A Randomized, Double-Blind, Placebo-Controlled Phase IIa Study of the Safety and Efficacy of Intravenous Delivery of Allogeneic Mesenchymal Stem Cells in Cardiomyopathy Patients and Implanted Left Ventricular Assist Device
Phase: PHASE2
Conditions: Ischemic Heart Disease, Non-ischemic Cardiomyopathy
Sponsor: Medstar Health Research Institute

PROTOCOL 
 
TITLE: 
A randomized, Multi-center, Double-Blind, Placebo-Controlled Phase IIa Study of 
the Safety and Efficacy of Intravenous Delivery of Allogeneic Mesenchymal Stem 
Cells in Patients with a Cardiomyopathy and Severe Heart Failure who Required 
Implantation of a Left Ventricular Assist Device (LVAD) 
 
 
IND NUMBER: 
IND 18457 
 
 
 
PROTOCOL NUMBER:  STEMVAD-001 
 
 
 
INVESTIGATIONAL 
 
PRODUCT: 
Allogeneic Mesenchymal Bone Marrow Cells, (MSCs) (adult human) 
 
 
 
 
MEDICAL MONITOR: 
William S. Weintraub, MD 
 
 
 
 
SPONSOR: 
 
 
 
CENTERS:
 
 
 
 
CONTACT: 
MedStar Heart and Vascular Institute 
 
 
 
 
Up to 2 
 
 
Samer Najjar, MD 
 
MedStar Heart and Vascular Institute 
110 Irving St NW, Suite 1F-19 
Washington, DC 20010 
Ph: 202-877-8085 
Fax: 202-877-8032
 
 
 
 
 
 
 
 
 
 

 
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PROTOCOL ACCEPTANCE FORM ................................................................................................... 5 
PROTOCOL SYNOPSIS ..................................................................................................................... 7 
ABBREVIATIONS ............................................................................................................................... 9 
BACKGROUND ................................................................................................................................ 11 
1 Left ventricular assist device therapy for advanced ischemic heart failure ..................................... 11 
1.1 Ischemic heart failure .................................................................................................................. 11 
1.2 Left ventricular assist devices ..................................................................................................... 11 
1.3 Persistent inflammation as a cause of progressive cardiac dysfunction. .................................... 12 
2 MESENCHYMAL STEM CELLS .................................................................................................... 13 
2.1 Modifying MSCs for enhanced production rate and enhanced functionality ................................ 13 
2.2 Potentiation of MSCs with Hypoxic Culture ................................................................................ 14 
2.3 Potency of MSCs Cultured in a Hypoxic Environment ............................................................... 14 
3 
STUDY OBJECTIVES ............................................................................................................... 27 
3.1 Primary ........................................................................................................................................ 27 
3.2 Secondary ................................................................................................................................... 27 
4 
STUDY DESIGN ........................................................................................................................ 28 
4.1 Description of the Study ............................................................................................................. 28 
SUBJECT PARTICIPATION ............................................................................................................. 29 
CONCOMITANT THERAPY AND CLINICAL PRACTICE ................................................................. 31 
4.2 Endpoints .................................................................................................................................. 32 
PRIMARY ENDPOINT ...................................................................................................................... 32 
SECONDARY ENDPOINT ................................................................................................................ 33 
EXPLORATORY ENDPOINTS ......................................................................................................... 33 
4.3 Safety Plan ................................................................................................................................ 34 
4.4 Compliance with Laws and Regulations .................................................................................... 34 
5 
STUDY ENROLLMENT ............................................................................................................. 34 
5.1 SUBJECT SELECTION .............................................................................................................. 34 
INCLUSION CRITERIA ..................................................................................................................... 34 
EXCLUSION CRITERIA .................................................................................................................... 35 
5.2 Method of Treatment Assignment and Blinding ......................................................................... 37 
5.3 Subject Discontinuation and Withdrawal ..................................................................................... 37 
5.4 Study Termination ....................................................................................................................... 38 
6. INVESTIGATIONAL PRODUCT ................................................................................................... 38 
6.1 Formulation, Packaging, Preparation, Randomization of MSCs or Placebo .............................. 38 
6.2 IV Administration of MSCs or Placebo ....................................................................................... 40 
6.3 Product Storage and Stability .................................................................................................... 41 

 
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6.4 Concomitant Medications and Rehabilitation ............................................................................. 41 
7. 
STUDY ASSESSMENTS AND SCHEDULE .............................................................................. 41 
7.1 General Assessments ................................................................................................................. 41 
7.2 Schedule of Assessments ........................................................................................................... 45 
7.2.1 Screening, Baseline and Randomization (Day -12- -11) .......................................................... 45 
7.2.2 
Assessments and treatment ........................................................................................... 46 
Pre-infusion: ...................................................................................................................................... 46 
During infusion: ................................................................................................................................. 47 
Post- infusion: ................................................................................................................................... 47 
7.3 Follow-up Assessments ............................................................................................................. 47 
7.4 Early Termination Visit ............................................................................................................... 49 
8 
ASSESSMENT OF SAFETY ..................................................................................................... 50 
8.1 Safety Parameters ..................................................................................................................... 50 
8.1.1 
Adverse Event (AE) ........................................................................................................ 50 
8.1.2 
Serious Adverse Event (SAE) ......................................................................................... 52 
8.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters ................... 53 
8.2.1 
Adverse Event Reporting Period ..................................................................................... 53 
8.2.2 
Assessment of Adverse Events ...................................................................................... 53 
8.2.3 
Recording Adverse Events on the CRF .......................................................................... 54 
8.3 Expedited Reporting Requirements for Serious Adverse Events ............................................... 54 
8.4 Type and Duration of Follow-Up of Subjects After Adverse Events ........................................... 55 
8.5 Data Safety and Monitoring Board (DSMB) ............................................................................... 55 
9 
STATISTICAL CONSIDERATIONS ........................................................................................... 56 
9.1 Randomization ........................................................................................................................... 56 
9.2 Primary Safety Analysis ............................................................................................................. 56 
9.3 Determination of Sample Size ................................................................................................... 57 
9.4 Interim Analysis ......................................................................................................................... 57 
9.5 Data Quality Assurance ............................................................................................................. 57 
10 INVESTIGATOR REQUIREMENTS .......................................................................................... 57 
10.1 Study Initiation ........................................................................................................................... 57 
10.2 Study Completion ...................................................................................................................... 58 
10.3 Informed Consent ...................................................................................................................... 59 
10.4 Institutional Review Board ......................................................................................................... 59 
10.5 Study Monitoring Requirements ................................................................................................. 59 
10.6 Case Report Forms ................................................................................................................... 60 
10.7 Source Data Documentation ...................................................................................................... 60 
10.8 Investigational Product Accountability ....................................................................................... 60 
10.9 Retention of Records (for approval enabling studies only) ......................................................... 61 

 
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APPENDIX A: SCHEDULE OF ASSESSMENTS .............................................................................. 66 
APPENDIX B: QUESTIONNAIRES ................................................................................................... 68 
 
 
 
 

 
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PROTOCOL ACCEPTANCE FORM 
 
 
TITLE: 
A randomized, Multi-center, Double-Blind, Placebo-Controlled 
Phase IIa Study of the Safety and Efficacy of Intravenous 
Delivery of Allogeneic Mesenchymal Stem Cells in Patients 
with a Cardiomyopathy and Severe Heart Failure who 
Required Implantation of a Left Ventricular Assist Device 
(LVAD) 
 
 
 
 
PROTOCOL NUMBER: 
STEMVAD-001 
 
INVESTIGATIONAL 
PRODUCT(S): 
Allogeneic  
Mesenchymal Bone Marrow Cells (MSCs) (adult human) 
 

 
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I have read the protocol, including all appendices, and agree that it contains all necessary details for 
my staff and me to conduct this study as described. I will conduct this study as outlined herein and 
will make a reasonable effort to complete the study within the time designated. 
 
I understand that I am not allowed to make changes to this protocol. 
 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by CardioCell, Inc. I will discuss this material with them to ensure that they are 
fully informed about the investigational products and the study, and with Good Clinical Practice 
(GCP). 
 
 
 
 
Principal Investigator’s Name (print) 
Samer Najjar, MD 
 
 
 
 
Principal Investigator’s Signature 
Date 
 
 
 
 
 
 

 
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PROTOCOL SYNOPSIS 
 
 
 
TITLE: 
A randomized, Multi-center, Double-Blind, Placebo-Controlled Phase IIa Study of the 
Safety and Efficacy of Intravenous Delivery of Allogeneic Mesenchymal Stem Cells in Patients with a 
Cardiomyopathy and Severe Heart Failure who Required Implantation of a Left Ventricular Assist 
Device (LVAD) 
 
 
 
 
PROTOCOL NUMBER: 
STEMVAD-001 
 

INVESTIGATIONAL PRODUCTS:Allogeneic Mesenchymal Bone Marrow Cells, (MSCs) (adult human) 
 
 
PHASE: 
IIa 
 
INDICATION: 
heart failure with an implanted LVAD 
 
IND/IDE NUMBER: 
IND 18457 
 
 
SPONSOR: 
MedStar Heart and Vascular Institute 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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ABBREVIATIONS 
Abbreviation 
Definition 
2 D 
Two Dimensional 
3 D 
Three-Dimensional 
ACE 
Angiotensin-Converting Enzyme 
AE 
Adverse Event 
aGVHD 
Acute Graft-Vs-Host Disease 
AHA 
American Heart Association 
ALT 
Alanine Amino Transferase 
AMI 
Acute Myocardial Infarction Cardiomyopathy 
AST 
Aspartate Amino Transferase 
Bi-VAD 
Biventricular Assist Device  
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary Artery Bypass Graft Surgery  
CAD 
Coronary Artery Disease 
CBC 
Complete Blood Count 
CD 
Cluster Of Differentiation 
CK 
Creatine Kinase 
COPD 
Chronic Obstruction Pulmonary Disease  
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CTA 
Computed Tomography Angiography 
CV 
Curricula Vitae  
DNA 
Deoxyribonucleic Acid  
DSMB 
Data And Safety Monitoring Board  
ECG  
Electrocardiogram 
Fas 
First Apoptosis Signal 
FDA 
Food And Drug Administration 
FEV1 
Forced Expiratory Volume In One Second 
FVC 
Forced Vital Capacity  
GCP 
Good Clinical Practice 
GCSF 
Granulocyte-Colony Stimulating Factor  
HF 
Heart Failure 
HFrEF 
HF With Reduced Left Ventricular Ejection Fraction 
HIV 
Human Immunodeficiency Virus  
HLA 
Human Leukocyte Antigen  
HS-CRP  
High Sensitivity CRP 
ICAM 
Intercellular Adhesion Molecule 
ICD 
Implantable Cardioverter-Defibrillator  
ICF 
Informed Consent Form 
ICH 
International Conference On Harmonization 
ICM 
Ischemic Cardiomyopathy 
IFNγ 
Interferon Gamma 
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 

 
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IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IHF 
Ischemic heart failure 
IL 
Interleukin 
IND 
Investigational New Drug 
IP 
Interferon Gamma-Induced Protein 
IRB 
Institutional Review Board 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LAD 
Left Anterior Descending Coronary Artery 
LFTs 
Liver Function Tests 
LRS 
Lactated Ringer’s Solution 
LV 
Left Ventricular  
LVAD 
Left Ventricular Assist Device 
LVEF 
Left Ventricular Ejection Fraction 
MCP 
Monocyte Chemoattractant Protein 
MDRD 
Modification of Diet In Renal Disease  
MedDRA 
Medical Directory For Regulatory Activities 
MHC 
Major Histocompatibility  
MIF 
Macrophage Migration Inhibitory Factor 
MSCs 
Mesenchymal Stem Cells  
MUGA 
Multiple Gated Cardiac Blood Pool Imaging 
NICM 
Non-Ischemic Cardiomyopathy 
NK 
Natural Killer 
NOD/SCID 
Severe Combined Immunodeficiency  
NT-proBNP 
N-Terminal Prohormone Of Brain Natriuretic Peptide 
NYHA 
New York Heart Association Classification 
PAI 
Plasminogen Activator Inhibitor 
PCI 
Percutaneous Coronary Intervention 
QTc 
Rate-Corrected QT Interval  
RAGE 
Receptor For Advanced Glycation End Products 
RV 
Right Ventricular 
SAE 
Serious Adverse Event 
SDF 
Stromal Derived Factor 
SPECT 
Single-Photon Emission Computerized Tomography  
ST-2 
Soluble Suppression Of Tumorigenicity 2 
TNF alpha 
 Tumor Necrosis Factor Alpha 
TREM 
Triggering Receptor Expressed On Myeloid Cells 
uPAR 
Urokinase-Type Plasminogen Activator Receptor 
VCAM 
Vascular Cell Adhesion Molecule 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cells 
 
 

 
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BACKGROUND 
1 Left ventricular assist device therapy for advanced ischemic heart failure 
1.1 Heart failure 
Ischemic heart failure 
Coronary artery disease (CAD) is one of the two most common risk factors for heart failure (HF) and portends 
poor outcomes1-5. Ischemic etiology of HF is defined as 1) a prior history of myocardial infarction (MI), or 2) 
coronary revascularization (coronary artery bypass grafting (CABG) or percutaneous coronary intervention 
(PCI)), or 3) obstructive CAD (≥75% stenosis of the left main or proximal left anterior descending coronary artery 
or ≥75% stenosis of two or more major epicardial coronary arteries).  
Non-ischemic heart failure 
Non-ischemic heart failure is defined as heart failure caused by mechanisms other than myocardial ischemia or 
infarction. Dilated cardiomyopathy is the most common cause of non-ischemic heart failure. 
1.2 Left ventricular assist devices  
Advanced HF is refractory HF in which the disease has progressed despite standard medications to a point 
where there is a need for cardiac replacement therapies. Approximately 10% of the 3 million patients with HF 
with reduced left ventricular ejection fraction (HFrEF) in the United States (US) have advanced (end stage or 
stage D) HF (AHF) and are in need for cardiac replacement therapy or end of life care6-9. Because of the limited 
supply of cardiac donors (approximately 3273 hearts transplanted in the US in the year 2017) and instability of 
some transplant candidates awaiting organs, durable left ventricular assist devices (LVADs) have emerged as an 
alternative or as a bridge to transplantation6, 10. Improvement of LVAD technology has revolutionized the field of 
AHF, with markedly improved survival and quality of life for thousands of individuals compared with medical 
therapy alone. Hence, the rate of LVAD utilization is steadily growing in the US and worldwide10.  
However, despite mechanical support of the left ventricle, approximately 50% of the patients die over the 
course of the 4 years following LVAD implantation10. Right ventricular dysfunction and failure frequently occurs in 
the LVAD population and contributes to the high incidence of re-hospitalization and mortality10.  Adding to the 
complexity is the fact that progressive right HF augments susceptibility to developing one or more of the other 

 
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causes of death in these patients. 
 
