5 x 108 cells per patient for a 70 kg body weight patient), or placebo administered via pe-
ripheral IV injection, and followed for six months.  There were no deaths reported in the study; 
no toxicity was observed with the administration of the allogeneic MSCs (which were found to be 
well-tolerated at all dose levels administered, with 5.3 adverse events per patient in the MSC-
treated group vs. 7.0 in the placebo group); and no serious adverse events were attributed to 
MSC administration. 
 
 
A phase I/II randomized trial was conducted to assess the safety and efficacy of allogeneic and 
autologous MSCs delivered via transendocardial injection in patients with ICM5. In the Percuta-
neOus StEm Cell Injection Delivery Effects On Neomyogenesis (POSEIDON) trial 
(NCT01087996), 30 patients were divided into 6 subgroups based on type of MSC (allogeneic 
or autologous) and dose (20 million, 100 million, and 200 million).  The primary outcome was 
30-day post-catheterization incidence of predefined treatment-emergent serious adverse events 
(SAEs).  Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Liv-
ing with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, 
EF, early enhancement defect (EED), a measure of infarct size based on CT imaging tech-
niques, and sphericity index.  Within 30 days, the treatment-emergent SAE rate was 6.7% (one 
patient in each group), well below the pre-specified stopping event rate of 25%. The one-year 
incidence of SAEs was 33.3% (n=5) in the allogeneic group and 53.3% (n=8) in the autologous 
group (p=0.46). Relative to baseline, autologous but not allogeneic MSC therapy was associ-
ated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved 
exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, 
−43.61% to −22.81%; p<0.001) and sphericity index, but did not increase EF. Allogeneic MSCs 
reduced LVEDV. Low-dose concentration MSCs (20 million cells) produced greatest reductions 
in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific 
alloimmune reactions. In summary, MSC injection favorably affected patient functional capacity, 
quality of life, and ventricular remodeling.  
 
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The Transendocardial Autologous Cells in ischemic Heart Failure Trial (TAC-HFT)7 was con-
ducted in order  to evaluate the  safety of transendocardial stem cell injection with autologous 
MSCs and bone marrow mononuclear cells (BMCs) in patients with ICM. This was a phase 1/2 
randomized, blinded, placebo-controlled study involving 65 patients with ICM and left ventricular 
(LV) ejection fraction less than 50% The study compared injection of MSCs (n=19) with placebo 
(n = 11) and BMCs (n = 19) with placebo (n = 10) following patients for 1 year. No patient had a 
treatment-emergent serious adverse event at day 30. Over 1 year, the MLHFQ score improved 
with MSCs (-6.3; 95% CI, -15.0 to 2.4; p=0.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; 
p=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; p=0.38). The 6-minute walk distance 
increased with MSCs only (repeated measures model, p = 0.03). Infarct size as a percentage of 
LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, p = 0.004) Re-
gional myocardial function as peak Eulerian circumferential strain at the site of injection im-
proved with MSCs (-4.9; 95% CI, -13.3 to 3.5; p = 0.03) . The authors concluded that transendo-
cardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ICM 
and LV dysfunction. 
 
The Cardiopoietic stem Cell therapy in heart failURE (C-CURE) trial71 assessed the feasibility 
and safety of autologous bone marrow-derived and cardiogenically oriented mesenchymal stem 
cell therapy to probe for signs of efficacy in patients with chronic HF.  In the cell therapy arm, 
bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardio-
genic cocktail. Derived cardiopoietic stem cells were delivered by map guided endomyocardial 
injections. The target dose was attained in 75% and delivery without complications in 100% of 
cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic 
cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 
34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.001) and 
was associated with a reduction in left ventricular end-systolic volume (-24.8 ± 3.0 ml vs. -8.8 ± 
3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. -15 ± 20 
m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters 
in tandem with New York Heart Association functional class, quality of life, physical perfor-
mance, hospitalization, and event-free survival. 
 
A recent trial supported by Mesoblast Ltd. was performed at six centers in the US between 
8/2008 and 5/2010 to assess the safety and efficacy of bone marrow-derived allogeneic mesen-
chymal precursor cells (MPCs) STRO-1bright cells on LV function (NCT00721045). This was a 
Phase II, single blind, randomized dose-escalation study of 60 subjects with fifteen subjects per 
group (10 treated and 5 controls in each group) exploring three doses of cells (i.e., 25 million, 75 
million or 150 million).  Subjects were injected via the transendocardial route utilizing the 
NOGA® XP Mapping and Navigation System (NOGA) into viable myocardium.  Outcomes were 
a) immunological safety; b) safety of the injection procedure; c) 6-month surrogate efficacy find-
ings of no change in LVEF and 6-minute walk test, significant decrease in both LVESV and 
LVEDV in the 150 million group; and d) MACE evaluations to 36 months in all groups. For is-
chemic MACE (i.e., death, MI and revascularization) pooled MPC had significantly lower events 
but no significant difference between any cell dose group and control patients.  For HF MACE 
(i.e., cardiac death or HF re-hospitalization) there were no events in the 150 million cell group.  
HF-related MACE was seen in all other groups. These data were partially presented at AHA 
2013 and published in Circulation Research in 201572. 
 
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2.3.3 Human experience with cardiac-derived cells 
The first two trials employing cell products developed from human myocardium were SCIPIO73 
and CADUCEUS74; however, given concerns that have been raised regarding the work of Dr. 
Piero Anversa and colleagues, only the CADUCEUS study will be described.  
 
CADUCEUS74 (CArdiosphere-Derived aUtologous stem CElls to reverse ventricular dysfunction) 
was a phase I trial which utilized endomyocardial biopsy (EMB) specimens. The cardiosphere-
derived cells were infused via intracoronary route at 1.5-3 months after myocardial infarction to 
assess safety and evaluate effects seen previously in pre-clinical models (i.e. reduced scarring, 
increased viable myocardium, improved cardiac function). No complications were associated 
with the infusion and, by six months, no deaths, cardiac tumors, or MACE were observed in ei-
ther the active group (n=17) or standard care group (n=8).  The active group demonstrated sig-
nificant change over the standard care group in reduced scar mass (8.4g ± 5.1, p=0.001) and 
regional systolic wall thickening (7.7% vs -5.9%; p=0.045).  Similarly, the active group showed 
increases in viable heart mass (13.0g ± 11.4 vs 0.9g ± 6.2; p=0.01) and improved regional con-
tractility (-2.0% ± 6.3 vs 1.5% ±7.3; p=0.009) when compared to the standard care group.  The 
trial demonstrates the safety of infusing cell products derived from human myocardium, while 
lending credence to pre-clinical findings of increased viable myocardium. 
 
2.4 Advances in Cardiac Imaging 
Members of the CCTRN clinical research team have extensive experience in the evaluation of 
myocardial scar and LV function. Using an IV injection of Gadolinium-DTPA, the study team is 
able to determine infarct size non-invasively with T1-weighted delayed-enhanced MRI (DEMRI). 
Specifically, the DEMRI data were analyzed to identify the area at risk in the peri-infarct region 
and evaluate the clinical impact of the heterogeneity of myocardial injury75-77. Several experi-
ments have validated DEMRI as an accurate and viable method for quantification of myocardial 
fibrosis by comparing the measured scar area to those from thallium scintigraphy, electrocardi-
ography, and histopathology in animals and humans78-81. The prognostic implications of DEMRI 
have been studied extensively in a variety of pathologies and have also been compared to and 
proven superior to other imaging modalities. DEMRI is the current gold standard to predict re-
gional functional recovery.  Another area of significant interest is the use of tagged MRI scan-
ning to detect and quantify alterations in regional myocardial mechanics in animal models of 
ICM82,83.  Non-surgical animal models have been developed for studying cardiac mechanics, 
perfusion, and interventional procedures84-87.  New MR imaging and analysis methods that ena-
ble the rapid determination of myocardial function in infarction and ischemia have recently been 
developed88,89. This technique, Harmonic Phase (HARP) MRI88,90,91 is based on tagged MRI 
techniques.  Computationally, the analysis of HARP MRI can be performed much more rapidly 
than the traditional tag tracking MRI. HARP MRI, similar to tagged MRI, yields quantitative mo-
tion and strain parameters on a regional basis that can be used for comparison across patients 
or at serial time points after intervention.  Thus, HARP MRI analysis represents a rapid and re-
peatable method to assess LV function serially in a quantitative manner.  HARP provides fast, 
accurate assessment of myocardial strains in humans with and without coronary artery dis-
ease92.  Similar techniques have been used to assess structural and functional changes after MI 
in rats93,94.   
 
Furthermore, T1 myocardial mapping techniques will be employed (at select qualified centers 
with such capabilities) as an essential adjunctive tool to garner a more complete picture of the 
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myocardial condition following stem cell therapy over DEMRI which will also be performed.  Re-
cently, T1 mapping has been shown to effectively demonstrate fibrotic changes in a myriad of 
pathologic conditions95-97. While the DEMRI is very sensitive to small areas of regional fibrosis, 
this method enables a comparison to the signal from the "normal" myocardial reference areas in 
relation to the fibrotic regions.  In patients with more diffuse fibrosis, which include those with 
chronic ICM, T1 mapping will provide a more sensitive method by which both interstitial and re-
placement fibrosis can be quantified in the myocardium. 
 
2.5 Rationale for Dual Therapy 
This trial is based upon the hypothesis that the combination of two cell types will have a greater 
effect on LV function and functional status than either cell type alone or than placebo.  The hy-
pothesis arose from work showing that bone marrow-derived MSCs stimulate a number of en-
dogenous cardiac c-kit cells in porcine models of infarction24.  Additionally, ex vivo, MSCs en-
hance the survival and proliferation of c-kit+ cells. To test the therapeutic response of dual ther-
apy, a prospective porcine study was designed and conducted to test whether dual therapy en-
hances the reduction in MI scar size23.  As detailed above, this study, indeed, documented an 
enhanced reduction in the burden of MI scar and LV dysfunction with  dual therapy vs. mono 
therapy, a concept that was confirmed by other studies in pigs and rats17-19,23. One of these 
studies18 used a porcine model in which autologous c-kit+ cells and MSCs were delivered 3 
months after MI using transendocardial injection, and thus is highly relevant to CONCERT-HF. 
Thus, the CONCERT-HF trial is designed to reproduce the effect seen in the porcine studies 
and to test the impact of cell therapy using dual therapy (MSCs plus c-kit+ cells) compared to 
placebo and to either cell type alone.  The endpoints will allow us to determine if dual therapy 
has an enhanced effect relative to placebo, an enhanced effect relative to mono therapy, and if 
it is well-tolerated in humans with ICM. 
 
2.6 Dose Rationale 
Many considerations are involved in selecting optimal doses of cells. The idea that the combina-
tion of MSCs plus c-kit+ cells is effective is predicated on animal data23. The key principle for 
our selection of doses for the combined cell product is optimizing the dose of each individual cell 
rather than a ratio of the cells.  We evaluated a significant amount of data from which we se-
lected the individual cell doses. 
 
MSCs: Clinical studies have utilized cell doses that were over 200 million MSCs4,5 and doses of 
1 x 1010 MSCs70 – as much as sixty-five times greater than the MSC cell dose proposed herein 
(150 x 106). In two preclinical studies in a porcine model61,98 and in the TAC-HFT32 and POSEI-
DON trials5 MSC therapy was safely administered via intramyocardial injection at doses of up to 
200 x 106 cells. The MSC dose comes from data from the POSEIDON study5 published two 
years ago by the University of Miami group (a CCTRN center) that compared autologous vs. al-
logeneic MSCs, as well as a trial supported by Mesoblat Ltd. which included subjects from two 
CCTRN centers and used multiple doses of Mesoblast’s MPCs including 150 x 106 cells.  In this 
dose escalation study72 of 60 subjects, MSC therapy was safely administered via intramyocar-
dial injection at doses of up to 150 x 106 cells.  Specifically, increasing doses of MSCs were as-
sociated with decreasing LVEDV and decreasing LVESV. This benefit was maximized at the 
dose of 150 million MSCs. In addition, no serious adverse events were reported at the 150 mil-
lion MSC dose.  These studies support using the dose level of 150 x 106 for the MSC prepara-
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tion in this clinical study. The target MSC dose was chosen based on data from previous stud-
ies, as well as practical considerations and the ability to grow this quantity of cells for most sub-
jects within approximately 28 days.  
 
 
c-kit+ cells: The entire body of pre-clinical work done on c-kit+ cells strongly supports the safety 
of a dose of cells greater than 1x106 cells. Doses of c-kit+ cells used in animal studies,normal-
ized to body weight, have ranged enormously, from 20 cells/gram body weight in pigs21,23 to 40 
cells/gram body weight in pigs18,19 to as high as 2 x 105 cells/gram body weight in rats37; the cor-
responding total doses were 1 x 106 cells in pigs21,23 , 1 x 106 cells in minipigs18,19 and 36 x 106 
in rats37. No adverse effects were noted in any study. The target dose used in CONCERT-HF (5 
x 106 cells or 63 cells/gram body weight) is at the lower end of this range. It should be noted that 
in pigs, doses much higher than 1 x 106 have been found to be safe; Bolli et al. at the University 
of Louisville (a CCTRN center) performeda study in pigs in which they infused 20 x 106 human 
c-kit+ cells into the LAD, which is roughly equivalent to 40-60 x 106 cells in humans, and found 
no adverse safety signals38.  No adverse effects of c-kit+ cells have been reported in published 
studies or seen in unpublished data, as assessed by cardiac enzymes, myocardial function or 
histology. In clinical trials, other similar sized cardiac-derived cells have been safely given at a 
dose of 25 x 106 74.  For CONCERT-HF, the target dose of c-kit+ cells will be 5 x 106 c-kit+ cells. 
This dose was selected based on the safety data in pigs described above38 and on our experi-
ence with successful isolation and expansion of c-kit+ cells from tissue samples (EMBs) ac-
quired from a diverse population of patients with ICM.  From a practical standpoint, our experi-
ence indicates that in many patients 5 x 106 c-kit+ cells is the highest number of cells that can 
be grown from the EMBs without resorting to more than six passages. 
 
Combined MSCs and c-kit+ cells: Preclinical studies have demonstrated that the use of c-kit+ 
cells in combination with MSCs generates improved cardiac function in pigs17-19,23 and support 
the hypothesis that dual therapy is well-tolerated and may signal improved heart function in sub-
jects with ICM.  In a pre-clinical swine study of intramyocardial injections at 14 days post-MI, the 
dose used was a combination of 1 x 106 human c-kit+ cells plus 200 x 106 human MSCs23.  The 
same does have been used in two subsequent pig studies18,19.  While these studies demon-
strated improved cardiac function at these cell doses, the dose of c-kit+ cells was relatively 
small and it is possible that greater efficacy could be achieved by increasing it.   The upper limit 
on the total number of all cells was carefully considered because: 1) data show efficacy can be 
reduced when doses are too high (possibly due to the viscosity or lack of oxygenation of the 
mixture); and 2) it is important to limit the concentration of cells that will be passed through the 
various catheter systems to avoid cell clumping.  
 
In conclusion, the target cell doses for CONCERT-HF will be 150 x 106 MSCs and 5 x 106 c-kit+ 
cells, alone or in combination, striving to reach maximal cell numbers in each group.  These 
doses have a strong safety profile and yield compelling evidence for the potential to improve LV 
function and functional status in subjects with HF of ischemic etiology. 
 
3.0 INVESTIGATIONAL PLAN 
3.1 Research Questions 
• Can MSCs and c-kit+ cells, both alone and in combination, be manufactured and deliv-
ered to subjects with ischemic cardiomyopathy? 
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• Are MSCs and c-kit+ cells, alone or in combination, well-tolerated by subjects with is-
chemic cardiomyopathy? 
• Do MSCs combined with c-kit+ cells, MSCs alone, or c-kit+ cells alone improve LV func-
tion and functional status when compared with placebo from baseline to 6 months and 
baseline through 12 months post treatment with study product? 
• Do MSCs combined with c-kit+ cells improve LV function and functional status when 
compared with either MSCs alone or c-kit+ cells alone from baseline to 6 months and 
baseline through 12 months post treatment with study product? 
• When compared with each other, do either MSCs alone or c-kit+ cells alone offer a rela-
tive advantage in improving LV function and functional status from baseline to 6 months 
and baseline through 12 months post treatment with study product? 
 
3.2 Study Design 
This study will evaluate one-hundred sixty (160) subjects and will be undertaken in two stages.  
 
Stage 1 (open label lead-in) consists of sixteen (16) subjects randomized 1:1 to either a stand-
ard of care (SOC) group (i.e., receive no study intervention procedures) or to Combo therapy. 
Data from this stage will be assessed for safety of the study procedures and bioactivity of the 
product. Following successful review of the lead-in data by the DSMB (see Section 7.7), this will 
be followed by the second stage consisting of a double-blind, placebo-controlled, clinical trial en-
rolling 144 subjects.  Those subjects randomized to Combo therapy will continue to be followed 
per protocol for 12 months.  Those randomized to the SOC control group will have the option to 
be evaluated for enrollment in the trial conducted in Stage 2. 
 
Stage 2 is a phase II, randomized, placebo-controlled clinical trial designed to evaluate the fea-
sibility, safety and effect of Combo, MSCs alone, and c-kit+ cells alone compared with placebo 
as well as each other in subjects with HF of ischemic etiology.  
 
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. Within 60 days of signing informed consent, all subjects will un-
dergo bone marrow aspiration (BMA) and right heart catheterization (RHC). The RHC will in-
clude endomyocardial biopsy (EMB) for the 72 subjects randomized to the Combo and c-kit+ 
cell groups. All subjects will undergo study product injection using the NOGA® XP Mapping and 
Navigation System. After randomization, baseline imaging, harvest procedures, and study prod-
uct injection, subjects will be followed up at 1 day, 1 week, 1 month, 3 months, 6 months and 12 
months post study product injection (SPI).  All subjects will have DEMRI scans to assess scar 
size and LV function and structure at baseline and at 6 and 12 months post study product ad-
ministration.  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, we will utilize an “intention-to-treat” 
study population. An as-treated analysis will also be conducted. 
 
3.3 Study Treatment Assignments and Dosages 
One hundred forty-four (144) subjects meeting all inclusion/exclusion criteria will be evaluated at 
baseline. Subjects will be randomized 1:1:1:1 to one of four treatment strategies:  
1. Group A (36 subjects) – Combo: Target dose is a mixture of 150 x 106 (150 million) 
MSCs and 5 x 106 (5 million) c-kit+ cells delivered in 15 injections each of 0.4 ml volume  
2. Group B (36 subjects) – Autologous MSCs: Target dose is 150 x 106 (150 million) MSCs 
delivered in 15 injections each of 0.4 ml volume 
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3. Group C (36 subjects) – Autologous c-kit+ cells: Target dose is 5 x 106 (5 million) c-kit+ 
cells delivered in 15 injections each of 0.4 ml volume 
4. Group D (36 subjects) – Placebo: 15 injections each of 0.4 ml cell-free PlasmaLyte-A me-
dium 
 
Minimum doses are outlined in Section 5.8 of this protocol.  In order to maintain study blinding, if 
a subject in group A does not meet the minimum dose of c-kit+ cells, the subject will receive 
MSCs and conversely, if they do not meet the minimum dose of MSCs, the subject will receive 
c-kit+ cells; should both products fail to meet release criteria, the subject would receive placebo.  
If a subject in group B or C does not meet the minimum dose, the subject will receive placebo. 
For statistical analysis purposes, all subjects will be analyzed in the group to which they were 
randomized in accordance to the “intention-to-treat” principle. 
 
The study product for Group A will contain at most 155 million cells (150 million MSCs plus 5 
million c-kit+ cells). The product delivery goal is to keep the number of injections, the volume per 
injection and the cell concentration per injection moderate.  Administering 15 injections of 0.4 ml 
volume each provides 6.0 ml of total study product volume with a cell concentration of no more 
than 25.833 million total cells/ml (+10%), or a maximum of 10.333 million cells/0.4ml (+10%), 
per dose, per injection site. While the number of injections (n=15) and the volume per injection 
(0.4 ml) will remain unchanged, smaller numbers of cells will result in a lower concentration of 
cells per injection. See Section 5.8 for additional details. 
 
3.4 Feasibility Assessment 
To demonstrate that MSCs and c-kit+ cells, both alone and in combination, can be manufac-
tured and delivered to subjects with ICM, the following measures will be reported. 
The number and percent of subjects who have: 
• Events between randomization and SPI that preclude the subject from getting SPI 
• Failed bone marrow aspiration procedure 
• Failed endomyocardial biopsy procedure 
• Failed release criteria (including minimum number of cells) for receiving the MSC product 
• Failed release criteria (including minimum number of cells) for receiving the c-kit+ cell 
product  
• Less than 15 injections during the SPI procedure 
• 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 
 
3.5 Safety Assessment 
Adverse event monitoring is discussed in detail in Section 7. In order to assess the relative 
safety of MSCs and c-kit+ cells delivered alone or in combination when compared with placebo, 
the following safety data will be collected and analyzed by therapy group between baseline and 
a) 6 months and b) 12 months: 
 
Major adverse cardiac events (MACE)1 including: death, hospitalization for worsening HF, 
and/or  exacerbation of HF (non-hospitalization) 
• Other significant clinical events including: non-fatal stroke, non-fatal myocardial infarction, 
coronary artery revascularization, ventricular tachycardia/fibrillation, and/or pericardial 
tamponade 
• All adverse events that are at least grade 2 in severity (see Section 7.3.1)   
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3.6 Study Endpoints 
 
3.6.1 Efficacy Objective 
To assess whether cell therapy (Combo, MSC, and c-kit+ cell) improves LV function and func-
tional status when compared with placebo and whether the improvement in subjects receiving 
the combined cell product is greater than the improvement in those receiving either individual 
cell product alone.  LV function and functional status are assessed at baseline, 6 months, and 
12 months. 
 
3.6.2 Prospectively Declared Efficacy Endpoint Measures 
To assess the overall effect of the cell types used in CONCERT-HF, multiple endpoints have 
been selected from different categories of effects (domains)99.  Each having the same priority for 
the efficacy analyses, the domains and endpoint measures for CONCERT-HF are: 
• Myocardial evaluations by cardiac MRI (cMRI) over time: 
− Function: 
 Change in LVEF 
 Change in global and regional strain (HARP MRI) 
− Structure: 
 Change in LVEDVI 
 Change in LVESVI 
 Change in LV Sphericity Index 
− Morphology:  
 Change in infarct/scar volume (DEMRI) 
• Functional capacity over time: 
− Change in VO2 max (treadmill) 
− Change in exercise tolerance (6MWT)  
− Change in MLHF Questionnaire (subject reported) 
• Clinical outcomes over time: 
− MACE 
− Cumulative days alive and out of hospital for HF 
• Biomarkers over time: 
− Change in NT-proBNP  
 
3.6.2.1 Comparisons 
Each of the following comparisons will be made between: 
1. Combo versus MSC 
2. Combo versus c-kit+ cell 
3. Combo versus placebo 
4. MSC versus placebo 
5. c-kit+ cell versus placebo 
6. MSC versus c-kit+ cell 
 
3.6.2.2 Analyses 
The reported effect for each of the endpoints will be: 
• Difference between baseline and 6 months when all subjects have completed their six 
month evaluations  
 
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And, when all subjects have completed their 12 month evaluation: 
• Difference in the trajectories from baseline through 12 months  
• Difference between baseline and 12 months 
• Difference between 6 months and 12 months 
 
3.6.2.3 Sub-study Analysis 
Change in global diffuse fibrosis will be evaluated as a sub-study.  This experimental endpoint will only 
be performed at clinical sites that have the necessary sequencing software and are qualified to partici-
pate in this sub-study by the MRI core lab.  
 
