Clinical trial NCT02467387
Conditions: Non-Ischemic Heart Failure
Keywords: Non-ischemic Heart Failure Stem Cells
Sponsor: CardioCell LLC
Start date: 2014-06-01; Completion date: 2017-05-11
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A phase IIa study to assess the safety and preliminary efficacy of intravenous dose of ischemia-tolerant Allogeneic Mesenchymal Bone Marrow Cells in subjects with non-ischemic heart failure.

Detailed description:
A phase IIa, single-blind, placebo-controlled, crossover, multi-center, randomized study to assess the safety, tolerability, and preliminary efficacy of a single intravenous dose of ischemia-tolerant allogeneic mesenchymal bone marrow cells to subjects with heart failure of non-ischemic etiology.

Arms: arm 1: Intervention: One time intravenous infusion of 1.5 million (aMBMC) per kg administered at approximately 2mL/min. Maximum dose as for 100kg subject or 150 million cells for any subject 100kg or more. arm 2: Intervention: One time intravenous infusion of 1.5mL/kg Lactated Ringer's Solution (LRS) administered at a constant rate of approximately 2mL/min.
Interventions: intervention 1: Allogeneic Mesenchymal Bone Marrow Cells (aMBMC) intervention 2: Lactated Ringer's Solution
Intervention descriptions: intervention 1: One time infusion Allogeneic Mesenchymal Bone Marrow Cells (aMBMC) 1.5 million cells/kg. intervention 2: One time infusion 1.5mL/kg

Protocol documents:
Prot_SAP_000.pdf: 
Protocol: 
STEM-104-M-CHF 
1  
 19FEB2014 
PROTOCOL 
TITLE: 
A phase IIa, single-blind, placebo-controlled, crossover, multi-center, randomized 
study to assess the safety, tolerability, and preliminary efficacy of a single 
intravenous dose of ischemia-tolerant allogeneic mesenchymal bone marrow cells  
to subjects with heart failure of non-ischemic etiology 
NCT NUMBER: 
PROTOCOL NUMBER: STEM-104-M-CHF 
INVESTIGATIONAL 
PRODUCT: 
Ischemia-Tolerant Allogeneic Mesenchymal Bone Marrow Cells, (aMBMC) (adult 
human) 
SPONSOR: 
 
CardioCell, LLC 
5375 Mira Sorrento Place, Suite 100, San Diego, CA 
92121 
NCT02467387


Protocol:   STEM-104-M-CHF         
      2 
 19FEB2014 
TABLE OF CONTENTS ............................................................................................... PAGE 
PROTOCOL ACCEPTANCE FORM .................................................................................... 4 
PROTOCOL SYNOPSIS ..................................................................................................... 5 
1 
BACKGROUND ......................................................................................................... 12 
1.1 
Non-Ischemic Heart Failure ........................................................................... 12 
1.2 
Bone Marrow Mononuclear Cells (BMMNC) for N-IHF ................................... 12 
2 
MESENCHYMAL STEM CELLS ................................................................................ 12 
2.1 
Mechanisms of Action of MSCs ..................................................................... 12 
2.2 
Preclinical Experience with MSCs for Heart Disease ..................................... 13 
2.3 
Allogeneic versus Autologous MSCs.............................................................. 14 
2.4 
Modifying MSCs for Cardiac Regeneration .................................................... 14 
2.5 
Potentiation of MSCs with Hypoxic Culture .................................................... 14 
2.6 
Potency of MSCs Cultured in a Hypoxic Environment .................................... 14 
2.7 
Clinical Experience with Stemedica itMSCs ................................................... 15 
2.8 
Clinical Trials with MSCs in Heart Disease..................................................... 15 
2.9 
Rationale for Study Design ............................................................................ 16 
3 
OBJECTIVES ............................................................................................................ 16 
3.1 
Primary Objective ........................................................................................... 16 
3.2 
Secondary Objective ...................................................................................... 16 
4 
STUDY DESIGN ....................................................................................................... 16 
4.1 
Description of the Study ................................................................................. 16 
4.2 
Endpoints ....................................................................................................... 17 
4.3 
Safety Plan .................................................................................................... 18 
4.4 
Compliance with Laws and Regulations ......................................................... 18 
5 
STUDY ENROLLMENT ............................................................................................. 18 
5.1 
Subject Selection ........................................................................................... 18 
5.2 
Method of Treatment Assignment and Blinding .............................................. 19 
5.3 
Subject Discontinuation and Withdrawal ........................................................ 19 
5.4 
Study Termination .......................................................................................... 20 
6 
INVESTIGATIONAL PRODUCT ................................................................................ 20 
6.1 
Formulation, Packaging, Preparation, Randomization of aMBMC or Placebo 20 
6.2 
IV Administration of aMBMC or Placebo ........................................................ 20 
6.3 
Product Storage and Stability ......................................................................... 20 
6.4 
Concomitant Medications and Rehabilitation .................................................. 21 
7 
STUDY ASSESSMENTS AND SCHEDULE .............................................................. 21 
7.1 
General Assessments .................................................................................... 21 
7.2 
Schedule of Assessments .............................................................................. 22 
7.3 
Follow-up Assessments ................................................................................. 24 
7.4 
Early Termination Visit ................................................................................... 25 
8 
ASSESSMENT OF SAFETY ..................................................................................... 25 
8.1 
Safety Parameters ......................................................................................... 25 
8.2 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters ......................................................................................... 27 
8.3 
Expedited Reporting Requirements for Serious Adverse Events .................... 29 
8.4 
Type and Duration of Follow-Up of Subjects After Adverse Events ................ 29 
8.5 
Stopping Rules .............................................................................................. 29 
8.6 
Data Safety and Monitoring Board (DSMB) .................................................... 29 
9 
STATISTICAL CONSIDERATIONS ........................................................................... 30 
9.1 
Randomization ............................................................................................... 30 
9.2 
Primary Safety Analysis ................................................................................. 30 
9.3 
Efficacy Analyses ........................................................................................... 30 
9.4 
Determination of Sample Size ........................................................................ 30 


 
Protocol:   STEM-104-M-CHF                                                       3                                                                       19FEB2014 
9.5 
Interim Analysis ............................................................................................. 30 
1 
10 
INVESTIGATOR REQUIREMENTS .......................................................................... 31 
10.1 
Study Initiation ............................................................................................... 31 
10.2 
Study Completion........................................................................................... 31 
10.3 
Informed Consent Process ............................................................................. 31 
10.4 
Institutional Review Board or Ethics Committee ............................................. 32 
10.5 
Study Monitoring Requirements ..................................................................... 32 
10.6 
Case Report Forms ........................................................................................ 32 
10.7 
Source Data Documentation .......................................................................... 32 
10.8 
Use of Computerized Systems ....................................................................... 33 
10.9 
Investigational Product Accountability ............................................................ 33 
10.10 Disclosure of Data .......................................................................................... 33 
10.11 Retention of Records (for approval enabling studies only) ............................. 33 
REFERENCES .................................................................................................................. 35 
APPENDIX A: SCHEDULE OF ASSESSMENTS .............................................................. 41 
APPENDIX B: QUESTIONNAIRES ................................................................................... 42 
APPENDIX C: FINAL FORMULATION SKIN TEST ........................................................... 46 
 
 
 
 


 
Protocol:   STEM-104-M-CHF                                                       4                                                                       19FEB2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I have read the protocol, including all appendices, and agree that it contains all necessary details for my staff 
and me to conduct this study as described.  I will conduct this study as outlined herein and will make a 
reasonable effort to complete the study within the time designated. 
 
I understand that I am not allowed to make changes to this protocol. 
 
I will provide all study personnel under my supervision copies of the protocol and access to all information 
provided by CardioCell, Inc. I will discuss this material with them to ensure that they are fully informed about 
the investigational products and the study, and with Good Clinical Practice (GCP). 
 
 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
   
 
Please fax a copy to (760) 520-0608 and retain the original for your study files. 
 
                      PROTOCOL ACCEPTANCE FORM 
 
 
TITLE: 
 
A phase IIa, single-blind, placebo-controlled, crossover, multi-
center, randomized study to assess the safety, tolerability, 
and preliminary efficacy of a single intravenous dose of 
ischemia-tolerant allogeneic mesenchymal bone marrow cells 
to subjects with heart failure of non-ischemic etiology 
 
PROTOCOL NUMBER: 
 
STEM-104-M-CHF 
 
INVESTIGATIONAL 
PRODUCT(S): 
 
Ischemia-Tolerant Allogeneic Mesenchymal Bone Marrow 
Cells, (aMBMC) (adult human) 
 
 
 
 
 
 
 
 
 
 


 
Protocol:  STEM-104-M-CHF 
  
19FEB2014 
PROTOCOL SYNOPSIS 
TITLE: 
A phase IIa, single-blind, placebo-controlled, crossover, 
multi-center, randomized study to assess the safety, 
tolerability, and preliminary efficacy of a single intravenous 
dose of ischemia-tolerant allogeneic mesenchymal bone 
marrow cells to subjects with heart failure of non-ischemic 
etiology 
PROTOCOL NUMBER: 
STEM-104-M-CHF 
INVESTIGATIONAL 
PRODUCTS: 
Ischemia-Tolerant Allogeneic Mesenchymal Bone Marrow 
Cells (aMBMC), (adult human)  
PHASE: 
IIa 
INDICATION: 
Heart failure of non-ischemic etiology 
IND/IDE NUMBER: 
 
SPONSOR: 
CardioCell, LLC 
 
 
 
 
 
 
 
 


 
Protocol:   STEM-104-M-CHF                                                       6                                                                       19FEB2014 
STUDY OBJECTIVES 
 
Primary: 
To assess the safety of human ischemia-tolerant allogeneic mesenchymal bone marrow cells (aMBMC) 
administered intravenously to subjects with heart failure (HF) of non-ischemic etiology (N-IHF). 
 
Secondary: 
To assess the effects of intravenously delivered human aMBMC on (a) left ventricular (LV) structure and 
function, and (b) clinical status of subjects with N-IHF. 
 
STUDY DESIGN 
This is a Phase IIa, single blind, placebo-controlled, crossover, multi-center, randomized study in subjects with 
NIHF.  The study will enroll 20 subjects and will consist of 2 cohorts.  Enrolled subjects will be randomized at 
1:1 into an experimental group (n=10) or a placebo group (n=10), respectively. Subjects in the experimental 
group will receive 1.5 million cells per kg and subjects in the placebo group will receive 1 mL/kg Lactated 
Ringer’s Solution. At 90 days the two groups will change arms and the placebo group will receive 1.5 million 
cells per kg and the initially treated group will receive a Lactated Ringer’s Solution (LRS) at a volume of 1 
mL/kg. 
 
SUBJECT PARTICIPATION 
To be eligible for screening, participants must be diagnosed with N-IHF with previous angiographically or 
cardiac CTA documented no or non-significant coronary artery disease (less than 30% left main or <50% 
stenosis of any other major coronary artery and no clinical history of myocardial infarction). The screening 
evaluation will include obtaining written informed consent, collection of a complete medical history, including 
current and past medications, physical examination and laboratory tests. A quantitative echocardiogram ≤6 
months prior to evaluation is also required for assessment of LV function. If the subject’s LV ejection fraction 
(LVEF) is ≤40% determined by echocardiography in the past twelve months, the patient will be eligible for 
screening for the study.   
 
A baseline cardiac magnetic resonance imaging (MRI) scan will be obtained with delayed contrast 
enhancement to measure cardiac structure and function prior to study product infusion. A T2 image will also be 
obtained in all subjects to provide information about tissue edema, which in turn will provide information about 
whether ischemia has occurred over the past several days [to determine whether ischemia is in fact present—
which presumably would be on the basis small vessel disease]. A full 2D and Doppler transthoracic 
echocardiography with speckle tracking will be performed also prior to study product infusion.   
 
Eligible subjects will receive either a stem cell or placebo infusion based on randomization at the two clinical 
sites as approved by the sponsor. 
 
Follow-up visits will occur at days 30, 60 and 90.  At 90 days the two groups will change arms and the placebo 
group will receive the stem cell infusion also and the initially treated group will receive a LRS at a volume of 1 
mL/kg. All patients will be evaluated at 30, 60 and 90, days after this new infusion treatment. Information on 
adverse events, concomitant medications, vital signs, clinical laboratory tests and physical examination will be 
collected according to the schedule of assessments (Appendix A).  All concomitant guideline based medical 
care will continue as prescribed by the subject's personal physician(s). Use of other investigational agents or 
treatments is not allowed during this study. 
 
 
 
 
 
 
 
 


 
Protocol:   STEM-104-M-CHF                                                       7                                                                       19FEB2014 
STUDY ENDPOINTS 
 
PRIMARY ENDPOINT 
Safety 
Baseline and days 30, 60, and 90 post-initial infusion. After the crossover phase all patients will be evaluated 
at days 30, 60, and 90 days post the new infusion 
1. Procedural complications 
2. Vital signs 
a. Temperature 
b. Systolic blood pressure/diastolic blood pressure 
c. Heart rate 
d. Respiratory rate 
e. Weight 
3. Changes in heart failure medications  
4. Clinical arrhythmias, defibrillator firing and anti-tachycardia pacing 
5. Laboratory tests 
a. CBC/PLT/differential 
b. Chemistry-12, including liver function tests 
c. Creatinine kinase 
d. Troponin-I 
6. Electrocardiogram  
7. Composite of all-cause mortality all-cause admission and need for co-intervention. E.g. IV diuretics for 
worsening heart failure (RADIENCE trial criteria).  
 
Baseline and day 90 post stem cell infusion 
Pulmonary function test  
 
SECONDARY ENDPOINT 
Efficacy 
Change in LVEF from baseline to day 90 post initial infusion. After the crossover phase all patients will be 
evaluated for change from the new baseline (day 90 after the initial phase) to day 90 post new infusion.  
 
