A Phase I, First-in-Human, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Study of the Safety and Efficacy of Allogeneic Mesenchymal Stem Cells in Cancer Survivors With Anthracycline-Induced Cardiomyopathy
Phase: PHASE1
Conditions: Cardiomyopathy Due to Anthracyclines
Sponsor: The University of Texas Health Science Center, Houston

Official Study Title: A Phase I, First-in-Human, Multicenter, Randomized, Double-Blinded, Placebo- 
Controlled Study of the Safety and Efficacy of Allogeneic Mesenchymal Stem Cells in Cancer Survivors 
with Anthracycline-Induced Cardiomyopathy 
Short Title: Stem Cell Injection in Cancer Survivors (SENECA) 
NCT: NCT02509156 
Date of Final Study Protocol: IRB approval date 10/19/2018 
 

CONFIDENTIAL AND PROPRIETARY
 
 
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SENECA: Version 1.7 
Effective Date: October 16, 2018 
 
 
 
 
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 I, First-in-Human, Multicenter, Randomized, Double-Blinded, Placebo-
Controlled Study of the Safety and Efficacy of Allogeneic Mesenchymal Stem Cells in 
Cancer Survivors with Anthracycline-Induced Cardiomyopathy 
 
Short Title: StEm cell iNjEction in CAncer survivors (SENECA) 
 
 
 
IND Number: 16414 
 
 
 
 
 
IRB NUMBER: HSC-SPH-15-0443
IRB APPROVAL DATE: 10/19/2018

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SPONSOR INFORMATION PAGE 
 
Data Coordinating Center Contact Information: 
 
Medical and Safety 
 
Lem Moyé, 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 #E1009 
 
 
 
1200 Pressler Street #W220 
Houston, TX 77030  
 
 
 
 
Houston, TX 77030 
832-721-6736 
 
 
 
 
 
713-500-9507 
Lemmoye@msn.com 
 
 
 
 
Linda.B.Piller@uth.tmc.edu 
 
Lara Simpson, PhD 
 
 
 
 
 
Co-Investigator- Safety 
 
 
 
Data Coordinating Center  
 
 
 
 
University of Texas-Health  
 
 
 
 
1200 Pressler Street #W938 
 
 
 
Houston, TX 77030  
 
 
 
 
 
713-500-9503 
 
 
 
 
 
Lara.M.Simpson@uth.tmc.edu 
 
 
 
Project Management Team 
 
Judy Bettencourt, MPH  
 
 
 
Rachel Vojvodic, MPH 
Data Coordinating Center  
 
 
 
Data Coordinating Center 
University of Texas-Health  
 
 
 
University of Texas-Health 
1200 Pressler Street #E1005 
 
 
 
1200 Pressler Street #E1007 
Houston, TX 77030  
 
 
 
 
Houston, TX 77030 
713-500-9527 
 
 
 
 
 
713-500-9528 
Judith.L.Bettencourt@uth.tmc.edu 
 
 
Rachel.W.Vojvodic@uth.tmc.edu 
 
Shelly Sayre, MPH  
 
 
 
 
Michelle Cohen, MPH 
Data Coordinating Center  
 
 
 
Data Coordinating Center 
University of Texas-Health  
 
 
 
University of Texas-Health 
1200 Pressler Street #E1013 
 
 
 
1200 Pressler Street #E1003Q 
Houston, TX 77030  
 
 
 
 
Houston, TX 77030 
713-500-9529 
 
 
 
 
 
713-500-9513 
Shelly.L.Sayre@uth.tmc.edu 
 
 
 
Michelle.L.Cohen@uth.tmc.edu 
 
 
 
 
IRB NUMBER: HSC-SPH-15-0443
IRB APPROVAL DATE: 10/19/2018

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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 
Joshua Hare, MD 
 
 
University of Miami  
Timothy Henry, MD  
 
Minneapolis Heart Institute 
Carrie Lenneman, MD 
 
University of Louisville 
Keith March, MD, PhD 
 
Indiana University 
Kathy D. Miller, MD  
 
Indiana University 
Lemuel Moyé, MD, PhD  
 
The University of Texas-Houston School of Public Health  
Carl Pepine, MD 
 
 
University of Florida 
Emerson Perin, MD, PhD  
Texas Heart Institute 
Jay Traverse, MD 
 
 
Minneapolis Heart Institute 
Robert Simari, MD  
 
Kansas University Medical Center 
Rachel Vojvodic, MPH 
 
The University of Texas-Houston School of Public Health 
Phillip Yang, MD 
 
 
Stanford University 
 
 
 
 
 
 
Supported by: 
 
 
The National Heart, Lung, and Blood Institute (NHLBI) 
 
Ray Ebert, PhD 
Jerome Fleg, MD 
David Gordon, MD, PhD 
 
Grant number 5UM1HL087318 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-SPH-15-0443
IRB APPROVAL DATE: 10/19/2018

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SENECA Signature Page 
 
 
I have read this protocol and any updates provided within and I agree to conduct the study as 
described 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 
identifying appropriate trained individuals to carry out the responsibilities of the protocol and will 
notify 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-15-0443
IRB APPROVAL DATE: 10/19/2018

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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 I, First-in Human, Multicenter, Randomized, Double-Blinded, Placebo-
Controlled Study of the Safety and Efficacy of Allogeneic Mesenchymal Stem Cells in Cancer Survivors 
with Anthracycline-Induced Cardiomyopathy”. Additionally, any information revealed during meetings in 
any form or manner will not be provided by me to any third party for any purpose 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 
public 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 
obligation 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."  
(check only one) 
 
  I have read the above referenced policy and have reviewed the proposed research.  I hereby certify 
that, based on the information provided to me, I do not have a conflict of interest with the 
proposed 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-15-0443
IRB APPROVAL DATE: 10/19/2018

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List of Abbreviations and Definitions of Terms 
 
6MWT 
 
 
 
Six Minute Walk Test 
ACE  
 
 
 
Angiotensin-Converting Enzyme inhibitor  
AE 
 
 
 
 
Adverse Event 
AIC 
 
 
 
 
Anthracycline-Induced Cardiomyopathy 
allo-MSC 
 
 
 
allogeneic human Mesenchymal Stem Cells  
ARB  
 
 
 
Angiotensin Receptor Blocker 
BMC  
 
 
 
Bone Marrow Cell 
CAD  
 
 
 
Coronary Artery Disease 
CBC  
 
 
 
Complete Blood Count 
CFR  
 
 
 
Code of Federal Regulations  
CHF  
 
 
 
Congestive Heart Failure 
CMP  
 
 
 
Comprehensive Metabolic Panel  
DCM  
 
 
 
Dilated Cardiomyopathy 
DSMB  
 
 
 
Data and Safety Monitoring Board 
EF 
 
 
 
 
Ejection Fraction 
EPC  
 
 
 
Endothelial Progenitor Cells 
ESR  
 
 
 
Expedited Safety Report 
GCP  
 
 
 
Good Clinical Practice 
GFR  
 
 
 
Glomerular Filtration Rate 
GVHD  
 
 
 
Graft Versus Host Disease 
HIPAA 
 
 
 
Health Insurance Portability and Accountability Act 
HIV 
 
 
 
 
Human Immunodeficiency Virus 
HLA  
 
 
 
Human Leukocyte Antigen 
HSC  
 
 
 
Hematopoietic Stem Cells 
HTLV  
 
 
 
Human T-cell Lymphotropic Virus  
ICAM  
 
 
 
Intracellular Adhesion Molecule 
ICD 
 
 
 
 
Implantable Cardioverter Defibrillator 
ICF 
 
 
 
 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical 
Requirements of Pharmaceuticals for Human Use 
IND 
 
 
 
 
Investigational New Drug 
INR 
 
 
 
 
International Normalized Ratio 
IRB 
 
 
 
 
Institutional Review Board 
LAD  
 
 
 
Left Anterior Descending 
LFT 
 
 
 
 
Liver Function Test 
LV 
 
 
 
 
Left Ventricle, Left Ventricular 
LVEDV 
 
 
 
Left Ventricular End Diastolic Volume 
IRB NUMBER: HSC-SPH-15-0443
IRB APPROVAL DATE: 10/19/2018

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LVEF  
 
 
 
Left Ventricular Ejection Fraction 
LVESV 
 
 
 
Left Ventricular End Systolic Volume 
MACE  
 
 
 
Major Adverse Cardiac Events 
MHC  
 
 
 
Major Histocompatibility Complex  
MI 
 
 
 
 
Myocardial Infarction 
MLHFQ 
 
 
 
Minnesota Living with Heart Failure Questionnaire 
MRI 
 
 
 
 
Magnetic Resonance Imaging 
 
MSC  
 
 
 
Mesenchymal Stem Cell 
NAT  
 
 
 
Nucleic-Acid-based Test  
NMDP 
 
 
 
National Marrow Donor Program 
NT-proBNP  
 
 
N-Terminal pro-Brain Natriuretic Peptide 
NYHA  
 
 
 
New York Heart Association 
PCI 
 
 
 
 
Percutaneous Coronary Intervention 
PTT 
 
 
 
 
Partial ThromboplastinTime 
SAE  
 
 
 
Serious Adverse Event 
SCA-1  
 
 
 
Stem Cell Factor Antigen 
SCF  
 
 
 
Stem Cell Factor 
SDF-1  
 
 
 
Stromal-Cell-Derived Factor 1  
 
 
 
SENECA 
 
 
 
StEm cell iNjEction in CAncer survivors 
SPI 
 
 
 
 
Study Product Injection 
URL  
 
 
 
Upper Reference Limit 
VEGF  
 
 
 
Vascular Endothelium Growth Factor 
VEGFR2 
 
 
 
Vascular Endothelial Growth Factor Receptor-2  
WBC  
 
 
 
White Blood Cell 
WNV  
 
 
 
West Nile Virus 
 
IRB NUMBER: HSC-SPH-15-0443
IRB APPROVAL DATE: 10/19/2018

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Table of Contents 
SPONSOR INFORMATION PAGE ..............................................................................................................................2 
CCTRN AUTHORSHIP TEAM .....................................................................................................................................3 
SENECA SIGNATURE PAGE .....................................................................................................................................4 
CONFIDENTIALITY AND NON-DISCLOSURE OF MATERIALS AND PROCEEDINGS AGREEMENT ..................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .....................................................................................6 
TABLE OF CONTENTS ...............................................................................................................................................8 
1.0 STUDY OBJECTIVES .........................................................................................................................................14 
1.1 Primary Objective ......................................................................................................14 
1.2 Secondary Objective .................................................................................................14 
1.3 Hypotheses ................................................................................................................14 
1.4 Relevance to the CCTRN ..........................................................................................14 
2.0 BACKGROUND ...................................................................................................................................................14 
2.1 Population ..................................................................................................................14 
2.2 Study Rationale .........................................................................................................16 
2.3 Background of Regenerative Therapy in Cancer ......................................................17 
2.4 Therapy Rationale .....................................................................................................19 
2.4.1 Mesenchymal Stem Cells (MSCs) .......................................................................19 
2.4.2 Immunological Properties of MSC and Human Leukocyte Antigen (HLA)-Matching 
20 
2.4.3 Potential Mechanisms for MSC Mediated Improvements in Cardiac Function ....20 
2.5 Background Preclinical ..............................................................................................21 
2.6 Background Clinical ...................................................................................................22 
2.6.1 Previous Clinical Trials of Allogeneic Mesenchymal Stem Cells (allo-MSCs) .....22 
2.6.2 Ongoing/Future Clinical Trials of Allogeneic Mesenchymal Stem Cells ..............23 
2.6.3 Previous Clinical Experience with Intramyocardial Delivery of Stem Cells ..........23 
2.7 Dose and Delivery Rationale .....................................................................................25 
2.7.1 Dose Rationale ....................................................................................................25 
2.7.2 Delivery Rationale ................................................................................................25 
3.0 STUDY DESIGN ..................................................................................................................................................26 
3.1 Research Questions ..................................................................................................26 
3.2 Study Design .............................................................................................................26 
3.3 Study Treatment Assignments and Dosages ............................................................27 
3.4 Study Endpoints ........................................................................................................27 
3.4.1 Safety Assessment ..............................................................................................27 
3.4.2 Feasibility Measures ............................................................................................27 
3.4.3 Prospectively Declared Efficacy Endpoint Measures: .........................................28 
3.4.4 Sub-study Analysis: .............................................................................................28 
3.5 Sample Size ..............................................................................................................28 
4.0 IDENTIFICATION AND ENROLLMENT OF SUBJECTS ....................................................................................29 
4.1 Recruitment and Screening (prior to consent) ...........................................................29 
4.2 Consent .....................................................................................................................29 
4.3 Inclusion Criteria ........................................................................................................30 
4.4 Exclusion Criteria .......................................................................................................30 
4.5 Baseline Testing Window ..........................................................................................32 
4.6 Randomization Procedures and Timing ....................................................................32 
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5.0 STUDY PRODUCTS AND DELIVERY ................................................................................................................33 
5.1 Allogeneic Mesenchymal Stem Cells (allo-MSCs) ....................................................33 
5.1.1 Shipment of Cryopreserved allo-MSC Allografts .................................................33 
5.1.2 Preparation for Administration of-MSC Allografts ................................................34 
5.2 Placebo Group ...........................................................................................................34 
5.3 Blinding of the Interventionalist and Study Team ......................................................35 
5.4 NOGA Catheterization Procedure .............................................................................35 
5.5 Circumstances That May Affect Study Product Delivery ...........................................36 
6.0 CLINICAL AND LABORATORY PROCEDURES ...............................................................................................37 
6.1 Schedule of Procedures (Table 3) .............................................................................37 
6.2 Baseline Testing ........................................................................................................38 
6.3 Schedule of Laboratory Examinations (Table 4) .......................................................39 
6.4 Day of Study Production Injection (SPI) – Day 0 .......................................................39 
6.5 Follow-up Tests Performed After SPI ........................................................................40 
6.5.1 Day 1 (within the first 24 hours after SPI) ............................................................40 
6.5.2 Week 1 (± 3 days after SPI) .................................................................................40 
6.5.3 Month 1 (± 7 days after SPI) ................................................................................40 
6.5.4 Month 6 (± 30 days after SPI) ..............................................................................40 
6.5.5 Month 12 (± 30 days after SPI) ............................................................................41 
6.5.6 Month 24 Telephone Contact ..............................................................................41 
6.5.7 Follow-up Windows ..............................................................................................41 
6.5.8 Lost to Follow-up .................................................................................................41 
6.6 Collection of Endpoints ..............................................................................................41 
6.6.1 Six-minute Walk Test (6MWT) .............................................................................41 
6.6.2 Minnesota Living with Heart Failure Questionnaire (MLHFQ) .............................42 
6.6.3 Cardiac Magnetic Resonance Imaging (cMRI) Evaluation ..................................42 
6.7 Collection of Biospecimens .......................................................................................44 
6.7.1 Peripheral Blood ..................................................................................................44 
6.7.2 Allo-MSC Allografts ..............................................................................................44 
6.7.3 Explanted Hearts .................................................................................................44 
7.0 
EVENT MONITORING AND REPORTING ..........................................................................................45 
7.1 Definitions Related to Adverse Events ......................................................................45 
7.1.1 Adverse Events (AEs) ..........................................................................................45 
7.1.2 Suspected Adverse Reaction (SARs) ..................................................................45 
7.1.3 Serious Adverse Events (SAEs) or Serious Suspected Adverse Reaction (SSAR) 45 
7.2 Role of Abnormal Test Findings and Hospitalizations in Classifying an Event ..........45 
7.2.1 Abnormal Test Findings .......................................................................................45 
7.2.2 Hospitalizations ....................................................................................................45 
7.3 Reporting Responsibilities of the Investigator ...........................................................46 
7.3.1 Severity Assessment ...........................................................................................46 
7.3.2 Causality Assessment .........................................................................................47 
7.3.3 Expectedness Assessment ..................................................................................47 
7.4 Reporting Responsibilities of the Sponsor (DCC) .....................................................48 
7.4.1 Safety Monitoring Program and Reporting ..........................................................48 
7.4.2 Sponsor Reporting Requirements to the EC, NHLBI and DSMB ........................48 
7.4.3 Sponsor Reporting Requirements to FDA ...........................................................49 
7.5 Unanticipated Problems (UPs) ..................................................................................49 
7.6 NHLBI DSMB Criteria ................................................................................................49 
7.7 Review of Open Label Lead-in (six subjects) ............................................................49 
IRB NUMBER: HSC-SPH-15-0443
IRB APPROVAL DATE: 10/19/2018