Multiple mechanisms are postulated to contribute to right HF after LVAD implantation. Inflammation 
contributes to progressive myocardial dysfunction in acute myocardial infarction and in chronic HF of ischemic or 
non-ischemic etiology11-15 and inflammatory cytokines are higher in HF patients with LVAD than HF or healthy 
controls and remain persistently elevated during at least 9 months of follow up16, 17 
1.3 Persistent inflammation as a cause of progressive cardiac dysfunction.   
1.3.1 Overview. Considerable evidence has now emerged that is compatible with the concept that the 
progressive deterioration of cardiac function seen both in acute myocardial infarction (AMI) and ischemic 
cardiomyopathy (ICM)/non-ischemic cardiomyopathy (NICM) is in part caused by an excessive, persistent 
inflammatory response11, 13-15, 18 (Fig 1.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1.1. Inflammatory and immune responses, influencing a diverse array of pathways, importantly contribute to 
progressive myocardial dysfunction and adverse LV remodeling observed in patients post-AMI or with 
cardiomyopathy.  
1.3. 2.  Proof of the validity of this concept was recently provided by the results of investigations in mouse 
models of AMI and of ICM. We developed a monoclonal antibody approach to depleting natural killer (NK) cells, 
which are major orchestrators of the inflammatory response.  Intravenous administration of the anti-NK antibody 

 
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depleted NK cells from the spleen and from the heart, and decreased myocardial neutrophils.  Importantly, these 
anti-inflammatory effects led to marked improvements in LV remodeling and function (See figure 3.2, 3.3, and 
3.5 and related text).  
1.3.3 Specific data indicating the presence of a marked inflammatory response in patients with LVAD 
implantation. 
  
 
 
 
 
Figure 1.2. Evidence that a persistent inflammatory response exists in LVAD patients.  
Figure 1.2 derives from the study by Grosman-Rimon and colleagues17. They investigated the levels of 
inflammatory markers in continuous flow-LVAD recipients before and after LVAD implantation.  They found that, 
compared to normal, common inflammatory biomarkers (MCP-1, IP-10, and C-reactive protein (CRP)) are 
markedly elevated and that, despite improvements in LV dimensions and BNP levels after LVAD implantation, 
markers of inflammation remained markedly elevated in the LVAD recipients. 
We therefore hypothesize that the same disease process that contributes importantly to progressive LV 
dysfunction in patients with AMI and with chronic HF--persistent inflammation--also contributes to 
progressive right ventricular (RV) dysfunction in LVAD patients. 
2 MESENCHYMAL STEM CELLS 
2.1 
Modifying MSCs for enhanced production rate and enhanced functionality 
Experimentally, several modifications in MSCs have resulted in their enhanced functionality19-23. The strategy 
we have adopted for optimization of MSC functionality for preclinical studies and clinical translation is use of 
MSCs grown in hypoxic culture conditions24-26. 

 
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2.2 
Potentiation of MSCs with Hypoxic Culture 
Stem cells reside in defined microenvironmental niches and oxygen conditions critically regulate cellular 
responses. For example, oxygen tension in human bone marrow is ~3.0%. Hypoxic culture conditions can 
maintain MSCs in an undifferentiated state that favors stem cell self-renewal. It enhances expression of 
genes involved in developing mesodermal and non-mesodermal cell lines, increases multipotency and 
transdifferentiation, increases the half- life of vascular endothelial growth factor (VEGF) mRNA significantly 
(6–8h in low oxygen conditions compared to 30–40 minutes in normoxia), and decreases transversions from 
oxidative damage25-27. 
2.3 
Potency of MSCs Cultured in a Hypoxic Environment 
Stemedica has obtained a patent for culture of human donor MSCs in hypoxic conditions.  The biological 
potency of these cells has been studied in in vitro experiments and compared to MSCs cultured in normoxic 
conditions.  MSCs grown in hypoxic conditions formed more colonies in culture assays, had a greater 
proliferation rate, produced greater quantities of VEGF, Stromal derived factor 1 (SDF-1), HIF-1alpha, and 
angiopoeitin-1.  These MSCs also demonstrated greater migratory capacity in response to chemokines and 
cytokines. In summary, MSCs grown under hypoxic conditions compared to those grown in normoxic 
conditions have 1) a higher proliferation rate, 2) higher clonogenicity as determined by colony forming unit 
assay, 3) increased production of cytokines participating in homing of host stem cells to the site of injury 
(SDF-1) and in neovascularization (VEGF), 4) higher resistance to factors adversely affecting performance of 
MSC at the site of injury such as tumor necrosis factor, and 5) increased migration towards the factors 
produced at the ischemic site such as Hepatocyte Growth Factor.  These properties of the MSCs we will be 
using in this trial—Stemedica’s MSCs grown under hypoxic conditions from harvest until injection into the 
patient--will likely increase those activities involved in myocardial healing and thereby stand a greater chance 
of leading to beneficial effects on myocardial dysfunction.  All of the following preclinical studies we report 
below that originated in our preclinical laboratory were performed using Stemedica’s MSCs. 
3. MSCs improve LV function in experimental AMI and in ICM in large part through their paracrine-
induced anti-inflammatory activities.  

 
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Until recently, the prevailing view of the mechanisms responsible for any potential benefit of stem cells in 
patients with acute myocardial infarction (AMI) or with HF was that benefit derived from local effects—once 
engrafted in damaged myocardium, the stem cells either transdifferentiate into functional myocardium, stimulate 
resident myocardial stem cells to expand and repopulate the heart with functioning myocytes, or secrete 
substances leading to myocardial healing. This mechanistic perspective implied that the greater the number of 
engrafted cells in the myocardium, the greater the cardiac benefit. Because few intravenously administered stem 
cells engraft in injured myocardium, invasive strategies providing direct delivery of stem cells to the heart were 
uniformly adopted. This necessarily involved 
either catheter-based delivery (intracoronary or 
transendocardial injection), or surgical delivery 
(direct intramyocardial injection).  
A transformative concept relating to stem cell 
treatment of patients with AMI or with HF has 
recently evolved—i.e., that the intravenous 
administration of stem cells will improve left 
ventricular (LV) function in patients with AMI or 
with HF and that the major mechanism 
responsible for this resides in the systemic anti-
inflammatory effects of stem cells12.  
The concept’s validity derives from compelling preclinical data and from two new mechanistic insights; first, that 
the progressive deterioration of cardiac function seen both in AMI and HF is, as noted above, in part caused by 
an excessive, persistent inflammatory response7, 11, 13, 14, 28; and second, that if stem cells improve cardiac 
function, improvement is not caused by repopulating the myocardium with new myocytes, but rather by stem 
cells secreting numerous molecules with a diverse array of activities11, 13, 29-31. These paracrine activities include 
those related to angiogenesis, tissue healing, apoptosis, mitochondrial dysfunction, microvascular dysfunction, 
collagen deposition4 and, perhaps most importantly, through potent systemic anti-inflammatory actions12, 11, 14, 32 
Figure 3.1. MSCs secrete multiple anti-inflammatory 
molecules (From Aggarwal et al22). 

 
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(Fig 3.1) These anti-inflammatory effects cause in vivo suppression of both innate and adaptive immune 
responses to AMI11, 14, 15, 18, 32.     
As examples of the anti-inflammatory effects of MSCs, intramyocardial injection of MSCs in a rat model of AMI 
reduces myocardial levels of TNF-α, IL-1β, IL-6, MMP-1, TIMP-1, and reduces collagen deposition. These 
changes are associated with reduced infarct size and improved LV function33. In addition, it was shown in mice 
with AMI that intravenously administered MSCs improve LV function and decrease inflammation through factors 
secreted by MSCs lodged in organs outside the heart33. Because immunocompromised (NOD/SCID) mice were 
used in this study, it was uncertain what the paracrine-mediated immunomodulatory and salutary cardiac effects 
of the MSCs would be in an immunocompetent animal.   
Our group addressed this issue and demonstrated in immunocompetent mice that intravenously administered 
human MSCs 24h following AMI decreased splenic and myocardial NK cells, as well as myocardial neutrophils14 
(Fig 3.2). 
 
 
Figure 3.2. Anti-inflammatory effects of IV administration of MSCs. MSCs were injected IV 24h post AMI and hearts 
and spleens were harvested 7 days post AMI. 
These anti-inflammatory effects were associated with significantly attenuated adverse LV remodeling in mice 
with large infarcts. We recently performed a similar experiment in mice with chronic ICM14(Fig 3.3).  

 
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Figure 3.3. Effects of IV administration of MSCs in mice 
with ischemic cardiomyopathy. 
Infarcts were produced by LAD ligation followed in 45 
minutes by restoration of flow; by 4-weeks the mice 
developed LV dysfunction with decrease in left ventricular 
ejection fraction (LVEF) and adverse remodeling. IV 
injection of MSCs at 4 weeks after AMI (Time 0) and then 
repeated 3 weeks later led to marked improvements in ejection fraction and LV remodeling14. 
Thus, compelling preclinical evidence indicates that intravenously administered MSCs improve cardiac outcomes 
in AMI and in ICM, and appear to do so, at least in part, through anti-inflammatory activities. The inflammatory 
targets are in large part involved in systemic pathways originating in multiple tissues responsible for responding 
to tissue injury and generating inflammatory responses, such as the spleen. 
In this regard, an important concept relating to the initiation and propagation of inflammatory responses resides 
in the concept of a cardiosplenic axis. Myocardial injury (indeed, injury involving any tissue) signals the spleen, 
either through neural or humoral pathways, causing increased splenic inflammatory cell populations, with 
subsequent release of these cells into the circulation where they then home to sites of injury34.  A cardiosplenic 
axis may also participate in HF, as spleens of mice with ICM are enlarged, and splenectomy not only decreases 
cardiac macrophages and dendritic cells but also attenuates adverse LV remodeling35. 

 
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Figure 3.4.  The 
cardiosplenic axis and the 
target of IV injected MSCs. 
(From Epstein et al13) 
Inflammatory and immune 
responses, influencing a 
diverse array of pathways, 
importantly contribute to 
progressive myocardial 
dysfunction and adverse LV 
remodeling.  IV administered 
MSCs inhibit many of these 
proinflammatory pathways, 
an effect constituting one of 
the major mechanisms 
responsible for the beneficial 
myocardial effects of this 
intervention. [IL-1β indicates 
interleukin-1 beta; IL-6, 
interleukin-6; PGE2, 
prostaglandin E2; TNF-α, 
tumor necrosis factor alpha; 
and VEGF, vascular 
endothelial growth factor.] 
The capacity of MSCs to decrease NK cell activity and other components of the innate immune system in the 
setting of AMI is well known. We were particularly interested in the question of whether MSC-induced reduction 
in NK cells played a causal role in improving myocardial function following AMI, as NK cells play a major role in 
coordinating the innate immune response. We proved the validity of this hypothesis by demonstrating that when 
NK cells were depleted not by MSCs but by an anti-NK cell antibody administered 24h prior to AMI, infarct size 
significantly decreased and LV function significantly improved14 (Fig 3.5).  
Figure 3.5 Proof that the anti-inflammatory effects of MSCs are 
critical to their ability to improve LV function in ischemic 
cardiomyopathy: effects of primary antibody-induced NK cell 
depletion. (From Luger et al14.) Injection of an antibody 4 weeks post 
AMI that induces NK cell depletion improves LV function and 
adverse remodeling.  
Of note, improved LVEF occurs within 7 days of 
administration, suggesting that one mechanism contributing 
substantively to the impaired LV function is caused by the 
presence of dysfunctional, but still viable, myocardium. We 
hypothesize that the dysfunctional but viable myocardium responds to the anti-inflammatory activities of the 
MSCs (and perhaps to other MSC-based effects) such that contractile activity is restored. 

 
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4. Anti-inflammatory effects of IV administration of MSCs in patients with NICM and correlation with the 
magnitude of MSC-induced decrease in NK cells with improved left ventricular ejection fraction. 
One of the investigators of the present trial was co-PI of a trial testing the effects of IV administration of MSCs in 
patients with NICM36. The MSCs used in the present trial will derive from the same donor and will have 
undergone the same growth and expansion methods (undertaken by Stemedica) as were used in the prior trial. 
The study was a Phase 2a randomized, single blind, placebo controlled, crossover, multicenter trial consisting of 
23 patients with NICM. Crossover occurred at 90 days after study initiation and study termination occurred at 
180 days. 
Compared to placebo, IV MSCs: 
• 
Significantly increased 6-minute walk distance. 
• 
Significantly improved Kansas City Cardiomyopathy scores.  
• 
However, there were no significant changes from baseline in LV function between the two groups. 
Of great interest, IV administration of MSCs decreased circulating NK cells, and the magnitude of MSC-induced 
decrease in NK cells correlated with the magnitude of improvement in LV function36 (Fig 4.1). 

 
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Figure 4.1. Effects of IV administration of patients with non-ischemic cardiomyopathy36. 
These results provide evidence compatible with the concept that in patients with HF intravenous administration 
of MSCs decreases circulating NK cells, and further suggest that the magnitude of the anti-inflammatory effect 
produced in the individual patient relates to the magnitude of the beneficial effect exerted on myocardial function. 
 
5. Suggestion that MSCs residing in inflamed tissue exert less efficacious paracrine activity than MSCs 
derived from non-inflamed tissue; evidence suggesting greater efficacy derived from IV injected MSCs 
(residing mainly in lungs, liver, and spleen) vs. MSCs injected directly into ischemic myocardium.  
5.1. An important study relating to the immunomodulatory effects of MSCs was published by Naftali-Shani et al37. 
These investigators demonstrated that MSCs derived from the hearts of mice with persistent LV dysfunction, 
when tested in vitro, changed to an inflammatory phenotype, and when administered into the periinfarction 
region of mice 28 days following AMI did not improve LV function--they actually worsened anterior wall thinning.  
Importantly, MSCs derived from a non-inflamed tissue--subcutaneous fat--did not switch to an inflammatory 
phenotype.  Of relevance to this is the fact that the vast majority of MSCs administered IV to mice with AMI 

 
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embed in tissues other than the heart14. Although speculative at this point, these observations suggest that 
intravenously administered MSCs actually may lead to greater myocardial benefit than would direct delivery of 
the cells to the myocardium.  
5.2. Moreover, evidence suggests that MSCs residing in inflamed tissue will be detected more easily by the 
immune surveillance system, a change that would lead to shorter half-lives.  Thus, Le Blanc et al38 demonstrated 
that undifferentiated MSCs express HLA class I but not class II molecules, leading to the conclusion these cells 
are less likely to be eliminated by the immune surveillance system. However, addition of IFNγ for 48 hours 
induced greater than 90% of cells to express HLA class II molecules.  This finding suggests that MSCs 
administered directly into an inflamed area, such as the myocardium in patients with AMI or HF, will begin 
expressing HLA class II molecules and will be more effectively eliminated by the immune surveillance system.  In 
contrast, it appears that when MSCs are administered IV, where most of the cells reside in non-cardiac, non-
inflamed tissue, they will be more immune evasive and persist longer, thereby having a greater opportunity to 
exert their beneficial effects on inflammation and myocardial function. In this regard, it is possible that prolonged 
persistence of MSCs, once injected, is not necessary to result in beneficial effects, but that efficacy results from 
a “hit-and-run” mechanism mediated by the secretion, through paracrine activities, of immunomodulatory factors 
during the initial days following MSC injection39-41. 
 