EXPLORATORY ENDPOINTS 
Changes between baseline and days 90 post-initial infusion. After the crossover phase all patients will be 
evaluated for changes from the new baseline (day 90 after the initial phase) to day 90 post new infusion.  
MRI 
1. Left ventricular end systolic volume index 
2. Wall motion segmental score  
3. LV end-systolic and end-diastolic dimensions 
4. T2 MRI imaging for tissue edema (an index of recent ischemia)  
 
Changes between baseline and days 90 post initial infusion. After the crossover phase all patients will be 
evaluated for changes from the new baseline (day 90 after the initial phase) to day 90 post new infusion.  
Echocardiogram 
1. Changes in LV mechanics by speckle-tracking echocardiography (longitudinal and circumferential strain 
and strain rate) 
2. Estimated systolic pulmonary artery pressures 
3. Changes in MR severity (most patients have mild to moderate MR)  
 
Changes between baseline and days 30, 60, and 90 post-initial infusion.  After the crossover phase all patients 
will be evaluated for changes from the new baseline (day 90 after the initial phase) to day 30 and 90 post new 
infusion   
Exercise capacity 
 
6 minute walk distance  


 
Protocol:   STEM-104-M-CHF                                                       8                                                                       19FEB2014 
 
Health status  
a. New York Heart Association Class (NYHA) class  
b. Kansas City Cardiomyopathy Questionnaire 
Heart failure status 
Clinical Congestion Score  
Biomarkers 
1. Brain natriuretic peptide, troponin 
2. Growth factors (FGF, VEGF)  
 
SUBJECT SELECTION 
Subjects will be selected using the following inclusion and exclusion criteria: 
 
INCLUSION CRITERIA 
1. Males and females ≥18 years of age 
2. LVEF ≤35% on echocardiogram within 6 months of randomization to undergo MRI 
3. Screening cardiac MRI at baseline with 
a. Ejection fraction ≤40% 
b. No evidence of hyper-enhancement 
4. Absent or non-obstructive coronary artery disease on x-ray angiography or coronary computed 
tomography within the past 3 years 
5. On standard therapy medical therapy (at the discretion of the investigator) including ACE-inhibitors, 
beta-blockers, and mineralocorticoid receptor antagonists, as tolerated, for at least 3 months  
6. NYHA class II-III symptoms 
7. Ability to understand and provide signed informed consent 
8. Reasonable expectation that patient will receive standard post-treatment care and attend all scheduled 
safety follow-up visits 
 
KEY EXCLUSION CRITERIA  
1. Pregnant or nursing women or those of childbearing age and not using an effective method of 
contraception  
2. History of stroke within 3 months 
3. Cardiac surgery within 3 months prior to randomization or the likelihood of a requirement for such 
procedures during the study period 
4. Current ICD or CRT or implantation planned with 6 months of infusion 
5. Presence of clinically significant, uncorrected valvular heart disease, hypertrophic or restrictive 
cardiomyopathy, active myocarditis, or uncontrolled hypertension 
6. History of cardiac arrest or life-threatening arrhythmias within 3 months  
7. Treatment with parenteral inotropic agents within 1 month of randomization 
8. Anticipated cardiac transplantation within 1 year 
9. Illness other than heart failure with life expectancy less than 1 year 
10. Received an experimental drug or device within 30 days of randomization 
11. Left ventricular assist device or implantation planned in the next 6 months  
12. Patients with complex congenital heart disease  
13. Uncontrolled seizure disorder 
14. Presence of immune deficiency 
15. Clinically significant hematologic, hepatic, or renal impairment as determined by screening clinical 
laboratory tests 
16. Presence of any other clinically-significant medical condition, psychiatric condition, or laboratory 
abnormality, that in the judgment of the investigator or sponsor for which participation in the study 
would pose a safety risk to the subject 
17. Inability to comply with the conditions of the protocol 
 


 
Protocol:   STEM-104-M-CHF                                                       9                                                                       19FEB2014 
18. Malignancy within the previous five years, except basal cell carcinoma, provided that it is neither 
infiltrating nor sclerosing, and carcinoma in situ of the cervix 
19. Active myocarditis or early postpartum cardiomyopathy (within six months). 
20. Systemic corticosteroids, cytostatics, immunosuppressive drug therapy (cyclophosphamide, 
methotrexate, cyclosporine, azathioprine, etc.), and DNA depleting or cytotoxic drugs taken within four 
weeks prior to study treatment 
21. Porphyria 
22. Allergy to sodium citrate or any “caine” type of local anesthetic 
23. Any contraindication for gadolinium use for MRI 
24. Patient scheduled for hospice care 
25. Clinically relevant abnormal findings in the clinical history, physical examination, ECG, or laboratory 
tests at the screening assessment that would interfere with the objectives of the study or would 
preclude safe completion of the study. Abnormal findings could include: known HIV infection or other 
immunodeficiency state, chronic active viral infection (such as hepatitis B or C), acute systemic 
infections (defined as patients undergoing treatment with antibiotics), gastrointestinal tract bleeding, or 
any severe or acute concomitant illness or injury 
26. Any other medical, social, or geographical factor that would make it unlikely that the patient could 
comply with study procedures (e.g., alcohol abuse, lack of permanent residence, severe depression, 
disorientation, distant location, or noncompliance) 
 
STUDY TREATMENT 
Study subjects will receive infusion at two study sites under the supervision of the site Principal Investigator or 
qualified co-investigator.  Study product administration will be performed 7 ± 3 days after randomization.   
 
Administration of Human Ischemia-Tolerant Allogeneic Mesenchymal Bone Marrow Cells (aMBMC)   
The study will enroll a minimum of 20 subjects and will consist of 2 cohorts.  Enrolled subjects will be 
randomized at 1:1 into an experimental group (n=10) or a placebo group (n=10).  Subjects in the experimental 
group will receive 1.5 million cells per kg and subjects in the placebo group will receive 1 mL/kg LRS. At 90 
days the placebo group will receive 1.5 million cells per kg and the initially treated group will receive 1 mL/kg 
LRS. 
 
Once the subject is randomized into one of the two cohorts, the final formulation of aMBMC or placebo will be 
prepared. Within 8 hours of infusion, the appropriate number of cells will be thawed at the study site pharmacy 
and re-suspended in LRS at a concentration of 1x106 cells/mL Subjects in placebo group will receive LRS at a 
volume of 1 mL/kg. The study solution (cells or placebo) will be labeled to indicate that it is an investigational 
agent and will contain subject’s information, date, and time of formulation. 
 
On the day of infusion, prior to study product administration, a skin test will be administered using 0.1 mL 
aliquot of the Final Formulation (Appendix C).   
 
An intravenous line will be placed into an appropriate vein on the upper extremity and 0.9% sodium chloride 
solution will be run to keep the vein open.  The study product will be drawn using an 18-gauge needle into a 60 
mL syringe with an eccentric (offset) tip.  The needle will be removed and infusion tubing will be attached to the 
syringe.  The syringe with infusion tubing will be placed in a metered dose syringe pump positioned horizontally 
with the syringe rotated such that the syringe tip is at the lowest position.  The product will be infused 
intravenously into the subject’s arm at a constant rate of approximately 2 mL/min.  The applicable volume for 
the target dose will be delivered within  2mL.  Depending on subject’s weight, up to three 60 ml syringes of 
product may be infused.  After the entire product volume is delivered, 25mL of LRS (without cells) will be 
infused at 2ml/min to deliver cells from the infusion line for more accurate dosing.  Subjects in the placebo 
group will receive intravenous LRS.  Their syringes will be labeled as above to preserve blinding and followed 
by 25 ml of LRS infusion as above.   
If the subject has an adverse reaction during the infusion, the infusion may be interrupted or slowed according 
to the severity of the reaction.  


 
Protocol:   STEM-104-M-CHF                                                       10                                                                       19FEB2014 
 
 
 All appropriate treatment will be given to reduce any discomfort and ensure the subject's safety.  The infusion 
may be restarted, if interrupted, if the subject is not considered to be at risk by the Investigator and the subject 
consents.  
 
All subjects will receive the follow-up tests and evaluations as per Appendix A. 
 
CONCOMITANT THERAPY AND CLINICAL PRACTICE 
Subjects will continue all of their regular medications unless contraindicated. Subjects may be administered 
beta-blockers, ACE inhibitors or angiotensin receptors blockers, mineralocorticoid receptor antagonists, statin 
agents, or other medications, as tolerated.  
 
STATISTICAL METHODS 
All randomized subjects who receive at least part of a dose of aMBMC or LRS will be included in the safety 
analysis.  Subject safety data will be analyzed by actual dose level (i.e., number of cells/kg).  Adverse events 
will be coded according to the MedDRA adverse event dictionary.  The results will be tabulated to examine 
their frequency, affected organ systems, severity and relationship to study stem cell administration.  The 
results of laboratory tests will be similarly evaluated.  The efficacy analyses will include subjects that received 
the full dose of aMBMC or LRS and have the appropriate follow-up completed at the scheduled assessments 
(i.e., efficacy evaluable population).  Safety measures include the composite of all-cause mortality, admission 
for worsening HF and all-cause admissions.  Measurement of left ventricle end diastolic volume, left ventricle 
end systolic volume, left ventricular ejection fraction (LVEF), longitudinal strain and strain rate, global and 
segmental strain and strain rate, exercise capacity by 6 minute walk distance test, biomarkers, Kansas City 
Cardiomyopathy Questionnaire (KCCQ) and the New York Heart Association (NYHA) Classification will be 
completed in the entire efficacy evaluable population.  A formal statistical analysis plan will be completed 
before the end of the study and used for the final analysis of study data. This study will be conducted in 
accordance with the guidelines of Good Clinical Practice (GCP), including the archiving of essential 
documents.


 
Protocol:   STEM-104-M-CHF                                                       11                                                                       19FEB2014 
ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AHA 
American Heart Association 
ALT 
Alanine amino transferase 
AST 
Aspartate amino transferase 
BMMNC 
Bone marrow mononuclear cells 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CK 
Creatine kinase 
CRF 
Case report form 
CRP 
C-reactive protein 
CVD 
Cardiovascular disease 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FGF 
Fibroblast growth factor 
GCP 
Good Clinical Practice 
HF 
Heart failure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LFT 
Liver function test 
LVEF 
Left ventricular ejection fraction 
MACE 
Major adverse cardiac events 
aMBMC 
Allogeneic mesenchymal bone marrow cells 
MedDRA 
Medical Directory for Regulatory Activities 
N-IHF 
Non-ischemic heart failure 
NTproBNP 
N-Terminal Prohormone of Brain Natriutic Peptide 
NYHA 
New York Heart Association Classification 
SAE 
Serious adverse event 
SDF-1 
Stromal derived factor 1 
STEMI 
ST segment elevation myocardial infarction 
VEGF 
Vascular Endothelial Growth Factor 


 
Protocol:   STEM-104-M-CHF                                                       12                                                                       19FEB2014 
BACKGROUND 
1.1 
Non-Ischemic Heart Failure  
Heart failure (HF) is a major cause of morbidity and mortality worldwide, affecting in the United States more 
than 5.1 million people.1  Projections show that by 2030, the prevalence of HF will increase 25% from 2013 
estimates.2  The lifetime risk of developing HF is 20% for Americans ≥40 years of age.3  In the United States, 
HF incidence has largely remained stable over the past several decades, with >650,000 new HF cases 
diagnosed annually.1, 4  HF incidence increases with age, rising from approximately 20 per 1,000 individuals 65 
to 69 years of age to >80 per 1,000 individuals among those >85 years of age.4  In 2009, HF as an underline 
cause of mortality was 56,410.1  
 
Non-ischemic cardiomyopathy is defined as disease of the myocardium associated with mechanical or 
electrical dysfunction exhibiting inappropriate ventricular hypertrophy or dilatation. There are numerous causes 
leading to non-ischemic cardiomyopathy. Non-ischemic cardiomyopathy may be either primary or secondary to 
systemic diseases. In this study we will evaluate patients with dilated cardiomyopathy, which is a primary 
mixed disease, who have heart failure symptoms. Prevalence of non-ischemic HF (N-IHF),5-7 in large-scale 
therapeutic trials the proportion of patients with N-IHF ranged from 18% to 53%.8-14 There is a relation between 
sex, age and etiology of HF; non-ischemic cardiomyopathy is more frequent in women and in younger 
individuals. The prognosis for HF is poor, with an overall mortality of 50% within 4 years, and a 1-year mortality 
of 50% in patients with severe HF.1  Although the prognosis of N-IHF was shown to be better than that in IHF, 
mortality is high in N-IHF reported from 23% in 1 year, 48% in 2 years and 60% in 5 years.7, 15 Although there 
has been some progress in the past decades in the treatment of HF by using pharmacological therapy, surgery 
and device-based therapy,16 current interventional and pharmacological therapies for HF have limits and the 
need for a more efficient regenerative therapeutic strategy is urgent. This treatment could delay disease 
progression and reduce mortality and morbidity by helping injured myocardium recovery and/or facilitating 
cardiac repairing and regeneration. 
 
1.2 
Bone Marrow Mononuclear Cells (BMMNC) for N-IHF  
To date, limited number of randomized controlled trials has investigated intracoronary or intracardiac infusion 
of BMMNCs in patients with N-IHF.17-19 The First-in-Man ABCD (Autologous Bone Marrow Cells in Dilated 
Cardiomyopathy) Trial was a prospective, randomized, open, and parallel 2-arm study in a stable HF 
population with a history of dilated cardiomyopathy.17 In this study autologous bone marrow–derived stem cells 
were used which were administered intracoronary. This study showed a significant improvement in the left 
ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) Functional Classification.17 The 
Transplantation of Progenitor Cells and Functional Regeneration Enhancement Pilot Trial in Patients with 
Nonischemic Dilated Cardiomyopathy (TOPCARE-DCM) was a prospective, open-label study testing the 
efficacy of selective intracoronary infusion of BMMNC on LV function.18 This study showed that intracoronary 
administration of bone marrow–derived progenitor cells seems to be associated with improvements in cardiac 
contractile and microvascular function.18 The results of the first randomized, double blind, placebo-controlled 
trial worldwide investigating the role of G-CSF and BMMNC for cardiac function improvement are expected.19  
 
2 
MESENCHYMAL STEM CELLS 
Mesenchymal stem cells (MSCs), also known as marrow stromal cells, represent 0.001%–0.01% of all 
nucleated bone marrow cells.20-21  They are self-renewing, multipotent progenitor cells with the capacity to 
differentiate into several distinct mesenchymal lineages including osteoblasts, chondrocytes, adipocytes, 
endothelial cells, vascular smooth muscle cells, and cardiomyocytes.20, 22,23  Although MSCs were initially 
identified in the bone marrow, they have been isolated from a number of tissues including muscle, adipose and 
connective tissues.24-27  Human MSCs have been defined as cells that (1) are plastic-adherent, (2) express 
CD105, CD73 and CD90, and lack expression of CD45CD34, CD14 or CD11b, CD79a or CD19 and HLA-DR 
surface molecules, and (3) differentiate to osteoblasts, adipocytes and chondroblasts in vitro.28-29, 30  Even after 
expansion in vitro, mesenchymal differentiation potential of MSCs is retained.31, 32  
 
2.1 
Mechanisms of Action of MSCs 
Although there is in vitro and preclinical evidence that MSCs differentiate into cardiomyocyte-like cells with 
sarcomeric organization when injected into the adult myocardium, it appears that a low percentage of cells 