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8.0 
STATISTICAL PROCEDURES ............................................................................................................50 
8.1 Randomization Strategy and Monitoring ...................................................................50 
8.2 Delays and Early Withdrawal from the Study ............................................................50 
8.3 Statistical Analyses ....................................................................................................50 
8.3.1 Baseline Analyses ...............................................................................................51 
8.3.2 Outcome Analyses ...............................................................................................51 
8.4 Subgroup Evaluations ...............................................................................................52 
8.5 Sub-study Evaluation .................................................................................................52 
8.6 Multiplicity Issues .......................................................................................................53 
9.0 
TRIAL MANAGEMENT ........................................................................................................................53 
9.1 Institutional Review Board (IRB) Review and Informed Consent ..............................53 
9.1.1 Informed Consent Process ..................................................................................53 
9.1.2 Risks Associated with Study Product Injection ....................................................53 
9.1.3 Adequacy of Protection Against Risks .................................................................55 
9.1.4 Potential Benefits of the Proposed Research to the Subjects and Others ..........55 
9.1.5 Risk Benefit Analysis ...........................................................................................55 
9.1.6 Importance of the Knowledge to be Gained ........................................................56 
9.2 Clinical Monitoring .....................................................................................................56 
9.2.1 Pre-Investigation Visits ........................................................................................56 
9.2.2 Interim Site Visits .................................................................................................56 
9.2.3 Monitor Role ........................................................................................................57 
9.2.4 Monitor Recording ...............................................................................................57 
9.3 Investigator Responsibilities ......................................................................................57 
9.3.1 Investigator Performance .....................................................................................57 
9.3.2 Site Requirements: ..............................................................................................57 
9.3.3 Institutional Review Board Approval ....................................................................58 
9.3.4 Informed Consent ................................................................................................58 
9.3.5 Reporting Requirement of the Sites .....................................................................58 
9.4 Sponsor Responsibilities ...........................................................................................58 
9.4.1 Introduction ..........................................................................................................58 
9.4.2 Routine Duties .....................................................................................................58 
9.4.3 Site Training .........................................................................................................58 
9.4.4 Reporting to the FDA ...........................................................................................58 
9.5 Database ...................................................................................................................58 
9.5.1 Framework ...........................................................................................................59 
9.5.2 Information Security .............................................................................................59 
9.5.3 Follow-up .............................................................................................................59 
9.5.4 Laboratory Data Processing Support ...................................................................59 
9.5.5 Data Quality .........................................................................................................60 
9.5.6 Computing Infrastructure .....................................................................................60 
9.5.7 Backup Procedure ...............................................................................................60 
9.6 Dissemination ............................................................................................................60 
9.6.1 Web Site ..............................................................................................................61 
9.6.2 Manuscripts and Presentations ...........................................................................61 
9.6.3 Methodologic Developments ...............................................................................61 
10.0 
REFERENCES .....................................................................................................................................62 
APPENDIX A: NORMAL DONORS FOR GENERATION OF ALLO-MSCS .............................................................72 
APPENDIX B: NYHA CLASSIFICATION ..................................................................................................................73 
 
 
IRB NUMBER: HSC-SPH-15-0443
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EXECUTIVE SUMMARY 
Study Centers: Centers of the NHLBI CCTRN 
Phase of Development: Phase I 
Study Therapy: Transendocardial delivery of allogeneic human mesenchymal stem cells (allo-MSCs) 
Study Title: A Phase I, First-in-Human, Multicenter, Randomized, Double-Blinded, Placebo Controlled Study 
of the Safety and Efficacy of Allogeneic Human Mesenchymal Stem Cells in Cancer Survivors with 
Anthracycline-Induced Cardiomyopathy, a.k.a. StEm cell iNjEction in CAncer survivors (SENECA ) 
Objectives: To demonstrate safety and feasibility of allo-MSCs administered by transendocardial injection in 
subjects with anthracycline-induced cardiomyopathy (AIC). 
Subject Population: Subjects with AIC and who are eligible to undergo cardiac catheterization/NOGA. 
Design and Investigational Plan: Approximately thirty-six (36) subjects (including six actively treated lead-
in participants and up to thirty-one randomized clinical trial participants) will be enrolled.  The six subjects 
participating in the open-label lead-in will receive allo-MSC as described below in Group A.  The remaining 
approximately subjects will be randomized 1:1 to one of two treatment strategies:  
o Group A (15 subjects): 100 x 106 (100 million) allo-MSCs delivered in twenty 0.4 ml injections. 
o Group B (15 subjects): 20 injections of 0.4 ml cell-free Buminate solution. 
 
For patients randomized to Group A, the allo-MSCs will be derived from allogeneic bone marrow 
isolated from normal, healthy donors by standard iliac crest aspiration. 
 
Cells or placebo will be administered via the NOGA Myostar injection system. 
 
The injections will be administered transendocardially during cardiac catheterization using the NOGA 
Myostar Injection System.  Injections will be targeted throughout the left ventricle based on NOGA 
mapping and assessment of scar / fibrosis.  
 
All consented and eligible subjects will have study product injection within 45 days of signing 
informed consent. 
 
Following cardiac catheterization and allo-MSC or placebo injections, subjects will be followed at day 
1, week 1, and months 1, 6, and 12 to complete all safety and efficacy assessments. 
Eligibility Criteria:   
Inclusion Criteria 
     To participate, a subject MUST: 
1. Be ≥ 18 and < 80 years of age 
2. Be a cancer survivor with diagnosis of AIC 
3. Have an LVEF ≤ 45% by cMRI 
4. Be in NYHA class II-III 
5. Have received the initial diagnosis of AIC at least six months earlier and be on stable, optimally-
tolerated therapy with beta-blockers, ACE inhibitors/ARBs, and/or aldosterone antagonists for 3 
months, unless contraindicated  
6. Have a period of at least two years of clinical cancer-free state* and low likelihood of recurrence 
(a five-year risk of recurrence estimated at 30% or less), as determined by an oncologist, based 
on tumor type, response to therapy, and negative metastatic work-up at the time of diagnosis 
*exceptions to this are carcinoma in situ or fully resected basal and squamous cell cancer of the 
skin. 
7. Be a candidate for cardiac catheterization 
Exclusion Criteria 
     To participate, a subject MUST NOT HAVE: 
1. A life expectancy <12 months  
2. A CT scan or baseline cardiac MRI showing new tumor or suspicious lymphadenopathy raising 
concern of malignancy 
3. Presence of obstructive CAD as determined via imaging within 5 years prior to study enrollment 
provided there have been no symptoms or evidence of CAD since the test (see section 4.1 for 
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imaging guidance)) 
4. Had a previous myocardial infarction 
5. A history of radiation therapy AND evidence of constrictive physiology and/or evidence of other 
patterns of non-ischemic cardiomyopathy on cardiac MRI (e.g., amyloidosis, sarcoidosis, 
hemochromatosis, pure radiation-induced cardiomyopathy, etc.) not consistent with AIC being the 
dominant etiology of heart failure 
6. Valvular heart disease including 1) mechanical or bioprosthetic heart valve; or 2) severe valvular 
(any valve) insufficiency/regurgitation within 12 months of consent  
7. Aortic stenosis with valve area ≤ 1.5cm2    
8. A history of LV reduction surgery or cardiomyoplasty 
9. Evidence of cardiogenic shock 
10. A history of ischemic or hemorrhagic stroke within 90 days of baseline testing 
11. Liver dysfunction during baseline testing, as evidenced by enzymes (e.g., AST, ALT, alkaline 
phosphatase) greater than 3 times upper limit of normal  
12. Diabetes with poorly controlled blood glucose levels (HbA1c > 8.5%) 
13. An underlying autoimmune disorder or current immunosuppressive therapy (e.g., chronic 
corticosteroid, rheumatologic or immune modulating therapy) or likelihood of use of 
immunosuppressive therapy during participation in the trial (medications will be considered on a case by 
case basis) 
14. A baseline eGFR <35 ml/min/1.73m2 
15. A contrast allergy that cannot adequately be managed by premedication 
16. Received gene or cell-based therapy from any source within the previous 12 months 
17. A hematologic abnormality during baseline testing as evidenced by hemoglobin < 9 g/dl; hematocrit 
< 30%; absolute neutrophil count < 2,000 or total WBC count more than 2 times upper limit of 
normal; or platelet values < 100,000/ul 
18. Evidence of active systemic infection at time of study product delivery 
19. HIV and/or active HBV or HCV 
20. Coagulopathy (INR > 1.5) not due to a reversible cause (e.g., warfarin and/or Factor Xa inhibitors) 
(see Section 6.4 re: injection procedure and anticoagulation therapy) Note: Subjects who cannot be 
withdrawn from anticoagulation will be excluded.  
21. Presence of LV thrombus (see guidance in Section 6.6.3) 
22. 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 
contraindicated 
23. Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without an ICD are 
not excluded)  
24. A cardiac resynchronization therapy (CRT) device implanted < 3 months prior to consent  
25. Other MRI contraindications (e.g. patient body habitus incompatible with MRI) 
26. An appropriate ICD firing or anti-tachycardia pacing (ATP) for ventricular fibrillation or ventricular 
tachycardia within 30 days of consent 
27. 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 
28. A 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 
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alcohol or drugs within the past 24 months 
29. Cognitive or language barriers that prohibit obtaining informed consent or any study elements 
(interpreter permitted) 
30. Participation (currently or within the previous 30 days) in a cardiac related investigational therapeutic 
(including stem cell based therapies) or device trial 
31. Pregnancy, lactation, plans to become pregnant in the next 12 months, or is unwilling to use 
acceptable forms of birth control during study participation 
32. Any other condition that, in the judgment of the Investigator or Sponsor, would be a contraindication 
to enrollment, study product administration, or follow-up 
Primary Endpoints 
Safety: To demonstrate the relative safety of allo-MSCs 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: 
1. Major adverse cardiac events (MACE) including: death, hospitalization for worsening heart failure 
(HF), and/or other exacerbation of HF (non-hospitalization) 
2. Other significant clinical events including: non-fatal stroke, non-fatal myocardial infarction, coronary 
artery revascularization, ventricular tachycardia/fibrillation, pericardial tamponade, infectious 
myocarditis, hypersensitivity reaction, neoplasm, and/or any other potential deleterious late effects 
detected and corroborated by clinical presentation, laboratory investigations, image analysis, and 
when necessary with biopsy from suspected target sites in the body 
3. All adverse events (AEs) at least grade 2 in severity 
Feasibility: To assess the practicality of study procedures, the following measures will be reported. 
The number and percent of subjects who: 
1. Have events between randomization and SPI that preclude the subjects from getting SPI  
2. Receive less than 20 injections during the SPI procedure 
3. Do not receive the intended dose of cells (100 million), reason, and actual dose delivered 
4. Have at least one cardiac MRI endpoint measure that is uninterpretable due to issues related to the 
device, including, but not limited to, inability to undergo the procedure 
5. Fail to complete follow-up 
Secondary Endpoints 
Prospectively Declared Efficacy Endpoint Measures: 
To explore whether allo-MSCs produce a trend toward improved LV function and functional status when 
compared with placebo, the following domains and measures will be evaluated: 
• 
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 area of injury (e.g., inflammation, edema, fibrosis)  
• 
Functional capacity over time: 
 
Change in exercise tolerance (6MWT)  
 
Change in MLHF Questionnaire (subject reported) 
• 
Clinical outcomes over time: 
 
MACE 
 
Cumulative days alive and out of hospital 
• 
Biomarkers over time: 
 
Change in NT-proBNP 
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Duration of Study Follow-Up: Following discharge from the hospital, subjects will be assessed at week 1, 
and months 1, 6, and 12 (including assessment for cancer recurrence). 
 
1.0 STUDY OBJECTIVES 
1.1 Primary Objective 
The primary purpose of this study is to examine the safety and feasibility of delivering allogeneic 
human mesenchymal stem cells (allo-MSCs) by transendocardial injection to cancer survivors 
with left ventricular (LV) dysfunction secondary to anthracycline-induced cardiomyopathy (AIC). 
1.2 Secondary Objective 
The secondary purpose of this study is to obtain preliminary evidence for therapeutic efficacy of 
allo-MSCs delivered by transendocardial injection to cancer survivors with LV dysfunction 
secondary to AIC. 
1.3 Hypotheses 
Ho 1: Allo-MSCs delivered transendocardially in subjects with LV dysfunction, secondary to AIC, 
are well-tolerated. 
Ho 2: Allo-MSCs can be delivered to subjects with LV dysfunction, secondary to AIC, and the 
outcome measures can be collected. 
Ho 3: Compared with placebo, allo-MSCs promote myocardial repair, thereby producing a trend 
toward reduced scar burden and improved cardiac performance, functional capacity, and 
quality of life from baseline to six months and/or from baseline to 12 months post 
treatment with study product. 
1.4 Relevance to the CCTRN 
This study is consistent with the goal of the Cardiovascular Cell Therapy Research Network 
(CCTRN), which is to investigate the safety and effectiveness of new cell therapies in 
cardiovascular disease.  It is also consistent with the scope of the CCTRN, which is to 
accelerate research in use of cell-based therapies for the management of cardiovascular 
disease.  This study will collect important clinical and mechanistic information on the safety, 
feasibility, and impact of administering stem cells in cancer survivors with AIC.  AIC is a growing 
problem that is associated with a grim prognosis and disproportionately affects women and 
young adults. Currently, no effective treatment exists for this lethal syndrome. 
2.0 BACKGROUND 
2.1 Population 
Anthracycline-based chemotherapies remain common and effective treatments for breast 
cancer, lymphomas, leukemias, and sarcomas.  Unfortunately, the use of anthracyclines is 
limited by their cardiotoxic effects, which may manifest as late as 20 years from initial 
exposure1. Studies in cells and animals suggest that the mechanism of anthracycline-induced 
cardiomyopathy (AIC) is multifactorial2. Anthracyclines induce multiple forms of cellular injury by 
free radical production2. In addition, anthracyclines alter nucleic acid biology by intercalation into 
DNA and modulate intracellular signaling, leading to cell death and the disruption of homeostatic 
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processes such as sarcomere maintenance2.  In an effort to decrease AIC, many strategies 
have been tested, but no specific therapies are universally acknowledged to prevent or treat 
anthracycline-induced cardiac dysfunction.  Moreover, cardioprotective agents available in the 
market such as dexrazoxone and liposomal delivery systems of doxorubicin have shown 
disappointing results, diminishing tumor response or causing debilitating hand-foot-and-mouth 
disease3.  Current therapies are palliative, and AIC remains an incurable and often fatal disease 
for which no effective treatment is available.  
 
The broad use of anthracyclines for over 50 years has dramatically improved cancer survival 
statistics. For example, prior to the 1960s, children with leukemia had an overall 5-year survival 
of 30%. With the increased use of anthracycline-based chemotherapy and early detection, 5-
year survival in children is now 80%4. Unfortunately, though mortality rates decrease with 
anthracyclines, life-altering cardiac sequelae from anthracyclines remain a problem, with a 
range of 5–23% of patients developing late-onset heart failure secondary to anthracycline-
induced cardiotoxicity5,6.  
 