6. Need for repeated administration of stem cells 
While chronic inflammation existing in many patients with HF might be transiently suppressed by a single 
injection of a therapeutic agent, it will almost certainly not be curative. These patients probably would experience 
recrudescence of the inflammation, with continuing long-term myocardial damage.  
The concept of the need for repeated administration of stem cells was recently demonstrated in preclinical 
models of ICM41-44. These investigators hypothesized that in the setting of ICM, greater stem cell efficacy would 
be achieved by injecting the cells multiple times, thereby providing more prolonged exposure of diseased 
myocardium to the paracrine actions of the cells than could be achieved by a single injection. They 
demonstrated that cardiac progenitor cells administered 3 times, 35 days apart, into the LV cavity of rats with 30-

 
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day old myocardial infarctions improved myocardial function more than did a single injection. Similar results were 
observed in mice in which cardiac mesenchymal cells were injected. 
This concept is illustrated by the following figure: 
Figure 6.1. Proposed concept of the need for 
repeated intravenous MSC injections to maintain 
anti-inflammatory effects and thereby to modulate, 
over time, the progressive deterioration of 
myocardial function that otherwise occurs in 
patients with heart failure. (From Epstein et al45)  The 
upper graph represents ventricular function plotted 
against time.  The lower graph represents the intensity 
of the inflammatory response plotted against time. The 
graphs depict the hypothetical response to a single 
injection of MSCs (in red) vs. the hypothetical 
response to repeated MSC injections (in green). 
 
 
 
If the concept is valid that treatment of HF patients will require repeated injections of MSCs, the strategy of 
intravenous delivery of MSCs provides a safe and efficient means for repeated administration of the MSCs, a 
fact that we believe will be transformative to the field of cardiovascular stem cell therapeutics. 
 
7. Safety of MSC administration 
In a 2016 publication Ankrum et al39 noted that nearly 350 clinical trials had been, or were being, conducted with 
MSC preparations; 190 of these used allogeneic cells. These authors concluded that “Importantly, allo-MSC 
therapy has consistently been shown to be safe…”  In 2012 Lalu and associates published a meta-analysis of 
clinical trials examining the safety of systemic MSC administration46. These authors concluded that: “Our 
analysis was unable to detect associations between MSC treatment and the development of acute infusional 
toxicity, organ system complications, infection, death, or malignancy. There was, however, a significant 
association between MSC administration and transient fever….aside from fever, the published current clinical 
trials suggest that the administration of MSCs is safe”.  Importantly, hyperacute rejection-like symptoms have not 

 
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been reported in human patients who receive allogeneic MSC therapy47  
Of relevance, the MSCs being used in the present study are the same (CardioCell/Stemedica) as used in a study 
of patients with NICM36. This was a Phase 2a study in which MSCs were administered intravenously to 23 
patients, the results of which are outlined in the Background, Section 2. There were no clinically significant 
adverse effects observed.  
8. Safety issues surrounding development of immune responses to allogeneic MSCs with repeated 
injections.   
The safety of a single dose of MSCs has been compellingly demonstrated. Although the safety of multiple 
injections of MSCs has as yet to be definitively determined, multiple intravenous injections have frequently been 
given to patients with no, or minimal serious sequela. This experience is summarized in the following 
paragraphs. 
Patients with graft vs. host disease (an immunocompromised cohort of patients). 
Chen et al reported a systematic review and meta-analysis of patients with steroid-refractory acute graft-vs-host 
disease (aGVHD) given multiple intravenous allogeneic MSC injections48. A total of 301 patients from thirteen 
studies were included.  Of these, 9 patients (3%) developed responses that were deemed either not likely, or 
possibly, related to the MSC infusion. Of particular note is the study by Kurtzberg et al49.  Seventy-five pediatric 
patients were studied. The mean total number of infusions received was 9.7 ± 3.97, with a median of 10.0 
(range, 1 to 20), with 40 patients (53.3%) receiving >8 infusions. Only 1 patient (1.3%) experienced an infusion-
related reaction (ie, rise in body temperature, increased breathing, and decreased oxygen saturation) after the 
third and fourth infusions, which resolved without sequela. The authors concluded that MSC infusion “…appears 
to have a benign safety profile”. Infusions were well tolerated, with only 2 reported reactions occurring in the 
same patient out of more than 500 infusions administered during the course of the study. There were no cases 
of ectopic tissue formation. The number and type of events reported are consistent with a severely 
immunocompromised aGVHD patient population. At study entry, these patients had a complicated history and 
suffered from a variety of severe medical conditions. Treatment…did not lead to apparent additional toxicities 
and was well tolerated in this population. Furthermore, this therapy was not associated with hematologic or renal 

 
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toxicity.” 
Patients with Chronic Obstruction Pulmonary Disease (an immunocompetent cohort of patients). 
Sixty-two patients with chronic obstruction pulmonary disease (COPD) were randomized to double-blinded IV 
infusions of either allogeneic MSCs or vehicle control. Patients received four monthly infusions (100 x 106 
cells/infusion) and were subsequently followed for 2 years. The authors report that “There were no infusional 
toxicities and no deaths or serious adverse events (SAEs) deemed related to MSC administration. There were 
no significant differences in the overall number of adverse events, frequency of COPD exacerbations, or 
worsening of disease in patients treated with MSCs.” 
In our study, during MSC infusion, we will carefully observe our patients to determine whether clinically important 
safety-related immune response issues arise acutely.   
We will also test for long-term development of immune cell reactivity, development of anti-HLA antibodies, and 
whether any positive test responses are associated with adverse clinical outcomes.   
9. Issue of development of immune responses to allogeneic MSCs interfering with potential beneficial 
effects of MSCs.  
Because it had been demonstrated that MSCs do not constitutively express Major Histocompatibility Class 
(MHC) II antigens or the B7 and CD40 ligand costimulatory molecules, and because MSCs have 
immunosuppressive and immunomodulatory properties, it became commonly accepted that MSCs are 
immunoprivileged and not eliminated by the immune surveillance system when administered to HLA mismatched 
recipients39. However, studies also demonstrated that while MSCs do not constitutively express HLA class II 
molecules, the addition of IFNγ for 48 hours induced greater than 90% of cells to express HLA class II29,40. This 
finding constitutes one of a large number of studies demonstrating that MSCs are not immunoprivileged—rather, 
they do generate immune responses when administered to HLA mismatched recipients and are cleared more 
rapidly than syngeneic MSCs39, 47, 50. 
 Despite this lack of persistence, it appears MSCs are relatively protected from immune detection. Thus, Ankrum 
and colleagues presented the results of a study in which the relative persistence of allo-fibroblasts vs. allo-MSCs 

 
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was compared39. The study showed that fibroblasts died by day 10 and MSCs by day 20—in other words, 
although the MSCs were not immune privileged, they had some protection against immune rejection (the authors 
refer to this as immune evasive) resulting in longer persistence than the non-MSCs. This concept was also 
documented by Galipeau et al51 who used murine MSCs transfected with the gene expressing erythropoietin as 
a reporter for persistent MSC functionality. MSCs were injected subcutaneously in either MHC-mismatched 
allogeneic or matched syngeneic mice.  Although expression of erythropoietin lasted for a longer time in the 
syngeneic mice, the mismatched MSCs still produced erythropoietin for over 30 days 
It therefore has been unequivocally demonstrated that MSCs are not immune-privileged, as originally proposed. 
They eventually are eliminated from mismatched hosts through immune responses. However, MSCs do persist 
for a limited time (longer than other types of mismatched cells) and are, thus, immune evasive. The issue 
relating to potential efficacy therefore becomes whether MSCs persist long enough to exert a therapeutic effect. 
The literature supports a positive response to this question, as the concept has been advanced that the relevant 
activities of the MSCs need only a limited time to produce their effects. Such a mechanism has been referred to 
as a “hit-and-vanish” or “hit and run” mechanism39, 40. 
The results of our own studies in mice with either AMI or ICM14 (reviewed in part; see Background, Section 3, 
and Figure 3.2 and 3.3) relate to this issue.  AMI or ICM was created and the mice were treated by intravenous 
administration of human MSCs. This therefore was a xenograft model, susceptible to the immune surveillance 
issues discussed above. We found:  
• 
Human MSCs, injected IV into mice with AMI, persist in a viable state in the heart for at least 7 days, and 
when injected into mice with ICM, persist in a viable state in the heart for at least 20 days.   
• 
The number and duration of the persisting MSCs are sufficient to exert biologically important effects—IV 
administered MSCs led to a) significant immune modulatory effects (among these, and perhaps most 
important, a decrease in spleen and heart NK cells) and b) marked improvement in LV function in both 
AMI and in ICM models. 

 
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• 
Importantly, in the ICM model MSCs were injected at time 0 and a repeat dose was administered 3 
weeks later. No acute adverse effects occurred following the second injection. Additionally, the double 
injection led to a marked beneficial effect in myocardial function as measured by echocardiography at 
weekly intervals, with a final measurement at 7 weeks (see Background, Section 2). 
It therefore appears that a beneficial myocardial functional effect is not dependent on MSCs persisting 
indefinitely in the host—benefit appears to accrue from MSCs secreting anti-inflammatory and other factors early 
after their injection.  Perhaps intravenous administration is a desirable strategy, as most of the MSCs injected 
intravenously embed in non-cardiac tissue (lungs, spleen, kidneys)—i.e., in tissues that are not the site of 
inflammation, a factor that avoids exposing the MSCs to activation factors, such as IFNγ, that are present at high 
levels in inflamed tissues and that lead to the expression of HLA class II molecules, which would lead to more 
rapid immune-mediated removal of the cells.  
This intravenous strategy, along with the potential efficacy of a “hit and vanish” mechanism, could effectively 
reduce the deleterious effects of persistent inflammation (as we postulate exists in LVAD patients) even without 
long-term persistence of a single MSC injection.  Our trial is also important from the perspective of testing the 
efficacy and safety of multiple IV injections of MSCs, as it will be the first study undertaken in cardiac patients to 
test a multi-injection strategy.  
And while safety of MSC administration has been compellingly demonstrated (at least over the short term), the 
long-term effects have not been extensively documented.  It is perhaps encouraging to know that because MSCs 
do elicit immune responses that eliminate the cells over weeks or months, long term problems would not be 
anticipated.   
 
10. Central hypotheses for carrying out the proposed study: 
Compelling preclinical data indicate that chronic inflammation contributes to the progressive myocardial 
dysfunction occurring post-AMI and in HF. It has now also been definitively demonstrated in preclinical models 
that intravenously delivered MSCs to mice with either AMI or ICM improves myocardial function, an effect 

 
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caused at least in part by systemic MSC-induced anti-inflammatory effects. And a recently published phase 2a 
clinical study provides evidence suggesting that intravenous administration of MSCs to patients with NICM 
decreases circulating NK cells; importantly, the magnitude of the MSC-induced decrease in NK cells was 
significantly associated with the magnitude of improvement in LV function. Experimental data are also 
compatible with the conclusion that the beneficial anti-inflammatory effects are transient, and that multiple 
injections would likely be necessary to achieve persistent beneficial effects on myocardial function. Finally, LVAD 
patients have persistent, and strikingly, elevated markers of inflammation. 
We hypothesize that the same disease processes—in particular, persistent inflammation—that 
contribute to progressive LV dysfunction in mice with ICM and in patients with chronic HF, whether of 
ischemic or non-ischemic etiology, also contribute to progressive RV dysfunction found in many LVAD 
patients. 
Therefore… 
• 
We further hypothesize that intravenous delivery of MSCs to patients with LVADs and RV failure 
will improve both LV and RV function, and therefore patient outcomes. 
• 
In addition, by reducing the excessive systemic inflammatory responses that exist in HF, the 
MSC-induced decrease in inflammation may improve multiple non-cardiac mechanisms that 
contribute to poor outcomes. 
 
3 
STUDY OBJECTIVES 
3.1 Primary 
To assess the safety of human allogeneic MSCs derived from bone marrow and administered intravenously—
3 times at monthly intervals—to subjects with advanced HF of ischemic etiology (ischemic heart failure; IHF) 
or non-ischemic etiology (NICM) who underwent implantation of LVAD. 
3.2 Secondary 
To assess the efficacy of human allogeneic MSCs administered intravenously—3 times at monthly 

 
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intervals—to subjects with advanced HF who underwent implantation of LVAD  : Specifically, effect on 1) 
right (RV) and left ventricular (LV) structure and function, 2) inflammatory and cardiac biomarkers, and 3) 
clinical status. 
 
4 
STUDY DESIGN 
4.1 
Description of the Study 
This is a Phase IIa, double blind, placebo-controlled, multi-center, randomized study in subjects with advanced 
HF who are supported by LVADs. 
The study will enroll 30 subjects and will consist of 2 cohorts. Enrolled subjects will be stratified by LVAD device 
type (HeartWare HVAD, HeartMate II or HeartMate III) and randomized at 1:1 into an experimental group (n=15) or 
a placebo group (n=15), respectively. Subjects in the experimental group will receive 1.5 million cells per kg, and 
subjects in the placebo group will receive 1.5 mL/kg Lactated Ringer’s Solution at baseline, 1 month and 2 months. 
All study participants will receive the MSCs or placebo within ±7 days of the specified timing. 
Figure 4.1 Study Design 
Safety of study participants will be evaluated after each visit, as detailed in Appendix A. Physical examination 
and concomitant medications will be recorded at each infusion visit as well 90, 180, and 360 days. Complete 
examinations will be used to assess disability and functional status at baseline (prior to treatment) and at the 
visits scheduled at 1, 2, and 3 months after the initial administration. A baseline 2D and 3D and Doppler 

 
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transthoracic echocardiography with speckle-tracking and gated blood pool SPECT ventriculography for 
assessment of right and left ventricular systolic function and volumes will be performed at baseline and at 
specific time points during follow-up. All echocardiograms will be assessed in a blinded core lab. All SPECT 
ventriculograms will be assessed by a blinded observer.  
Subjects will continue all of their regular medications unless contraindicated. Subjects may be administered 
beta-blockers, ACE inhibitors, angiotensin receptor blockers or angiotensin receptor neprilysin inhibitor, 
mineralocorticoid receptor antagonists, isosorbide, hydralazine, mineralocorticoid receptor antagonists, statins, 
or other medications, as tolerated. Goal mean arterial blood pressure will be <85 mmHg. LVAD pump speed 
will not be adjusted unless the rationale for speed change is discussed with and approved by the principal 
investigator with the exception of an emergency situation.  
SUBJECT PARTICIPATION 
Eligible participants must have advanced HF of ischemic etiology, defined as 1) a prior history of myocardial 
infarction and/or 2) angiographically (invasive or cardiac CT angiography) documented significant CAD (defined 
as a prior history of coronary revascularization (CABG or PCI) and/or obstructive CAD (≥75% stenosis of the left 
main or proximal LAD or ≥75% stenosis of two or more major epicardial coronary arteries)) or non-ischemic 
cardiomyopathy etiology.  
Enrollment window will open after discharge from index implant hospitalization and once the patient has been 
deemed stable with their LVAD implantation. 
The screening evaluation will include obtaining written informed consent, collection of a complete medical 
history, including current and past medications, physical examination and laboratory tests. LVAD implantation is 
required for inclusion in the study.  
A comprehensive 2D and 3D and 3D and Doppler transthoracic echocardiography with speckle tracking and 
gated blood pool SPECT ventriculography for assessment of right and left ventricular systolic function and 
volumes will be performed at baseline and at the specific time points during follow-up. 
Eligible subjects will receive repeated infusions of either MSCs or placebo based on randomization at time 0 
and at day 30 (±7 days) and day 60 (±7 days). 