 
Protocol:   STEM-104-M-CHF                                                       13                                                                       19FEB2014 
engraft, independently of cell source, dose, and route of delivery.  In ischemic settings and on appropriate 
growth factor and/or cytokine stimulation, MSCs readily acquire an endothelial cell phenotype in vitro, form 
capillary-like networks in extracellular matrix gels, express and secrete proangiogenic growth factors, and 
increase blood vessel growth in vivo.44-49  MSCs also participate in the formation of the vessel media by 
differentiating into smooth muscle cells and fibroblasts, and the vascular tree is a predominant reservoir for 
tissue-specific MSCs that express CD146, NG2, and PDGFRB (platelet-derived growth factor receptor, β 
polypeptide) but no hematopoietic, endothelial, or myogenic markers.33-35  MSCs delay scar formation due to 
connective tissue remodeling indicating that they may directly interact with extracellular matrix components.36, 
37   
 
MSCs secrete a wide spectrum of growth and other paracrine factors including vascular endothelial growth 
factor (VEGF), HGF, insulin-like growth factor (IGF)-1, TGF-β, basic fibroblast growth factor (bFGF), leukemia 
inhibitory factor (LIF), stromal-derived factor (SDF)-1, angiopoietin, interleukins, numerous chemoattractants, 
and “survival factors” that exert antiapoptotic effects.55-58  Their secretion profile is importantly influenced by the 
inflammatory milieu, hypoxia, and mechanical stress.38-40  These paracrine actions may be sufficient to 
enhance repair and regeneration even in remote tissues.41, 42  Evidence suggests that secreted phospholipid 
particles (exosomes) rather than or in addition to cytokine proteins mediate MSC cardioprotection.43  In the in 
vivo setting, reduced numbers of apoptotic cells are found in the vicinity of transplanted MSCs that may explain 
the reduction in infarct size despite absence of formation of new cardiomyocytes.44 
 
MSCs also reduce myocardial fibrosis and thereby attenuate LV dilatation by modulating the expression of 
extracellular matrix proteins and matrix metalloproteinases.45  They secrete antiapoptotic and antifibrotic 
factors including hepatocyte growth factor and adrenomedullin.  Indeed, MSC-conditioned medium decreases 
type I and III collagen expression, attenuates proliferation of fibroblasts, and upregulates expression of elastin, 
resulting in reduction of myocardial fibrosis and favorable changes in remodeling.46, 47 MSCs increased 
proliferation of endogenous CSCs, enhanced lineage commitment of the CSCs, and reconstitution of niche-like 
structures.  Importantly, cardiac MRI documented a reduction of infarct size as early as 4 days after cell 
injection, which was progressive over 8 weeks. 47 
 
2.2 
Preclinical Experience with MSCs for Heart Disease 
MSC transplantation using either autologous or allogeneic cells in animal models leads to reduction of 
ischemia, reduced apoptosis, and increased angio- and arteriogenesis in ischemic tissue, leading to improved 
tissue vascularization and function.  Successful delivery strategies include intravenous, intramyocardial, and 
intracoronary administration22, 28, 48-52 not only in ischemic but models of non-ischemic cardiomyopathy.50, 53  
 
Intravenous injection of 3 and 10 million allogeneic porcine MSCs/kg at the onset of reperfusion in a closed-
chest pig model of acute MI increased vascular density, hyperemic infarct region blood flow, and LV contractile 
function evaluated by pressure–volume indices after 12 weeks compared to the controls.28  The functional and 
vascular density data suggest that the 1 million MSCs/kg dose may represent the lowest effective dose for 
protection.  In another study, apical infarction in swine was created and bone marrow derived MSCs injected 
intravenously 30 min post-reperfusion. At 3 months, treated animals had higher LVEF and less wall thickening 
of non-infarcted myocardium compared to controls.54 Similarly, Kocher et al. reported an increase in 
microvascularity in the rat infarct model with intravenous injection of human endothelial progenitors.55  In a 
porcine model of occlusion-reperfusion, LV function measured by MRI 8 weeks after MI was better in hearts 
receiving MSCs by intramyocardial injection 3 days after infarction.48, 56 Others reported improved LV function 
in the absence of observable MSCs one month after transplantation.49   
 
In contrast to administration of stem cells by direct myocardial injection or intracoronary administration, 
intravenous delivery results in entrapment of cells mainly in the lungs during initial distribution reducing 
recruitment to the site of infarction. Intravenous infusion resulted in a lower efficiency of cell uptake compared 
to direct intramyocardial injection.57  However, a recent comparative study with intracoronary or intravenous 
injection of BMMNCs found accumulation of cells in the infarcted myocardium although more cells accumulate 
after intracoronary than after intravenous injection.58  It is therefore likely that paracrine release by MSCs of 
growth factors and cytokines is largely responsible for their therapeutic effect after intravenous administration.   


 
Protocol:   STEM-104-M-CHF                                                       14                                                                       19FEB2014 
 
2.3 
Allogeneic versus Autologous MSCs  
Bone marrow-derived MSCs are to some extent immunoprivileged, and allogeneic MSCs may escape 
elimination by the host immune system because they do not express MHC class II receptors and only low 
levels of MHC class I receptors.48, 59  As with endothelial progenitor cells, MSCs are subject to age- and 
disease-related changes, decreasing in number in the bone marrow with age.60, 61 Although terminal 
differentiation is preserved in older MSCs,62 it is lower when compared to younger cells.86-88  The gene 
expression profile of aging MSCs shows increased abundance of differentiation- and growth arrest-related 
transcripts and downregulation of transcripts involved in RNA processing.63  Moreover, these MSCs did not 
improve cardiac function.64  These findings support the concept that allogeneic MSCs from young donors may 
have greater regenerative capacity than autologous cells from older subjects with CAD.   
 
2.4 
Modifying MSCs for Cardiac Regeneration  
Overexpression of antiapoptotic proteins and growth factors, and inhibition of MSC differentiation by blocking 
Wnt and BMP signaling pathways, have proven powerful strategies to enhance the cardiac regeneration 
capacity of MSCs, but their clinical application remains problematic at present.44, 65-68  Experimentally, several 
modifications in MSCs have resulted in their enhanced functionality.  Among these strategies are MSCs 
enriched for Stro-1 expression, treatment with heat shock proteins, preconditioning by oxidative stress, 
diazoxide-mediated NF-κB activation, and nitric oxide donors, hyperbaric oxygenation of the recipient heart, 
adjunct pharmacologic therapy with statins and estradiol, sildenafil, and oxytocin.94-69  Mechanical pre-
stimulation by microbubbles and embedding MSCs in extracellular matrix components or artificial polymer 
scaffolds  may facilitate cell retention.53, 103-107 One strategy that is ready for clinical translation is use of 
enhanced MSCs grown in hypoxic culture conditions.70 
 
2.5 
Potentiation of MSCs with Hypoxic Culture 
It is well known that stem cells reside in defined microenvironmental niches and that oxygen conditions 
critically regulate cellular responses.  For example, oxygen tension in human bone marrow is ~3.0%.  Hypoxic 
culture conditions can maintain MSCs in an undifferentiated state that favors stem cell self-renewal.  It 
enhances expression of genes involved in developing mesodermal and non-mesodermal cell lines, increases 
multipotency and transdifferentiation, increases the half- life of VEGF mRNA significantly (6-8h in low oxygen 
conditions compared to 30-40 min. in normoxia), and decreases transversions from oxidative damage.109-110  
 
2.6 
Potency of MSCs Cultured in a Hypoxic Environment   
Stemedica has obtained a patent for culture of human donor MSCs in hypoxic conditions (ischemia-tolerant 
MSCs, itMSCs).  The biological potency of these cells has been studied in vitro experiments compared to 
MSCs cultured in normoxic conditions.  itMSCs formed more colonies in culture assays, had a greater 
proliferation rate,  produced greater quantities of VEGF, SDF-1, HIF-1alpha, and angiopoeitin 1.  itMSCs also 
demonstrated greater migratory capacity in response to chemokines and cytokines, and formed more gap 
junctions than normoxic MSCs.  In summary,  itMSCs compared to those grown in normoxic conditions have 
(1) a higher proliferation rate, (2) higher clonogenicity as determined by colony forming unit assay, (3) 
increased production of cytokines participating in homing of host stem cells to the site of injury (SDF-1) and in 
neovascularization (VEGF), (4) higher resistance to factors adversely affecting performance of MSC at the site 
of injury such as tumor necrosis factor, (5) higher expression of connexins, proteins involved in cell 
communication via gap junctions, (6) accelerated and enhanced differentiation into certain types of tissues 
such as cartilage, and (7) increased migration towards the factors produced at the ischemic site such as 
Hepatocyte Growth Factor.  These properties of itMSCs likely increase their ability to migrate to ischemic 
tissues, enhance angiogenesis and arteriogenesis through paracrine effects, inhibit apoptosis, and mobilize 
host progenitors to promote tissue regeneration. 
 
In vivo bio-distribution studies after intravenous injection in a rat model of ischemic stroke demonstrate a 
greater retention of human itMSC cells in stroke animals as compared to controls.  With radiolabelled cells, it 
was clear that most of the itMSCs reside in lungs after 1 hour of intravenous injection, but a greater number 
are present in stroke animals compared to controls.  After 24 hrs, the majority of itMSCs were found in the 
kidneys and liver, but were also greater in stroke animals compared to controls.  After 72 hours, very little 


 
Protocol:   STEM-104-M-CHF                                                       15                                                                       19FEB2014 
activity was detected in control animals, while there was significant activity detected in the liver and spleen of 
stroke animals.  Very little activity in either group was noted after 5 days.   
 
2.7 
Clinical Experience with Stemedica itMSCs   
Two clinical studies are currently ongoing using cells prepared at Stemedica’s cGMP manufacturing facility. 
The first study targets ischemic stroke and is being conducted at the University of California, San Diego 
(UCSD), and at Mercy Gilbert Medical Center in Gilbert, Arizona using Stemedica’s specially formulated 
ischemic adult allogeneic mesenchymal stem cells under US IND 14328.  Stemedica completed the Phase I 
enrollment and treatment of 15 patients. All safety data were provided to DSMB for review. Only one mild event 
was possibly related to the study product. There were no clinically significant abnormalities reported on any 
post-administration scans or on post-administration physical examinations.  In the second study “Intravenous 
Administration of Ischemic Tolerant Allogeneic Mesenchymal Stem Cells for Acute Coronary Syndrome 
Patients,” Stemedica Cell Technologies, Inc. provided cGMP allogeneic itMSCs to the National Scientific 
Medical Center (NSMC) in Astana, Kazakhstan to conduct a clinical study in patients with STEMI, Principal 
Investigators: Professors A.U. Djolbasbekova, MD, PhD and Daniyar Jumaniyazov, MD, PhD .  itMSCs were 
provided under 21 CFR §312.110 (4)(b) regulations and the study was conducted in compliance with the ICH-
E6 (Good Clinical Practice) guidelines and all subjects provided signed informed consent. Nineteen subjects in 
the itMSC group received intravenously. There were no deaths and no SAEs reported to be related to the 
study drug.  In 19 itMSC treated and 15 open control patients, i.v. injection of 45-50 million cells 7 days after 
stenting for STEMI was administered without any SAEs reported.  LVEF improved significantly from 42.1% to 
52.3% and 54.7% after 3 and 6 months, respectively.  In contrast there was no improvement in LVEF in the 
control group; LVEF 42.3%, 42.8% and 46.1%, at baseline, 3 and 6 months respectively.   Similar changes in 
end-systolic and end-diastolic volumes were noted.  There was also an increase reported in circulating levels 
of growth factors (VEGF and FGF) in the itMSC treated group, and CRP and BNP levels were lower in the 
treated group compared to controls during follow-up.  
 
2.8 
Clinical Trials with MSCs in Heart Disease  
A few studies using either allogeneic or autologous MSCs employing different delivery strategies have been 
performed in subjects with a variety of cardiac diseases including HF, STEMI, and chronic ischemia.   
 
2.8.1 STEMI Trials with MSCs   
In 3 studies where autologous bone marrow-derived MSCs were injected i.c. into the infarct artery of patients 
with STEMI, there were no serious adverse events reported, and regional and global LV function improved. 
Intracoronary infusion of bone-marrow-derived MSCs in 69 patients with STEMI showed improvement in 
perfusion defects at 3 months after the therapy with improvement of LVEF and LV chamber size.71  In 11 
patients with STEMI treated with a combination of autologous bone marrow MSCs and endothelial progenitor 
cells, LV function and perfusion were better in MSC-treated patients and there was a reduction in malignant 
arrhythmia that indicated a reduced arrhythmogenic potential.72, 73   
 
An allogeneic MSC product (Prochymal by Osiris Therapeutics, Columbia, MD) was administered 
intravenously in 53 patients with STEMI using a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 
million cells/kg) design.74  This demonstrated that intravenous infusion of hMSCs was safe, ventricular 
tachycardia episodes were lowered, and pulmonary function improved (forced expiratory volume) compared to 
placebo. Global symptom score in all patients and LVEF in the subset of anterior MI patients were both 
significantly better in hMSCs versus placebo subjects.  In the cardiac MRI substudy, hMSC treatment 
increased LVEF and led to reverse remodeling.74 
 
 
2.8.2 MSC Trials in Heart Failure and Chronic Ischemia  
In a randomized trial in patients with severe chronic ischemic cardiomyopathy, MSC-treated patients had 
significantly improved LVEF, exercise capacity, and change of New York Heart Association (NYHA) class.75 
The POSEIDON trial studied patients with ischemic cardiomyopathy and compared autologous and allogeneic 
MSCs administered transendocardially via injection catheters.76  Thirty patients were randomly assigned to 1of 
6 permutations of cell origin (self or donor) and dosage (n=5 patients each), and the safety and efficacy of self-


 
Protocol:   STEM-104-M-CHF                                                       16                                                                       19FEB2014 
derived MSCs with allogeneic MSCs was studied.  Twenty million, 100 million, or 200 million cells were 
delivered by transendocardial injection into 10 LV sites.  Relative to baseline, autologous but not allogeneic 
MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither 
improved exercise VO2 max.  Low-dose concentration MSCs (20 million cells) produced greatest reductions in 
LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune 
reactions.76 
 
2.9 
Rationale for Study Design 
Allogeneic MSCs are excellent for consideration for cell therapy in patients with IHF for the following reasons: 
(a) Human MSCs are accessible and their isolation and expansion to clinical scale in a relatively short 
period of time is feasible32, 77  
(b) Patients are spared the discomfort of harvesting procedures  
(c) Early therapy is feasible without the delay imposed by autologous cell cultures   
(d) MSCs can be biopreserved with minimal loss of potency and stored for point-of-care delivery78, 79  
(e) Human trials of MSCs thus far have shown no adverse reactions to allogeneic versus autologous 
MSC transplants, enabling creation of an inventory of third-party donor MSCs to widen the number of 
patients treated by a single isolation80-82  
(f) MSC transplantation is considered safe and has been tested in Phase I clinical trials of cardiovascular, 
neurological, and immunological disease with encouraging results123-128  
(g) Preliminary Phase I studies with Stemedica itMSCs administered in patients with ischemic stroke and 
STEMI has proven to be safe and associated with some improvement in clinical outcomes. 
 