The risk of AIC is primarily related to the lifetime cumulative dose of anthracyclines. At a 
cumulative dose of 400 mg/m2, there is a 5% risk of developing heart failure, which increases to 
25% at 700 mg/m2 7. An empiric cutoff of 500 mg/m2 has been suggested to minimize the 
cardiotoxic effects of doxorubicin7. If patients have other predisposing risk factors for AIC such 
as age at two extremes (older age >65 years, and young age < 18 years), prior cardiac 
pathology (hypertension, LV hypertrophy, coronary artery disease), diabetes, or prior radiation 
exposure, the recommended total cumulative exposure is decreased to 450 mg/m2. Even at low 
cumulative doses, however, such as standard-dose therapy for breast cancer, 5% of patients 
will have evidence of AIC8. Thus, every exposure to an anthracycline carries some risk of 
inducing cardiac dysfunction. 
 
While ongoing trials suggest that the addition of Angiotensin-Converting Enzyme (ACE) 
inhibitors, angiotensin receptor blockers (ARB), beta-blockers, and statins may help treat AIC, 
there continues to be a subset of patients that will develop progressive symptoms and end-
stage heart failure despite optimal medical therapy6,9-11. Despite the use of optimal medical 
therapy for heart failure, AIC is often irreversible and carries a grim prognosis, to the point that 
an increasing number of AIC patients have required heart transplantation over the last 13 years 
(Figure 1, see below)12. The prognosis for AIC remains worse than that of ischemic or 
other forms of idiopathic cardiomyopathy, with a 3.5 higher relative risk of dying within 
five years13. Many patients with AIC are relative young, and approximately 70% of them are 
women14. 
 
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Figure 1. Statistically significant increase in percentage of orthotopic heart transplantations annually 
from 1987 to 2011 for the diagnosis of DCA (p <0.001)12 
2.2 Study Rationale  
The technique of transplanting progenitor cells into a region of damaged myocardium, termed 
cellular cardiomyoplasty15, is a potential, new therapeutic modality designed to replace or repair 
necrotic, scarred, or dysfunctional myocardium.  Ideally, graft cells should be readily available, 
easy to culture to ensure adequate quantities for transplantation, and able to survive in host 
myocardium16-18, often a hostile environment of limited blood supply and immune rejection.  
Whether effective cellular regenerative strategies require that administered cells differentiate 
into adult cardiomyocytes and couple electromechanically with the surrounding myocardium is 
increasingly controversial and recent evidence suggests that this may not be required for 
effective cardiac repair.  Most importantly, transplantation of graft cells should improve cardiac 
function and prevent adverse ventricular remodeling.  To date, a number of candidate cells have 
been transplanted in experimental models, including fetal and neonatal cardiomyocytes19, 
embryonic stem cell-derived myocytes20,21, tissue-engineered contractile grafts22, skeletal 
myoblasts23, several cell types derived from adult bone marrow24-29, and cardiac precursors 
residing within the heart itself30.  There has been substantial clinical development in the use of 
whole bone marrow, select bone marrow cells, skeletal myoblasts, adipose derived cells, and 
cardiac stem cells in studies enrolling both post-infarction patients and patients with chronic 
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ischemic left ventricular dysfunction and heart failure. The effects of allogeneic bone marrow 
derived mesenchymal stem cells (MSCs) have also been studied clinically.  
 
Currently, bone marrow or bone marrow-derived cells represent a promising modality for cardiac 
repair. The totality of evidence from trials investigating autologous whole bone marrow infusions 
into patients following myocardial infarction supports the safety of this approach31.  In terms of 
efficacy, increases in LVEF are reported in meta-analyses of the randomized controlled trials31.  
Chronic ischemic left ventricular dysfunction resulting from heart disease is a common and 
problematic condition; definitive therapy in the form of heart transplantation is available to only a 
tiny minority of eligible patients.  Cellular cardiomyoplasty for chronic heart failure has been 
studied less than for acute myocardial infarction (MI), but represents a potentially important 
alternative for this disease. 
Therapies for AIC remain limited; other than heart transplant, therapy is largely palliative. Given 
the limited availability of donor hearts and the bleak prognosis of this disease, new strategies 
for the treatment of AIC refractory to optimal heart failure therapy are sorely needed.  
This is indeed an important unmet need in contemporary cardiovascular medicine. Accordingly, 
this trial will test the safety and feasibility of administering allogeneic MSCs in subjects with AIC 
and focus on the impact of the cells for treating heart failure in this population. 
2.3 Background of Regenerative Therapy in Cancer 
A major concern in the application of cell-based regenerative therapies after cancer is whether 
these new treatments will increase the risk of tumor recurrence.  Below is a review of what is 
known concerning interactions between stem cells / regenerative tissue and the potential risks 
of regenerative therapy after cancer treatment. 
The interaction of proliferating multipotent mesenchymal stem cells MSCs with tumor cells have 
been addressed in co-culture demonstrating that the chemokine CCL5 by bone marrow-derived 
MSC (BM-MSCs) increase the motility of breast cancer cell lines in in vitro models of tumor 
invasion32-34. Because these studies utilized immortalized cancer cell lines that grow rapidly in 
culture, they fail to model the crucial aspects of tumor heterogeneity, tumor dormancy, and 
reactivation of occult tumor cells. 
 
While research shows that MSC’s promote tumor growth in immortalized cell lines there are 
other contradictory studies, which demonstrate that MSCs inhibit tumor growth. For example 
MSCs reportedly inhibit tumorgenesis from Kaposi’s sarcoma cells35 and hepatoma cells36, bone 
metastasis of prostate cancer37, and in vitro growth of hepatoma, lymphoma, and insulinoma cell 
lines38. Multiple mechanisms have been invoked to relate these findings to the cytokines, 
chemokines, and prostaglandins secreted by MSCs39. Since the data with MSCs with various 
tumor cell lines is conflicting, more data is needed on MSCs and phenotypically similar cells 
lines in other experimental systems and clinical studies to determine the tumorigenic potential of 
MSCs.  
There is significant similarity between MSCs and adipose-derived stem / stromal cells (ASCs) 40. 
ASCs phenotypically resemble bone marrow derived MSCs (BM-MSCs) and share their multi-
potentiality and many surface markers (predominantly CD105+ / CD73+ / CD90+ / CD44+) 41,42. 
Like BM-MSCs, ASCs are able to give rise to differentiated progeny with characteristics of bone, 
cartilage, fat, and blood vessels. ASCs and BM-MSCs are both promising candidates for cellular 
therapy, but the potential risk of promoting tumor reactivation remains controversial. The utility 
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of ASCs, as cellular therapy after breast tumor resection, is germane since autologous fat 
transfers with ASCs have been used for breast reconstruction post mastectomy43,44. Despite the 
potential concern that self-renewing adipose tissue may promote tumor recurrence by 
reactivation of occult breast cancer cells, studies have not shown that stem cell-augmented 
adipose transplantation for breast reconstruction increases cancer reoccurrence45,46.  
 
Both autologous fat transfers and autologous tissue flaps pose little risk of reoccurrence in 
breast cancer patients who are adequately treated with surgery, chemotherapy, and radiation 
due to the notion that the cancer cells / tumor beds are dormant and thus low potential for 
transformation. The concept of dormancy, although ill-defined in oncology literature, refers to 
cells that are out of cell cycle (i.e., G0), or persisting in a dynamic state of balanced proliferation 
and death. The same can be said for normal tissue stem cells47. Dormancy is an intrinsic 
characteristic of the resting tumor cell, perhaps imposed by epigenetic programming48. As such, 
transition between dormant and active states requires genetic reprogramming and not merely 
the presence of signals from hormones or angiogenic factors. If increased local vascularization 
with adipose tissue flaps at the site of a tumor bed was an independent risk factor for 
recurrence, this fact would have become clear after observing former breast cancer patients 
with reconstructed tissue flaps. Immediate autologous tissue flap reconstruction has not been 
correlated with increased recurrence rates49.  It is believed that patients who are appropriately 
treated for breast cancer and selected for adipose tissue flap are in a state of remission (tumor 
dormancy) and thus at a low risk for reoccurrence.  Current data on adipose tissue flap 
reconstruction supports this notion.  
 
During the 1990s, autologous hematopoietic transplantation was widely used to rescue the bone 
marrow of breast cancer patients undergoing dose-intensive chemotherapy. This practice was 
discontinued when randomized trials failed to show superiority over conventional therapy50.  
However, the massive damage to all proliferative tissues by high-dose therapy and the ensuing 
tissue regeneration did not promote breast cancer relapse. Therefore, when a solid tumor 
malignancy such as breast cancer was treated with regenerative cell-based therapy the data 
demonstrated safety without increasing the risk of local tumor reoccurrence.  
 
A similar parallel can be drawn from the allogeneic and autologous hematopoietic stem cell 
transplantation for hematologic malignancies, where there are decades of experience51,52.  
When patients are given a bone marrow transplant during first remission (tumor dormancy) 
patients often have extended periods of disease free survival.  In contrast, when hematologic 
malignancy is active (i.e., the patient has had multiple remissions or has active disease at the 
time of myeloablative therapy), relapse often occurs early in the peri-transplant period when 
bone marrow regeneration is at its peak53. A similar argument can be made for cytokine 
mobilization during autologous hematopoietic stem cell transplantation, where patients in 
remission are treated with consolidation chemotherapy and the hematopoietic growth factor 
granulocyte colony stimulating factor (G-CSF)54. The patients experience bone marrow 
suppression followed by explosive regeneration without triggering early relapse. In all these 
examples of breast cancer tissue flap reconstruction, bone marrow transplantation, and 
cytokine-mediated marrow stimulation, appropriate patient selection with good tumor response 
(remission / tumor dormancy) is essential to minimize the risk of cancer reoccurrence.  
 
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Available evidence from cell lines, case reports, and clinical studies favors the interpretation that 
regenerating cell / tissue based therapy stimulates the growth of active, high-grade tumors. In 
contrast, dormant cancer / cancer in remission does not appear to be activated by cell / tissue 
regeneration.  However, the data does support that regenerative-based therapies should be 
deferred until cancer remission has been firmly established and the patients are felt to have low 
risk of reoccurrence. 
2.4 Therapy Rationale 
Since therapy with stem cells promises to be a safe and effective treatment for regenerating 
myocardium and improving cardiac function in ischemic cardiomyopathy55,56, we propose that 
stem cells may also be beneficial in AIC. In both cases, the underlying cause of HF is loss of 
viable myocytes with replacement fibrosis.  Cancer survivors, however, differ importantly from 
patients with ischemic heart failure with respect to the potential source of stem cells. In patients 
with AIC, the use of allogeneic cells is necessitated by the concern that autologous cells 
may lead to dissemination of the original malignancy for which patients were treated with 
anthracyclines; causing recurrence or dissemination of the original malignancy would be 
so catastrophic that this risk prohibits the use of autologous cell therapy. Therefore, in 
this trial, we will use allo-MSCs rather than autologous MSCs. 
 
The bone marrow harbors a variety of cells that may contribute to vasculogenesis or 
cardiomyogenesis, either directly, or by facilitating endogenous repair mechanisms.  Bone 
marrow cells have been prepared on the basis of being: 1) endothelial precursor cells that are 
CD34+; 2) MSCs purified without an antigen panning technique on the basis of their fibroblast 
morphology, ability to divide in culture, and to differentiate into mesodermal lineages57; and 3) 
cells that express the stem cell factor receptor, c-Kit58.  Endothelial progenitor cells (EPCs) 
express the surface markers CD34, CD133, c-kit, and the vascular endothelial growth factor 
receptor-2 (VEGFR2; KDR; Flk-1)59-64. Hematopoietic stem cells (HSCs) exhibit self-renewal 
and differentiation.  Their cell-surface phenotype is CD34+, stem cell factor antigen (SCA-1)+, c-
kit+, and Lin- (review65).  While there has been controversy regarding the ability of bone marrow-
derived cells to trans-differentiate into cardiomyocytes66, clinical trials of whole bone marrow 
therapies continue to suggest potential benefit in terms of improving cardiac function or reducing 
the burden of scarred myocardium31. 
2.4.1 Mesenchymal Stem Cells (MSCs) 
MSCs are a particularly promising bone marrow-derived cell for cardiac regenerative therapy 
because of their availability, immunologic properties, and track-record of safety and efficacy18.  
Studies of MSC engraftment in rodent and swine models of myocardial infarction have shown 
that the administration of MSCs produces: 1) functional benefit in post- MI recovery of 
ventricular function; 2) evidence of neo-angiogenesis at the site of the infarct; 3) decrease in 
collagen deposition in the region of the scar; and 4) some evidence of cells expressing 
contractile and sarcomeric proteins but lacking true sarcomeric functional organization67,68.  
Moreover, MSCs are thought to be ideal candidate cells for allogeneic transplantation because 
they show minimal major histocompatibility complex (MHC) class II and intercellular adhesion 
molecule (ICAM) expression and lack B-7 co-stimulatory molecules necessary to cause a T-cell 
mediated immune response18,69. 
 
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 which they 
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express this cell surface marker.  C-kit is a tyrosine kinase receptor for stem cell factor70. Some, 
but not all, groups have purified MSCs expressing c-kit directly from bone marrow that have the 
capacity to form cardiac myocytes71. This is of functional significance given the demonstration 
that stem cell factor stimulates cardiac repair post-MI72. 
2.4.2 Immunological Properties of MSC and Human Leukocyte Antigen (HLA)-Matching 
The use of allogeneic cellular products typically requires matching of the graft HLA to the donor. 
Mismatched grafts can result in graft rejection and can induce graft versus host disease 
(GVHD). However, MSCs represent a unique cell population for allogeneic cellular therapy. 
MSCs have been shown to exert anti-proliferative, immune-modulatory, and anti-inflammatory 
effects. Human MSCs fail to induce proliferation of allogeneic lymphocytes in vitro73. Also, MSCs 
suppress proliferation of T cells activated by allogeneic cells or mitogens74. The suppression 
appears to be mediated, at least in part, by soluble factors and affects several types of immune 
cells.   
 
Several hundred patients have received MSCs in clinical trials that used an allogeneic source 
for the cell product. Infusion of MSCs was well tolerated and no side effects were noted75. 
Several patients have been treated with MSCs to treat severe graft versus host disease 
(GVHD). In a 9-year old boy who received a matched, unrelated donor hematopoietic stem cell 
transplant for leukemia, severe acute steroid-resistant GVHD of the gut and liver was reversed 
by infusion of haplo-identical MSCs derived from the patient’s mother76.  
 
These data suggest that human MSCs may be a unique cell population for regenerative 
medicine with minimal immune reactivity, which decreases the potential of graft 
rejection and/or GVHD. 
2.4.3 Potential Mechanisms for MSC Mediated Improvements in Cardiac Function 
As noted above, prior studies have shown that a variety of cellular sources are capable of 
differentiating into phenotypes that strongly resemble the three principal cell types in the 
myocardium: cardiomyocytes, smooth muscle, and vascular endothelium.  Preliminary data from 
Hare’s group, and reports from other labs cited above, suggest that MSCs have the potential to 
form all three cell types within infarcted myocardium in vivo. Nevertheless, it is important to 
consider that MSCs may exert other favorable effects on cardiac repair above and beyond 
differentiation18.  For example, these cells may also participate in the recruitment and/or 
stimulation of other cells to differentiate into a cardiac phenotype. 
 
