Pilot Study of Safety and Efficacy of Cord Tissue Derived Mesenchymal Stromal Cells (hCT-MSC) in COVID-19 Related Acute Respiratory Distress Syndrome (ARDS)
Phase: PHASE1
Conditions: COVID, Corona Virus Infection, COVID19
Sponsor: Joanne Kurtzberg, MD

 Pilot Study of Safety and Efficacy of Cord Tissue Derived Mesenchymal 
Stromal Cells (hCT-MSC) in COVID-19 Related Acute Respiratory Distress 
Syndrome (ARDS) 
 
 
IND 19968 
 
 
NCT04399889 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Protocol Version 
Number 
Date 
Version 7.0 
16MAR2021 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is privileged and contains confidential information of the 
Marcus Neuroscience Institute from Boca Raton Regional Hospital. Any other distribution, copying or 
disclosure is strictly prohibited unless such disclosure is required by federal or state law or as 
authorized in writing by the Boca Raton Regional Hospital. Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further disclosed by 
them. 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 2 of 32 
PRINCIPAL INVESTIGATORS 
 
 
Joanne Kurtzberg, M.D. 
Jerome Harris Distinguished Professor of Pediatrics Professor of Pathology 
Director, Marcus Center for Cellular Cures 
Director, Pediatric Blood and Marrow Transplant Program Director, Carolinas Cord Blood Bank 
Co-Director, Stem Cell Transplant Laboratory Duke University School of Medicine/Duke Health 2400 Pratt 
Street, Room 9026 
Durham, NC 27705 
<Joanne.kurtzberg@duke.edu> 
Office Phone: 919-668-1102 or 919-668-1119 
 
Joshua M. Hare, MD 
Chief Sciences Officer 
Senior Associate Dean for Experimental and Cellular Therapeutics 
Director, Interdisciplinary Stem Cell Institute (ISCI) 
Louis Lemberg Professor of Medicine 
University of Miami Miller School of Medicine 
Don Soffer Clinical Research Center 1124 
<Jhare@med.miami.edu> 
 
 
CO-INVESTIGATORS 
 
 
Krishnendu Roy, Ph.D. 
Robert A. Milton Chair 
Director, Marcus Center for Cell-Therapy Characterization and Manufacturing (MC3M) 
Director, NSF Engineering Research Center for Cell Manufacturing Technologies 
Technical Lead, National Cell Manufacturing Consortium 
Director, Center for ImmunoEngineering 
The Wallace H. Coulter Department of Bioengineering at Georgia Tech and Emory 
The Parker H. Petit Institute for Bioengineering and Biosciences 
Georgia Institute of Technology 
<krish.roy@gatech.edu> 
 
Aisha Khan, MSc, MBA 
Executive Director of Laboratory Operations, 
Interdisciplinary Stem Cell Institute (ISCI) 
University of Miami Miller School of Medicine 
<akhan@miami.edu> 
 
Dushyantha T. Jayaweera, MD 
Professor of Medicine 
Senior Associate Dean for Research 
University of Miami Miller School of Medicine 
<djayawee@miami.edu> 
 
 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 3 of 32 
Frank Vrionis, M.D., M.P.H., Ph.D. 
Institute Director and Chairman of Neurosurgery 
Boca Raton Regional Hospital 
Marcus Neuroscience Institute 
800 Meadows Road 
Boca Raton, Florida 33486 
Affiliate Professor of Surgery 
Florida Atlantic University, Charles E. Schmidt College of Medicine 
777 Glades Road 
Boca Raton, Florida 33486 
<fvrionis@brrh.com> 
813-810-4220 
 
Khalid A. Hanafy, M.D., Ph.D. 
Assistant Professor, Harvard Medical School 
Neurological Director, Neuro-ICU 
Division of Neuro-Intensive Care Medicine 
Beth Israel Deaconess Medical Center 
<khanafy@bidmc.harvard.edu> 
 
Ralph Palumbo M.D., F.C.C.P. 
Medical Director of Critical Care at Boca Raton Regional Hospital 
Medical Director of Respiratory Care Services at Boca Raton Regional Hospital 
Director of Quality at Select Specialty Hospital 
Medical Director of Critical Care at Bethesda Memorial Hospital 
Florida Atlantic University, Charles E. Schmidt College of Medicine Clinical Affiliate Professor 
2151 W. Hillsboro Blvd., Ste. 100 Deerfield Beach, FL 33442 
<ralph.palumbo@yahoo.com> 
1-800-481-3870 
 
