Double-blind, Randomized, Sham-procedure-controlled, Parallel-Group Efficacy and Safety Study of Allogeneic Mesenchymal Precursor Cells (Rexlemestrocel-L) in Chronic Heart Failure Due to LV Systolic Dysfunction (Ischemic or Nonischemic) Dream HF-1
Phase: PHASE3
Conditions: Chronic Heart Failure
Sponsor: Mesoblast, Inc.

 
Official Title: Double-blind, Randomized, Sham–procedure–controlled, Parallel-
group Efficacy and Safety Study of Allogeneic Mesenchymal 
Precursor Cells (rexlemestrocel-L) in Patients with Chronic Heart 
Failure Due to Left Ventricular Systolic Dysfunction of Either Ischemic 
or Nonischemic Etiology: DREAM HF-1 
NCT Number: NCT02032004   
Document Date: Protocol Version 7.0: 06-October-2017 
 
 
 

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INVESTIGATOR’S SIGNATURE (HEART FAILURE SPECIALIST) 
 
Study Title:  Double-blind, Randomized, Sham–procedure–controlled, Parallel-group 
Efficacy and Safety Study of Allogeneic Mesenchymal Precursor Cells (rexlemestrocel-L) 
in Patients with Chronic Heart Failure Due to Left Ventricular Systolic Dysfunction of 
Either Ischemic or Nonischemic Etiology: DREAM HF-1 
 
I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will 
only make changes in a protocol after notifying the Sponsor, except when necessary to protect 
the safety, rights, or welfare of subjects.  
 
I agree to personally conduct or supervise the described investigation(s).  
 
I agree to inform any patients, or any persons used as controls, that the drugs are being used for 
investigational purposes. 
 
I agree to report to the Sponsor adverse experiences that occur in the course of the 
investigation(s)  
 
I have read and understand the information in the investigator’s brochure, including the potential 
risks and side effects of the drug.  
 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
study(ies) are informed about their obligations in meeting the above commitments.  
 
I agree to maintain adequate and accurate records in accordance and to make those records 
available for inspection.  
 
I will ensure that an IRB/EC completed the initial and continuing review and approval of the 
clinical investigation. I also agree to promptly report to the IRB/EC all changes in the research 
activity and all unanticipated problems involving risks to human subjects or others. Additionally, 
I will not make any changes in the research without IRB/EC approval, except where necessary to 
eliminate apparent immediate hazards to human subjects.  
 
Agreement Signature: 
 
______________________ __________________________ 
_________________ 
Principal Investigator  
Principal Investigator  
 
Date 
(Please print)  
 
(Signature) 
 

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INTERVENTIONAL CARDIOLOGIST’S SIGNATURE 
 
Study Title:  Double-blind, Randomized, Sham–procedure–controlled, Parallel-group 
Efficacy and Safety Study of Allogeneic Mesenchymal Precursor Cells (rexlemestrocel-L) 
in Patients with Chronic Heart Failure Due to Left Ventricular Systolic Dysfunction of 
Either Ischemic or Nonischemic Etiology: DREAM HF-1 
 
I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will 
only make changes in a protocol after notifying the Sponsor, except when necessary to protect 
the safety, rights, or welfare of subjects.  
 
I agree to personally conduct or supervise the described investigation(s).  
 
I agree to inform any patients, or any persons used as controls, that the drugs are being used for 
investigational purposes. 
 
I agree to report to the Sponsor adverse experiences that occur in the course of the 
investigation(s)  
 
I have read and understand the information in the investigator’s brochure, including the potential 
risks and side effects of the drug.  
 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
study(ies) are informed about their obligations in meeting the above commitments.  
 
I agree to maintain adequate and accurate records in accordance and to make those records 
available for inspection.  
 
I will ensure that an IRB/EC completed the initial and continuing review and approval of the 
clinical investigation. I also agree to promptly report to the IRB/EC all changes in the research 
activity and all unanticipated problems involving risks to human subjects or others. Additionally, 
I will not make any changes in the research without IRB/EC approval, except where necessary to 
eliminate apparent immediate hazards to human subjects.  
 
Agreement Signature: 
 
______________________ __________________________ 
_________________ 
Interventional Cardiologist 
Interventional Cardiologist 
 
Date 
(Please print)  
 
(Signature) 
 
 

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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS 
 
Central Clinical Laboratory 
For United States and Canada: 
Pharmaceutical Product Development Inc. (PPD) Global Central Lab 
2 Tesseneer Road 
Highland Heights, Kentucky 41076 
USA 
 
For Europe: 
PPD Global Central Laboratory 
Cluster Park 
Kleine Kloosterstraat 19 
B-1932 Zaventem, Belgium 
 
Immunogenicity Testing Laboratory 
For panel-reactive antibody (PRA) and donor-specific antibody (DSA): 
Rabin Medical Center 
Petach Tikva, Israel 49100 
 
For anti-murine and anti-bovine antibody: 
Global Bioassays & Technology Israel 
Teva Pharmaceutical Industries, Ltd. 
12 Hatrufa Street 
PO Box 8077 
Sapir Industrial Zone 
Netanya, Israel 42504 
 
Electronic Data Capture 
INC Research/inVentiv Health  
504 Carnegie Center 
Princeton, New Jersey 08540 
USA 
 
 
 

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Central Institutional Review Board (IRB) 
Quorum IRB  
1601 Fifth Avenue, Suite 1000 
Seattle, Washington 98101 
USA 
 
Core Cardiac Imaging and Electrocardiography Laboratory 
BioTelemetry Research 
One Preserve Parkway, Suite 600 
Rockville, Maryland 20852 
USA 
 
Interactive Response Technology (IRT) 
Almac Clinical Technologies 
25 Fretz Road 
Souderton, Pennsylvania 18964 
USA 
 
Medical Device Manufacturer 
Biosense Webster, Inc. 
3333 Diamond Canyon Road 
Diamond Bar, California 91765 
USA 
 NOGA® XP Cardiac Navigation System and NovaStar® Catheter 
 CARTO® 3 Cardiac Navigation System  and NovaStar® Catheter 
 MyoStar™ Injection Catheter. 

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CLINICAL STUDY PERSONNEL CONTACT INFORMATION 
For medical issues, contact the medical monitors listed below: 
 
In the USA, Canada, and rest of the world outside of the European Union: 
Medical Monitor (Blinded) 
 MD 
 INC Research/inVentiv Health  
Tel: 
Fax: 
 
Medical Monitor (Unblinded) 
 MD 
, INC Research/inVentiv Health  
Tel: 
Fax: 
 
In the European Union: 
 MD 
Medical Monitor, INC Research/inVentiv Health  
Tel: 
 
Fax:
Cel:
 
For operational issues, contact the operational lead: 
 
INC Research/inVentiv Health  
Tel: 
Fax: 
Cell: 

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FOR SERIOUS ADVERSE EVENTS (SAES): 
 
Contact the Clinical Study Medical Monitor responsible for medical issues (see above) only if 
needed. 
 
For events which occur from Day 0 through hospital discharge for the index cardiac 
catheterization, contact the unblinded medical monitor. For events which occur after hospital 
discharge for the index cardiac catheterization, contact the blinded medical monitor. 
 
Any serious adverse event (SAE), whether deemed related or not to the investigational product, 
must be reported. To report the SAE, the investigator or designee will complete the SAE 
information electronically in the electronic case report form (eCRF). When it is completed, 
Mesoblast Safety personnel will be notified electronically. If the event meets serious criteria and 
it is not possible to access the eCRF, the investigator or designee should complete the backup 
paper SAE form and e-mail it at
to Mesoblast Safety with 24 hours of 
awareness. In case of difficulty transmitting the form, contact the Sponsor study personnel 
identified in the front matter of this protocol for further instruction. 

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CLINICAL STUDY PROTOCOL SYNOPSIS 
Sponsor: Mesoblast Inc., Inc. 
 
Title of Study: A Double-blind, Randomized, Sham–procedure–controlled, Parallel-group 
Efficacy and Safety Study of Allogeneic Mesenchymal Precursor Cells (rexlemestrocel-L) in 
Patients with Chronic Heart Failure Due to Left Ventricular Systolic Dysfunction of Either 
Ischemic or Nonischemic Etiology: DREAM HF-1 
 
Study Number: MSB-MPC-CHF001 
 
Name of Active Ingredient: Human bone marrow-derived allogeneic mesenchymal precursor 
cells (MPCs) 
 
Name of Investigational Product: Rexlemestrocel-L 
 
Phase of Clinical Development: 3 
 
Number of Investigational Centers Planned: Approximately 80-100 sites are planned. 
 
Countries Planned: United States, Canada, Europe, Australia, and Singapore 
 
Number of Patients Planned: Approximately 600 heart failure (HF) patients (approximately 
300 patients per treatment group).  However, since this is an events-driven study, the total 
number of patients may change.  It is anticipated that at least 531 recurrent (multiple events per 
patient) non-fatal heart failure–related major adverse cardiac events (HF-MACE) will be 
obtained and positively adjudicated by an independent Clinical Endpoints Adjudication 
Committee (CEC) to complete the study.  These non-fatal HF-MACE will include patients with 
recurrent non-fatal decompensated HF events and/or successfully resuscitated cardiac death 
(RCD) events. 
 
Study Population: Adult men and women with chronic HF due to left ventricular (LV) systolic 
dysfunction of either ischemic or nonischemic etiology who have received optimal medical and 
coronary revascularization therapy 
 
Estimated Planned Study Period: 2014 to 2020 
 

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Primary Objectives: The primary objectives of this study are to: 
1. Determine whether transendocardial delivery of 150 million (M) allogeneic human bone 
marrow-derived MPCs (rexlemestrocel-L) administered during a single index cardiac 
catheterization and intracardiac mapping procedure is more effective than a scripted sham 
cardiac mapping and cell delivery procedure in risk reduction for recurrent (multiple 
events per patient) non-fatal decompensated HF events and/or successfully RCD events, 
in the presence of TCEs in patients with chronic HF due to LV systolic dysfunction of 
either ischemic or non-ischemic etiology who have received optimal medical and 
coronary revascularization therapy.  
2. Evaluate the safety and tolerability of transendocardial delivery of rexlemestrocel-L in 
patients with chronic HF due to LV systolic dysfunction of either ischemic or non-
ischemic etiology who have received optimal medical and coronary revascularization 
therapy.  
 
Key Secondary Objective:  The key secondary objective of this study is the assessment of time 
from Day 0-to-first terminal cardiac event (TCE) (cardiac death, left ventricular assist device 
[LVAD] placement, heart transplant, or artificial heart implantation), whichever event occurred 
first, to assure that any improvement in recurrent non-fatal HF-MACE is not associated with the 
worsening in time-to-first TCE for the Cell Therapy vs. Control (Sham) group.  
 
Day 0 Definition: Day 0 for all time-to-event analyses is defined as follows: 
1. For patients who are randomized but DO NOT undergo the index cardiac catheterization 
as the date of the disqualifying event (i.e., violation of at least 1 inclusion/exclusion 
criterion);  
2. For patients who are randomized and DO undergo the index cardiac catheterization as the 
date of the index cardiac catheterization.  
 
Secondary Objectives: The secondary objectives of this study are the assessment of various 
aspects of recurrent non-fatal HF-MACE (i.e., decompensated HF events and/or successfully 
RCD events).  Other secondary objectives of the study relate to LV remodeling by 
echocardiography, functional exercise capacity using the 6-minute walk test, functional status 
assessed by New York Heart Association Classification, and quality of life [QoL].  
 

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coronary arteries, documented prior coronary revascularization, and/or documented 
prior MI.  
c. The patient is on stable, optimally tolerated dosages of HF therapies including 
beta-blockers (approved for country-specific usage), angiotensin-converting enzyme 
(ACE) inhibitors or angiotensin-receptor blockers (ARBs), and/or aldosterone 
antagonists and/or neprilysin inhibitor, without change in dose for at least 1 month 
before study intervention (i.e., hospitalization on Day 0 for index cardiac 
catheterization with or without intracardiac mapping and cell delivery). 
d. Inclusion criterion d was replaced by d1  
(d1) The patient is on a stable, outpatient, oral diuretic dosing regimen in which the 
patient remains clinically stable during screening. Flexible diuretic dosing that allows 
the patient to titrate the dose or add a dose of a second diuretic during screening is 
permitted provided that the dosing regimen is not further altered and the patient 
remains stable during this period or the patient is not on a regular dose of diuretics but 
takes diuretics as needed based on daily weight or the appearance of symptoms. 
e. The patient is not a candidate for either percutaneous coronary intervention (PCI) or 
coronary artery bypass graft (CABG) surgery as determined by the Principal 
Investigator (or designee) during screening. 
f. Inclusion criterion f was replaced by f1. 
(f1) The patient may be on the cardiac transplant list. However, the patient must have 
low priority status with low probability of having a transplant procedure performed 
over the next 12 months (i.e., cannot be United Network for Organ Sharing [UNOS] 
status 1A or 1B).  
g. The patient has a LVEF by the Core Cardiac Image Laboratory of 40% or less as 
measured by 2-D echocardiogram, or 35% or less as measured by radionuclide 
ventriculography (RVG) within 42 days prior to study intervention (i.e., 
hospitalization on Day 0 for index cardiac catheterization with or without intracardiac 
mapping and cell delivery). 

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h. Inclusion criterion h was replaced by h1 
(h1) The patient has 1 or more of the following: 
 at least 1 HF hospitalization more than 1 month, but 9 months or less before 
initiation of screening procedures 
 at least 1 outpatient visit requiring intravenous (IV) diuretic, vasodilator, and/or 
positive inotropic therapy more than 1 month, but 9 months or less before 
initiation of screening procedures 
 plasma levels of NT-proBNP as measured by the central laboratory of greater than 
1000 pg/mL (1000 ng/L SI units; 118 pmol/L) or 1200 pg/mL (1200 ng/L SI 
units; 141.6 pmol/L) for patients with atrial fibrillation. 
i. Inclusion criterion i was replaced by i1 
If the patient has an implantable cardioverter defibrillator (ICD) (or any implanted 
device capable of defibrillation) in place, the placement must have occurred at least 1 
month before initiation of screening procedures. 
j. If the patient has had cardiac resynchronization therapy (CRT), the procedure must 
have occurred at least 3 months before screening. 
k. The patient has an LV end-diastolic wall thickness of at least 8 mm at potential 
myocardial target sites for cell delivery. 
l. Women must be surgically sterile, 1 year post-menopausal, or must have a negative 
urine or serum pregnancy test at screening. 
m. Inclusion criterion m1 was replaced by m2 
(m2) Women must be surgically sterile, 1 year post-menopausal, or, if of childbearing 
potential, currently using a medically accepted method of contraception, and must 
agree to continue to use this method of contraception after initiation of screening 
procedures and for 6 months after study intervention (i.e., hospitalization on Day 0 
for index cardiac catheterization with or without intracardiac mapping and cell 
delivery). Acceptable methods of contraception include barrier method with 
spermicide, abstinence, intrauterine device (IUD) (known to have a failure rate of less 
than 1% per year), or steroidal contraceptive (oral, transdermal, implanted, or 
injected) in conjunction with a barrier method. Men must be surgically sterile, or, if 
capable of producing offspring, currently using an approved method of contraception 
and must agree to continue to use this method of contraception after initiation of 
screening procedures and for 16 weeks after study intervention. Acceptable methods 
of contraception include abstinence, female partner’s use of steroidal contraceptive 
(oral, implanted or injected) in conjunction with a barrier method, female partner’s 
use of an IUD (known to have a failure rate of less than 1% per year), or if female 

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partner is surgically sterile or 1 year post-menopausal. In addition, men may not 
donate sperm for16 weeks after study intervention. 
n. The patient must be willing to return for required follow-up visits. 
o. Written informed consent is obtained for the study before any study-specific 
procedures are performed. A separate written informed consent for an exploratory 
PGx substudy will be obtained before any PGx-specific procedures are performed. 
Participation in the PGx substudy is optional and consent may be collected at a later 
stage than screening (though preferred as early as possible). A patient will not be 
excluded from participation in the study if he/she chooses not to provide consent for 
the additional procedures that are required as part of the exploratory PGx substudy. 
p. Prior to the initiation of any procedures on Day 0, the cell injection center will ensure 
that an institution-specific informed consent document is obtained, if applicable. 
q. The patient must be able to receive systemic anticoagulant therapy. 
 