There is a wealth of evidence suggesting that stem cell homing to damaged myocardium is 
directed by injury signal(s) emanating from the area within or surrounding the infarct.  For 
example, stromal-cell-derived factor 1 (SDF-1), a chemokine that is a natural ligand for the 
CXCR4 receptor, is crucial for bone marrow retention of hematopoietic stem cells77,78, 
cardiogenesis79, recruitment of endothelial progenitor cells to sites of ischemic tissue80 and, 
potentially, migration of tissue-committed stem/progenitor cells81.  Interestingly, it was recently 
shown that the CXCR4 receptor is strongly expressed by a subset of MSCs and plays an 
important role in MSC mobilization82.  Expression of SDF-1 dramatically increases over the first 
week following infarction, and exogenous expression of SDF-1 increases the number of 
mobilized bone marrow cells (BMCs) homing to the heart at time periods remote from 
infarction83.  These findings suggest that MSCs participate in the complex autocatalytic cascade 
of cytokines and growth factors that is activated following MI.  Indeed, human MSCs are capable 
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of secreting several cytokines, including stem cell factor (SCF) and G-CSF80, and 
intramyocardial administration of MSCs is associated with increases in vascular endothelium 
growth factor (VEGF) levels29.  Furthermore, it has been shown that MSCs participate in 
angiogenesis and arteriogenesis, differentiating into endothelium and vascular smooth muscle in 
a VEGF-dependent manner84.  
 
Once cells successfully home and engraft in the heart, they must survive in a hostile 
environment if they are to effect successful cardiac repair.  It is thought that apoptosis within the 
infarct region is responsible for the fact that only a fraction of cells injected directly into the heart 
will engraft and survive, and that such cell death reduces the efficacy of cellular 
cardiomyoplasty.  In a dramatic proof of principle study, Mangi et al. genetically engineered rat 
MSCs using ex vivo retroviral transduction to overexpress the anti-apoptotic protein Akt1, a 
serine-threonine kinase67.  Transplantation of 5x106 cells overexpressing Akt into the ischemic 
rat myocardium led to dramatic improvements in structure and function that far exceeded those 
seen with injection of control MSCs transduced with Lac-Z.  MSCs reduced inflammation, 
collagen deposition and cardiomyocyte hypertrophy, regenerated 80-90% of lost myocardium, 
and completely normalized systolic and diastolic cardiac function in a dose-dependent fashion. 
2.5 Background Preclinical 
De Angelis et al. induced AIC in rats with 3 weeks of doxorubicin treatment; these investigators 
showed that subsequently treatment of these rats with syngeneic c-kit+ cardiac stem cells 
resulted in a 66% decrease in mortality at 6 weeks and a significant improvement in multiple 
parameters of LV function compared with control rats treated with vehicle85.  
 
Psaltis et al. examined the safety and utility of allogeneic MSCs delivered transendocardially in 
a sheep model of AIC86. In this study, MSCs were prepared from ovine bone marrow by 
immunoselection using the tissue nonspecific alkaline phosphatase, or STRO-3, monoclonal 
antibody. Fifteen sheep with AIC were assigned to catheter-based, transendocardial injections 
of ovine MSCs (n = 7) or placebo (n = 8), under electromechanical mapping guidance. Each 
animal received 20 injections of 0.2ml/injection of placebo or cell product distributed throughout 
the left ventricle 10 weeks after first exposure to doxorubicin. Follow-up was for 8 weeks, with 
end points assessed by cardiac MRI, echocardiography, and histology. Intramyocardial 
injections of MSCs with the NOGA MyoStar injection system were distributed similarly 
throughout the left ventricle in both groups. Cell transplantation was associated with 1 death late 
in follow-up, compared with 3 early deaths among control animals. At 8 weeks after treatment, 
LV end-diastolic volume increased in both cohorts; however, MSC therapy attenuated the 
increase in end-systolic volume, which was not statistically significant, whereas in the control 
group there was a statistically significant increase in end-systolic volume (P< 0.01). Importantly, 
LV ejection fraction increased from 37.3 ± 2.8% before cell therapy to 39.2 ± 1.4% at 8 weeks 
after cell therapy (P=NS) in treated sheep, whereas in control animals it decreased from 38.8 ± 
4.4% to 32.5 ± 4.9% (P<0.05) at corresponding time points. Histological analysis showed that 
MSC therapy was associated with less fibrosis burden than in the control group and an 
increased density of karyokinetic cardiomyocytes and arterioles (P< 0.05 for each). These 
changes occurred in the presence of modest cellular engraftment after transplantation. This 
study, conducted in a large preclinical animal model of AIC, provides robust evidence for 
the therapeutic utility of allogeneic MSCs in the treatment of AIC, and thus supports the 
rationale for the present study. 
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2.6 Background Clinical 
2.6.1 Previous Clinical Trials of Allogeneic Mesenchymal Stem Cells (allo-MSCs) 
Allo-MSCs have been used in several recent FDA-approved trials. The cumulative experience 
in these studies demonstrates an outstanding safety margin and a significant potential 
for cardiac regeneration. 
In a multi-center, randomized, double-blinded, placebo-controlled clinical study by Hare et al. 53 
patients with recent acute MI (3 to 10 days) were treated with allo-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 peripheral intravenous injection, and followed for six 
months87.  There were no deaths reported in the study; no toxicity was observed with the 
administration of the allo-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. The 
group of patients treated with MSCs demonstrated reduced ventricular tachycardia episodes 
(P=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 
s (P=0.003) in the MSC-treated patients. In addition, left ventricular ejection fraction (LVEF) in 
the important subset of anterior MI patients was significantly better in MSCs versus control 
subjects, with a 7.3% absolute improvement in EF at 6 months over baseline. In the cardiac MRI 
substudy, MSC treatment, but not placebo, increased LVEF and led to reverse remodeling. 
 
The POSEIDON trial was a phase 1/2 randomized controlled study in which 30 patients with 
chronic ischemic cardiomyopathy were randomized to 20 million, 100 million, or 200 million 
autologous MSCs or allo-MSCs (5 patients were given each cell type for each dose of cells)56. 
The cells were delivered by transendocardial injection into 10 LV sites in a volume of 0.5 mL for 
each injection. The primary outcome was incidence of severe adverse events at 30 days. At 1 
year, there was no difference between allogeneic and autologous MSCs with regards to serious 
adverse events. In addition, at 1 year, there were no ventricular arrhythmia serious adverse 
events (SAEs) observed among allo-MSC recipients compared with 4 patients (26.7%) in the 
autologous MSC group (P = .10). Although there was no significant improvement in LVEF in any 
group, there was a sizeable reduction in scar size in both allogeneic and autologous groups. 
Importantly, allo-MSCs did not stimulate significant donor-specific allo-immune reactions.  
 
The CTSN LVAD study88 was an NHLBI-sponsored multi-center, double-blind, sham-procedure 
controlled trial to assess the safety and feasibility of MSC implantation into the LVAD-assisted 
heart. Thirty patients were randomized (2:1) to intramyocardial injection of 25 million 
mesenchymal precursor cells (MPCs) (Mesoblast, Inc.) or medium during LVAD implantation 
and followed until transplant or 12 months whichever came first. No safety events were 
observed. At 90 days, successful temporary LVAD weaning was achieved in 50% of MPC and 
20% of control patients (P=0.24).  Three deaths (30%) occurred in control patients and none 
occurred in MPC patients. Mean left ventricular ejection fractions after successful wean were 
24.0% (MPC=10) and 22.5% (control=2; P=0.56). At 12 months, 30% of MPC patients and 40% 
of control patients were successfully temporarily weaned from LVAD support (P=0.69), and 6 
deaths occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 
control patients and resolved by 12 months. 
 
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In addition, Perin et al. (NCT00721045) investigated the safety of allo-MSCs in the setting of 
acute MI. This study was supported by Mesoblast and performed at six centers in the US 
between 8/2008 and 5/2010 to assess the safety and effect of bone marrow derived allogeneic 
MPC's STRO-1bright cells on LV function. This was a Phase II, single-blind, randomized, dose-
escalation study of 60 subjects with fifteen subjects per 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 system into viable myocardium.  Outcomes were a) immunological safety; b) 
safety of the injection procedure; c) 6-month surrogate efficacy findings of no change in LVEF 
and 6-minute walk test (control corrected 34 meters’ improvement but not significant in the 150 
million cell group), significant decrease in both left ventricular end systolic volume (LVESV) and 
end diastolic volume (LVEDV) in the 150 million group; and d) MACE evaluations to 36 months 
in all groups. For ischemic 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 heart failure (HF) MACE (i.e., cardiac death or HF re-hospitalization) there 
were no events in the 150 million cell group, and there were no significant differences between 
any cell dose group and control patients.  For all events, there were 12 events in total combined 
three cell groups (n=45) compared with 11 events in the control group (n=15). These are 
unpublished data, partially presented at AHA 2013 and currently submitted and under review for 
publication. 
Taken together, these trials of allo-MSCs demonstrate not only an excellent safety profile 
of this therapy but also a considerable potential for allo-MSCs to exert beneficial effects 
in patients with heart failure56,87.   
2.6.2 Ongoing/Future Clinical Trials of Allogeneic Mesenchymal Stem Cells 
There are several ongoing studies of allo-MSCs in cardiac diseases. The safety study of 
Allogeneic Mesenchymal Precursor Cell Infusion in MyoCardial Infarction (AMICI) 
(NCT01781390) is a multi-center randomized clinical trial in which 225 patients with new acute 
MI in the left anterior descending (LAD) artery territory are randomized to intracoronary infusion 
of 12.5 or 25 million allo-MSCs or placebo (cells are injected at the time of primary coronary 
intervention).  
Allogeneic stem cells are also under investigation in patients with dilated cardiomyopathy 
(DCM). PercutaneOus StEm Cell Injection Delivery Effects On Neomyogenesis in Dilated 
CardioMyopathy (the POSEIDON-DCM Study) (NCT01392625) is an ongoing study that is 
actively recruiting 36 patients with DCM and randomizing to receive autologous MSCs vs. allo-
hMSCs via intramyocardial injection; patients will receive 100 million MSCs (autologous or 
allogeneic) delivered in 10 injections via the transendocardial route utilizing the NOGA system.  
2.6.3 Previous Clinical Experience with Intramyocardial Delivery of Stem Cells 
There is substantial clinical experience with the transendocardial delivery of autologous bone 
marrow-derived mononuclear cells (BMCs) as well as autologous MSCs and allo-MSCs in the 
setting of chronic LV dysfunction.  The aforementioned POSEIDON trial56, the TAC-HFT trial89, 
the FOCUS-CCTRN trial90 and the RENEW trial (NCT01508910), are only a few examples of 
the application of this delivery method for cell therapy in patients with cardiovascular disease.  In 
addition, multiple ongoing trials are using intramyocardial injection as the mode of delivery for 
stem cells. Table 1 (see below) lists the 11 studies in which intramyocardial delivery of BMCs 
was performed91-101. Cell delivery has been performed via either i) direct intramyocardial (IM) 
injection during coronary artery bypass graft (CABG) surgery, or ii) catheter-based 
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intramyocardial injection (transendocardial delivery). Taken together, these studies clearly 
support the clinical safety of the intramyocardial injection delivery method. 
 
Table 1. Studies utilizing Intramyocardial Delivery of BMCs
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Study 
N 
Cell Delivery 
Method 
Cell Source      
& Type 
Cell Doses    
(x 106) 
Safety 
Efficacy Results 
Stamm99 
6 
Direct IM 
injection during 
CABG surgery 
Autologous, 
AC133* BMCs 
1.2 - 3.4 
No arrhythmias;   
no neoplasia 
↑ global 
contractility (EF) 
Tse101 
8 
Catheter-based 
IM injection 
Autologous 
BMCs 
2.6 – 21.2 
No arrhythmias 
↑ wall motion & 
thickening 
Fuchs100 
10 
Catheter-based 
IM injection 
Autologous 
BMCs 
32.6 ± 27.5 
No arrhythmias 
or other SAEs 
↓ angina score;     
↓ ischemia 
Perin97 
14 
Catheter-based 
IM injection 
Autologous 
CD34* BMCs 
25.5 ± 6.3 
No arrhythmias 
at 6-mo. F/U 
↑ global 
contractility (EF); 
↓ ESV 
Beeres91 
25 
Catheter-based 
IM injection 
Autologous 
BMCs 
84.1 + 28.7 
No arrhythmias 
or pericardial 
effusion 
↑ global 
contractility (EF); 
↓ ESV 
Briguori92 
10 
Catheter-based 
IM injection 
Autologous 
CD34* BMCs 
4.6 ± 1.5 
No arrhythmias 
or AMI 
↑ quality of life;     
↑ perfusion 
de La Fuente93 
10 
Catheter-based 
IM injection 
Autologous 
CD34* BMCs 
86 ± 3 
No arrhythmias 
at 12-mo. F/U 
↑ global 
contractility (EF) 
Mocini96 
36 
Direct IM 
injection during 
CABG surgery 
Autologous 
CD34* BMCs 
292 + 232 
No SAEs 
↑ global 
contractility (EF) 
Hendrikx94 
20 
Direct IM 
injection during 
CABG surgery 
Autologous 
BMCs 
60.1 ± 31.1 
Possible 
inducible VT 
↑ global 
contractility (EF) 
Stamm98 
55 
Direct IM 
injection during 
CABG surgery 
Autologous, 
CD133* BMCs 
3.85 – 103.0 
No arrhythmias 
↑ global 
contractility (EF) 
Li95 
6 
Direct IM 
injection during 
CABG surgery 
Autologous 
BMCs 
50 - 100 
No arrhythmias;   
no neoplasia 
Not Assessed 
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 
The proposed transendocardial injection system, the NOGA MyoStar injection system, has been 
utilized in multiple clinical trials of transendocardial injection including, but not limited to, the 
ACT34-CMI102, FOCUS-HF103, FOCUS-CCTRN90, RENEW (NCT01508910), and NOGA-
DCM104 studies. Again, this vast experience has shown this system to be safe, with minimal 
SAEs. In a retrospective safety study of the NOGA MyoStar injection system, data from 71 
patients who had undergone intramyocardial mapping and/or injection in the context of clinical 
trials were pooled and analyzed105. Although there were no mechanical complications, NOGA 
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mapping followed by direct intramyocardial injections led to CK-MB rises exceeding three times 
the upper limit of normal in 8 patients (17%) who received a volume of 0.3 mL per injection, 
compared with none in NOGA mapping alone105.  
2.7 Dose and Delivery Rationale 
2.7.1 Dose Rationale 
The clinical experience with the administration of MSCs in the trials performed to date provides 
substantial evidence of safety at cell doses up to 200 million MSCs as well as preliminary 
evidence of efficacy. In SENECA, we propose to administer a total of 100 million allo-MSCs, 
divided into 20 injections of 5 million cells each. A dose of 100 million MSCs delivered 
transendocardially has already been used in clinical trials, namely, the POSEIDON56 and TAC-
HFT trials89, and found to be safe. This dose is within the range of doses (20 to 200 million 
MSCs) used in previous human studies of MSCs56,89. In the ongoing POSEIDON-DCM trial 
(NCT01392625), a dose of 100 million allo-MSCs is being used. The rationale for selecting 100 
million cells is that in the POSEIDON trial56, there was an inverse dose response, leading the 
authors to speculate that higher doses may be less efficacious due to deleterious effects on cell 
retention, survival, or performance.  
 