Bryan David Kraft, M.D. 
Assistant Professor of Medicine 
Division of Pulmonary, allergy, and Critical Care Medicine 
Department of Medicine 
Duke University Medical Center 
DUMC Box 3315, Durham, NC 27710 
<bryan.kraft@duke.edu> 
Tel:  (919) 681-8792 
Fax:  (919 684-6002 
 
David A. Pearce, Ph.D. 
President of Innovation and Research 
Sanford Health 
2301 E. 60th St. North Sioux Falls, SD 57104  
<david.pearce@sanfordhealth.org> 
Tel: (605)-312-6004 
 
 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 4 of 32 
Mitchell S. Cairo, MD 
Chief, Pediatric Hematology, Oncology, and Stem Cell Transplantation 
Director, Children and Adolescent Cancer and Blood Diseases Center 
Medical and Scientific Director, WMC Cellular and Tissue Engineering Laboratory 
Medical Director, WMC Hematotherapy Program 
Associate Chairman, Department of Pediatrics 
Professor of Pediatrics, Medicine, Pathology, Microbiology & Immunology and Cell Biology & Anatomy, 
Maria Fareri Children’s Hospital 
Westchester Medical Center (WMC) 
New York Medical College 
Website: www.nypedscbc.org 
T: (914) 594-2150  Fax: (914) 594-2151 
19 Skyline Drive | Hawthorne, NY 10532 
 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 5 of 32 
 
 
Pilot study of Safety and Efficacy of Cord Tissue Derived Mesenchymal Stem Cells (hCT-MSC) 
in COVID-19 Related Acute Respiratory Distress Syndrome (ARDS) 
 
 
 
 
 
 
PROTOCOL SIGNATURE PAGE 
 
 
I agree to conduct the patient treatment according to the protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the treatment in accordance 
with Good Clinical Practice and with the applicable regulatory requirements. 
 
 
 
 
 
 
 
 
Principal Investigator Printed Name 
Principal Investigator Signature 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator Printed Name 
Principal Investigator Signature 
Date 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 6 of 32 
TABLE OF CONTENTS 
PRINCIPAL INVESTIGATORS 
 
 
 
 
 
 
 
 
 
2 
CO-INVESTIGATORS 
2 
INVESTIGATOR SIGNATURE PAGE 
 5 
1. 
LIST OF ABBREVIATION 
8 
2. 
PROTOCOL SYNOPSIS 
8 
3. 
BACKGROUND AND RATIONALE                                                                                                                             10 
3.1. 
SARS-CoVID-19                                                                                                                                                            10 
3.2. 
Rationale for Treatment Plan 
10 
3.3. 
Objectives 
12 
3.4. 
Allogeneic, human cord tissue-derived MSC- Duke 
12 
3.5. 
Allogeneic, human cord tissue-derived MSC- Miami 
13 
3.6. 
Clinical Experience with HCT-MSC 
13 
3.6.1. 
Safety ............................................................................................................................................ 14 
3.7. 
Treatment Protocol Procedures Rationale 
15 
3.7.1. 
Clinical Dose Selection .................................................................................................................. 15 
3.7.2. 
Cell shipment, preparation for administration and Infusion ........................................................ 15 
• 
Infusion Flow Rate ..................................................................................... 16 
Should the patient develop symptoms suggestive of intolerance of the maintenance flow rate, the rate 
of infusion may be reduced or the infusion stopped and restarted at the discretion of the treating 
physician. If a serious hypersensitivity reaction occurs (hypoxia, hypotension), the infusion may be 
terminated ................................................................................................................................................. 16 
4. 
ENROLLMENT AND WITHDRAWAL 
16 
4.1. 
Inclusion Criteria 
16 
4.2. 
Exclusion Criteria 
17 
4.3. 
Patient Withdrawal or Termination 
17 
5. 
TREATMENT PLAN 
17 
5.1. 
Study Schema 
 