Criteria for Exclusion: Patients will be excluded from participating in this study if they meet 
any of the following criteria: 
a. The patient has NYHA Functional Class I or Functional Class IV symptoms. 
b. The patient has had an acute MI within 1 month before initiation of the screening 
procedures. 
c. The patient has unstable angina pectoris within 1 month before initiation of screening 
procedures; unstable angina is defined as the occurrence of chest pain more 
frequently than usual, pain at rest or upon minimal exertion, or protracted episodes of 
pain without any discernible trigger, and/or chest pain that persists despite use of 
vasodilatory therapy (e.g., nitroglycerin) and or aggravation of stable angina or new 
onset angina. 
d. The patient has peri- or postpartum cardiomyopathy (CM). 
e. The patient has ischemic or hemorrhagic stroke as diagnosed by computed 
tomography (CT) or magnetic resonance imaging (MRI) within 3 months prior to 
study enrollment. 
f. The patient has had a coronary arterial or peripheral arterial revascularization 
procedure within 2 months before initiation of screening procedures. 
g. The patient has had IV therapy with diuretic, vasodilator, and/or positive inotropes or 
aquapheresis within 1 month before initiation of screening procedures, and/or during 
the screening period.  
 

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h. Exclusion criterion h was replaced by h1 
(h1) The patient, who in the absence of an ICD (or any implanted device capable of 
defibrillation), has a history of malignant ventricular arrhythmia or sustained 
ventricular tachycardia (VT), with sustained VT demonstrated by QRS complexes 
wider than 120 milliseconds, lasting more than 30 seconds, and with a rate of more 
than 100 beats per minute on screening ECG or other data supporting this diagnosis. 
i. The patient has restrictive, obstructive, or infiltrative CM, pericardial constriction, 
amyloidosis, or uncorrected thyroid disease. 
j. The patient has moderate to severe aortic stenosis as determined by the Core Cardiac 
Imaging Laboratory echocardiography-Doppler assessment with a valve area less 
than 1.0 cm2. 
k. The patient requires valve or other cardiac (e.g., pericardectomy) surgery. 
l. The patient has had LV reduction surgery, implanted LVAD, cardiac transplantation 
or artificial heart placement. The patient may be on the cardiac transplant list, but 
must have low probability of having a transplant procedure over the next 12 months. 
m. The patient has an LV thrombus diagnosed by echocardiography, left ventriculogram, 
or other cardiac imaging. 
n. The patient has cardiogenic shock that is dependent upon mechanical or inotropic 
support at the time of study intervention (i.e., hospitalization on Day 0 for index 
cardiac catheterization with or without intracardiac mapping and cell delivery), as 
defined by Killip Class IV physiology indicative of cardiogenic shock and/or 
requirement of intra-aortic balloon pump or IV inotropic support for the maintenance 
of mean arterial blood pressure at least 60 millimeters of mercury (mmHg). 
o. The patient is known to have unprotected left main CAD greater than 50%. 
p. Exclusion criterion p1 was replaced by p2. 
(p2) The patient has known hypersensitivity to radiocontrast media or dimethyl 
sulfoxide (DMSO), murine, and/or bovine products with the exception of patients 
with mild hypersensitivity to radiocontrast media, who may be pretreated with 
corticosteroids and/or antihistamines. 
q. The patient has a known active malignancy within the past 3 years except for 
localized prostate cancer, cervical carcinoma in situ, breast cancer in situ, or non-
melanoma skin cancer that has been definitively treated. 
r. Exclusion criterion r was replaced by r1 
(r1) The patient has acute bacterial or viral infectious disease, or acute exacerbation 
of a chronic infectious disease at the time that Day 0 intervention is planned. 
However, patients with an upper respiratory infection diagnosed at screening that is 

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cleared by Day 0 (maximum of 42 days from signing of informed consent form) may 
undergo the procedure. 
s. Exclusion criterion s was replaced by s1 
(s1) Patients with severe chronic obstructive pulmonary disease (COPD) or who 
require home oxygen for any kind of pulmonary disease; home oxygen use as part of 
CPAP (continuous positive airway pressure) for the indication of sleep apnea in 
patients living at high altitude is permitted, and as-needed home oxygen use solely as 
therapy for HF is permitted. A patient with moderate COPD without severe right 
ventricular dilatation and dysfunction on echocardiogram may be included in the 
study if the patient has a documented HF history that meets qualifying HF criteria. A 
patient who has a forced expiratory volume in one second (FEV1) of less than 1.0 L 
will be excluded. A given patient will be excluded from serial echocardiographic 
imaging assessments if his/her heart is difficult to image adequately using standard 
precordial echocardiographic techniques. In that case, RVG estimations of LVEF will 
be used for screening inclusion criteria as well as for serial changes in overall cardiac 
performance after study intervention (i.e., hospitalization on Day 0 for index cardiac 
catheterization with or without intracardiac mapping and cell delivery). A patient with 
clinically meaningful COPD will be excluded from serial 6MWT evaluations if the 
patient’s exercise limitation is thought to be due predominantly to the patient’s 
intrinsic pulmonary disease rather than from the patient’s HF state. 
t. The patient has a bleeding diathesis disorder such as abnormal coagulation profile, 
precluding study intervention (i.e., hospitalization on Day 0 for index cardiac 
catheterization with or without intracardiac mapping and cell delivery). 
u. Exclusion criterion u was replaced by u1 
(u1) The patient has 1 or more clinical laboratory test value(s) performed by the 
Central Clinical Laboratory that are outside the range for 1 or more of the tests 
specified below, or any other clinically significant abnormality as determined by the 
investigator or medical monitor as follows (note: repeat of suspected spurious 
laboratory abnormalities may be permitted after consultation with the medical 
monitor): 
 aspartate aminotransferase (AST/SGOT)/alanine aminotransferase (ALT/SGPT) 
greater than 3 times upper limit of normal (ULN) range 
 estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2 
(calculated by the central clinical laboratory using the Modification of Diet in 
Renal Disease (MDRD) formula); measures to minimize the risk of contrast-
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 hemoglobin less than 9 g/dL 
 platelets less than 100 × 103/mm3 
 hemoglobin A1c (HBA1c) of 10% or greater 
v. The patient has any concurrent disease or condition that in the opinion of the 
investigator would make the patient unsuitable for participation in the study. 
w. The patient has previously participated in any stem cell or regenerative medicine 
study, in which he/she received active agent. 
x. The patient has received hematopoietic growth factors within 12 months preceding 
study intervention (i.e., hospitalization on Day 0 for index cardiac catheterization 
with or without intracardiac mapping and cell delivery). 
y. Exclusion criterion y was replaced by y1 
(y1) The patient has had treatment and/or an uncompleted follow-up treatment of any 
investigational therapy within 6 months before study intervention and/or intends to 
participate in any other investigational drug or cell therapy study in the 3 years after 
study intervention (i.e., hospitalization on Day 0 for index cardiac catheterization 
with or without intracardiac mapping and cell delivery). 
z. The patient has hemodynamically compromised, complex congenital heart disease. 
aa. Exclusion criterion aa1 was replaced by aa2.  
(aa2) A patient with an ICD (or any implanted device capable of defibrillation) in 
place who has had a device firing within 1 month of Day 0. 
bb. A patient has had angina on the average of more than 3 times per week. 
cc. New exclusion criterion  
The patient completes two 6MWTs with either test being a distance >450 meters 
during screening 
dd. New exclusion criterion 
The patient is unable to perform the 6MWT due to concurrent medical conditions; the 
exception is those patients with NT-proBNP >2000 pg/mL (2000 ng/L SI units; 
236 pmol/L). 
ee. New exclusion criterion  
The patient has an aortic valve prosthesis. 
 
Study Drug Dose, Mode of Administration, and Administration Rate 
 
Investigational Product: Rexlemestrocel-L consists of human bone marrow-derived allogeneic 
MPCs that have been isolated from bone mononuclear cells with anti-STRO 3 antibodies, 
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Definition of Treatment:  Treatment is defined as all patients who underwent Day 0 index 
cardiac catheterization (with or without intracardiac mapping and cell delivery) and in whom the 
interventional cardiologist was able to advance the pigtail catheter across the aortic valve and 
into the LV chamber. 
 
Duration of Follow-up:  Duration of treatment for an individual patient will be determined from 
Day 0 to either death or the end of the study for that patient. 
 
Method of Blinding and Randomization:  This is a double-blind study. Patients enrolled in the 
study will be randomly assigned in a 1:1 ratio to receive active treatment (i.e., intracardiac 
mapping and transendocardial delivery of rexlemestrocel-L) or control treatment (i.e., a scripted 
sham intracardiac mapping and cell delivery procedure without rexlemestrocel-L).  
 
After confirmation of all eligibility criteria, patients will be randomly assigned to the active or 
control treatment group (approximately 300 patients per group) by means of a computer-
generated randomization list, and stratified by the following:  
 baseline NYHA Class (Functional Class II versus Functional Class III)  
 geographic region (US versus ex US), and  
 presence of epicardial coronary artery disease (CAD) (ischemic versus nonischemic).  
 
Epicardial CAD is defined as documented stenosis of at least 50% in one or more major 
epicardial coronary arteries, documented prior coronary revascularization, and/or documented 
prior MI. The randomization list and treatment group will be assigned via interactive response 
technology (IRT). The IRT will be used to track and monitor enrollment of female patients as 
well as patients with baseline NYHA Class III versus Class II functional status in the study. To 
ensure that approximately 20% of the patient population in the study will be women, frequent 
discussions with the site staff will take place during the recruitment phase and will include 
discussion of the current rate of recruitment of women to the study. If there is a large disparity 
between the number of men and the number of women randomized to the study, the 
randomization may be limited to women until women represent approximately 20% of the study 
population.  
 
Patient enrichment and replenishment will be performed such that by the end of the trial, the 
ratio of enrolled patients with baseline NYHA Class III to baseline NYHA Class II will be 
approximately 2:1.  With this ratio, it is estimated that approximately 600 randomized patients 
will be needed to achieve a minimum of 531 recurrent non-fatal HF-MACE at the end of the 

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trial.  Based on current enrollment projections, at the end of the trial it is estimated that there will 
be ~200 baseline NYHA Class II patients and ~400 baseline NYHA Class III patients who have 
undergone the Day 0 index cardiac catheterization resulting in a baseline Class III/Class II ratio 
of 2:1.  In order to achieve this target, an enrollment cap of ~200 baseline NYHA Class II 
patients will be instituted.  It is anticipated that any baseline NYHA Class II patients who are 
inadvertently screened but not randomized during the suspension of NYHA Class II enrollment 
will be considered screen failures. The enrollment process will be overseen by the trial’s 
treatment blinded Medical Monitor in conjunction with current computer-generated 
randomization and interactive response technology (IRT) enrollment methodologies. 
 
The success of this study depends on several factors including: a) the safety of patients enrolled 
and randomly assigned to treatment; b) demonstration of the potential clinical benefit from 
transendocardial delivery of rexlemestrocel-L; c) maintenance of the treatment blind as it relates 
to clinical follow up and decision making.  
 
Patients will be screened at recruiting HF study centers. The timing of randomization relative to 
Day 0 will vary based on study drug availability and Biologics Delivery System [BDS] 
availability.  Guidelines tailored to each site will be provided in order to minimize the time 
between randomization and Day 0 while allowing sufficient time for operational logistics.  Every 
attempt should be made to minimize the time between randomization and Day 0.   
 
Hospitalization for index cardiac catheterization (with or without intracardiac mapping and cell 
delivery) will occur at a cell injection center; the interventional cardiologist who will perform the 
catheterization procedure will be unblinded to treatment assignment. Not all HF study sites will 
be cell injection centers and not all cell injection centers will be HF study centers. However, it is 
anticipated that the majority of cell injection centers will also be HF study centers. Screening and 
follow-up evaluations will be performed at HF study sites by study personnel who will be 
blinded to study treatment for the duration of the study. The interventional cardiology site staff, 
who are unblinded to study treatment, may participate in screening procedures but will not be 
involved in follow-up evaluations. 
 
Study intervention (i.e., hospitalization on Day 0 for index cardiac catheterization with or 
without intracardiac mapping and cell delivery) for all randomized patients who DO NOT 
experience an inclusion/exclusion criterion violation after randomization but before the 
scheduled index cardiac catheterization  will be performed at a cell injection center by an 
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efficacy evaluations during the follow-up period. Patients, as well as noninterventional 
investigators and HF study center personnel responsible for efficacy and safety evaluations of 
patients after hospital discharge, will remain blinded to the study treatment provided to the 
patients at the cell injection center. Once a physician has been designated as either the blinded or 
unblinded cardiologist, he/she may not change his/her blinded vs. unblinded role within the trial.  
 
Maintaining the blind of study participants and study site personnel during the follow-up period 
will help to protect the integrity of study data and may reduce the risk of introducing physician 
bias into the clinical decision-making process. Knowledge of which treatment was received by a 
patient could influence a treating physician’s decision to hospitalize a patient for HF. For 
example, knowledge that a given patient did not receive rexlemestrocel-L could result in a lower 
threshold for hospitalization because the physician would not expect the sham intracardiac 
mapping and cell delivery procedure to have a beneficial effect on the patient’s long-term 
clinical state. Maintenance of the blind is particularly important in this study because a biased 
decision relating to HF hospitalization would directly impact the study’s primary efficacy 
endpoint.  
 
During the course of the study, the Sponsor Pharmacovigilance team will be responsible for 
oversight of all safety data and for determining the expectedness of all SAEs, expedited reporting 
of individual cases, and safety updates to regulatory authorities.  
 
There will be three oversight committees: an independent Data Monitoring Committee (DMC), 
an Executive Steering Committee (ESC), and an independent CEC. Both the ESC and the CEC 
will be blinded to study treatment; the DMC will be unblinded. 
 
The Data Monitoring Committee (DMC), which will be unblinded to study treatment, will 
oversee the study with primary responsibility for ensuring patient safety. Specific goals and 
responsibilities of the DMC are outlined in the Data Monitoring Committee Manual of 
Operations. These responsibilities include the following: 
 Oversight of the study with primary responsibility for insuring patient safety 
 Review on a regular predefined basis the occurrence of adverse events including TCEs 
(cardiac death, LVAD placement, heart transplant, or artificial heart implantation), non-
fatal HF-MACE (including recurrent non-fatal decompensated HF events and/or 
successfully RCD events), overall survival, non-fatal CVA, non-fatal MI, and other 
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 Perform pre-specified serial assessments of patient safety and monitor treatment effects 
to assess whether the objectives of the ongoing trial can be met. Periodically, the DMC 
will conduct unblinded analyses of clinical events that have been adjudicated by the 
independent CEC. Additionally, the DMC may formulate recommendations to the 
unblinded sponsor study team regarding the conduct and execution of the protocol as 
issues arise (see Blinding Plan for more information). 
 Review of planned interim analyses. 
 
The Executive Steering Committee (ESC) will perform the following: 
 Oversight for the operation of the study, including working with national leaders and 
local HF study site investigators to achieve goals for enrollment of patients into the study 
 Reviewing recommendations from the project team for study conduct 
 Reviewing recommendations from the DMC for patient safety 
 Reviewing recommendations from the DMC for Interim Analysis #2. 
 
The independent Clinical Endpoints Adjudication Committee (CEC), which will be blinded to 
study treatment, will adjudicate all potential efficacy endpoint events and cardiac events of 
special interest in accordance with pre-specified criteria. The events include all-cause death (i.e., 
including non-cardiac and cardiac death), LVAD placement, heart transplant, artificial heart 
implantation, hospitalization for non-fatal decompensated HF, urgent care outpatient HF visit, 
successfully RCD, non-fatal MI, hospitalization for unstable angina, non-fatal CVA, coronary 
artery revascularization, and 
 (refer to the CEC charter). 
 
Duration of Study/Patient Participation: This is an events-driven study and the study duration 
will be determined by a minimum length of time and cumulative total number of recurrent non-
fatal HF-MACE (i.e., recurrent non-fatal decompensated HF events and/or successfully RCD 
events). Patients are expected to participate in this study until the required minimum number of 
recurrent non-fatal HF-MACE occur. The End-of-Study will occur when the two following 
conditions have been met: 1) at least 531 recurrent non-fatal HF-MACE have occurred and 2) all 
surviving patients without a TCE and without study discontinuation prior to the Month 6 visit 
have completed a minimum of 6 months of follow-up.  
 