Preclinical investigations are also consistent with an inverse dose response. Hamamoto et al. 
demonstrated in an ovine model of acute MI treated with transendocardial injection of 25, 75, 
225, and 450 million STRO-3 MSCs that, compared with control animals, low doses (25 and 75 
× 106 cells) of MSCs significantly attenuated the increase in LV end diastolic (LVEDV) and end 
systolic (LVESV) volumes; the 225 million dose improved only the LVESV over control, whereas 
the 450 million dose did not produce any salutary remodeling effect relative to controls106. In 
addition, infarct expansion was attenuated only in the 25, 75, and to some extent the 225 million 
groups although EF improved at all cell doses. CD31 and smooth muscle actin (SMA) 
immunohistochemical staining demonstrated increased vascular density in the border zone only 
at the two lower cell doses (more so in the 75 million group albeit, statistically insignificant 
between 25 and 75 million cell groups)106. Another ovine study used a protocol and allo-MSC 
doses similar to the above study and found that the LVEDV increase was significantly 
attenuated only in the 25 and 75 million groups compared with controls whereas the drop in EF 
was uniform across all doses of allo-MSCs in comparison to the control animals (P<0.05)107; 
both findings in Dixon et al.107 were analogous to the findings by Hamamoto et al106. 
2.7.2 Delivery Rationale 
The choice of the transendocardial delivery route is based on both preclinical and clinical data. 
In a preclinical study, Psaltis et al. (2010) demonstrated in an ovine model that cell therapy 
delivered by the NOGA device is safe and effective in the treatment of doxorubicin-induced 
cardiomyopathy86.  Moreover, there is substantial clinical experience in humans with the 
transendocardial delivery of autologous bone marrow-derived mononuclear cells (BMCs) as well 
as autologous MSCs and allo-MSCs in the setting of chronic LV dysfunction.  POSEIDON56, 
TAC-HFT89, FOCUS-HF103, FOCUS-CCTRN90, RENEW (NCT01508910), NOGA-DCM104, and 
Perin et al.’s study (NCT00721045) clearly demonstrate that NOGA can be carried out safely in 
humans with cardiomyopathy.  Table 1’s tabulation of the numerous studies utilizing direct 
intramyocardial injection adds to the weight of favorable clinical experience with this technique.   
Intracoronary delivery of allo-MSCs is not recommended in our protocol because of the 
likelihood, or at least the possibility, of producing microvascular obstruction with resultant dose 
dependent myocardial damage108,109. In addition, no published clinical trial supports the efficacy 
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of intracoronary MSC delivery, in contrast to the copious literature supporting the efficacy of 
transendocardial MSC delivery as discussed previously.   
 
Studies by Tham110 and Steinherz5 demonstrate that fibrosis in AIC patients is diffuse with a 
unique cardiac MRI profile. Our injections will target areas of diffuse fibrosis. The use of NOGA 
technology in preclinical models of anthracycline-induced cardiomyopathy, as well as idiopathic 
dilated cardiomyopathy, justifies its use in this protocol.  Taken together, the available literature 
and ongoing experience support the clinical safety of the intramyocardial injection delivery 
method and suggest that this route of cell administration is efficacious. 
 
3.0 STUDY DESIGN 
3.1 Research Questions 
 Question 1: Are allo-MSCs well-tolerated by subjects with LV dysfunction secondary to 
AIC? 
 Question 2: Can allo-MSCs be delivered to subjects with LV dysfunction secondary to 
AIC, and can the outcome measures be collected? 
 Question 3: Do allo-MSCs produce a trend toward improved LV function and functional 
status when compared with placebo from baseline to six months and/or from baseline to 
12 months post treatment with study product? 
3.2 Study Design 
This study will evaluate approximately thirty-six subjects. The first six subjects will receive allo-
MSC therapy (open label) and will be assessed for safety and feasibility of the study 
procedures. Following 1 month data review of each of the six subjects by the NHLBI Gene and 
Cell Therapy Data and Safety Monitoring Board; this will be followed by a randomized, double-
blind clinical trial enrolling approximately thirty subjects (see Section 7.7). These subjects will be 
randomized 1:1 to receive allo-MSCs or placebo. All subjects will undergo cardiac 
catheterization and study product administration using the NOGA Myostar catheter injection 
system. Subjects will be followed at 1 day, 1 week, 1 month, 6 months, and 12 months post 
study product injection. All endpoints will be assessed at the 6 and 12 month visits which will 
occur 180 ±30 days and 365 ±30 days, respectively, after the day of study product injection 
(Day 0).  
 
For the purpose of the safety evaluations and endpoint analysis, we will utilize an “intention-to-
treat” study population. In addition, because this phase I study is the first cell therapy study in 
this population, at 12 months all available standard-of-care medical records for cancer 
surveillance will be reviewed for cancer recurrence. Approximately thirty-six subjects will be 
enrolled over a 12-18 month accrual period. 
3.3 Study Treatment Assignments and Dosages 
Approximately thirty-six (36) subjects (including six actively treated lead-in participants and up to 
thirty-one randomized clinical trial participants) will be enrolled.  The six subjects participating in 
the open-label lead-in will receive allo-MSC as described below in Group A.  The remaining 
subjects will be randomized 1:1 to one of two treatment strategies:  
 Group A – Receive allo-MSCs: 20 endomyocardial injections of 5 million cells each (for a 
total of 100 million allo-MSCs); with each injection administered in a volume of 0.4ml.  
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 Group B – Receive placebo: 20 endomyocardial injections of cell-free Buminate solution; 
with each injection administered in a volume of 0.4 ml.  
The study product for Group A will be supplied from an allogeneic human MSC source 
(Appendix A); cells will be isolated from bone marrow of normal human donors and 
manufactured at a CCTRN cell manufacturing facility (CMF).  Administering 20 injections of 0.4 
ml each provides 8.0 ml of total study product volume with a cell concentration of 12.5 million 
total cells per ml, or 5 million cells per injection site. Twenty injections will be performed to treat 
the entire left ventricle (see section 5.4). 
3.4 Study Endpoints 
3.4.1 Safety Assessment 
To demonstrate the relative safety of allo-MSCs 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: 
1. Major adverse cardiac events (MACE) including death, hospitalization for worsening 
heart failure (HF), and/or exacerbation of HF (non-hospitalization) 
2. Other significant clinical events including non-fatal stroke, non-fatal myocardial infarction, 
coronary artery revascularization, ventricular tachycardia/fibrillation, pericardial 
tamponade, infectious myocarditis, hypersensitivity reaction, neoplasm, or any other 
potential deleterious late effects detected and corroborated by clinical presentation, 
laboratory investigations, image analysis, and when necessary with biopsy from 
suspected target sites in the body 
3. All adverse events (AEs) at least grade 2 in severity (see section 7.3.1) 
3.4.2 Feasibility Measures 
To assess the practicality of study procedures, the following measures will be reported. 
The number and percent of subjects who: 
1. Have events between randomization and SPI that preclude the subjects from getting SPI 
2. Receive less than 20 injections during the SPI procedure 
3. Do not receive the intended dose of cells (100 million), reason, and actual dose delivered 
4. Have at least one cardiac MRI endpoint measure that is uninterpretable due to issues 
related to the device, including, but not limited to, inability to undergo the procedure 
5. Fail to complete follow-up 
3.4.3 Prospectively Declared Efficacy Endpoint Measures: 
To explore whether allo-MSCs produce a trend toward improved LV function and functional 
status when compared with placebo, the following domains111 and measures will be evaluated: 
 
• 
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 area of injury (e.g., inflammation, edema, fibrosis)  
• 
Functional capacity over time: 
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 Change in exercise tolerance (6MWT)  
 Change in MLHF Questionnaire (subject reported) 
• 
Clinical outcomes over time: 
 MACE 
 Cumulative days alive and out of hospital 
• 
Biomarkers over time: 
 Change in NT-proBNP 
 
The comparisons above will be made between the allo-MSC and placebo groups. 
3.4.4 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 
participate in this sub-study by the MRI core lab.  
3.5 Sample Size 
This phase I study will recruit approximately 36 subjects who will have baseline and follow-up 
assessments to assess the changes over time in LV function and functional status.  It is hoped 
that we will establish the precision of these estimates 111. These measures will then be used to 
adequately power subsequent studies that will be able to determine the effect of therapy with 
statistical regularity and precision. The following measures will be assessed:  
1. LV End Diastolic Volume (LVEDV) Index 
2. LV End Systolic Volume (LVESV) Index 
3. LV Ejection Fraction (LVEF) 
4. Area of Injury (e.g., inflammation, edema, fibrosis) 
5. Sphericity Index criteria 
6. MLHF Questionnaire 
7. Exercise tolerance (6MWT) 
8. Global and regional strain 
 
This study will recruit 31 patients with the addition of 6 patients to account for loss-to-follow-up. 
Subjects will be followed for one year; this is six months more than our FOCUS study which 
experienced a 10% follow-up loss rate. Increasing the estimation for loss-to-follow-up in 
SENECA to 15% over the 12 month course of follow-up would produce 4.5 patients potentially 
lost, administratively rounded up to 6 patients. 
 
4.0 IDENTIFICATION AND ENROLLMENT OF SUBJECTS 
Potential subjects will be identified by the study team and medical records will be reviewed for 
possible consent to the study.   
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 
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 
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registry, 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 subjects includes reviewing medical records for inclusion/exclusions prior to consent, 
as well as subjects’ imaging studies. Subjects who are determined to have a diagnosis of AIC, 
have NYHA class of II or higher, have LVEF ≤ 45% by cMRI, and are a candidate for cardiac 
catheterization, and do not have evidence in their medical record of study exclusions, should be 
approached about consenting to the study.  EF ≤ 45% can be defined by gated blood pool scan 
(MUGA), cMRI, left ventriculogram, or EF ≤ 40% by two-dimensional echocardiogram.   
In order to exclude those with ischemic heart disease, available imaging in the patient’s chart 
will be reviewed.  Acceptable imaging for the detection of obstructive CAD includes coronary 
arteriogram or any non-invasive test within five years prior to enrollment in the study provided 
that there have been no symptoms or evidence of CAD since the test. If the subject has not had 
one of these tests done in the corresponding timeframe, then the individual should have one of 
these tests as standard of care (institutional choice) to be reviewed for entry into the study.  If a 
test is not otherwise authorized under a patient’s insurance under standard of care, a stress 
echo will be included as part of the baseline testing and paid for by the study, to be reviewed for 
eligibility.   
Prior to study entry an oncological assessment form will be completed by the subject’s 
oncologist to assess the risk of cancer recurrence.  Current medical records will be reviewed to 
verify the absence of any new metastatic disease, stage 4, or recurrence. 
4.2 Consent 
Before being admitted to the clinical study, all subjects must consent in writing to participate.  An 
informed consent form (ICF) will be given to each subject which will contain all United States 
federally required elements, all International Conference of Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH)-required elements, and 
Health Insurance Portability and Accountability Act Authorization (HIPAA) information in 
language that is understandable to the subject.  
A separate consent form will be utilized for six subjects participating in the open-label lead-in. 
These subjects will undergo the same screening and baseline procedures as those who will 
participate in the randomized phase of the study (see Section 6.0 below); however, all lead-in 
subjects will receive the allo-MSC product. 
 
Potential participants will be approached by one of the study investigators or research 
coordinators.  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 participant, and the time commitment involved with participating.  The ICF and 
review must be in a form understandable to the subject.  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 Investigator or his/her designee must emphasize to the 
subject that study participation 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. 
All consent forms will have IRB approval.  Individuals who agree to participate will receive a 
copy of the signed informed consent.  The research staff member obtaining consent will 
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document the informed process in the subject’s chart for monitoring purposes.   Translation of 
ICFs will be done in accordance with local IRB procedures. 
4.3 Inclusion Criteria 
     To participate, a subject MUST: 
1. Be ≥ 18 and < 80 years of age 
2. Be a cancer survivor with diagnosis of AIC 
3. Have an LVEF ≤ 45% by cMRI 
4. Be in NYHA class II-III 
5. Have received the initial diagnosis of AIC at least six months earlier and be on stable, 
optimally-tolerated therapy with beta-blockers, ACE inhibitors/ARBs, and/or 
aldosterone antagonists for 3 months, unless contraindicated  
6. Have a period of at least two years of clinical cancer-free state* and low likelihood of 
recurrence (a five-year risk of recurrence estimated at 30% or less), as determined by 
an oncologist, based on tumor type, response to therapy, and negative metastatic 
work-up at the time of diagnosis  
*exceptions to this are carcinoma in situ or fully resected basal and squamous cell cancer of 
the skin. 
7. Be a candidate for cardiac catheterization 
4.4 Exclusion Criteria 
     To participate, a subject MUST NOT HAVE: 
1. A life expectancy <12 months  
2. A CT scan or baseline cardiac MRI showing new tumor or suspicious lymphadenopathy 
raising concern of malignancy 
3. Presence of obstructive CAD as determined via imaging within 5 years prior to study 
enrollment provided there have been no symptoms or evidence of CAD since the test 
(see section 4.1 for imaging guidance) 
4. Had a previous myocardial infarction 
5. A history of radiation therapy AND evidence of constrictive physiology and/or 
evidence of other patterns of non-ischemic cardiomyopathy on cardiac MRI (e.g., 
amyloidosis, sarcoidosis, hemochromatosis, pure radiation-induced cardiomyopathy, 
etc.) not consistent with AIC being the dominant etiology of heart failure 
6. Valvular heart disease including 1) mechanical or bioprosthetic heart valve; or 2) severe 
valvular (any valve) insufficiency/regurgitation within 12 months of consent  
7. Aortic stenosis with valve area ≤ 1.5cm2   
8. A history of LV reduction surgery or cardiomyoplasty 
9. Evidence of cardiogenic shock 
10. A history of ischemic or hemorrhagic stroke within 90 days of baseline testing 
11. Liver dysfunction during baseline testing, as evidenced by enzymes (e.g., AST, ALT, 
alkaline phosphatase) greater than 3 times upper limit of normal  
12. Diabetes with poorly controlled blood glucose levels (HbA1c > 8.5%) 
13. An underlying autoimmune disorder or current immunosuppressive therapy (e.g., 
chronic corticosteroid, rheumatologic or immune modulating therapy) or likelihood of use 
of immunosuppressive therapy during participation in the trial (medications will be 
considered on a case by case basis) 
14. A baseline eGFR <35 ml/min/1.73m2 
15. A contrast allergy that cannot adequately be managed by premedication 
16. Received gene or cell-based therapy from any source within the previous 12 months 
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17. A hematologic abnormality during baseline testing as evidenced by hemoglobin < 9 g/dl; 
hematocrit < 30%; absolute neutrophil count < 2,000 or total WBC count more than 2 
times upper limit of normal; or platelet values < 100,000/ul 
18. Evidence of active systemic infection at time of study product delivery 
19. HIV, and/or active HBV or HCV 
20. Coagulopathy (INR > 1.5) not due to a reversible cause (e.g., warfarin and/or Factor Xa 
inhibitors) (see Section 6.4 re: injection procedure and anticoagulation therapy) Note: 
Subjects who cannot be withdrawn from anticoagulation will be excluded.  
21. Presence of LV thrombus (See guidance in Section 6.6.3) 
22. 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 
contraindicated 
23. Pacemaker-dependence with an ICD (Note: pacemaker-dependent candidates without 
an ICD are not excluded)  
24. A cardiac resynchronization therapy (CRT) device implanted less than 3 months prior to 
consent  
25. Other MRI contraindications (e.g. patient body habitus incompatible with MRI) 
26. An appropriate ICD firing or anti-tachycardia pacing (ATP) for ventricular fibrillation or 
ventricular tachycardia within 30 days of consent 
27. 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 
28. A 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 
29. Cognitive or language barriers that prohibit obtaining informed consent or any study 
elements (interpreter permitted) 
30. Participation (currently or within the previous 30 days) in a cardiac related investigational 
therapeutic (including stem cell based therapies) or device trial 
31. Pregnancy, lactation, plans to become pregnant in the next 12 months, or is unwilling to 
use acceptable forms of birth control during study participation 
32. Any other condition that, in the judgment of the Investigator or Sponsor, would be a 
contraindication to enrollment, study product administration, or follow-up 
4.5 Baseline Testing Window 
The baseline testing period extends from the date the ICF is signed until the study product 
injection (SPI) procedure.  This period will not exceed 45 days.  Should subjects fail baseline 
testing for a reason that is likely to change over time, they may be considered for re-testing.  
See section 6.2 for procedures and assessments to be performed during the baseline testing 
period. 
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Individuals meeting enrollment criteria will be scheduled to undergo the SPI procedure (see 
section 5.4) and randomized to cells or placebo (see section 4.6). The SPI procedure will occur 
no less than three days after randomization and no more than 45 days from signing the ICF. 
4.6 Randomization Procedures and Timing 
Randomization to treatment assignment (cells or placebo) will be conducted using a web access 
database created and maintained by the Data Coordinating Center (DCC). The research 
coordinator (RC) will randomize the subject via the CCTRN web-based database which will 
perform the computer-generated randomization assignment and send automatic emails notifying 
the study team that the treatment assignment can be accessed by unblinded study team 
members with appropriate security credentials. The RC will not randomize the subject until the 
following criteria are met: i) the subject has provided written informed consent, ii) baseline 
evaluations are complete, iii) the inclusion and exclusion criteria for the study have been 
satisfied, and iv) MSC product is available at the cell manufacturing facility (CMF) should the 
subject be randomized to the cell group. Randomization should occur no less than 3 days prior 
to the scheduled SPI procedure (to allow time for cell shipping and local product preparation) 
and no more than 7 days prior to the scheduled SPI procedure (to minimize the risk of 
randomizing subjects who do not receive treatment). 
 