3.6.2.4 c-kit+ cell Product Characterization Analysis 
Characterization of c-kit+ cell products, i) hematopoietic and other stem/progenitor cell markers, ii) cardi-
ogenic markers, and iii) senescence) will be reported. Means and medians will be used for central ten-
dency and dispersion will be depicted with the standard deviation and interquartile range.  
 
3.7 Sample Size Computations and Assumptions 
The sample size computation is based on general linear model under the assumption of inde-
pendence and normality of the observations. For the sample size computation, we assume that 
this four armed study is balanced.   
 
We write yk is the change between the baseline and follow-up measures in accordance with 
Section 3.6 above and let xi =1 if the ith subject receives MSC alone, 0 otherwise, and wi =1 if the 
ith subject receives c-kit+ cell alone, 0 otherwise and zi =1 if the ith subject receives Combo, 0 
otherwise. Then we construct the model  
[ ]
0
1
2
3
i
i
i
i
y
x
w
z
β
β
β
β
=
+
+
+
E
. 
 
3.7.1 Efficacy Hypotheses and Testing 
Using this model for a given endpoint in Section 3.6.2 and for a given analysis in Section 
3.6.2.2, we can address each of the six comparisons in Section 3.6.2.1 as follows: 
 
• Hypothesis 1: Combo improves LV function and functional status when compared with 
placebo from baseline to 6 months and baseline through 12 months. 
Addressed by the hypothesis 
3
3
:
0
.
:
0
vs
β
β
=
≠
0
a
H
H
  
• Hypothesis 2: MSCs alone improve LV function and functional status when compared 
with placebo from baseline to 6 months and baseline through 12 months. 
Addressed by 
1
1
:
0
.
:
0
vs
β
β
=
≠
0
a
H
H
 
• Hypothesis 3: c-kit+ cells alone improve LV function and functional status when com-
pared with placebo from baseline to 6 months and baseline through 12 months. 
Addressed by 
2
2
:
0
.
:
0
vs
β
β
=
≠
0
a
H
H
 
• Hypothesis 4: Combo improves LV function and functional status when compared with 
MSCs from baseline to 6 months and baseline through 12 months. 
Addressed by 
3
1
3
1
:
.
:
vs
β
β
β
β
=
≠
0
a
H
H
 
• Hypothesis 5: Combo improves LV function and functional status when compared with 
c-kit+ cells from baseline to 6 months and baseline through 12 months. 
Addressed by 
3
2
3
2
:
.
:
vs
β
β
β
β
=
≠
0
a
H
H
 
• Hypothesis 6: MSCs or c-kit+ cells improve LV function and functional status when com-
pared with each other from baseline to 6 months and baseline through 12 months. 
Addressed by 
2
1
2
1
:
.
:
vs
β
β
β
β
=
≠
0
a
H
H
 
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Effective Date: November 19, 2019 
 
Assume 
ib  is the least square estimator of 
iβ  for each of the four parameters (i = 1,2,3,4) in the 
model above. Then, in general, we need to compute the variance of several linear combinations 
of the 
ib ’s. We write the model above as 
=

E y
Xb  where y is a 4n-tuple vector of the changes 
in the measurement over time, X is the design matrix for the model above, and b  is the 4 by 1 
vector of parameter estimates. If we write this linear combination in general as a'b   where a  is 
a 4 by 1 vector of constants, then we may write the variance as 
(
)
(
)
1
Var
'
MSE
−


= 

a'b
a X'X
a
.  
Note that 
 
4
0
0
'
0
0
0
0
n
n
n
n
n
n
n
n
n
n












X X =
 is a function of n, the number of subjects in each treatment group.  
 
The power of the hypothesis test  
 
 
0
H :
0
vs H :
0
a
=
≠
a'β
a'β
 
is then computed as  
(
)
1
/2
1
'
1
1
'
1
Z
F
Z
MSE
f
α
β
−
−






−
= −
−







−


a b
a X'X
a
 
 
where  
α 
= Type I error 
β 
= Type II error 
Zc 
= the cth percentile from the standard normal probability distribution 
MSE   = the variance in the change over time (incorporates the correlation over time) pooled be-
tween the active and placebo groups. 
FZ      = Cumulative distribution function of the standard normal distribution 
X   
= the 4n by 4 design matrix for this model 
b   
= the 4 x 1 vector of parameter estimates. 
a         = 4 x 1 vector of constants in which terms the statistical hypothesis  '
0
=
a β
 is expressed.  
f 
= percentage of subjects lost to follow-up. 
 
In this model assuming a balanced design,  
 
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(
)
1
4
4
1
1
1
1
1
1
1
0
0
1
1
0
0
1
2
1
1
1
'
:
'
.
0
0
1
0
1
0
1
1
2
1
0
0
1
0
0
1
1
1
1
2
n
n
n
n
n
n
n
n
n
n
n
n
−
−
−
−












−






=






−






−






X X =
X X
=
  
 
To compute the variance of, for example, the hypothesis that 
3
3
:
0
.
:
0
vs
β
β
=
≠
0
a
H
H
, we write 
that if 
[
]
'
0
0
0
1
=
a
 so 
[
]
0
1
3
2
3
0
0
0
1
.
β
β
β
β
β






=
=






a'β
  Thus, 
(
)
[
]
1
1
1
1
1
0
1
2
1
1
0 1
2
'
0
0
0
1
1
1
2
1
0
1
1
1
2
1
n
n
−
−
−
−




−



=
=




−


−


a X'X
a
 
 
Where n is the number per therapy group and the trial size 
4
N
n
=
  
 
All models will be run adjusting for baseline values allowing for a smaller mean square error and 
slightly greater power. In the following tables, the standard error  
.
MSE
σ ∆=
 
 
Evaluations of efficacy are literature based. Measures of ejection fraction variability are from 
LateTIME67. Effect size measures of LVESVI, LVEDVI, VO2 max, and 6MWT are from FO-
CUS56. Infarct size estimates are from personal communication with the lab of Dr. Roberto Bolli. 
Sphericity Index estimates come from TAC-HFT100. The following computations demonstrate the 
power available from thirty-six subjects in each group.  
 
3.7.2 Left Ventricular Ejection Fraction (LVEF) 
We estimate the standard deviation of the difference (
)
σ ∆  as 8. Based on Williams et al.23, the 
expected change in the LVEF for the Combo group over time compared with the change over 
time in the placebo group is 13.4, providing power > 99%. We conservatively estimate the effect 
size of the Combo vs. MSC comparison as 7 generating 91% power assuming  the standard de-
viation of the difference over time is 8 (Table 4). We do not expect that the Combo vs. c-kit+ cell 
comparison will produce this level of effect, instead anticipating that this comparison will pro-
duce an effect size of 5.5 which can be detected with 74% power.  
 
3.7.3 Infarct Size 
We expect a change in infarct size (Dr. Bolli, personal communication), of 8 grams in the Combo 
group with a standard deviation of 7.0 when compared with the MSC group. This produces a 
power of greater than 99% (Table 5). The expected change in infarct size of Combo vs. the 
change in c-kit+ cell over time is anticipated to be 6 detectable at a power of 97%. The compari-
sons of cell types with placebo will produce greater power since the effect of Combo vs. placebo 
is greater than the effect seen from cell to cell comparisons.   
 
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3.7.4 Left Ventricular End Systolic Volume Index (LVESVI) 
The standard deviation of the change in LVESVI is estimated to be 20 ml. Based on personal 
communication from Dr. Bolli and an article by Williams et al.23, the expected change in Combo 
when compared with MSC is estimated to be 24 ml producing greater than 99% power (Table 
6). The expected change in Combo compared with c-kit+ cell is 18 ml which is detectable with 
93% power. The comparisons of cell types with placebo will produce greater power since the ef-
fect of Combo vs. placebo is greater than the effect seen from cell to cell comparisons.  
 
3.7.5 Left Ventricular End Diastolic Volume Index (LVEDVI) 
The standard deviation of the change in LVEDVI is estimated to be 40 ml. The expected change 
in LVEDVI of Combo is 45 ml (Dr. Bolli, personal communication) when compared with MSCs 
alone, producing 99% power (Table 7). The expected change in Combo vs. the c-kit+ cell alone 
group is 30 ml generating 81% power. The comparisons of cell types with placebo will produce 
greater power since the effect of Combo vs. placebo is greater than the effect seen from cell to 
cell comparisons. 
 
3.7.6 VO2 max 
FOCUS56 produced a small change 1 ml/kg/min increase in VO2 max when compared with pla-
cebo and a standard deviation of 2.9. This small difference is not likely to be detectable and 
would be of less interest to the clinical community. However, given that this estimate of effect 
size could be wrong there is value in stating our prospective interest in analyzing this variable. 
Based on a standard deviation of 2.9, the smallest difference that we could detect for any treat-
ment group comparisons would be a 2.5 ml/kg/min increase with 91% power (Table 8).  
 
3.7.7 Six Minute Walk Test (6MWT) 
The effect size will be based on the mean of two measures at each time point per subject rather 
than on a single measurement. The standard deviation for the change in 6MWT is anticipated to 
be approximately 121.92 meters based on the FOCUS56 data with its intrasubject correction of 
0.44 and incorporation of the intraclass correlation structure. We anticipate that cell therapy will 
produce an increase of 28.96 meters in the Combo vs. MSC comparison (Table 9). The compar-
isons of cell types with placebo will produce greater power since the effect of Combo vs. pla-
cebo is greater than the effect seen from cell to cell comparisons. Power will be low for each of 
the evaluations, but we nevertheless have a prospective interest in assessing the effect of cell 
therapy on the 6MWT. 
 
3.7.8 Minnesota Living with Heart Failure Questionnaire (MLHFQ) 
We anticipate that the standard deviation of the change in the mean MLHFQ is 22. We expect 
that the change in Combo compared with MSC will produce a 20 point change, generating a 
power of 93% (Table 10). We believe that Combo compared with c-kit+ cell will produce a 16 
unit difference (79% power). The comparisons of cell types with placebo will produce greater 
power since the effect of Combo vs. placebo is greater than the effect seen from cell to cell 
comparisons. 
 
3.7.9 Sphericity Index 
Based on TAC-HFT100 and assuming a standard error 0.10, we anticipate a 0.14 increase in 
sphericity index in Combo when compared with MSC (greater than 99% power) and 0.10 when 
Combo is compared with c-kit+ cells alone (97% power) (Table 11). The comparisons of cell 
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types with placebo will produce greater power since the effect of Combo vs. placebo is greater 
than the effect seen from cell to cell comparisons. 
 
3.8 
Interim Analysis 
A formal interim efficacy analyses will be conducted after the first 50% (72/144) of subjects have 
had, or should have had, 6 months of follow-up.  Details are provided in section 8. 
 
 
Table 4. Power for LVEF Change Over Time
Table 5. Power for Infarct Size Change  Over Time
Type I error = 0.05; N = 144; 20% followup loss
Type I error = 0.05; N = 144; 20% followup loss
Treatment Effect 
Treatment Effect 
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
9
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
Std Dev 6.0
0.72
0.81 0.89
0.94 0.97
0.98
0.99 1.00 1.00 1.00 1.00
Std Dev
5.0 0.86
0.93
0.97
0.99
1.00
1.00 1.00
1.00
1.00
1.00
of Diff
7.0
0.58
0.68 0.77
0.85 0.90
0.94
0.97 0.98 0.99 1.00 1.00
of Diff
6.0 0.72
0.81
0.89
0.94
0.97
0.98 0.99
1.00
1.00
1.00
(σΔ)
8.0
0.48
0.57 0.66
0.74 0.81
0.87
0.91 0.94 0.97 0.98 0.99
(σΔ)
7.0 0.58
0.68
0.77
0.85
0.90
0.94 0.97
0.98
0.99
1.00
9.0
0.39
0.48 0.56
0.64 0.72
0.78
0.84 0.89 0.92 0.95 0.97
8.0 0.48
0.57
0.66
0.74
0.81
0.87 0.91
0.94
0.97
0.98
Table 6. Power for LV End Systolic Volume Change
Table 7. Power for LV End Diastolic Volume Change
Type I error = 0.05; N = 144; 20% followup loss
Type I error = 0.05; N = 144; 20% followup loss
Treatment Effect 
Treatment Effect 
6
8
10
12
14
16
18
20
22
24
26
10
15
20
25
30
35
40
45
50
55
Std Dev 15.0
0.33
0.53 0.72
0.86 0.94
0.98
1.00 1.00 1.00 1.00 1.00
Std Dev 31.3
0.23
0.44
0.68
0.86
0.95
0.99 1.00
1.00
1.00
1.00
of Diff
20.0
0.21
0.33 0.48
0.62 0.76
0.86
0.93 0.97 0.99 1.00 1.00
of Diff
35.8
0.18
0.36
0.56
0.76
0.89
0.96 0.99
1.00
1.00
1.00
(σΔ)
25.0
0.15
0.23 0.33
0.44 0.57
0.68
0.78 0.86 0.92 0.95 0.98
(σΔ)
40.2
0.15
0.29
0.47
0.65
0.81
0.91 0.96
0.99
1.00
1.00
30.0
0.11
0.17 0.24
0.33 0.43
0.53
0.62 0.72 0.79 0.86 0.91
44.7
0.13
0.25
0.40
0.56
0.72
0.84 0.92
0.97
0.99
1.00
Table 8. Power for VO2max Change
Table 9. Power for Six Minute Walk Change
Type I error = 0.05; N = 144; 20% followup loss
Type I error = 0.05; N = 144; 20% followup loss; 2 meas per time pt.
Treatment Effect 
Treatment Effect 
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
70
75
80
85
90
95
100
105
110
115
Std Dev 2.7
0.10
0.29 0.56
0.80 0.94
0.99
1.00 1.00 1.00 1.00 1.00
Std Dev
120 0.60
0.66
0.72
0.77
0.81
0.85 0.89
0.91
0.94
0.95
of Diff
2.8
0.10
0.27 0.53
0.77 0.92
0.98
1.00 1.00 1.00 1.00 1.00
of Diff
125 0.57
0.62
0.68
0.73
0.78
0.82 0.86
0.89
0.92
0.94
(σΔ)
2.9
0.10
0.26 0.50
0.74 0.91
0.98
1.00 1.00 1.00 1.00 1.00
(σΔ)
150 0.43
0.48
0.53
0.58
0.62
0.67 0.72
0.76
0.79
0.83
3
0.09
0.24 0.48
0.72 0.89
0.97
0.99 1.00 1.00 1.00 1.00
175 0.33
0.37
0.41
0.45
0.50
0.54 0.58
0.62
0.66
0.70
Table 10. Power for MLHF Change
Table 11. Power for Sphericity Index Change
Type I error = 0.05; N = 144; 20% followup loss
Type I error = 0.05; N = 144; 20% followup loss
Treatment Effect 
Treatment Effect 
8
10
12
14
16
18
20
22
24
26
28
0.04
0.06
0.08
0.1
0.12
0.14
0.2
0.18
0.2
0.22
Std Dev 21
0.30
0.44 0.58
0.72 0.82
0.90
0.95 0.98 0.99 1.00 1.00
Std Dev 0.08 0.48
0.81
0.97
1.00
1.00
1.00 1.00
1.00
1.00
1.00
of Diff
22
0.28
0.41 0.54
0.68 0.79
0.87
0.93 0.97 0.99 0.99 1.00
of Diff
0.10 0.33
0.62
0.86
0.97
1.00
1.00 1.00
1.00
1.00
1.00
(σΔ)
23
0.26
0.38 0.51
0.64 0.75
0.84
0.91 0.95 0.98 0.99 1.00
(σΔ)
0.12 0.24
0.48
0.72
0.89
0.97
0.99 1.00
1.00
1.00
1.00
24
0.24
0.35 0.48
0.60 0.72
0.81
0.89 0.94 0.97 0.98 0.99
0.14 0.19
0.37
0.58
0.77
0.90
0.97 0.99
1.00
1.00
1.00  
4.0 IDENTIFICATION AND ENROLLMENT OF SUBJECTS 
Details of Stage 1: Instructions for enrollment of Stage 1 (open label lead-in) subjects are 
included in Appendix E.  Instructions include all activities and the visit schedule from 
consent through follow-up.   
 
4.1 Recruitment and Screening (prior to consent) 
The study Sponsor (Data Coordinating Center) will provide participating clinical centers with a 
variety of materials to aide in recruitment.  This may include, but is not limited to, informational 
DVDs and brochures which provide education about heart failure and include information about 
the study; physician referral letter templates which can be used to promote awareness of the 
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study in the cardiovascular community; templates for flyers which can be utilized at approved 
clinic locations and as part of health fair materials; templates for print advertisements which can 
be utilized in newsprint and media campaigns; Research Match, the non-profit free, secure reg-
istry, may also be utilized to identify potential candidates for trial participation.  Not all materials 
have been developed prior to trial initiation; however each of these methods (the templates, final 
products, and services) will be reviewed and approved by both the Sponsor IRB and the clinical 
center IRB prior to use.   
 
Screening of subjects includes reviewing medical records and imaging studies for inclusion/ex-
clusions prior to consent.  From the review of subjects’ medical records and imaging studies on 
file, subjects who are determined to have a diagnosis of chronic ischemic LV dysfunction sec-
ondary to MI, have EF ≤ 40%, are candidates for cardiac catheterization, and have NYHA class 
of II or III, as stated in Section 4.3, and also do not have evidence in their medical record of 
study exclusions stated in Section 4.4, are eligible to be consented to the study.   
 
At the time of screening, subjects must have 1) documented CAD with evidence of myocardial 
injury, LV dysfunction, and clinical evidence of HF and  2) have a "detectable" area of myocar-
dial injury defined as ≥ 5% LV involvement (infarct volume) and any subendocardial involvement 
by cMRI.   In addition, EF ≤ 40% can be defined by gated blood pool scan (MUGA), cMRI, left 
ventriculogram, or EF ≤ 35% by two-dimensional echocardiogram.   
 
Note: Imaging studies (cMRI, ECG, SPECT, MUGA, echo, and/or left ventriculogram) are 
acceptable within 12 months prior to consent, and the PI will determine the need to re-
peat any standard of care imaging modalities to use for screening. 
 
4.2 Consent 
Before being enrolled, all subjects must consent in writing to participate.  An informed consent 
form (ICF) will be given to each subject.  The ICF will contain all United States federally required 
elements, all International Conference of Harmonisation of Technical Requirements for Regis-
tration of Pharmaceuticals for Human Use (ICH)-required elements, and Health Insurance Port-
ability and Accountability Act Authorization (HIPAA) information in language that is understanda-
ble to the subject. The informed consent includes descriptions of all study related procedures, all 
possible risks to participant, and the time commitment involved with participating.  All consent 
forms will have IRB approval.  The ICF and review must be in a form understandable to the sub-
ject.  Translation of ICFs will be done in accordance with local IRB procedures. 
 
 
Potential participants will be approached by one of the study investigators or research coordina-
tors.  Information regarding study participation will be provided to the potential participant prior 
to consent.  Subjects will be given ample time to review the ICF and ask questions before sign-
ing.  The Investigator or designee and the subject must both sign and date the ICF after review, 
and before the subject can participate in the study.  The subject will receive a copy of the signed 
and dated form, and the original will be retained in the site study files.  The research staff mem-
ber obtaining consent will document the informed process in the subject’s chart for monitoring 
purposes.  The Investigator or his/her designee must emphasize to the subject that study partici-
pation is entirely voluntary and that consent regarding study participation may be withdrawn at 
any time without penalty or loss of benefits to which the subject is otherwise entitled.   
 
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4.3 Inclusion Criteria 
To participate, a subject MUST: 
1. Be ≥ 21 and <80 years of age 
2. Have documented 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 (see Appendix C) 
8. If a female of childbearing potential, be willing to use one form of birth control for the du-
ration of the study, and undergo a pregnancy test at baseline and within 36 hours prior to 
injection 
4.4 Exclusion Criteria 
To participate, a subject MUST NOT HAVE: 
1. Indication for standard-of-care surgery (including valve surgery, placement of left-ventric-
ular 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 un-
dergo 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 revasculariza-
tion following enrollment should undergo revascularization without delay. Indication for 
imminent heart transplantation is defined as a high likelihood of transplant prior to collec-
tion of the 12 month study endpoint.  Candidates cannot be UNOS 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 
valvular (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 ICD generator with any of the following limitations/con-
ditions: 
- 
manufactured before the year 2000 
- 
leads implanted < 6 weeks prior to consent 
- 
non-transvenous epicardial or abandoned leads 
- 
subcutaneous ICDs 
- 
leadless pacemakers 
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- 
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 con-
sent, or symptomatic Mobitz II or higher degree atrioventricular block without a function-
ing pacemaker within 3 months of consent 
12. Presence of LV thrombus (See guidance in section 6.3.3) 
13. Evidence of active myocarditis 
14. Baseline VO2 max greater than 75% of age and gender based predictive values (see 
Section 6.3.7) 
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 ULN 
19. Coagulopathy (INR ≥ 1.3) not due to a reversible cause (e.g., warfarin and/or Factor Xa 
inhibitors) (see Sections 6.2.2 and 6.2.3 re: study procedures and anticoagulation ther-
apy).  Subjects who cannot be withdrawn from anticoagulation will be excluded. 
20. HIV and/or active HBV or HCV 
21. Allergy to radiographic contrast material that cannot adequately be managed by premedi-
cation 
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 aris-
ing 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 
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28. Cognitive or language barriers that prohibit obtaining informed consent or any study ele-
ments 
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 en-
rollment, study product administration, or follow-up 
 
4.5 Baseline Testing 
The baseline testing period extends from the date the ICF is signed until completion of both of 
the BMA and RHC with and without EMB (RHC/EMB) procedures (see Appendices A & B).  This 
period will not exceed 60 days.   
 