General Design and Methodology: This is a multinational, multicenter, double-blind, 
randomized, scripted sham procedure-controlled, parallel-group study to evaluate the efficacy 
and safety of rexlemestrocel-L (human bone marrow-derived adult allogeneic MPCs) during a 
single treatment index cardiac catheterization involving intracardiac mapping in patients with 

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chronic HF due to LV systolic dysfunction of either ischemic or nonischemic etiology who have 
received optimal medical and coronary revascularization therapy. Overall, it is anticipated that 
known epicardial CAD (documented stenosis of at least 50% in one or more major epicardial 
coronary arteries, documented prior MI, and/or documented coronary artery revascularization) 
will be present in approximately 60% of patients who are randomly assigned to treatment. The 
randomization code for the study will be maintained by a Mesoblast-independent third party 
provider. 
 
The study comprises 3 main time periods:  
 Screening and randomization designation period: A patient’s eligibility to participate in 
the study will be determined during this period and will be based on the study’s inclusion 
and exclusion criteria for screening. If the patient is deemed eligible to participate in the 
study, randomization will occur. 
 Study intervention: Study intervention will involve hospitalization on Day 0 for a single 
index cardiac catheterization (with or without intracardiac mapping and cell delivery). 
For all patients who are randomized and DO NOT experience an inclusion/exclusion 
criterion violation after randomization but before the scheduled index cardiac 
catheterization, study intervention will be performed at a cell injection center by an 
interventional cardiology team not involved with long-term follow-up of patients’ safety 
and efficacy evaluations. Interventional cardiologists and the unblinded team performing 
the study intervention may participate in screening evaluations (follow-up evaluations 
will be performed by blinded team members only). 
 Follow-up period: For patients who are randomized and DO undergo the index cardiac 
catheterization, the follow-up period begins after hospital discharge from the cell 
injection center and includes safety and efficacy evaluations for a minimum of 6 months 
for all surviving patients without a TCE and without study discontinuation prior to the 
Month 6 visit; and until the minimum of 531 required recurrent non-fatal HF-MACE is 
obtained. Patients, as well as non-interventional investigators and study site personnel at 
the HF study sites who conduct screening and follow-up (including long-term follow-up) 
evaluations after hospital discharge of patients from the cell injection center, will remain 
blinded to the study treatment provided at the cell injection center. In general, mid-term 
safety and efficacy evaluations for patients who are randomized and DO undergo the 
index cardiac catheterization will be conducted through 12 months follow-up while long-
term follow-up after Month 12 will continue every 6 months until study conclusion. Also, 
any patients who are randomized but DO NOT undergo the index cardiac catheterization 
must be followed for determination of vital status (alive or dead), AEs, potential primary 

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and key secondary efficacy endpoint events, and ICD interrogation via telephone contact 
at all regularly scheduled study visit times, including clinic visit times, for the duration of 
the study; additional assessments other than vital status and AE and endpoint collection 
will NOT be performed. Similarly, any patients who are randomized, DO undergo index 
cardiac catheterization procedure but discontinue the study after Day 0 will be followed 
for determination of vital status (alive or dead), AEs, potential primary and key 
secondary efficacy endpoint events, and ICD interrogation via telephone contact at the 
regularly scheduled time points for the duration of the study. Every attempt should also 
be made to obtain vital status, at a minimum, from patients who withdraw consent to 
participate in the study after randomization. 
 
Written informed consent will be obtained for the study before any study-specific procedures are 
performed. A separate written informed consent for an exploratory pharmacogenomics (PGx) 
substudy will be obtained before any PGx-specific procedures are performed. Participation in the 
PGx substudy is optional and consent may be collected at a later stage than screening (though 
preferred as early as possible). A patient will not be excluded from participation in the study if 
he/she chooses not to provide consent for the additional procedures that are required as part of 
the exploratory PGx substudy. 
 
After informed consent is obtained, the patients will be screened for eligibility to participate in 
the study. This will be based during the screening period on the study’s pre-specified inclusion 
and exclusion criteria. During the screening period, patients will undergo cardiac imaging, which 
will consist, at a minimum, of 2-D echocardiogram (with or without contrast). Contrast imaging 
will be performed for enhanced LV chamber imaging as determined by the investigator or 
designee. If echocardiographic imaging is of insufficient technical quality for LV volume and 
LV ejection fraction estimation, then a radionuclide ventriculogram (RVG) will be performed to 
assess LV ejection fraction as part of the patient’s screening procedures for inclusion in the trial. 
The Principal Investigator (or designee) will assess the need for coronary revascularization 
before the patient is randomly assigned to receive active or control treatment. If it is determined 
that a patient requires coronary revascularization, it should be performed at least 2 months before 
reinitiating any study screening procedures. Patients who are screen failures may be re-screened 
with approval from the medical monitor. Randomization should occur as close as possible to the 
scheduled index cardiac catheterization date for potential delivery of study product. The pre-
randomization criteria, such as echocardiographic criteria (restrictive, constructive or obstructive 
physiology, LV wall thickness, mural or arterial thrombus and prosthetic valve) are to be met by 
all patients and confirmed by both HF referral physician and the interventional cardiologist. 

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Echocardiographic criteria must be confirmed and signed off by interventional cardiologist prior 
to randomization. 
 
Patients who are randomized and experience an inclusion/exclusion criterion violation after 
randomization but before the scheduled index cardiac catheterization procedure will be included 
as part of the ITT analysis and cannot be re-screened. Also, any patients who are randomized but 
DO NOT undergo the index cardiac catheterization must be followed for determination of vital 
status (alive or dead), AEs, potential primary and key secondary efficacy endpoint events, and 
ICD interrogation via telephone contact at all regularly scheduled study visit times, including 
clinic visit times, for the duration of the study; additional assessments other than vital status and 
AE and endpoint collection will NOT be performed. Similarly, any patients who are randomized, 
DO undergo index cardiac catheterization procedure but discontinue the study after Day 0 will 
be followed for determination of vital status (alive or dead), AEs, potential primary and key 
secondary efficacy endpoint events, and ICD interrogation via telephone contact at the regularly 
scheduled time points for the duration of the study.  Every attempt should also be made to obtain 
vital status, at a minimum, from patients who withdraw consent to participate in the study after 
randomization. 
 
Patients who meet all inclusion criteria and none of the exclusion criteria will be enrolled in the 
study and randomly assigned in a 1:1 ratio to receive either active treatment (i.e., intracardiac 
mapping and transendocardial delivery of rexlemestrocel-L) or control treatment (i.e., a scripted 
sham intracardiac mapping and cell delivery procedure without rexlemestrocel-L). After 
randomization, all patients who DO NOT experience an inclusion/exclusion criterion violation 
before the scheduled index cardiac catheterization procedure  will be hospitalized at a cell 
injection center for index cardiac catheterization (with or without intracardiac mapping and cell 
delivery) and will remain hospitalized on telemetry for a minimum of 1 night. Prior to the 
initiation of any procedures, the study personnel at the cell injection center will ensure that an 
institution-specific informed consent document is obtained, if applicable. 
 
All patients randomly assigned to the active treatment group who DO NOT experience an 
inclusion/exclusion criterion violation after randomization but before the scheduled index cardiac 
catheterization will undergo an index cardiac catheterization with left ventriculography followed 
by cardiac mapping and transendocardial delivery of rexlemestrocel-L. Myocardial locations for 
transendocardial delivery of rexlemestrocel-L will be defined by means of imaging and left 
ventricular electrical mapping of the myocardium using the NOGA® or CARTO® Cardiac 
Navigational System in combination with the NogaStar® Mapping Catheter. Fifteen to 

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20 appropriate myocardial sites will be identified (20 sites is ideal) by imaging and electrical 
mapping as viable for cell delivery. The injection sites will be captured by NOGA® or CARTO® 
and transcribed into EDC. Independent of whether the NOGA® or CARTO® imaging system was 
employed to identify viable myocardium, the MyoStar™ Injection Catheter will be used for 
transendocardial delivery of rexlemestrocel-L. A 0.2 mL suspension of cells will be injected with 
each injection to the imaging identified myocardial locations; the total volume of study product 
administered must not exceed 4.0 mL. The total duration of the transendocardial delivery 
procedure must not exceed 90 minutes from the time of completion of thaw of rexlemestrocel-L. 
 
All patients randomly assigned to the control group who DO NOT experience an 
inclusion/exclusion criterion) violation after randomization but before the scheduled index 
cardiac catheterization will undergo a scripted sham cardiac mapping and cell delivery procedure 
that will include index cardiac catheterization with left ventriculography and a simulation of 
cardiac mapping and cell delivery. The scripted sham cardiac mapping and cell delivery 
procedure will be staged to script and will not include actual cardiac mapping or transendocardial 
delivery of rexlemestrocel-L but is designed to correspond to the operational steps that are used 
for intracardiac transendocardial delivery. These patients will not undergo placement of the 
NogaStar® navigation catheter and the MyoStar™ catheters. The scripted sham cardiac mapping 
and cell delivery procedure will be led by the interventional cardiologist and will be 
approximately 60 to 90 minutes in duration. As with the active treatment group, after the 
completion of the mapping procedure, 15 to 20 appropriate myocardial sites will be identified, 
but by means of a scripted sham cardiac mapping procedure followed by a scripted sham cell 
delivery procedure, and will simulate the exact full procedural requirements used for the actual 
treatment cohort. Thus, the patients will be blinded to study treatment. The total duration of the 
scripted sham cell delivery procedure will not exceed 90 minutes. 
 
Index cardiac catheterization (with or without intracardiac mapping and cell delivery) will be 
performed only by interventional cardiologists who have successfully completed the NOGA® 
System/MyoStar™ Catheter or CARTO® System/MyoStar™ Catheter training program required 
by BDS.  In addition, these individuals must be confirmed as having an active status in the BDS 
database and are experienced in performing cardiac interventional procedures. Retraining in the 
use of Global NOGA® System/MyoStar™ Catheter or CARTO® /MyoStar™ Catheter must take 
place for interventionalists who have not performed the NOGA® or CARTO® system procedure 
in over 1 year. Current American College of Cardiology/American Heart Association/European 
Society of Cardiology (ACC/AHA/ESC) Practice Guidelines will be followed in managing any 
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Cardiac events that occur on Day 0 will be included in the primary endpoint if they meet the 
definition of a recurrent non-fatal HF-MACE and are positively adjudicated as per the Cardiac 
Adjudication Manual. Cardiac deaths that occur on Day 0 will be considered as a TCE. All 
cardiac events after time of randomization that are deemed potential endpoints by the 
investigator will be reported by the investigator in the RAVE system. All cardiac deaths post 
randomization are considered a TCE. The first TCE (cardiac death, LVAD implantation, heart 
transplant, artificial heart placement) for a patient that occurs after randomization will be 
adjusted for in the primary analysis and included in the key secondary analysis.  
 
For randomized patients who DO undergo study treatment in the cardiac catheterization 
laboratory, the following assessments will be performed at follow-up: evaluations of LVEF, 
exercise capacity as determined by the 6MWT, biomarkers (NT-proBNP and hsCRP), functional 
status by the NYHA functional class assessment, QoL as measured by the MLHF and EQ-5D 
questionnaires, immunogenicity testing, and safety evaluations of adverse events, CVA, and MI, 
clinical laboratory tests, urinalysis, vital signs measurements, physical examinations, ECG 
recordings, 24-hour Holter monitor recordings (randomized patients across the US and EU), and 
use of concomitant medication and therapy. In addition, for echo-qualifying patients only, serial 
assessment of cardiac remodeling will be performed based on 2-D echocardiographic estimations 
(without or with contrast) of left ventricular end systolic volume (LVESV) and left ventricular 
end diastolic volume (LVEDV) and reviewed by the core imaging laboratory. Serial assessment 
of LVEF will be performed in selected patients using either echocardiographic imaging or RVG, 
depending upon which technique was used to qualify the patient during screening. Separate serial 
assessments will be performed for RVGs and echocardiograms, as applicable. For patients with 
an ICD (or any implanted device capable of defibrillation), rhythm analysis by device 
interrogation (performed at regularly scheduled intervals by appropriate site personnel) will be 
conducted. These episodes will be assessed at each site and captured as adverse events or non-
fatal HF-MACE, as appropriate.  When a non-fatal HF-MACE or a TCE is suspected, the rhythm 
strips obtained by device interrogation and relevant clinical context will be provided to the CEC 
for their review and adjudication. 
 
The immunogenic potential of rexlemestrocel-L will be evaluated by testing for the development 
of anti-human leukocyte antigen (HLA) DSA formation. Blood serum samples for 
immunogenicity analyses will be collected during the screening period, and on Day 10, at 
Months 1, 3, 6, and 12 from randomized patients who do not experience a disqualifying event 
after randomization but before the scheduled index cardiac catheterization; immunogenicity 
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primary and key secondary efficacy endpoint events, and ICD interrogation via telephone contact 
at the regularly scheduled time points for the duration of the study. Every attempt should also be 
made to obtain vital status, at a minimum, from patients who withdraw consent to participate in 
the study after randomization. 
 
Enrollment in this study will end at or before the time that a minimum number of pre-specified 
recurrent non-fatal HF-MACE (i.e., decompensated HF events and/or successfully RCD events) 
have been positively adjudicated and all surviving patients without a TCE and without study 
discontinuation prior to the Month 6 visit have completed a minimum of 6 months of follow-up. 
Patients are expected to participate in this study until the required minimum number of recurrent 
non-fatal HF-MACE occur; they will remain in the study until the Sponsor declares the study has 
reached completion. Patients who complete or withdraw from the study before or after the 
Month 12 follow-up visit will be evaluated at the time of study completion/withdrawal, using the 
same assessments that are specified for the Month-12 visit. Any surviving patient with a prior 
history of TCE may have their EOS visit conducted by phone. When a minimum of 95% of the 
positively adjudicated non-fatal HF-MACE has occurred, patients may have EOS assessments 
performed at their next scheduled visit if they already have a minimum of 18 months of follow-
up. An echocardiogram or RVG will also be performed if more than 6 months have passed since 
the patient’s last echocardiogram or RVG.  
 
During the course of the study, the occurrence of AEs, SAEs, TCEs, non-fatal HF-MACE (i.e., 
decompensated HF events and/or successfully RCD events), overall survival, coronary artery 
revascularization procedure,
), non-fatal CVA, and non-fatal MI will be reviewed, evaluated, processed, and/or reported 
in accordance with the protocol. 
 
Additionally, the occurrence of all AEs/SAEs on Day 0 through hospital discharge following 
index cardiac catheterization (with or without intracardiac mapping and cell delivery) will be 
reported to the the unblinded medical monitor. In addition, Mesoblast Safety will report any 
AEs/SAEs that have been assessed to be related to either mapping or injection catheters to the 
medical device manufacturer of the cardiac navigation system and associated catheters 
(Bioscience Webster, Inc.) within 30 calendar days from the event awareness date. . For 
reporting of SAEs to the sponsor, the investigator or designee will complete the SAE information 
electronically in the electronic case report form (eCRF). When it is completed, Mesoblast Safety 
personnel will be notified electronically. If the event meets serious criteria and it is not possible 

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to access the eCRF, the investigator or designee should complete the backup paper SAE form 
and e-mail it at
to Mesoblast Safety with 24 hours of awareness (see 
Section 7.1.6.3). 
 
The Sponsor Pharmacovigilance team will be responsible for oversight of all safety data and for 
determining the expectedness of all SAEs, expedited reporting of individual cases, and safety 
updates to regulatory authorities. Additionally, there will be 3 oversight committees: the ESC, an 
independent CEC, and an independent DMC as described previously. 
 
Primary Efficacy Variable and Endpoint:  The primary efficacy measure and endpoint for this 
study is time-to recurrent non-fatal HF-MACE, which consists of recurrent (multiple events per 
patient) non-fatal decompensated HF events and/or successfully resuscitated cardiac death 
events. The primary efficacy endpoint only considers non-fatal HF-MACE that occur prior to the 
first TCE. However, all recurrent and terminal HF-MACE following non-fatal TCEs will be 
collected and adjudicated for sensitivity analysis based on different definitions of recurrent and 
TCEs. The following definitions apply to the TWO components of the primary endpoint: 
 Non-fatal decompensated HF event will be adjudicated when the diagnosis of a non-
fatal decompensated HF event demonstrates the presence of signs and symptoms 
consistent with clinical decompensation of the patient’s HF state requiring an in-hospital 
stay or intravenous (IV) diuretic therapy or aquapheresis during an urgent care outpatient 
HF visit;  
 Successfully resuscitated cardiac death (RCD) events will be adjudicated when a 
subject experiences sudden death or cardiac death and is successfully resuscitated by 
cardioversion, defibrillation or cardiopulmonary resuscitation with a meaningful recovery 
of consciousness. Patients who have loss of consciousness (LOC) or syncope and receive 
a successful appropriate shock from an implantable cardioverter-defibrillator with 
meaningful recovery will also be designated as successful RCD event. These events will 
be considered recurrent (non-terminal) events for the purpose of the primary efficacy 
analysis, and will be considered terminal events in sensitivity analyses. 
 