5.0 STUDY PRODUCTS AND DELIVERY  
The study products (allo-MSCs and placebo) are each individually described but shall be 
referred to throughout the protocol as “study product”. 
5.1 Allogeneic Mesenchymal Stem Cells (allo-MSCs) 
The MSC cell bank will be prepared at the Center for Cell and Gene Therapy (CAGT) GMP 
Facility at Baylor College of Medicine which will be referred to as the Central Cell Manufacturing 
Facility (CCMF). The CCMF has a Facility Masterfile at the FDA describing its infrastructure and 
operations. In brief, the facility consists of 22 ISO 7 clean rooms in which manufacturing is 
performed. The MSC will be manufactured using the Terumo Quantum Cell Expansion system. 
This is a functionally-closed computer-controlled bioreactor. The cells adhere to hollow fibers 
that are pre-coated with recombinant Fibronectin. The cells are fed by continuous flow of 
medium through the bioreactor. After 48 hours the non-adherent cells are flushed from the 
bioreactor and feeding continues. Cell growth is assessed by measurement of glucose 
consumption and lactate production. When lactate levels reach 4mM/liter the flow of medium is 
doubled to 0.2 ml/min. This process is repeated until the flow rate has reached 0.4ml/min and 
the lactate levels are above 4mM. At this point the bioreactor is flushed with 2.5 times the 
reactor volume of phosphate- buffered saline. 180ml of recombinant trypsin (TrypLE Select) is 
added to the reactor for 15min to detach the cells. These are then automatically harvested into a 
bag containing growth medium. 
For passage two the cells are seeded into the Fibronectin coated bioreactor cartridge at ~1x104 
cells/ cm2  . Growth kinetics are monitored as described above. Harvesting is performed when 
the flow rate reaches 1.6ml/min and the lactate concentration reaches 4mM/liter. 
All operations are programmed into the bioreactor and reagent transfers are performed using 
sterile connect devices or aseptic connectors. Samples are taken for testing aseptically within 
an ISO 5 biological safety cabinet. This procedure has been reviewed by the Food and Drug 
Administration and approved for use in a separate IND submission. 
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For subjects randomized to receive allo-MSCs, allogeneic bone marrow donor-derived MSCs 
will be provided (Appendix A), according to established protocols, by the CCMF. The availability 
of allo-MSCs offers the potential for an “off the shelf” product for patients. Significant data have 
been generated (see section 2.4) to demonstrate that allo-MSCs are immunosuppressive73-75. In 
addition, allo-MSCs are immune-privileged and can be infused without immune rejection despite 
disparate HLA phenotypes56. 
5.1.1 Shipment of Cryopreserved allo-MSC Allografts 
The cells will be cryopreserved at the CCMF according to their standard operating procedures 
(SOPs) using a controlled-rate freezer and stored in the vapor-phase of liquid nitrogen in 
continuously monitored cell storage banks. Twenty-four hours prior to shipment, a validated 
liquid nitrogen dry shipper will be charged with liquid nitrogen. The following morning any 
remaining non-absorbed liquid nitrogen will be decanted from the dry shipper and the vials 
containing the frozen MSC will be transferred to the shipper. The Data Logger (temperature 
monitor) located in the lid will be activated and the shipper sent via Federal Express to the local 
cell processing laboratories (CPLs) following CCMF SOPs within one week prior to the 
scheduled injection procedure. The CCMF will also provide all relevant SOPs for product 
preparation for administration. Certificates of Analysis (COA) will be provided by the CCMF with 
each product shipped to the local CPL.  
5.1.2 Preparation for Administration of-MSC Allografts 
Relevant SOPs and worksheets used for thawing, washing, and testing of allo-MSC product will 
be provided by the CCMF.  The allo-MSC product will undergo QC testing before injection as 
indicated in Table 2a.   
1X108 allo-MSCs will be provided in a final volume of 8.0 ml of Buminate solution 5% HSA, at a 
cell concentration of approximately 12.5X106 total cells / ml. The physician will administer 20 
individual doses of 5X106 cells/0.4ml, per dose, per injection site. The 20th injection will be 
followed by 0.1 ml of saline to flush any residual cells from the line into the 20th injection site. It 
is permissible to prepare more than 8.0 ml of cell suspension, at a maximum concentration of 
12.5X106 cells / ml. However, any excess volume remaining after delivery of the 20 injections 
shall not be injected and shall be discarded according to institutional guidelines. 
Table 2a. Testing of allo-MSCs for Injection 
Assay 
Test Method 
Specification 
Viability* 
Trypan blue 
≥70 
Cell Count* 
Manual 
1x108  
Rapid Sterility* 
Gram Stain 
No organisms 
Endotoxin* 
EndoSafe PTS 
< 5EU/kg** 
Aerobic, Anaerobic, and Fungal 
14 day Bactec/BacT/ALERT 
assay or equivalent 
No Growth 
* Tests done for release criteria specification prior to injection 
** Based on recipient weight and product volume 
5.2 Placebo Group 
Subjects randomized to the placebo group will undergo the same baseline testing and imaging 
as those in the allo-MSC group. The placebo will be kept on site at the local CPLs. The fifteen 
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patients in the placebo group will receive transendocardial injections of cell-free Buminate 
solution in 20 injection sites. The placebo product will undergo QC testing before injection as 
indicated in Table 2b.  
 
Table 2b. Testing of Placebo for Injection 
Assay 
Test Method 
Specification 
Rapid Sterility* 
Gram Stain 
No organisms 
Endotoxin* 
EndoSafe PTS 
< 5EU/kg** 
Aerobic, Anaerobic, and Fungal 
14 day Bactec/BacT/ALERT 
assay or equivalent 
No Growth 
* Tests done for release criteria specification prior to injection 
** Based on recipient weight and product volume 
5.3 Blinding of the Interventionalist and Study Team 
With regard to safety, the interventionalist must be able to visualize the study product to inspect 
that it looks safe (e.g., free of air bubbles, clumping, etc.).  As the study product cannot be 
effectively masked, the process of blinding resides with endpoint and adverse event 
determination.  The cMRI endpoint will be determined by core laboratories.  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, 
and the MLHFQ endpoint data will also be blinded to the therapy assignment. 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 (see section 4.6) in order to assist with product 
preparation; however, the research teams (investigators, coordinators and other staff involved 
with endpoint data collection and event data) will be blinded to the treatment assignment.  If for 
important medical reasons unblinding is thought to be necessary, the Investigator may identify 
the treatment assignment by contacting the DCC who is responsible for maintaining 
randomization records for all subjects.  
5.4 NOGA Catheterization Procedure 
Intramyocardial cell delivery by 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. 
Left ventricular (LV) cine angiocardiography will be performed in orthogonal planes (typically 
RAO 30 and LAO 60 degree projections). End-diastolic endocardial contours 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 catheter(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. The mapping catheter is retrogradely 
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advanced across the aortic valve into the LV cavity. 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 MyoStar 
NOGA injection catheter will be prepared by adjusting the needle extension at 0° and 90° flex 
and priming the catheter by injecting the study product until a drop is observed at the extended 
needle tip (approximately 0.1 cc). All study product will be retained to complete the 20 required 
injections.  To ensure safety and limit potential for extracardiac administration of the injectate, 
the needle extension will be adjusted to ensure that the needle length is ≤ 0.5 mm and will 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 placed into the LV in retrograde fashion.  
Priority for selecting the 20 injection sites will be based upon the objective of delivering the study 
product in a minimum of four myocardial segments according to the AHA 17 segment polar 
map) selected by the investigator to be a territory which is: a) safely treatable with low risk of 
perforation or other complications; b) avoiding the true LV apex and other areas known to be < 6 
mm in myocardial thickness, and avoiding the left bundle branch site of earliest activation; c) 
clinically important based on viability assessments provided below; and, d) accessible with the 
tip of the selected MyoStar catheter.  
The NOGA map obtained will be unique in that it will display heterogeneous distribution of 
unipolar voltage in the LV, typical of patients with dilated cardiomyopathy. This is thought to 
represent areas of relative fibrosis and will serve as the basis for selection of the target injection 
area. The operator will proceed to delineate an injection area using the criteria mentioned above 
and ideally select injection sites that demonstrate intermediate level unipolar voltage (4 to 8mV). 
This range can be expanded to include areas with unipolar voltage of up to 12mV if necessary. 
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 will be placed at a 
site with a voltage threshold of ≥ 4mV and ≤ 8mV. When selecting sites for injection generally 
those with a voltage < 4mV will be avoided unless there are no higher unipolar voltage values 
present on the unipolar voltage map.  
Each of the 20 injections will contain either 0.4 ml of cell suspension with 5 million allo-MSCs per 
injection site for the active cell treatment arm or 0.4 ml of cell-free Buminate solution for the 
placebo group. 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 myocardium, constituting the 20th 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 
accompanied by a reference to injection number and presence or absence of needle-induced 
extrasystole. Sites of injection may also be recorded on cine fluoroscopy, and demarcated as a 
dot with the corresponding injection series number on 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 (within 6 hours).  Additional echocardiographic assessments for 
pericardial effusion will be done only as clinically indicated.  Troponin I or T will be collected 8 
(+/- 2) hours post-injection catheter procedure and again prior to discharge. An analysis of the 
impact of biomarker elevations on measures of LV function and MACE will be carried out. We 
believe this will demonstrate that biomarker elevations are not related to study outcomes. 
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5.5 Circumstances That May Affect Study Product Delivery 
If any of the following symptoms occur before or during SPI, they could indicate a serious 
clinical deterioration. If any of the following events/symptoms occurs, the procedure should be 
temporarily 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 20 mmHg not 
responsive to fluid administration 
2. Hemodynamically significant arrhythmia requiring antiarrhythmic therapy 
3. Two episodes of sustained ventricular tachycardia/ventricular fibrillation requiring cardioversion 
4. Hemodynamically unstable 
5. Fever (temperature increase to ≥100.4oF) 
6. Cardiac perforation 
7. Clinical signs and symptoms indicating a cerebrovascular accident 
6.0 CLINICAL AND LABORATORY PROCEDURES  
6.1 Schedule of Procedures (Table 3) 
SENECA           
Study Procedure 
BSL 
D0      
(SPI) 
D1 
Wk1     
(+/-3 
days) 
M1      
(+/-7 
days) 
M6      
(+/-30 
days) 
M12     
(+/-30 
days) 
M24     
(+/-30 
days) 
Call7 
Informed Consent 
X 
  
  
  
  
  
  
  
Complete Medical 
History 
X 
  
  
  
  
  
  
  
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
  
Vital Signs 
X 
X1 
X 
X 
X 
X 
X 
  
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
  
Con Medications 
X 
X 
X 
X 
X 
X 
X 
  
NYHA 
X 
  
  
  
X 
X 
X 
  
MLHFQ 
X 
  
  
  
  
X 
X 
  
12-lead ECG 
X 
X2 
X2 
X 
  
X 
X 
  
Stress Echo 
O 
 
 
 
 
 
 
 
2D Echoes 
  
X2 
 
  
  
  
  
  
Telemetry 
  
X3 
  
  
  
  
  
  
Labs and 
Biomarkers (PB)4 
X 
X 
X 
X 
X 
X 
X 
  
Cardiac MRI 
X 
  
  
  
  
X 
X 
  
ICD Interrogation5 
X 
X 
  
  
  
X 
X 
  
6 Minute Walk 
X 
  
  
  
  
X 
X 
  
Randomization 
X 
  
  
  
  
  
  
  
Catheterization / 
NOGA 
  
X 
  
  
  
  
  
  
Temp. Log 
  
  
X6 
  
  
  
  
  
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Telephone 
Interview 
  
  
  
  
  
  
  
X 
O= indicates optional test; dependent upon available imaging in the patient chart to assess CAD. 
Baseline testing, randomization, and SPI will take place within 45 days of ICF. 
 
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 catheterization procedure and again before discharge; 
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 for specific tests done at each time point. 
5. ICD interrogation (if applicable) done before and after every MRI as part of MRI protocol as well as before 
the SPI procedure. 
 
6. Temperature log 2x/day x 7 days. 
7. 24-Month contact is a telephone visit only. 
 
 
 
 
6.2 Baseline Testing  
See Table 3 above for the procedures and assessments to be performed during this phase of 
the study.  All baseline tests, procedures, and randomization, will occur within 45 days of signing 
informed consent form (ICF). No baseline testing will take place until the subject is fully informed 
of the research and signs the ICF unless the evaluations were being performed as part of 
routine medical care. After the subject has consented to the study, the subject will have a series 
of assessments to establish eligibility to receive study product. Randomization will take place 
after subject eligibility has been determined. 
 
Subjects will undergo the following tests and procedures during the baseline testing period: 
 
1. Comprehensive medical and surgical history, including smoking history and notation of the 
cumulative dose of anthracycline, time from anthracycline exposure to development of HF, and 
the time from diagnosis of HF to study enrollment 
2. Concomitant medication and adverse event assessment 
3. Physical examination including systems review 
4. Vital signs (blood pressure [BP], temperature, heart rate, respiratory rate)  
5. Height and weight 
6. NYHA class assessment (Appendix B)  
7. Questionnaire: Minnesota Living with Heart Failure Questionnaire (MLHFQ) (Section 6.6.2)  
8. cMRI (Section 6.6.3, MRI Core Lab Manual of Operations) 
9. ICD interrogation (if applicable).  Reports will be generated for the interrogations conducted 
before the MRIs at baseline and at the 6 month and 12 month visits.  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 adjudication). 
10. A 6-minute walk test (6MWT) (Section 6.6.1, Protocol Manual of Operations) 
11. 12-lead ECG 
12. Laboratory evaluations (Section 6.3) including pregnancy test on women of childbearing 
potential only 
13. For participants with no recent (within past 5 years) available imaging to assess CAD, and for 
which an updated test is not otherwise authorized under a patient’s insurance under standard of 
care, a stress echo will be obtained as part of the baseline testing and paid for by the study, to 
be reviewed for eligibility.  This test should only be done, if recent imaging is not otherwise 
available or obtainable. 
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6.3 Schedule of Laboratory Examinations (Table 4) 
Table 4. Laboratory Testing
BSL
Day 0   
(SPI)
Day 111
Wk 1
M 1
M 6
M 12
CMP/Chemistry Tests1  
X
X
X
X
X
X
X
CBC with Differential2
X
X6        
X       
X
X
X
X
Panel of reactive antibodies (PRA)
X
X
X
X
Liver Function Tests3
X
X
X
Pregnancy (childbearing women)
X
X4        
X
X
NT-proBNP5
X
X
X
Troponin I or T
X
X6        
X       
X
HbA1c
X
X
X
PT, INR, PTT7
X
X12
Infectious Disease Tests8
X
Peripheral Blood Collection (Biorepository)9
X10
X
X
X
X
 
 
1. 
Complete Metabolic Panel/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 
8. 
Infectious Disease Tests – HBc, HBsAg, HBV, HCV, HIV-1 groups M&O RNA, and Anti-HIV 
9. 
With appropriate consent, twenty (20) mL of peripheral blood will also be collected and transported to the 
CCTRN biorepository for scientific study (See Section 6.7 Collection of Biospecimens) 
10. 
Collected prior to sedation for the 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 SPI 
6.4 Day of Study Production Injection (SPI) – Day 0 
For subjects receiving systemic anticoagulation therapy, an INR measurement will be performed 
on the morning of the planned procedure.  Research teams should follow institutional and 
interventionalist standard of practice for managing anticoagulation before the SPI procedure.  
The following guideline could also be used.  Anticoagulation 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.112  Perform INR measurement on morning of planned procedure.  Require 
an INR of < 1.6 for these subjects to proceed with SPI.  For subjects on Factor Xa inhibitors, 
stop 2 days prior to planned SPI procedure.  
 