 
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Follow-up visits will occur at days 7 (±2 days), 30 (±7 days), 37 (±2 days), 60 (±7 days), 67 (±2 days), 90 (±7 
days), 180 (±7 days), and 360 (±7 days). Information on AEs, concomitant medications, vital signs, clinical 
laboratory tests and physical examination will be collected according to the schedule of assessments 
(Appendix A). All guideline-based medical care will continue as prescribed by the subject's personal 
physician(s). Use of other investigational agents or treatments is not allowed during this study. 
Administration of Human Allogeneic MSCs  
The study will enroll a minimum of 30 subjects and will consist of 2 cohorts. Enrolled subjects will be 
randomized at 1:1 into an experimental group (n=15) or a placebo group (n=15). Subjects in the experimental 
group will receive 1.5 million cells per kg, and subjects in the placebo group will receive 1 mL/kg LRS at days 
0, 30 and 60. 
After the subject is randomized into one of the two cohorts, the final formulation of MSC or placebo will be 
prepared. Within 8 hours of infusion, the appropriate number of cells will be thawed at the study site pharmacy 
and re-suspended in LRS at a concentration of 1x106 cells/mL Subjects in placebo group will receive LRS at a 
volume of 1.5 mL/kg. The study solution (MSCs or placebo) will be labeled to ensure investigator blinding. The 
solution will be labeled to indicate that it is an investigational agent and will contain subject’s identifying 
information, date, and time of formulation. 
An intravenous line will be placed into a peripheral vein, and 0.9% sodium chloride solution will be run to keep 
the vein open. The study product will be drawn using an 18-gauge needle into a 60 mL syringe with an eccentric 
tip. The needle will be removed, and infusion tubing will be attached to the syringe. The syringe with infusion 
tubing will be placed in a metered dose syringe pump positioned horizontally with the syringe rotated such that 
the syringe tip is at the lowest position. The product will be infused intravenously into the subject’s arm at a 
constant rate of approximately 2 mL/min. The applicable volume for the target dose will be delivered within ±2 
mL. Depending on subject’s weight, up to three 60 ml syringes of product may be infused. After the entire 
product volume is delivered, 25 mL of LRS (without cells) will be infused at 2 ml/min to deliver cells from the 
infusion line for more accurate dosing. Subjects in the placebo group will receive intravenous LRS. Their 
syringes will be labeled as above to preserve blinding and followed by 25 ml of LRS infusion as above. 

 
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If the subject has an adverse reaction during the infusion, the infusion may be interrupted or slowed according 
to the severity of the reaction. 
The following symptoms, if noted, during infusion may lead to slowing or cessation of the infusion session: 
• 
Temperature ≥39°C. 
• 
Unexplainable shaking chills. 
• 
Angioedema. 
• 
Respiratory distress. 
• 
Wheezing/bronchospasms. 
• 
Hypotension (Drop in MAP by ≥20 mmHg to an absolute MAP<60 mmHg). 
• 
Hypoxemia (persistently reduced SpO2 of <88%). 
• 
Any symptoms of signs, which in the investigator’s opinion indicate clinical instability or a 
significant infusion reaction. 
In the event the infusion session is prematurely stopped the investigator may opt to resume if the symptoms 
subside, however this will be at the discretion of the investigator.  Adverse reaction duration the infusion, slowing 
or cessation of the infusion and any resuming of the infusion will be recorded on the case report form.  If a session 
is prematurely stopped for adverse reaction, the patient will continue with the next interval follow up per the 
schedule of events.    
All appropriate treatment will be given to reduce any discomfort and ensure the subject's safety. The infusion may 
be restarted, if interrupted, if the subject is not considered to be at risk by the Investigator and the subject consents. 
All subjects will receive the follow-up tests and evaluations as detailed in Appendix A. 
CONCOMITANT THERAPY AND CLINICAL PRACTICE 
Subjects will continue all of their regular medications unless contraindicated. Subjects may be administered 
beta-blockers, ACE inhibitors, angiotensin receptor blockers or angiotensin receptor neprilysin inhibitor, 
mineralocorticoid receptor antagonists, isosorbide, hydralazine, statins, or other medications, as tolerated. Goal 
mean arterial BP will be <85 mmHg. LVAD speed will be maintained, unless there is a compelling clinical 
indication to change it. Changes in pump speed should be approved by the PI, unless emergency.  

 
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4.2 
Endpoints  
PRIMARY ENDPOINT 
Safety of MSCs assessed at the following time-intervals: 
Baseline and days 30, 60, 90, 180, and 360 post-initial infusion 
1. Procedural complications 
2. Vital signs 
a. Temperature 
b. Mean arterial blood pressure 
c. Heart rate 
d. Respiratory rate 
e. Weight 
f. LVAD parameters: Pump speed, flow, pulsatility and power 
3. Uncontrolled systemic infection. 
4. Hemodynamically unstable clinical arrhythmias that require appropriate defibrillator shock, anti-tachycardia 
pacing or initiation or escalation of antiarrhythmic medications.  
5. Laboratory tests 
a. Complete blood count (CBC)/ differential. 
b. Comprehensive Metabolic Panel: Sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen (BUN), creatinine, glucose, calcium, magnesium and liver function tests (ALT, AST, 
alkaline phosphatase, bilirubin and albumin) 
c. Troponin-I. 
d. Allosensitization (change in antibodies against HLA (panel reactive antibody test) from baseline 
for strong HLA antibody specificities (MFI>2000)) 
6. Electrocardiogram. 
7. All-cause mortality. This will be reviewed by the DSMB. The LVAD population is a high risk group with very 

 
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high mortality, which will be taken into account when reviewing safety. Survival rate among HF patients with 
LVAD is 95% at 1 month, 81% at 1 year, 70% at 2 years, 59% at 3 years and 49% at 4 years. For patients 
enrolled within our study window, we would expect a 20% mortality rate in our patient population. 
 
SECONDARY ENDPOINT 
All secondary end points will be assessed pre-MSC infusion at days 0, 30, and 60, and also at days 90, 180, and 
360. In addition, blood will be drawn 1 week after each infusion for potential biomarker analysis, depending on 
analysis of pre-infusion data. These 1-week post infusion blood samples will be frozen and stored. 
Efficacy 
1. Change in the following inflammatory cytokines at 90 days:  
CD14, CD163, CD40, CRP, E-Selectin, Fas, (TNFRSF6/Apo-1), Fas Ligand (TNFSF6), GCSF, ICAM-1 
(CD54), IL-1 alpha (IL-1 F1), IL-1 beta, IL-1 R4, IL-10, IL-12 p70, IL-13, IL-18, IL-2, IL-2 R alpha, IL-4, IL-6, 
IL-8, Lipocalin-2, MCP-1, MCP-2, MIF, MIP-1 alpha, MIP-1 beta, Osteopontin, PAI-1, Platelet Factor 4, 
Procalcitonin, RAGE, Resistin, Thrombomodulin, TNF alpha, TREM-1, Troponin I, uPAR, VCAM-1, VEGF-A 
using a biomarker array kit. 
2. NK cell depletion, defined as % reduction in NK cells from baseline to day 90.  
 
EXPLORATORY ENDPOINTS  
1. Change in the following cardiac biomarkers: N-Terminal Prohormone of Brain Natriuretic Peptide (NT-
proBNP) and soluble suppression of tumorigenicity 2 (sST2) between baseline and day 90 post initial infusion. 
2. Change in RV systolic function and volumes assessed by 2D and 3D echocardiography and gated blood pool 
SPECT ventriculography scan between baseline and day 90 post initial infusion. 
3. Hospitalizations due to right HF (as defined by INTERMACs) at day 90. 
4. 6 minute walk distance changes between baseline and day 90 post initial infusion.  
5. Change in Quality of life (Kansas City Cardiomyopathy Questionnaire; KCCQ) between baseline and day 90 
post initial infusion. 

 
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6. Frequency and severity of gout flares at day 90.  
4.3 
Safety Plan 
The safety of subjects will be carefully monitored by the investigators and reviewed by an independent Data 
and Safety Monitoring Board (DSMB). Details of AE description and procedures for reporting are detailed in 
section 8.  
4.4 
Compliance with Laws and Regulations 
This study will be conducted in accordance with the International Conference on Harmonisation (ICH) E6 
Guideline for Good Clinical Practice (GCP), the principles of the Declaration of Helsinki (October 1996) and 
applicable local, state, and federal laws, as well as other applicable country laws. 
 
5 
STUDY ENROLLMENT 
Subjects will participate in this study for about 360 days as follows: Patients will be deemed enrolled once the 
patient is randomized. 
 
5.1 SUBJECT SELECTION 
The study will enroll at least 30 subjects and will consist of 2 cohorts. Enrolled subjects will be randomized at 
1:1 into an experimental group (n=15) or a placebo group (n=15), stratified by LVAD type. Subjects in the 
experimental group will receive 1.5 million cells per kg, and subjects in the placebo group will receive 1.5 
mL/kg Lactated Ringer’s Solution at day 0 (±7 days), day 30 (±7 days) and day 60 (±7 days).  
Subjects will be selected using the following inclusion and exclusion criteria: 
INCLUSION CRITERIA 
1. Age ≥18 years. 
2. One of the two following HF etiologies: 
a. Ischemic HF etiology, defined as 1) a prior history of myocardial infarction and/or 2) angiographically or 
cardiac CTA documented significant CAD (defined as a prior history of coronary revascularization (CABG 
or PCI) and/or obstructive CAD (≥75% stenosis of the left main or proximal LAD or ≥75% stenosis of two or 

 
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more major epicardial coronary arteries)) prior to LVAD implantation (any coronary angiogram ever prior 
to LVAD implantation can be used, but an angiogram is not  required to confirm non-ischemic etiology, 
imaging is acceptable). 
b. Non-ischemic cardiomyopathy 
3. Advanced HF defined as HF requiring LVAD implantation and deemed stable on his/her LVAD. 
4. On stable medical therapy (per the discretion of the treating physician) including beta-blockers, ACE-
inhibitors, angiotensin receptors blockers, angiotensin receptor neprilysin inhibitor, mineralocorticoid 
receptor antagonists, isosorbide, hydralazine, and mineralocorticoid receptor antagonists) and optimized 
pump speed for at least a month prior to randomization. 
5. HS-CRP level≥2 mg/l. 
6. NYHA class II-III symptoms. 
7. Ability to understand and provide signed informed consent. 
8. Reasonable expectation that patient will receive standard post-treatment care and attend all scheduled 
safety follow-up visits. 
 
EXCLUSION CRITERIA 
1. Women of childbearing potential. Postmenopausal women or women with permanent 
contraception method (defined as total hysterectomy) will not be excluded. 
2. History of debilitating stroke (modified Rankin Score > 3) within 3 months. 
3. The likelihood of requirement of cardiac surgery during the study period. 
4. Presence of clinically significant, uncorrected left sided valvular heart disease, active acute 
myocarditis, or uncontrolled hypertension defined as Persistently elevated mean arterial blood 
pressure (>100 mmHg). Echocardiography within 12 months of screening. Patients can be re-
evaluated, at the discretion of the investigator. 
5. QTc >550 ms (in the absence of bundle branch block, interventricular conduction delay or 
ventricular pacing). Electrocardiogram (ECG) within 60 days. 

 
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6. History of cardiac arrest within 3 months. 
7. Hypertrophic or infiltrative cardiomyopathy.  
8. Considered or listed for organ transplantation or history of organ transplantation 
9. Illness other than HF with life expectancy less than 12 months. 
10. Enrolled in an interventional trial or received an experimental drug or device within 30 days of 
randomization. 
11. Biventricular assist device (Bi-VAD) support. 
12. Severe COPD defined by FEV1<1L, and FEV1/FVC<70% within 12 month if known history of 
COPD, otherwise FEV1<1L, and FEV1/FVC<70% within 24 months  
13. Uncontrolled seizure disorder. 
14. Clinically significant hematologic, hepatic, or renal impairment as determined by screening 
clinical laboratory tests within the last 30 days: 
• 
Liver disease = ALT or AST > 3x normal, alkaline phosphatase or bilirubin >2x normal 
• 
Renal disease = End stage renal disease on long term dialysis Hematologic = Unexplained 
persistent leukocytosis (WBC >11 K/UL) or hemoglobin < 8.5 gm/dl 
15. Presence of any other clinically-significant medical condition, psychiatric condition, or laboratory 
abnormality, that in the judgment of the investigator or sponsor may affect compliance with the study 
protocol or pose a safety risk to the subject. 
16. Inability to comply with the conditions of the protocol. 
17. Acute coronary syndrome within 4 weeks (clinical diagnosis, confirmed by electrocardiographic 
abnormalities and elevation of troponin-I). 
18. Malignancy within the previous five years, except adequately treated basal cell carcinoma, 
provided that it is neither infiltrating nor sclerosing, and carcinoma in situ of the cervix 
19. Active uncontrolled systemic infection. Positive blood or deep tissue cultures or clinical or imaging 
evidence of systemic infection despite complete course of effective antimicrobial therapy as 
determined by infectious diseases. Localized (non-systemic) infection is not an exclusion criterion. 

 
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Patients can be re-evaluated, at the discretion of the investigator. 
20. Early postpartum cardiomyopathy (within six months of diagnosis). 
21. Presence of inherited or acquired immune deficiency or human immunodeficiency virus infection 
(HIV). Negative HIV test within the preceding 12 months is required. 
22. Systemic corticosteroids, immunosuppressive drug therapy (cyclophosphamide, methotrexate, 
cyclosporine, tacrolimus, azathioprine, mycophenolate, sirolimus, etc.), and DNA depleting or 
cytotoxic drugs taken within four weeks prior to study treatment. 
23. Known Porphyria. 
24. Allergy to sodium citrate or any “caine” type of local anesthetic. 
25. Patient enrolled in hospice care. 
 
5.2 Method of Treatment Assignment and Blinding 
This study is a Phase IIa, double-blind, placebo-controlled, multi-site (up to 2), randomized trial comprised of 
30 subjects with an experimental group (stem cell infusion; n=15) and a placebo group (n=15; LRS at a 
volume of 1.5 mL/kg). Each group will receive 3 repeated doses of the assigned treatment (no cross-over) at 
times 0, 30 and 60 days. The infusion bags of stem cells or placebo will be identical. 
 
In the event that a patient is unable to receive an infusion on or within the window of 30 or 60 days, the 
earliest infusion will be scheduled once it has been deemed safe for infusion.  The primary endpoint 
measurement at day 90 (or within window) will remain irrespective to the number of infusions 
completed.  More specifically, if infusion #2 (day 60) is missed then it will be schedule as soon as the 
patient is deemed stable.  The infusion #3 will occur 30 days from infusion # 2 but before day 90 (plus 
window) primary endpoint imaging evaluation.  In the event that infusion # 3 would fall after the upper 
bound of the 90 day primary endpoint window then this infusion will be skipped.   
5.3 Subject Discontinuation and Withdrawal 

 
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Subjects have the right to withdraw from the study at any time. Subjects will be given the option to provide a 
reason for withdrawal. In case of early withdrawal, the reason for withdrawal will be recorded on the 
appropriate Case report form (CRF). Attempts to complete early termination exam as defined in 7.4 will be 
made. The Investigator has the right to discontinue a subject from the study for any medical reason that the 
investigator determines may jeopardize the subject’s safety if he or she continues in the study, or for reasons of 
noncompliance (e.g., missed visits, use of other investigational drugs, etc.).  
 