3 
OBJECTIVES 
3.1 
Primary Objective 
To assess the safety of human allogeneic mesenchymal bone marrow cells (aMBMC) administered 
intravenously to subjects with N-IHF. 
 
3.2 
Secondary Objective 
To assess the effects of intravenously delivered human aMBMC on (a) left ventricular (LV) structure and 
function, and (b) clinical status of subjects with N-IHF. 
 
4 
STUDY DESIGN 
4.1 
Description of the Study  
This is a Phase IIa, single-blind, placebo-controlled, crossover, multi-center, randomized study in subjects with 
N-IHF.  Within 3 ±2 days all study participants who meet the eligibility criteria will receive the treatment.   
 
The study will enroll a minimum of 20 subjects and will consist of 2 cohorts.  Enrolled subjects will be 
randomized at 1:1 into an experimental group (n=10), or a placebo group (n=10). Subjects in the experimental 
group will receive 1.5 million cells per kg and subjects in the placebo group will receive 1 mL/kg LRS. At 90 
days the two groups will change arms and the placebo group will receive 1.5 million cells per kg and the initially 
treated group will receive a Lactated Ringer’s Solution (LRS) at a volume of 1 mL/kg . 
 
After discharge, subjects will have safety evaluations per Appendix A. Adverse events, concomitant 
medications, and assessments will be recorded at each follow-up visit.  Complete examinations will be used to 
assess disability and functional status at baseline (prior to treatment), and at the visits scheduled at 30, 60, and 
90, after the initial administration. The same process will be followed at visits scheduled at 30, 60, and 90 days 
after the new administration (crossover phase).  A baseline magnetic resonance imaging (MRI) with delayed 
contrast enhancement and T2 imaging, as well as a full 2D and Doppler transthoracic echocardiography with 
speckle-tracking will be performed at baseline and at specific time points during follow-up.  All performed MRIs 
will be assessed in a blinded core lab. 
 
Subjects will continue all of their regular medications unless contraindicated. Subjects may be administered 
beta-blockers, ACE inhibitors or angiotensin receptors blockers, mineralocorticoid receptor antagonists, statin 
agents, or other medications, as tolerated. 


 
Protocol:   STEM-104-M-CHF                                                       17                                                                       19FEB2014 
 
4.2 
Endpoints  
PRIMARY ENDPOINT 
Safety 
Baseline and days 30, 60, and 90 post-initial infusion. After the crossover phase all patients will be evaluated 
at days 30, 60, and 90 days post the new infusion  
8. Procedural complications 
9. Vital signs 
a. Temperature 
b. Systolic blood pressure/diastolic blood pressure 
c. Heart rate 
d. Respiratory rate 
e. Weight 
10. Changes in heart failure medications  
11. Clinical arrhythmias, defibrillator firing and anti-tachycardia pacing 
12. Laboratory tests 
a. CBC/PLT/differential 
b. Chemistry-12, including liver function tests 
c. Creatinine kinase 
d. Troponin-I 
13. Electrocardiogram  
14. Composite of all-cause mortality all-cause admission and need for co-intervention. E.g. IV diuretics for 
worsening heart failure (RADIENCE trial criteria).  
 
Baseline and day-90 post infusion 
Pulmonary function test  
 
SECONDARY ENDPOINT 
Efficacy 
Change in LVEF from baseline to day 90 post-initial infusion. After the crossover phase all patients will be 
evaluated for change from the new baseline (day 90 after the initial phase) to day 90 post new infusion  
 
EXPLORATORY ENDPOINTS 
Changes between baseline and days 90 post–initial infusion. After the crossover phase all patients will be 
evaluated for changes from the new baseline (day 90 after the initial phase) to day 90 post new infusion.  
MRI 
5. Left ventricular end systolic volume index 
6. Wall motion segmental score  
7. LV end-systolic and end-diastolic dimensions 
8. T2 MRI imaging  
 
Changes between baseline and days 90 post-initial infusion. After the crossover phase all patients will be 
evaluated for changes from the new baseline (day 90 after the initial phase) to day 90 post new infusion. 
Echocardiogram 
4. Changes in LV mechanics by speckle-tracking echocardiography (longitudinal and circumferential strain 
and strain rate) 
5. Estimated systolic pulmonary artery pressures 
6. Changes in MR severity (most patients have mild to moderate MR).  
 
Changes between baseline and days 30, 60, and 90 post-initial infusion. After the crossover phase all patients 
will be evaluated for changes from the new baseline (day 90 after the initial phase) to day 30 and 90 post new 
infusion. 
Exercise capacity 
 
6 minute walk distance  


 
Protocol:   STEM-104-M-CHF                                                       18                                                                       19FEB2014 
Health status  
a. New York Heart Association Class (NYHA) class  
b. Kansas City Cardiomyopathy Questionnaire 
Heart failure status 
Clinical Congestion Score  
Biomarkers 
3. Brain natriuretic peptide, troponin 
4. Growth factors (FGF, VEGF)  
  
4.3 
Safety Plan 
The safety of subjects will be carefully monitored and reviewed by an independent Data and Safety Monitoring 
Board (DSMB).   
 
4.4 
 Compliance with Laws and Regulations 
This study will be conducted in accordance with the International Conference on Harmonisation (ICH) E6 
Guideline for Good Clinical Practice (GCP), the Declaration of Helsinki (October 1996) and applicable local, 
state, and federal laws, as well as other applicable country laws. 
 
5 
STUDY ENROLLMENT 
Subjects will participate in this study for 180 days as follows: up to 3±2 days after screening, followed by 
aMBMC or placebo (LRS) administration, follow-up, crossover phase and follow-up.  
 
5.1 
Subject Selection 
The study will enroll a minimum of 20 subjects and will consist of 2 cohorts.  Enrolled subjects will be 
randomized at 1:1 into an experimental group (n=10) or a placebo group (n=10).  Subjects in the experimental 
group will receive 1.5 million cells per kg and subjects in the placebo group will receive 1 mL/kg Lactated 
Ringer’s Solution. At 90 days the two groups will change arms and the placebo group will receive the stem cell 
infusion also and the initially treated group will receive a LRS at a volume of 1 mL/kg. 
 
Eligibility will be determined by the inclusion and exclusion criteria listed below. 
 
INCLUSION CRITERIA 
1. Males and females ≥18 years of age 
2. LVEF ≤35% on echocardiogram within 6 months of randomization to undergo MRI 
3. Screening cardiac MRI at baseline with 
a. Ejection fraction ≤40% 
b.  No evidence of hyper-enhancement 
4. Absent or non-obstructive coronary artery disease on x-ray angiography or coronary computed 
tomography within the past 3 years 
5. On standard therapy medical therapy (at the discretion of the investigator) including ACE-inhibitors, 
beta-blockers, and mineralocorticoid receptor antagonists, as tolerated, for at least 3 months  
6.  
7. NYHA class II-III symptoms 
8. Ability to understand and provide signed informed consent 
9. Reasonable expectation that patient will receive standard post-treatment care and attend all scheduled 
safety follow-up visits 
 
KEY EXCLUSION CRITERIA  
1. Pregnant or nursing women or those of childbearing age and not using an effective method of 
contraception.  
2. Acute myocardial infarction, acute coronary syndrome, or stroke within 3 months 
3. Cardiac surgery within 3 months prior to randomization or the likelihood of a requirement for such 
procedures during the study period 
4. Current ICD or CRT or implantation planned with 6 months of infusion 


 
Protocol:   STEM-104-M-CHF                                                       19                                                                       19FEB2014 
5. Presence of clinically significant, uncorrected valvular heart disease, hypertrophic or restrictive 
cardiomyopathy, active myocarditis, or uncontrolled hypertension 
6. History of cardiac arrest or life-threatening arrhythmias within 3 months  
7. Treatment with parenteral inotropic agents within 1 month of randomization 
8. Anticipated cardiac transplantation within 1 year 
9. Illness other than heart failure with life expectancy less than 1 year 
10. Received an experimental drug or device within 30 days of randomization 
11. Left ventricular assist device or implantation planned in the next 6 months  
12. Patients with complex congenital heart disease  
13. Uncontrolled seizure disorder. 
14. Presence of immune deficiency. 
15. Clinically significant hematologic, hepatic, or renal impairment as determined by screening clinical 
laboratory tests 
16. Presence of any other clinically-significant medical condition, psychiatric condition, or laboratory 
abnormality, that in the judgment of the investigator or sponsor for which participation in the study 
would pose a safety risk to the subject 
17. Inability to comply with the conditions of the protocol. 
18. Malignancy within the previous five years, except basal cell carcinoma, provided that it is neither 
infiltrating nor sclerosing, and carcinoma in situ of the cervix. 
19. Active myocarditis or early postpartum cardiomyopathy (within six months). 
20. Systemic corticosteroids, cytostatics, immunosuppressive drug therapy (cyclophosphamide, 
methotrexate, cyclosporine, azathioprine, etc.), and DNA depleting or cytotoxic drugs taken within four 
weeks prior to study treatment. 
21. Porphyria. 
22. Allergy to sodium citrate or any “caine” type of local anesthetic. 
23. Any contraindication for gadolinium use for MRI 
24. Patient scheduled for hospice care. 
25. Clinically relevant abnormal findings in the clinical history, physical examination, ECG, or laboratory 
tests at the screening assessment that would interfere with the objectives of the study or would 
preclude safe completion of the study. Abnormal findings could include: known HIV infection or other 
immunodeficiency state, chronic active viral infection (such as hepatitis B or C), acute systemic 
infections (defined as patients undergoing treatment with antibiotics), gastrointestinal tract bleeding, or 
any severe or acute concomitant illness or injury. 
26. Any other medical, social, or geographical factor that would make it unlikely that the patient could 
comply with study procedures (e.g., alcohol abuse, lack of permanent residence, severe depression, 
disorientation, distant location, or noncompliance) 
 
5.2 
Method of Treatment Assignment and Blinding 
This study is a Phase IIa, single-blind, placebo-controlled, crossover, two-site, randomized trial with blinded 
endpoints comprised of 20 subjects with an experimental groups (n=10 in each group) and a placebo group 
(n=15).  At 90 days the two groups will change arms and the placebo group will receive the stem cell infusion 
also and the initially treated group will receive a LRS at a volume of 1 mL/kg. 
 
5.3 
Subject Discontinuation and Withdrawal 
Subjects may voluntarily withdraw from the study at any time. In the event of early withdrawal, the reason for 
withdrawal will be recorded on the appropriate CRF.  Attempts to complete early termination exam as defined 
in 7.4 will be made. The Investigator has the right to discontinue a subject from the study for any medical 
reason that the investigator determines may jeopardize the subject’s safety if he or she continues in the study, 
or for reasons of noncompliance (e.g., missed visits, use of other investigational drugs, etc.). Each site 
Investigator may enroll up to 3 additional subjects to each group to offset subjects that are withdrawn or 
terminated. 
 


 
Protocol:   STEM-104-M-CHF                                                       20                                                                       19FEB2014 
5.4 
Study Termination 
The Sponsor has the right to terminate the study at any time.  Reasons for terminating the study may include, 
but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a potential health hazard to 
subjects. 
 
Subject enrollment is unsatisfactory. 
 
Data recording is inaccurate or incomplete. 
 
6 
INVESTIGATIONAL PRODUCT 
6.1 
Formulation, Packaging, Preparation, Randomization of aMBMC or Placebo 
The study will enroll a minimum of 20 subjects and will consist of 2 cohorts.  Enrolled subjects will be 
randomized at 1:1 into an experimental group (n=15) or a placebo group (n=15).  Subjects in the experimental 
group will receive 1.5 million cells per kg and subjects in the placebo group will receive 1 mL/kg Lactated 
Ringer’s Solution. 
Once the subject is randomized into one of the two cohorts, the cells or placebo will be prepared. Within 8 
hours of infusion, the appropriate number of cells will be thawed at the study site pharmacy and re-suspended 
in Lactated Ringer’s Solution (LRS) at a concentration of 1x106 cells/mL Subjects in placebo group will receive 
LRS at a volume of 1 mL/kg. The study solution (cells or placebo) will be labeled to indicate that it is an 
investigational agent and will contain a subject’s information, date, and time of formulation. 
 
After discharge, subjects will have safety and efficacy evaluations as per Appendix A.   
 
6.2 
IV Administration of aMBMC or Placebo 
On the day of infusion, prior to study product administration, a skin test will be administered using 0.1 mL 
aliquot of the Final Formulation (Appendix C). 
 
An intravenous line will be placed into an appropriate vein on the upper extremity or hand with 0.9% sodium 
chloride solution running to keep the vein open. The study solution described above will be taken up in an 18-
gauge needle into a 60 mL syringe with an eccentric (offset) tip.  The needle will be removed and infusion 
tubing will be attached to the syringe.  The syringe with infusion tubing will be placed in a metered dose syringe 
pump positioned horizontally with the syringe rotated such that the syringe tip is at the lowest position.  The 
product will be infused intravenously into the subject’s arm at a constant rate of approximately 2 mL/min.  The 
applicable volume for the target dose will be delivered within  2 mL. Depending on subject’s weight, up to 
three 60 mL syringes of product may be infused.  After the entire product volume is delivered, 25 mL of LRS 
(without cells) will be infused at 2 mL/min to deliver cells from the infusion line for more accurate dosing.  
Subjects in the placebo group will receive intravenous LRS.  Their syringes will be labeled as above to 
preserve blinding and followed by 25 mL of LRS infusion as above. 
 
If the subject has an adverse reaction during the infusion, the infusion may be interrupted or slowed according 
to the severity of the reaction.  All appropriate treatment will be given to reduce any discomfort and ensure the 
subject's safety.  The infusion may be restarted, if interrupted, if the subject is not considered to be at risk by 
the Investigator and the subject consents.   
 
All subjects will receive the follow-up tests and evaluations as per Appendix A. 
 
6.3 
Product Storage and Stability 
Once the cell suspension is prepared for administration to a subject as described above, the dose of allogeneic 
mesenchymal bone marrow cells will be stored at +4ºC until the time of administration.  All cells will be 
administered to the subject within 8 hours of preparation.  Cells that are not used within this time period will be 
discarded.  
 