NOTE:  Terminal cardiac events (defined as a composite of cardiac death, LVAD placement, 
heart transplant, or artificial heart implantation) are not a direct component of the primary 
efficacy endpoint. Rather, they will be analyzed jointly with recurrent non-fatal HF-MACE 
within the Joint Frailty Model analysis. It is the intent that a “terminal cardiac event” occurs 
when the left ventricle (LV) is no longer functioning as an independent viable pumping chamber 
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key secondary endpoint that will be evaluated using only TCEs.  This analysis, which will be 
performed utilizing a proportional hazards model, will help assure that any improvement in 
recurrent non-fatal HF-MACE for the Cell Therapy group is not associated with worsening in 
time-to-terminal event for the Cell Therapy vs. Control (Sham) group.  This analysis will provide 
assurance that any beneficial difference in recurrent non-fatal HF-MACE for the Cell Therapy vs 
Sham groups is not due to disproportionate early and/or late TCE rate for the Cell Therapy 
group.  
 
Cardiac events that occur on Day 0 will be included in the primary endpoint if they meet the 
definition of a recurrent non-fatal HF-MACE and are positively adjudicated as per the Cardiac 
Adjudication Manual.  Cardiac deaths that occur on Day 0 will be considered as a TCE. All 
cardiac events after time of randomization that are deemed potential endpoints by the 
investigator will be reported by the investigator in the RAVE system. All cardiac deaths post 
randomization are considered a TCE. The first TCE (cardiac death, LVAD implantation, heart 
transplant, artificial heart placement) for a patient that occurs after randomization will be 
adjusted for in the primary analysis and included in the key secondary analysis.  
 
Adjudication of all potential non-fatal HF-MACE or TCEs will be performed by an independent, 
blinded CEC. Once the first TCE has occurred for a patient, subsequent TCEs and/or non-fatal 
HF-MACE for that patient will be excluded from the primary JFM analysis.  All recurrent non-
fatal HF-MACE and TCEs will be collected and adjudicated through end-of-study or patient’s 
death for safety and sensitivity efficacy analysis purposes. (For details on the role and 
responsibilities of the CEC, please see the CEC Manual of Operations.)   
 
Transendocardial delivery of rexlemestrocel-L into the myocardium will require the placement 
of the injection catheter needle into the left ventricle wall. In order to accomplish this procedure, 
there will be significant catheter manipulation within the LV chamber. This normally causes 
premature ventricular contractions (PVCs) and multiple brief episodes of nonsustained VT 
during the cardiac mapping and cell delivery procedure. These arrhythmias are usually 
self-terminated. Sustained ventricular arrhythmias such as VT or ventricular fibrillation (VF) 
may occasionally be triggered even in the normal heart. Because of the underlying pathology in 
patients who will be enrolled in this study (which specifies significant LV systolic dysfunction as 
an inclusion criterion), ventricular arrhythmias may be more pronounced and occur more often 
than in less ill patients. Because of the close association between ventricular arrhythmias due to 
LV catheter manipulation and the cell delivery procedure, the occurrence of sustained ventricular 
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(with or without intracardiac mapping and cell delivery) on Day 0 is expected and will not be 
considered a non-fatal HF–MACE.  Cardiac deaths that occur on Day 0 will be considered as a 
TCE. All cardiac events after time of randomization onward that are deemed potential endpoints 
by the investigator will be reported by the investigator in the RAVE system. All cardiac deaths 
post randomization are considered a TCE. The first TCE (cardiac death, LVAD implantation, 
heart transplant, artificial heart placement) for a patient that occurs after randomization will be 
adjusted for in the primary analysis and included in the key secondary analysis. 
 
Secondary Efficacy Variables and Endpoints: 
The key secondary endpoint, time from Day 0-to-first TCE, will be evaluated to assure that any 
improvement in recurrent non-fatal HF-MACE is not associated with the worsening in time-to-
TCE for the Cell Therapy vs. Control (Sham) group.  
 
The key secondary endpoint relating to TCEs is as follows: 
 Time from Day 0-to-first TCE (cardiac death, LVAD placement, heart transplant, or 
artificial heart implantation, whichever occurs first).  
 
A non-inferiority analysis will be performed to test if rexlemestrocel-L is non-inferior to control. 
 
Secondary efficacy measures and endpoints for this study comprise a comparison of study 
treatment groups for the following: 
 time-to-hospital admissions for decompensated HF events beginning on Day 1  
 time-to-urgent care outpatient HF visits beginning on Day 1  
 time-to-successfully RCD events beginning on Day 1  
 total length of in-hospital stay in intensive care unit for decompensated HF events 
beginning on Day 1  
 time-to-first major cardiac event, defined as a composite of hospital admissions for 
decompensated HF, urgent care outpatient HF visits, and successfully RCD events. 
 time-to-first major cardiac event defined as a composite of hospital admissions for 
decompensated heart failure, urgent care outpatient HF visits, successfully RCD events, 
or TCE 
 time-to-cardiac death 
 time-to-all-cause death 
 time-to-non-fatal MI, non-fatal CVA, or coronary artery revascularization, whichever 
comes first. 
 

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Other secondary efficacy measures and endpoints relating to LV remodeling, functional exercise 
capacity, functional status, and QoL, and comprise the following: 
 LV remodeling as assessed by change from baseline in LVESV as determined by 
2-dimensional (2-D) echocardiography (echo-qualifying patients only).   
 Sensitivity analyses would, at a minimum, include the following: 
o Correlations between baseline LVESV <100 mL and LVESV >100 mL and clinical 
outcomes (including recurrent non-fatal HF-MACE and/or TCE) 
o Correlations between baseline LVESV <100 mL and LVESV >100 mL and change in 
month 6 – baseline LVESV (increase or no change vs. decrease) and clinical 
outcomes (including recurrent non-fatal HF-MACE and/or TCE) 
 LV remodeling as assessed by change from baseline in LVEDV as determined by 2-D 
echocardiography (echo-qualifying patients only) 
 LV systolic performance as assessed by change from baseline in left ventricular 
ejection fraction (LVEF)  
 functional exercise capacity as assessed by change from baseline in distance covered 
during the 6-minute walk test (6MWT) 
 functional status as assessed by change from baseline in NYHA Functional Class 
 QoL as assessed by change from baseline in the Minnesota Living With Heart Failure 
(MLHF) questionnaire score 
 QoL as assessed by change from baseline in the EuroQol 5-dimensional Quality of 
Life (EQ-5D) questionnaire score. 
 
Safety Variables and Endpoints: The safety and tolerability of rexlemestrocel-L will be 
assessed throughout the study by evaluating AEs, clinical laboratory test results, vital signs 
measurements, concomitant medication and therapy usage, ECG, 24-hour Holter monitoring 
(randomized patients across the US and EU), echocardiographic, and physical examination 
results. In addition, important cardiovascular safety events will be reviewed from CEC-
adjudicated data. The safety variables and endpoints for this study are as follows: 
 occurrence of adverse events relative to index cardiac catheterization (with or without 
intracardiac mapping and cell delivery) on Day 0 hospitalization through discharge for 
that hospitalization 
 occurrence of adverse events 
 clinical laboratory tests (serum chemistry and hematology) results  
 urinalysis 
 vital signs measurements 
 ECG findings 

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 Telemetry findings 
 rhythm analysis by ICD device (or any implanted device capable of defibrillation) 
interrogation, if applicable 
 24-hour Holter monitoring (randomized patients across the US and EU) 
 physical examination findings 
 review of important cardiovascular safety events from CEC adjudicated data for all-cause 
death (i.e., including non-cardiac and cardiac death) and hospitalizations for non-fatal 
decompensated HF, successfully RCD events, overall survival, coronary artery 
revascularization procedure, pre-specified ventricular arrhythmic events that do not fulfill 
criteria for positively adjudicated HF-MACE, non-fatal CVA, and non-fatal MI. 
 
Immunogenicity Variables and Endpoints: The immunogenicity variables and endpoints are 
as follows: 
 PRA 
 DSA (if the test for PRA is positive) 
 antibodies against bovine or murine proteins (i.e., BSA and MIgG). 
 
 
 
: 
 biomarkers as assessed by changes from baseline in NT-proBNP and hsCRP 
 
 
 
 
 
 
 
 
 PGx analyses to determine whether gene variants found in some patients will predict how 
they respond to rexlemestrocel-L therapy. 
 
 
 
 
Pharmacodynamics: Blood samples for analysis of the biomarkers NT-proBNP and hsCRP will 
be collected at screening and at Months 3, 6, and 12 (randomized and treated patients who DO 
NOT experience a disqualifying event). Blood samples will be collected every 12 months 
thereafter during long-term follow-up evaluations until study conclusion. 

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 median follow-up period of at least 2 years (patients who were enrolled early in the study 
and followed for recurrent non-fatal HF-MACE through the end-of-study would have a 
follow-up period substantially longer than 2 years, unless they experienced a TCE). 
 
The assumption regarding TCE rate was based on data from the Phase 2 study (
 and 
ESSENTIAL study (evaluated patients with entry criteria similar to this study1 and was assumed 
to be between 25% and 31% based on an approximate 2-year median follow-up (27% was used 
in the simulation for the sample size in this study). This sample size of 600 patients also 
considers and includes a potential 4% patient drop-out rate during the study. 
 
Two interim analyses were planned and have been conducted. Details for both interim analyses 
are provided in the statistical analysis plan (SAP) V5.0. 

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TABLE OF CONTENTS 
 
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ..............................6 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................8 
TABLE OF CONTENTS ................................................................................................36 
LIST OF TABLES ...........................................................................................................42 
LIST OF FIGURES .........................................................................................................43 
LIST OF APPENDICES .................................................................................................43 
LIST OF APPENDIX FIGURES ...................................................................................44 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................45 
1. 
BACKGROUND INFORMATION ........................................................................49 
1.1 
Introduction .....................................................................................................49 
1.2 
Name and Description of Investigational Product ..........................................53 
1.3 
Findings from
and Clinical Studies .............................................53 
53 
5 
1.4 
Identified and Potential Risks and Benefits of Rexlemestrocel-L to Humans62 
1.4.1 
Immunogenic Response ...................................................................63 
1.4.2 
Reaction to Dimethyl Sulfoxide.......................................................64 
1.4.3 
Transmission of Infectious Agents ..................................................64 
1.4.4 
Tumor Development ........................................................................64 
1.4.5 
Possible Effects of Cells on Fetus ....................................................65 
1.4.6 
Cardiac Procedures Risks and Complications .................................66 
1.4.7 
Cardiac Potential Benefits of Rexlemestrocel-L..............................67 
1.5 
Selection of Drugs and Dosage .......................................................................67 
1.6 
Compliance Statement ....................................................................................68 
1.7 
Population to be Studied .................................................................................69 
1.8 
Relevant Literature and Data ..........................................................................69 

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3.9.2 
Procedures before Study Intervention (Day 0 [Visit 2.0]) .............113 
3.9.3 
Procedures during Study Intervention (Day 0 [Visit 2.1]) .............114 
3.9.4 
Procedures After Study Intervention .............................................118 
3.9.5 
Procedures for Follow-up Period ...................................................120 
3.9.6 
Procedures for Long-term Follow-up ............................................124 
3.9.7 
Unscheduled Visits ........................................................................127 
4. 
SELECTION AND WIITHDRAWAL OF PATIENTS .....................................127 
4.1 
Patient Inclusion Criteria ..............................................................................127 
4.2 
Patient Exclusion Criteria .............................................................................130 
4.3 
Withdrawal Criteria and Procedures .............................................................133 
5. 
TREATMENT OF PATIENTS .............................................................................135 
5.1 
Study Drug Administered .............................................................................135 
5.2 
Restrictions ...................................................................................................136 
5.3 
Prior and Concomitant Therapy or Medication ............................................136 
5.4 
Procedures for Monitoring Patient Compliance ...........................................137 
5.5 
Total Blood Volume .....................................................................................137 
6. 
ASSESSMENT OF EFFICACY ...........................................................................137 
6.1 
Primary Efficacy Variable ............................................................................137 
6.2 
Secondary Efficacy Variables .......................................................................139 
6.2.1 
Key Secondary Efficacy Variable ..................................................139 
6.2.2 
Secondary Efficacy Variables ........................................................140 
6.2.3 
Other Secondary Efficacy Variables ..............................................140 
45 
6.4 
Methods and Timing of Assessing, Recording, and Analyzing Efficacy                
Data ..............................................................................................................145 
7. 
ASSESSMENT OF SAFETY ................................................................................145 
7.1 
Adverse Events .............................................................................................146 
7.1.1 
Definition of an Adverse Event .....................................................146 

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7.1.2 
Recording and Reporting Adverse Events .....................................147 
7.1.3 
Severity of an Adverse Event ........................................................148 
7.1.4 
Relationship of an Adverse Event to the Investigational Product .148 
7.1.5 
Relationship of an Adverse Event to the Medical Specialty                  
Device ............................................................................................149 
7.1.6 
Serious Adverse Events .................................................................150 
7.1.7 
Withdrawal Due to an Adverse Event ...........................................159 
7.1.8 
Medical Emergencies .....................................................................159 
7.1.9 
Protocol Deviations Because of an Adverse Event........................159 
7.2 
Pregnancy .....................................................................................................160 
7.3 
Clinical Laboratory Tests .............................................................................161 
7.3.1 
Serum Chemistry ...........................................................................161 
7.3.2 
Hematology ....................................................................................162 
7.3.3 
Urinalysis .......................................................................................163 
7.3.4 
Other Clinical Laboratory Tests.....................................................163 
7.4 
Vital Signs ....................................................................................................164 
7.5 
Electrocardiography ......................................................................................164 
7.5.1 
Telemetry .......................................................................................164 
7.5.2 
Electrocardiograms ........................................................................165 
7.5.3 
Holter Monitor Assessment ...........................................................165 
7.5.4 
Implantable Cardioverter Defibrillator ..........................................165 
7.6 
Physical Examinations ..................................................................................165 
7.6.1 
Body Weight ..................................................................................166 
7.7 
Other Safety Measures and Variables ...........................................................166 
7.7.1 
Cardiovascular Safety Events ........................................................166 
7.7.2 
Concomitant Therapy or Medication .............................................166 
7.8 
Methods and Timing of Assessing, Recording, and Analyzing Safety Data 166 
7.8.1 
Executive Steering Committee ......................................................167 

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9.5.4 
General Medical History ................................................................177 
9.5.5 
Prior Medications ...........................................................................177 
9.5.6 
Protocol Violations ........................................................................177 
9.5.7 
Childbearing Potential ...................................................................177 
9.6 
Efficacy Analysis ..........................................................................................177 
9.6.1 
Primary Efficacy Endpoint ............................................................178 
9.6.2 
Secondary Efficacy Endpoints .......................................................179 
81 
9.6.4 
Planned Method of Analysis ..........................................................181 
9.7 
Multiple Comparisons and Multiplicity ........................................................187 
9.8 
Safety Variables and Analyses .....................................................................187 
9.8.1 
Safety Variables .............................................................................188 
9.8.2 
Safety Analysis ..............................................................................188 
9.9 
Immunogenicity Variables and Analysis ......................................................192 
9.10 
Planned Interim Analyses .............................................................................192 
9.11 
Reporting Deviations From the Statistical Plan ............................................193 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..................................193 
11. QUALITY CONTROL AND QUALITY ASSURANCE ...................................194 
11.1 
Protocol Amendments and Protocol Deviations and Violations ..................194 
11.1.1 
Protocol Amendments ....................................................................194 
11.1.2 
Protocol Deviations ........................................................................194 
11.2 
Information to Study Personnel ....................................................................194 
11.3 
Study Monitoring ..........................................................................................195 
11.4 
Audit and Inspection .....................................................................................196 
12. ETHICS ...................................................................................................................196 
12.1 
Informed Consent .........................................................................................196 
12.2 
Health Authorities and Independent Ethics Committees/Institutional Review     
Boards ...........................................................................................................196 