The following evaluations will be carried out at baseline: 
• Comprehensive medical and surgical history, vital signs and physical examination (Section 
6.3.1) 
• Current use of prescription and OTC medications (Section 6.3.1) 
• Baseline blood tests (Section 6.3.2)  
• Infectious disease panel (Section 6.3.2)  
• 
Pregnancy test (for women of childbearing potential) (Section 6.3.2) 
• 
cMRI imaging (Section 6.3.3, MRI Core Lab Manual of Operations) and ICD interrogation 
(Section 6.3.8) (if applicable) 
• 
Six-minute walk test (Section 6.3.4, Protocol Manual of Operations) 
• 
Questionnaires including MLHFQ and sexual function (Section 6.3.5) 
• 
12 lead ECG (Section 6.3.6) 
• 
Treadmill-based VO2 max (Section 6.3.7) 
 
4.6 Post-Consent Review and Randomization 
Prior to randomization, baseline evaluations and eligibility criteria will be reviewed by Network 
investigators. The purpose of the post-consent case review is to determine if a combination of 
factors suggests the subject may be a poor research risk beyond whether or not they meet indi-
vidual eligibility criteria. In addition, if a change in the subject’s status has occurred such that the 
subject no longer meets all of the eligibility criteria, randomization will be postponed, or if the 
condition is not resolvable, the individual will be excluded from participation.  Following success-
ful completion of baseline testing and favorable case review, subjects will be randomized either 
to A) Combo (MSCs plus c-kit+ cells), B) MSCs alone, C) c-kit+ cells alone, or D) placebo (see 
Section 8.1).   
 
 
 
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5.0 CELL PRODUCTION AND DELIVERY 
 
5.1 Procurement and Shipment of Bone Marrow for MSC Production 
The Central Cell Manufacturing Facility (CCMF) will receive email notifications from the DCC 
when a subject has been enrolled (consented), when a subject has been determined eligible to 
participate in the study (upon completion of baseline testing), and when the bone marrow aspi-
ration (BMA) procedure has been scheduled.  
 
Approximately 90ml (+10ml) of bone marrow (BM) will be harvested from the posterior iliac crest 
of all subjects by a trained physician as described in Appendix A. The marrow will be aspirated 
into pre-heparinized syringes containing preservative-free heparin for a final effective dose of 
100 units of heparin / ml of BM. Specific guidelines are provided in Appendix A. Subjects on as-
pirin and Plavix (Clopidogrel) at the time of consent should remain on these medications for the 
harvest procedure.   
 
The harvested material will be transported to each local cell processing laboratory (CPL) facility 
according to its standard operating procedure (SOP) for transfer of fresh BM.   
 
Upon arrival at the local CPL, samples will be taken for the following QC tests (see Table 12): 
Sterility using aerobic, anaerobic and fungal cultures, nucleated cell count, and viability. 
 
Table 12. QC Tests on BM at Local CPL 
Assay 
Test Method 
Specification 
Viability 
Trypan Blue 
Report Results 
Aerobic, Anaerobic, and Fungal 
14 day Bactec/BacT/ALERT 
assay or equivalent 
No Growth 
 
BM Release test results prior to shipping to CCMF: 
• Viability of the cells will be measured and documented.  
• In the event that sterility testing (culture) becomes positive, the CPL staff will immediately 
inform the CCMF, the CPQAL, and the Biorepository of the positive result. 
 
The marrow will be split and samples shipped to both the CCMF for production of MSCs and to 
the CCTRN biorepository with appropriate consent (see Section 6.4.1).  Sixty-five mL (+/- 5 mL) 
of bone marrow will be sent to the CCMF per manufacturer’s SOP, and the remainder of the 
bone marrow suspension (~25 mL), will be shipped to the CCTRN biorepository with appropriate 
consent (see Section 6.4.2).  Personnel from the local CPL will communicate with the CCMF re-
garding subject information, exact time of harvest, volume of BM suspension shipped, QC test 
results, time of shipment, carrier, estimated delivery, tracking information, etc. 
 
5.2 Procurement and Shipment of Endomyocardial Biopsy (EMB) for c-kit+ cell Produc-
tion 
Individuals meeting enrollment criteria will be scheduled to undergo right heart catheterization 
(RHC) with or without right ventricle endomyocardial biopsy (EMB), depending on randomization 
assignment.  Subjects on aspirin and Plavix (Clopidogrel) at the time of consent should remain 
on these medications for the procedure.  Up to six EMB samples will be harvested as described 
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in Appendix B. Site harvesters will attend a best practices session prior to study initiation to re-
view EMB procedures to optimize safety and assure that they are standardized across sites. 
 
The biopsied material will be transported to the local CPL on wet ice, or equivalent, to be pre-
pared for overnight shipment to the CCMF per manufacturer’s SOP.  Personnel from the CPL 
will communicate with the CCMF for subject information, exact time of harvest, number of cryo-
vials shipped, time of shipment, carrier, estimated delivery, tracking information, etc. 
 
Table 13. Sterility Testing of Ham’s F-12 Medium & Complete Growth Medium for EMB 
Tissue Processing and c-kit+ cell procurement 
Assay 
Test Method 
Specification 
Aerobic, Anaerobic, and Fungal 
14 day Bactec/BacT/ALERT 
assay or equivalent 
No Growth 
 
5.3 Receipt of harvest samples at the CCMF 
Upon arrival at the CCMF, the products will be inspected for quality and maintenance of temper-
ature during shipping. A temperature deviation will be reported and investigated. After receipt 
and inspection, the products will be taken to the clean room laboratory for further processing per 
manufacturer’s SOP.  Samples will be taken for the following QC tests (see Table 14): Sterility 
using aerobic, anaerobic, and fungal cultures and cell viability (BM only).   
 
Table 14. QC Tests on BM at the CCMF 
Assay 
Test Method 
Specification 
Viability 
Trypan Blue/Crystal Violet 
Report Results 
Aerobic, Anaerobic, and Fungal 
14 day Bactec/BacT/ALERT 
or equivalent or conven-
tional culture assay 
No Growth 
 
 
5.4 Production and Cryopreservation of MSC Product 
BM products meeting specifications will be processed to obtain a mononuclear cell (MNC) en-
riched fraction as illustrated in Figure 1.  
 
Figure 1. MNC enrichment using Ficoll technique  
 
 
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After Ficoll separation, the cells will be washed twice and cultured in heparin-free media.  MNCs 
of subjects randomized to either Combo or MSC alone treatment group will be cultured to gener-
ate the designated target dose of 150 million MSCs.   
 
After 14 days of culture, the cells are harvested. Figure 2 below shows how the cells look as 
they expand from Passage 0 (P0) to Passage 1 (P1).  
 
Figure 2. MSC expansion from P0 to P1 
 
 
Samples of MSC products will be characterized by the CCMF to assure that they meet predeter-
mined specifications. Cell count, phenotype, potency, mycoplasma testing, and other QC tests, 
as indicated in Table 15, are performed on a sample of cell suspension taken from the last pas-
sage which represents the harvest of the final product prior to cryopreservation.  
 
Table 15. QC Testing of MSC Cell Culture Prior to Cryopreservation 
Assay 
Test Method 
Specification 
Mycoplasma PCR* 
VenorGeM® (Cells in Con-
ditioned Medium prior to 
cryopreservation) 
Negative 
Viability* 
Trypan Blue 
≥70% 
CFU-F 
Colony Formation, 14 Days 
Growth 
Phenotype/Cell Characterization 
CD 105+ 
CD45+ 
Flow Cytometry 
CD105+ >80%  
CD45+ <2% 
Aerobic, Anaerobic, and Fungal 
14 day Bactec/BacT/ALERT 
assay or equivalent 
No Growth 
Cell Count – MSCs 
Hemocytometer 
>75x106  
* Tests done prior to cryopreservation  
 
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The MSC products are frozen and stored in liquid nitrogen (LN2) vapor phase at the CCMF until 
ready to be shipped.  Sterility testing for aerobic, anaerobic, and fungal cultures is performed on 
a sample of product after adding cryopreservation medium immediately before freezing, as indi-
cated below in Table 16.  
 
Table 16. Sterility Testing of MSC Final Product Post Adding Cryopreservation Medium 
Assay 
Test Method 
Specification 
Endotoxin 
EndoSafe PTS 
≤ 5EU/ml 
Aerobic, Anaerobic, and Fungal 
14 day Bactec/BacT/ALERT 
assay or equivalent 
No Growth 
 
Bacteriostasis and Fungistasis (B&F) testing will also be performed on the first 3 MSC products 
and/or when any significant changes are made in the manufacturing process or materials of an 
existing product. B&F testing is designed to validate the procedure used to test a given product 
for sterility by demonstrating that microorganisms present on the product can be detected in the 
course of the sterility test.  
 
MSC products will be held frozen in LN2 vapor phase and will not be released for injection until 
final results of endotoxin and sterility testing are obtained by the CCMF. The release will require 
negative sterility test results before and after adding cryopreservation medium, as well as nega-
tive mycoplasma by PCR before adding cryopreservation medium, as indicated above in Tables 
14 and 15. Products with positive sterility results will be discarded and a complete investigation 
report will be generated by CCMF according to the facility SOP. A copy of the report will be sent 
to DCC and CPQAL, as well as to local CPL. 
 
5.5 MNCs for non-MSC Treatment Groups 
MNCs of the subjects randomized to c-kit+ cells alone or to placebo will be cryopreserved by the 
CCMF.  With appropriate subject consent, cryopreserved MNC products from subjects random-
ized to c-kit+ cells alone or to placebo will be shipped in a LN2 dry shipper to the CCTRN biore-
pository (see Section 6.4).   
 
5.6 Production and Cryopreservation of c-kit+ cells 
EMB samples will be received at the CCMF. For subjects randomized to Combo or c-kit+ cell 
alone treatment groups, culture and subsequent production of c-kit+ cells will follow a modified 
version of established protocols for cell expansion on file with the FDA (IND 14647) to generate 
the designated target dose of 5 million c-kit+ cells.   
 
Cells are expanded in culture for approximately 3 to 4 weeks and then enriched for c-kit+ cells 
using immune-magnetic beads73 (CD117 MicroBead Kit, Miltenyi Biotec). The c-kit+ CPCs are 
further expanded to produce the final target dose range of 0.8 X 106 to 5 X 106 c-kit+ cells.   
 
Samples of the c-kit+ cells will be characterized by the CCMF with respect to 7AAD, CD45, 
CD31, CD34, CD133, CD14, CD16, CD11b, CD19, CXCR4, CD90 (or 105), NKx2.5, GATA-4, 
MEF2c, a-sarcomeric actin, alpha myosin heavy chain for myocyte lineage, smooth muscle actin 
for VSMC lineage, vWF for endothelial lineage, p16INK4a expression, doubling time, telomere 
length, and telomerase activity. 
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To assure they meet all predetermined specifications, cell count, phenotype (CD117 positivity), 
mycoplasma testing, and other QC tests as indicated in Table 17 are performed on a sample of 
the cell suspension taken from the last passage which represents the harvest of the final prod-
uct prior to cryopreservation.  
 
Table 17. QC Testing of c-kit+ cell Cell Culture Prior to Cryopreservation 
Assay 
Test Method 
Specification 
Mycoplasma PCR* 
VenorGeM® (Cells in Con-
ditioned Medium prior to 
cryopreservation) 
Negative 
Viability* 
Trypan Blue 
≥70% 
Phenotype/Cell Characterization 
CD 117+ 
CD45+ 
Flow Cytometry 
CD117+ ≥70% 
CD45+<2%  
Aerobic, Anaerobic, and Fungal 
14 day Bactec/BacT/ALERT 
assay or equivalent (super-
natant medium) 
No Growth 
Cell Count – c-kit+ cells 
Manual 
>0.8 x106  
* Tests done prior to cryopreservation 
 
The c-kit+ cell products are frozen and stored in LN2 vapor phase at the CCMF until ready to be 
shipped.  Sterility testing for aerobic, anaerobic, and fungal cultures is performed on a sample of 
product after adding cryopreservation medium immediately before freezing as indicated below in 
Table 18.   
 
Table 18. Sterility Testing of c-kit+ cell Final Product Post Adding Cryopreservation Me-
dium 
Assay 
Test Method 
Specification 
Endotoxin 
EndoSafe PTS 
≤ 5EU/ml 
Aerobic, Anaerobic, and Fungal 
14 day Bactec/BacT/ALERT 
assay or equivalent 
No Growth 
 
B&F testing will also be performed on the first 3 c-kit+ cell products and/or when any significant 
changes are made in the manufacturing process or materials of an existing product.  
 
c-kit+ cell products will be frozen in LN2 vapor phase and will not be released for injection until 
final results of endotoxin and sterility testing are obtained by the CCMF. The release will require 
negative sterility test results on c-kit+ cell products before and after adding cryopreservation me-
dium, as well as negative mycoplasma by PCR before adding cryopreservation medium, as indi-
cated above in Tables 16 and 17. Products with positive sterility results will be discarded and a 
complete investigation report will be generated by CCMF according to the facility SOP. A copy 
of the report will be sent to DCC and CPQAL, as well as to the local CPL.  
 
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5.7 Shipment of Cryopreserved MSC and c-kit+ cell Products 
The CCMF will use validated liquid nitrogen dry shippers (a.k.a. cryoshipper) with built-in data 
loggers to monitor temperatures. Cryopreserved MSC and/or c-kit+ cell products will be shipped 
to the local CPLs within one week before the scheduled injection procedure. The CCMF will en-
sure that the cryoshipper is charged for at least 24 hours prior to each shipment. Labeling re-
quirements mandated by regulatory agencies will be fulfilled. All required documents as de-
scribed in shipping SOPs of the CCMF will accompany the cryoshipper. 
 
The CCMF will also provide all relevant SOPs, worksheets, forms, labels, etc. for product prepa-
ration for administration. The local CPL, DCC and CCMF will work with the clinical research 
team to coordinate the injection date and product shipment according to the randomization 
schedule outlined in Section 8.1. 
 
Since MSCs and c-kit+ cell cultures require different times for manufacturing, all subjects will re-
ceive study product approximately 14 weeks from the date of the harvest procedures.  
 
5.8 Preparation for Administration of MSC and c-kit+ cell Products 
The products will undergo cell counts and QC testing before injection as indicated in Table 19. 
 
Table 19. QC Tests on Thawed Washed MSC and c-kit+ cell products at CPL 
Assay 
Test Method 
Specification 
Rapid Sterility* 
Gram Stain 
No organisms seen (negative) 
Viability* 
Trypan Blue 
≥70% 
Endotoxin* 
EndoSafe PTS 
≤ 5EU/kg ** 
Aerobic, Anaerobic, and    
Fungal 
14 day Bactec/BacT/ALERT 
assay or equivalent 
No Growth 
Cell Count – c-kit+ cells* 
Manual 
Minimum 0.8x106 final dose 
Maximum 5x106 final dose 
Cell Count – MSCs* 
Manual 
Minimum 75x106 final dose 
Maximum 150x106 final dose 
* Tests done for release criteria specification prior to injection; for cell counts, the product must meet the minimum 
count for release 
** Based on recipient weight and product volume  
 
5.8.1 Final Release Criteria Specifications for Autologous MSCs and c-kit+ cells 
As stated above in Table 19, all MSC and c-kit+ cell thawed washed products must meet Gram 
stain, viability, endotoxin, and cell count release criteria specifications prior to injection.  In addi-
tion, all MSC and c-kit+ cell cell cultures prior to cryopreservation (see Tables 14 and 16) must 
meet Mycoplasma PCR specifications prior to injection. Finally, all MSC and c-kit+ cell final 
products after adding cryopreservation medium (see Tables 15 and 17) must meet aerobic, an-
aerobic and fungal sterility testing specifications prior to injection.   
 
 
 
 
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5.8.2 Cell Suspensions 
 
5.8.2.1 MSCs alone 
MSCs (150 x 106) are suspended in a final volume of 6.1 ml (±0.5 ml) of thaw medium (Plasma-
Lyte-A 1%HSA) to suspend the MSC pellets in 0.4 ml injection volume, times 15 injections for a 
total of 150 million MSCs. The physician will administer 15 individual doses of 10 x 106 
cells/0.4ml (+10%), per dose, per injection site. The 15th injection will be followed by 0.1ml of sa-
line to flush any residual cells from the line into the 15th injection site. Any cell suspension re-
maining after delivery of the 15 injections must not be injected and shall be discarded according 
to institutional guidelines. 
 
5.8.2.2 c-kit+ cells alone 
c-kit+ cells (5.0 x 106) are suspended in a final volume of 6.1 ml (±0.5 ml) of thaw medium (Plas-
maLyte-A 1%HSA) to suspend the c-kit+ cell pellets in 0.4 ml injection volume, times 15 injec-
tions for a total of 5 million c-kit+ cells. The physician will administer 15 individual doses of ap-
proximately 0.333X106 cells/0.4ml (+10%), per dose, per injection site.  Any cell suspension re-
maining after delivery of the 15 injections must not be injected and shall be discarded according 
to institutional guidelines. 
 
5.8.2.3 Combo   
The mixture of MSCs (150 x 106) and c-kit+ cells (5 x 106) is suspended in a final volume of 6.1 
ml (±0.5 ml) of thaw medium (PlasmaLyte-A 1%HSA) to suspend the combined cell pellets in 
0.4 ml injection volume, times 15 injections for a total of 150 million MSCs and 5 million c-kit+ 
cells. The physician will administer 15 individual doses of a maximum of 10.333 x 106 
cells/0.4ml (+10%), per dose, per injection site. Any cell suspension remaining after delivery of 
the 15 injections shall not be injected and shall be discarded according to institutional guide-
lines.  
 
5.9 Placebo Group 
Subjects randomized to the placebo group will undergo baseline testing, BMA and RHC proce-
dures. Approximately 14 weeks after the BMA and RHC procedures, the placebo group will re-
ceive transendocardial injections of 0.4ml PlasmaLyte-A supplemented with 1% HSA in 15 injec-
tion sites. The placebo product will undergo QC testing before injection as indicated in Table 20.  
 
Table 20. Sterility Testing of Placebo for Injection 
Assay 
Test Method 
Specification 
Rapid Sterility* 
Gram Stain 
No organisms seen (negative) 
Endotoxin* 
EndoSafe PTS 
≤ 5EU/kg** 
Aerobic, Anaerobic, and Fungal 
14 day Bac-
tec/BacT/ALERT assay or 
equivalent 
No Growth 
* Tests done for release criteria specification prior to injection 
** Based on recipient weight and product volume 
 
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5.10 Positive 14-day Sterility After Injection 
Should the final 14-day sterility culture produce a positive result after the study product has 
been administered to the subject, then the following steps will take place: 
a) The local CPL staff will immediately contact CPQAL and the local research team. The lo-
cal CPL will remain in contact with the CPQAL and local research team regarding the 
identity of the organism and its antibiotic sensitivities as soon as this information is availa-
ble for the local team to consider antibiotic prophylaxis. 
b) CPQAL will contact the DCC immediately to notify of a positive result on a sterility test 
sample of an administered product. CPQAL will also inform the CCMF.  
c) The subject will remain in the study and be monitored for clinical signs of infection. The 
local research team will report to the DCC any resultant adverse events per protocol (see 
Section 7.3).   
d) The CCMF will conduct a complete laboratory investigation according to the facility SOP 
and generate a report that will be sent to the DCC, CPQAL, and local CPL. 
e) The DCC will report the sterility failure, results of the investigation of the cause, and a 
corrective action plan to the FDA within 30 days after the initial receipt of the positive cul-
ture test result. 
 
Every effort will be made to protect the blinding of those involved in the study endpoint and 
safety event collection. 
 
5.11 Blinding and Study Teams 
The study will remain double-blind by having both blinded and unblinded study teams at each 
center.  All subjects, cell and cell-free groups, will undergo BMA, RHC with or without EMB, as 
well as injections by NOGA® XP Mapping and Navigation System (NOGA).  The only unblinded 
research team members are those performing activities directly related the RHC/EMB procedure 
and possibly the interventionalist delivering injections if they also peform the RHC/EMB proce-
dure, or if they are able to discern the study product.  In the interest of safety, the interventional-
ist must be able to visualize the study product to inspect that it looks safe (e.g., free of air bub-
bles, clumping, etc.).  Cardiac MRI and VO2 max endpoints will be determined by core laborato-
ries.  Core laboratory evaluation of endpoint measures will be conducted by personnel who are 
blinded to therapy assignment.  Coordinators and other personnel participating in the collection 
of cMRI, 6MWT, VO2 max, and the MLHFQ endpoint data also will be blinded to the therapy as-
signment.  In addition, each of the clinical centers will take steps to ensure that adverse event 
assessments are carried out in a blinded fashion.  
 
Local CPL and CCMF staff will be unblinded in order to assist with sample and product prepara-
tion (see Section 5.8).  With the exception of the unblinded research team members described 
above, the majority of the research team (investigators, coordinators and other staff involved 
with subject recruitment, baseline testing, endpoint data collection and event data) will be 
blinded to the treatment assignment.   
 
If for important medical reasons unblinding of additional team members is thought to be neces-
sary, the Investigator may identify the treatment assignment by contacting the DCC who is re-
sponsible for maintaining randomization records for all subjects.  
 
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5.12 NOGA Catheterization Procedure 
Intramyocardial cell delivery by NOGA® XP Mapping and Navigation System (NOGA) will be 
used in this trial. All investigators performing the catheter‐based study procedures will receive 
appropriate training in the use of the catheters by the catheter manufacturer (Biologic Delivery 
Systems). All interventionalists will be certified under this training program.  Site interventional 
cardiologists will meet routinely by teleconference to review injection procedures to assure that 
they are standardized across sites. 
 
LV cine angiocardiography will be performed in orthogonal planes (typically right anterior oblique 
(RAO) 30 and left anterior oblique (LAO) 60 degree projections). End-diastolic endocardial con-
tours will be saved as angiographic image recordings in both projections, to provide guidance 
regarding location of LV borders during fluoroscopic manipulation of the injection catheter. 
 
LV electromechanical mapping (EMM) will be performed using NOGASTAR® Mapping Cathe-
ter(s), sized appropriately for the LV dimension. An 8 French femoral artery sheath of sufficient 
length will be chosen to aid operators in negotiating pelvic vasculature with the NOGA catheter. 
Unfractionated Heparin will be used to maintain an activated clotting time (ACT) between 200 
and 250 seconds during NOGA mapping and injection. EMM will be performed according to 
standard clinical practice, with attention to achieving a smooth endocardial contour and accurate 
representations of the long and short axes of the LV chamber. 
 
For the cell or cell-free transendocardial study product injection (SPI) procedure, the MYO-
STAR™ Injection Catheter (MyoStar) will be prepared by adjusting the needle extension at 0° 
and 90° flex and by placing 0.1 cc of study product in the needle dead space (e.g. priming). All 
study product will be retained to complete the 15 required injections.  To ensure safety and limit 
potential for extracardiac administration of the injectate, the needle extension/wall thickness will 
be set at a ratio of ≤0.5. The needle length should not exceed 50% of target tissue thickness 
when assessed at both 0° and 90°. The injection catheter will be advanced to the aortic valve, 
and retrograde into the LV. The catheter tip will then be positioned against the endocardium at 
the target area.  
 
Priority for injection site selection will be based upon the objective of encircling an area of myo-
cardium in one (or more) infarct territory, selected by the investigator to be a territory which is: a) 
safely treatable with low risk of perforation or other complications – avoiding the true LV apex 
and other areas known to be <6mm in myocardial thickness, and avoiding the left bundle branch 
site of earliest activation; b) clinically important based on viability assessments provided below; 
and, c) accessible with the tip of the selected MyoStar catheter.  
 