17 
5.2. 
Dose 
19 
5.3. 
Interruption or Discontinuation of Infusion 
19 
6. 
TREATMENT PROCEDURES AND OBSERVATIONS 
20 
6.1. 
Safety Evaluation 
20 
6.1.1. 
Laboratory and clinical Evaluations .............................................................................................. 20 
6.1.2. 
Other Safety Considerations......................................................................................................... 21 
7. 
TREATMENT VISIT SCHEDULE 
22 
8. 
ASSESSMENT OF SAFETY 
24 
8.1. 
Specification of Safety Parameters 
24 
8.1.1. 
Definition of Adverse Events (AE) ................................................................................................. 24 
8.1.2. 
Definition of Serious Adverse Events (SAE) .................................................................................. 24 
8.2. 
Classification of an Adverse Event 
24 
8.2.1. 
Grading of Adverse Event ............................................................................................................. 24 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 7 of 32 
8.2.2. 
Relationship to INVESTIGATIONAL Agent ..................................................................................... 24 
8.2.3. 
Expectedness ................................................................................................................................ 25 
8.3. 
Time Period and Frequency for Event Assessment and Follow-Up 
25 
8.3.1. 
Adverse Event Reporting .............................................................................................................. 25 
8.3.2. 
Serious Adverse Event Reporting ................................................................................................. 25 
8.4. 
Stopping Rules 
25 
9. 
STATISTICAL CONSIDERATIONS 
26 
9.1. 
Sample size justification 
26 
9.1.1. 
Phase I .......................................................................................................................................... 26 
9.1.2. 
Phase II ......................................................................................................................................... 26 
9.2. 
Randomization Plan 
26 
9.3. 
Analysis Populations 
27 
9.4. 
Analysis Plan 
27 
10. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
27 
10.1. 
Ethical Conduct of Treatment Plan 
27 
10.2. 
Institutional Review Board 
28 
10.3. 
DATA AND SAFETY MONITORING BOARD 
28 
10.4. 
Informed Consent Process 
28 
10.4.1. Consent and Other Informational Documents Provided To Patients ........................................... 28 
10.4.2. Consent Procedures and Documentation .................................................................................... 29 
10.5. 
Patient and Data Confidentiality 
29 
11. 
LITERATURE REFERENCES 
30 
 
 
 
 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 8 of 32 
1. LIST OF ABBREVIATIONS 
 
 
ABG 
Arterial blood gas 
AE 
Adverse event 
ALC 
Absolute Lymphocytic Count 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CCBB 
Carolinas Cord Blood Bank 
COVID 
Coronavirus (COVID-19) or SARSoCoV-2, 2019 Novel Coronavirus, nCov 
CRP 
C-reactive protein 
CT 
Computerized tomography 
CT CAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
ECMO 
Extracorporeal membrane oxygenation 
ESR 
Erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
GCS 
Glasgow coma scale 
hCT-MSC 
Human cord tissue mesenchymal stromal cells 
HLA 
Human leukocyte antigen 
INR 
International normalized ratio 
LAR 
Legally Authorized Representative 
LDH 
Lactic acid dehydrogenase 
MAP 
Mean arterial pressure 
MSC 
Mesenchymal stromal cells 
NCI 
National Cancer Institute 
PaO2/FiO2 arterial oxygen partial pressure/fractional inspired oxygen 
PCR 
Polymerase chain reaction 
PEEP 
Positive end expiratory pressure 
pH 
power of hydrogen, refers to acidity or alkalinity 
PT 
Prothrombin time 
RT-PCR 
reverse transcription-polymerase chain reaction 
UOP 
Urinary output 
SAE 
Severe adverse event 
SARS-CoV-2 Severe acute respiratory syndrome 
WBC 
White blood count 
 
 
2. PROTOCOL SYNOPSIS 
 
 
This is a 50 patient, Phase 1/2a multi-center pilot study to test the safety and to describe the 
preliminary efficacy of intravenous administration of allogenic human cord tissue mesenchymal 
stromal cells (hCT- MSC) as an investigational agent, under U.S. INDs 19968 (Duke) and 19937 (U 
Miami) to patients with acute respiratory distress syndrome (ARDS) due to COVID-19 infection 
(COVID-ARDS). Patients will be eligible for treatment with 3 daily consecutive doses of hCT-MSC at 1 
million cells/kg (max dose 100 million cells) in the phase 1 portion of the study or a fixed dose of 100 
million cells daily x 3 days, 12-36 hours apart in the phase 2 portion of the study, if they have a 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 9 of 32 
confirmed diagnosis of COVID-19 and meet clinical and radiographic criteria for ARDS. The primary 
endpoint is short-term safety of hCT-MSC infusions given on this schedule. The key secondary 
endpoints are 28 day survival, an increase in PaO2/FiO2 ratio by 50% at 96 hours, days to hospital 
discharge to home or rehab, and number of days requiring mechanical or non-invasive ventilation or 
high flow nasal cannula. 
 
The study will be executed in two phases.  The first 10 consecutive patients will all receive 
investigational product. The second part of the study is a randomized, controlled trial in 40 additional 
patients. The overall aim of the study is to establish safety and to gain critical information as to 
whether patients with COVID-ARDS will benefit from MSC infusions. Results from the first 10 patients 
will be compared with concurrent outcomes utilizing standard of care treatments in participating 
hospitals and in published reports in the medical literature. Results from the additional 40 patients 
will be analyzed as a randomized placebo control trial. The trial is relying on focused eligibility of the 
participants (patients with ARDS), single cohort with short trial time (4 weeks), and simple 
assessment of clinical outcome (survival, improvement of ARDS). This is a sequential design in the 
sense that after the first 10 patients are evaluated a decision will be made by the PIs and the Data 
Safety Monitoring Board whether to proceed with the exploratory randomized portion of the study. 
 