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Appendix 4:  6-Minute Walk Test Procedures ................................................................ 223 
Appendix 5:  Minnesota Living with Heart Failure® Questionnaire Completion  
Instructions ................................................................................................ 225 
Appendix 6:  EQ-5-D Questionnaire English (USA) Version 2.0 ................................... 226 
 
LIST OF APPENDIX FIGURES 
Figure A- 1:  Diagrammatic Representation of Left Anterior Oblique and Right Anterior 
Oblique Views of the Left Ventricle Obtained During Contrast    
Angiography .............................................................................................. 213 
Figure A- 2:  Diagrammatic Representation of Left Anterior Oblique and Right Anterior 
Oblique Views of the Left Ventricle Obtained During Contrast   
Angiography .............................................................................................. 217 
Figure A- 3:  Diagrammatic Representation of Left Anterior Oblique and Right Anterior 
Oblique Views of the Left Ventricle Obtained During Contrast   
Angiography .............................................................................................. 220 
 
 
 

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1. 
BACKGROUND INFORMATION 
1.1 
Introduction 
A number of therapeutic approaches have been developed in an effort to treat patients with the 
most severe forms of cardiovascular disease, including chronic heart failure (HF). These 
approaches have included small molecules, biologics, devices, biventricular pacing, gene 
therapy, and cellular therapy. 2,11, 17  Whereas some of these therapies have been effective, 
especially initially, the natural history of advanced chronic HF remains progressive with poor 
long-term prognosis. For those patients with end-stage disease, very limited options are 
available, including placement of a left ventricular assist device (LVAD) and heart 
transplantation. However, an LVAD is costly and generally only provides a short-term solution, 
and heart transplantation is limited by organ availability and the need for long-term monitoring 
and complex immunosuppressive therapy. For patients with advanced chronic HF there is an 
important unmet clinical need to intervene in a manner that halts or, at a minimum, delays 
disease progression. The use of cellular therapies, such as stem cells, to repair and/or restore the 
structure and function of the damaged myocardium has the potential to alter the natural history of 
advanced chronic HF. Indeed, several clinical studies using stem cell therapy have reported 
promising hypothesis-generating results.7,12,15,17-21 
 
Despite substantial advances in the multi-modal treatment of patients with cardiovascular 
disease, HF continues to place a significant burden on the health care system. In the United 
States (US), approximately 5.8 million (M) people currently have HF and approximately 
670,000 new patients will be diagnosed with HF every year. 22-24  The prevalence of HF is 
estimated to be 1% to 2% in developed countries, increasing with age. 25 
 
In the United States, HF is the leading cause of hospitalization for patients older than 65 years of 
age, raising concerns about the economic burden of this condition.23-26 Indeed, HF is the only 
cardiovascular disease that currently has an increasing incidence.27 
 
In 2010, the cost of HF in the United States was estimated to be $39.2 billion, a figure that 
includes health care services, medications, cardiac transplantation, and lost work 
productivity.28,29  In 2013, one in nine death certificates (284,388 deaths) in the United States 
mentioned HF. Heart failure was the underlying cause in 58,309 of those deaths. The number of 
any-mention deaths attributable to HF was approximately as high in 1995 (287,000) as it was in 
2013 (284,000). Additionally, hospital discharges for HF remained stable from 2000 to 2010, 
with first-listed discharges of 1,008,000 and 1,023,000, respectively.22,23 
 

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In Europe, HF is also the single biggest reason for acute hospital admission in individuals older 
than 65 years. Approximately 14 M people in Europe have HF, and the incidence is increasing, 
with more cases being identified, more people living to an older age, and more patients surviving 
an acute myocardial infarction (MI) with subsequent adverse ventricular remodeling. More than 
3.5 million people are newly diagnosed with HF every year in Europe alone. 25 Similar 
distribution patterns are seen in European countries as the US national health care budget (~2%) 
and the percentage of the cost related to hospitalization (60%).29 According to the Study Group 
on Heart Failure Awareness and Perception in Europe (SHAPE), the number of people suffering 
from HF is expected to increase to 30 million by the year 2020. 
 
Heart failure represents the final common pathway in a pathological continuum of clinical, 
biological, and cellular events that leads to progressive maladaptive ventricular  
remodeling. 6,30-32  Despite diverse underlying etiologies of structural heart disease (ischemic and 
nonischemic in etiology), the diseased left ventricle adapts physiologically in order to maintain 
cardiac output and meet metabolic demands. Ultimately, progressive ventricular dilatation with 
associated derangements in molecular biodynamics and signaling pathways lead to cellular and 
genomic responses that ultimately result in adverse remodelling.33-35  The left ventricular 
(LV) remodeling process following an MI begins with myocardial necrosis and thinning of the 
wall of the heart.36,37  Although fibroblasts and collagen strengthen the necrotic area through a 
wound-healing response, this thin weakened area is unable to withstand the pressure and volume 
load on the heart, resulting in LV chamber dilation, decreased myofibril shortening, cardiac 
dysfunction and circulatory disturbances. Eventually, systolic and diastolic performance decline 
leading to associated increases in left ventricular end-systolic volume (LVESV) reflecting 
predominantly diminished contractile performance and increased ventricular afterload, and left 
ventricular end-diastolic volume (LVEDV) reflecting predominantly increased fiber lengthening 
or preload immediately prior to ventricular systole.6,30-32  At a critical juncture in the disease 
process, symptoms and signs of HF become manifest as a reflection of pulmonary venous 
hypertension, compromised systemic cardiac output, renal hypoperfusion with sodium and water 
retention, and neuroendocrine and metabolic derangements.38-44  The ultimate consequence is 
significantly increased risk of sudden death due to arrhythmias or death due to progressive pump 
failure.  
 
Beneficial LV remodeling in patients with HF due to LV systolic dysfunction has been shown in 
numerous interventional long term follow-up studies to be an important surrogate for improved 
clinical outcomes.  A standard measurement of LV remodeling is 6-month or 12-month change 
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a. A meta-analysis by Kramer et al of patients with HF and reduced ejection fraction 
showed a statistically significant positive correlation between long-term mortality and LV 
remodeling assessments performed at a mean follow up of 6-months post-baseline.45 
When measurements of beneficial remodeling using LVESV were compared with LVEF, 
the volume measurement demonstrated a higher incidence of improved longer-term 
mortality and was a better predictor of therapeutic effects on mortality.   
b. In the REVERSE Trial, which included 508 HF patients with systolic dysfunction who 
received CRT-D (CRT defibrillator) devices, patients were randomized to a CRT ON 
group or a CRT OFF group.46,47  There were no significant demographic differences 
between groups at baseline. In the CRT ON group, those patients with reverse 
remodeling (significant decrease in echo LVESV at 12-month compared to baseline) had 
a reduced incidence of VT/VF compared with those patients without LV remodeling 
(p =.001).  Furthermore, the presence of beneficial LV remodeling (decrease in echo 
LVESV at Month 6 compared to baseline) was associated with a >50% reduction in long 
term mortality rate.   
c. Thus, beneficial LV remodeling (as assessed by decrease in LVESV) should be a goal of 
therapies designed to treat systolic HF and is an important target for interventions aiming 
to optimize therapy. 
 
Current treatments for patients with HF, including the administration of neurohormonal 
antagonists (e.g., ACE inhibitors, ARBs, beta blockers and/or aldosterone antagonists), use of 
implantable cardioverter defibrillators (ICDs), and/or cardiac resynchronization devices have 
greatly benefitted many patients with advanced chronic HF as manifested by the following: 
 stabilized or improved LVEF and ventricular volumes. 12, 48-50 
 reduced mortality 51,52decreased number of HF hospitalizations.10, 53,54 
 improved quality of life.55 
 
However, while the administration of neurohormonal antagonists may delay the progression of 
HF, current treatments usually do not halt the disease.56,57  In general, pharmacologic attempts at 
improving exercise capacity in patients with chronic HF due to significant LV systolic 
dysfunction have met with very limited success. This may reflect the use of drug strategies that 
attempt to interrupt a single pathologic pathway (e.g., beta adrenergic blockade) rather than 
addressing the more complex multifactorial nature of the disease process itself. 
 
Whereas ICDs prevent sudden cardiac death due to ventricular fibrillation (VF), they do not 
diminish the proportion of patients who develop worsening HF.58  Indeed, because of prolonged 

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attributable, at least in part, to the secretion of bioactive molecules that mediate tissue protection 
and repair. 
 
Data from the Phase 2 chronic HF study (Study
 performed with rexlemestrocel-L 
suggest that there is a concordance of long-term benefit relating to clinical outcomes, LV 
remodeling, and submaximal exercise performance. These findings support the conduct of the 
current Phase 3 study (Study MSB-MPC-CHF001), which will evaluate the efficacy and safety 
of rexlemestrocel-L delivered transendocardially into the LV myocardium in patients with 
chronic HF due to LV systolic dysfunction of either ischemic or nonischemic etiology who have 
received optimal medical and coronary revascularization therapy. 
 
1.2 
Name and Description of Investigational Product 
The investigational product rexlemestrocel-L consists of human bone marrow-derived allogeneic 
MPCs isolated from bone mononuclear cells with an anti-STRO-3 antibody, expanded ex vivo, 
and cryopreserved. A description of rexlemestrocel-L is provided in Section 3.4. 
 
1.3 
Findings from
and Clinical Studies 
Cellular therapy using MPCs was initially investigated by Angioblast Systems, Inc., a subsidiary 
of Mesoblast, Ltd. (Melbourne, Australia).  In 2006, Mesoblast (doing business as Angioblast) 
incorporated a United States office (New York, New York) and began the clinical development 
of its cellular therapy products, including rexlemestrocel-L, for cardiovascular and non-
cardiovascular conditions.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.4 
Identified and Potential Risks and Benefits of Rexlemestrocel-L to Humans 
A number of identified and potential risks associated with rexlemestrocel-L and the products that 
are used to manufacture rexlemestrocel-L have been recognized. In addition, procedure-related 
risks associated with cardiac catheterization, transendocardial delivery of MPCs, angiographic 

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1.4.2 
Reaction to Dimethyl Sulfoxide 
DMSO 7.5% is used as part of the rexlemestrocel-L cryopreservation process. The therapeutic 
and toxic effects of DMSO include its own rapid penetration and enhanced penetration of other 
substances across biologic membranes, free radical scavenging, and effects on coagulation, 
anticholinesterase activity, and DMSO-induced histamine release by mast cells. The systemic 
toxicity of DMSO is considered to be low. The DMSO exposure in this therapy is minimal and is 
locally applied. Subjects with any hypersensitivity to DMSO, including mild hypersensitivity, 
will be excluded from study. 
 
1.4.3 
Transmission of Infectious Agents 
Potential for disease transmission from cell source and animal derived materials is minimized via 
thorough risk assessment in line with the Committee for Medicinal Products for Human Use/ 
Committee for Medicinal Products for Veterinary Use (CHMP/CVMP) Note for Guidance on 
Minimizing the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human 
and Veterinary Medicinal Products (European Medicines Agency [EMEA]/410/01). The risk of 
potential viral contamination is minimized by comprehensive evaluation of prospective donors, 
which includes completion of a Clinical Bone Marrow Donor Program application, infectious 
disease testing, hematology, metabolic profiling, and ABO/Rh and HLA typing. 
 
MPCs are an allogeneic, immunoselected, ex-vivo expanded cell product, which has the potential 
to become contaminated and subsequently cause infection in the study subject at the time of 
surgical implantation. This risk is greatly minimized by the use of a GMP-compliant production 
facility. Prior to the release of MPCs from the GMP facility, rigorous screening tests for multiple 
infectious agents are performed and sterility testing is conducted in order to ensure that no 
contaminated product is released for use. 
 
There have been no cases of disease transmission reported to date and review of the cumulative 
safety experience does not suggest an increased risk in the MPC treated group. 
 
1.4.4 
Tumor Development 
MPCs are living cells that have undergone ex vivo expansion and there is a theoretical risk that 
these cells could directly or indirectly cause the formation of unwanted tissue growth or a tumor. 
The possibility of tumor formation consequent to administration of MPCs can be the result either 
of in vitro transformation of the cells resulting in acquisition of a cell autonomous tumor-forming 
capacity or through the potential for MPCs to augment the growth of nascent/dormant tumors.  In 

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the case in vitro transformation of MPCs, nonclinical in vitro and in vivo data suggest that the 
theoretical risk of MPC tumorigenicity is very low.75,76  Nevertheless, the Sponsor remains 
vigilant in monitoring for signs of tumorigenic potential of rexlemestrocel-L.  As part of the 
CMC process, karyotypic analysis on MPC master cell banks (MCBs) is routinely performed to 
screen for chromosomal abnormalities. In addition, the in vivo tumorigenic potential of MCBs in 
immunodeficient mice is also assessed. MCBs must be shown to be karyotypically normal and 
free of tumor-forming cells prior to use in the manufacture of rexlemestrocel-L.  
 
An important factor in the potential risk of MPCs stimulating tumor formation by augmenting 
growth of malignant cells is the persistence of MPCs following administration.  Nonclinical data 
shown that intramyocardial administration of human and ovine and allogeneic MPC 
transplantation into animal models of heart failure was associated with short-term and low-level 
persistence of MPCs.72,73  These data suggest that MPCs are rapidly cleared following 
administration, minimizing the risk that MPCs may augment the growth of nascent/dormant 
tumors.  
 
Tumor formation has not been noted in the Sponsor’s preclinical studies employing MPCs 
delivered by systemic or local routes of administration to various animal models of disease. 
 
To minimize the theoretical risk of tumorigenesis and taking into consideration indication 
specific risk-benefit, patients with a prior history of malignancy, with the exception of certain 
treated cancers such as skin cancer and carcinoma in situ, are excluded (see Exclusion Criterion 
“q” in Section 4.2). 
 
1.4.5 
Possible Effects of Cells on Fetus 
Because of potential or unknown side effects of the study on the fetus, if the subject is a female 
of childbearing potential, the subject must have a negative pregnancy test prior to study entry as 
well as a negative pregnancy test immediately prior to day of the mapping/injection procedure. 
In addition, women of childbearing potential and men of childbearing age will be included in 
study participation provided that she or he is willing to use adequate contraception (including 
hormonal or barrier method or abstinence) from the time of screening and for a period of at least 
16 weeks (for men) and 6 months (for women) after study intervention. 
 
In the event that the study subject is confirmed to be pregnant during the study, the Principal 
Investigator must immediately report and follow the procedure as discussed in Section 7.2. 
 

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1.4.6 
Cardiac Procedures Risks and Complications 
Potential complications during cardiac catheterization include: death, MI, transient ischemic 
attack and stroke, vascular complications (including bleeding, hematoma, acute thrombosis, 
distal embolization, pseudoaneurysm, arteriovenous fistula), arrhythmias, perforation of the heart 
or great vessels, allergic reactions, atheroembolism, acute renal failure, infection, radiation 
exposure, arterial dissection (aortic), air embolism, and valvular injury. 
 
Potential complications related to the NOGA® XP or CARTO®3 Cardiac Navigation System 
(also referred to as NOGA® or CARTO®, respectively) used to administer rexlemestrocel-L are 
perforation, abnormal heart conduction, stroke, MI, pericardial effusion and tamponade, 
pulmonary embolism, and death.  
 
Possible complications include, but are not limited to: 
 vascular bleeding/local hematomas 
 thrombosis 
 arteriovenous fistula 
 pseudoaneurysm formation 
 thromboembolism 
 vasovagal reactions 
 cardiac perforation 
 cardiac tamponade 
 thrombus 
 air embolism 
 arrhythmias 
 valvular damage 
 pneumothorax 
 pericardial effusion 
 pulmonary embolism 
 hemothorax 
 infection 
 abnormal heart conduction 
 stroke 
 MI 
 Death. 
 

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the protocol will be documented in separate study agreements with the Sponsor and other forms 
as required by national authorities. 
 
Each investigator is responsible for ensuring the privacy, health, and welfare of the patients 
during and after the study and must ensure that trained personnel are immediately available in 
case of a medical emergency. Each investigator must be familiar with the background to and 
requirements of the study and with the properties of rexlemestrocel-L as described in the current 
version of the IB for rexlemestrocel-L. 
 
The Principal Investigator at each recruiting HF study site has the overall responsibility for the 
conduct and administration of the study at that site and for contacts with study management, with 
the Independent Ethics Committee (IEC) / Institutional Review Board (IRB), and with local 
authorities. 
 