 
Protocol:   STEM-104-M-CHF                                                       21                                                                       19FEB2014 
6.4 
 Concomitant Medications and Rehabilitation 
Concomitant medications (any prescription and/or over-the-counter preparations) and therapies (nondrug or 
procedures) used by a subject while participating in this clinical trial will be optimized per AHA Guidelines and 
recorded at screening and until the end of the study or the end of a subject’s participation in the study.  
Subjects may be administered beta-blockers, ACE inhibitors or angiotensin receptors blockers, 
mineralocorticoid receptor antagonists, statin agents, or other medications, as tolerated.  All other prescription 
and over-the-counter preparations approved by the patients’ physician will be permitted. 
 
7 
STUDY ASSESSMENTS AND SCHEDULE 
7.1 
General Assessments  
Clinical Assessments 
 
Complete medical history, including medication use and lifestyle history 
 
Physical and cardiac examination, including vital signs (temperature, systolic blood pressure/diastolic 
blood pressure, weight, heart rate, respiratory rate) 
 
Cardiac Examination 
 
Composite of all-cause mortality, admission for worsening HF and all-cause admissions. 
 
Exercise capacity: 6 minute walk distance  
 
Kansas City Cardiomyopathy Questionnaire (KCCQ)(Appendix B) 
 
New York Heart Association (NYHA) Classification (Appendix B)   
 
Clinical Laboratory Assessments 
 
Hematology (CBC):  hemoglobin, hematocrit, platelet count, red blood cell count, white blood cell count, 
automated differential  
 
Serum Chemistry:  includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), 
creatinine, glucose, calcium, phosphorous, total bilirubin, albumin and total protein, and the following 
liver function tests (LFT’s): alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) 
 
Immunoglobulin A (IgA), immunoglobulin E (IgE), immunoglobulin G (IgG), immunoglobulin M (IgM), 
and Lymphocyte Proliferation Panel 
 
Serum Pregnancy test: only for women with child-bearing potential 
 
Vascular Endothelial Growth Factor (VEGF) 
 
Fibroblast Growth Factor (FGF) 
 
NT-pro Brain Natriuretic Peptide (NT-proBNP) and cardiac troponin 
 
 
ECG 
A 12-lead ECG will be performed at all study visits.  Standard interval assessments, including QT and QTc, will 
be calculated from a single lead (typically lead II).  QTc will be calculated on the baseline ECG in order to 
determine if the subject meets enrollment criteria.  QTc must be <550ms in order for the subject to be 
randomized.   
 
Echocardiography 
 
A full 2D and Doppler echocardiogram will be performed at screening, at day 90, after initial infusion. After 
the crossover phase a full 2D and Doppler echocardiogram will be performed at day 90 after the new 
infusion.   
 
Images will be acquired with the patient positioned in the recumbent lateral position.  Left ventricular 
volumes will be determined at end-diastole and end-systole by quantitative biplane assessment.  
Endocardial borders will be manually traced from apical four-chamber and two-chamber views.   Left 
ventricular volumes will be used to calculate ejection fraction using the biplane modified Simpson’s 
summation-of-disks method recommended by the American Society of Echocardiography.  
 
High frame-rate images of the LV in the three apical views (4-chamber, 2-chamber, and apical long axis) 
will be acquired for speckle tracking echocardiography. Images will be analyzed offline on a dedicated 
workstation using EchoPAC BTO 12 (GE Healthcare) software for calculation of segmental and global 


 
Protocol:   STEM-104-M-CHF                                                       22                                                                       19FEB2014 
longitudinal strain and strain rate. Global longitudinal strain and strain rate will be calculated from all 18 
segments of the LV. Segmental strain and strain rate will be calculated for each segment separately. To 
assess effect of therapy on impaired regions, we will average strain and strain rate of the dysfunctional 
segments at baseline and compare the average of these segments over time.      
 
Cardiac MRI 
 
Cardiac MRI with gadolinium contrast will be performed at baseline and after 90 days after initial infusion. 
After the crossover phase an MRI with gadolinium contrast will be performed at new baseline (day 90 after 
the initial phase) and after 90 days.  MRI sequences will include balanced steady state free precession 
sequence (b_SSFP) and a delayed contrast enhanced imaging sequence using IV gadolinium contrast, 
and T2 imaging. Image analysis will be performed by an experienced central laboratory blinded to the 
subjects’ treatment.  Efficacy endpoints evaluated by MRI will include: LV end diastolic volume EDV, LV 
end systolic volume, ESV, and global Left Ventricular Ejection Fraction, and assessment of T2 images for 
assessing the tissue status 
 
End-diastolic and end-systolic endocardial traces from contiguous short axis slices will be used to 
determine end-diastolic and end-systolic left ventricular volumes and ejection fraction. Subjects with 
contraindications (e.g. implanted devices, surgical prosthesis, renal impairment or claustrophobia) will not 
undergo MRI. 
 
Holter monitoring 
Those patients who do not have dual chamber defibrillators implanted will undergo twenty four hour Holter 
monitoring at baseline, day of infusion, at day 30, 60, and 90, after initial infusion and at 30, 60, and 90 days 
post the new infusion after the crossover phase. For the purposes of this study, life-threatening arrhythmias are 
defined as ventricular tachycardia (defined as 3 or more consecutive beats arising below the atrioventricular 
node with a rate >120 beats/min, and complete heart block).  
 
Pulmonary Function Tests 
Spirometry will be used to assess lung function at screening and at 90 days for the initial phase and at 90 days 
after the crossover phase.  Spirometry tests should be conducted in accordance with the American Association 
for Respiratory Care (AARC) Spirometry Clinical Practice Guidelines 
(www.rcjournal.com/cpgs/spirupdatepg.html). Tests will obtain information about FEV1 (L) and Percent 
Predicted FEV1.  Prior to lung function testing, subjects will be advised to avoid the following activities: 1) 
Smoking within at least 2 hours of testing, 2) consuming alcohol within 4 hours of testing, 3) vigorous exercise 
within 4 hours of testing, 4) eating a large meal within 2 hours of testing, 5) consuming caffeine such as coffee, 
tea, cola drinks, or chocolate on the day of testing. 
Diffusing capacity of the lungs for carbon monoxide (DLCO) will also be used to assess lung function at 
screening and at 90 days. DLCO will be conducted in accordance with the American Thoracic Society and 
European Respiratory Society guidelines for standardization of the test.83 
 
7.2 
Schedule of Assessments 
7.2.1 Screening (Day 1-2) 
All screening evaluations must be within 1-2 days after identification of possible eligible patients. 
 
Study participants must meet eligibility criteria (inclusion/exclusion criteria review).    
 
Signed the written informed consent 
 
Full 2D and Doppler transthoracic echocardiography with speckle-tracking with LVEF ≤40% 
If the patient is eligible based on the evaluation above, then 
 
Complete medical history, including medications history 
 
Complete physical and cardiac examination, including vital signs (oral temperature, blood pressure, and 
pulse rate), weight, and height 
 
12-lead ECG  
 
Cardiac MRI, with delayed gadolinium contrast enhancement – Subjects with contraindications to MRI 
because of cardiac devices (pacemakers and defibrillators) will undergo an MRI scan after deactivation 


 
Protocol:   STEM-104-M-CHF                                                       23                                                                       19FEB2014 
of their device by an electrophysiologist. Other contraindicated patients, e.g. surgical prosthesis, renal 
impairment or claustrophobia, will not undergo MRI. 
 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
New York Heart Association (NYHA) Classification    
 
Spirometry/DLCO 
 
Clinical labs:  serum chemistry including BUN & creatinine, CBC with diff, LFT’s, total protein and 
albumin,  
 
Cardiac Biomarkers (CK, CK-MB fraction)  
 
Pregnancy test, when appropriate 
 
Serum chemistry 
 
Serum/plasma stored for VEGF, FGF, NT-proBNP, troponin   
 
HIV test 
 
Pulse oximetry 
 
24 Hour Holter ECG recording or ICD assessment 
 
Randomization into experimental or control group 
 
6 minute walk test 
 
7.2.2 Assessments and Treatment 
Day 7 ± 3 Days (day of infusion) 
Pre-infusion: 
 
Inclusion/exclusion criteria review. 
 
Review and record any changes in medical history, including concomitant medications from screening.  
 
Confirm Informed Consent Form (ICF) is complete with signature of subject, or legal guardian & witness.  
 
Measure and record weight and vital signs (oral temperature, blood pressure, pulse rate) after subjects 
rest quietly in a supine or semi-recumbent position. 
 
Final Formulation Skin Test.  Performed prior to infusion (Appendix C) 
 
Physical and Cardiac Examination 
 
Draw and store blood samples for IgA, IgE, IgG, IgM and for Lymphocyte Proliferation Panel 
 
Place an IV line in the upper extremity or hand with 0.9% sodium chloride running to keep the vein open 
 
During infusion: 
 
IV infusion of the study product or placebo  
 
Monitoring for any signs of adverse reaction, record adverse event/s and concomitant medications  
 
Record vital signs every 2 hours, and as clinically indicated 
 
Continuous ECG monitoring during infusion of study product 
 
Pulse oximetry continuously during and for 2 hours post infusion 
 
Post- infusion: 
 
12-lead ECG  
 
Monitoring for any signs of adverse reaction, record adverse event/s and concomitant medications  
 
Record vital signs every 2 hours till discharge 
 
Continuous ECG monitoring for 2 hours  
 
Pulse oximetry continuously for 2 hours  
 
Cardiac biomarkers (CK and CK-MB fraction, troponin I). 
 
Serum/plasma stored for VEGF, FGF, NT-proBNP, troponin   
 
Subjects will be observed for a minimum of 6 hours ± 30 minutes post infusion or until deemed stable in 
the opinion of the investigator 
 
Subject is free to ambulate according to investigators discretion 
 
Physical exam, prior to discharge if clinically stable 
 
Provide subject or responsible individual accompanying the subject with the phone number for 
contacting the study nurse and/or investigator for any questions, concerns or changes in health status. 


 
Protocol:   STEM-104-M-CHF                                                       24                                                                       19FEB2014 
 
7.3 
Follow-up Assessments 
Day 30 (±7) days post-infusion 
 
Measure and record vital signs 
 
12-lead ECG 
 
Pulse Oximetry 
 
24 hour Holter ECG recording or ICD assessment 
 
Record the composite of all-cause mortality, admission for worsening HF and all-cause admissions, and 
concomitant medication use 
 
Physical and cardiac examination 
 
Clinical labs:  serum chemistry including BUN & creatinine, CBC with diff, LFT’s, total protein and 
albumin  
 
Cardiac biomarkers (CK and CK-MB fraction, troponin I) 
 
Serum/plasma stored for VEGF, FGF, NT-proBNP, troponin   
 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
New York Heart Association (NYHA) Classification    
 
6 minute walk test 
 
Day 60 (±7) days post infusion) 
 
Measure and record vital signs 
 
12-lead ECG 
 
Pulse Oximetry 
 
24 hour Holter ECG monitoring or ACD assessment 
 
Record the composite of all-cause mortality, admission for worsening HF and all-cause admissions, and 
concomitant medication use 
 
Physical and cardiac examination 
 
Clinical labs:  serum chemistry including BUN & creatinine, CBC with diff, LFT’s, total protein and 
albumin 
 
Cardiac biomarkers (CK and CK-MB fraction, troponin I) 
 
Serum/plasma stored for VEGF, FGF, NT-proBNP, troponin   
 
Draw and store blood samples for IgA, IgE, IgG, IgM and for Lymphocyte Proliferation Panel 
 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
New York Heart Association (NYHA) Classification    
 
Spirometry/DLCO  
 
6 minute walk test 
 
 
Day 90 (±7) days post initial infusion, day of crossover infusion)  
 
Measure and record vital signs 
 
Final Formulation Skin Test.  Performed prior to infusion (Appendix C) 
 
12-lead ECG 
 
Pulse Oximetry 
 
24 hour Holter ECG monitoring or ACD assessment 
 
Record the composite of all-cause mortality, admission for worsening HF and all-cause admissions, and 
concomitant medication use 
 
Physical and cardiac examination 
 
Clinical labs:  serum chemistry including BUN & creatinine, CBC with diff, LFT’s, total protein and 
albumin,  
 
Cardiac biomarkers (CK and CK-MB fraction, troponin I) 
 
Serum/plasma stored for VEGF, FGF, NT-proBNP, troponin   
 
Draw and store blood samples for IgA, IgE, IgG, IgM and for Lymphocyte Proliferation Panel 


 
Protocol:   STEM-104-M-CHF                                                       25                                                                       19FEB2014 
 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
New York Heart Association (NYHA) Classification   
 
Spirometry/DLCO  
 
6 minute walk test 
 
Cardiac MRI, with delayed contrast enhancement 
 
Full 2D and Doppler transthoracic echocardiography with speckle-tracking 
 
Pregnancy test for women of childbearing potential  
 
7.4 
Early Termination Visit 
 
Measure and record weight and vital signs 
 
12-lead ECG 
 
Pulse Oximetry 
 
24 hour Holter ECG monitoring or ACD assessment 
 
Record the composite of all-cause mortality admission for worsening HF and all-cause admissions, and 
concomitant medication use 
 
Physical and cardiac examination 
 
Clinical labs:  serum chemistry including BUN & creatinine, CBC with diff, LFT’s, total protein and 
albumin  
 
Serum/plasma stored for VEGF, FGF, NT-proBNP, troponin   
 
Blood sample for IgA, IgE, IgG, IgM and for Lymphocyte Proliferation Panel  
 
6 minute walk test 
 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
New York Heart Association (NYHA) Classification  
 
Cardiac MRI, with delayed contrast enhancement 
 
Full 2D and Doppler transthoracic echocardiography with speckle-tracking  
 
The same follow-up visits will be performed after the crossover phase. 
 
8 
ASSESSMENT OF SAFETY  
8.1 
Safety Parameters 
Safety assessments will consist of monitoring and recording adverse treatment events.  Changes in clinical 
laboratory, clinical status and physical examination values will be used for evaluation.  
 
 
8.1.1 Adverse Event (AE) 
ICH E6 defines an AE as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product regardless of its causal relationship to the study stem cell 
administration. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) product. The 
occurrence of an AE may come to the attention of study personnel during study visits and interviews of a study 
recipient presenting for medical care, or upon review by a study monitor.  
 
All AEs including local and systemic reactions not meeting the criteria for “serious adverse events” will be 
captured on the appropriate CRF. Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis) which would include MD, DO, PA or NP and time of resolution/stabilization of 
the event. All AEs occurring while on study must be documented appropriately regardless of relationship. All 
AEs will be followed to adequate resolution.  
 
Any medical condition that is present at the time that the subject is screened will be considered as baseline 
and not reported as an AE. However, if it deteriorates at any time during the study, it should be recorded as an 
AE. 