The MSCs are manufactured from allogeneic cord tissue donated to the Carolinas Cord Blood Bank 
(CCBB) at Duke University. The CCBB is an FDA licensed public cord blood bank (licensed name 
DUCORD). Cord tissue is donated by mothers delivering healthy term male babies by Cesarean 
section, after written informed consent from the newborn infant’s mother. Full donor screening and 
testing is performed in accordance with regulatory requirements (21CFR 1271). The hCT-MSCs will 
be manufactured in the Marcus Center for Cellular Cures in the Robertson GMP Cell Manufacturing 
Laboratory and the Clinical Research Cell Manufacturing Program (CRCMP) laboratory, 
Interdisciplinary Stem Cell Institute (ISCI), Miller School of Medicine, University of Miami. These hCT-
MSCs are already being utilized in clinical trials to treat pediatric patients with autism spectrum 
disorder (IND 17313), cerebral palsy (IND 17921), hypoxic ischemic encephalopathy (IND 17313) and 
adults with osteoarthritis of the knee (IND18414). To date, over 210 doses of cells have been 
delivered to patients on these clinical trials with an excellent safety profile.  At University of Miami, 
hCT-MSCs are used in the clinical trial to evaluate cytokine suppression in patients with chronic 
inflammation due to metabolic syndrome (IND 17324), 12 subjects in the pilot phase of the study 
had completed the dose without any treatment emergence SAE. 
 
The rationale for using this approach for patients infected with COVID-19 is that ARDS, the rate-
limiting complication impacting survival, is caused, at least in part, by a cytokine release syndrome 
(CRS) which results is severe immune dysregulation. Involved cytokines include IL-6, IL-8, IL-10, THP-
1M, TNF-alpha, and others. MSCs have strong anti-inflammatory and immune-modulatory activities 
without apparent toxicity or further immunosuppression. Approximately 3-5 % of patients with 
COVID-19 develop ARDS which carries a very high mortality rate (30-60%)   due to multi-system organ 
failure. Effective treatment of ARDS, the most feared complication of COVID-19, may convert the 
COVID-19 pandemic into a more manageable “flu-like” illness that every American is expected to 
experience, and most will survive, on an annual basis. 
 
 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 10 of 32 
3. 
BACKGROUND AND RATIONALE 
 
 
3.1. SARS-COVID-19 
Infection with systemic acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 
COVID-19, has led to a global pandemic.1 Postulated to have originated from a zoological source, this 
disease is characterized by the hallmark feature of respiratory illness. Currently, transmission is 
occurring rapidly from human to human with an array of different clinical features ranging from 
asymptomatic carriers to a frequently fatal acute respiratory distress syndrome requiring intubation 
and mechanical ventilation.2,3,4 Common clinical features include fever, dry cough and dyspnea. 
However, the majority of patients are asymptomatic or have minimal flu-like symptoms. At this time, 
diagnosis is confirmed by real time PCR (qPCR) of a respiratory or nasopharyngeal isolate. Chest 
radiographs may show alveolar or interstitial opacities and CT imaging of the chest typically shows 
areas of ground glass and/or consolidation. In its most severe form, COVID-19 leads to acute 
respiratory distress syndrome (ARDS), thought to be due to inflammatory and oxidant injury 
resulting in increased alveolar permeability and impaired gas exchange.5-8 Other than supportive 
care, there is no effective treatment for ARDS, and patients commonly die from sepsis or multi organ 
failure.9,10 To date, multiple drug regimens have been tested in clinical trials for the treatment of 
COVID-19 induced ARDS, including Remdesivir (Gilead) which reduced recovery time by 31% and was 
recently approved by the FDA for emergency use authorization, however drug availability is 
extremely limited and not routinely clinically available at this time. Other immunomodulators, such 
as IL-6 inhibitors and anti-malarials have shown conflicting results. However, the use of MSCs offers 
a unique therapeutic option for patients with ARDS that might shorten time to lung injury 
resolution.11,12 Seven patients with COVID-19 infection received 1 x10 6 MSCs/Kg in Shanghai, China 
with significant improvement in all patients 2 days after infusion.13 After treatment, their C- reactive 
protein and TNF-α decreased, and the over activated cytokine-secreting immune T and NK cells 
disappeared. There were no adverse effects due to the MSCs infusion. The investigators concluded 
that MSCs were safe and effective in patients with COVID-19 pneumonia, especially those in critical 
condition. An additional recent report of a meta-analysis of MSC therapies (all sources) for COVID-
ARDS reviewed 9 studies reporting outcomes of 200 participants and showed a favorable safety 
profile with a trend towards improved X-Ray findings, pulmonary functions, and inflammatory 
biomarker levels.14 
 