Correlation with other imaging modalities (including, when clinically available, electrocardiog-
raphy, echocardiography, coronary angiography, MRI, scintigraphy, PET, and LV angiography) 
is encouraged in selecting the target territory.  Boundaries of myocardial scar will be demon-
strated in the NOGA map using a color coding scheme to easily identify areas of unipolar local 
voltage of greater or less than 7 mV. Transendocardial injections will be placed so as to encircle 
the scar, with injection sites in both a) the viable border zone encircling the area of scar (charac-
terized by the presence of unipolar voltage ≥ 7mV), and b) scar adjacent to the viable border 
zone.  
 
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Sites for injection should satisfy the following criteria: 1) perpendicular position of the catheter to 
the LV wall, and 2) loop stability <4mm.  Ideally the majority of injections would be placed in via-
ble zone with a voltage threshold of ≥7mV with the demonstration of a premature ventricular 
contraction on extension of the needle.  Some injections will be placed in scar border zone with 
a voltage threshold of ≥ 4mV without the requirement of a premature ventricular contraction.  
When selecting sites for injection in the border zone, those with unipolar voltage in the upper 
range of 4-7 mV would generally be preferred to those in the lower range, and those with a volt-
age <4 mV would generally be avoided.  
 
Each of the 15 injections will contain 0.4 ml of cell suspension with up to 10 million MSCs and/or 
up to 0.333 million c-kit+ cells for the MSC alone, c-kit+ cell alone, or Combo cell treatment 
arms.  For the final injection, 0.1 cc of saline should be placed in the catheter and injected. This 
will allow the 0.1 cc already in the catheter (from priming) to be administered into the myocar-
dium, constituting the 15th injection.  Each injection should be infused over 60 seconds. 
 
Sites of injection will be marked and recorded by a solid circular tag on the NOGA map accom-
panied by a reference to injection number and presence or absence of needle-induced extrasys-
tole. At the investigator’s discretion, sites of injection may also be recorded on cine fluoroscopy, 
and demarcated as a dot with the corresponding injection series number on the overlay tracings 
in both RAO and LAO projections.  
 
After the injection procedure, subjects will be monitored overnight.  A 2-D echocardiogram will 
be performed post SPI procedure (within 6 hours).  Additional echocardiographic assessments 
for pericardial effusion will be done only as clinically indicated.  Myocardial necrosis markers 
(Troponin I or T) will be collected 8 (+/- 2) hours post-injection catheter procedure and again 
prior to discharge. 
 
Following the cardiac catheterization procedure and the cell or cell-free injections, all subjects 
will be followed at Day 1, Week 1, and months 1, 3, 6 and 12 to complete all safety and efficacy 
assessments.  
 
5.13 Circumstances that may affect study product delivery 
If any of the following symptoms occur before or during SPI, they could indicate a serious clini-
cal deterioration.  If any of the following events/symptoms occurs, the procedure should be tem-
porarily halted and the patient should be reevaluated for suitability to continue with the treatment 
under investigation: 
1. Hypotensive episode defined as a sustained drop in blood pressure exceeding 20mm/Hg 
not responsive to fluid administration 
2. Hemodynamically significant arrhythmia requiring anti-arrhythmic therapy 
3. Two episodes of sustained ventricular tachycardia/ventricular fibrillation requiring cardio-
version 
4. Hemodynamic instability 
5. Fever (Temperature increase to ≥100.4oF) 
6. Cardiac perforation 
7. Clinical signs and symptoms indicating a cerebrovascular accident 
 
 
 
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6.0 CLINICAL AND LABORATORY EVALUATIONS 
Instructions for enrollment of Stage 1 (open label lead-in) subjects are included in Appendix E.  
Instructions include all activities and the visit schedule from consent through follow-up 
 
6.1 Schedule of Procedures Stage 2 (Table 21b)  
 
 
Baseline testing and harvest procedures will take place within 60 days of ICF, and SPI will occur approximately 14 
weeks after harvest procedures. 
1. Subjects will have assessments of vitals (BP, temperature, pulse rate) pre- and post-procedure. 
2. ECGs will be performed within 6 hours following the SPI catheterization procedure and again before dis-
charge; a 2-D echocardiogram will be performed post-SPI (within 6 hours). 
3. Subjects will be monitored on simple telemetry up to 24 hours post-procedure or until discharge, whichever is 
sooner. 
4. See Section 6.3.2 for specific tests done at each time point. 
5. A cardiac MRI will be performed within 30 days prior to SPI (baseline measure; see Section 6.2.3). 
6. ICD interrogation: (if applicable) done before and after every MRI as part of MRI protocol, as well as before the 
SPI procedure. 
7. Temperature log 2x/day x 7 days.  
 
 
 
Informed Consent
X
Complete Medical 
History
X
Physical Exam
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X1
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Con Medications
X
X
X
X
X
X
X
X
X
NYHA & CCS
X
X
X
X
X
X
X
MLHFQ
X
X
X
X
Sexual Function 
Surveys
X
X
X
12-lead ECG
X
X2
X2
X
X
X
2D Echoes
X8
X2
Telemetry
X3
Laboratory Testing4
X
X
X
X
X
X
X
X
X
X
Cardiac MRI
X
X
X
X
ICD                 
Interrogation6
X
X
X 
X
X
Treadmill           
(VO2 max)
X
X
X
6 Minute Walk
X
X
X
Randomization
X
Bone Marrow 
Aspiration
X 
Sham/Heart         
Biopsy (RHC/EMB)
X
Catheterization 
(NOGA)
X
Temp. Log
X7
D0      
(SPI)
Base-
line 
Testing
Harvest
M24     
(+/-30 
days) 
Call8
D1
MRI 
Visit5
Wk1     
(+/-3 
days)
M1      
(+/-7 
days)
M3      
(+/-14 
days)
M6      
(+/-30 
days)
M12     
(+/-30 
days)
CONCERT-HF     
Study Procedures
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8. Two 2-D echocardiograms will be performed on all subjects on the day of harvest: 1) a pre-RHC procedure 
echo to assess for pre-existing pericardial effusion, and 2) a post-RHC (with or without EMB) procedure echo 
within 6 hours to ensure no post-procedure effusion (even if subject is stable).   
 
6.2 Study Phases and Visits 
 
6.2.1 Baseline Phase 
After the subject has consented to the study, the subject will have a series of assessments to 
establish eligibility to receive treatment.   
 
All baseline tests and procedures, and harvest procedures, will occur within 60 days of signing 
informed consent form (ICF), with the exception of the cMRI to be used for the baseline meas-
urement (see below). No baseline exams will take place until the subject is fully informed of the 
research and signs the ICF. BMA (see Appendix A) and RHC/EMB procedures (see Appendix 
B) will take place after the subject has been determined eligible and has been randomized (see 
Section 4.6).  
 
6.2.2 BMA and RHC Procedures 
After randomization, all subjects will undergo BMA and RHC. For subjects randomized to the 
MSCs alone and placebo groups, only a RHC will be performed (a.k.a. “sham biopsy”).  A RHC 
will include EMB for subjects randomized to the Combo and c-kit+ cells alone groups.   
 
Subjects determined to be eligible during baseline testing will be scheduled for their BMA (see 
Section 5.1 and Appendix A) and RHC with or without EMB (RHC/EMB) (see Section 5.2 and 
Appendix B), depending on randomization assignment. The RHC will include EMB for the 72 
subjects randomized to the Combo and c-kit+ cell only groups.  A script for the sham biopsy can 
be found in the Manual of Operating Procedures.  BMA and RHC/EMB procedures will be per-
formed on the same day.  Before the procedures, all subjects will have a physical exam includ-
ing vital signs, weight, assessment of NYHA class (Appendix C), CCS class (Appendix D), re-
view of AEs and concomitant medications and laboratory assessments (see Section 6.3.2). Two 
2-D echocardiograms will be performed on all subjects on the day of harvest: 1) a pre-
RHC/EMB procedure echo to assess for pre-existing pericardial effusion, and 2) a post-
RHC/EMB procedure echo within 6 hours to ensure no post-procedure effusion (even if subject 
is stable). For subjects receiving systemic anticoagulation therapy, an INR measurement will be 
performed on the morning of the planned procedures.  Aspirin therapy or dual antiplatelet ther-
apy will not be interrupted for BMA and RHC/EMB procedures.   Pressures collected during the 
procedure should be measured at end-expiration at end diastole.  
 
Research teams should follow institutional and interventionalist standard of practice for manag-
ing anticoagulation before the BMA and RHC/EMB procedures.  The following guideline could 
also be used.  Anticoagulation management guideline:  Stop warfarin 4 days prior to the date of 
planned BMA and RHC/EMB.  Careful consideration for bridging anticoagulation should be 
given to assess risk of occurrence of thrombotic events for subjects off anticoagulation.101  Per-
form INR measurement on morning of planned procedures.  Require an INR of < 1.6 for these 
subjects to proceed with BMA and RHC/EMB.  For subjects on Factor Xa inhibitors, stop 2 days 
prior to planned BMA and RHC/EMB.  
 
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Following successful procedures, the bone marrow and EMB tissue (if procured) will be pre-
pared and sent to the CCMF for processing. BMA and RHC/EMB procedures will occur within 
60 days from subject signing informed consent and approximately 14 weeks prior to SPI. 
 
6.2.2.1 Circumstances that would halt or terminate the RHC/EMB procedure 
 
If any of the following occur before or during RHC/EMB, they could indicate a serious clinical de-
terioration.   
• If any of these conditions/events occur, the procedure should be temporarily halted and 
the subject should be reevaluated for suitability to continue with the procedure: 
o the systolic blood pressure (SBP) taken the day of harvest is <80 mmHg and con-
stitutes a significant change from baseline, e.g., SBP change from ≥ 100 mmHg 
(at baseline) to <80 mmHg (at harvest);  
o the heart rate (HR) taken the day of harvest is >100 and constitutes a significant 
change from baseline, e.g., HR change from ≤ 80 (at baseline) to >100 (at har-
vest).  
o the baseline pulmonary artery (PA) systolic pressure taken during the RHC is 50-
59 mmHg; 
o the baseline right ventricle (RV) systolic pressure taken during the RHC is 50-59 
mmHg; 
o the baseline wedge pressure taken during the RHC is 30-34 mmHg; (note: if 
wedge pressure is >30 mmHg, collect an O2 sat measure); 
 
• If any of these conditions/events occur, the procedure should be terminated (subject can 
be evaluated for rescheduling if condition/event resolves): 
o change in NYHA Class to Class IV; 
o the baseline PA systolic pressure is ≥ 60 mmHg; 
o the baseline RV systolic pressure is ≥ 60 mmHg; 
o the baseline wedge pressure is ≥ 35 mmHg. 
 
6.2.3 MRI Evaluation and Day 0 Study Product Injection (SPI) 
MRI Evaluation Visit 
Within the 30 days prior to the scheduled NOGA procedure (Day 0), a cMRI will be done and 
compared with the initial cMRI done during baseline testing to demonstrate any change in EF 
between baseline testing and the intervention.  The initial cMRI will be used to determine eligibil-
ity. The cMRI just prior to treatment will be used for the baseline measurement. A local read of 
this cMRI is required as part of a pre-SPI safety review.  If MACE occurs (see Section 3.5) be-
tween baseline testing and Day 0, a cMRI will be performed and can be used for the baseline 
measurement. 
 
Day 0 (SPI) 
Before the SPI, all subjects will have a physical exam including vital signs, weight, assessment 
of NYHA class (Appendix C), CCS class (Appendix D), review of AEs and concomitant medica-
tions and laboratory assessments (see Section 6.3.2) including a pregnancy test (females of 
childbearing potential) within 36 hours prior to SPI.  For subjects receiving systemic anticoagula-
tion therapy, an INR measurement will be performed on the morning of the planned procedure.   
 
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Research teams should follow institutional and interventionalist standard of practice for manag-
ing anticoagulation before the SPI procedure.  The following guideline could also be used.  Anti-
coagulation management guideline:  Stop warfarin 4 days prior to the date of planned SPI.  
Careful consideration for bridging anticoagulation should be given to assess risk of occurrence 
of thrombotic events for subjects off anticoagulation.101  Perform INR measurement on morning 
of planned procedure.  Require an INR of < 1.6 for these subjects to proceed with SPI.  For sub-
jects on Factor Xa inhibitors, stop 2 days prior to planned SPI procedure. 
 
With appropriate biorepository consent, peripheral blood will be drawn before sedation for the 
SPI procedure. Subjects will have assessments of vitals (BP, temperature, pulse rate) immedi-
ately pre- and post-procedure. After the injection procedure, subjects will be monitored over-
night.  Subjects will be monitored on simple telemetry up to 24 hours post-procedure or until dis-
charge, whichever is sooner. A 2-D echocardiogram will be performed post SPI (within 6 hours).  
Additional echocardiographic assessments for pericardial effusion will be done as clinically indi-
cated.   
 
6.2.4 Day 1 Post Catheterization 
All subjects will have laboratory assessments (see Section 6.3.2), with Troponin I or T per-
formed 8 (+/- 2) hours post cardiac catheterization/NOGA and again prior to discharge.  Sub-
jects will also have ECGs performed within 6 hours following the catheterization procedure and 
again before discharge.  The subject will keep a daily temperature log for seven days following 
the catheterization procedure to help assess the early development of an infection. 
 
6.2.5 Week 1 Evaluations 
After one week, subjects will return to the clinic for a physical exam and laboratory assessments 
including Troponin I or T (see Section 6.3.2), as well as collection of the temperature log. 
 
6.2.6 Month 1 – Month 12 Visits 
Outpatient visits should be completed as close to the scheduled visit dates as possible adhering 
to the visit schedule and follow-up windows stated in Section 6.2.8.  If required, outpatient visit 
procedures may take place over more than one day.  If procedures are performed on more than 
one day, the date of the physical exam will be considered the visit day. 
 
6.2.6.1 Transplants, CRT, or LVADs before Months 6 or 12 
If subjects are transplanted, receive CRT, or receive an LVAD prior to the month 6 or 12 visits, 
every attempt should be made to collect the endpoint measures (see Section 3.6.2) before 
transplant, CRT, or LVAD procedure.  Labs and pathology (explanted heart) will be collected 
from those providing appropriate consent (see Section 6.4).  Participants will continue to be fol-
lowed for safety (provided they are not withdrawn from the study) and seen for study visits, but 
no further endpoint collection (MRI, 6MWT, MVO2, MLHFQ, NT-proBNP) will be completed after 
the transplant, CRT, or LVAD procedure.  Adverse event reporting will continue as per section 
7.3 of the protocol. 
 
6.2.7 Follow-up windows 
The timeline for follow up will initiate with the day of SPI (Day 0). The time windows for each of 
the subsequent follow up visits will be as follows: 
1. The 1-week visit will be 7 ±3 days (from day of SPI). 
2. The 1-month visit will be at 30 ±7 days. 
3. The 3-month visit will be at 90 ±14 days. 
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4. The 6-month visit will be at 180 ±30 days. 
5. The 12-month visit will be at 365 ±30 days. 
 
6.2.8 Lost to Follow-up 
Randomized subjects will be followed for up to two years.  Subjects will be considered lost to fol-
low-up after 3 consecutive failed telephone contacts AND one certified letter returned to the site.  
Contact attempts will be documented in the subject’s study chart. 
 
6.3 Procedure Details 
The timing of procedures is based on Day 0 being the day of SPI.  Follow-up procedures take 
place at Day 1, Week 1, and at 1, 3, 6, and 12 months following the NOGA catheterization pro-
cedure to deliver the study product. 
 
6.3.1 Medical History and Physical Exam 
A complete medical history will be conducted during baseline testing including: vital signs, 
height and weight; assessment of NYHA classification (Appendix C) and CCS classification (Ap-
pendix D); medical, surgical, and smoking history; and review of current use of prescription and 
OTC medications. Similar physical exams will be conducted at each additional clinic visit during 
the study including vital signs, weight, assessment of NYHA and CCS classifications, review of 
AEs, and concomitant medications. 
 
NOTE: Laboratory Testing for enrollment of Stage 1 subjects is included in Appendix E.   
6.3.2 Schedule of Laboratory Testing Stage 2 (Table 22b) 
 
 
 
1. Chemistry Tests - sodium, potassium, chloride, bicarbonate (CO2), glucose, blood urea nitrogen (BUN), 
creatinine, and eGFR. 
2. Complete Blood Count with Differential - CBC: WBC, RBC, hemoglobin, hematocrit, MCV, and platelets; 
Diff: neutrophils, lymphocytes, monocytes, eosinophils, and basophils. 
3. Liver Function Tests - albumin, alkaline phosphatase, alanine transaminase (ALT), aspartate transaminase 
(AST), total bilirubin, direct bilirubin, and total protein. 
4. Will be completed within 36 hours prior to injection. 
5. NT-proBNP required; send to outside lab if applicable. 
6. Will be performed once in the morning and once 8 (+/- 2) hours post cardiac catheterization/NOGA.  
7. Later time points if indicated. 
CONCERT-HF Laboratory Testing
BSL
Harvest
MRI   
visit
Day 0   
(SPI)
Day 111
Wk 1
M 1
M 3
M 6
M 12
Chemistry Tests1 
X
X
X
X
X
X
X
X
CBC with Differential2 
X
X13
X
X
X
X
Liver Function Tests3
X
X
X
X
Pregnancy (childbearing women)
X
X4       
X
X
X
X
NT-proBNP5
X
X
X
X
Troponin I or T
X
X6       
X      
X
HbA1c
X
X
X
X
PT, INR, PTT7
X
X12
X12
Infectious Disease Tests8
X
Biomarkers (PB) (Biorepository)9
X10
X
X
X
X
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8. Infectious disease tests should be the bone marrow donor panel used per local institutional guidelines, in-
cluding HIV, Hep B (HBsAG, Anti-HBs, Anti-HBc), and Hep C (Anti-HCV), and results must be known prior 
to harvest. Donor tests are conducted within 60 days of harvest procedures. If for some reason these tests 
expire prior to either harvest, they will be performed again. 
9. With appropriate consent, twenty (20) mL of peripheral blood (PB) will also be collected and transported to 
the CCTRN biorepository for scientific study (See Section 6.4 Collection of Biospecimens). Stage 1 partici-
pants will not be offered biorepository participation. 
10. Collected prior to sedation for SPI procedure. 
11. Day 1 labs will be collected 24 hours post-procedure or immediately prior to discharge, whichever is 
sooner.  
12. For subjects receiving systemic anticoagulation therapy, an INR measurement will be performed on the 
morning of the planned procedure; must be <1.6 to proceed with procedure. 
13. CBC drawn on day of MRI with hematocrit recorded on the MRI worksheet. 
 
6.3.3 cMRI Procedure 
All subjects will undergo cMRI during baseline testing, within 30 days prior to the NOGA proce-
dure, and at 6 and 12 months (+/- 30 days) post study product injection.  The cMRI within 30 
days prior to SPI will be the baseline measure.  
 
Cardiac MRI will be performed using 1.5 T scanners with multi-channel (8, 16, or 32 channels) 
cardiac coil, simultaneous ECG recording, and gadolinium.  Prior to the cMRI examination, sub-
jects will be screened for contraindication and coached on performing adequate breath-holds. 
Electrocardiographic leads and a blood pressure cuff will be positioned. The cardiac phased-ar-
ray coil will be wrapped around the subject’s chest and correctly positioned over the precordium. 
Participants will lie supine on the magnet table and enter feet-first into the center of the scanner. 
All cardiac images will be obtained during approximately 12-15 heartbeat breath- hold at end-
expiration, averaging 10-15 seconds with adequate rest periods between the breath-holds 
(about 10-15 seconds). The imaging protocol will first include sagittal, axial and oblique scout 
images to localize the heart. It is anticipated that each cMRI session will last 60 minutes in dura-
tion.  See MRI Core Lab Manual of Operations for acquisition details. 
 
Guidance to the Principal Investigator: MRI was selected as the imaging modality for end-
point collection due to its excellent capability to identify scar and changes in LV function. The 
resolution of the imaging is such that it can also detect LV thrombi that may not otherwise be 
found using the standard echocardiogram. This includes many old, small, organized, endotheli-
alized, mural thrombi that may or may not rise to the level of clinical significance.  
 
Identification and clinical evaluation of LV thrombus: The MRI core lab will provide their interpre-
tation about the presence of a thrombus to the local center. The MRI core lab will differentiate 
between the LV thrombi that meet the definition of an exclusion on the one hand from the 
smaller LV thrombi that would likely not appear on echo. The MRI core lab will describe the lat-
ter by stating, "cannot rule out small LV thrombus". For these, it will then be up to the site study 
PI and the harvester and/or NOGA operator to follow up in making the determination of clinical 
significance of any finding and whether (and when) they would proceed with study procedures. 
This leaves the decision to proceed in the presence of the smaller LV thrombi identified by MRI 
in the hands of the site study PI based on their assessment of clinical significance. If they pro-
ceed, documentation of that determination must be included in the participant’s chart. 
 
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The MRI core lab provides the statement of any findings and also provides to the clinical team a 
weblink to the actual MRI images with instruction on the location of the finding(s) (i.e., which se-
ries/views will highlight their review). This allows the PI/interventionalist at the center to readily 
identify the location, view the images, and request additional info if needed. All studies are re-
viewed by the local radiologist for clinical findings for the PI’s consideration before enrollment. 
The site is responsible for having a local read (safety or professional) of baseline MRIs prior to 
SPI and to ensure there is local documentation on file regarding presence of thrombus. 
 
6.3.3.1 Performance of cMRI in subjects with implantable cardiac devices (ICD/pacemakers)  
The presence of a pacemaker or implanted defibrillator device is not a contraindication to MRI 
scanning102,103. 
The procedures use are based upon the safety recommendations as listed in “Safety of Mag-
netic Resonance Imaging in Subjects With Cardiovascular Devices: An American Heart Associ-
ation Scientific Statement”102. In particular, the recommendations include: 
1. Written and verbal informed consent is obtained. Specific risks are documented, including 
a. pacemaker/ICD dysfunction and/or damage 
b. arrhythmia 
c. device dislodgement 
d. thermal injury 
e. death 
2. There is direct involvement of a cardiologist or specifically trained Registered Nurse with 
pacemaker/ICD expertise, to oversee pre-scan device measurements, device changes 
including therapy (ICD) disabling for the duration of the scan, and post-scan measure-
ments and re-enabling of therapy and other device parameters. 
3. Advanced Cardiovascular Life Support (ACLS) trained personnel and a “crash cart,” in-
cluding defibrillator, are available throughout the procedure to address an adverse event. 
4. Maintenance of visual and voice contact with the subject throughout the procedure. 
5. At all times during which the device is disabled, continuous ECG telemetry and pulse oxi-
metry, blood pressure measurements every 5 minutes, and symptoms are monitored in-
cluding throughout the scan. 
 
Regarding specific implanted device parameter measurements and programming changes, pro-
tocols of Johns Hopkins University104 is used as follows:   
1. Exclusion of subjects whose devices were manufactured before 2000 
2. Exclusion of subjects with nontransvenous epicardial, or abandoned (capped) leads 
3. Exclusion of pacemaker-dependent subjects with ICDs 
4. ICD therapies are disabled during the study to avoid unwarranted anti-tachycardia pacing 
or shocks 
5. Limitation of the estimated whole-body averaged SAR to <2.0 W/kg for MR scan acquisi-
tion 
6. Exclusion of subjects with leads implanted less than six weeks prior to study enrollment 
 
As a part of the training process, personnel who are highly experienced with MR imaging on pa-
tients with pacemakers and ICDs will oversee the initial cases at each site until adequate profi-
ciency is reached by each site’s imaging staff members. 
 