5.4 Study Termination 
The Sponsor has the right to terminate the study at any time. Reasons for terminating the study may include, 
but are not limited to, the following: 
• 
The incidence or severity of AEs in this or other studies indicates a potential health hazard to subjects. 
• 
Unsatisfactory subject enrollment. 
• 
Rate of enrollment of < one subject per 3 months.  
• 
An excess drop out of subjects (a total of ≥5 subjects per each arm, but not due to VAD –related 
mortality). 
 
• 
Inaccurate or incomplete data recording. 
• ≥20% missing data for the primary safety endpoints. 
• ≥30% missing data for the efficacy endpoints. 
 
6. INVESTIGATIONAL PRODUCT 
6.1 Formulation, Packaging, Preparation, Randomization of MSCs or Placebo 
The final product will be stored and handled as described in Stemedica’s Pharmacy Manual (referenced in their 
Investigator’s Brochure). 
The product being administered to the patient is the exact product being referenced in IND 14328 and will not be 
altered prior to use. 
The following tests--gram stain, endotoxin, cell count, viability, and appearance--will be conducted with final 
results available prior to administration of the drug per Stemedica's formulation protocol. Sterility testing is 

 
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conducted per USP requirements by an approved testing lab for sterility testing after thawing the product, with 
results available post administration to the patient. 
Endotoxin, appearance, and gram testing are done by our collaborators at the Cell Processing Lab at Children’s 
Hospital (Cellular Therapy Lab) prior to administration. This Laboratory is located across the street from the 
MedStar Washington Hospital Center, where patient processing is performed and the cells will be infused. 
The only test that will not be available prior to patient administration is the sterility test.  
The following steps will be followed: 
1. The Cellular Therapy Lab will send samples to an approved testing lab for sterility testing by BacT/Alert 
(culture for 14 days bacterial, 21 day fungal) immediately after thawing the product.  
2. Retention samples will be sent from the Cellular Therapy Lab to Medstar when the product is transported. 
The Medstar clinical trial team will keep the retention samples (in case sterility results come back positive).  
3. If sterility test is negative the retained sterility sample will be destroyed.  
4. If sterility test is positive (i.e. the sample is not sterile) the following action plan will be followed. 
Action plan for a positive sterility testing: 
1. Microbiology testing lab will notify the PI, the clinical trial manager or designee, and the Cellular Therapy Lab 
of any positive cultures immediately.  
2. Further testing for organism speciation and antibiotic sensitivity will be conducted by the microbiology lab and 
reported to the PI in a timely fashion to guide patient management. 
3. The PI is responsible for ensuring patient safety and will ensure that the patient is notified of the test results, 
assessed for adverse events and treated in a timely fashion as medically appropriate.  
4. The PI/designee will notify Stemedica point person within 24 hours of receipt of report from lab.  
5. The PI will determine whether the FDA and IRB need to be notified immediately (e.g. if there is a serious 
adverse event) or if this will be included in the progress report. Standard reporting of adverse events will be 
followed as specified in the protocol. 
6. The notification and workup for positive culture form will be completed (form attached). 
7. All products with positive cultures will be marked with a biohazard label.  

 
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8. The retention sample will be sent to the microbiology lab for testing. 
9. All the materials will be maintained until further instruction is received from Stemedica. 
10. Stemedica staff to investigate failure and determine if further formulation activities or testing is required to 
support investigation of the issue. 
The study will enroll a minimum of 30 subjects and will consist of 2 cohorts.  Enrolled subjects will be randomized 
at 1:1 into an experimental group (n=15) or a placebo group (n=15).  Subjects in the experimental group will 
receive 1.5 million cells per kg and subjects in the placebo group will receive 1.5 mL/kg Lactated Ringer’s 
Solution. 
Once the subject is randomized into one of the two cohorts, the cells or placebo will be prepared. Within 8 
hours of infusion, the appropriate number of cells will be thawed at the study site pharmacy and re-suspended 
in Lactated Ringer’s Solution (LRS) at a concentration of 1x106 cells/mL Subjects in placebo group will receive 
LRS at a volume of 1.5 mL/kg. The study solution (cells or placebo) will be labeled to indicate that it is an 
investigational agent and will contain a subject’s information, date, and time of formulation. 
 
6.2 IV Administration of MSCs or Placebo 
An intravenous line will be placed into an appropriate peripheral vein with 0.9% sodium chloride solution 
running to keep the vein open. The study solution described above will be taken up in an 18 gauge needle into 
a 60 mL syringe with an eccentric (offset) tip. The needle will be removed and infusion tubing will be attached 
to the syringe. The syringe with infusion tubing will be placed in a metered dose syringe pump positioned 
horizontally with the syringe rotated such that the syringe tip is at the lowest position. The product will be 
infused intravenously into the subject’s arm at a constant rate of approximately 2 mL/min. The applicable 
volume for the target dose will be delivered within 2 mL. Depending on subject’s weight, up to three 60 mL 
syringes of product may be infused. After the entire product volume is delivered, 25 mL of LRS (without cells) 
will be infused at 2 mL/min to deliver cells from the infusion line for more accurate dosing. Subjects in the 
placebo group will receive intravenous LRS. Their syringes will be labeled as above to preserve blinding and 
followed by 25 mL of LRS infusion as above. 

 
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If the subject has an adverse reaction during the infusion, the infusion may be interrupted or slowed according 
to the severity of the reaction.  All appropriate treatment will be given to reduce any discomfort and ensure the 
subject's safety.  The infusion may be restarted, if interrupted, if the subject is not considered to be at risk by 
the Investigator and the subject consents. 
 
6.3 Product Storage and Stability 
Once the cell suspension is prepared for administration to a subject as described above, the dose of allogeneic 
mesenchymal bone marrow cells will be stored at +4ºC until the time of administration. All cells will be 
administered to the subject within 8 hours of preparation. Cells that are not used within this time period will be 
discarded. 
 
6.4 
Concomitant Medications and Rehabilitation 
Concomitant medications (any prescription and/or over-the-counter preparations) and therapies (nondrug or 
procedures) used by a subject while participating in this clinical trial will be optimized per the AHA Guidelines 
and recorded at screening and until the end of the study or the end of a subject’s participation in the study. 
Subjects may be administered beta-blockers, ACE inhibitors, angiotensin receptor blockers or angiotensin 
receptor neprilysin inhibitor, mineralocorticoid receptor antagonists, isosorbide, hydralazine, statins, or other 
medications, as tolerated.  All other prescription and over-the-counter preparations approved by the patients’ 
physician will be permitted. 
 
7. STUDY ASSESSMENTS AND SCHEDULE 
7.1 General Assessments  
Clinical Assessments 
• 
Complete medical history and concomitant medications. 
• 
Physical and cardiac examination, including vital signs (temperature, mean arterial blood pressure, 
weight, heart rate, respiratory rate, oxygen saturation, LVAD parameters: pump speed, power, flow, 

 
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pulsatility). 
• 
All-cause mortality, admission for worsening HF and all-cause admissions. 
• 
Exercise capacity: 6 minute walk distance. 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) (Appendix B). 
• 
New York Heart Association (NYHA) Classification (Appendix B). 
 
Clinical Laboratory Assessments 
• 
Hematology (CBC): hemoglobin, hematocrit, platelet count, red blood cell count, white blood cell count, 
automated differential and platelet count. 
• 
Serum Chemistry: includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
calcium, magnesium, phosphorous, total bilirubin, albumin and total protein, and the following liver 
function tests (LFTs): alkaline phosphatase, alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) and lactate dehydrogenase (LDH) 
• 
Immunoglobulin A (IgA), immunoglobulin E (IgE), immunoglobulin G (IgG), immunoglobulin M (IgM),  
• 
Troponin I, NT-pro Brain Natriuretic Peptide (NT-proBNP) and ST 2 
• 
CK and CK-MB 
• 
Uric Acid 
• 
HLA 
• 
hsCRP 
• 
Inflammatory/immune biomarkers: 
In-vivo immune responses. 
1.1 Quantitative Immune Response - biomarkers Array. 
At all time points blood samples from all patients will be analyzed for the following 40 immune response 
biomarkers. Samples from normal donors will serve as reference. 
Quantibody® Human Immune Response Biomarker Array 1 Kit (RayBiotech).  
CD14 
CD163 
CD40 
CRP 
E-Selectin 

 
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Fas 
(TNFRSF6/Apo-1) 
Fas Ligand 
(TNFSF6) 
GCSF 
ICAM-1 
(CD54) 
IL-1 alpha 
(IL-1 F1) 
IL-1 beta 
IL-1 R4 
IL-10 
IL-12 p70 
IL-13 
IL-18 
IL-2 
IL-2 R alpha 
IL-4 
IL-6 
IL-8 
Lipocalin-2 
MCP-1 
MCP-2 
MIF 
MIP-1 alpha 
MIP-1 beta 
Osteopontin 
PAI-1 
Platelet 
Factor 4 
Procalcitonin 
RAGE 
Resistin 
Thrombomodulin 
TNF alpha 
TREM-1 
Troponin I 
uPAR 
VCAM-1 
VEGF-A 
 
1.2. Antibody Isotype assay – Analyzing the effect of treatment with MSCs on the humoral response; levels 
of antibodies and isotype switch. 
2. Cellular response 
At all-time points leukocytes will be isolated from blood samples and will be frozen for further analysis. 
Leukocytes will be analyzed for: 
Immune phenotyping by flow cytometry, to determine the effect of treatment with MSCs on the cellular 
immune response. (Expected effect - changing the balance from pro to anti-inflammatory phenotype). 
Functional assays. 
Proliferation assay – evaluating the suppressive effect of MSCs on T cells. 
In-vitro cytokine secretion – testing the effect of MSCs treatment on leukocytes potential to secret 
cytokines following general stimulation. 
Cytotoxicity assay – co-culture of leukocytes with MSCs will test the cytotoxic effect of leukocytes toward 
MSCs on the axis of time and repeated treatments. This assay will help evaluating the effectiveness of 
repeated treatments with MSCs.  
B. Future assays (Biobanking) 
It is to be expected that from the blood collected (listed above in 1.1-2) for all of the analyses detailed 
above, approximately 20ml of serum will remain unused.  We plan to bank this serum for future use.  Future 
analyses of the serum will derive from questions that are unanticipated at the initiation of the study but that 
usually arise once the analyses as per protocol are performed.  The availability of serum to perform these 

 
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new analyses provide the potential to importantly supplement insights we can derive from this study. 
ECG 
A 12-lead ECG will be performed. Standard interval assessments, including QT and QTc, will be calculated 
from a single lead (typically lead II). QTc will be calculated on the screening ECG in order to determine if the 
subject meets enrollment criteria. QTc must be <550 ms in order for the subject to be randomized. 
Echocardiography 
• 
A full 2D, 3D and Doppler echocardiogram will be performed at baseline and day 30, 60, 90, 180, and 360. 
Images will be acquired with the patient positioned in the recumbent lateral position. Left ventricular 
volumes will be determined at end-diastole and end-systole by quantitative biplane assessment. 
Endocardial borders will be manually traced from apical four-chamber and two-chamber views. Left 
ventricular volumes will be used to calculate LVEF using the biplane modified Simpson’s summation-of-
disks method recommended by the American Society of Echocardiography. 
• 
High frame-rate images of the LV in the three apical views (4-chamber, 2-chamber, and apical long axis) 
and the RV in the RV focused apical long axis will be acquired for speckle tracking echocardiography. 
Images will be analyzed offline on a dedicated workstation using TOMTEC software (TOMTEC 
Corporation) for calculation of segmental and global longitudinal strain and strain rate. Global 
longitudinal strain and strain rate will be calculated from all 18 segments of the LV and the 6 segments of 
the RV. Segmental strain and strain rate will be calculated for each segment separately.  
 
Gated blood pool SPECT ventriculography  
Gated blood pool SPECT ventriculography will be performed at baseline and days 90 and 180. Efficacy 
endpoints evaluated by quantitative 3D gated blood pool SPECT ventriculography will include: LV and RV end 
diastolic volumes, LV and RV end systolic volumes and global LV and RV ejection fractions.  
 
Zio patch monitoring 
Patients without an ICD will undergo periods of 7 day monitoring for arrhythmias using a Zio patch (iRhythm 

 
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Technologies, Inc). For the purposes of this study, life-threatening arrhythmias are defined as 
hemodynamically unstable sustained ventricular tachycardia or new- onset complete heart block. 
 
7.2 Schedule of Assessments 
7.2.1 Screening, Baseline and Randomization (Day -12- -11) 
• 
Study participants must meet eligibility criteria (inclusion/exclusion criteria review). 
• 
Sign the written informed consent. 
• 
Complete medical history, including medications history. 
• 
Complete physical and cardiac examination, including vital signs (temperature, mean arterial blood 
pressure, weight, heart rate, respiratory rate, peripheral arterial oxygen saturation, LVAD parameters: 
pump speed, power, flow, pulsatility), weight, and height. 
• 
12-lead ECG. 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ). 
• 
New York Heart Association (NYHA) Classification. 
• 
6 minute walk test 
• 
Clinical labs: serum chemistry including BUN & creatinine, CBC with differential, LFTs, total 
protein, and albumin and LDH. 
• 
Troponin, NT-pro Brain Natriuretic Peptide (NT-proBNP)  
• 
Uric acid 
• 
Biomarkers of inflammatory/immune response 
• 
HIV test 
• 
HS-CRP 
• 
Zio patch recording or ICD interrogation 
• 
Gated blood pool SPECT ventriculography   
• 
 Full 2D and 3D and Doppler transthoracic echocardiography with speckle-tracking.  
• 
Randomization into experimental or control group 

 
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7.2.2 Assessments and treatment  
Day 0 ± 7 Days, day 30 ± 7 Days and Day 60 ± 7 Days (day of first, second and third infusion, respectively)  
Pre-infusion: 
• 
Review and record any changes in medical history, including concomitant medications from before 
visit(s). 
• 
Measure and record weight and vital signs (temperature, mean arterial blood pressure, weight, heart 
rate, respiratory rate, oxygen saturation, LVAD parameters: speed, power, flow, pulsatility) after 
subjects rest quietly in a supine or semi-recumbent position. 
• 
Physical and cardiac examination. 
• 
Draw and process blood samples for IgA, IgE, IgG, IgM  
• 
Troponin, NT-pro Brain Natriuretic Peptide (NT-proBNP) and SST2. 
• 
CK and CK-MB 
• 
Zio patch or ICD assessment if not still on or done from baseline visit for the Zio patch patients 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ). (30 and 60 day only) 
• 
New York Heart Association (NYHA) Classification. (30 and 60 day only) 
• 
6 minute walk test (30 and 60 day only) 
• 
Full 2D and 3D and Doppler transthoracic echocardiography with speckle-tracking (30 and 60 day only) 
• 
Place an IV line in the upper extremity or hand with 0.9% sodium chloride running to keep the vein open 
• 
CBC with differential 
• 
CMP 
• 
Uric Acid  
• 
HLA and HS-CRP 
• 
Biomarkers of inflammatory/immune response: A panel of inflammatory biomarkers: CD14, CD163, 
CD40, CRP, E-Selectin, Fas, (TNFRSF6/Apo-1), Fas Ligand (TNFSF6), GCSF, ICAM-1 (CD54), IL-1 
alpha (IL-1 F1), IL-1 beta, IL-1 R4, IL-10, IL-12 p70, IL-13, IL-18, IL-2, IL-2 R alpha, IL-4, IL-6, IL-8, 

 
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Lipocalin-2, MCP-1, MCP-2, MIF, MIP-1 alpha, MIP-1 beta, Osteopontin, PAI-1, Platelet Factor 4, 
Procalcitonin, RAGE, Resistin, Thrombomodulin, TNF alpha, TREM-1, Troponin I, uPAR, VCAM-1, 
VEGF-A using a biomarker array kit and other markers as previously detailed using a biomarker array kit.  
 