1.7 
Population to be Studied 
Patients with chronic HF due to LV systolic dysfunction of either ischemic or nonischemic 
etiology who have received optimal medical and coronary revascularization therapy are eligible 
for enrollment, provided they meet all additional entry criteria as defined in Section 4. 
 
1.8 
Relevant Literature and Data 
Relevant literature is cited above. Further literature and data may be found in the current version 
of the IB for rexlemestrocel-L. 
 
2. 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
The purpose of this study is to assess the efficacy and safety of a single cardiac catheterization 
involving transendocardial delivery of 150 M human bone marrow-derived allogeneic MPCs 
(rexlemestrocel-L) in improving clinical outcomes (HF-MACE), preventing cardiac remodeling 
(LVESV), and increasing exercise capacity (6MWT) in patients with chronic HF due to LV 
systolic dysfunction of either ischemic or nonischemic etiology who have received optimal 
medical and coronary revascularization therapy. 
 

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2.2 
Study Objectives 
2.2.1 
Primary Objectives 
The primary objectives of this study are to: 
1. Determine whether transendocardial delivery of 150 M allogeneic human bone marrow-
derived MPCs (rexlemestrocel-L) when administered during a single index cardiac 
catheterization and intracardiac mapping procedure is more effective than a scripted sham 
cardiac mapping and cell delivery procedure in risk reduction for recurrent (multiple 
events per patient) non-fatal decompensated HF events and/or successfully RCD events, 
in the presence of terminal cardiac events (TCEs) in patients with chronic HF due to LV 
systolic dysfunction of either ischemic or non-ischemic etiology who have received 
optimal medical and coronary revascularization therapy.  
2. Evaluate the safety of transendocardial delivery of rexlemestrocel-L in patients with 
chronic HF due to LV systolic dysfunction of either ischemic or non-ischemic etiology 
who have received optimal medical and coronary revascularization therapy.  
 
2.2.2 
Secondary Objectives 
2.2.2.1 Key Secondary Objective 
The key secondary objective of the study is the assessment of time from Day 0-to-first TCE 
(cardiac death, left ventricular assist device [LVAD] placement, heart transplant, or artificial 
heart implantation), whichever event occurred first, to assure that any improvement in recurrent 
non-fatal HF-MACE is not associated with the worsening in time-to-TCE for the Cell Therapy 
vs. Control (Sham) group.  
 
Day 0 Definition: Day 0 for all time-to-event analyses is defined as follows:  
1. For patients who are randomized but DO NOT undergo the index cardiac catheterization 
as the date of the disqualifying event (i.e., violation of at least 1 inclusion/exclusion 
criterion);  
2. For patients who are randomized and DO undergo the index cardiac catheterization as the 
date of the index cardiac catheterization. 
 
2.2.2.2 Secondary Objectives 
The secondary objectives of this study are the assessment of various aspects of recurrent non-
fatal HF-MACE (i.e., decompensated HF events and/or successfully RCD events).  Other 

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secondary objectives of the study relate to LV remodeling by echocardiography, functional 
exercise capacity using the 6-minute walk test, functional status assessed by New York Heart 
Association Classification, and QoL. 
 
2.2.3 
Immunogenicity Objective 
The immunogenicity objective of this study is to evaluate the immunogenic potential of 
rexlemestrocel-L by evaluating the results of the following assays performed as specified in the 
protocol: 
 PRA (panel reactive antibodies) 
 DSA (if the test for PRA is positive) 
 antibodies against bovine or murine proteins (i.e., BSA [bovine serum albumin] and 
MIgG [mouse immunoglobulin G]). 
 
 
 
 study the association of changes from baseline levels of the biomarkers hsCRP and NT-
proBNP with disease severity and clinical outcomes 
 
 collect and store blood samples for possible use in future PGx analyses in the assessment 
of possible associations between genetic polymorphisms and the response to 
rexlemestrocel-L therapy in patients with chronic HF due to LV systolic dysfunction of 
either ischemic or non-ischemic etiology who have received optimal medical and 
coronary revascularization therapy. 
 
3. 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is a global, multicenter, double-blind, randomized, scripted sham-procedure controlled, 
parallel-group, study to evaluate the efficacy and safety of transendocardial delivery of 
rexlemestrocel-L (human bone marrow-derived adult allogeneic MPCs) during a single treatment 
index cardiac catheterization involving intracardiac mapping in patients with chronic HF due to 
LV systolic dysfunction of either ischemic or nonischemic etiology who have received optimal 
medical and coronary revascularization therapy. Overall, it is anticipated that known epicardial 

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CAD (documented stenosis of at least 50% in one or more major epicardial coronary arteries, 
documented prior coronary artery revascularization, and/or documented prior MI) will be present 
in at least 60% of the patients who are randomly assigned to treatment. 
 
The study comprises 3 main time periods: 1) a screening and randomization designation period; 
2) study intervention (i.e., hospitalization on Day 0 for a single index cardiac catheterization with 
or without intracardiac mapping and cell delivery); and 3) a follow-up period that continues until 
the required minimum number of recurrent non-fatal HF-MACE (i.e., at least 531 
decompensated HF events and/or successfully resuscitated cardiac death events) is obtained and 
a minimum follow-up of at least 6 months for all surviving subjects without TCEs is achieved. 
The follow-up period for patients who were randomized and DID undergo index cardiac 
catheterization includes patients’ safety and efficacy evaluations for a minimum of 6 months 
(assuming the patient has survived for that period of time without a TCE and has not 
discontinued from the study) and long-term safety and efficacy evaluations after the Month-12 
visit (every 6 months) until study conclusion. However, if a patient was randomized but DID 
NOT undergo the index cardiac catheterization, the patient will be followed for vital status, AEs, 
potential primary and key secondary endpoint events, and ICD interrogation via telephone 
contact at all regularly scheduled study visit times, including clinic visit times, for the duration of 
the study. Similarly, any patients who are randomized, DO undergo index cardiac catheterization 
but discontinue the study after Day 0 will be followed for determination of vital status (alive or 
dead), AEs, potential primary and key secondary efficacy endpoint events, and ICD interrogation 
via telephone contact at the regularly scheduled time points for the duration of the study. Every 
attempt should also be made to obtain vital status, at a minimum, from patients who withdraw 
consent to participate in the study after randomization. 
 
Written informed consent will be obtained for the study before any study-specific procedures are 
performed. A separate written informed consent for an exploratory PGx substudy will be 
obtained before any PGx-specific procedures are performed. Participation in the PGx substudy is 
optional and consent may be collected at a later stage than screening (though preferred as early 
as possible). A patient will not be excluded from participation in the study if he/she chooses not 
to provide consent for the additional procedures that are required as part of the exploratory PGx 
substudy. 
 
After informed consent is obtained, the patients will be screened for eligibility to participate in 
the study. During the screening period this will be based on the study’s pre-specified inclusion 
and exclusion criteria. During the screening period, patients will undergo a 2-D echocardiogram 

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with Doppler. The use of echocardiographic contrast for enhanced LV chamber imaging will be 
determined by the investigator or designee. If echocardiographic imaging is of insufficient 
technical quality for LV volume and LV ejection fraction estimation, then a RVG will be 
performed to assess LV ejection fraction as part of the patient’s screening procedures for 
inclusion in the trial. The Principal Investigator (or designee) will assess the need for coronary 
revascularization before the patient is randomly assigned to receive active or control treatment. If 
it is determined that a patient requires coronary revascularization, it should be performed at least 
2 months before reinitiating any study screening procedures. Patients who are screen failures 
may be re-screened with approval from the medical monitor. Randomization should occur as 
close as possible to the scheduled index cardiac catheterization date for potential delivery of 
study product. The pre-randomization criteria, such as echocardiographic criteria (restrictive, 
constructive or obstructive physiology, LV wall thickness, mural or arterial thrombus and 
prosthetic valve) are to be met by all patients and confirmed by both HF referral physician and 
the interventional cardiologist. Echocardiographic criteria must be confirmed and signed off by 
interventional cardiologist prior to randomization.  
 
Patients who experience an inclusion/exclusion criterion violation after randomization but before 
the scheduled index cardiac catheterization procedure will be included as part of the ITT analysis 
and cannot be re-screened.  
 
Patients who meet all inclusion criteria and none of the exclusion criteria will be enrolled in the 
study and randomly assigned in a 1:1 ratio to receive either active treatment (i.e., intracardiac 
mapping and transendocardial delivery of rexlemestrocel-L) or control treatment (i.e., scripted 
sham intracardiac mapping and cell delivery procedure without rexlemestrocel-L) by means of a 
computer-generated randomization list, and stratified by baseline NYHA Functional Class 
(Class II versus Class III), geographic region (US versus ex US) and presence of epicardial CAD 
(ischemic versus nonischemic); randomization will not be stratified by site. The randomization 
list and treatment group will be assigned via Interactive Response Technology (IRT). The IRT 
will be used to track and monitor enrollment of female patients as well as patients with baseline 
NYHA Class III versus Class II status in the study. To ensure that approximately 20% of the 
patient population in the study will be women, frequent discussions with the site staff will take 
place during the recruitment phase and will include discussion of the current rate of recruitment 
of women to the study. If there is a large disparity between the number of men and the number of 
women randomized to the study, the randomization may be limited to women until women 
represent approximately 20% of the study population. 
 

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Patient enrichment and replenishment will be performed such that by the end of the trial, the 
ratio of enrolled patients with baseline NYHA Class III to baseline NYHA Class II will be 
approximately 2:1.  With this ratio, it is estimated that approximately 600 randomized patients 
will be needed to achieve a minimum of 531 recurrent non-fatal HF-MACE at the end of the 
trial.  Based on current enrollment projections, at the end of the trial it is estimated that there will 
be ~200 baseline NYHA Class II patients and ~400 baseline NYHA Class III patients who have 
undergone the Day 0 index cardiac catheterization resulting in a baseline Class III/Class II ratio 
of 2:1.  In order to achieve this target, an enrollment cap of ~200 baseline NYHA Class II 
patients will be instituted.  It is anticipated that any baseline NYHA Class II patients who are 
inadvertently screened but not randomized during the suspension of NYHA Class II enrollment 
will be considered screen failures. The enrollment process will be overseen by the trial’s 
treatment blinded Medical Monitor in conjunction with current computer-generated 
randomization and interactive response technology (IRT) enrollment methodologies. 
 
After randomization, all patients who DO NOT experience an inclusion/exclusion criterion 
violation after randomization but before the scheduled index cardiac catheterization will undergo 
the index cardiac catheterization at a cell injection center and will remain hospitalized on 
telemetry after index cardiac catheterization for a minimum of one night. Prior to the initiation of 
any study procedures on the date of index cardiac catheterization, the cell injection center will 
ensure that an institution-specific informed consent document is obtained, if applicable. 
 
All patients randomly assigned to the active treatment group who DO NOT experience at least 
one inclusion/exclusion criterion violation after randomization but before the scheduled index 
cardiac catheterization will undergo an index cardiac catheterization with left ventriculography 
followed by cardiac mapping and transendocardial delivery of rexlemestrocel-L. Myocardial 
locations for transendocardial delivery of rexlemestrocel-L will be defined by means of imaging 
and left ventricular electrical mapping of the myocardium using the NOGA® or CARTO® 
Cardiac Navigational System in combination with the NogaStar® Mapping Catheter (Appendix 1 
and Appendix 3). Fifteen to 20 appropriate myocardial locations will be identified (20 sites is 
ideal) by imaging and electrical mapping as viable for cell delivery. The injection sites will be 
captured by NOGA® or CARTO® and transcribed into electronic data capture (EDC). 
Independent of whether the NOGA® or CARTO® imaging system was employed to identify 
viable myocardium, the MyoStar™ Injection Catheter will be used for transendocardial delivery 
of rexlemestrocel-L. A 0.2 mL suspension of cells will be injected with each injection to imaging 
identified myocardial locations; the total volume of study product administered must not exceed 

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4.0 mL. The total duration of the transendocardial delivery procedure must not exceed 90 
minutes from the time of completion of thaw of rexlemestrocel-L. 
 
All patients randomly assigned to the control group who DO NOT experience at least one 
inclusion/exclusion criterion violation after randomization but before the scheduled index cardiac 
catheterization will undergo a scripted sham cardiac mapping and cell delivery procedure that 
will include catheterization with left ventriculography and a simulation of cardiac mapping and 
cell delivery (Appendix 2). The scripted sham cardiac mapping and cell delivery procedure will 
be staged to script and will not include actual intracardiac mapping or transendocardial delivery 
of rexlemestrocel-L. The scripted sham cardiac mapping and cell delivery procedure will be led 
by the interventional cardiologist and will be approximately 60 to 90 minutes in duration. As 
with the active treatment group, 15 to 20 appropriate myocardial locations will be identified but 
by means of a scripted sham cardiac mapping procedure followed by a scripted sham cell 
delivery procedure, and will simulate the exact full procedural requirements used for the actual 
treatment cohort. The total duration of the scripted sham cell delivery procedure will not exceed 
90 minutes. 
 
Index cardiac catheterization (with or without intracardiac mapping and cell delivery) will be 
performed only by interventional cardiologists appropriately trained (including successful 
completion of the NOGA®/MyoStar™ or CARTO®/MyoStar™ Cardiac Navigation System 
training program and retraining for any interventionalist who has not performed the procedure 
using this system in over 1 year) and experienced in performing cardiac interventional 
procedures. Current American College of Cardiology/American Heart Association/European 
Society of Cardiology (ACC/AHA/ESC) Practice Guidelines will be followed in managing any 
procedure-related cardiac arrhythmias.  
 
Cardiac events that occur on Day 0 will be included in the primary endpoint if they meet the 
definition of a recurrent non-fatal HF-MACE and are positively adjudicated as per the Cardiac 
Adjudication Manual. Cardiac deaths that occur on Day 0 will be considered as a TCE. All 
cardiac events after time of randomization that are deemed potential endpoints by the 
investigator will be reported by the investigator in the RAVE system. All cardiac deaths post 
randomization are considered a TCE. The first TCE (cardiac death, LVAD implantation, heart 
transplant, artificial heart placement) for a patient that occurs after randomization will be 
adjusted for in the primary analysis and included in the key secondary analysis.  
 

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During the course of the study, the occurrence of adverse events, SAEs, TCEs, non-fatal 
decompensated HF-MACE or successfully resuscitated cardiac death events, overall survival 
(includes all-cause deaths), coronary artery revascularization procedure,
 CVA, and MI will be reviewed, evaluated, processed, and/or reported in 
accordance with the protocol. Additionally, the occurrence of all adverse events on Days 0 
through 7 and all SAEs on Days 0 through Day 30 following index cardiac catheterization (with 
or without intracardiac mapping and cell delivery) will be reported to the device manufacturer 
(Bioscience Webster, Inc. for the NOGA®/MyoStar™ or CARTO®/MyoStar™ Cardiac 
Navigation System) and the unblinded medical monitor (See Appendix 4). For reporting of 
SAEs, see Section 7.1.6.3).  
 
The Sponsor Pharmacovigilance team will be responsible for oversight of all safety data and for 
determining the expectedness of all SAEs, expedited reporting of individual cases, and safety 
updates to regulatory authorities. Additionally, there will be 3 oversight committees: an 
Executive Steering Committee (ESC), an independent CEC, and an independent DMC.  
 
Both the ESC and CEC will be blinded to study treatment; the DMC will be unblinded.  
 
The Data Monitoring Committee (DMC), which will be unblinded to study treatment, will 
oversee the study with primary responsibility for ensuring patient safety. Specific goals and 
responsibilities of the DMC are outlined in the Data Monitoring Committee Manual of 
Operations. The DMC will review on a regular predefined basis the occurrence of AEs as well as 
adjudicated clinical endpoints. The DMC will perform prespecified serial assessments of patient 
safety and monitor treatment effects to assess whether the objectives of the ongoing study can be 
met (see the DMC charter for more information). The DMC also reviewed the results of futility 
IA2 and provided pre-specified blinded information regarding study continuation to the ESC and 
the Sponsor. 
 