6.3.4 Six-minute Walk Test (6MWT) 
6MWTs will be performed to assess functional capacity. Subjects will perform a 6MWT at base-
line and at 6 and 12 months. See Protocol Manual of Operations for acquisition details.   
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To minimize external sources of test-retest variability, 6MWTs will be administered by testers 
blinded to treatment arm.   
 
Two tests will be done at each of the 3 visits (baseline, 6 and 12 months) separated by at least 
30 minutes.  If the variance between test 1 and test 2 for total distance walked is >10%, a third 
test will be done.  If 6MWTs and VO2 max test are done on the same day, they will be done in 
consistent order at each visit and at consistent intervals, with 6MWTs completed either at least 
30 minutes before or starting at least 1 hour after the VO2 max test. 
 
6.3.5 Questionnaires 
The subjects’ quality of life will be assessed with the MLHFQ at baseline and at 3, 6, and 12 
months. The subjects’ sexual function will be assessed for males with the International Index of 
Erectile Function (IIEF) and for females with the Female Sexual Function Index (FSFI) at base-
line and at 6 and 12 months. 
  
6.3.6 Electrocardiograms (ECGs) 
A 12-lead ECG will be performed at baseline, on Day 0 (4-6 hours post procedure), on Day 1 
before discharge, at 1 week, and at 6 and 12 months. If there is a sustained run of ventricular 
tachycardia (≥20 beats) on the 12-lead ECG obtained during baseline testing, the subject will be 
removed from the study. 
 
6.3.7 Treadmill Testing (VO2 max) 
Treadmill testing with VO2 max assessment will be performed at baseline and at 6 and 12 
months to assess whether cell therapy improves aerobic capacity. 
During baseline testing, the subject must not have a VO2 max greater than 75% of age and gen-
der based predicted values in order to be eligible for the trial.  The values for VO2 max in normal 
persons105 and the values reflecting 75% of normal (exclusion criteria) are as follows:  
 
Age 
Males 
Females 
20-29 years old 
Normal 43±7.2 ml/kg/min;            
Exclusion criteria ≥ 32.3. ml/kg/min  
Normal 36±6.9 ml/kg/min; 
Exclusion criteria ≥ 27.0 ml/kg/min  
30-39 years old 
Normal 42±7.0 ml/kg/min;             
Exclusion criteria ≥ 31.5 ml/kg/min  
Normal 34±6.2 ml/kg/min;  
Exclusion criteria ≥ 25.5 ml/kg/min 
40-49 years old 
Normal 40±7.2 ml/kg/min;             
Exclusion criteria ≥ 30.0 ml/kg/min  
Normal 32±6.2 ml/kg/min;  
Exclusion criteria ≥ 24.0 ml/kg/min  
50-59 years old 
Normal 36±7.1 ml/kg/min;            
Exclusion criteria ≥ 27.0 ml/kg/min  
Normal 29±5.4 ml/kg/min;  
Exclusion criteria ≥ 21.8 ml/kg/min  
60-69 years old 
Normal 33±7.3 ml/kg/min;            
Exclusion criteria ≥ 24.8 ml/kg/min  
Normal 27±4.7 ml/kg/min;  
Exclusion criteria ≥ 20.3 ml/kg/min  
70-79 years old 
Normal 29±7.3 ml/kg/min;             
Exclusion criteria ≥ 21.8 ml/kg/min  
Normal 27±5.8 ml/kg/min;  
Exclusion criteria ≥ 20.3 ml/kg/min 
 
6.3.8 Implantable Cardioverter Defibrillator (ICD) Interrogation 
An ICD interrogation is a standard non-invasive assessment of the function of the ICD. This as-
sessment (interrogation) identifies the occurrence of any significant ventricular arrhythmias over 
a certain time period and identifies any potential therapeutic interventions (such as shocks or 
antitachycardia pacing) that were used by the ICD to treat any ventricular arrhythmia. ICD inter-
rogation will occur before and after every cMRI,  as well as before the SPI procedure.  Reports 
will be generated for the interrogations conducted before the MRIs at baseline (image collected 
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within 30 days of SPI) and at the 6 month and 12 month visits.  Local electrophysiology person-
nel will review the device report for the presence of reportable clinical events.  Copies of the re-
ports should remain on site as source documentation (de-identified copies may be requested by 
the Sponsor for endpoint adjudication).  
 
6.3.9 Echocardiograms 
Two 2-D echocardiograms will be performed on all subjects the day of harvest: 1) a pre-RHC 
procedure echo to assess for pre-existing pericardial effusion, and 2) a post-RHC (with or with-
out EMB) procedure echo within 6 hours to ensure no post-procedure effusion (even if subject is 
stable). A 2-D echocardiogram will also be performed post-SPI procedure (within 6 hours) to as-
sess for adverse events potentially related to study product delivery (e.g. pericardial effusion, 
wall motion abnormalities, etc.).  Additional echocardiographic assessments for pericardial effu-
sion will be done as clinically indicated.  
 
6.4 Collection of Biospecimens 
A central CCTRN biorepository will be utilized in this study.  Discussion of biorepository sam-
pling is included in the consent form and subjects will have the option of participating in sample 
donation.  Participation in the study does not equate with participation in donating to the biore-
pository; subjects can decline the biorepository donation and still participate in the trial. 
 
 
The goals of this biorepository are: 1) to provide storage of critical biomaterials derived from 
subjects enrolled in clinical protocols within the CCTRN 2) to provide long-term integrity (up to 
10 years) of these biospecimens and samples, and 3) to provide management of samples for 
ancillary studies of immunologic, immunohistochemical, cellular, and molecular analyses of col-
lected samples; as well as phenotypic and functional analyses of cells and plasma samples with 
an aim toward gaining insight into diagnostics of disease progression and prognostics of suc-
cessful intervention.  
 
 
These biospecimens will be used for research purposes only (not for profit), will be stored with-
out personal identifying information, and will be shared with approved researchers who will con-
duct studies to improve the understanding of the effects of cell therapies and/or of cardiovascu-
lar disease. All such biospecimens will be destroyed after 10 years. 
 
6.4.1 Bone Marrow 
During the bone marrow aspiration procedure, approximately 90 mL (± 10 ml) of bone marrow 
will be harvested from active and placebo subjects. The bone marrow will be then transported to 
the local cell processing lab for preparation, packaging, and shipping to the CCMF or when ap-
propriate to the CCTRN biorepository. Sixty-five mL (+/- 5 mL) of bone marrow will be sent to 
the CCMF.  The remainder of the bone marrow suspension (~25 mL) will be shipped to the 
CCTRN biorepository with appropriate consent.   
 
In addition, cryopreserved MNC products of subjects randomized to both the placebo and to the 
c-kit+ cell only groups will be shipped using a LN2 dry shipper from the CCMF to the CCTRN bi-
orepository with appropriate consent. 
 
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6.4.2 Peripheral Blood (PB) 
Twenty mL of PB will be collected  on Day 0 (day of injection, prior to sedation), on Day 1, Week 
1, and at the 1, and 6 month visits. This blood will be sent to the CCTRN biorepository for addi-
tional characterization studies.  
 
6.4.3 MSC and/or c-kit+ cell Autografts 
Remaining MSC and/or c-kit+ cell product in excess of the target doses for the subject will be 
provided to the CCTRN biorepository (with appropriate consent).   
 
6.4.4 Explanted hearts 
Included in the informed consent is a request for the explanted heart in cases of transplant or in 
the event of the participant’s death.  These donated hearts will be studied to assess the result of 
study product delivery (e.g. cell proliferation, increased capillary density). With appropriate con-
sent, the explanted heart will be sent to the CCTRN biorepository for further study. 
 
7.0 EVENT MONITORING AND REPORTING 
The safety monitoring program is a comprehensive, data driven program that provides ongoing 
capture and analyses of safety data and issues timely notifications, event specific reports, and 
scheduled cumulative trial reports of safety issues to appropriate study personnel, the NHLBI 
Program Director, the Data and Safety Monitoring Board (DSMB), and the Food and Drug Ad-
ministration (FDA).  The program complies with applicable U.S. law, regulations, and guidance.  
 
7.1 Definitions Related to Adverse Events 
The following definitions arise from recently modified FDA reporting regulations and Interna-
tional Conference on Harmonization (ICH) guidelines for use in this study: 
 
7.1.1 Adverse Events (AEs) 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. An AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally as-
sociated with the study.  The event does not need to have a causal relationship with treatment. 
 
7.1.2 Suspected Adverse Reaction (SARs) 
A suspected adverse reaction (SAR) is defined as any adverse event for which there is a rea-
sonable possibility that the drug caused the adverse event.  For the purposes of IND safety re-
porting, “reasonable possibility” means there is evidence to suggest a causal relationship be-
tween the study product/procedures and the adverse event. 
 
7.1.3 Serious Adverse Events (SAEs) or Serious Suspected Adverse Reaction (SSAR) 
A serious adverse event (SAE) or serious suspected adverse reaction (SSAR) is defined as an 
AE/SAR which, in the view of the Investigator or Sponsor, results in: 1) Death; 2) a life-threaten-
ing event (i.e. an event in which the subject was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were more severe); 3) 
inpatient hospitalization of > 24 hours or prolongation of existing hospitalization; 4) a significant 
disability/incapacity; or 5) a congenital anomaly/birth defect.  Other important medical events 
may be considered SAEs/SSARs if, in the opinion of the Investigator or DCC, they jeopardize 
the subject or require intervention to prevent one of the other outcomes listed above. 
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7.2 Role of Abnormal Test Findings and Hospitalizations in Classifying an Event 
 
7.2.1 Abnormal Test Findings 
If a test result is associated with accompanying symptoms, and/or the test result requires addi-
tional diagnostic testing or medical/surgical intervention, and/or the test result is considered to 
be an AE/SAR by the Investigator or Sponsor it should be reported as an adverse event. NOTE: 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not con-
stitute an AE/SAR. Any abnormal test result that is determined to be an error does not require 
reporting as an AE/SAR. 
 
7.2.2 Hospitalizations 
AE/SARs associated with hospitalization, or prolongation of hospitalization, are classified as se-
rious. Admission also includes transfer within the hospital to an acute/intensive care unit (e.g., 
from the cardiac wing to the medical floor for an infection, or from the medical division to the 
neurologic unit for a stroke).   
 
Hospitalization does not include rehabilitation facilities, hospice facilities, respite care (i.e., care-
giver relief), skilled nursing facilities or homes, routine emergency room admissions, or same 
day surgeries (as outpatient/same day/ambulatory procedures). 
 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE/SAR is not in itself an SAE/SSAR. 
 
7.3 Reporting Responsibilities of the Investigator 
For all events (AE/SAR and SAE/SSAR), monitoring and reporting to the DCC begins at the 
time that the subject provides informed consent, which is obtained prior to the subject’s partici-
pation in the study, i.e., prior to undergoing any study related procedure and/or receiving investi-
gational product, through and including 30 calendar days after the subject completes the 12 
month clinic visit. Events should be recorded on the Adverse Event eCRF.  Do not delay the ini-
tial reporting of an event in order to obtain resolution or follow up information. 
 
For all events, the Investigator must pursue and obtain adequate information both to determine 
the severity and causality of the event. For events with a causal relationship to the investiga-
tional product, follow-up by the Investigator is required until the event or its sequelae resolve or 
stabilize at a level acceptable to the Investigator, and the DCC concurs with that assessment. 
 
In the event that the Investigator does not become aware of the occurrence of a SAE/SSAR im-
mediately (i.e., if an outpatient study subject initially seeks treatment elsewhere), the Investiga-
tor is to report the event within 24 hours after learning of it and document the time of his/her first 
awareness of the event. 
 
7.3.1 Severity Assessment 
The DCC uses the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for 
detailed descriptions of Severity Grades.  The CTCAE schema is classified by body system and 
event using the MedDRA hierarchy and provides descriptions of events that qualify under each 
severity rating. The following table contains general descriptions of Adverse Event Severity 
Grades. 
 
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Please note: Grade 1 (Mild) AE/SARs are not entered in the electronic CRF in the CCTRN data-
base.  
 
 
 
Notice that severity and seriousness are different concepts.  For example, a headache may be 
severe (interferes significantly with subject's usual function) but would not be classified as seri-
ous unless it met one of the criteria for SAE/SSARs (see Section 7.1.3 above). 
 
7.3.2 Causality Assessment 
The DCC nomenclature for assessing the causal relationship between the study product/proce-
dure and an event is listed in the following table.   
 
Adverse Event/Suspected Adverse Reaction Relationship to Study Product/Procedure 
 
Unrelated 
No temporal association to study product/procedure. 
 An alternate etiology has been established. 
Unlikely 
Clinical events which are likely to be caused by subject’s clinical state, envi-
ronment or administration of other therapies or exposure to toxins. 
Possibly related 
Reasonable temporal relationship to study product/procedure. 
Connection to study product/procedure cannot be ruled out. 
Probably related 
There is a reasonable temporal association with the study product/proce-
dure.  There is a high degree of certainty that the event is related to the 
study product/procedure. 
Definitely related 
There is a direct temporal relationship to the study product/procedure. 
The event follows a known pattern of response to the study 
product/procedure.  
 
The Investigator chooses the category that overall best describes the relationship between the 
event and the study product/procedure and records the evaluation on the Adverse Event eCRF.  
Note:  If the Investigator does not know whether or not the study product/procedure caused the 
event, then the event will be handled as “possibly related to investigational product” for reporting 
purposes. 
 
Severity 
Grade 
  Description 
1 
Mild. Asymptomatic or mild symptoms; clinical or diagnostic observations only; inter-
vention is not indicated.  
2 
Moderate. Minimal, local, or non-invasive intervention indicated or limiting activities 
of daily living (i.e. preparing meals, shopping for groceries/clothes, managing 
money, using telephone, etc.) 
3 
Severe or medically significant but not immediately life-threatening. Hospitaliza-
tion or prolongation of hospitalization indicated OR disabling OR limiting self-care 
(e.g. bathing, dressing, feeding self, using toilet, taking medications, etc.) 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death. Death related to adverse event. 
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7.3.3 Expectedness Assessment  
The DCC nomenclature for assessing whether an event is expected or unexpected with regard to 
the study product/procedure is listed in the following table.   
 
Expected 
Any event for which the nature or severity is consistent with information 
in study Investigator Brochure 
Unexpected 
Any event for which the nature or severity is not consistent with infor-
mation in study Investigator Brochure 
 
7.4 Reporting Responsibilities of the Sponsor (DCC) 
 
7.4.1 Safety Monitoring Program and Reporting 
The Safety Monitoring Program uses a combination of, email notifications, event specific re-
ports, and scheduled cumulative trial reports to keep the NHLBI Program Director and NHLBI 
DSMB informed about real and potential safety issues.  
 
Email Notifications are comprised of an email to the NHLBI Program Director and 
NHLBI DSMB Executive Secretary with available information on the date and nature of 
the event, the site Investigator’s evaluation of the severity, expectedness, and related-
ness to study product/procedure; and a Sponsor assessment of the event given the infor-
mation known at the time of the initial reporting.   
 
Event specific reports are formal written reports providing the details of the event (in-
cluding circumstances surrounding the event, laboratory testing, concomitant medica-
tions, and any formal diagnoses made via medical intervention).  These reports include a 
full sponsor assessment of the severity, expectedness, and relatedness to study prod-
uct/procedure as well as any available status update on the subject. 
 
Scheduled cumulative trial reports are prepared semi-annually by the DCC.  These 
are used by the NHLBI DSMB to assess recruitment, subject safety, and continued trial 
feasibility.  These reports include total numbers of AE/SARs and SAE/SSARs experi-
enced in the overall trial.  The information provided includes both new events reported 
since the last DSMB meeting and cumulative events reported during the life of the trial. 
 
7.4.2 Sponsor Reporting Requirements to the EC, NHLBI and DSMB  
Once the event has been reported to the DCC by the Investigator, the DCC uses the Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Classification (SOC) to classify all 
AEs/SARs (including SAEs/SSARs assessed by Investigator or DCC).  Additional supporting 
documentation may be requested from the site Investigator and his/her team to enable the DCC 
Safety Officer to accurately assess the event for reporting.   
 
Type of SAE/SSAR 
 
Type of Report 
Reporting Timeframe 
Event is NEITHER grade 3 or higher, NOR 
unexpected, NOR related 
 
Cumulative DSMB report 
Every six months 
Event is ONE OF: grade 3 or higher OR 
unexpected OR related 
 
Email notification to DSMB  
Within 15 days 
Event is grade 3 AND EITHER  
unexpected OR related 
 
Email notification to DSMB 
Within 15 calendar days 
Event specific report to DSMB 
Within 30 calendar days 
Event is unexpected AND related AND 
(grade 2-grade 5) 
 
Email notification to DSMB 
Within 72 hrs 
Event specific report to DSMB 
Within 7 calendar days 
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7.4.3 Sponsor Reporting Requirements to FDA 
Once the DCC has been notified of a SAE/SSAR the following are the DCC’s reporting require-
ments to the FDA: 
 
Type of SAE/SSAR 
Report to 
Timeframe 
Fatal or life-threatening, unexpected, 
and associated with study product/pro-
cedure 
FDA 
MedWatch submitted within 7 calen-
dar days of learning of event 
Other SAE/SSARs that are non-fatal or 
life-threatening but are unexpected and 
associated with study product/proce-
dure  
FDA 
MedWatch submitted within 15 calen-
dar days of learning of event 
 
7.5 Unanticipated Problems (UPs) 
An UP is an incident, experience, or outcome that specifically causes increased risk to the study 
or to its participants which may be of medical or non-medical etiology, and meets the following 
criteria: 
• Unexpected (in terms of nature, severity, or frequency), given (a) the research proce-
dures that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the sub-
ject population being studied; 
• Definitely, probably, or possibly related to participation in the research (i.e., there is a rea-
sonable possibility that the incident, experience, or outcome may have been caused by 
the procedures or materials involved in the research); and 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recog-
nized. 
 
All UP reporting will follow the same guidelines as noted above for SAE/SSAR reporting, and 
must include a corrective action plan/measures to prevent recurrence. 
 
7.6 NHLBI DSMB Criteria 
All SAEs and SSARs will be evaluated by the NHLBI DSMB in accordance with its charter and 
review procedures.  This includes an assessment of expectedness, relationship to the study 
product or procedures, and severity. The CCTRN Study Sponsor will rely on the NHLBI DSMB 
to identify conditions or events that would trigger further action, including a temporary halt, modi-
fication, or termination of the study for safety reasons.  
 
7.7 Review of Open Label Lead-in (16 subjects) 
The following outlines the process for the collection and review of data for the 16 subjects partic-
ipating in the open label lead-in portion of the study: 
 
1. Sixteen subjects who consent and meet all inclusion and exclusion criteria will be ran-
domized 1:1 to SOC vs. Combo cell therapy. 
2. The eight subjects in the Combo group will undergo a bone marrow aspiration and endo-
myocardial biopsy, and after cell manufacturing, receive the study product via transendo-
cardial injections using NOGA (per protocol).  
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3. All subjects will be observed for complications or adverse effects of baseline testing and 
non-intervention study procedures.  Subjects in the Combo group will also be observed 
for any complications or adverse effects of the bone marrow or endomyocardial harvests, 
electromechanical mapping, or delivery of cell therapy.  
4. Events will be reported to regulatory oversight groups as outlined above in section 7.4. 
5. The DSMB will review safety and bioactivity data (LV function and functional status) at 
three months for the sixteen subjects.  This data will also be forwarded to the FDA in a 
subsequent amendment. 
6. Upon successful DSMB review of the lead-in data, the study will be permitted to recruit 
subjects into both the active and placebo groups to the specified protocol sample size of 
144. 
8.0 STATISTICAL PROCEDURES 
8.1 Randomization Strategy  
 
8.1.1 Randomization in Stage 1 (open label lead-in) 
Randomization to treatment assignment will be conducted using a web access database cre-
ated and maintained by the Data Coordinating Center (DCC).  Following successful completion 
of baseline testing, clinical sites will enter results of the testing in the web-based program.  Sub-
jects will be randomized either to 1) SOC (no study procedures) or 2) Combo (MSCs plus c-kit+ 
cells). We will use a block size of 2.  
 
8.1.2 Randomization in Stage 2 (double-blind, placebo-controlled phase) 
The size of this study requires explicit consideration of the losses to follow-up after the subject 
has been randomized. In CONCERT-HF, two periods of time are vulnerable to subject attrition: 
1) during the approximately 14 week period after subjects are randomized but before they are 
treated; and 2) the period that begins when the subject receives study treatment and is subse-
quently followed for one year.  
 
Despite investigators’ best efforts, some subjects who are randomized will not continue in the 
study (e.g., clinical events between randomization and end of follow-up, inability to complete fol-
low-up measures, etc.). Based on the ACCLAIM106 and FOCUS56 experiences, we anticipate 
20% follow-up loss between randomization and the end of the one year follow-up, and we have 
therefore set our sample size at 144 subjects. The ACCLAIM106 investigators evaluated the ef-
fect of a non-specific immunomodulation therapy in subjects with NYHA functional class II-IV 
chronic heart failure, LV systolic dysfunction, and hospitalization for heart failure or intravenous 
drug therapy in an outpatient setting within the past 12 months. During a mean follow-up of 10.2 
months, out of 2226 patients a total of 341 patients (15.3%) were unable to complete the study. 
In FOCUS56, out of 92 randomized patients, 13 were excluded post treatment (14.1% at the six 
month follow-up).  The attrition rate for these two trials that enrolled a patient population compa-
rable to the CONCERT-HF population was approximately 15%.  Since we are following subjects 
for 12 months, we increased the CONCERT-HF attrition rate to 20%, and we increased the 
sample size and power. 
 
Randomization, or the random allocation of therapy, is a well-accepted mechanism for reducing 
potential bias in evaluating treatment effects. Randomization to treatment assignment will be 
conducted using a web access database created and maintained by the Data Coordinating Cen-
ter (DCC).  Subjects will be randomized either to 1) Combo (MSCs plus c-kit+ cells), 2) MSCs 
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alone, 3) c-kit+ cells alone, or 4) placebo. Subjects will be stratified by center, and randomly se-
lected variable block sizes of 4 or 8 will be implemented.   
 
When a subject is pre-screened and entered in the web-based program, an identification (ID) 
number will be assigned. When the subject is consented and demographic information entered 
to the web-based program, an acrostic will be generated.  The DCC will monitor recruitment by 
providing reports to the NHLBI Project Office as appropriate during the recruitment phase.  Up-
dated reports will be maintained on an Internet site accessible to Network members.  Goals for 
recruitment will be set and will be reviewed by the DCC and the NHLBI Project Office. 
 