 
Protocol:   STEM-104-M-CHF                                                       26                                                                       19FEB2014 
 
All AEs must be graded for severity and relationship to study product.  
 
Severity of Event:  All AEs will be assessed by the clinician using the following grading system of AE 
intensity.  
 
Mild: events require minimal or no treatment and do not interfere with the subject’s daily activities. 
 
Moderate: events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
 
Severe: events interrupt a subject’s usual daily activity and may require systemic drug therapy or other 
treatment. Severe events are usually incapacitating. 
 
Life threatening:  any adverse drug experience that places the subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it 
occurred in a more severe form, might have caused death. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at 
each level of intensity to be performed. Adverse events characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Relationship to Study Products:  The clinician’s assessment of an AE’s relationship to investigational 
product is part of the documentation process, but it is not a factor in determining what is or is not reported in 
the study. If there is any doubt as to whether a clinical observation is an AE, the event will be reported. All AEs 
must have their relationship to investigational product assessed. In a clinical trial, the investigational product 
must always be suspect. To help assess, the following guidelines are used. 
 
Related – There is a plausible temporal relationship between the onset of the AE and administration of the 
investigational product, and the AE cannot be readily explained by the subject’s pre-existing clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to the 
investigational product; and/or the AE abates or resolves upon discontinuation of the investigational 
product and, if applicable, reappears upon re-challenge. 
 
Not Related – There is good evidence that the AE has an etiology other than the investigational product 
(e.g., pre-existing medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to administration of the investigational product (e.g., 
cancer diagnosed 2 days after treatment). 
 
8.1.2 Serious Adverse Event (SAE) 
An SAE is an AE that results in any of the following outcomes: 
 
Death (i.e., the AE actually causes or leads to death) 
 
Life threatening event (i.e., the AE, in the view of the Investigator, places the subject at immediate risk of 
death) 
 
Requires or prolongs inpatient hospitalization 
 
Results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the 
subject’s ability to conduct normal life functions) 
 
A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational 
product(s) 
 
Any other important medical event that may not result in death, be life threatening, or require hospitalization, 
may be considered a serious adverse experience when, based upon appropriate medical judgment, the event 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization. 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of an AE (as in mild, 
moderate, or severe pain); the event itself may be of relatively minor medical significance (such as severe 
headache).  “Serious” is a regulatory definition and is based on subject or event outcome or action criteria 


 
Protocol:   STEM-104-M-CHF                                                       27                                                                       19FEB2014 
usually associated with events that pose a threat to a subject’s life or vital functions.  Seriousness (not severity) 
serves as the guide for defining regulatory reporting obligations. 
 
Severity and seriousness will be independently assessed when recording AEs and SAEs on the CRF. 
 
8.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
The Investigator is responsible for ensuring that all study-emergent AEs and SAEs (as defined in Section 7.1) 
are recorded on the CRF and reported to the sponsor in accordance with protocol instructions.  For each SAE 
observed, the investigator will obtain all of the information available about the event, including (but not limited 
to):  hospital discharge diagnoses, hospital discharge note, death certificate, appropriate laboratory findings 
(including autopsies and biopsy results), and clinical examinations (including radiological examinations and 
clinical consultations).  
 
8.2.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after initiation of study treatment and 
ends at study completion or study discontinuation/termination, whichever is earlier.  Any condition present 
between consenting and time of treatment will be considered as baseline and not recorded as an AE. After this 
period, investigators should report only SAEs that are attributed to study treatment. 
All AEs that are observed or reported prior to initiation of study treatment will be recorded as unrelated to 
treatment and those occurring after initiation of treatment will be recorded as treatment-emergent. 
 
8.2.2 Assessment of Adverse Events 
Investigators will seek information on AEs and SAEs at each subject contact by specific questioning and, as 
appropriate, by examination.  All AEs and SAEs, whether spontaneously reported by the subject or noted by 
authorized study personnel, will be recorded in the subject’s medical record and on the appropriate AE or SAE 
CRF page.  
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), severity, regulatory 
seriousness criteria if applicable, suspected relationship to the investigational product, and actions taken.  
 
Note:  The investigator’s assessment of causality for individual AE reports is part of the study documentation 
process.  Regardless of the “Yes” or “No” causality assessment for individual AE reports, the sponsor will 
promptly evaluate all reported SAEs against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators and applicable regulatory authorities.  Attribution of 
SAEs will be reviewed on an ongoing basis, and may be changed as additional clinical data emerge 
(e.g., reversibility of AE, new clinical findings in subject with AE, effects of retreatment, AEs in other subjects). 
 
 
8.2.3 Recording Adverse Events on the CRF 
Investigators will use correct medical terminology/concepts when recording AEs or SAEs on the CRF.  Avoid 
colloquialisms and abbreviations. 
AEs will be recorded either on an AE CRF page (if no serious criteria are met) or SAE CRF page, but not both.  
For each SAE observed, the investigator must report the triggering event for that particular episode of illness 
as the primary event. 
Only one medical concept will be recorded in the event field on the AE or SAE CRF page. 
 
a. Diagnosis versus Signs and Symptoms 
If known, a diagnosis will be recorded on the CRF rather than individual signs and symptoms (e.g., record only 
liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event will be recorded as an AE or SAE on the CRF.  If a diagnosis is 
subsequently established, it will be reported as follow-up information. 
 


 
Protocol:   STEM-104-M-CHF                                                       28                                                                       19FEB2014 
b. Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) will be 
identified by their primary cause.  For example, if severe diarrhea is known to have resulted in dehydration, it is 
sufficient to record only diarrhea as an AE or SAE on the CRF.  
 
However, medically significant AEs occurring secondary to an initiating event that are separated in time will be 
recorded as independent events on the CRF.  For example, if a severe gastrointestinal hemorrhage leads to 
renal failure, both events will be recorded separately on the CRF. 
 
c. Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between subject evaluation time points.  
Such events will only be recorded once in the CRF unless their severity increases.  If a persistent AE becomes 
more severe, it will be recorded again on an AE or SAE CRF page.   
A recurrent AE is one that occurs and resolves between subject evaluation time points and subsequently 
recurs.  All recurrent AEs will be recorded on an AE or SAE CRF page. 
 
d. Abnormal Laboratory Values 
Laboratory data collection will be limited to those laboratory parameters that are relevant to safety, study 
outcome measures, and/or clinical outcome.  Only clinically significant laboratory abnormalities that require 
active management will be recorded as AEs or SAEs on the CRF (e.g., abnormalities that require more 
frequent follow-up assessments, further diagnostic investigation, etc.)  If the Investigator is uncertain about the 
appropriateness of reporting particular laboratory data, he/she will contact the Medical Monitor for the study. 
 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline phosphatase 
and bilirubin five times the upper limit of normal associated with cholecystitis), only the diagnosis (e.g., 
cholecystitis) needs to be recorded on the AE or SAE CRF page. 
 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the abnormality itself 
will be recorded as an AE or SAE on the CRF.  If the laboratory abnormality can be characterized by a precise 
clinical term, the clinical term will be recorded as the AE or SAE.  For example, an elevated serum potassium 
level of 7.0mEq/L will be recorded as “hyperkalemia.” 
 
Observations of the same clinically significant laboratory abnormality from visit to visit will not be repeatedly 
recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or etiology changes.  
 
e. Deaths 
For any deaths that occur during the study, regardless of attribution, the investigator will report the death 
immediately to the Medical Monitor for the study at the telephone number provided on the cover of this protocol 
and record the death on the appropriate SAE CRF page. 
 
When recording a death, the event or condition that caused or contributed to the fatal outcome will be recorded 
as the single medical concept on the SAE CRF page.  If the cause of death is unknown and cannot be 
ascertained at the time of reporting, record “Unexplained Death” on the SAE CRF page. 
 
f. Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  This includes any abnormal 
physical examination finding noted during screening.  Such conditions will be recorded on the Medical and 
Surgical History CRF page. 
 
A pre-existing medical condition will be re-assessed throughout the trial and recorded as an AE or SAE only if 
the frequency, severity, or character of the condition worsens during the study.  When recording such events 
on an AE or SAE CRF page, it is important to convey the concept that the pre-existing condition has changed 
by including applicable descriptors (e.g., “more frequent headaches”). 
 


 
Protocol:   STEM-104-M-CHF                                                       29                                                                       19FEB2014 
h. Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization will be documented and reported as an SAE 
unless specifically instructed otherwise in this protocol.  Any condition responsible for surgery will be 
documented as an AE if the condition meets the definition of an AE.  Surgical procedures are not to be 
recorded as SAEs or AEs. 
 
i. Pregnancy 
If a female subject becomes pregnant during the study, a Pregnancy Report CRF page will be completed and 
expeditiously submitted to the sponsor to facilitate outcome follow-up.  Pregnancy is not an SAE.   
 
Abortion, whether accidental, therapeutic, or spontaneous, will always be classified as serious, recorded on an 
SAE CRF page, and expeditiously reported to the sponsor.  Similarly, any congenital anomaly/birth defect in a 
child born to a female subject exposed to the investigational product will be recorded and reported as an SAE. 
 
8.3 
 Expedited Reporting Requirements for Serious Adverse Events 
Any life-threatening (i.e., imminent risk of death) or fatal AE that is attributed by the investigator to the 
investigational product will be telephoned to the Medical Monitor (or alternate) immediately. 
Medical Monitor: 
Nikolai Tankovich, MD, PhD 
Office Telephone No.:     858-658-0910, ext. 7214  
Mobile Phone: 
 858-610-2588 
For initial SAE reports, investigators will record all case details that can be gathered within 24 hours on an SAE 
CRF page.  The completed SAE CRF page will be faxed immediately upon completion to the attention of xxx 
 
Relevant follow-up information will be submitted as soon as it becomes available and/or upon request. 
 
8.4 
 Type and Duration of Follow-Up of Subjects After Adverse Events 
The Investigator will follow all unresolved study-emergent AEs and SAEs until the events are resolved, 
stabilized, the subject is lost to follow-up, or until it has been determined that the study treatment or 
participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs (with dates) will be documented on 
the appropriate AE or SAE CRF page and in the subject’s medical record to facilitate source data verification. 
For some SAEs, the sponsor or its designee may follow-up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details deemed necessary to appropriately evaluate the SAE report 
(e.g., hospital discharge summary, consultant report, or autopsy report). 
 
8.5 
Stopping Rules 
The following findings will trigger a temporary halt in enrollment and administration of the product to new 
subject pending a safety review: 
 
Allergic reaction after product administration which resulted in severe anaphylactic reaction 
 
Occurrence of a severe cardiovascular event or pulmonary embolism in a minimum of two patients as 
evidenced by clinical and CT findings 
 
 
8.6 
Data Safety and Monitoring Board (DSMB)  
An independent DSMB appointed by the Sponsor will review the protocol and will thereafter provide medical 
and ethical guidance related to the conduct of this trial.  During the study, the board will conduct ongoing 
review of the nature, frequency and severity of safety data.  The DSMB Chairperson has the option to 
recommend suspension of enrollment in the study if, upon initial deliberation by the DSMB, urgent safety 
issues or alarming trends in summary safety data are identified that require further investigation.  
 
The study sponsor will report all serious adverse events to the study DSMB. The DSMB will determine whether 
enrollment will be continued, suspended, or terminated. In the event that the DSMB determines that the study 
will be suspended or terminated, the study sponsor will notify the Institutional Review Boards and the 
appropriate regulatory agencies. 
 


 
Protocol:   STEM-104-M-CHF                                                       30                                                                       19FEB2014 
9 
STATISTICAL CONSIDERATIONS 
Statistical analyses will be descriptive.  Summary statistics will consist of sample size (N), means, standard 
deviations, medians, and minimum and maximum values for continuous variables, and counts and 
percentages for categorical variables.  Tables will summarize all safety and efficacy outcome measures by 
actual treatment received.  Summary tables will indicate the number of subjects with complete data for each 
measurement, event or outcome.  No substitutions will be made for missing data.  All analyses will be based 
on available data. 
 
A detailed Statistical Analysis Plan will be written prior to data analysis.  Significant deviations from the original 
statistical analysis plan will be detailed in the final study report. 
 
9.1 
Randomization 
Once eligibility and consent are confirmed, participants will be randomly assigned to the experimental or 
placebo group in a 1:1 allocation ratio, stratified by site. At 90 days the two groups will change arms and the 
placebo group will receive the stem cell infusion and the initially treated group will receive a LRS at a volume of 
1 mL/kg. 
 
9.2 
Primary Safety Analysis 
All safety outcomes will be summarized in tables and listings presented by experimental group.  Continuous 
measures will be summarized with descriptive statistics (N, mean, SD, median, min, max).  Categorical 
measures will be summarized using counts and percentages.  The incidence of adverse events will be 
presented by toxicity grade, MedDRA system organ class and preferred term, and by relationship of the 
adverse events to the study treatment and compared using a Fisher’s Exact Test.  Laboratory and vital signs 
data will be presented using shift tables and summaries of change from baseline to the maximum post-
administration value and compared using analysis of covariance (ANCOVA) models. 
 
9.3 
Efficacy Analyses 
The actual score and calculated change from baseline for each outcome measure (LV end diastolic volume, 
LVEF, Ventricular Arrhythmias, Kansas City Cardiomyopathy Questionnaire and the New York Heart 
Association Classification) will be tabulated for each scheduled assessment visit.  Summary statistics will 
consist of sample size (N), means, standard deviations, medians, and minimum and maximum values will be 
used to summarize the data.  Subjects who receive complete dose of investigational product or LRS and have 
post-administration assessments will be used as the efficacy evaluable population for statistical analysis. 
 
The primary efficacy endpoint will be evaluated and is the change from baseline to Day 90, and 180 on the 
above measures.  For each of the efficacy endpoints, a mixed-effect repeated measures (MMRM) analysis will 
be conducted to determine if the change from baseline to six months in the experimental group is different than 
that for the placebo group. The model will include the change in endpoint score from baseline to each post-
baseline visit as the outcome variable, the baseline score, time, study site, treatment group and time-by-
treatment interaction as fixed effects, and participant as a random effect. An unstructured covariance matrix 
will be used to model the within-subject variance-covariance errors. Time (0, 30d, 90d, and 180d) will be 
treated as a categorical variable in the analysis. The mixed model seamlessly accommodates different times of 
measurement as well as missed measurement and data from participants who are lost to follow up. 
 
9.4 
Determination of Sample Size 
This Study is exploratory and its sample size is not determined by statistical power considerations, but is 
considered appropriate for an early phase safety trial. 
 
9.5 
Interim Analysis 
No formal interim analysis for efficacy is planned, as this is a study with careful monitoring of subject safety in 
an ongoing manner by the principal investigator, Sponsor and independent Data Safety Monitoring Board.   
 