Because rexlemestrocel-L is given at a single time point (Day 0) and there is no specific 
treatment or agent that can reverse the effect of rexlemestrocel-L after administration, it is 
anticipated that there will be no need to unblind the treatment code to the Sponsor or to the HF 
study site personnel involved in the follow-up evaluations of the patient. However, for a serious 
and unexpected adverse event considered related to rexlemestrocel-L or study procedures, the 
unblinded team (CRO) will have access to unblind the study treatment (on a case-by-case basis) 
specifically for regulatory reporting purposes. If the treatment code is revealed for this reason, 
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CEC personnel, Sponsor Pharmacovigilance team), will remain blinded to treatment. In the case 
of an emergency, if it is necessary to know what treatment a patient has received, the investigator 
may determine the patient’s treatment using IRT after consultation with the Sponsor. In an 
extreme emergency, if the investigator is unable to contact the Sponsor, the investigator may 
determine the patient’s treatment using IRT without prior authorization. For such an occurrence, 
the investigator must contact the individual identified in the clinical study personnel contact 
information section of this protocol immediately. Proper documentation must be maintained 
when a treatment code is revealed.  
 
The Executive Steering Committee (ESC) will perform the following: 
 Oversight for the operation of the study, including working with national leaders and 
local HF study site investigators to achieve goals for enrollment of patients into the study 
 Reviewing recommendations from the project team for study conduct 
 Reviewing recommendations from the DMC for patient safety 
 Reviewing recommendations from the DMC for Interim Analyses #1 and #2. 
 
The independent Clinical Endpoints Committee (CEC), which will be blinded to study treatment, 
will adjudicate all potential cardiovascular events and survival in accordance with prespecified 
criteria. The events include all-cause death (i.e., including non-cardiac and cardiac death), 
LVAD placement, heart transplant, artificial heart implantation, hospitalization for recurrent 
non-fatal decompensated HF, urgent care outpatient HF visit, successfully RCD events, nonfatal 
MI, hospitalization for unstable angina, nonfatal CVA, coronary artery revascularization, and 
 
 
Cardiac events that occur on Day 0 will be included in the primary endpoint if they meet the 
definition of a recurrent non-fatal HF-MACE and are positively adjudicated as per the Cardiac 
Adjudication Manual. Cardiac deaths that occur on Day 0 will be considered as a TCE. All 
cardiac events after time of randomization that are deemed potential endpoints by the 
investigator will be reported by the investigator in the RAVE system. All cardiac deaths post 
randomization are considered a TCE. The first TCE (cardiac death, LVAD implantation, heart 
transplant, artificial heart placement) for a patient that occurs after randomization will be 
adjusted for in the primary analysis and included in the key secondary analysis. 
 
Two planned interim analyses have been conducted during the study (Section 9.10). 
 

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3.2 
Primary and Secondary Measures and Endpoints 
3.2.1 
Primary Efficacy Measure and Endpoint 
The primary efficacy measure and endpoint for this study is time from Day 0-to recurrent non-
fatal HF-MACE, which consists of recurrent (multiple events per patient) non-fatal 
decompensated HF events and/or successfully resuscitated cardiac death events.  
 
Day 0 Definition: Day 0 for all time-to-event analyses is defined as follows: 
 
1. For patients who are randomized but DO NOT undergo the index cardiac catheterization 
as the date of the disqualifying event (i.e., violation of at least one inclusion/exclusion 
criterion);  
2. For patients who are randomized and DO undergo the index cardiac catheterization as the 
date of index cardiac catheterization. 
 
The following definitions apply to the TWO components of the primary endpoint: 
 Non-fatal decompensated HF event will be adjudicated when the diagnosis of a non-
fatal decompensated HF event demonstrates the presence of signs and symptoms 
consistent with clinical decompensation of the patient’s HF state requiring an in-hospital 
stay or intravenous (IV) diuretic therapy or aquapheresis on an urgent care outpatient HF 
visit;  
 Successfully resuscitated cardiac death (RCD) events will be adjudicated when a 
subject experiences sudden death or cardiac death and is successfully resuscitated by 
cardioversion, defibrillation or cardiopulmonary resuscitation with a meaningful recovery 
of consciousness. Patients who have loss of consciousness (LOC) or syncope and receive 
a successful appropriate shock from an implantable cardioverter-defibrillator with 
meaningful recovery will also be designated as successful RCD event. 
 
NOTE:  Terminal cardiac events (defined as a composite of cardiac death, LVAD placement, 
heart transplant, or artificial heart implantation) are not a direct component of the primary 
efficacy endpoint. Rather, they will be analyzed jointly with recurrent non-fatal HF-MACE 
within the Joint Frailty Model analysis. It is the intent that a “terminal cardiac event” occurs 
when the left ventricle (LV) is no longer functioning as an independent viable pumping chamber 
that provides pulsatile blood flow to the systemic circulation. Time from Day 0-to-first TCE is a 
key secondary endpoint that will be evaluated using only TCEs. This analysis, which will be 
performed utilizing a proportional hazards model, will help assure that any improvement in 
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time-to-terminal event for the Cell Therapy vs. Control (Sham) group. This analysis will provide 
assurance that any beneficial difference in recurrent non-fatal HF-MACE for the Cell Therapy vs 
Sham groups is not due to disproportionate early and/or late TCE rate for the Cell Therapy 
group.  
 
Cardiac events that occur on Day 0 will be included in the primary endpoint if they meet the 
definition of a recurrent non-fatal HF-MACE and are positively adjudicated as per the Cardiac 
Adjudication Manual. Cardiac deaths that occur on Day 0 will be considered as a TCE. All 
cardiac events after time of randomization that are deemed potential endpoints by the 
investigator will be reported by the investigator in the RAVE system (Section 7.1.6.4). All 
cardiac deaths post randomization are considered a TCE. The first TCE (cardiac death, LVAD 
implantation, heart transplant, artificial heart placement) for a patient that occurs after 
randomization will be adjusted for in the primary analysis and included in the key secondary 
analysis.  
 
Adjudication of all potential non-fatal HF-MACE, TCEs, or cardiac events of special interest 
(regardless of whether they are serious or nonserious) are to be considered by the investigator as 
events for adjudication by an independent, blinded CEC (Section 7.1.6.4). Once the first TCE 
has occurred for a patient, subsequent TCEs and/or non-fatal HF-MACE for that patient will be 
excluded from the primary JFM analysis. All recurrent non-fatal HF-MACE and TCEs will be 
collected and adjudicated through end-of-study or patient’s death for safety and sensitivity 
efficacy analysis purposes. (For details on the role and responsibilities of the CEC, please see the 
CEC Manual of Operations.)   
 
Transendocardial delivery of rexlemestrocel-L into the myocardium will require the placement 
of the injection catheter needle into the left ventricle wall. In order to accomplish this procedure, 
there is significant catheter manipulation that occurs within the LV chamber. This normally 
causes premature ventricular contractions (PVCs) as well as multiple brief episodes of 
nonsustained VT during the cardiac mapping and cell delivery procedure. These arrhythmias are 
usually self-terminated. Sustained ventricular arrhythmias such as VT or VF may occasionally be 
triggered even in the normal heart. Because of the underlying pathology in patients enrolled in 
this study (which specifies significant LV systolic dysfunction as an inclusion criterion), 
ventricular arrhythmias may be more pronounced and occur more often than in less ill patients. 
Because of the close association between ventricular arrhythmias due to LV catheter 
manipulation and the cell delivery procedure, the occurrence of sustained ventricular arrhythmias 
that may require cardioversion or defibrillation during index cardiac catheterization (with or 

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without intracardiac mapping and cell delivery) on Day 0 is expected and will not be considered 
a non-fatal HF-MACE.  
 
3.2.2 
Secondary Efficacy Measures and Endpoints 
3.2.2.1 Key Secondary Measures and Endpoints Relating to Terminal Cardiac Events 
Time from Day 0-to-first TCE will be evaluated to assure that any improvement in recurrent 
non-fatal HF-MACE is not associated with the worsening in time-to-first TCE for the Cell 
Therapy vs. Control (Sham) group. 
 
The key secondary endpoint relating to TCEs is as follows: 
 Time from Day 0-to-first TCE (cardiac death, LVAD placement, heart transplant, or 
artificial heart implantation), whichever occurs first.  
A non-inferiority analysis will be performed to test if rexlemestrocel-L is non-inferior to control. 
 
3.2.2.2 Secondary Measures and Endpoints 
Secondary efficacy measures and endpoints of the study comprise the following: 
 time-to-hospital admissions for decompensated HF events beginning on Day 1  
 time-to-urgent care outpatient HF visits beginning on Day 1  
 time-to-successfully RCD events beginning on Day 1  
 total length of in-hospital stay in intensive care unit for decompensated HF events 
beginning on Day 1  
 time-to-first major cardiac event defined as a composite of hospital admissions for 
decompensated HF, urgent care outpatient HF visits, and successfully RCD events 
 time-to-first major cardiac event defined as a composite of hospital admissions for 
decompensated heart failure, urgent care outpatient HF visits, successfully RCD events, 
or TCE 
 time-to-cardiac death 
 time-to-all-cause death 
 time-to-non-fatal MI, non-fatal CVA, or coronary artery revascularization, whichever 
comes first. 
 
 

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Other secondary efficacy measures and endpoints for this study relate to  LV remodeling, 
functional exercise capacity, functional status, and QoL, and comprise the following: 
 LV remodeling as assessed by change from baseline in left ventricular end-systolic 
volume (LVESV) as determined by 2-dimensional (2-D) echocardiography (echo-
qualifying patients only). 
Sensitivity analyses would, at a minimum, include the following: 
 Correlations between baseline LVESV ≤100 mL and LVESV >100 mL and clinical 
outcomes (including recurrent non-fatal HF-MACE and/or TCE) 
 Correlations between baseline LVESV ≤100 mL and LVESV >100 mL and change in 
month 6 - baseline LVESV (increase or no change vs. decrease) and clinical outcomes 
(including recurrent non-fatal HF-MACE and/or TCE). 
 LV remodeling as assessed by change from baseline in left ventricular end-diastolic 
volume (LVEDV) as determined by 2-D echocardiography (echo-qualifying patients 
only) 
 LV systolic performance as assessed by change from baseline in left ventricular 
ejection fraction (LVEF)  
 functional exercise capacity as assessed by change from baseline in distance covered 
during the 6-minute walk test (6MWT) 
 functional status as assessed by change from baseline in NYHA Functional Class 
 QoL as assessed by change from baseline in the Minnesota Living With Heart Failure 
(MLHF) questionnaire score 
 QoL as assessed by change from baseline in the EuroQol 5-dimensional Quality of 
Life (EQ-5D) questionnaire score. 
 
3.2.3 
Safety Measures and Endpoints 
The safety and tolerability of rexlemestrocel-L in patients with chronic HF due to left ventricular 
systolic dysfunction of either ischemic or nonischemic etiology who have received optimal 
medical and coronary revascularization therapy will be assessed throughout the study (according 
to the schedule provided in Table 4 and Table 5 by evaluating adverse events, clinical laboratory 
test results, vital signs measurements, concomitant medication and therapy usage, ECG, 24–hour 
Holter monitoring (randomized patients across the US), and physical examination results.  In 
addition, important cardiovascular safety events will be reviewed from CEC-adjudicated data. 
 
 
 

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Functional Class III), geographic region (US versus ex-US) and presence of epicardial CAD 
(ischemic versus nonischemic); randomization will not be stratified by site.  Patients will be 
randomly assigned to the treatment groups (approximately 300 patients per group) by means of a 
computer-generated randomization list after confirmation of all eligibility criteria.  The 
randomization list and treatment group will be assigned via IRT. The IRT will be used to track 
and monitor the enrollment of women as well as patients with baseline NYHA Class III versus 
Class II functional status in the study.  To ensure that at least 20% of the patient population in the 
study will be women, frequent discussions with the site staff will take place during the 
recruitment phase and will include discussion of the current rate of recruitment of women to the 
study. If there is a large disparity between the number of men and the number of women 
randomized to the study, the randomization may be limited to women until women represent 
approximately 20% of the study population.  
 
Patient enrichment and replenishment will be performed such that by the end of the trial, the 
ratio of enrolled patients with baseline NYHA Class III to baseline NYHA Class II will be 
approximately 2:1.  With this ratio, it is estimated that approximately 600 randomized patients 
will be needed to achieve a minimum of 531 recurrent non-fatal HF-MACE at the end of the 
trial.  Based on current enrollment projections, at the end of the trial it is estimated that there will 
be ~200 baseline NYHA Class II patients and ~400 baseline NYHA Class III patients who have 
undergone the Day 0 index cardiac catheterization resulting in a baseline Class III/Class II ratio 
of 2:1.  In order to achieve this target, an enrollment cap of ~200 baseline NYHA Class II 
patients will be instituted.  It is anticipated that any baseline NYHA Class II patients who are 
inadvertently screened but not randomized during the suspension of NYHA Class II enrollment 
will be considered screen failures. The enrollment process will be overseen by the trial’s 
treatment blinded Medical Monitor in conjunction with current computer-generated 
randomization and interactive response technology (IRT) enrollment methodologies. 
 
Patients will be screened at recruiting HF study centers. The timing of randomization relative to 
Day 0 will vary based on study drug availability and BDS availability.  Guidelines tailored to 
each site will be provided in order to minimize the time between randomization and Day 0 while 
allowing sufficient time for operational logistics.  Every attempt should be made to minimize the 
time between randomization and Day 0. Note that any patients who are randomized but DO 
NOT undergo the index cardiac catheterization must be followed for determination of vital status 
(alive or dead), AEs, and potential primary, key secondary efficacy endpoint events, and ICD 
interrogation via telephone contact at all regularly scheduled study visit times, including clinic 
visit times, for the duration of the study.  Similarly, any patients who are randomized, DO 

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undergo index cardiac catheterization procedure but discontinue the study after Day 0 will be 
followed for determination of vital status (alive or dead), AEs, potential primary and key 
secondary efficacy endpoint events, and ICD interrogation via telephone contact at the regularly 
scheduled time points for the duration of the study. Every attempt should also be made to obtain, 
at a minimum, vital status from patients who withdraw consent to participate in the study after 
randomization. 
 
Hospitalization for index cardiac catheterization (with or without intracardiac mapping and cell 
delivery) will occur at a cell injection center; the interventional cardiologist performing the 
catheterization procedure will be unblinded to treatment assignment. Not all HF study centers 
will be cell injection centers and not all cell injection centers will be HF study centers. However, 
it is anticipated that the majority of cell injection centers will also be HF study centers. Screening 
and follow-up evaluations will be performed at HF study sites by study personnel who will be 
blinded to study treatment for the duration of the study. The interventional cardiologist and the 
unblinded team performing the study procedure (index cardiac catheterization with or without 
intracardiac mapping and cell delivery) may participate in screening procedures but will not be 
involved in follow-up evaluations (follow-up evaluations will be performed by blinded team 
members only). 
 
During the screening period, all patients (rexlemestrocel-L and control) will undergo cardiac 
imaging, which will consist, at a minimum, of a 2-D echocardiogram with Doppler. The use of 
echocardiographic contrast for enhanced LV chamber imaging will be determined by the 
investigator or designee. If echocardiographic imaging is of insufficient technical quality for LV 
volume and LV ejection fraction estimation, then a radionuclide ventriculogram (RVG) will be 
performed to assess LV ejection fraction as part of the patient’s screening procedures for 
inclusion in the trial. All randomized patients who DO NOT experience an inclusion/exclusion 
criterion violation after randomization but before the scheduled index cardiac catheterization will 
undergo placement of a femoral sheath through which a pigtail catheter will be advanced 
retrograde to the left ventricle for performance of contrast ventriculography to assess regional 
wall motion and define chamber anatomy. All patients randomly assigned to the rexlemestrocel-
L group who DO NOT experience an inclusion/exclusion criterion violation after randomization 
but before the scheduled index cardiac catheterization will undergo transendocardial 
administration of rexlemestrocel-L using the NOGA® /MyoStar™ catheter or 
CARTO®/MyoStar™ catheter, which use internal cardiac mapping to identify myocardial 
locations for cell delivery (Appendix 1 and Appendix 3, respectively).  
 

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All patients randomly assigned to the control group who DO NOT experience an 
inclusion/exclusion criterion violation after randomization but before the scheduled index cardiac 
catheterization will undergo a scripted sham cardiac mapping and cell delivery procedure 
simulating the exact full procedural requirements used for the actual treatment cohort 
transendocardial delivery of rexlemestrocel-L to the myocardium (Appendix 2). These patients 
will not undergo placement of the NogaStar® and MyoStar™ catheters. The scripted sham cardiac 
mapping and cell delivery procedure will not include internal mapping, but will be written to 
correspond to the operational steps that are used for intracardiac transendocardial delivery of 
rexlemestrocel-L using the NOGA® /MyoStar™ or CARTO®/MyoStar™ Cardiac Navigation 
System. These patients will not receive treatment with rexlemestrocel-L. This approach to 
blinding of actual treatment in the cardiac catheterization laboratory (which was used in the 
Phase 2 HF study with rexlemestrocel-L [Study
]) is essential for a subsequent 
objective and unbiased assessment of study endpoints. 
 