 
During infusion: 
• 
IV infusion of the study product or placebo 
• 
Monitoring for any signs of adverse reaction, record AE/s and concomitant medications 
• 
Record vital signs and LVAD parameters every 2 hours, and as clinically indicated 
• 
Continuous ECG monitoring during infusion of study product 
• 
Pulse oximetry continuously during and for 2 hours post infusion 
 
Post- infusion: 
• 
12-lead ECG 
• 
Monitoring for any signs of adverse reaction, record AE/s and concomitant medications 
• 
Record vital signs and LVAD parameters every 2 hours till discharge 
• 
Continuous ECG monitoring for 2 hours 
• 
Pulse oximetry continuously for 2 hours 
• 
Subjects will be discharged from the hospital when he/she is stable in the opinion of the investigator  
• 
Physical exam, prior to discharge if clinically stable 
• 
Provide subject or responsible individual accompanying the subject with the phone number for 
contacting the study nurse and/or investigator for any questions, concerns or changes in health status. 
7.3 
Follow-up Assessments 
One week post infusion (7 days ± 2 days)  
• Biomarkers of inflammatory/immune response: A panel of inflammatory biomarkers: CD14, CD163, 
CD40, CRP, E-Selectin, Fas, (TNFRSF6/Apo-1), Fas Ligand (TNFSF6), GCSF, ICAM-1 (CD54), IL-1 

 
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alpha (IL-1 F1), IL-1 beta, IL-1 R4, IL-10, IL-12 p70, IL-13, IL-18, IL-2, IL-2 R alpha, IL-4, IL-6, IL-8, 
Lipocalin-2, MCP-1, MCP-2, MIF, MIP-1 alpha, MIP-1 beta, Osteopontin, PAI-1, Platelet Factor 4, 
Procalcitonin, RAGE, Resistin, Thrombomodulin, TNF alpha, TREM-1, Troponin I, uPAR, VCAM-1, 
VEGF-A using a biomarker array kit and other markers as previously detailed using a biomarker array 
kit.  
 
Day 90, 180, and 360 (±7) days post initial infusion 
• 
Measure and record vital signs 
• 
12-lead ECG 
• 
Pulse Oximetry 
• 
Zio patch or ICD assessment 
• 
Record all-cause mortality, admission for worsening HF and all-cause admissions, AEs and 
concomitant medication use 
• 
Physical and cardiac examination 
• 
Changes in medical history  
• 
Clinical labs: serum chemistry including BUN & creatinine, CBC with differential, LFTs, total 
protein, albumin and LDH. 
• 
HS-CRP 
• 
Cardiac Biomarkers:NT-pro Brain Natriuretic Peptide (NT-proBNP) and ST 2 
• 
Biomarkers of immune response: A panel of inflammatory biomarkers: CD14, CD163, CD40, CRP, E-
Selectin, Fas, (TNFRSF6/Apo-1), Fas Ligand (TNFSF6), GCSF, ICAM-1 (CD54), IL-1 alpha (IL-1 F1), IL-1 
beta, IL-1 R4, IL-10, IL-12 p70, IL-13, IL-18, IL-2, IL-2 R alpha, IL-4, IL-6, IL-8, Lipocalin-2, MCP-1, MCP-2, 
MIF, MIP-1 alpha, MIP-1 beta, Osteopontin, PAI-1, Platelet Factor 4, Procalcitonin, RAGE, Resistin, 
Thrombomodulin, TNF alpha, TREM-1, Troponin I, uPAR, VCAM-1, VEGF-A using a biomarker array kit 
using a biomarker array kit. Antibody Isotype assays, leukocyte cytokine secretory assays, and leukocyte 
cytotoxic effects toward MSCs. Blood sample for IgA, IgE, IgG, IgM,  

 
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• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• 
New York Heart Association (NYHA) Classification 
• 
6 minute walk test 
• 
Full 2D and 3 D and Doppler transthoracic echocardiography with speckle-tracking.  
• 
Gated blood pool SPECT ventriculography (only 90 and 180 days) 
• 
Uric Acid  
• 
HLA 
 
 
7.4 
Early Termination Visit 
• 
Measure and record weight and vital signs 
• 
LVAD parameters 
• 
12-lead ECG 
• 
Pulse Oximetry 
• 
Zio patch or ICD assessment 
• 
Record the all-cause admission for worsening HF and all-cause admissions, AEs and concomitant 
medication use 
• 
Physical and cardiac examination 
• 
Changes in medical history  
• 
Clinical labs: serum chemistry including BUN & creatinine, CBC with differential, LFTs, total protein, 
albumin, LDH, and uric acidBiomarkers of immune response: A panel of inflammatory biomarkers: CD14, 
CD163, CD40, CRP, E-Selectin, Fas, (TNFRSF6/Apo-1), Fas Ligand (TNFSF6), GCSF, ICAM-1 (CD54), 
IL-1 alpha (IL-1 F1), IL-1 beta, IL-1 R4, IL-10, IL-12 p70, IL-13, IL-18, IL-2, IL-2 R alpha, IL-4, IL-6, IL-8, 
Lipocalin-2, MCP-1, MCP-2, MIF, MIP-1 alpha, MIP-1 beta, Osteopontin, PAI-1, Platelet Factor 4, 
Procalcitonin, RAGE, Resistin, Thrombomodulin, TNF alpha, TREM-1, Troponin I, uPAR, VCAM-1, 
VEGF-A using a biomarker array kit. Antibody Isotype assays, leukocyte proliferation and cytokine 
secretory assays, and leukocyte cytotoxic effects toward MSCs. Hs-CRPBlood sample for IgA, IgE, IgG, 

 
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IgM 6 minute walk test 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• 
New York Heart Association (NYHA) Classification 
• 
Full 2D and 3D and Doppler transthoracic echocardiography with speckle-tracking 
• 
Cardiac Biomarkers:NT-pro Brain Natriuretic Peptide (NT-proBNP) and ST 2 
• 
Gated blood pool SPECT ventriculography  
 
8 
ASSESSMENT OF SAFETY 
8.1 
Safety Parameters 
Safety assessments will consist of monitoring and recording adverse treatment events.  Changes in clinical 
laboratory, clinical status and physical examination values will be used for evaluation. 
To allow for the assessment of potential infusion toxicity at least 1 day will pass between the infusions of the 
Investigational Product/Placebo for each of the first five (5) subjects. 
 
8.1.1 Adverse Event (AE) 
ICH E6 defines an AE as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product regardless of its causal relationship to the study stem cell 
administration. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) product. The 
occurrence of an AE may come to the attention of study personnel during study visits and interviews of a study 
recipient presenting for medical care, or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for “serious adverse events” will be 
captured on the appropriate CRF. Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis) which would include MD, DO, PA or NP and time of resolution/stabilization of 
the event. All AEs occurring while on study must be documented appropriately regardless of relationship. All 
AEs will be followed to adequate resolution. 

 
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Any medical condition that is present at the time that the subject is screened will be considered as baseline 
and not reported as an AE. However, if it deteriorates at any time during the study, it should be recorded as an 
AE. 
All AEs must be graded for severity and relationship to study product. 
 
Severity of Event:  All AEs will be assessed by the clinician using the following grading system of AE 
intensity. 
• 
Mild: events require minimal or no treatment and do not interfere with the subject’s daily activities. 
• 
Moderate: events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• 
Severe: events interrupt a subject’s usual daily activity and may require systemic drug therapy or other 
treatment. Severe events are usually incapacitating. 
• 
Life threatening:  any adverse drug experience that places the subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it 
occurred in a more severe form, might have caused death. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at 
each level of intensity to be performed. AEs characterized as intermittent require documentation of onset and 
duration of each episode. 
 
Relationship to Study Products:  The clinician’s assessment of an AE’s relationship to investigational 
product is part of the documentation process, but it is not a factor in determining what is or is not reported in 
the study. If there is any doubt as to whether a clinical observation is an AE, the event will be reported. All AEs 
must have their relationship to investigational product assessed. In a clinical trial, the investigational product 
must always be suspect. To help assess, the following guidelines are used. 
• 
Related – There is a plausible temporal relationship between the onset of the AE and administration of the 
investigational product, and the AE cannot be readily explained by the subject’s pre-existing clinical state, 

 
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intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to the 
investigational product; and/or the AE abates or resolves upon discontinuation of the investigational product 
and, if applicable, reappears upon re-challenge. 
• 
Not Related – There is good evidence that the AE has an etiology other than the investigational product 
(e.g., pre-existing medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to administration of the investigational product 
(e.g., cancer diagnosed 2 days after treatment). 
 
8.1.2 Serious Adverse Event (SAE) 
An SAE is an AE that results in any of the following outcomes: 
• 
Death (i.e., the AE actually causes or leads to death) 
• 
Life threatening event (i.e., the AE, in the view of the Investigator, places the subject at immediate risk of 
death) 
• 
Requires or prolongs inpatient hospitalization 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the 
subject’s ability to conduct normal life functions) 
• 
A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational 
product(s) 
Any other important medical event that may not result in death, be life threatening, or require hospitalization, 
may be considered a serious adverse experience when, based upon appropriate medical judgment, the event 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization. 
 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE (as in mild, 
moderate, or severe pain); the event itself may be of relatively minor medical significance (such as severe 

 
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headache). “Serious” is a regulatory definition and is based on subject or event outcome or action criteria 
usually associated with events that pose a threat to a subject’s life or vital functions.  Seriousness (not severity) 
serves as the guide for defining regulatory reporting obligations. 
Severity and seriousness will be independently assessed when recording AEs and SAEs on the CRF. 
 
8.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
The Investigator is responsible for ensuring that all study-emergent AEs and SAEs are recorded on the CRF 
and reported to the sponsor in accordance with protocol instructions. For each SAE observed, the 
investigator will obtain all of the information available about the event, including (but not limited to): hospital 
discharge diagnoses, hospital discharge note, death certificate, appropriate laboratory findings (including 
autopsies and biopsy results), and clinical examinations (including radiological examinations and clinical 
consultations). 
 
 
8.2.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after initiation of study treatment and 
ends at study completion or study discontinuation/termination, whichever is earlier.  Any condition present 
between consenting and time of treatment will be considered as baseline and not recorded as an AE. After this 
period, investigators should report only SAEs that are attributed to study treatment. 
All AEs that are observed or reported prior to initiation of study treatment will be recorded as unrelated to 
treatment and those occurring after initiation of treatment will be recorded as treatment-emergent. 
 
8.2.2 Assessment of Adverse Events 
Investigators will seek information on AEs and SAEs at each subject contact by specific questioning and, as 
appropriate, by examination.  All AEs and SAEs, whether spontaneously reported by the subject or noted by 
authorized study personnel, will be recorded in the subject’s medical record and on the appropriate AE or SAE 

 
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CRF page. 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), severity, regulatory 
seriousness criteria if applicable, suspected relationship to the investigational product, and actions taken. 
 
Note: The investigator’s assessment of causality for individual AE reports is part of the study documentation 
process.  Regardless of the “Yes” or “No” causality assessment for individual AE reports, the sponsor will 
promptly evaluate all reported SAEs against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators and applicable regulatory authorities.  Attribution of 
SAEs will be reviewed on an ongoing basis, and may be changed as additional clinical data emerge 
(e.g., reversibility of AE, new clinical findings in subject with AE, effects of retreatment, AEs in other subjects). 
 
 
8.2.3 Recording Adverse Events on the CRF 
Investigators will use correct medical terminology/concepts when recording AEs or SAEs on the CRF.  Avoid 
colloquialisms and abbreviations. 
AEs will be recorded either on an AE CRF page (if no serious criteria are met) or SAE CRF page, but not both. 
For each SAE observed, the investigator must report the triggering event for that particular episode of illness 
as the primary event. 
Only one medical concept will be recorded in the event field on the AE or SAE CRF page. 
 
8.3 
Expedited Reporting Requirements for Serious Adverse Events 
Any life-threatening (i.e., imminent risk of death) or fatal AE that is attributed by the investigator to the 
investigational product will be telephoned to the Medical Monitor (or alternate) immediately. 
Medical Monitor: 
TBD 
 
 
 

 
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For initial SAE reports, investigators will record all case details that can be gathered within 24 hours on an SAE 
CRF page. The completed SAE CRF page will be faxed immediately upon completion to the attention of: 
Dr. Nikolai I. Tankovich, M.D., Ph.D.,  
President and Chief Medical Office, Stemedica Cell Technologies, Inc  
Office Telephone No.: 
 
Mobile Phone: 858 610-2588      
Email: ntankovich@stemedica.com 
 
Relevant follow-up information will be submitted as soon as it becomes available and/or upon request. 
 
8.4 
Type and Duration of Follow-Up of Subjects After Adverse Events 
The Investigator will follow all unresolved study-emergent AEs and SAEs until the events are resolved, 
stabilized, the subject is lost to follow-up, or until it has been determined that the study treatment or 
participation is not the cause of the AE/SAE. Resolution of AEs and SAEs (with dates) will be documented on 
the appropriate AE or SAE CRF page and in the subject’s medical record to facilitate source data verification. 
For some SAEs, the sponsor or its designee may follow-up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details deemed necessary to appropriately evaluate the SAE report 
(e.g., hospital discharge summary, consultant report, or autopsy report). 
 
8.5 
Data Safety and Monitoring Board (DSMB) 
An independent DSMB appointed by the Sponsor will review the protocol and will thereafter provide medical 
and ethical guidance related to the conduct of this trial.  During the study, the board will conduct ongoing 
review of the nature, frequency and severity of safety data.  The DSMB Chairperson has the option to 
recommend suspension of enrollment in the study if, upon initial deliberation by the DSMB, urgent safety 
issues or alarming trends in summary safety data are identified that require further investigation. 
The study sponsor will report all SAEs to the study DSMB. The DSMB will determine whether enrollment will be 

 
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continued, suspended, or terminated. In the event that the DSMB determines that the study will be suspended 
or terminated, the study sponsor will notify the Institutional Review Boards and the appropriate regulatory 
agencies. 
 
9 
STATISTICAL CONSIDERATIONS 
Statistical analyses will be descriptive.  Summary statistics will consist of sample size (N), means, standard 
deviations, medians, and minimum and maximum values for continuous variables, and counts and 
percentages for categorical variables. Tables will summarize all safety and efficacy outcome measures by 
actual treatment received. Summary tables will indicate the number of subjects with complete data for each 
measurement, event or outcome. No substitutions will be made for missing data.  All analyses will be based 
on available data. 
 
A detailed Statistical Analysis Plan will be written prior to data analysis. Significant deviations from the original 
statistical analysis plan will be detailed in the final study report. 
 
This study intentionally is not powered and will enrolled 30 patients with 15 in each of the two randomization 
arms.  
 