 


 
Protocol:   STEM-104-M-CHF                                                       31                                                                       19FEB2014 
9.6 
Data Quality Assurance 
The following steps will be taken to ensure the accuracy, consistency, completeness, and reliability of the data: 
 Investigator meeting 
 Routine study site monitoring 
 CRF review against source documents 
 Data management quality control checks 
 Sponsor medical review 
The sponsor or designee (e.g., contract research organization (CRO)) will be responsible for the data 
management of this clinical trial.  The responsible party will design and distribute the case report forms (CRFs), 
and also conduct monitoring of the CRFs.  The responsible party will generate queries in the event of 
incomplete or inconsistent data to be reconciled by the study site.   
 
10 INVESTIGATOR REQUIREMENTS 
10.1 Study Initiation 
Before the release of investigational products to the study site, the following documents must be on file with 
CardioCell LLC or its designee: 
 
U.S. FDA Form 1572 signed by the Principal Investigator or equivalent for non-U.S. sites if applicable. 
o 
The names of any sub-investigators must appear on this form.  Investigators must also complete all 
regulatory documentation as required by local and national regulations. 
 
Current curricula vitae (CV) of the Principal Investigator and all subinvestigators 
 
subinvestigators  
 
Complete financial disclosure forms for the Principal Investigator and all subinvestigators 
 
Written documentation of Institutional Review Board (IRB)/Ethics Committee (EC) approval of the protocol 
(identified by protocol number or title and date of approval) and Informed Consent Form (identified by 
protocol number or title and date of approval) 
 
A copy of the IRB/EC-approved Informed Consent Form 
 
IRB/EC composition or assurance letter as applicable 
 
Current laboratory certification of the clinical laboratory performing sample analysis, as well as current 
references ranges for all laboratory tests (if applicable) 
 
A Clinical Trial Agreement signed and dated by the study site 
 
Investigator Brochure receipt signed and dated by the Principal Investigator (if applicable) 
 
A Protocol Acceptance Form signed and dated by the Principal Investigator 
 
10.2 Study Completion 
The following data and materials are required before a study can be considered complete or terminated: 
 
All essential documents (e.g., curriculum vitae for the Principal Investigator and subinvestigator, U.S. FDA 
Form 1572 or equivalent (non-U.S.) 
 
Copies of protocol amendments, IRB/EC approval/notification, and signed and dated Protocol Amendment 
Acceptance Form(s) (if applicable) 
 
All data collection and query resolution complete Original, final SAE reports and all supporting 
documentation (i.e., discharge summaries, laboratory results) 
 
Original, final Pregnancy Information forms and all supporting documentation (if applicable) 
 
Complete and accurate investigational product accountability records and inventory log 
 
Laboratory results, clinical data, and all special test results from screening through the end of the study 
 
A summary of the study prepared by the principal investigator (IRB/EC summary close out letter is 
acceptable) 
 
10.3 Informed Consent Process 
CardioCell, LLC Informed Consent Form (ICF) will be provided to the hospital site. CardioCell, LLC or its 
designee must review and approve any proposed deviations from the ICF or any alternate consent forms 
proposed by the site before IRB/EC submission.  Subjects must be re-consented to the most current version of 


 
Protocol:   STEM-104-M-CHF                                                       32                                                                       19FEB2014 
the ICF during their participation in the study.  The final IRB/EC-approved ICF must be provided to CardioCell, 
LLC or its designee for regulatory purposes. 
 
The ICF must be signed by the subject or the subject’s legally authorized representative before his or her 
participation in the study.  The case history for each subject shall document the informed consent process and 
that written informed consent was obtained prior to participation in the study.  A copy of each signed ICF must 
be provided to the subject or the subject’s legally authorized representative.  It will be provided in a certified 
translation of the local language(s). 
 
All signed and dated ICF must remain in each subject’s study file and must be available for verification by 
study monitors at any time. 
 
The ICF will be revised whenever there are changes to procedures outlined in the informed consent or when 
new information becomes available that may affect the willingness of the subject to participate. 
 
10.4  Institutional Review Board or Ethics Committee 
This protocol, the ICF, any information to be given to the subject and relevant supporting information must be 
submitted to the IRB/EC by the Principal Investigator for review and approval before the study is initiated as 
required by the country regulatory authority.  In addition, any subject recruitment materials must be approved 
by the IRB/ EC.  
The Principal Investigator is responsible for providing written summaries of the status of the study to the 
IRB/EC annually or more frequently in accordance with the regulatory requirements and policies and 
procedures established by the IRB/EC.  Investigators are also responsible for promptly informing the IRB/EC of 
any protocol changes or amendments and of any unanticipated problems involving risk to human subjects 
or others. In addition to the requirements to report protocol-defined AEs to the Sponsor, Investigators may be 
required to promptly report to their respective IRB/EC all unanticipated problems involving risk to human 
subjects.  Some IRB/ECs may want prompt notification of all SAEs, whereas others require notification only 
about events that are serious, assessed to be related to study stem cell administration, and are unexpected.  
Investigators may receive written Investigational New Drug (IND) safety reports or other safety-related 
communications from CardioCell, LLC.  Investigators are responsible for ensuring that such reports are 
reviewed and processed in accordance with regulatory requirements and with the policies and procedures 
established by their IRB and archived in the site’s Study File.  
 
10.5  Study Monitoring Requirements 
Site visits will be conducted by an authorized CardioCell, LLC representative to inspect study data, subjects’ 
medical records, and CRFs.  The Principal Investigator will permit CardioCell, LLC monitors/representatives 
and collaborators, the U.S. FDA or other regulatory agencies, Ethics Committees and the respective national 
or local health authorities to inspect facilities and records relevant to this study, in accordance with GCP and 
the ICH E6 guidance.  If the investigator is notified of an audit pertaining to this study by the U.S. FDA or other 
applicable regulatory authorities, the Investigator must notify CardioCell, LLC immediately. 
 
The Investigator must provide sufficient space and allocate sufficient time for the monitor to inspect subject 
source records, CRFs, investigational product accountability records, and regulatory documents.   
 
10.6  Case Report Forms 
CRFs will be supplied by CardioCell, LLC or its designee and will be handled in accordance with the 
instructions. All CRFs will be filled out completely by designated personnel.  
 
10.7 Source Data Documentation 
Study monitors will perform ongoing source data verification to confirm that critical protocol data (i.e., source 
data) transcribed on the CRFs by authorized site personnel are accurate, complete, and verifiable from 
source documents. Source documents are where subject data are recorded and documented for the first time.  
They include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, 
subject diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 


 
Protocol:   STEM-104-M-CHF                                                       33                                                                       19FEB2014 
instruments, copies of transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, subject files, and records kept at the 
pharmacy, laboratories, and medico-technical departments involved in a clinical trial. Source documents that 
are required to verify the validity and completeness of data transcribed on the CRFs must never be obliterated 
or destroyed. To facilitate source data verification, the investigator(s) and institution(s) must provide the 
sponsor direct access to applicable source documents and reports for trial-related monitoring, sponsor audits, 
and IRB/EC review.  The investigational site must also allow inspection by applicable regulatory authorities. 
 
10.8  Use of Computerized Systems 
When clinical observations are entered directly into an investigational site’s computerized medical record 
system (i.e., in lieu of original hardcopy records), the electronic record can serve as the source document if the 
system has been validated in accordance with ICH requirements pertaining to computerized systems used in 
clinical research.  An acceptable computerized data collection system (for clinical research purposes) would be 
one that (1) allows data entry only by authorized individuals; (2) prevents the deletion or alteration of previously 
entered data and provides an audit trail for such data changes (e.g., modification of file); (3) protects the 
database from tampering; and (4) ensures data preservation. If a site’s computerized medical record system is 
not adequately validated for the purposes of clinical research (as opposed to general clinical practice), 
applicable hardcopy source documents must be maintained to ensure that critical protocol data transcribed on 
the CRFs can be verified. 
 
10.9  Investigational Product Accountability 
All investigational products required for completion of this study will be provided by CardioCell, LLC.  The 
recipient will acknowledge receipt of the drug by returning the appropriate documentation form indicating 
shipment content and condition.  Damaged supplies will be replaced. 
 
Accurate records of all study drug received at, dispensed from, returned to and disposed of by the study site 
will be recorded. 
 
Investigational product will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to CardioCell, LLC with the appropriate documentation, as 
determined by the study site.  If the study site chooses to destroy investigational product, the method of 
destruction must be documented. 
 
CardioCell, LLC must evaluate and approve the study site’s drug destruction standard operating procedure 
prior to the initiation of drug destruction by the study site. 
 
10.10  Disclosure of Data 
Subject medical information obtained by this study is confidential, and may only be disclosed to third parties as 
permitted by the ICF and Authorization Form (or separate authorization to use and disclose personal health 
information) signed by the subject or unless permitted or required by law. 
 
Medical information may be given to the subject’s personal physician or other appropriate medical personnel 
responsible for the subject’s welfare for treatment purposes. 
 
Data generated by this study must be available for inspection upon request by representatives of the 
applicable regulatory agencies, national and local health authorities, CardioCell, LLC monitors/representatives 
and collaborators, and the IRB/EC for each study site, if appropriate. 
 
10.11  Retention of Records (for approval enabling studies only) 
United States FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (E6) require that records 
and documents pertaining to the conduct of this study and the distribution of investigational drug, including 
CRFs, consent forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 2 years after the last marketing application approval in an ICH region or after at least 


 
Protocol:   STEM-104-M-CHF                                                       34                                                                       19FEB2014 
2 years have elapsed since formal discontinuation of clinical development of the investigational product.  All 
state and local laws for retention of records also apply.  
 
No records will be disposed of without written approval from CardioCell, LLC.  Written notification will be 
provided to CardioCell, LLC for transfer of any records to another party or moving them to another location. 
 
 
 


 
Protocol:   STEM-104-M-CHF                                                       35                                                                       19FEB2014 
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Grinnemo KH, Mansson A, Dellgren G, Klingberg D, Wardell E, Drvota V, Tammik C, Holgersson J, 
Ringden O, Sylven C, Le Blanc K. Xenoreactivity and engraftment of human mesenchymal stem cells 
transplanted into infarcted rat myocardium. J Thorac Cardiovasc Surg. 2004;127:1293-1300 
60. 
Sethe S, Scutt A, Stolzing A. Aging of mesenchymal stem cells. Ageing Res Rev. 2006;5:91-116 
61. 
Tokalov SV, Gruner S, Schindler S, Wolf G, Baumann M, Abolmaali N. Age-related changes in the 
frequency of mesenchymal stem cells in the bone marrow of rats. Stem Cells Dev. 2007;16:439-446 
62. 
Roura S, Farre J, Soler-Botija C, Llach A, Hove-Madsen L, Cairo JJ, Godia F, Cinca J, Bayes-Genis A. 
Effect of aging on the pluripotential capacity of human CD105+ mesenchymal stem cells. Eur J Heart 
Fail. 2006;8:555-563 
63. 
Hacia JG, Lee CC, Jimenez DF, Karaman MW, Ho VV, Siegmund KD, Tarantal AF. Age-related gene 
expression profiles of rhesus monkey bone marrow-derived mesenchymal stem cells. J Cell Biochem. 
2008;103:1198-1210 
64. 
Zhang H, Fazel S, Tian H, Mickle DA, Weisel RD, Fujii T, Li RK. Increasing donor age adversely 
impacts beneficial effects of bone marrow but not smooth muscle myocardial cell therapy. Am J Physiol 
Heart Circ Physiol. 2005;289:H2089-2096 
65. 
Alfaro MP, Vincent A, Saraswati S, Thorne CA, Hong CC, Lee E, Young PP. sFRP2 suppression of 
bone morphogenic protein (BMP) and Wnt signaling mediates mesenchymal stem cell (MSC) self-
renewal promoting engraftment and myocardial repair. J Biol Chem. 2010;285:35645-35653 
 


 
Protocol:   STEM-104-M-CHF                                                       39                                                                       19FEB2014 
66. 
Fan L, Lin C, Zhuo S, Chen L, Liu N, Luo Y, Fang J, Huang Z, Lin Y, Chen J. Transplantation with 
survivin-engineered mesenchymal stem cells results in better prognosis in a rat model of myocardial 
infarction. Eur J Heart Fail. 2009;11:1023-1030 
67. 
Huang J, Zhang Z, Guo J, Ni A, Deb A, Zhang L, Mirotsou M, Pratt RE, Dzau VJ. Genetic modification 
of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and 
capillary density in the injured myocardium. Circ Res. 2010;106:1753-1762 
68. 
Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. Mesenchymal stem cells 
modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 
2003;9:1195-1201 
69. 
Kim YS, Kwon JS, Hong MH, Kim J, Song CH, Jeong MH, Cho JG, Park JC, Kang JC, Ahn Y. 
Promigratory activity of oxytocin on umbilical cord blood-derived mesenchymal stem cells. Artif Organs. 
2010;34:453-461 
70. 
Chacko SM, Ahmed S, Selvendiran K, Kuppusamy ML, Khan M, Kuppusamy P. Hypoxic 
preconditioning induces the expression of prosurvival and proangiogenic markers in mesenchymal 
stem cells. Am J Physiol Cell Physiol. 2010;299:C1562-1570 
71. 
Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao LM, Lin S, Sun JP. 
Effect on left ventricular function of intracoronary transplantation of autologous bone marrow 
mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol. 2004;94:92-95 
72. 
Katritsis DG, Sotiropoulou PA, Karvouni E, Karabinos I, Korovesis S, Perez SA, Voridis EM, 
Papamichail M. Transcoronary transplantation of autologous mesenchymal stem cells and endothelial 
progenitors into infarcted human myocardium. Catheterization & Cardiovascular Interventions. 
2005;65:321-329 
73. 
Katritsis DG, Sotiropoulou P, Giazitzoglou E, Karvouni E, Papamichail M. Electrophysiological effects of 
intracoronary transplantation of autologous mesenchymal and endothelial progenitor cells. Europace. 
2007;9:167-171 
74. 
Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, 
Denktas AE, Gammon RS, Hermiller JB, Jr., Reisman MA, Schaer GL, Sherman W. A randomized, 
double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem 
cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009;54:2277-2286 
75. 
Chen M, Fan ZC, Liu XJ, Deng JL, Zhang L, Rao L, Yang Q, Huang DJ. Effects of autologous stem cell 
transplantation on ventricular electrophysiology in doxorubicin-induced heart failure. Cell Biol Int. 
2006;30:576-582 
76. 
Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M, 
Ghersin E, Johnston PV, Brinker JA, Breton E, Davis-Sproul J, Schulman IH, Byrnes J, Mendizabal AM, 
Lowery MH, Rouy D, Altman P, Wong Po Foo C, Ruiz P, Amador A, Da Silva J, McNiece IK, Heldman 
AW. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered 
by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized 
trial. Jama. 2012;308:2369-2379 
77. 
Colter DC, Class R, DiGirolamo CM, Prockop DJ. Rapid expansion of recycling stem cells in cultures of 
plastic-adherent cells from human bone marrow. Proc Natl Acad Sci U S A. 2000;97:3213-3218 
78. 
Kotobuki N, Hirose M, Takakura Y, Ohgushi H. Cultured autologous human cells for hard tissue 
regeneration: preparation and characterization of mesenchymal stem cells from bone marrow. Artif 
Organs. 2004;28:33-39 
79. 
Lee MW, Yang MS, Park JS, Kim HC, Kim YJ, Choi J. Int J Hematol. 2005;81:126-130 
80. 
Fouillard L, Chapel A, Bories D, Bouchet S, Costa JM, Rouard H, Herve P, Gourmelon P, Thierry D, 
Lopez M, Gorin NC. Infusion of allogeneic-related HLA mismatched mesenchymal stem cells for the 
treatment of incomplete engraftment following autologous haematopoietic stem cell transplantation. 
Leukemia. 2007;21:568-570 
81. 
Le Blanc K, Ringden O. Immunobiology of human mesenchymal stem cells and future use in 
hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11:321-334 
 