8.2 Guiding Analysis Plan 
The primary analyses in CONCERT-HF will be intention-to-treat for all endpoints. 
 
8.3 Delays 
Circumstances that may result in delaying SPI could be related to an issue with cell processing 
or to a change in the clinical condition of the subject.   
• If a fatal cell processing related issue or contamination occurs during the window be-
tween randomization and the scheduled SPI procedure, the subject may undergo a sec-
ond bone marrow aspiration and/or endomyocardial biopsy at a time to be determined by 
the Medical Monitor and CONCERT-HF Clinical Center PI upon review of the case de-
tails.   
• If a cell processing related issue arises on the day of the SPI procedure and additional 
product can be thawed and delivered at a later time, the subject will have their SPI post-
poned.   
 
A randomized subject who has a resolvable change in their clinical condition and their cells not 
yet prepared for injection will be allowed to have their SPI postponed to a time to be determined 
by the Medical Monitor and CONCERT-HF Clinical Center PI upon review of the case details. 
The subject must remain eligible for the study in order to proceed with SPI, which may include 
repeat baseline testing.  A subject who cannot be treated will no longer qualify for inclusion in 
the study, though will be included in all analyses for which they have data in accordance with 
the "intention-to-treat" principle. 
 
8.4 Statistical Analyses  
Biostatisticians at the DCC, with the assistance of scientific programmers, have adapted or de-
veloped a number of statistical programs for analyzing study data. Data are analyzed for both 
data monitoring purposes, as described above, and for the purpose of detecting beneficial or ad-
verse treatment effects.  The DCC uses standard statistical packages such as SAS, S-PLUS, R 
and Stata to perform statistical analyses.  
 
8.4.1 Baseline Analyses 
Although the stratified random assignment of participants to the various treatments should en-
sure comparability with respect to known and unknown variables, imbalance may occur by 
chance.  Descriptive statistics for baseline characteristics known or suspected to be associated 
with outcomes will be prepared for the treatment groups.  The variables considered in such a 
description can be categorized as: 1) demographic characteristics; 2) medical history; 3) physi-
cal examination; 4) laboratory data; and (5) quality of life / psychosocial data.  Exact testing for 
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categorical variables and Student t testing (or Wilcoxon rank sum test for non-normally distrib-
uted variables) for continuous variables will be used to evaluate the differences in baseline vari-
ables between treatment groups.  
 
8.4.2 Outcome Analyses 
Safety data from Stage 1 will consist of clinical events that occur between randomization and 
the three month follow-up period and will be included in the formal analysis of the study.  Feasi-
bility data (as referenced in section 3.4) will be collected on all treated patients in Stage 1 and 
will be included in the formal analysis of the study.  Outcome data from Stage 1 will consist of 
LV function and functional status measures collected at baseline and the three month follow-up 
time point on all patients; however these subjects will not be included in the formal analysis for 
efficacy as described below for Stage 2.  
 
8.4.2.1 Feasibility Evaluations 
To assess the practicality of study procedures, the feasibility assessments outlined in Section 
3.4 will be reported by the distribution of occurrences across subjects.  The number of uninter-
pretable cMRI endpoint measures will be assessed at baseline, and at 6 and 12 months. 
 
8.4.2.2 Safety Evaluations 
The safety assessments outlined in Section 3.5 will be carried out.  For MACE and other signifi-
cant clinical events defined in Section 3.5, we will carry out a time-to-first-event analysis using 
standard life table techniques.  For all categories of events, the total numbers of each event will 
be tabulated and evaluated using Fisher’s Exact Test.  
 
8.4.2.3 Prospectively Declared Endpoints 
To meet the efficacy objective stated in Section 3.6.1 and assess the prospectively declared effi-
cacy endpoint measures outlined in Section 3.6.2, the analyses will be carried out as follows.  
 
All endpoints listed in Section 3.6.2 except MACE are continuous and will be assessed individu-
ally using a general linear mixed model in an intention-to-treat analysis. The within subject com-
ponent will reflect the measures obtained at baseline, six months, and twelve months. The be-
tween subject component will reflect the effects of the cell types or placebo. The model to be as-
sessed will be an effect modification or interaction model  
 
                                         
0
1
2
3
1
1
[
]
k
m
i
j
ij
j
ij
i
i
i
j
j
E y
z
u
w
x
z
β
α
γ
β
β
β
=
=
=
+
+
+
+
+
∑
∑
            
                                             
where the dependent variable, yi is the dependent variable,  The predictor variables are a bat-
tery of covariate variables obtained at baseline variables (zj j=1 to k), the effect of MSCs wi (di-
chotomous)  the effect of c-kit+ cells xi (dichotomous) and the effect of Combo zi (dichotomous). 
The random effects are contained in uij j= 1 to m. This permits a test of the effect of each of 
these study products both against placebo, and against each other.  
 
We will also carry out an analysis that tests whether there is true synergy produced by Combo 
(that is, whether the effect of the combined cell product improves LV function and functional sta-
tus above and beyond that expected by the sum of the c-kit+ cells and MSCs alone) even 
though this assessment is underpowered. Both unadjusted and adjusted treatment effects will 
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be computed; adjustments will be for baseline covariates whose association with the dependent 
variable is generally accepted. Adjustments will also be made for clinical center.  
 
The MACE endpoint is dichotomous and these data will be analyzed and reported by both the 
time to first occurrence of event and the total number of each event that contributes to the 
MACE endpoint. These data will be analyzed by therapy group between baseline and a) 6 
months and b) 12 months. 
 
8.4.2.4 Variability Management 
The power of CONCERT-HF is sensitive to the variability of its endpoint measure.  For example, 
from Table 4 a standard deviation of 8 provides 81% power in order to detect a 6 absolute unit 
increase in LVEF (36 subjects per treatment arm). An increase in the standard deviation from 8 
to 9 decreases the power to 72%. It is important for CONCERT-HF to maintain control of the 
standard deviation.  
 
For cMRI based endpoints, the DCC will work with the MR core lab to monitor the standard devi-
ations of randomizing centers using only placebo data. The DCC will issue reports to the SC to 
review the standard deviations of endpoints by center. Center outliers will be identified and an 
investigation will ensue to determine factors that are likely contributing to the variability. The 
DCC and MR core lab will work with the center(s) to employ strategies to reduce variability (e.g., 
assess technicians’ abilities to obtain imaging measures and provide additional training when 
required, evaluate changes in equipment at centers and/or need for software/hardware updates, 
monitor rate of staff turnover and impact, etc.).   
 
8.4.2.5 Adaptive Design and Sample Size Adjustments 
The assumptions used to compute the sample size may result in an overestimation or an under-
estimation (e.g., if there were more deaths). In order to maintain a sample size for CONCERT-
HF that achieves our statistical goals, CCTRN proposes an adaptive design for finalizing the 
sample size. While we will manage variability in CONCERT-HF through quality control as out-
lined above, we also propose to monitor and possibly alter the sample size based on observed 
standard deviation (
ds ) of change in LVEF and change in infarct size for the placebo group.  
 
See Table 23 (LVEF) and Table 24 (infarct size) below for information to guide the recommen-
dations and decisions to adapt the CONCERT-HF sample size.  Evaluations will take place 
when 34% and 66% of the placebo cohort has completed Month 6 data collection, labeled infor-
mation time (IT) in the tables below.  It is anticipated that one change might be recommended at 
the first time point, i.e., 34% IT, and be confirmed at the second time point, i.e., 66% IT. The in-
terim analyses will be submitted to the NHLBI DSMB for review and recommendation for actions 
to be taken if warranted. 
 
The decision to decrease the sample size is based on the upper bound of the confidence inter-
val (CI), while the decision to increase the sample size is based on the lower bound of the CI.  
The table for LVEF follows: 
 
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Table 23
Draft Proposal to Monitor and Adjust Sample Size
LVEF
Findings to Decrease Sample Size
Confidence Interval
% IT
N per arm
CI
sd
LB
UB
34
12
0.99
3.5
2.3
7.3
66
24
0.99
4.5
3.3
7.3
Findings to Increase Sample Size 
% IT
N per arm
CI
sd
LB
UB
34
12
0.99
13.0
8.4
27.0
66
24
0.99
12.1
8.8
19.6
 
 
The table for infarct size follows: 
 
Table 24
Draft Proposal to Monitor and Adjust Sample Size
Infarct Size
Findings to Decrease Sample Size
Confidence Interval
% IT
N per arm
CI
sd
LB
UB
34
12
0.99
3.0
1.9
6.2
66
24
0.99
4.0
2.9
6.5
Findings to Increase Sample Size 
% IT
N per arm
CI
sd
LB
UB
34
12
0.99
11.5
7.5
23.9
66
24
0.99
10.0
7.3
16.2
 
 
The CI upper and lower bounds are computed from the approximate 99% CI for σ  based on 
ds
as follows: 
(
)
(
)
(
)
(
)
2
2
2
2
0.995
0.005
1
1
1
1
d
d
n
s
n
s
n
n
σ
χ
χ
−
−
≤
≤
−
−
 
 
These tables provide thresholds that when crossed suggest an action might be warranted. The 
simple observation of an 
ds  of the difference between baseline and Month 6 measures that ap-
pears “too large” or “too small” would not result in an automatic change in CONCERT-HF’s sam-
ple size. The following should also be considered upon NHLBI DSMB review of the data for rec-
ommendation and action to be taken: 
 
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• Was training in obtaining MR images sufficiently in place at each of the recruiting cen-
ters? 
• Has there been recent staff turnover at least one center? 
• Has there been a change in equipment for at least one center?  
• Is there new literature on the topic of variability of MR measured LVEF or infarct size vari-
ability? 
• Have other clinical trials reported relevant values of 
ds  for MR measured LVEF or infarct 
size? 
• Are the recommendations for adapting the sample size based on change in LVEF and 
change in infarct size coherent? 
 
These sources of information can provide a broader perspective on the interim findings of CON-
CERT-HF and will be considered before the sample size is changed.  In addition, a decision at 
34% IT may be preliminary to a confirmatory final decision at 66% IT.  
 
8.4.2.5.1 c-kit+ cell growth failure 
The CCTRN will be informed by the CCMF about c-kit+ cell manufacturing performance using 
aggregate data that do not unblind the Steering Committee to any subject’s treatment assign-
ment. If the number of subjects with final c-kit+ cell counts less than 800,000 c-kit+ cells is pro-
hibitively large, CCTRN will consult with NHLBI on the feasibility of adding additional subjects to 
the study (i.e., randomized to either the Combo arm or the c-kit+ cells only arm) to ensure mini-
mum power (80%) in assessing the prospectively specified hypotheses for the effects of cell 
therapy on study endpoints. 
 
8.4.2.6 Subgroup Evaluations 
The effect of subgroup stratum on the relationship between cell delivery and the endpoints will 
be assessed. If a treatment effect is demonstrated, it is not likely to behave identically among all 
important subgroups. The subgroups of interest are the following: age; gender; race; diabetes; 
hypertension; extent of left ventricular disease (single vessel vs diffuse chronic disease); pres-
ence of a cardiac device; and characteristics of the bone marrow and c-kit+ cell and MSC prod-
ucts, including function of progenitor cells (hematopoietic and mesenchymal), expression of sur-
face markers, RNA and protein expression, growth kinetics and metabolic patterns, and the 
number of cells delivered. These additional analyses can sometimes be helpful in identifying ex-
treme differences in the effects of treatment among subgroups, although the literature wisely 
warrants that caution be used in interpreting subgroup analyses.  
 
8.4.2.7 Sub-study Evaluation 
Centers qualified to assess change in global diffuse fibrosis (via T1 mapping) through the MRI 
Core Lab will collect the requisite sequences for this sub-study evaluation. The analysis plan is 
as stated in 8.4.2.3 above. 
 
8.4.2.8 As-Treated Evaluation 
In addition to the intention-to-treat analysis, an as-treated analysis will be conducted. In this 
evaluation, subjects will be placed in treatment groups based on what they received, not in the 
group to which they were randomized. The primary endpoint analysis will then be repeated with 
these reassignments. 
 
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8.4.2.9 Dose-Response Evaluation 
Anticipating that there will be variability in c-kit+ cell dose, an analysis of the relationship be-
tween the effect of therapy and c-kit+ cell dose received will be conducted for all efficacy end-
points.  
 
8.4.2.10 Multiplicity Issues 
In this phase II study, no adjustments are made for multiple comparisons. The reported 
measures of effect will be effect size, the standard error of the effect size, the 95% confidence 
interval for the effect size, and the p-value. P-values will be interpreted at nominal 0.05 levels in 
accordance with Hare et al.99.  
 
8.4.3 Interim Analysis 
Interim analyses are a well accepted procedure required by many DSMB’s107. One formal in-
terim efficacy analyses will be conducted after the first 50% (72/144) of subjects have reached 
or exceed their six month evalution. Consideration of the current drop out rate suggests that this 
will produce 58 evaluable subjects (i.e., individuals with six month MR results). The interim anal-
yses will give the DSMB an opportunity to conduct unblinded reviews of interim results and to 
use the information as the basis for recommendations to NHLBI regarding the study. 
 
For efficacy/harm significance tests, Lan-DeMets alpha-spending function based on O’Brien-
Fleming108 boundaries will be used to control overall Type I error rate at α = 0.05109.   The ad-
vantage of the Lan-DeMets approach is that it can be used even when the looks are not equally 
spaced. In this case the boundaries would change somewhat. For looks at exactly 50% and 
100% of the completed intention-to-treat evaluable subjects, the cumulative α will equal 0.003 
and 0.05, respectively. 
 
Another extremely useful monitoring tool is conditional power110,111. The conditional probability 
of obtaining a statistically significant result at the end of the trial is computed under different hy-
pothesized treatment effects. Unlike the O'Brien-Fleming or Lan-DeMets boundaries, conditional 
power is usually used to justify terminating a trial which has no realistic chance of producing a 
statistically significant result. If one uses such a rule, the chance of a type 2 error (accepting the 
null hypothesis when it is false) is slightly greater than it would be without stochastic curtailment. 
This is because one could accept the null hypothesis at the end of the study or at an interim 
point. 
 
8.4.3.1 Plan for CONCERT Interim Monitoring 
In Section 3.7 of the CONCERT-HF protocol, there are 6 proposed hypotheses involving 8 dif-
ferent outcomes reflecting the change in (LVEF, infarct size, LVESV, LVEDV, VO2max, six mi-
nute walk distance, MLHFQ score, sphericity index) . For a given hypothesized change, with as-
sumed standard deviation of change, the study has 80-90% power, for the evaluable subject 
sample size of 116, for any given hypothesis. There were no adjustments of multiple testing.  
 
Guidelines proposed to the DSMB:  
• Futility: It would seem reasonable to examine futility for the 3 major comparisons of 
Combo vs. placebo, MSCs vs. placebo, and c-kit+ cells vs. placebo for each of the 8 out-
comes. If all are futile, i.e., for each comparison using the hypothesized change for 90% 
power for each outcome yields a probability of < 0.05 that the test statistic would fall into 
the critical region, then the trial would seem futile.  
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• Efficacy-based termination:  To declare efficacy, it would seem that the Combo vs. pla-
cebo would have to yield a significant result (p<0.003) for at least the first 4 declared out-
comes (placebo-adjusted changes in LVEF, LVESV, LVEDV, and infarct size).  
• Harm-based termination:  Similar to efficacy-based termination. It would seem that the 
Combo vs. placebo would have to yield a significant result (p<0.003) for harm for at least 
the first 4 declared outcomes (placebo-adjusted changes in LVEF, LVESV, LVEDV, and 
infarct size). 
 
If the criteria for each of 1) futility-termination, 2) efficacy-termination, and 3) harm-termination 
are not met, then the trial would be permitted to continue.  
 
The proposed stopping guidelines are: 
  
1) Use Lan-DeMets version of O'Brien-Fleming for harm/benefit.  
2) The boundaries will be symmetric.  
3) Information time will be calculated as proportion of expected evaluable subjects.   
4) Examine the data at 50% information time. 
5) Use conditional power under the protocol-specified alternative hypotheses for futility. 
 
9.0 TRIAL MANAGEMENT 
 
9.1 Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent document and any subsequent modifications will be re-
viewed and approved by the IRB or ethics committee responsible for oversight of the study.  A 
signed consent form will be obtained from the subject.  The consent form will describe the pur-
pose of the study, the procedures to be followed, and the risks and benefits of participation.  A 
copy of the consent form will be given to the subject and this fact will be documented in the sub-
ject’s record. 
 
9.1.1 Informed Consent Process 
Potential participants will be approached by one of the study investigators or research coordina-
tors.  Information regarding study participation will be provided to the potential participant.  The 
informed consent includes descriptions of all study related procedures, all possible risks to par-
ticipant, and the time commitment involved with participating.  All consent forms will have IRB 
approval.  Individuals who agree to participate will receive a copy of the signed informed con-
sent.  The research staff member obtaining consent will document the informed process in the 
subject’s chart for monitoring purposes.   Translation of ICFs will be done in accordance with lo-
cal IRB procedures. 
 
9.1.2 Risks Associated with the Procurement, Processing, Injection, and Assessment of 
the Study Product 
 
9.1.2.1 Harvest Procedures 
 
Anticoagulation Medications  
For subjects taking anticoagulation medications (i.e. blood thinners) at the time of the harvest 
procedures (bone marrow aspiration and right heart catheterization), some of these medications 
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(i.e., warfarin and/or Factor Xa inhibitors) may be stopped for a short period before the proce-
dures; during which time the subject may be at an increased risk of a stroke.  It is very important 
that subjects be instructed to inform the research team immediately of any symptoms indicative 
of this (e.g. headache, dizziness, light-headedness, blurred vision, slurred speech, facial droop-
ing, decrease sensations anywhere on the body, or weakness or a decrease in strength of the 
arms or legs). Subjects will be closely monitored during any interruption in anticoagulation ther-
apy for the events listed above.   
 
Bone Marrow Aspiration 
Possible risks of bone marrow aspiration include bruising, bleeding, infection, hematoma at site 
of biopsy, brief discomfort in the hip area and faintness from the procedure.  There is a possibil-
ity the subject could experience worsening of heart failure symptoms.  There is a possibility of a 
fat embolism leading to shortness of breath, confusion, drowsiness, rash, fever, or seizure.   
 
Right Heart Catheterization with/without Endomyocardial Biopsy 
During the right heart catheterization the subject will receive some radiation (see the Radiation 
Risks Section below).  Possible discomforts include stinging from the numbing medicine (topical 
cream), bruising, and discomfort from lying flat on the exam table for 20-30 minutes.  Possible 
risks include decreases in blood pressure and ICD firing due to abnormal heart rhythms that last 
only a few seconds and go away.  Less likely risks include bleeding, infection, serious and long-
lasting heart rhythm problems, injury to the pulmonary artery, blood clots in the lungs, damage 
to the walls of the heart, and puncture of the heart wall with a risk of death.  One patient in this 
study has died from a puncture of the heart wall following biopsy. 
 
9.1.2.2 Cell Processing Procedure 
Processing the cells is done under strict sterile conditions; however, there is a rare chance that 
the cells could become contaminated while being processed.  Testing will be done on the cells, 
and if the tests reveal contamination, the subject will be notified and instructed on whether or not 
he/she should be treated with antibiotics.  The subject will keep a daily temperature log to help 
determine the development of an infection before the test results are known. If the subject notes 
a fever, he/she will be requested to notify the investigator/study team.  
 
9.1.2.3 Cardiac Catheterization and NOGA mapping  
Potential risks of this procedure include bleeding, hematoma at catheter insertion site, allergic 
reaction to the angiography dye, abdominal pain, formation of a blood clot which could lead to 
loss of function or surgical intervention. It is possible the subject may experience worsening 
heart failure symptoms. Other problems that could happen are: local nerve damage, infection, 
arrhythmias, stroke, and heart attack. Some temporary problems that might happen are: tempo-
rary movements (spasm) of a muscle, vein, or artery; separation of the layers of the walls of a 
blood vessel; or sudden blockage of a blood vessel. A very rare complication could result in 
death or a need for cardiac procedures such as percutaneous coronary intervention (with or 
without stent placement) or an urgent coronary artery bypass graft (open heart surgery).  Seri-
ous complications, including death, happen in less than 1 in every 1,000 tests that are per-
formed. 
 
The risks of the use of the iodine that is in the contrast media for the heart angiography proce-
dure are rare.  Some problems that might occur are hypersensitivity or even severe allergic re-
actions, or decreased kidney function, particularly in those patients with underlying kidney prob-
lems. 
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The possible risks of NOGA mapping include, but are not limited to, damage to blood vessels, 
bleeding, infection, inflammation of the sac surrounding the heart, damage to kidneys, a small 
risk of heart attack, stroke, damage to the heart valves, perforation (a small hole) in the heart 
causing blood to accumulate around the heart, irregular heartbeats (including ventricular tachy-
cardia and ventricular fibrillation), possible ICD firing, decreased blood pressure, dislodgement 
of material into other arteries leading to possible blockage, radiation exposure and a very small 
risk of death. 
 
9.1.2.4 Study Product Injection 
Some problems that might happen include (but others could occur): decreased blood pressure, 
irregular heartbeats, chest pain or discomfort, possible firing of ICD, damage to the heart mus-
cle, perforation of the heart causing blood to accumulate around the heart, bleeding, heart at-
tack, stroke, dislodgement of material into other arteries (possibly causing blockage), need for 
emergency surgery, and death.  It is possible that a small amount of cells will enter the blood-
stream of the heart rather than the heart muscle.  If the injection catheter penetrates through the 
heart (from inside to outside) and cells appear in the fluid filled area surrounding the heart which 
cushions the heart as it moves (pericardial space) there is a possibility of potentially harmful ef-
fects which could cause an inflammatory response.  Injection directly into the heart muscle also 
may cause inflammation or irritability.   
 
There may be some circumstances where the research team is unable to give the subject the 
study product (cells or placebo); such as change in the coronary anatomy, equipment failure, or 
poor quality of the stem cells. The option of cell donation will be discussed with the subject by 
the research team.  
 
9.1.2.5 cMRI Procedure 
Risks associated with administration of contrast dye are nausea, vomiting, and headache.  Aller-
gic reactions to contrast dye are rare, but there are extremely rare instances of reactions caus-
ing death.  The contrast dye used in the cMRI procedure is referred to as a gadolinium based 
contrast agent (GBCAs); after administration, GBCAs leave the body mostly through the kid-
neys.   Recent publications report some deposits from GBCAs remain in the brains of some pa-
tients who undergo four or more contrast MRI scans, long after the last dose is received.    Re-
cent studies conducted in humans and animals have confirmed that these deposits can remain 
in the brain, even in people with normal kidney function. It is unknown whether these deposits 
are harmful or can lead to adverse health effects. Available information does not identify any ad-
verse health effects.  However, this issue continues to be studied by the FDA and subjects will 
be informed should any new specific adverse health concerns emerge.  
 
Less common risks of contrast dye are kidney damage or nephrogenic systemic fibrosis (NSF), 
allergic reactions (rare), and death (extremely rare). The risk of kidney damage or NSF is in-
creased with patients who already had some evidence of kidney disease or diabetes, or are de-
hydrated.  
 