1. Incremental medical history 
2. Physical exam including vitals (BP, temperature, pulse rate) and weight 
3. Laboratory examinations (see section 6.3) 
4. ICD interrogation prior to SPI 
5. Cardiac catheterization and injection of study product (see section 5.4) including vitals 
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6. 12-lead ECG will be performed within 6 hours following the catheterization procedure and 
again before discharge 
7. A 2-D echocardiogram will be performed post SPI (within 6 hours). Additional 
echocardiographic assessments for pericardial effusion will be done only as clinically 
indicated. 
6.5 Follow-up Tests Performed After SPI  
Randomized subjects will be followed up at 1 week and 1, 6, and 12 months after study product 
injection for regular history and clinical examination. The MLHFQ will be repeated at 6 and 12 
months after SPI. To further evaluate their functional capacity, subjects will also undergo a 
6MWT at 6 and 12 months after SPI.  Subjects will be assigned a functional class during the 
month 1, 6, and 12-month follow-up visits based on the standard NYHA classification.  Patients 
treated with allo-MSCs or placebo will undergo the following tests at various time points after the 
procedure (Table 3): 
6.5.1 Day 1 (within the first 24 hours after SPI) 
1. Subjects will be monitored on simple telemetry up to 24 hours post-procedure or until 
discharge, whichever is sooner.  
2. Incremental medical history 
3. Physical exam including vitals (BP, temperature, pulse rate)  
4. Laboratory examinations (Section 6.3) 
5. 12-lead ECG will be performed within 6 hours following the catheterization procedure 
and again before discharge 
6. The subject will keep a daily temperature log for seven days following the catheterization 
procedure to help assess the early development of an infection. 
6.5.2 Week 1 (± 3 days after SPI) 
1. Incremental medical history 
2. Physical exam including vitals (BP, temperature, pulse rate) and weight 
3. Laboratory examinations (Section 6.3) 
4. 12-lead ECG 
5. Collect temperature log from subject 
6.5.3 Month 1 (± 7 days after SPI) 
1. Incremental medical history 
2. Physical exam including vitals (BP, temperature, pulse rate) and weight 
3. Laboratory examinations (section 6.3) 
4. NYHA classification (Appendix B) 
6.5.4 Month 6 (± 30 days after SPI) 
1. Incremental medical history 
2. Physical exam including vitals (BP, temperature, pulse rate) and weight 
3. Laboratory examinations (see section 6.3) 
4. NYHA classification (Appendix B) 
5. cMRI (Section 6.6.3, MRI Core Lab Manual of Operations) 
6. Questionnaire: MLHFQ (Section 6.6.2) 
7. 12-lead ECG 
8. 6MWT (Section 6.6.1, Protocol Manual of Operations) 
6.5.5 Month 12 (± 30 days after SPI) 
1. Incremental medical history 
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2. Physical exam including vitals (BP, temperature, pulse rate) and weight  
3. Laboratory examinations (Section 6.3) 
4. NYHA classification (Appendix B) 
5. cMRI (Section 6.6.3, MRI Core Lab Manual of Operations) 
6. Questionnaire: MLHFQ (Section 6.6.2) 
7. 12-lead ECG 
8. 6MWT (Section 6.6.1, Protocol Manual of Operations) 
9. A standard of care visit with subject oncologist (or post-cancer follow-up care provider) 
within 3 months after study completion (to assess cancer recurrence during the study 
period). 
 
6.5.5.1 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 6.7.3). 
6.5.6 Month 24 Telephone Contact 
A Month 24 telephone contact will be made to assess current medications, as well as morbidity 
and mortality in study subjects. 
6.5.7 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 6-month visit will be at 180 ±30 days. 
4. The 12-month visit will be at 365 ±30 days. 
5. The 24-month phone call will be at 730 ±30 days. 
6.5.8 Lost to Follow-up 
Randomized subjects will be followed for up to two years.  Subjects will be considered lost to 
follow-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. 
6.6 Collection of Endpoints 
6.6.1 Six-minute Walk Test (6MWT) 
6MWTs will be performed to assess functional capacity. Subjects will perform a 6MWT during 
baseline and at 6 and 12 months. See Protocol Manual of Operations for acquisition details. 
 
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.  The tests will be done at consistent intervals. 
6.6.2 Minnesota Living with Heart Failure Questionnaire (MLHFQ) 
The subjects’ quality of life will be assessed with the MLHFQ during baseline and at 6, and 12 
months. The questionnaire includes details of subjects’ symptoms specifically related to 
functional status and development of HF. 
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6.6.3 Cardiac Magnetic Resonance Imaging (cMRI) Evaluation 
Cardiac MRI is a new diagnostic modality that provides superior assessment of the cardiac 
function, myocardial scar size measurement, and myocardial perfusion evaluation. Steady state 
free precession (SSFP) cardiac MR imaging will provide valuable information regarding cardiac 
anatomy and will assess the myocardium, including myocardial mass and zones of acute 
infarction. Cine MRI will also be performed on study patients and it is used to evaluate left and 
right ventricular function and size, and valvular and shunt lesions. Contrast-enhanced MRI will 
also be used to assess myocardial viability and scar quantification. 
 
In addition to these more traditional cardiac MR techniques, we will be using T1 myocardial 
mapping techniques (at centers which have this capability and are qualified by the MRI Core 
Lab) to help garner a more complete picture of the myocardial condition.  Recently, T1 mapping 
has been shown to effectively demonstrate fibrotic changes in myriad pathologic conditions114-
116. While the delayed gadolinium enhancement is very sensitive to small areas of regional 
fibrosis, the method is dependent on the comparison to the signal from “normal myocardial” 
reference areas. In patients with more diffuse fibrosis (such as those with AIC), T1 mapping will 
be an essential adjunctive tool. Preliminary studies involving AIC and T1 mapping are 
promising117.  
 
In addition to the evaluation of myocardial fibrosis, the utility of cardiac MR studies for gauging 
functional indices is also quite robust. However, while LVEF has been used as a “gold standard” 
of therapeutic response, it may lack the sensitivity required to measure subtler, yet clinically 
relevant changes. Conceptually, this correlation between decreased strain and clinical events 
has been well described. One seminal study included 147 patients with heart failure with LVEF ≤ 
45% (mean age, 64 ± 14 years; 74% men; mean LVEF, 29.9 ± 8.9%)119.  Clinical events were 
observed in 20% of patients during the 12-month follow-up period and global longitudinal strain 
was shown to have the highest prognostic value over conventional EF measurements with an 
area under the curve of 0.83 using a cutoff of -7%119. Specifically, in chemotherapy-induced 
cardiomyopathies, strain has been shown to have greater sensitivity and have similar predictive 
value120. Hence, using cardiac MR studies to measure these more sensitive indices of function 
may allow for a more informative and conclusive study of cell therapy mechanisms and benefits 
in this setting. Tagged MRI will be performed, and global and regional myocardial strains and 
strain rates will be computed using the harmonic phase method. 
This information, obtained before and after study product injection, will be crucial in estimating 
the benefit gained by injecting stem cells as well as evaluating the potential side effects.  
Cardiac MRI will be performed in all patients at baseline and at 6 and 12 months after SPI.  See 
MRI Core Lab Manual of Operations for acquisition details. 
Guidance to the Principal Investigator: MRI was selected as the imaging modality for 
endpoint 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, 
endothelialized, mural thrombi that may or may not rise to the level of clinical significance.  
 
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 
series/views will highlight it for 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 
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are reviewed by the local radiologist for clinical findings for the PI’s consideration before 
enrollment. 
 
Identification and clinical evaluation of LV thrombus: The MRI core lab will provide their 
interpretation 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 latter by stating, "cannot rule out small LV thrombus". For these, it will then be up to the site 
study Principal Investigator and the interventionalist 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 proceed, documentation of that determination must be included in the 
participant’s chart. 
 
 
6.6.3.1 Performance of MR examinations in subjects with implantable cardiac devices 
(ICD/pacemakers)  
The presence of a pacemaker or implanted defibrillator device is not a contraindication to MRI 
scanning121,122. 
 
The procedures use are based upon the safety recommendations as listed in “Safety of 
Magnetic Resonance Imaging in Subjects With Cardiovascular Devices: An American Heart 
Association Scientific Statement”121. 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 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 measurements and re-enabling of therapy and other 
device parameters. 
3. Advanced Cardiovascular Life Support (ACLS) trained personnel and a “crash cart,” 
including 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 
oximetry, blood pressure measurements every 5 minutes, and symptoms are monitored 
including throughout the scan. 
Regarding specific implanted device parameter measurements and programming changes, 
protocols of Johns Hopkins University123 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 
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5. Limitation of the estimated whole-body averaged SAR to <2.0 W/kg for MR scan 
acquisition 
6. Exclusion of subjects with leads implanted less than six weeks prior to study enrollment 
As a part of the training process, experienced personnel with large volume experience in MR 
imaging patients with pacemakers and ICDs will oversee the initial cases at each site until 
adequate proficiency is reached by each site’s imaging staff members. 
6.7 Collection of Biospecimens 
A central CCTRN biorepository will be utilized in this study.  The biorepository will be included in 
the consent form and subjects will have the option of participating in the sample donation.  
Participation in the study does not equate with participation in donating to the biorepository; 
subjects can decline the biorepository donation and still participate in the overall trial. 
The goal of this biorepository is three-fold: 1) to provide storage of critical biomaterials (i.e., 
subject peripheral blood and donor allo-MSC product) 2) to provide long-term integrity (up to 10 
years) of these biospecimens and products, and 3) to provide management of samples for 
ancillary studies of immunologic, immunohistochemical, cellular, and molecular analyses of 
donor allo-MSC product and subject serum 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 successful intervention.  
These biomaterials will be used for research purposes only (not for profit), will be stored without 
personal identifying information, and will be shared with approved researchers who will conduct 
studies to improve the understanding of the effects of cell therapies. Biomaterials will be 
destroyed after 10 years. 
6.7.1 Peripheral Blood 
Twenty ml of peripheral blood will be collected on Day 0 (day of injection, before sedation for 
SPI procedure), Day 1 (within 24 hours after SPI), Week 1, 1 month, and 6 months. This blood 
will be sent to the CCTRN biorepository per core lab SOP. 
6.7.2 Allo-MSC Allografts 
A sample of the allo-MSC cell bank will be provided to the CCTRN biorepository for additional 
characterization studies. 
6.7.3 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.  With appropriate consent, the explanted heart will be sent 
to the CCTRN biorepository for further study. 
All surplus biospecimens (bone marrow and blood) will be cryopreserved up to 10 years. 
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 and Monitoring Board (DSMB), and the Food and Drug 
Administration (FDA).  The program complies with applicable U.S. law, regulations, and 
guidance.  
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7.1 Definitions Related to Adverse Events 
The following definitions arise from recently modified FDA reporting regulations and 
International 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 
associated 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 
reasonable possibility that the drug caused the adverse event.  For the purposes of IND safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between 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-
threatening 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. 
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 
additional 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 constitute 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 
serious. 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., 
caregiver 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. 
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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 
participation in the study, i.e., prior to undergoing any study related procedure and/or receiving 
investigational product, through and including 30 calendar days after the subject completes the 
12-month clinic visit. Events should be recorded on the Adverse Event electronic case report 
form (eCRF).  Do not delay the initial 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 
investigational 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 
immediately (i.e., if an outpatient study subject initially seeks treatment elsewhere), the 
Investigator 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. 
Please note: Grade 1 (Mild) AE/SARs are not entered in the electronic CRF in the CCTRN database.  
 
Severity
Grade
Description
1
Mild. Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 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. Hospitalization 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.
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 
serious 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/procedure and an event is listed in the following table.   
Adverse Event/Suspected Adverse Reaction Relationship to Study Product/Procedure 
 
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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, environment 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/procedure. 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. 
 
7.3.3 Expectedness Assessment  
The DCC nomenclature for assessing whether an event is expected or unexpected with regard to 
the study product 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 information 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 
reports, 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 
relatedness to study product/procedure; and a Sponsor assessment of the event given 
the information known at the time of the initial reporting.   
Event specific reports are formal written reports providing the details of the event 
(including circumstances surrounding the event, laboratory testing, concomitant 
medications, and any formal diagnoses made via medical intervention).  These reports 
include a full sponsor assessment of the severity, expectedness, and relatedness to 
study product/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 
experienced in the overall trial.  The information provided includes both new events 
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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 
Email notification to DSMB 
Within 15 calendar days 
Event is grade 3 AND EITHER  
unexpected OR related 
 
Event specific report to DSMB 
Within 30 calendar days 
Email notification to DSMB 
Within 72 hrs 
Event is unexpected AND related AND 
(grade 2-grade 5) 
 
Event specific report to DSMB 
Within 7 calendar days 
 
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 
requirements to the FDA: 
Type of SAE/SSAR 
Report to 
Timeframe 
Fatal or life-threatening, unexpected, and 
associated with study product/procedure 
FDA 
MedWatch submitted within 7 calendar 
days of learning of event 
Other SAE/SSARs that are non-fatal or life-
threatening but are unexpected and associated 
with study product/procedure  
FDA 
MedWatch submitted within 15 calendar 
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 
procedures 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 subject population being studied; 
 Definitely, probably, or possibly related to participation in the research (i.e., there is a 
reasonable 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 
recognized. 
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. 
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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, 
modification, or termination of the study for safety reasons.  
 
7.7 Review of Open Label Lead-in (six subjects) 
The following outlines the process for the collection and review of data for the six subjects 
participating in the open label lead-in portion of the study: 
 
1. Six subjects who consent and meet all inclusion and exclusion criteria will receive allo-
MSC cell therapy per protocol. 
2. All subjects will be observed for any complications or adverse effects of 
electromechanical mapping or delivery of cell therapy.  
3. Events will be reported to regulatory oversight groups as outlined above in section 7.4. 
4. The DSMB will review 1 month safety and feasibility data from each of the six subjects. 
These data will also be forwarded to the FDA in a subsequent amendment. 
5. Upon successful DSMB review of the lead-in data, the study will be permitted to recruit 
the remaining approximately thirty subjects into both the active and placebo groups to the 
specified protocol sample size. 
 