For all randomized patients who DO NOT experience an inclusion/exclusion criterion violation 
after randomization but before the scheduled index cardiac catheterization), administration of 
study treatment (transendocardial delivery of rexlemestrocel-L or scripted sham cardiac mapping 
and cell delivery procedure) will be performed at a cell injection center by an unblinded 
interventional cardiology team not involved with review or assessment of subsequent study 
results. Thus, this separate team is unblinded to study treatment. 
 
Patients, as well as noninterventional investigators and study site personnel at the HF study 
centers who conduct screening and follow-up evaluations after hospital discharge of patients 
from the cell injection center, will remain blinded to the study treatment provided at the cell 
injection center. It is permissible for a physician trained as an interventional cardiologist to take 
on the role of the blinded HF specialist for this study as long as the physician is adequately 
experienced to perform this role. In that scenario, another interventional cardiologist at the site 
must be identified as the (unblinded) interventional cardiologist for this program. Once a 
physician has been designated as either the blinded or unblinded cardiologist, he/she may not 
change his/her blinded vs unblinded role within the trial. 
 
An overview of the study personnel blinding is presented in Figure 7. 
 
 

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(MyoStar™ Injection Catheter) that is inserted through a sheath that has been previously inserted 
into the femoral artery. This catheter is then advanced through the arterial system to the LV. 
Patients randomly assigned to control treatment who DO NOT experience an 
inclusion/exclusion criterion violation after randomization but before the scheduled index cardiac 
catheterization will undergo a single cardiac catheterization involving a scripted sham cardiac 
mapping and cell delivery procedure without actual intracardiac mapping or transendocardial 
delivery of rexlemestrocel-L. A more detailed description of administration procedures for both 
the active and control treatment groups is given in Section 5.1. 
 
During the index cardiac catheterization, contrast left ventriculography as well as evaluations for 
stable myocardium will be performed. The latter will utilize either the NOGA® or CARTO®. 
Data will be generated to visualize and map myocardial locations that are potential targets for 
delivery of rexlemestrocel-L.   
 
Instructions for intracardiac mapping and transendocardial delivery of rexlemestrocel-L and for 
the scripted sham intracardiac mapping and cell delivery procedure are provided in Appendix 1 
(NOGA®), Appendix 3 (CARTO®), and Appendix 2 (scripted sham), respectively. 
 
3.5 
Duration of Study/Patient Participation 
This is an events-driven study and the study duration will be determined by the number of 
recurrent non-fatal decompensated HF events.  Patients are expected to participate in this study 
until the required number of recurrent non-fatal HF-MACE occur and all surviving patients 
without a TCE and without study discontinuation prior to the Month 6 visit have completed a 
minimum of 6 months of follow-up.  Patients who have a minimum of 6 months follow-up at the 
time the required number of recurrent non-fatal HF-MACE occur will be evaluated as early as 
possible using the same assessments that are specified for the Month 12 visit. An 
echocardiogram or RVG will be performed only if more than 6 months have passed since the 
patient’s last echocardiogram or RVG.  At least 531 recurrent non-fatal HF-MACE and a 
minimum of 6 months of follow-up for all surviving patients without a TCE and without study 
discontinuation prior to the Month 6 visit should be met for study completion. 
 
3.6 
Stopping Rules and Discontinuation Criteria 
Patients are expected to participate in this study until the required number of recurrent non-fatal 
HF-MACE occur and all surviving patients without a TCE and without study discontinuation 
prior to the Month 6 visit have completed a minimum of 6 months of follow-up.  The End-of-
Study will occur when the two following conditions have been met: 1) at least 531 recurrent non-

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fatal HF-MACE have occurred, and 2) all surviving patients without a TCE who remain in the 
trial have completed a minimum of 6 months of follow-up. However, the Sponsor may 
discontinue the study due to poor recruitment or other operational issues. During the conduct of 
the study, SAEs will be reviewed (see Section 7.1.6.3) as they are reported from the 
investigational sites to identify safety concerns. 
 
The interventional cardiologist may abort the index cardiac catheterization, the cardiac mapping 
and cell delivery procedure, or the scripted sham cardiac mapping and cell delivery procedure at 
any time if any acute symptoms develop that may pose an immediate risk to a patient. Guidelines 
for temporarily halting or terminating the intracardiac mapping and cell delivery procedure or the 
scripted sham intracardiac mapping and cell delivery procedure are provided in Appendix 1 
(NOGA), Appendix 2 (scripted sham), and Appendix 3 (CARTO), respectively. 
 
A patient may discontinue participation in the study at any time for any reason. The investigator 
and/or Sponsor can withdraw a patient from the study at any time for any reason as discussed in 
Section 4.3. 
 
3.7 
Study Drug Supply and Accountability 
3.7.1 
Study Drug Storage and Security 
Rexlemestrocel-L must be stored in the vapor phase of liquid nitrogen at −140°C to −196°C. 
Rexlemestrocel-L will be maintained in a monitored freezer with adequate security and an 
audible alarm and will be appropriately identified and segregated from other products. 
Additional details regarding the storage and preparation of rexlemestrocel-L are provided in the 
Pharmacy Manual. 
 
3.7.2 
Study Drug Accountability 
The cell injection center pharmacist will maintain a record of rexlemestrocel-L received, 
dispensed, administered, or destroyed. The final disposition of all unused, empty, and partially 
used cryocyte vials will be handled in accordance with the institutional policy and procedures 
described in the Pharmacy Manual. 
 
The investigator will complete a record of the cardiac mapping and cell delivery products 
received, dispensed, administered, or destroyed. If the mapping and/or cell delivery (injection) 
catheter is defective or malfunctions during a procedure, the catheters should be returned to the 
medical device manufacturer (Biosense Webster, Inc.) as described in Appendix 4. 

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3.8 
Maintenance of Randomization and Blinding 
This is a double-blind study. The randomization code will be maintained by the Sponsor’s 
independent third party provider. At the time of analyses, when treatment codes are revealed, the 
randomization code will be provided to the statistician assigned to this study. In addition, the 
randomization code will be provided to the unblinded independent statistician for use in the 
conduct of the interim analyses and support of the DMC. 
 
The success of this study depends on several factors including: a) the safety of patients enrolled 
and randomly assigned to treatment; b) demonstration of the potential clinical benefit from 
transendocardial delivery of rexlemestrocel-L; and c) maintenance of the treatment blind as it 
relates to clinical follow up and decision making. 
 
This study is designed with 3 distinct time periods relative to knowledge of study treatment: 
 Screening and randomization designation period: A patient’s eligibility to participate 
in the study will be determined during this period and will be based on the study’s 
inclusion and exclusion criteria for screening. If the patient is deemed eligible to 
participate in the study, randomization will occur. 
 Study intervention: For all randomized patients who DO NOT experience an 
inclusion/exclusion criterion violation after randomization but before the scheduled index 
cardiac catheterization, study intervention will involve hospitalization for a single index 
cardiac catheterization with or without intracardiac mapping and cell delivery. For these 
patients, study intervention will be performed at a cell injection center by an 
interventional cardiology team not involved with follow-up of patients’ safety and 
efficacy evaluations. Interventional cardiologists and the unblinded team performing the 
study intervention may participate in screening evaluations (follow-up evaluations will be 
performed by blinded team members only). 
 Follow-up period: The follow-up period begins after hospital discharge from the cell 
injection center and continues until the required number of recurrent non-fatal HF-MACE 
(i.e., at least 531 recurrent non-fatal HF events or successfully RCD events) is obtained 
and a minimum follow-up of at least 6 months for all surviving subjects without TCEs is 
achieved. The follow-up period for patients who were randomized and DID undergo 
index cardiac catheterization includes patients’ safety and efficacy evaluations for a 
minimum of 6 months (assuming the patient has survived for that period of time without 
a TCE and has not discontinued from the study) and long-term safety and efficacy 
evaluations after the Month-12 visit (every 6 months) until study conclusion. However, if 
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patient will be followed for vital status (alive or dead), AEs, potential primary and key 
secondary endpoint events, and ICD interrogation via telephone contact at all regularly 
scheduled study visit times, including clinic visit times, for the duration of the study.  
Similarly, any patients who are randomized, DO undergo index cardiac catheterization 
procedure but discontinue the study after Day 0 will be followed for determination of 
vital status (alive or dead), AEs, potential primary and key secondary efficacy endpoint 
events, and ICD interrogation via telephone contact at the regularly scheduled time points 
for the duration of the study. Every attempt should also be made to obtain, at a minimum, 
vital status from patients who withdraw consent to participate in the study after 
randomization. 
 
The design and maintenance of a blinded follow-up period will help protect the integrity of study 
data and will help prevent the introduction of physician bias into the clinical decision-making 
process that could result from knowledge of study treatment.  Treatment bias could influence a 
treating physician’s decision to hospitalize a patient for HF.  For example, knowledge that a 
given patient did not receive rexlemestrocel-L could result in a lower threshold for 
hospitalization because the physician would not expect the sham cardiac mapping and cell 
delivery procedure to have beneficially affected the patient’s long-term clinical state. 
Maintenance of the blind during follow up is particularly important in this study because a biased 
decision relating to HF hospitalization would directly impact the study’s primary efficacy 
endpoint. Appropriate blinding over the duration of the follow-up period will also help define the 
“placebo effect” on subjective measurements including NYHA class, MLHF, and EQ-5D. 
 
Because of the basic study design and the need to minimize inadvertent unblinding to study 
treatment, this study will be supported by a blinded as well as an unblinded study team. The 
Blinding Plan includes an independent unblinded statistician who will perform the interim 
analyses.  The following summarizes the roles of these two teams for this study. 
 Unblinded Study Team: The individuals on the unblinded study team are unblinded to 
study treatment assignment as prespecified and required. If necessary, they can be 
unblinded to treatment-specific clinical data. They have the ability to aggregate 
treatment-specific clinical study information. Any activity associated with the cell 
injection center is the responsibility of the unblinded study team. 
 The unblinded Sponsor Pharmacovigilance team is responsible for the SAEs that occur 
during the period of Day 0 to hospital discharge for the index cardiac catheterization and 
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is unexpected and considered related to rexlemestrocel-L (see Section 7.8.4 for more 
information). 
 Immunogenicity testing for positive PRA results and for the anti-murine and anti-bovine 
analysis subsets (see Section 8.3 for more information). 
 
 Blinded Study Team: The blinded study team members are blinded to study treatment 
assignment, the Day 0 index cardiac catheterization procedures, and treatment-specific 
clinical data. Most activities associated with a HF study site (screening and any follow-up 
evaluations after the patient has been discharged from the cell injection center after the 
Day 0 index cardiac catheterization procedures) fall within the scope of the blinded team 
(an exception is the interventional cardiologist and the unblinded team who may 
participate in the screening process). Additionally, the following groups will be 
unblinded to treatment assignment only on a case-by-case basis: 
 The blinded Sponsor Pharmacovigilance team is responsible for the SAEs during 
screening and Day 8 onward but may be unblinded to treatment assignment only on a 
case-by-case basis for a SAE(s) that is unexpected and considered related to 
rexlemestrocel-L (see Section 7.8.4 for more information). If this occurs, the study site 
investigator will remain blinded to treatment but the Sponsor’s medical monitor may be 
unblinded to treatment in order to decide on the action taken as described in Section 3.6. 
 
Patients as well as noninterventional investigators and study site personnel at the HF study 
centers who conduct follow-up evaluations after hospital discharge of patients from the cell 
injection center will remain blinded to the study treatment provided at the cell injection center. It 
is permissible for a physician trained as an interventional cardiologist to take on the role of the 
blinded HF specialist as long as the physician is adequately experienced to perform this role. In 
that scenario, another interventional cardiologist at the site will be identified as the (unblinded) 
interventional cardiologist for this program. Once a physician has been designated as either the 
blinded or unblinded cardiologist, he/she may not change his/her blinded vs unblinded role 
within the trial. Further delineation of the responsibilities of the unblinded and blinded 
individuals can be found in the Blinding Plan. 
 
Because rexlemestrocel-L is given at a single time point (Day 0), and there is no specific 
treatment or agent that can reverse the effect of rexlemestrocel-L after administration, it is 
anticipated that there will be no need to unblind the treatment code to the Sponsor or to the study 
site personnel involved in the long-term follow-up evaluations of the patient. For information 
about personnel (interventional cardiology team) who may be aware of treatment assignments, 

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see Section 3.3. These individuals will not be involved in the conduct of any follow-up study 
procedures or assessment of clinical results. 
 
In the case of an emergency, if it is necessary to know what treatment a specific patient has 
received, the investigator may determine the patient’s treatment using IRT after consultation 
with the Sponsor. In an extreme emergency, if the investigator is unable to contact the Sponsor, 
the investigator may determine the patient’s treatment using IRT without prior authorization. 
When this occurs, the investigator must contact immediately the individual identified in the 
clinical study personnel contact information section of this protocol. Proper documentation must 
be maintained when a treatment code is revealed. 
 
There will be 3 oversight committees: an Executive Steering Committee (ESC), an independent 
CEC, and an independent DMC. Both the ESC and the CEC will be blinded to study treatment; 
the DMC will be unblinded. For further details, see Section 7.8. 
 
3.8.1 
Source Data Recorded on the Case Report Form 
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed onto the case report form (CRF). Data may not be 
recorded directly onto the CRF and considered as source data unless the investigational center 
obtains written documentation from the Sponsor, before the beginning of the study, indicating 
which data are permitted to be recorded directly onto the CRF. 
 
Data processed from other institutions (e.g., clinical laboratory, central image center, electronic 
diary data) will be sent to the investigational center, where they will be retained, but not entered 
into the CRF unless otherwise noted in the protocol. These data may also be sent electronically 
to the Sponsor (or organization performing data management) for direct entry into the clinical 
database (see Section 13.1). All data from other institutions will be available to the 
investigator(s). 
 
The CRFs are filed in the Sponsor’s central file. 
 
3.9 
Time Schedule 
The study started in 2014 and is expected to be completed in 2020. Because this study is 
endpoint driven, the actual duration of the study will be determined by the time required to 
achieve a minimum of 531 recurrent non-fatal HF-MACE that have been positively adjudicated 

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by the CEC, and all surviving patients without a TCE and without study discontinuation prior to 
the Month 6 visit have completed a minimum of 6 months of follow-up.  
Approximately 600 patients with chronic HF due to LV systolic dysfunction of either ischemic 
or non-ischemic etiology from approximately 80 to 100 study centers are planned to be enrolled 
in the study.  
This study comprises 3 main time periods: 1) screening and randomization designation period 
period; 2) study intervention (i.e., hospitalization on Day 0 for index cardiac catheterization with 
or without intracardiac mapping and cell delivery); and 3) a follow-up period that continues until 
the required number of recurrent non-fatal HF-MACE (i.e., at least 531 recurrent non-fatal 
decompensated HF events and/or successfully resuscitated cardiac death events) is obtained and 
a minimum follow-up of at least 6 months for all surviving subjects without TCEs is achieved. 
The follow-up period for patients who were randomized and DID undergo index cardiac 
catheterization includes safety and efficacy evaluations for a minimum of 6 months (assuming 
he/she has survived for that period of time without a TCE and has not discontinued from the 
study) and long-term safety and efficacy evaluations after the Month-12 visit (every 6 months) 
until study conclusion.  However, if a patient was randomized but DID NOT undergo the index 
cardiac catheterization, the patient will be followed for vital status, AEs, potential primary and 
key secondary endpoint events, and ICD interrogation via telephone contact at all regularly 
scheduled study visit times, including clinic visit times, for the duration of the study. Similarly, 
any patients who are randomized, DO undergo index cardiac catheterization procedure but 
discontinue the study after Day 0 will be followed for determination of vital status (alive or 
dead), AEs, potential primary and key secondary efficacy endpoint events, and ICD interrogation 
via telephone contact at the regularly scheduled time points for the duration of the study. Every 
attempt should also be made to obtain, at a minimum, vital status from patients who withdraw 
consent to participate in the study after randomization. 
Study procedures and assessments with their timing are summarized in Table 4.