There is no radiation exposure from cMRIs. There is a risk of heat injury from radiofrequency 
coils and the cables to the coil and monitoring equipment. There may be some discomfort with 
placement of an IV line, administration of medications or blood draw, and lying down in the MRI 
machine. 
 
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MRIs on subjects with pacemakers and ICDs 
The powerful magnetic fields and radio waves that are part of MRI scans could cause the ICD 
wires to overheat, potentially damaging heart tissue. MRIs can induce unwanted currents that 
could cause arrhythmias, or in the case of ICDs, cause an unnecessary shock. Pacemakers and 
ICDs can be temporarily reprogrammed so they do not react to an MRI’s magnetic field and will 
be monitored during the MRI scan.  During the scan there is an increased risk of experiencing 
an arrhythmia, which could be life threatening or fatal.  A cardiologist or specifically trained Reg-
istered Nurse with pacemaker/ICD expertise will check the device before, during, and after the 
scan, and trained life support staff and a defibrillator will be present and available during the pro-
cedure. 
 
9.1.2.6 Radiation Risks 
This research study involves exposure to radiation from cardiac catheterization laboratory x-ray 
procedures.  The expected total amount of radiation exposure to the subjects in this study is ap-
proximately 2.4 rem. 
 
9.1.3 Adequacy of Protection Against Risks 
The precautionary measures mentioned in the above sections will minimize the risk associated 
with bone marrow aspiration, right heart catheterization with/without endomyocardial biopsy, 
study product injection, and cMRI procedures for subjects. The procedures for bone marrow as-
piration, right heart catheterization, endomyocardial biopsy, and study product delivery using 
NOGA mapping and injection are well known, and in the hands of skilled interventionalists with 
proper training, events remain low. A favorable risk profile for the use of autologous cell therapy 
continues to emerge as new clinical trials demonstrate safety of these procedures. The use of 
established protocols in the MR imaging of subjects with devices, along with standardized train-
ing of technicians by experienced core lab personnel, will minimize the risk of the cMRI proce-
dure in those with devices. Subjects will be monitored throughout imaging and safety precau-
tions are included as described previously. 
 
9.1.4 Potential Benefits of the Proposed Research to the Subjects and Others 
Subjects with ICM are at risk for significant morbidity and mortality. This study has the potential 
to improve cardiac function by preserving or recovering functional myocardial tissue. This pro-
ject will also provide mechanistic insight into cell therapy which will be useful for finding new 
treatments for other diseases. 
 
9.1.5 Risk Benefit Analysis 
The administration of MSCs and c-kit+ cells, alone or in combination, offers an additional thera-
peutic option to subjects with ICM whose goal is to not just reduce the rate of LV deterioration 
but to actually stabilize and ameliorate HF. Having highly trained experts deliver and oversee 
the therapy, in conjunction with close study monitoring substantially reduces the likelihood of ad-
verse events.  The potential risks to the subjects remain reasonably low in relation to the possi-
ble benefit of improving their heart function above which can be obtained with standard of care 
treatment regimens. 
 
9.1.6 Importance of the Knowledge to be Gained 
The knowledge to be gained from this clinical trial is significant in that this will 1) demonstrate if 
promising cell types can be manufactured and delivered alone or in combination to subjects with 
ICM; 2) demonstrate whether promising cell types that heretofore have demonstrated the likeli-
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hood of few risks to the subject are well-tolerated, both individually and in combination, by sub-
jects with ICM; and 3) determine if the target doses of 150 million MSCs, 5 million c-kit+ cells, or 
the combination of these delivered transendocardially produces improvement in measures of 
myocardial function and/or quality of life. The trial has been designed to address critical limita-
tions in the previous published trials by including subjects with moderate to severe LV dysfunc-
tion, a group of subjects who are most likely to benefit from this form of therapy. The risks to the 
subjects are reasonable in relation to the knowledge gained from this study since this therapy 
may potentially reduce the incidence of ICM which is a leading cause of morbidity and mortality 
throughout the world. 
 
9.1.7 Data and Safety Monitoring Board (DSMB) 
The Data and Safety Monitoring Plan has been outlined in Section 7 above. 
 
9.2 Clinical Monitoring 
The DCC will be responsible for monitoring each site throughout the course of the study by fol-
lowing the FDA Guidelines for monitoring of a clinical trial (revised 1998). Source document re-
view will be performed against entries on the CRF and a quality assurance check will be per-
formed to ensure that the Investigator is complying with protocol and regulations.  At the time of 
the completion of the study, a close out monitoring visit will take place to ensure all trial materi-
als and subject data are properly documented. 
 
9.2.1 Pre-Investigation Visits 
The DCC team assures that the Investigator clearly understands and accepts the obligations in-
curred in undertaking a clinical investigation. 
 
Prior to the initiation of a clinical investigation, the DCC team will train the site of the clinical in-
vestigation to assure that the Investigator: 
1. Understands the investigational status of the test article and the requirements for this ac-
countability.  
2. Understands the nature of the protocol or investigational plan.  
3. Understands the requirements for an adequate and well-controlled study.  
4. Understands and accepts his or her obligations to obtain informed consent in accordance 
with 21 CFR Part 50. The monitor should review a specimen of each consent document 
to be used by the Investigator to assure that reasonably foreseeable risks are adequately 
explained.  
5. Understands and accepts his or her obligation to obtain IRB review and approval of a 
clinical investigation before the investigation may be initiated and to ensure continuing 
review of the study by the IRB in accordance with 21 CFR Part 56, and to keep the spon-
sor informed of such IRB approval and subsequent IRB actions concerning the study.  
6. Has access to an adequate number of suitable subjects to conduct the investigation.  
7. Have adequate facilities for product preparation and conducting the clinical investigation.  
8. Has sufficient time from other obligations to carry out the responsibilities to which the In-
vestigator is committed by applicable regulations.  
9. Understands periodic monitoring visits will occur. 
 
9.2.2 Interim site visits 
The monitor will visit the Investigator at the site of the investigation frequently enough to assure 
that: 
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1. The facilities used by the Investigator continue to be acceptable for purposes of the 
study. 
2. The study protocol or investigational plan is being followed.  
3. Changes to the protocol have been approved by the IRB and/or reported to the sponsor 
and the IRB.  
4. Accurate, complete, and current and current records are being maintained. 
5. Accurate, complete, and timely reports are being made to the sponsor and IRB. 
6. The Investigator is carrying out the agreed-upon activities and has not delegated them to 
other previously unspecified staff.  
7. Review of subject records will take place. 
 
9.2.3 Monitor Role 
The monitor will compare a representative number of subject records and other supporting doc-
uments with the Investigator’s reports to determine that: 
1. The information recorded in the Investigator’s report is complete, accurate, and legible.  
2. There are no omissions in the reports of specific data elements such as the administra-
tion to any subject of concomitant test articles or the development of an intercurrent ill-
ness. 
3. Missing visits or examinations are noted in the reports.  
4. Subjects failing to complete the study and the reason for each failure are noted in the re-
ports.  
5. Informed consent has been documented in accordance with 21 CFR Parts 50 and 56. 
 
9.2.4 Monitor Recording 
The monitor will maintain a record of the findings, conclusions, and action taken to correct defi-
ciencies for each on-site visit to an Investigator. Such a record may enable the FDA to deter-
mine that a sponsor’s obligations in monitoring the progress of a clinical investigation are being 
fulfilled. The record may include such elements as: 
1. The date of the visit;  
2. The name of the individual who conducted the visit; 
3. The name and address of the Investigator visited;  
4. A statement of the findings, conclusions and any actions taken to correct any deficiencies 
noted during the visit. 
 
9.3 Investigator Responsibilities 
 
9.3.1 Investigator Performance 
Prior to enrolling the first subject, each Investigator must read and understand the protocol.  Ad-
ditional requirement that must be met are: 
1. Signed Protocol Signature Page 
2. Current medical license 
3. Financial disclosure 
4. CV, signed and dated, for all primary Investigators and sub-Investigators 
5. Local stem cell processing lab certified 
6. Completed site training 
7. Follow all Good Clinical Practice requirements for clinical research 
 
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9.3.2 Site Requirements: 
Prior to enrollment of the first subject, the Investigator and institution will be asked to provide the 
following documents: 
1. Executed study contract between NHLBI and the clinical center 
2. IRB approved informed consent form 
3. IRB approved final protocol 
4. Current laboratory certification for all associated laboratories  
5. Current laboratory normal ranges 
 
9.3.3 Institutional Review Board Approval 
Prior to enrolling the first subject, the Investigator must obtain written approval from the IRB. 
The approval must contain the date the study was approved, the version of the informed con-
sent that was approved and the signature of the IRB chairperson.  The primary investigator and 
their staff will follow all Good Clinical Practice (GCP) requirements. 
 
9.3.4 Informed Consent 
The DCC must review and approve all informed consent forms prior to submitting to the IRB. All 
study subjects must provide written informed consent using an IRB- approved informed consent 
document. 
 
9.3.5 Reporting Requirement of the Sites 
See Investigator reporting responsibilities in Section 7 above. 
 
9.4 Sponsor Responsibilities 
 
9.4.1 Introduction 
The DCC will act as the study Sponsor, and thus have overall responsibility for the conduct of 
the study, including assurance that the study follows all standards and regulatory requirement of 
the U.S. Food and Drug Administration.  The DCC will adhere to Sponsor general duties as out-
lined by 21 CFR Subpart D; Part 312.50-312.70. 
 
9.4.2 Routine Duties 
The DCC will be responsible for obtaining and reviewing copies of IRB approvals. They are re-
sponsible for setting up all training for each site and reviewing all certification of their local labor-
atories for handling of study products. The DCC will ensure that the study is conducted accord-
ing to Good Clinical Practice (GCP), the Declaration of Helsinki, the Study Protocol, and any 
other applicable regulatory agency requirement. The DCC will also ensure proper clinical site 
monitoring. 
 
9.4.3 Site Training 
The DCC will be responsible for the setting up all training required in the protocol. 
 
9.4.4 Reporting to the FDA 
The DCC will hold the study IND and submit proper filings to obtain and maintain the IND. The 
DCC will submit all appropriate reports and fillings to the FDA as required by regulations. This 
includes unanticipated adverse events, withdrawal of IRB approval, and withdrawal of FDA ap-
proval, annual progress reports to the FDA and all final reports. The DCC will maintain all rec-
ords according to Good Clinical Practice Guidelines (GCP). 
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All Clinical Centers (CCs) and Core Laboratories (Cores) will comply with 21 CFR, part 312.62 
with regard to record retention. 
 
9.5 Database 
The DCC will maintain the CCTRN study database in a web-accessible electronic format.  De-
tailed documentation of study variables will be prepared and available to study Investigators, 
and where necessary, to external scientists.  Appropriate confidentiality and security of these 
files will be maintained at all times. 
 
9.5.1 Framework 
The DCC will develop and maintain a web-based online application for data entry using the 
state-of-the-art, Microsoft .NET framework.  A secure environment, requiring user login and au-
thentication, will be maintained for the entry of and/or access to subject data.  The data col-
lected from CCs and Cores will be stored on a secure database in the DCC computer facility.  
Training will be provided and DCC staff will be available to answer questions and resolve is-
sues.  Extensive data verification and validation will be implemented on the web application to 
check for data accuracy, completeness, and consistency within subjects. 
 
9.5.2 Information Security 
Several levels of security will be implemented to protect the confidentiality of the data.  All au-
thorized users will be provided a unique name/password and will be given access as identified 
by the Principal Investigator.  The server on which the data is stored will be behind a firewall and 
will be in the most secure zone (100) with no direct access to the internet.  In addition, data will 
be protected through the use of Secure Socket Layers, (SSL), the current standard for encrypt-
ing data between a client and a server as it is passed across the Internet.  In addition to these 
layers of security, every connection to a secured site will be recorded with data indicating which 
person connected, the time of the connection, and the area accessed.  The user’s password will 
be stored in binary, hashed format within the database for additional security.  Access to secure 
areas of the website will be logged with the users ID and the date and time of access.  This au-
dit table will be maintained throughout the life of the studies.  The servers that host the Network 
database are enrolled in the automated virus and operating system patch management system 
to protect against any virus attacks.  The database will be backed up nightly, and backup will be 
stored at an off-site University on-line storage facility that is secure and has restricted access. 
 
9.5.3 Follow-up 
The DCC will provide online web-based forms for follow-up data collection.  All the standards 
and security guidelines that were set for baseline forms will be implemented for these forms as 
well.  Data will be stored on a secure database and access will be limited and secure.  Training 
and documentation will be provided by DCC staff to all the CCs on the data entry process.  DCC 
staff will also be available to answer questions and help resolve issues as necessary.  Reports 
for follow-up data will also be made available. 
 
9.5.4 Laboratory Data Processing Support 
The DCC will develop and maintain online web forms for the CCs and Cores for data collection, 
both for baseline and annual follow-up.  The data will be validated with extensive edit rules and 
the CCs/Cores will be able to correct errors real time.  Access will be limited and will require se-
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cure login authentication.  The DCC will provide training and documentation to laboratory per-
sonnel on the data entry process and will be available to answer question and resolve issues as 
necessary.  The data collected will be stored on a secure database in the DCC and will be 
backed up every night.  Reports will be generated as necessary with real-time data. 
 
9.5.4.1 File transfers 
Provisions will be made for those sites that prefer to transfer files in a batch mode.  Files with 
data from the laboratory will be transferred to a secure server residing in the computer facility of 
the DCC.  Users transferring this data will be provided with user identification numbers and 
passwords for restricted and secure access.  Data transmitted will then be processed and 
checked for validity and completeness.  Only data that passes these edits will be stored in the 
database.  The rejected records will be sent back to the centers/lab for correction and re-trans-
mittal. 
 
9.5.5 Data Quality 
The case report forms used for data entry are created by the DCC project and programming 
staff in conjunction with the research personnel at each clinical site.  Once developed, individual 
forms are unit tested by the programming team and released to a test server.  The forms are 
then tested by both DCC and clinical site personnel for accuracy and utility.  Continuity and ac-
ceptance testing will be done by the clinical site research and laboratory personnel.  An iterative 
process of suggestions/corrections/retesting will occur until the application is accepted.  Person-
nel accessing the application for data submission will receive training on the web based system 
prior to the randomization of subjects. There will be defined a minimum data set that constitutes 
completeness. All data will have to pass through range and logical checks in addition to intra- 
and inter-form checks for consistency.  The sequence of events will be enforced by allowing 
subordinate forms to become accessible only after its primary form has been submitted.  If a re-
sponse to a question on a form requires ancillary forms to be completed, the user will receive 
reminder messages within the application to complete the proper form.  Weekly reports and au-
tomatic email notifications on the CC’s data entry and completeness will be generated.  If a CC 
has problems, action will be taken ranging from retraining through phone calls to a site visit, if 
necessary. 
 
9.5.6 Computing Infrastructure 
The University of Texas School of Public Health network consists of a fiber optic backbone us-
ing gigabit technology to provide the fastest and most state-of-the-art network communications 
possible.  A backbone of Cisco switches provides for client access to backend resources and 
servers at 100 megabits per second.  Aside from providing simple network access, Information 
Technology staff has real-time monitoring capabilities to diagnose and correct potential network 
problems.  The campus has also implemented a four-tier network firewall to protect all work-
stations and servers with varying degrees of security, based on the device’s security level within 
the organization. 
 
9.5.7 Backup Procedure 
The study data will be backed up on a nightly basis and the backup will be stored offsite at a 
University on-line storage facility that is secure and has restricted access. 
 
9.6 Dissemination 
Dissemination is the process by which the results of research efforts and their implications are 
promulgated to the target communities. The dissemination process begins early in the study. 
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Study Investigators will present regularly the design, progress, and results of the investigations 
at annual meetings at symposia and annual meetings such as the American Heart Association 
and the American College of Cardiology. 
 
9.6.1 www.ClinicalTrials.gov  
The DCC has a standard operating procedure (SOP) for the registration, posting, and uploading 
of trial information and results to www.ClinicalTrials.gov. Per 42 CFR part 11, the DCC serves 
as the responsible party for these responsibilities on behalf of the CONCERT-HF study. The trial 
is currently registered (NCT02501811). The informed consent document  includes corresponding 
language with respect to inclusion of trial data in the registry.  
 
9.6.2 NHLBI’s Data Repository (BIOLINCC)  
The DCC will also be the responsible party for preparing the CONCERT-HF dataset in accord-
ance with NHLBI data repository requirements for uploading to BIOLINCC. This will include a 
limited data set to be used for other research purposes. Following submission of trial results to 
www.ClinicalTrials.gov, the DCC generates a “package” of trial data (per BIOLINCC protocol) 
and supporting materials for upload to the Data Repository.   
 
9.6.3 Website 
A website has been created with objectives targeted to the study audience.  The CCTRN web-
site serves as one method of distribution of information about stem cell research in cardiovascu-
lar disease in general and about the specific study protocols.  For the general lay public, the 
goal is to promote a hospitable context for the research by informing the public about the kinds 
of research being done, including the source of the stem cells; what this research is and what it 
isn’t; plans for studies; study findings; and the potential for new treatments.  Physicians need in-
formation about the research that is closely tied to clinical trial opportunities and treatments for 
subjects.  This information should be tied to the normal places practitioners seek such re-
sources.  For the researcher, the website provides more in-depth technical information and pub-
lished works.  For the CCTRN investigators, the website provides a central location for meeting 
information, clinical trial information, and other resources. 
 
9.6.4 Manuscripts and Presentations 
A primary task of the DCC will be to provide data analyses for all manuscript proposals and 
presentations approved by the SC.  The CCTRN Investigators will take the lead in presenting 
study data at major scientific meetings and in the writing, preparation, and submission of manu-
scripts to appropriate peer-reviewed journals.  In addition, the Network Investigators will actively 
enlist the participation of junior Investigators in manuscript writing and presentations at scientific 
meetings.  The DCC will also make data sets available to the Clinical Centers (CCs), Cell Pro-
cessing and other Cores, will provide consultation and assistance to the CCs regarding the ap-
propriate data analysis methods, and will perform independent data analysis in order to verify 
the Investigators’ findings. 
 
The DCC plays an active role in preparing study publications in collaboration with other study 
Investigators and the NHLBI Project Office.  The DCC collaborates with CCTRN investigators to 
prepare all manuscripts for submission to the journals and will serve as the liaison between the 
lead author, and the journal.  A Publications and Ancillary Studies Committee organizes and 
monitors writing committees and provides oversight on what presentations and publication have 
priority within the study.  The DCC maintains and distributes progress reports on the status of all 
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active papers, as well as a study bibliography including abstracts, presentations, letters, editori-
als, etc. 
 
9.6.5 Methodologic Developments 
In addition to providing statistical support to PIs at CCs and NHLBI, Investigators at the DCC 
take leading roles in developing possible new statistical methods that may have the potential to 
improve statistical analysis for projects in CCTRN and beyond.  These new discoveries are pre-
sented to scientific meetings and in statistical journals as peer-reviewed articles. 
 
 
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tolic wall thickening using multidetector computed tomography. Eur J Radiol. 2009;72(1):92-97. 
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Appendix A: Bone Marrow Aspiration Standard Operating Procedure 
The following Standard Operating Procedure (SOP) is for carrying out bone marrow aspirations 
for subjects recruited in the Cardiovascular Cell Therapy Research Network (CCTRN) protocols.  
 
CCTRN subjects will undergo bone marrow aspiration to harvest cells for the protocol.   
 
Purpose: 
Bone marrow aspiration is a scheduled procedure performed by a trained Physician (e.g., hematol-
ogist, pathologist, or hematopathologist). Only physicians with substantial experience in carrying 
out bone marrow harvesting procedures (more than forty previous successful procedures) will per-
form the procedure.  Other medical personnel trained in bone marrow aspiration procedures (e.g. 
physician assistants, registered nurses, nurse practitioners, and medical technologists) will assist 
in the collection to ensure proper sample collection, preparation and processing of the specimen. 
The bone marrow aspiration is indicated for research regarding cell therapy for cardiovascular 
conditions.   
 
Scope: 
This SOP refers to bone marrow collections at the seven cell therapy centers and their associ-
ated satellite facilities involved in the CCTRN.  The seven centers are as follows: 
1. Texas Heart Institute Stem Cell Center 
2. Minneapolis Heart Institute Foundation 
3. University of Florida Department of Medicine 
4. Stanford University School of Medicine 
5. University of Miami Miller School of Medicine 
6. Indiana University School of Medicine 
7. University of Louisville School of Medicine 
  
PROCEDURE 
 
Supplies and transportation: 
1. Bone marrow aspiration supplies will comply with the site-specific institutional procedures 
and practices. 
2. All equipment, supplies, and reagents used in the process of bone marrow collection 
must be sterile with a lot number and date of expiration noted and able to be recorded on 
site-specific institutional data forms. 
3. The CCMF will be notified at the following time points:  1) when a subject is enrolled and 
the bone marrow aspiration/heart biopsy has been scheduled, 2) when the bone marrow as-
piration/heart biopsy procedure has begun, 3) and when the bone marrow aspiration/heart 
biopsy samples have been shipped.   
4. Bone marrow aspiration and heart biopsy specimen transportation to the cell processing la-
boratory will be treated as a STAT procedure. 
 
Subject preparation and specimen collection performed by Physician: 
1. Refer to Section 6.2.2 regarding anticoagulation management prior to the procedure. 
2. Verify subject identification with the subject. 
3. Explain the risks and benefits of bone marrow aspiration and anesthesia.  Give subjects an 
opportunity to ask questions and verbalize understanding.  Document the informed consent 
process by having the subject sign informed consent forms for bone marrow aspiration and 
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anesthesia. 
4. Sedative and analgesic medication for the bone marrow aspiration procedure, including 
conscious sedation will be left to the discretion of the performing or supervising physician 
per institutional guidelines for procedures of this volume with the exception of general 
anesthesia which will not be paid for by the study. 
5. Subjects on aspirin and/or Plavix (clopidogrel) at the time of consent should remain on 
aspirin and/or Plavix (clopidogrel) for the bone marrow aspiration procedure.   
6. All collection procedures must be performed with universal precautions and sterile 
aseptic technique. 
 