8.0 STATISTICAL PROCEDURES 
8.1 Randomization Strategy and Monitoring 
Randomization, or the random allocation of therapy, is a well-accepted mechanism for reducing 
potential bias in evaluating treatment effects. Randomization process, timing, and notification 
details are provided in section 4.6 above. Subjects will be randomized either to allo-MSCs or to 
placebo stratifying by center and using block sizes of 2.   
The DCC will monitor recruitment by providing reports to the NHLBI Project Office as 
appropriate during the recruitment phase.  Updated 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 Delays and Early Withdrawal from the Study 
There may be circumstances in which randomized subjects experience a delay in receipt of 
study product.  There may also be circumstances that do not allow for randomized subjects to 
receive study product. These circumstances are discussed further below. All randomized 
subjects who do not receive SPI in the expected timeframe will have their case reviewed by the 
Medical Monitor and SENECA Center PI to assess whether the subject should be withdrawn 
immediately or delay study procedures for another attempt. 
Circumstances that may result in delaying SPI could be related to a change in the clinical 
condition of the subject or to an issue with local cell processing and product preparation.  
1. A randomized subject who has a resolvable change in their clinical condition, and for 
whom the product has not yet been prepared for injection, will be allowed to have their 
SPI postponed.  
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2. If a cell processing related issue arises on the day of the SPI procedure and additional 
product can be delivered at a later time, the subject will have their SPI postponed.  
Length of postponement will be determined by the Medical Monitor and SENECA 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. 
In this first-in-human, phase I trial, SENECA's principal analysis will be "intention-to-treat".  The 
anticipated small number of patients who are randomized but do not receive treatment will have 
the reason for non-treatment tabulated. 
8.3 Statistical Analyses  
Biostatisticians at the DCC, with the assistance of scientific programmers, have adapted or 
developed 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 
adverse treatment effects.  The DCC uses standard statistical packages such as SAS, S-PLUS, 
R, and Stata to perform statistical analyses. The specific analysis plans follow: 
8.3.1 Baseline Analyses 
Although the stratified random assignment of participants to the various treatments should 
ensure 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) 
physical examination; 4) laboratory data; and 5) quality of life and psychosocial data. Exact 
testing for categorical variables and Wilcoxon two sample rank sum test for continuous variables 
will be used to evaluate the differences in baseline variables between treatment groups.  
8.3.2 Outcome Analyses 
All analyses will be performed on two cohorts; (1) the randomized cohort, and (2) the total 
cohort (randomized plus the six patients who received open label therapy in a nonrandomized 
fashion). 
 
8.3.2.1 Safety Evaluations 
To demonstrate the relative safety of allo-MSCs when compared with placebo, the following 
analyses will be carried out, and the data tabulated and analyzed by therapy group (Fisher’s 
Exact Test) between baseline and a) 6 months and b) 12 months: 
1. Major adverse cardiac events (MACE) including death, hospitalization for worsening 
heart failure (HF), and/or exacerbation of HF (non-hospitalization) 
2. Other significant clinical events including non-fatal stroke, non-fatal myocardial infarction, 
coronary artery revascularization, ventricular tachycardia/fibrillation, pericardial 
tamponade, infectious myocarditis, hypersensitivity reaction, neoplasm, or any other 
potential deleterious late effects detected and corroborated by clinical presentation, 
laboratory investigations, image analysis, and when necessary with biopsy from 
suspected target sites in the body 
3. All adverse events (AEs) at least grade 2 in severity (see section 7.3.1) 
 
8.3.2.2 Feasibility Evaluations 
To assess the practicality of study procedures, the following measures will be reported. 
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The number and percent of subjects who: 
1. Have events between randomization and SPI that preclude the subjects from getting SPI 
2. Receive less than 20 injections during the SPI procedure 
3. Do not receive the intended dose of cells (100 million), reason, and actual dose delivered 
4. Have at least one cardiac MRI endpoint measure that is uninterpretable due to issues 
related to the device, including, but not limited to, inability to undergo the procedure 
5. Fail to complete follow-up 
  
8.3.2.3 Prospectively Declared Efficacy Endpoints 
To explore whether allo-MSCs produce a trend toward improved LV function and functional 
status when compared with placebo, the following domains111 and measures will be evaluated: 
• 
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 area of injury (e.g., inflammation, edema, fibrosis)  
• 
Functional capacity over time: 
 Change in exercise tolerance (6MWT)  
 Change in MLHF Questionnaire (subject reported) 
• 
Clinical outcomes over time: 
 MACE 
 Change in days alive and out of hospital 
• 
Biomarkers over time: 
 Change in NT-proBNP 
 
All endpoints listed above are continuous and will be assessed with the following approaches. 
1. Examination of departures from normality will be assessed. A general linear mixed model 
approach: The within subject component of the twelve-month evaluation will reflect the 
measures obtained at baseline, six months, and twelve months. The between subject 
component will reflect the effects of the cell types (allo-MSCs versus placebo). We are 
interested in testing whether the trajectory over time of the change in each of the 
endpoints above is modified by treatment (allogeneic versus placebo.) 
2. The Wilcoxon two sample rank sum test, comparing the changes in the endpoint 
variables from a) baseline six months and b) baseline to twelve months. 
8.4 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 age, gender, race, diabetes, hypertension, 
presence of a cardiac device, type of malignancy, baseline LVEF≤40% vs >40%, and number of 
cells delivered.   For each endpoint, the effect of therapy will be determined within each 
subgroup stratum using the mixed general linear model with the subgroup strata as an explainer 
variable collection (i.e., a subgroup with p stratum will have p-1 indicator variables. Interactive 
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models are likely to be underpowered in this relatively small study. These additional analyses 
can sometimes be helpful in identifying extreme differences in the effects of treatment among 
subgroups, although the literature wisely warrants that caution be used in interpreting subgroup 
analyses.  
8.5 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 in 8.3 above. 
8.6 Multiplicity Issues 
This is the first study evaluating the effect of mesenchymal cells in patients with anthracycline-
induced cardiomyopathy.  No adjustments will be 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. 
Because of the high false discovery rate in our study, the findings from our study cannot be 
accepted by the research community as confirmatory, but must be treated as preliminary, 
requiring an additional study to confirm the SENECA results. 
 
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 
reviewed 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 
purpose 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 
subject’s record. 
9.1.1 Informed Consent Process 
Potential participants will be approached by one of the study investigators or research 
coordinators.  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 participant, 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 consent.  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 local IRB procedures. 
9.1.2 Risks Associated with Study Product Injection  
9.1.2.1 Cardiac Catheterization and NOGA Mapping 
Potential risks of this procedure include bleeding, hematoma at catheter insertion site, allergic 
reaction to the angiography dye, formation of a blood clot which could lead to loss of function or 
surgical intervention. It is possible the patient 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: temporary 
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 
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need for an urgent coronary artery bypass graft (open heart surgery).  Serious complications, 
including death, happen in less than 1 in every 1,000 tests that are performed. 
 
The risks of the use of the iodine that is in the contrast media for the heart angiography 
procedure are rare.  Some problems that might occur are hypersensitivity or even severe 
allergic reactions, or decreased kidney function, particularly in those patients with underlying 
kidney problems.   
 
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 in the heart causing blood to 
accumulate around the heart, irregular heartbeats (including ventricular tachycardia 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. Some radiation is involved as part of the NOGA study. 
9.1.2.2 Cell Processing 
For those patients receiving the allo-MSC cell product, it is possible that the body might react 
and reject the allo-MSC cells. Human clinical research studies with allo-MSCs in heart patients 
have provided evidence against the occurrence of rejection of the transplanted cells and also 
against the occurrence of GVHD, where healthy infused cells recognize the tissues of the 
person receiving the cells as "foreign" and mount an immunologic attack. 
Processing the cells is done under strict sterile conditions; however, there is a rare chance that 
the cells could get contaminated while being processed.  Testing will be done on the cells; 
however, it takes about 2 weeks to get the final results.  If the tests show cells were 
contaminated, the treatment team will be notified so that the patient may be treated with 
antibiotics.  Subjects will be taking their temperature twice a day for one week, which may help 
determine infection before the test results are known.  
 
There may be some circumstances where the patient is unable to receive the processed cells; 
such as a processing failure or poor quality of the cells. If events such as these occur, the 
patient will not receive the allo-MSC cells but will be asked to continue with follow up in the 
study.  Processes in place to prevent these failures include: the use of standard operating 
procedures for preparing the allo-MSC cell product, which will identify any problems with the 
study product before it is released, and continuous temperature monitoring of the product during 
shipment to the treatment facility. 
9.1.2.3 Study Product Injection 
Possible problems that might happen include (but others could occur): decreased blood 
pressure, irregular heartbeats, possible firing of ICD, chest pain or discomfort, damage to the 
heart muscle, perforation of the heart causing blood to accumulate around the heart, bleeding, 
heart attack, stroke, dislodgement of material into other arteries (possibly causing blockage), 
need for emergency surgery, and death.  It is possible that a small quantity of cells will enter the 
bloodstream 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 effects which could cause an inflammatory response.  Injection directly into the heart 
muscle also may cause inflammation or irritability.  
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9.1.2.4 MRI Procedure 
Risks associated with administration of contrast dye are nausea, vomiting, and headache. 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 kidneys.   Recent 
publications report some deposits from GBCAs remain in the brains of some patients who 
undergo four or more contrast MRI scans, long after the last dose is received.    Recent 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 adverse 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 
increased with patients who already had some evidence of kidney disease or diabetes, or are 
dehydrated.  
There is no radiation exposure from MRIs. 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. 
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 don’t react to an MRI’s magnetic field and will 
be monitored during the MRI scan. There is now enough experience with this strategy, which 
has proven to be safe.  During the scan there is an increased risk of experiencing an arrhythmia, 
which could be life threatening or fatal.  A cardiologist or specifically trained registered 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 procedure. 
9.1.2.5 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 
approximately 1.2 rem. 
9.1.3 Adequacy of Protection Against Risks 
Overall the study procedures are low risk and in our previous similar trials there were no 
complications related to study product delivery. 
9.1.4 Potential Benefits of the Proposed Research to the Subjects and Others 
Subjects with AIC 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 
project 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 allo-MSCs offers a new therapeutic option to subjects with LV dysfunction 
secondary to AIC; the goal of this new treatment is not just to reduce the rate of LV deterioration 
but to actually ameliorate heart failure. Having highly trained experts deliver and oversee the 
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therapy, in conjunction with close study monitoring, substantially reduces the likelihood of 
adverse events.  The potential risks to the subjects remain reasonably low in relation to the 
possible benefit of improving their heart function above that 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 
whether a promising cell type that heretofore has demonstrated the likelihood of few risks to the 
subject is well-tolerated by subjects with LV dysfunction secondary to AIC; and 2) determine if a 
dose of 100 million allo-MSCs delivered intramyocardially produces improvement in measures 
of myocardial function. The trial has been designed to address a novel area of study for a no-
option group with a grim prognosis. The risks to the subjects are reasonable in relation to the 
knowledge gained from this study since this therapy may potentially reverse AIC, which is a 
leading cause of morbidity and mortality throughout the world. 
9.1.6.1 Data and Safety Monitoring Board (DSMB) 
The Data and Safety Monitoring Plan has been outlined in Section 7 above. 
9.2 Clinical Monitoring 
9.2.1 Pre-Investigation Visits 
The DCC team assures that the Investigator clearly understands and accepts the obligations 
incurred in undertaking a clinical investigation. 
Prior to the initiation of a clinical investigation, the DCC team will train the site of the clinical 
investigation to assure that the Investigator: 
1. Understands the investigational status of the test article and the requirements for this 
accountability.  
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 
sponsor 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 
Investigator 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: 
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.  
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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 
documents 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 
administration to any subject of concomitant test articles or the development of an 
intercurrent illness. 
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 
reports.  
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 
deficiencies for each on-site visit to an Investigator. Such a record may enable the FDA to 
determine 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.  
Additional requirements 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 
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  
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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 
consent 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 
outlined by 21 CFR Subpart D; Part 312.50-312.70. 
9.4.2 Routine Duties 
The DCC is responsible for obtaining and reviewing copies of IRB approvals. They are 
responsible for setting up all training for each site and reviewing all certification of their local 
laboratories for handling of study products. The DCC will ensure that the study is conducted 
according 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 IND for this study 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 approval, annual progress reports to the FDA and all final reports. The DCC 
will maintain all records according to Good Clinical Practice Guidelines (GCP). 
 
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.  
Detailed 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.   
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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 
authentication, will be maintained for the entry of and/or access to subject data.  The data 
collected 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 
issues.  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 
authorized 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 encrypting 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 audit 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 
secure login authentication.  The DCC will provide training and documentation to laboratory 
personnel 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 
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database.  The rejected records will be sent back to the centers/lab for correction and re-
transmittal. 
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 
acceptance 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.  
Personnel 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 response 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 automatic 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 
using 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 workstations 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 
The overall usefulness of scientific research depends not only on the importance of the findings, 
but also on its eventual reach and effect on population health.  Therefore, research projects 
must integrate ways to promote the eventual diffusion of the results into their research plans.  
CCTRN will work with professional associations to access health care providers like the NHLBI 
has done for a number of initiatives including asthma and hypertension.  CCTRN will use two 
general dissemination methods that will be tailored for the target audiences. 
9.6.1 Web Site 
The web site has been created with objectives targeted to the study audience.  The CCTRN 
web site will serve as one method of distribution of information about stem cell research in 
cardiovascular 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 information about the research that is closely tied to clinical trial opportunities 
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and potential treatments for subjects.  This information should be tied to the normal places 
practitioners seek such resources.  For the researcher, the website provides more in-depth 
technical information and published works.  For the CCTRN investigators, the website provides a 
central location for meeting information, clinical trial information, and other resources. 
9.6.2 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 
manuscripts 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 Processing and other Cores, will provide consultation and assistance to the CCs regarding 
the appropriate 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 
active papers, as well as a study bibliography including abstracts, presentations, letters, 
editorials, etc. 
9.6.3 Methodologic Developments 
In addition to providing statistical support to PIs at CCs and NHLBI, Investigators at 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 
presented to scientific meetings and in statistical journals as peer-reviewed articles. 
 
 
 
 
 
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APPENDIX A: Normal Donors for Generation of Allo-MSCs 
 
Procurement of Bone Marrow for allo-MSC Production  
Bone marrow (BM) will be obtained from a normal volunteer, aged between 18 and 45, 
undergoing bone marrow harvest for transplantation to an allogeneic stem cell transplant 
recipient. 25-50 ml (+/-10 ml) additional marrow will be aspirated from the posterior iliac crest. 
The BM will be aspirated into pre-heparinized syringes containing preservative-free heparin for a 
final effective dose of ~100 units of heparin / ml of BM. The MSCs will be isolated and expanded 
to a final dose of 1x108 allo-MSCs according to standard operating procedures (SOPs) of the 
CCMF.  
 
Eligibility Criteria  
1. The donor must meet the eligibility criteria for normal allogeneic bone marrow donors 
established by the FACT accredited Stem Cell Transplant Program at Baylor College of 
Medicine, Houston, Texas. 
2. In addition, the donor must meet the eligibility requirements established under the Code 
of Federal regulations Title 21 CFR Part 1271 Subpart C – Donor Eligibility, which 
require official documentation of donor eligibility for donors of HCT/P based upon 
infectious disease testing, risk behaviors and clinical examination. 
 
  
Informed Consent 
Informed consent to donate additional bone marrow shall be obtained and documented. The 
procedure shall be explained in terms the donor can understand, and shall include information 
about the significant risks of the procedure. The donor shall have the right to review the results 
of tests. The donor shall have the opportunity to ask questions and the right to refuse to donate.    
 
Follow-up Schedule  
After discharge from the hospital, the BM donor will be followed up according to standard 
operating procedures in place at the Stem Cell Transplant Program at Baylor College of 
Medicine, Houston, Texas and described in the informed consent documentation. The donor 
will be provided with contact telephone numbers in the consent form for any questions or 
comments.   
 
 
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Appendix B: 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. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased. 
 
 
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