82. 
Marmont AM, Gualandi F, Piaggio G, Podesta M, Teresa van Lint M, Bacigalupo A, Nobili F. Allogeneic 
bone marrow transplantation (BMT) for refractory Behcet's disease with severe CNS involvement. Bone 
Marrow Transplant. 2006;37:1061-1063 


 
Protocol:   STEM-104-M-CHF                                                       40                                                                       19FEB2014 
83. 
Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, Burgos F, Casaburi R, 
Coates A, Enright P, Gustafsson P, Hankinson J, Jensen R, McKay R, Miller MR, Navajas D, Pedersen 
OF, Pellegrino R, Wanger J. Standardisation of the single-breath determination of carbon monoxide 
uptake in the lung. Eur Respir J. 2005;26:720-735 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 Protocol: 
STEM-104-M-CHF                                                             41                                                                                           19FEB2014 
APPENDIX A: SCHEDULE OF ASSESSMENTS 
Visit 
1 
3 
4 
5 
6 
7 
8 
9 
Early 
Termination  
Day 
Days 1 
to 2 
Day 
7±3 
Day 
30±7 
Day 
60±7 
Day 
90±7 
Day 
120±10 
Day   
150 ±7 
Day 
180±10 
Informed Consent Form 
X 
 
 
 
 
 
 
 
 
IV Infusion 
 
X 
 
 
X 
 
 
 
 
Final Formulation Skin Test× 
 
X 
 
 
X 
 
 
 
 
Pregnancy Test^ 
X 
 
 
 
X 
 
 
X 
X 
Troponin, HIV 
X 
 
 
 
 
 
 
 
 
Randomization into experimental or control group 
X 
 
 
 
 
 
 
 
 
Cardiac MRI 
X 
 
 
 
X 
 
 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
Spirometry/DLCO 
X 
 
 
 
X 
 
 
X 
 
Full 2D Doppler transthoracic echocardiography with speckle-tracking † 
X 
 
 
 
X 
 
 
X 
X 
SF-36 Health Assessment, Canadian Cardiovascular Society (CCS) 
angina classification, KCCQ, NYHA 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24 hour Holter ECG recording* 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetry** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6 minute walk test 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Diff 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry with BUN/Creatinine, LFT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VEGF, FGF, NT-proBNP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IgA, IgE, IgG, IgM and Lymphocyte Proliferation Panel 
 
X 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac Biomarkers (CK and CK-MB fraction, troponin I) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Composite of all-cause mortality, myocardial infarction, coronary 
revascularization, and admission for worsening HF and all-cause 
admissions 
 
 
X 
X 
X 
X 
X 
X 
X 
† Ejection fraction must be ≤ 40%. 
‡ A coronary angiogram performed during the index MI may be used to determine eligibility. 
×Skin Test (Appendix C) to be performed prior to IV infusion 
*24 hour Holter ECG recording must be completed prior to IV infusion.  
Collect 5mL of blood into tube for lymphocyte proliferation panel prior to IV infusion. Provide 2mL of serum in another tube of IgA, IgE, IgG and IgM test. Serum is taken from blood in 5mL tube, which is centrifuged for 15 minutes at 
3500 RPM.  
**Vital signs taken every 2 hours after infusion and pulse oximetry taken continuously for 2 hours after IV infusion. Vital signs include temperature, blood pressure, heart rate respiratory rate and weight 
†† A test will be taken prior to IV infusion to establish baseline. Another test will be taken 6 hours ± 30 minutes after infusion. If levels are significantly elevated, two more tests will be taken every 6 hours for the next 12 hours. 
Need continuous ECG monitoring during infusion 
Patient to go home with Holter monitor to assure no arrhythmias immediately post 
^Pregnancy test for women of childbearing potential only.  
 


 
 Protocol: 
STEM-104-M-CHF                                                             42                                                                                           19FEB2014 
APPENDIX B: QUESTIONNAIRES 
 
THE KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE (KCCQ) 
 
The following questions refer to your heart failure and how it may affect your life.  Please read and complete 
the following questions.  There are no right or wrong answers. Please mark the answer that best applies to 
you.  
1. Heart Failure affects different people in different ways.  Some feel shortness of breath while others feel 
    fatigue.  Please indicate how much you are limited by heart failure (shortness of breath or fatigue) in 
    your ability to do the following activities over the past 2 weeks. 
 
 
 
 
           Place an X in one box on each line 
Activity 
 
    Extremely Quite a bit     Moderately 
  Slightly          Not at all 
       Limited 
for other reasons 
 
 
     limited 
 limited 
          limited    limited 
             limited 
         or did 
not do the activity 
Dressing yourself 
         ⁯  
      ⁯ 
 
⁯      
    ⁯                       ⁯                                    ⁯ 
Showering/Bathing 
            ⁯ 
 
      ⁯ 
 
⁯     
    ⁯                       ⁯                                    ⁯ 
Walking 1 block on  
    level ground 
         ⁯                    ⁯                 ⁯      
    ⁯                       ⁯                                    ⁯ 
Doing yardwork, 
    housework or 
    carrying groceries           ⁯  
      ⁯                 ⁯   
    ⁯                       ⁯                                    ⁯ 
Climbing a flight of 
     stairs without 
     stopping 
⁯                   ⁯                 ⁯      ⁯                       ⁯                                    ⁯ 
Hurrying or jogging 
     (as if to catch a bus)       ⁯                   ⁯                 ⁯      
    ⁯                       ⁯                                    ⁯ 
 
2.   Compared with 2 weeks ago, have your symptoms of heart failure (shortness of breath, fatigue or ankle 
swelling)   
      changed?  My symptoms of heart failure have become… 
 
     Much worse 
 Slightly worse Not changed  Slightly better   Much better           I’ve had no symptoms 
  
 
 
 
 
 
 
 
 
 
   over the last 2 weeks 
      ⁯  
       ⁯ 
 
      ⁯                        ⁯                          ⁯  
 
⁯ 
 
3.  Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs when you woke 
up in  
      in the morning? 
 
      Every          3 or more times  
     1-2 times a           Less than once         Never over the 
       morning        a week, but not            week                     a week                   past 2 weeks 
                                every day 
 
         ⁯  
       ⁯ 
 
        ⁯                        ⁯                         ⁯  
 
4.  Over the past 2 weeks, how much has swelling in your feet, ankles or legs bothered you? 
     In has been… 
 
      
    Extremely Quite a bit 
Moderately 
 Slightly 
 
Not at all 
I’ve had no swelling 
     bothersome 
bothersome 
bothersome 
bothersome          bothersome 


 
Protocol:   STEM-104-M-CHF                                                       43                                                                       19FEB2014 
  
         ⁯  
       ⁯ 
 
      ⁯                        ⁯                           ⁯           ⁯ 
5.   Over the past 2 weeks, on average, how many times has fatigue limited your ability to do what you want? 
  
All of the time       Several times          At least once a         3 or more times 
1-2 times per Less than 
once a Never over 
                                  per day                         day                  per week but not            week                          week             
the past 2                                                                 
                                                                                                    every day                                                                         
weeks  
 
6.  Over the past 2 weeks, how much has your fatigue bothered you? 
     It has been… 
 
 Extremely Quite a bit 
Moderately 
Slightly 
 
Not at all 
I’ve had no fatigue 
    bothersome bothersome 
bothersome 
bothersome 
bothersome 
           ⁯  
       ⁯ 
 
      ⁯                        ⁯                        ⁯ 
                       ⁯ 
 
7. Over the past 2 weeks, on average, how many times has shortness of breath limited your ability to do what 
you wanted? 
 
All of the time       Several times          At least once a         3 or more times 
1-2 times per Less than 
once a Never over 
                                  per day                         day                  per week but not            week                          week             
the past 2                                                                 
                                                                                                    every day                                                                         
weeks  
       ⁯                     ⁯ 
 
      ⁯                        ⁯                        ⁯ 
 
          ⁯                  ⁯  
 
8.  Over the past 2 weeks, how much has your shortness of breath bothered you? 
 
  Extremely Quite a bit 
Moderately 
 Slightly 
 
Not at all               I’ve had no shortness 
     bothersome 
bothersome 
bothersome 
bothersome          bothersome                     of breath 
  
          ⁯  
       ⁯ 
 
      ⁯                        ⁯                        ⁯ 
                       ⁯ 
 
9.  Over the past 2 weeks, on average, how many times have you been forced to sleep sitting up in a chair or 
with at least 3  
     pillows to prop you up because of shortness of breath? 
 
     Every night 3 or more times 
1-2 times a 
Less than once 
Never over the  
                               a week, but not     week 
 
     a week 
  past 2 weeks 
  
 
every day 
        ⁯                       ⁯                      ⁯ 
 
10. Heart Failure symptoms can worsen for a number of reasons.  How sure are you that you know what to 
do, or whom to  
      call, if your heart failure gets worse? 
 
      Not at all  Not very sure Somewhat sure 
Mostly sure 
Completely sure 
          sure 
          ⁯  
       ⁯ 
 
        ⁯                       ⁯                     ⁯ 
 


 
Protocol:   STEM-104-M-CHF                                                       44                                                                       19FEB2014 
11. How well do you understand what things you are able to do to keep your heart failure symptoms from 
getting worse? (for  example, weighing  yourself, eating a low salt diet, etc.) 
 
        Do not 
   Do not 
 
Somewhat 
   Mostly 
 
Completely 
      understand 
understand            understand 
understand 
understand 
   at all 
 
very well 
         ⁯  
       ⁯ 
 
        ⁯                     ⁯                      ⁯ 
 
12.  Over the past 2 weeks, how much has your heart failure limited your enjoyment of life? 
 
 It has extremely 
It has limited     It has 
 
It has slightly It has not limited my 
    limited my my enjoyment moderately 
  limited my 
enjoyment of life 
  enjoyment of   of life quite  limited my 
enjoyment of         at all 
       life                     a bit 
 
enjoyment of life 
        life 
 
 
13. If you had to spend the rest of your life with your heart failure the way it is right now, how would you feel 
about this? 
 
     Not at all 
    Mostly 
Somewhat          Mostly satisfied 
Completely 
      satisfied 
dissatisfied 
  satisfied 
   
 
   satisfied         
         ⁯  
       ⁯ 
 
        ⁯                     ⁯                      ⁯ 
 
14. Over the past 2 weeks, how often have you felt discouraged or down in the dumps because of your heart 
failure? 
 
     I felt that way 
I felt that 
 way 
I occasionally 
I rarely felt that 
I never felt that  
     all of  the most of the 
felt that way 
         way 
        way   
         time 
    time  
        
 
          ⁯  
       ⁯ 
 
        ⁯                     ⁯                      ⁯ 
 
15.  How much does your heart failure affect your lifestyle?  Please indicate how your heart failure may have 
limited your  
       participation in the following activities over the past 2 weeks? 
  
 
 
 
Please place an X in one box on each line 
 
Activity 
 
    Severely 
Limited         Moderately 
  Slightly               Did not 
             Does 
not apply or did 
 
 
     limited             quite a bit         limited 
   limited 
             limit at all            not do for 
other reasons 
Hobbies, recreational 
       activities          ⁯  
      ⁯ 
 
⁯      
    ⁯                       ⁯                               ⁯ 
Working or doing  
    household chores          ⁯                    ⁯                 ⁯      
    ⁯                       ⁯                               ⁯ 
Visiting family or friends 
    out of your home            ⁯ 
 
      ⁯                 ⁯   
    ⁯                       ⁯                               ⁯ 
Intimate relationships 
   with loved ones 
⁯                   ⁯                 ⁯      ⁯                       ⁯                               ⁯ 
 
Developed by John Spertus et al.,  Mid America Heart Institute, Saint Luke’s Hospital, Kansas City, MO. 


 
Protocol: 
STEM-104-M-CHF                                                                        45                                                       19FEB2014 
 
NEW YORK HEART ASSOCIATION (NYHA)  
Protocol Number 
Site Number 
 
Subject 
Number 
 
Subject Initials 
 
Visit Date  
(dd-MMM-yyyy) 
 
_ _-_ _ _-_ _ _ _ 
 
Examination 
Not 
Done 
Result 
If abnormal findings, describe 
Yes 
No 
Class I: patients with no 
limitation of activities; 
they suffer no symptoms 
from ordinary activities 
 
 
 
 
Class II: patients with 
slight, mild limitation of 
activity; they are 
comfortable with rest or 
with mild exertion 
 
 
 
 
Class III: patients marked 
with limitation of activity; 
they are comfortable only 
at rest 
 
 
 
 
Class IV: patients who 
should be at complete 
rest, confined to bed or 
chair; any physical 
activity brings on 
discomfort and 
symptoms occur at rest 
 
 
 
 
 
 
 


 
Protocol:   STEM-104-M-CHF                                                       46                                                                       19FEB2014 
APPENDIX C: FINAL FORMULATION SKIN TEST 
 
Testing Materials: 
0.1 ml Aliquot of the Solution from Final Formulation Preparation (30 gauge needle syringe) 
 
Procedure to be performed prior to infusion:  
Testing is usually done on the volar surface of the forearm or lateral surface of the upper part of the arm.   
1. Intradermal test: raise a bleb by intradermal injection using the 0.1 mL of aliquot. Read the test results 
at 10-15 minutes.  A positive result disqualifies the subject. 
 
Interpretation: 
A positive reaction includes a wheal of at least 4mm accompanied by erythema. Questionable results will be 
repeated.