Bone marrow aspiration procedures: 
1. The media containers and/or heparin vials must be opened with sterile technique and 
medium prepared with the appropriate amount of anticoagulant.  The final concentration 
of heparin will be 100 units of heparin/mL of bone marrow.   
2. Position the subject in a prone or partial prone position. Evaluate pressure points with 
special attention to avoid pressure on arms, brachial plexus, breasts, genitalia, knees, 
vascular structures or other body parts. 
3. Verify location of posterior iliac crest. 
4. Prep and drape the location in sterile manner using institutionally approved preoperative 
skin antiseptic (e.g., chlorhexidine gluconate (ChloraPrep ®), betadine, isopropyl alcohol, 
alcohol 60) and sterile draping. Allow for the antiseptic to dry before applying local anes-
thesia. 
5. Begin induction sedation and analgesic medications (e.g. Propofol, Versed, Ativan, or 
morphine). 
6. After evidence of induction effect, apply local anesthesia (e.g., lidocaine 1% or bupiva-
caine) to the skin above the posterior iliac crest.  
7. With a longer needle (e.g., spinal needle) apply local anesthesia (e.g., lidocaine 1% or 
bupivacaine) to the periosteum of the posterior iliac crest region 
8. Holding the bone marrow aspiration needle and stylet in place, puncture skin and ad-
vance through subcutaneous tissue, periosteum and into the marrow cavity using a 
steady, controlled pressure with a twisting motion. When the needle is firmly in the bone 
and slight give in pressure is felt, the cavity has been entered. 
9. Remove the stylet and quickly attach the prepared syringe to the needle hub. 
10. Apply a strong, quick suction and obtain 5-10 mL of bone marrow. 
11. Rotate the aspiration needle by 60 to 90 degrees, and aspirate 5-10 mL of bone marrow. 
12. Repeat the rotation a total of two to six times per puncture, totaling 20 – 30 mL of bone 
marrow aspirate per puncture. 
13. Re-insert the stylet and remove the needle from the bone with a light twisting motion.  
14. While keeping the aspiration needle in the subcutaneous tissue, reposition the aspiration 
needle in an adjacent site of the posterior iliac crest. 
15. The target aspiration volume is approximately 90 mL (± 10 mL). Therefore a total of 10-
20 aspirations (5-10 mL) will be made. Since 2-6 aspirations are made in each puncture, 
then a total of 2-5 punctures will be required. Typically this is performed with only 1 to 2 
skin punctures. 
16. Physicians will perform the aspiration on one side. The only time aspiration will take place 
in the contralateral site is if the initial site produces a dry tap. 
17. In the event that no marrow is aspirable, then pressure will be applied to the injection site 
until hemostasis is achieved.  
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18. A sterile dressing will be applied to all puncture sites. A sterile pressure dressing (e.g., Elas-
toplast) will be applied if persistent venous oozing is present. 
19. Rotate the subject into a supine position and maintain that position for a minimum of 30 
minutes. 
20. The dressing over the puncture site should be checked after the 30 minutes of supine posi-
tioning to ensure no hemorrhage. The dressing may be removed 24 hours after the proce-
dure and the subject should observe for signs of infection, bleeding or any other drainage. 
The subject should notify the study coordinator if evidence for these signs. It is usual for the 
subject to observe bruising and feel aching for several days after the procedure. This may 
be relieved with a warm pack. The subject should notify the study coordinator if the pain 
persists beyond several days or worsening pain. 
21. Documentation of the procedure should be made by the Physician. 
22. All bone marrow collections will be sent to the site’s cell processing laboratory using site-
specific institutional transportation procedures.  Bone marrow aspiration transportation to 
the cell processing laboratory will be treated as a STAT procedure and arrive at the cell 
processing lab as soon as possible following the bone marrow aspiration procedure. 
 
Reporting requirements: 
1. Label the CCTRN Study Product Injection form and all specimens with the subject acrostic, 
study ID, date and time of collection, and label the form with the amount aspirated. 
2. Site-specific chain of custody forms must be used to document the chain of custody of the 
bone marrow aspirate from the site of the procedure to the local CPL to the CCMF and 
back. 
 
 
 
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Appendix B: Standard Operating Procedure for Right Heart Catheteri-
zation with and without Endomyocardial Biopsy (RHC/EMB)  
 
The following Standard Operating Procedure (SOP) is for carrying out right heart catheterization 
(RHC) with and without endomyocardial biopsies (EMB) for subjects recruited in CONCERT-HF. 
 
Purpose: 
RHC with right ventricle EMB (for subjects randomized to Combo or c-kit+ cell only arms) or 
RHC without EMB (for subjects randomized to placebo or MSC only arms) are scheduled proce-
dures performed by a trained Physician (e.g. cardiologist, heart failure specialist, or intervention-
alist).  Only physicians with specific training and substantial experience in carrying out RHCs 
with right ventricular EMBs (more than 100 successful procedures) will perform the procedure.  
Other medical personnel trained in EMB procedures (e.g. cath lab technologists, registered 
nurses, and medical technologists) will assist in the collection to ensure proper sample collec-
tion, preparation and processing of the specimen. The RHC with right ventricle EMB is indicated 
for research regarding cell therapy for cardiovascular conditions.  RHC with EMB is also an indi-
cated medical procedure for patients with heart failure and heart transplants.  The RHC without 
EMB is a sham procedure (see Manual of Operations for details of sham procedure including 
example of sham EMB script) for subjects randomized to placebo or MSC only arms. 
  
Scope: 
This SOP refers to RHCs with and without right ventricle EMB collections at the seven CCTRN 
cell therapy centers and their associated satellite facilities.  The seven centers are as follows: 
 
1. Texas Heart Institute Stem Cell Center 
2. Minneapolis Heart Institute Foundation 
3. University of Florida Department of Medicine 
4. Stanford University School of Medicine 
5. University of Miami Miller School of Medicine 
6. Indiana University School of Medicine 
7. University of Louisville School of Medicine 
 
PROCEDURE 
 
Preparation of all subjects prior to RHC/EMB procedure: 
1. Refer to Section 6.2.2 regarding anticoagulation management prior to the procedure.  
Subjects’ INR must be <1.6 on the day of procedure to proceed with the procedure.  
2. All subjects will have two 2-D echocardiograms: 1) a pre-RHC/EMB procedure echo 
to assess for pre-existing pericardial effusion, and 2) a post-RHC/EMB procedure echo 
within 6 hours to ensure no post-procedure effusion (even if subject is stable) (see sec-
tion 6.3.9).  
3. Verify subject identification with the subject. 
4. Explain the risks and benefits of RHC and right ventricle EMB.  Give subjects an oppor-
tunity to ask questions and verbalize understanding.  Document the informed consent 
process by having the subject sign informed consent forms for RHC and right ventricle 
EMB. 
5. Subjects on aspirin and/or Plavix (clopidogrel) at the time of consent should remain on 
aspirin and/or Plavix (clopidogrel) for the RHC and right ventricle EMB procedure. 
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6. Pressures collected during the procedure should be measured at end-expiration at 
end diastole. 
7. The CCMF will be notified when 1) a subject is randomized and 2) the RHC/EMB has 
been scheduled (automated emails sent from database upon form entry). 
 
 
For subjects having RHC with EMB (randomized to Combo or c-kit+ cells only arms): 
Additional guidances for physician consideration:  
1. Review of previous available imaging (e.g. screening MRI) pre-procedure to assess the 
cardiac anatomy prior to initiating the EMB procedure. 
2. Use of biplane imaging or echocardiography to assist with identifying location of bioptome 
on the septum. 
3. Have additional operators present for the procedure to provide ongoing independent as-
sessment. 
4. Patients with left bundle branch block and neither a pacer nor an ICD may have a tempo-
rary pacer at the discretion of the attending physician.   
 
 
Supplies and transportation for EMB tissue: 
1. Right ventricle EMB supplies will comply with the site-specific institutional procedures and 
practices, but will adhere to certain common principles across the sites.  
2. All equipment, supplies, and reagents used in the process of EMB must be sterile with a 
lot number and date of expiration noted and able to be recorded on site-specific institu-
tional data forms. 
 
 
 
3. The CCMF will be notified by the local team when 1) the heart biopsy procedure has be-
gun and  2) when the heart biopsy samples have been shipped. 
4. Heart biopsy specimen transportation to the cell processing laboratory will be treated as a 
STAT procedure. 
 
Specimen collection: 
1. All collection procedures must be performed with universal precautions and sterile asep-
tic technique. 
2. Prep and drape the sample collection table.   
3. Place the EMB media container on the sample collection table. 
4. Prep and drape right neck of patient for jugular access or right upper thigh for femoral ac-
cess.   
5. Position monitors either front facing at foot of table or side facing depending on access 
route. 
6. Single-use bioptomes are to be used; reusable bioptomes are not permitted.   
 
Supplies: 
o Biopsy Forceps (Argon Jawz™, Cordis, or St. Judes)-physician’s discretion. 
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o Size:  5-7F Maxi-Curve (dependent upon access route utilized-see below) 
o Swan Ganz thermodilution catheter-physician’s discretion per institutional guidelines 
o Micropuncture kit 
 
 
For subjects having RHC without EMB (randomized to placebo or MSCs only arms): 
Script:  
1. Cath lab personnel should follow a script (see Manual of Operations for example) that 
mimics what a subject would hear and feel if they were experiencing an EMB procedure. 
 
ACCESS ROUTES: 
 
Jugular: 
The 50 cm disposable Radiopaque Endomyocardial Biopsy Forceps are designed for 
Right ventricular biopsies using the Jugular Approach. 
 
Femoral: 
The 105 cm disposable radiopaque endomyocardial biopsy forceps are designed for Right or 
Left Ventricular biopsies using the femoral approach. 
 
CIRCUMSTANCES THAT WOULD HALT OR TERMINATE THE RHC/EMB PROCEDURE: 
 
If any of the following occur before or during RHC/EMB, they could indicate a serious clinical de-
terioration.   
• If any of these conditions/events occur, the procedure should be temporarily halted and 
the subject should be reevaluated for suitability to continue with the procedure: 
o the baseline pulmonary artery (PA) systolic pressure taken immediately prior to bi-
opsy procedure is 50-59 mmHg; 
o the baseline right ventricle (RV) systolic pressure taken immediately prior to biopsy 
procedure is 50-59 mmHg; 
o the baseline wedge pressure taken immediately prior to biopsy procedure is 30-34 
mmHg; (note: if wedge pressure is >30 mmHg, collect an O2 sat measure); 
o the systolic blood pressure (SBP) taken the day of harvest is <80 mmHg and con-
stitutes a significant change from baseline, e.g., SBP change from ≥ 100 mmHg 
(at baseline) to <80 mmHg (at harvest);  
o the heart rate (HR) taken the day of harvest is >100 and constitutes a significant 
change from baseline, e.g., HR change from ≤ 80 (at baseline) to >100 (at har-
vest).  
 
• If any of these conditions/events occur, the procedure should be terminated (subject can 
be evaluated for rescheduling if condition/event resolves)*: 
o change in NYHA Class to Class IV; 
o the baseline PA systolic pressure is ≥ 60 mmHg; 
o the baseline RV systolic pressure is ≥ 60 mmHg; 
o the baseline wedge pressure is ≥ 35 mmHg. 
 
*If a second procedure is undertaken and the conditions again meet the termination threshold, 
provided the subject is stable, a sham procedure will be performed to maintain subject and staff 
blinding. 
 
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METHOD:  
 
RHC: Upon arrival at the catheterization laboratory, the subject will be placed on the catheteri-
zation table in supine orientation and draped in the usual fashion. Percutaneous intravenous ac-
cess, utilizing the internal jugular or femoral vein, will then be established using sterile tech-
nique. After insertion of an appropriately sized intravenous sheath, baseline intracardiac hemo-
dynamic measures, including: right atrial, right ventricular, pulmonary artery, and pulmonary ca-
pillary wedge pressures will be recorded.   Both phasic and mean pressures will be obtained.  
The type of catheter used to monitor heart function and blood flow (e.g., Swan-Ganz catheter) 
will be left to the discretion of the performing physician per institutional guidelines. The RHC 
without EMB is a sham procedure (see Manual of Operations for details of sham procedure in-
cluding example of sham EMB script) for subjects randomized to placebo or MSC only arms.  
EMB: Following removal of the pressure transducer, a bioptome will be inserted and positioned 
adjacent to the distal interventricular septum.  The catheter will be positioned with the jaws of 
the bioptome closed.  Positioning of the bioptome will be confirmed visually by fluoroscopy (this 
can be supplemented with ultrasound 2-D echo), along with evidence of ventricular ectopy. After 
confirmation of correct positioning of bioptome, up to 6 EMB samples (a.k.a. “bites”) of heart tis-
sue will be harvested. Confirm the position of the long sheath introducer or guiding cathe-
ter in the ventricle prior to each and after each specimen collection.   
 
The jaws of the Biopsy Forcep should be opened only after the forcep has emerged from the 
distal end of the long sheath introducer or guiding catheter, and correct placement against the 
interventricular septum has been determined.  Following correct positioning the bioptome is 
withdrawn approximately 1 cm away from the septum, the jaw opened under fluoroscopic visual-
ization and gently advanced against the septum. 
 
The open jaws of the biopsy forcep should be positioned at the heart wall, closed firmly and suf-
ficient pressure should be maintained on the handle to assure retention of the specimen during 
withdrawal through the sheath introducer or guiding catheter. 
 
This procedure is repeated up to 6 times until adequate tissue is obtained for the cell expansion 
procedure.  The bioptome is rinsed in heparinized saline prior to each advancement into the 
sheath for a repeat biopsy. 
 
Following tissue acquisition, the aforementioned intracardiac hemodynamic measures will be 
repeated to ensure the absence of immediate complications related to the EMB procedure. If no 
complications occur as a result of the procedure, the sheath will be removed and the percutane-
ous access site will be bandaged using standard of care measures. 
 
At the conclusion of the procedure the sheath is withdrawn, gentle pressure is applied to 
achieve hemostasis. 
 
 
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Appendix C: NYHA Classification 
 
New York Heart Association (NYHA) Classification 
 
 
Class  
 
 
Participant Symptoms 
 
Class I (None) 
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath). 
 
Class II (Mild)  
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea. 
 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. Symp-
toms of cardiac insufficiency at rest. If any physical activity is under-
taken, discomfort is increased. 
 
 
 
 
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Appendix D: CCS Classification  
 
Canadian Cardiovascular Society (CCS) Functional Classification of Angina Pectoris 
 
 
Class Definition 
Specific Activity Scale 
 
I 
Ordinary physical activity, (e.g., walking and climbing stairs) does not cause 
angina; angina occurs with strenuous, rapid, or prolonged exertion at work or 
recreation. Ability to ski, play basketball, light jog (5 mph), or shovel snow 
without angina 
 
II 
Slight limitation of ordinary activity; angina occurs on walking or climbing 
stairs rapidly; walking uphill; walking or stair climbing after meals, in cold, in 
wind, or under emotional stress; or only during the few hours after awakening; 
when walking > 2 blocks on level ground; or when climbing more than 1 flight 
of stairs at a normal pace and in normal conditions. Ability to garden, rake, 
roller skate, walk at 4 mph on level ground, and have sexual intercourse with-
out stopping 
 
III 
Marked limitation of ordinary physical activity; angina occurs on walking 1 to 
2 blocks on level ground or climbing 1 flight of stairs at a normal pace in 
normal conditions. Ability to shower or dress without stopping, walk 2.5 mph, 
bowl, make a bed, and play golf 
 
IV 
Inability to perform any physical activity without discomfort; anginal symp-
toms may be present at rest. Inability to perform activities requiring 2 or fewer 
metabolic equivalents (METs) without discomfort 
 
 
 
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Appendix E: Stage 1- (Open label lead-in) Enrollment and Activities 
 
I. Recruitment and Screening 
Recruitment and screening of subjects in Stage1 will follow the same chart review and imaging 
evaluation as outlined in Section 4.1.  
 
II. Consenting 
A separate consent form will be utilized for Stage 1.  Please note there is no optional bioreposi-
tory for the the Stage 1 subjects. The Stage 1 consent form will describe the timeline and activi-
ties for the SOC control group versus the Combo therapy group.   
 
 
III. Activities and Follow Up 
 
a.  Baseline Testing  
The baseline testing period will not exceed 60 days (from the date the ICF is signed until ran-
domization). See below for activities during baseline. 
 
b.  Randomization and Treatment 
Prior to randomization, eligibility criteria will be reviewed. If a change in the subject’s status has 
occurred such that the subject no longer meets all of the eligibility criteria, randomization will be 
postponed, or if the condition is not resolvable, the individual will be excluded from participation.  
Following successful completion of baseline testing, clinical sites will enter results of the testing 
in the web-based program (Section 8.1.1).  Subjects will be randomized either to 1) SOC (no 
study procedures) or 2) Combo (MSCs plus c-kit+ cells).  Combo subjects will undergo harvest 
procedures per Sections 5.1 and 5.2 (Note: As there is no biorepository for stage 1 subjects, all 
90ml of bone marrow will be forwarded to CCMF for cell manufacturing).  Cell manufacturing will 
follow and is outlined in relevant subsections of 5.8.  Study product injection in subjects receiv-
ing Combo product is outlined in Sections 5.13 and 5.14. 
 
c.  Visits Schedule and Evaluations 
Subjects in the SOC group will attend 5-7 total visits (Baseline, Day 0, Week 1, Month 1, and 
Month 3.  Subjects in the Combo group will attend 10-11 total visits (Baseline, harvest, MRI visit, 
Day 0, Day 1, Week 1, Month 1, Month 3, Month 6, and Month 12).  For both groups, baseline 
testing (and 3 month visit) can be split over multiple days as needed.   
 
Please refer to the corresponding protocol sections for details related to the evaluations de-
scribed in Table 21a below: 
• 
Comprehensive medical and surgical history, vital signs and physical examinations (Section 
6.3.1) 
• 
Current use of prescription and OTC medications (Section 6.3.1) 
• 
Blood tests (Table 22a below)  
• 
Infectious disease panel (Table 22a below)  
• 
Pregnancy test (for women of childbearing potential) (Table 22a below) 
• 
cMRI imaging (Section 6.3.3, MRI Core Lab Manual of Operations) and ICD interrogation (Sec-
tion 6.3.8) (if applicable) 
• 
Six-minute walk test (Section 6.3.4, Protocol Manual of Operations) 
• 
Minnesota Living with Heart Failure Questionnaire  
• 
12 lead ECG (Section 6.3.6) 
• 
Treadmill-based VO2 max (Section 6.3.7, CPET Core Manual of Operations) 
IRB NUMBER: HSC-SPH-15-0413
IRB APPROVAL DATE: 12/04/2019

CONFIDENTIAL AND PROPRIETARY  
 
 
 
 
 
 
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CONCERT-HF: Version 1.9 
Effective Date: November 19, 2019 
 
Stage 1: Open label lead-in (Table 21a) 
 
*     Visit is scheduled approximately 10 weeks after completion of baseline testing, randomization, (and completion 
of harvest procedures in the Combo group). 
1.    Subjects will have assessments of vitals (BP, temperature, pulse rate) immediately pre- and post-procedure. 
2.    For the Combo group-ECGs will be performed within 6 hours following the SPI catheterization procedure and 
again before discharge; a 2-D echocardiogram will be performed post SPI procedure (within 6 hours). 
3.    Subjects will be monitored on simple telemetry up to 24 hours post-procedure or until discharge, whichever is 
sooner. 
4.    See Table 22a for specific tests done at each time point.  
5.    A cardiac MRI will be performed within 30 days prior to SPI (baseline measure). 
6.    ICD interrogation: (if applicable) done before and after every MRI as part of MRI protocol, as well as before the 
SPI procedure (in combo group).  Reports will be generated for the interrogations conducted before the MRIs at 
baseline (image collected within 30 days of SPI) and at the 3 month visit.  Local electrophysiology personnel 
will review the device report for the presence of reportable clinical events.  Copies of the reports should remain 
on site as source documentation (de-identified copies may be requested by the Sponsor for endpoint adjudica-
tion).  
7.   Temperature log 2x/day x 7 days. 
 
 
 
Baseline
D0*
W1 M1 M3 Baseline Harvest
MRI 
Visit5
D0 
(SPI)* D1 W1 M1 M3 M6 M12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X2
X2
X
X
X
X
X2
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
X
Bone Marrow Aspiraton
X
Heart Biopsy
X
Catheterization/NOGA
X
Temp Log
X7
Combo Group
ICD Interrogation6
Treadmill (VO2 max)
6 Minute Walk
12-lead ECG
2D Echoes
Telemetry
Laboratory Testing4 
Cardiac MRI
MLHFQ
SOC Group
Physical Exam
Vital Signs
Adverse Events
Con Medications
NYHA and CCS
Stage 1 (open label)
Procedure
Informed Consent
Complete Medical History
IRB NUMBER: HSC-SPH-15-0413
IRB APPROVAL DATE: 12/04/2019

CONFIDENTIAL AND PROPRIETARY  
 
 
 
 
 
 
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CONCERT-HF: Version 1.9 
Effective Date: November 19, 2019 
Stage 1 Laboratory Testing (Table 22a) 
 
 
 
1. Chemistry Tests - sodium, potassium, chloride, bicarbonate (CO2), glucose, blood urea nitrogen (BUN), creati-
nine, and eGFR. 
2. Complete Blood Count with Differential - CBC: WBC, RBC, hemoglobin, hematocrit, MCV, and platelets; Diff: 
neutrophils, lymphocytes, monocytes, eosinophils, and basophils. 
3. Liver Function Tests - albumin, alkaline phosphatase, alanine transaminase (ALT), aspartate transaminase 
(AST), total bilirubin, direct bilirubin, and total protein. 
4. Will be completed within 36 hours prior to injection. 
5. NT-proBNP required; send to outside lab if applicable. 
6. Will be performed once in the morning (both groups) and once 8 (+/- 2) hours post cardiac catheteriza-
tion/NOGA (Combo only).  
7. Later time points if indicated. 
8. Infectious disease tests should be the bone marrow donor panel used per local institutional guidelines, includ-
ing HIV, Hep B (HBsAG, Anti-HBs, Anti-HBc), and Hep C (Anti-HCV), and results must be known prior to har-
vest. Donor tests are conducted within 30 days of harvest procedures. If for some reason these tests expire 
prior to either harvest, they will be performed again. 
9. Day 1 labs will be collected 24 hours post-procedure or immediately prior to discharge, whichever is sooner. 
These labs are only collected on the Combo group. 
10. Month 6 and 12 labs are only collected on the Combo group. 
11. For either group (Combo or SOC), CBC drawn on day of MRI with hematocrit recorded on the MRI worksheet. 
12. For subjects receiving systemic anticoagulation therapy, an INR measurement will be performed on the morning 
of the planned procedure; must be <1.6 to proceed with procedure. 
 
IV. Event Monitoring and Reporting 
Sites will use the same process for subjects in Stage 1 as outlined in Section 7. 
 
V. DSMB Data Review 
Following successful three month data evaluation by the DSMB, those subjects randomized to 
Combo therapy will continue to be followed per protocol for 12 months.  Those randomized to 
the SOC control group will have the option to be evaluated for enrollment in the trial conducted 
in Stage 2.  Interested subjects will be consented under the trial consent form outlining all study 
related procedures, all possible risks, the time commitment, and the potential for randomization 
to a placebo group. 
CONCERT-HF Laboratory Testing
BSL
Harvest
MRI   
visit
Day 0   
(SPI)
Day 19
Wk 1
M 1
M 3
M 610
M 1210
Chemistry Tests1 
X
X
X
X
X
X
X
X
CBC with Differential2 
X
X11
X
X
X
X
Liver Function Tests3
X
X
X
X
Pregnancy (childbearing women)
X
X4       
X
X
X
X
NT-proBNP5
X
X
X
X
Troponin I or T
X
X6       
X      
X
HbA1c
X
X
X
X
PT, INR, PTT7
X
X12
X12
Infectious Disease Tests8
X
IRB NUMBER: HSC-SPH-15-0413
IRB APPROVAL DATE: 12/04/2019