9.1 
Randomization 
Once eligibility and consent are confirmed, participants will be randomly assigned to the experimental or 
placebo group in a 1:1 allocation ratio, stratified by LVAD type.  
 
9.2 
Primary Safety Analysis 
All safety outcomes will be summarized in tables and listings presented by experimental group.  Continuous 
measures will be summarized with descriptive statistics (N, mean, SD, median, min, max). Categorical 
measures will be summarized using counts and percentages. The incidence of AEs will be presented by 

 
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toxicity grade, MedDRA system organ class and preferred term, and by relationship of the AEs to the study 
treatment and compared using a Fisher’s Exact Test. Laboratory and vital signs data will be presented using 
shift tables and summaries of change from baseline to next infusion or follow up visit.   
 
9.3 
Determination of Sample Size 
This Study is exploratory and its sample size is not determined by statistical power considerations, but is 
considered appropriate for an early phase safety trial. 
 
9.4 
Interim Analysis 
No formal interim analysis for efficacy is planned, as this is a study with careful monitoring of subject safety in 
an ongoing manner by the principal investigator, Sponsor and independent Data Safety Monitoring Board. 
 
9.5 
Data Quality Assurance 
The following steps will be taken to ensure the accuracy, consistency, completeness, and reliability of the data: 
• Routine study site monitoring 
• CRF review against source documents 
• Data management quality control checks 
 
10 INVESTIGATOR REQUIREMENTS 
10.1 Study Initiation 
Before the release of investigational products to the study site, the following documents must be on file with the 
sponsor: 
• 
U.S. Food and Drug Administration (FDA) Form 1572 signed by the Principal Investigator or equivalent for 
non-U.S. sites if applicable. 
o 
The names of any sub-investigators must appear on this form. Investigators must also complete all 
regulatory documentation as required by local and national regulations. 

 
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• 
Current curricula vitae (CV) of the Principal Investigator and all subinvestigators 
• 
Complete financial disclosure forms for the Principal Investigator and all subinvestigators 
• 
Written documentation of Institutional Review Board (IRB)/Ethics Committee (EC) approval of the protocol 
(identified by protocol number or title and date of approval) and Informed Consent Form (ICF; identified by 
protocol number or title and date of approval) 
• 
A copy of the IRB-approved ICF 
• 
IRB composition or assurance letter as applicable 
• 
Current laboratory certification of the clinical laboratory performing sample analysis, as well as current 
references ranges for all laboratory tests (if applicable) 
• 
A Clinical Trial Agreement signed and dated by the study site 
• 
Investigator Brochure receipt signed and dated by the Principal Investigator (if applicable) 
• 
A Protocol Acceptance Form signed and dated by the Principal Investigator 
 
10.2 Study Completion 
The following data and materials are required before a study can be considered complete or terminated: 
• 
All essential documents (e.g., curriculum vitae for the Principal Investigator and subinvestigator, U.S. FDA 
Form 1572 or equivalent (non-U.S.) 
• 
Copies of protocol amendments, IRB/EC approval/notification, and signed and dated Protocol Amendment 
Acceptance Form(s) (if applicable) 
• 
All data collection and query resolution complete Original, final SAE reports and all supporting 
documentation (i.e., discharge summaries, laboratory results) 
• 
Original, final Pregnancy Information forms and all supporting documentation (if applicable) 
• 
Complete and accurate investigational product accountability records and inventory log 
• 
Laboratory results, clinical data, and all special test results from screening through the end of the study 
• 
A summary of the study prepared by the principal investigator (IRB/EC summary close out letter is 
acceptable) 

 
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10.3 
Informed Consent  
A sample ICF is provided as an attachment.  In conformance with Federal Regulations governing informed 
consent, the STEMVAD study informed consent form that is given to the subject or authorized representative 
must be in a language understood by the patient or his/ her legal representative.  
 
Prior to participation in the study, each patient must give written informed consent after having the study fully 
explained to him/her in the language that is most easily understood by the patient.  All patients must be given the 
opportunity to ask questions and to have those questions answered to his/her satisfaction.  All informed consent 
forms must be approved by the IRB before use and no patient may be consented unless such approval has been 
granted.  All ICFs must be written in accordance with the current guidelines as outlined by GCP, and ICH.   
All informed consent forms must be signed and dated by the person providing explanation of the study and 
signed and dated by the patient or his/her legal representative prior to participation in this research study.  A 
signed and dated copy of the informed consent form will be given to each patient.  
10.4 
Institutional Review Board  
A copy of the protocol, proposed ICFs, all written patient information, and any proposed advertising material 
must be submitted to the institution’s IRB for written approval.  No site may initiate study procedures/activities 
until such IRB approval had been granted in writing. A copy of the written IRB approval of the protocol and ICF 
must be received by the Sponsor of the trial before study supplies are shipped to the investigative site.   The 
Investigator must submit and, where necessary, obtain IRB approval for all protocol amendments and changes 
to the ICF.  If any investigator, co-investigator or sub-investigator participating in this study is a member of the 
IRB approving the study for the site, documentation must be provided by the IRB showing that the investigator 
did not vote on the approval of the study. 
10.5 
Study Monitoring Requirements 
The study site will be monitored by the Sponsor’s designee.  The Principal Investigator will permit said 
designee, the U.S. FDA or other regulatory agencies, Ethics Committees and the respective national or local 

 
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health authorities to inspect facilities and records relevant to this study, in accordance with GCP and the ICH.  
If the investigator is notified of an audit pertaining to this study by the U.S. FDA or other applicable regulatory 
authorities, the Investigator must notify the Sponsor immediately. 
The Investigator must provide sufficient space and allocate sufficient time for the monitor to inspect subject 
source records, CRFs, investigational product accountability records, and regulatory documents. 
 
10.6 
Case Report Forms 
All CRFs will be filled out completely by designated personnel. 
 
10.7 Source Data Documentation 
Study monitors will perform ongoing source data verification to confirm that critical protocol data (i.e., source 
data) transcribed on the CRFs by authorized site personnel are accurate, complete, and verifiable from  
source documents. Source documents are where subject data are recorded and documented for the first time. 
They include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, 
subject diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, subject files, and records kept at the 
pharmacy, laboratories, and medico-technical departments involved in a clinical trial. Source documents that 
are required to verify the validity and completeness of data transcribed on the CRFs must never be obliterated 
or destroyed. To facilitate source data verification, the investigator(s) and institution(s) must provide the 
sponsor direct access to applicable source documents and reports for trial-related monitoring, sponsor audits, 
and IRB review.  The investigational site must also allow inspection by applicable regulatory authorities. 
 
10.8 
Investigational Product Accountability 
All investigational products required for completion of this study will be provided by CardioCell, LLC. The 
recipient will acknowledge receipt of the drug by returning the appropriate documentation form indicating 

 
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shipment content and condition.  Damaged supplies will be replaced. 
Accurate records of all study drug received at, dispensed from, returned to and disposed of by the study site 
will be recorded. 
Investigational product will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to CardioCell, LLC with the appropriate documentation, as 
determined by the study site. If the study site chooses to destroy investigational product, the method of 
destruction must be documented. 
CardioCell, LLC must evaluate and approve the study site’s drug destruction standard operating procedure 
prior to the initiation of drug destruction by the study site. 
 
10.9 
Retention of Records (for approval enabling studies only) 
United States FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP require that records and 
documents pertaining to the conduct of this study and the distribution of investigational drug, including CRFs, 
consent forms, laboratory test results, and medication inventory records, must be retained by the Principal 
Investigator for 2 years after the last marketing application approval in an ICH region or after at least 2 years 
have elapsed since formal discontinuation of clinical development of the investigational product. All state and 
local laws for retention of records also apply. 
 
No records will be disposed of without written approval from the Sponsor. Written notification will be provided 
to Sponsor for transfer of any records to another party or moving them to another location. 
 
 

 
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REFERENCES 
 
1. Velagaleti RS and Vasan RS. Heart failure in the twenty-first century: is it a coronary artery disease or 
hypertension problem? Cardiol Clin. 2007;25:487-95; v. 
2. Bourassa MG, Gurne O, Bangdiwala SI, Ghali JK, Young JB, Rousseau M, Johnstone DE and Yusuf S. 
Natural history and patterns of current practice in heart failure. The Studies of Left Ventricular Dysfunction 
(SOLVD) Investigators. J Am Coll Cardiol. 1993;22:14A-19A. 
3. Dunlay SM, Weston SA, Jacobsen SJ and Roger VL. Risk factors for heart failure: a population-based case-
control study. Am J Med. 2009;122:1023-8. 
4. Felker GM, Shaw LK and O'Connor CM. A standardized definition of ischemic cardiomyopathy for use in 
clinical research. J Am Coll Cardiol. 2002;39:210-8. 
5. Bart BA, Shaw LK, McCants CB, Jr., Fortin DF, Lee KL, Califf RM and O'Connor CM. Clinical determinants of 
mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy. J Am Coll 
Cardiol. 1997;30:1002-8. 
6. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, 
Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jimenez MC, Jordan LC, 
Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, 
Matsushita K, Mussolino ME, Nasir K, O'Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, 
Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, 
Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P, American 
Heart Association Council on E, Prevention Statistics C and Stroke Statistics S. Heart Disease and Stroke 
Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018;137:e67-e492. 
7. Mancini D and Colombo PC. Left Ventricular Assist Devices: A Rapidly Evolving Alternative to Transplant. J 
Am Coll Cardiol. 2015;65:2542-55. 
8. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, Fonarow GC, Geraci SA, Horwich T, 
Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson 
PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ and Wilkoff BL. 2013 ACCF/AHA guideline for the 
management of heart failure: executive summary: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:1810-52. 
9. Writing Group M, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de 
Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, 
Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, 
Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, 
Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart 
Association Statistics C and Stroke Statistics S. Heart Disease and Stroke Statistics-2016 Update: A Report 
From the American Heart Association. Circulation. 2016;133:e38-360. 
10. Kirklin JK, Pagani FD, Kormos RL, Stevenson LW, Blume ED, Myers SL, Miller MA, Baldwin JT, Young JB 
and Naftel DC. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J 
Heart Lung Transplant. 2017;36:1080-1086. 
11. Kelkar AA, Butler J, Schelbert EB, Greene SJ, Quyyumi AA, Bonow RO, Cohen I, Gheorghiade M, Lipinski 
MJ, Sun W, Luger D and Epstein SE. Mechanisms Contributing to the Progression of Ischemic and Nonischemic 
Dilated Cardiomyopathy: Possible Modulating Effects of Paracrine Activities of Stem Cells. J Am Coll Cardiol. 
2015;66:2038-2047. 
12. Dick SA and Epelman S. Chronic Heart Failure and Inflammation: What Do We Really Know? Circ Res. 
2016;119:159-76. 
13. Epstein SE, Luger D and Lipinski MJ. Paracrine-Mediated Systemic Anti-Inflammatory Activity of 
Intravenously Administered Mesenchymal Stem Cells: A Transformative Strategy for Cardiac Stem Cell 
Therapeutics. Circ Res. 2017;121:1044-1046. 
14. Luger D, Lipinski MJ, Westman PC, Glover DK, Dimastromatteo J, Frias JC, Albelda MT, Sikora S, Kharazi 
A, Vertelov G, Waksman R and Epstein SE. Intravenously Delivered Mesenchymal Stem Cells: Systemic Anti-
Inflammatory Effects Improve Left Ventricular Dysfunction in Acute Myocardial Infarction and Ischemic 

 
STEMVAD V1.5_20200323 
63 
-confidential- 
 
Cardiomyopathy. Circ Res. 2017;120:1598-1613. 
15. Westman PC, Lipinski MJ, Luger D, Waksman R, Bonow RO, Wu E and Epstein SE. Inflammation as a 
Driver of Adverse Left Ventricular Remodeling After Acute Myocardial Infarction. J Am Coll Cardiol. 
2016;67:2050-60. 
16. Grosman-Rimon L, McDonald MA, Jacobs I, Tumiati LC, Pollock Bar-Ziv S, Shogilev DJ, Mociornita AG, 
Ghashghai A, Chruscinski A, Cherney DZ and Rao V. Markers of inflammation in recipients of continuous-flow 
left ventricular assist devices. ASAIO J. 2014;60:657-63. 
17. Grosman-Rimon L, Jacobs I, Tumiati LC, McDonald MA, Bar-Ziv SP, Fuks A, Kawajiri H, Lazarte J, 
Ghashghai A, Shogilev DJ, Cherney DZ and Rao V. Longitudinal assessment of inflammation in recipients of 
continuous-flow left ventricular assist devices. Can J Cardiol. 2015;31:348-56. 
18. Van Tassell BW, Toldo S, Mezzaroma E and Abbate A. Targeting interleukin-1 in heart disease. Circulation. 
2013;128:1910-23. 
19. Alfaro MP, Vincent A, Saraswati S, Thorne CA, Hong CC, Lee E and Young PP. sFRP2 suppression of bone 
morphogenic protein (BMP) and Wnt signaling mediates mesenchymal stem cell (MSC) self-renewal promoting 
engraftment and myocardial repair. J Biol Chem. 2010;285:35645-53. 
20. Fan L, Lin C, Zhuo S, Chen L, Liu N, Luo Y, Fang J, Huang Z, Lin Y and Chen J. Transplantation with 
survivin-engineered mesenchymal stem cells results in better prognosis in a rat model of myocardial infarction. 
Eur J Heart Fail. 2009;11:1023-30. 
21. Huang J, Zhang Z, Guo J, Ni A, Deb A, Zhang L, Mirotsou M, Pratt RE and Dzau VJ. Genetic modification of 
mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary 
density in the injured myocardium. Circ Res. 2010;106:1753-62. 
22. Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS and Dzau VJ. Mesenchymal stem cells modified 
with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 2003;9:1195-201. 
23. Kim YS, Kwon JS, Hong MH, Kim J, Song CH, Jeong MH, Cho JG, Park JC, Kang JC and Ahn Y. 
Promigratory activity of oxytocin on umbilical cord blood-derived mesenchymal stem cells. Artif Organs. 
2010;34:453-61. 
24. Chacko SM, Ahmed S, Selvendiran K, Kuppusamy ML, Khan M and Kuppusamy P. Hypoxic preconditioning 
induces the expression of prosurvival and proangiogenic markers in mesenchymal stem cells. Am J Physiol Cell 
Physiol. 2010;299:C1562-70. 
25. Haque N, Rahman MT, Abu Kasim NH and Alabsi AM. Hypoxic culture conditions as a solution for 
mesenchymal stem cell based regenerative therapy. ScientificWorldJournal. 2013;2013:632972. 
26. Basciano L, Nemos C, Foliguet B, de Isla N, de Carvalho M, Tran N and Dalloul A. Long term culture of 
mesenchymal stem cells in hypoxia promotes a genetic program maintaining their undifferentiated and 
multipotent status. BMC Cell Biol. 2011;12:12. 
27. Lee DE, Ayoub N and Agrawal DK. Mesenchymal stem cells and cutaneous wound healing: novel methods 
to increase cell delivery and therapeutic efficacy. Stem Cell Res Ther. 2016;7:37. 
28. Rich JD, Gosev I, Patel CB, Joseph S, Katz JN, Eckman PM, Lee S, Sundareswaran K, Kilic A, Bethea B, 
Soleimani B, Lima B, Uriel N, Kiernan M and Evolving Mechanical Support Research Group I. The incidence, 
risk factors, and outcomes associated with late right-sided heart failure in patients supported with an axial-flow 
left ventricular assist device. J Heart Lung Transplant. 2017;36:50-58. 
29. Phinney DG and Prockop DJ. Concise review: mesenchymal stem/multipotent stromal cells: the state of 
transdifferentiation and modes of tissue repair--current views. Stem Cells. 2007;25:2896-902. 
30. Peng Y, Pan W, Ou Y, Xu W, Kaelber S, Borlongan CV, Sun M and Yu G. Extracardiac-Lodged 
Mesenchymal Stromal Cells Propel an Inflammatory Response Against Myocardial Infarction via Paracrine 
Effects. Cell Transplant. 2016;25:929-35. 
31. Lipinski MJ, Luger D and Epstein SE. Mesenchymal Stem Cell Therapy for the Treatment of Heart Failure 
Caused by Ischemic or Non-ischemic Cardiomyopathy: Immunosuppression and Its Implications. Handb Exp 
Pharmacol. 2017;243:329-353. 
32. Aggarwal S and Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. 
Blood. 2005;105:1815-22. 
33. Guo J, Lin GS, Bao CY, Hu ZM and Hu MY. Anti-inflammation role for mesenchymal stem cells 
transplantation in myocardial infarction. Inflammation. 2007;30:97-104. 

 
STEMVAD V1.5_20200323 
64 
-confidential- 
 
34. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler 
RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R and Pittet MJ. Identification of 
splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325:612-6. 
35. Ismahil MA, Hamid T, Bansal SS, Patel B, Kingery JR and Prabhu SD. Remodeling of the mononuclear 
phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of 
the cardiosplenic axis. Circ Res. 2014;114:266-82. 
36. Butler J, Epstein SE, Greene SJ, Quyyumi AA, Sikora S, Kim RJ, Anderson AS, Wilcox JE, Tankovich NI, 
Lipinski MJ, Ko YA, Margulies KB, Cole RT, Skopicki HA and Gheorghiade M. Intravenous Allogeneic 
Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A 
Randomized Trial. Circ Res. 2017;120:332-340. 
37. Naftali-Shani N, Levin-Kotler LP, Palevski D, Amit U, Kain D, Landa N, Hochhauser E and Leor J. Left 
Ventricular Dysfunction Switches Mesenchymal Stromal Cells Toward an Inflammatory Phenotype and Impairs 
Their Reparative Properties Via Toll-Like Receptor-4. Circulation. 2017;135:2271-2287. 
38. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E and Ringden O. HLA expression and immunologic 
properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31:890-6. 
39. Ankrum JA, Ong JF and Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat 
Biotechnol. 2014;32:252-60. 
40. Chinnadurai R, Ng S, Velu V and Galipeau J. Challenges in animal modelling of mesenchymal stromal cell 
therapy for inflammatory bowel disease. World J Gastroenterol. 2015;21:4779-87. 
41. Tang XL, Nakamura S, Li Q, Wysoczynski M, Gumpert AM, Wu WJ, Hunt G, Stowers H, Ou Q and Bolli R. 
Repeated Administrations of Cardiac Progenitor Cells Are Superior to a Single Administration of an Equivalent 
Cumulative Dose. J Am Heart Assoc. 2018;7. 
42. Guo Y, Wysoczynski M, Nong Y, Tomlin A, Zhu X, Gumpert AM, Nasr M, Muthusamy S, Li H, Book M, Khan 
A, Hong KU, Li Q and Bolli R. Repeated doses of cardiac mesenchymal cells are therapeutically superior to a 
single dose in mice with old myocardial infarction. Basic Res Cardiol. 2017;112:18. 
43. Bolli R. Repeated Cell Therapy: A Paradigm Shift Whose Time Has Come. Circ Res. 2017;120:1072-1074. 
44. Tokita Y, Tang XL, Li Q, Wysoczynski M, Hong KU, Nakamura S, Wu WJ, Xie W, Li D, Hunt G, Ou Q, 
Stowers H and Bolli R. Repeated Administrations of Cardiac Progenitor Cells Are Markedly More Effective Than 
a Single Administration: A New Paradigm in Cell Therapy. Circ Res. 2016;119:635-51. 
45. Epstein SE, Lipinski MJ and Luger D. Persistent Inflammation, Stem Cell-Induced Systemic Anti-
Inflammatory Effects, and Need for Repeated Stem Cell Injections: Critical Concepts Influencing Optimal Stem 
Cell Strategies for Treating Acute Myocardial Infarction and Heart Failure. J Am Heart Assoc. 2018;7. 
46. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ and 
Canadian Critical Care Trials G. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic 
review and meta-analysis of clinical trials. PLoS One. 2012;7:e47559. 
47. Berglund AK, Fortier LA, Antczak DF and Schnabel LV. Immunoprivileged no more: measuring the 
immunogenicity of allogeneic adult mesenchymal stem cells. Stem Cell Res Ther. 2017;8:288. 
48. Chen X, Wang C, Yin J, Xu J, Wei J and Zhang Y. Efficacy of Mesenchymal Stem Cell Therapy for Steroid-
Refractory Acute Graft-Versus-Host Disease following Allogeneic Hematopoietic Stem Cell Transplantation: A 
Systematic Review and Meta-Analysis. PLoS One. 2015;10:e0136991. 
49. Kurtzberg J, Prockop S, Teira P, Bittencourt H, Lewis V, Chan KW, Horn B, Yu L, Talano JA, Nemecek E, 
Mills CR and Chaudhury S. Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a 
rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. Biol Blood Marrow 
Transplant. 2014;20:229-35. 
50. Klyushnenkova E, Mosca JD, Zernetkina V, Majumdar MK, Beggs KJ, Simonetti DW, Deans RJ and 
McIntosh KR. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and 
suppression. J Biomed Sci. 2005;12:47-57. 
51. Eliopoulos N, Stagg J, Lejeune L, Pommey S and Galipeau J. Allogeneic marrow stromal cells are immune 
rejected by MHC class I- and class II-mismatched recipient mice. Blood. 2005;106:4057-65. 
 
 
 

 
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APPENDIX A: SCHEDULE OF ASSESSMENTS 
Visit 
Screening 
Baseli
ne 
Rando
mizatio
n 
Infusio
n 1 
Post 
Infusio
n 1 
Infusio
n 2 
Post 
Infusio
n 2 
Infusio
n 3 
Post 
infusio
n 3 
3 
months 
6 
months 
12 
months 
Early 
Term 
Day 
Days 
-12 to -11 
Day -5 
to -1 
 
Day 0 
1 Week  
Day 
30±7 
1 Week  
Day 
60±7 
1 Week  
Day 
90±7 
Day 
180±7 
Day 
360±7 
 
Informed Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IV Infusion 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
HIV Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs and LVAD 
parameters** 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pulse Oximetry 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Medical History 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Concomitant 
medications 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Physical Examination 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
6 minute walk test 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
Health Assessment, 
KCCQ, NYHA 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
12-lead ECG 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Full 2D and 3 D  Doppler 
transthoracic 
echocardiography with 
speckle-tracking 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
Zio patch (for patients 
who do not have an 
ICD)* 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Gated blood pool 
SPECT ventriculography 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
ICD device check 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Serum Chemistry with 
BUN/Creatinine, LFT, 
total protein, albumin  
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
LDH 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
HLA 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
NT-proBNP 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
SST2 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Troponin I 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
IgA, IgE, IgG, and IgM  
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 

 
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Biomarkers of immune 
response: CD14 CD163 
CD40 CRP E-Selectin, 
Fas, (TNFRSF6/Apo-1) 
Fas Ligand, (TNFSF6) 
GCSF ICAM-1, (CD54) 
IL-1 alpha, (IL-1 F1), IL-
1 beta IL-1 R4 IL-10 IL-
12 p70 IL-13, IL-18 IL-2 
IL-2 R alpha IL-4 IL-6, 
IL-8 Lipocalin-2 MCP-1 
MCP-2 MIF, MIP-1 
alpha MIP-1 beta 
Osteopontin PAI-1 
Platelet Factor 4, 
Procalcitonin RAGE 
Resistin 
Thrombomodulin TNF 
alpha, TREM-1 Troponin 
I uPAR VCAM-1 VEGF-
A, Antibody Isotype, 
Immune phenotyping, 
Proliferation Assay, In-
vitor cytokine secretion, 
Cytokine assay (to be 
collected in 20 mL of 
blood—4 lavender 
tubes) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total CK 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
CK-MB 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Uric Acid 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
HS-CRP 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Adverse Events 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
‡ A coronary angiogram performed prior to LVAD implantation may be used to determine eligibility. 
*Zio patch recording or ICD device check must be completed prior to IV infusion.  
**Vital signs and LVAD parameters taken every 2 hours after infusion and pulse oximetry taken continuously for 2 hours after IV infusion. Vital 
signs include temperature, blood pressure, heart rate respiratory rate and weight, LVAD parameters include pump speed, power, flow and 
pulsatilityNeed continuous ECG monitoring during infusion 
 

 
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APPENDIX B: QUESTIONNAIRES 
 
THE KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE (KCCQ) 
 
The following questions refer to your heart failure and how it may affect your life. Please read and complete 
the following questions. There are no right or wrong answers. Please mark the answer that best applies to 
you. 
1. Heart Failure affects different people in different ways.  Some feel shortness of breath while others feel 
fatigue. Please indicate how much you are limited by heart failure (shortness of breath or fatigue) in 
your ability to do the following activities over the past 2 weeks. 
 
Place an X in one box on each line 
 
Activity 
Extremely  Quite a bit 
Moderately 
Slightly 
Not at all 
Limited 
for other reasons 
limited 
limited 
limited 
limited 
limited 
or did 
not do the activity 
Dressing yourself 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
Showering/Bathing 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
Walking 1 block on 
level ground 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
Doing yardwork, 
housework or 
carrying groceries 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
Climbing a flight of 
stairs without 
stopping 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
Hurrying or jogging 
(as if to catch a bus) 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
 
2. Compared with 2 weeks ago, have your symptoms of heart failure (shortness of breath, fatigue or ankle 
swelling) 
changed? My symptoms of heart failure have become… 
 
Much worse 
Slightly worse Not changed   Slightly better  Much better 
I’ve had no symptoms 
over the last 2 weeks 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
 
3. Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs when you woke 
up in 
in the morning? 
 
Every 
3 or more times 
1-2 times a 
Less than once 
Never over the 
morning 
a week, but not 
week 
a week 
past 2 weeks 
every day 
 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
4. Over the past 2 weeks, how much has swelling in your feet, ankles or legs bothered you? 
In has been… 
 

 
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Extremely  Quite a bit Moderately Slightly Not at all 
I’ve had no swelling 
bothersome 
bothersome 
bothersome 
bothersome 
bothersome 
Protocol: 
 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
5. Over the past 2 weeks, on average, how many times has fatigue limited your ability to do what you want? 
 
All of the time 
Several times 
At least once a 
3 or more times 
1-2 times per  Less than 
once a Never over 
 
the past 2 
weeks 
per day 
day 
per week but not 
week 
week 
 
every day 
6. Over the past 2 weeks, how much has your fatigue bothered you? 
It has been… 
 
Extremely Quite a bit 
Moderately 
Slightly 
Not at all 
I’ve had no fatigue 
bothersome bothersome 
⁯ 
⁯ 
bothersome 
⁯ 
bothersome 
⁯ 
bothersome 
⁯ 
⁯ 
 
7. Over the past 2 weeks, on average, how many times has shortness of breath limited your ability to do what 
you wanted? 
 
All of the time 
Several times 
At least once a 
3 or more times 
1-2 times per  Less than 
once a Never over 
the past 2 
weeks 
per day 
day 
per week but not 
week 
week 
 
every day 

 
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⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
 
8. Over the past 2 weeks, how much has your shortness of breath bothered you? 
 
Extremely  Quite a bit 
Moderately 
Slightly 
Not at all 
I’ve had no shortness 
bothersome 
bothersome 
bothersome 
bothersome 
bothersome 
of breath 
 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
 
9. Over the past 2 weeks, on average, how many times have you been forced to sleep sitting up in a chair 
or with at least 3 
pillows to prop you up because of shortness of breath? 
 
Every night 3 or more times 
1-2 times a 
Less than once 
Never over the 
a week, but not 
week 
a week 
past 2 weeks 
every day 
⁯ 
⁯ 
⁯ 
 
10. Heart Failure symptoms can worsen for a number of reasons. How sure are you that you know what 
to do, or whom to 
call, if your heart failure gets worse? 
 
Not at all  Not very sure Somewhat sure 
Mostly sure 
Completely 
sure sure 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
 
 
11. How well do you understand what things you are able to do to keep your heart failure symptoms 
from getting worse? (for  example, weighing yourself, eating a low salt diet, etc.) 
 
Do not       Do not            Somewhat         Mostly             Completely understand          
understand           understand          understand     understand at all                      very 
well 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
 
12. Over the past 2 weeks, how much has your heart failure limited your enjoyment of life? 
 
It has extremely 
It has limited 
It has  
It has slightly It has not limited 
my limited my 
my enjoyment moderately 
limited my 
enjoyment of life 
enjoyment of   of life quite 
limited my 
enjoyment of 
at 
all life 
a bit 
 
enjoyment of life
 
life 
 
 
 
13. If you had to spend the rest of your life with your heart failure the way it is right now, how would you 
feel about this? 
 
Not at all 
Mostly 
Somewhat 
Mostly satisfied 
Completely 
satisfied 
dissatisfied 
satisfied 
satisfied 
⁯ 
⁯ 
⁯ 
⁯ 
⁯
 
14. Over the past 2 weeks, how often have you felt discouraged or down in the dumps because of your 

 
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heart failure? 
 
I felt that way 
I felt that 
way 
I occasionally 
I rarely felt that 
I never felt that 
all of  the  most of the 
felt that way 
way 
way 
time 
time 
 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
 
15. How much does your heart failure affect your lifestyle?  Please indicate how your heart failure may 
have limited your 
participation in the following activities over the past 2 weeks? 
Please place an X in one box on each line 
 
Activity 
Severely 
Limited 
Moderately 
Slightly 
Did not
 
Does not apply or did 
limited 
quite a bit 
limited 
limited 
limit at all 
not do for 
 other reasons 
 
 
Hobbies, recreational 
activities 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
Working or doing 
household chores 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ Visiting 
family or friends 
out of your home 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
Intimate relationships 
with loved ones 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
⁯ 
 
Developed by John Spertus et al.,  Mid America Heart Institute, Saint Luke’s Hospital, Kansas City, MO. 
 
 
 
 

 
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NEW YORK HEART ASSOCIATION (NYHA) 
Protocol Number 
Site Number 
Subject 
Number 
Subject Initials 
Visit Date 
(dd-MMM-yyyy) 
_ _-_ _ _-_ _ _ _ 
 
Examination 
Not 
Done 
Result 
If abnormal findings, describe 
Yes 
No 
Class I: patients with no 
limitation of activities; 
they suffer no symptoms 
from ordinary activities 
Class II: patients with 
slight, mild limitation of 
activity; they are 
comfortable with rest or 
with mild exertion 
Class III: patients marked 
with limitation of activity; 
they are comfortable only 
at rest 
Class IV: patients who 
should be at complete 
rest, confined to bed or 
chair; any physical 
activity brings on 
discomfort and 
symptoms occur at rest