Here we propose the use of Mesenchymal Stromal Cells for treatment of severe infection 
characterized by ARDS in patients with a confirmed diagnosis of COVID-19. 
 
3.2. RATIONALE FOR TREATMENT PLAN 
MSCs from various sources (adipose tissue, bone marrow, and cord tissue) are in clinical trials for 
patients with a variety of pulmonary conditions including but not limited to pulmonary fibrosis,15-17 
non- CF bronchiectasis, asthma, bronchopulmonary dysplasia, and acute respiratory distress 
syndrome (ARDS).18 The rationale for this approach is that MSCs have anti-inflammatory properties 
without apparent toxicity and may provide similar to superior results with less toxicity than 
conventional pharmaceutical treatments.19-24 Furthermore, MSCs have been shown to have 
antimicrobial activities,25 which, in preclinical models, have been shown to eliminate certain 
bacteria and mycobacteria from animal, and tissue culture models of cystic fibrosis. Adipose derived 
MSCs from younger mice have also been shown to have superior activity compared to MSCs from 
older mice in a chronic mouse model of Bleomycin-induced pulmonary fibrosis.26 Human MSCs have 
been found to reduce influenza A H5N1- associated acute lung injury in mice with a direct impact on 
survival.27 In another study, 2 patients with severe ARDS were treated with MSCs on a 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 11 of 32 
compassionate basis at Karolinska Institute, and showed resolution of respiratory, hemodynamic, 
and multi-organ failure.28 A decrease in multiple pulmonary and systemic markers of inflammation 
was seen as well as suppression of T-cell responses and induction of regulatory phenotypes in T-
cells, monocytes, and neutrophils. Furthermore, a 17 patient group with influenza H7N9 ARDS 
treated with menstrual-blood derived MSCs in China had substantially lower mortality than the 
control group of untreated ARDS patients (17.6% versus 54.5% death).29 Ongoing, unpublished work 
from investigators at the University of Miami and Duke has shown that cord tissue derived MSCs 
have higher potency compared to bone marrow and adipose derived MSC from young mice and 
older mice. MSCs also can differentiate into alveolar epithelial cells in vitro, although their capacity 
to do this in vivo is not known.30 This has led to the hypothesis that MSCs may work through both 
anti-inflammatory, immune-modulatory, and regenerative mechanisms in vivo.31-40 
In this study, we will test the safety and describe the efficacy of human cord tissue derived MSCs 
(hCT-MSC) in patients with COVID-ARDS. It is hypothesized that COVID-ARDS occurs as a 
consequence of a cytokine storm (or cytokine release syndrome, CRS) and occurs in ~3-5% of 
COVID-19 infected patients. Involved cytokines include IL-6, IL-8, IL-10, THP-1M, TNF-alpha, and 
others. hCT-MSCs have been shown to suppress RNA expression and secretion of these cytokines 
by macrophages and T-cells in vitro. They also have a higher proliferative capacity than MSCs 
derived from adult derived bone marrow or adipose tissue.41 hCT-MSCs, manufactured at Duke 
in the Robertson GMP Cell Manufacturing Laboratory in the Marcus Center for Cellular Cures, 
have been tested in 115patients in clinical trials under INDs 17313, 17921 and 18414 over the 
past 4 years.42 Safety profiles have been extremely favorable. We now propose to utilize these 
cells in a sequential study where part I is a Phase 1 safety study in 10 consecutive adult patients 
with COVID-ARDS dosing at 1 million cells/kg (max dose 100M cells) given intravenously, daily x 
3. The primary endpoint of this study is safety. Key secondary endpoints are 28 days survival, an 
increase in PaO2/FiO2 ratio by 50% at 96 hours, days to hospital discharge to home, and number 
of days requiring mechanical ventilation. If safety is demonstrated in this 10 patient cohort, a 
second phase of this trial will describe the efficacy of hCT-MSCs in an additional cohort of 40 
patients who will be randomized in a blinded fashion 2:1:1 to placebo, hCT-MSC manufactured 
at Duke, or hCT-MSC manufactured at Miami. This randomization plan will yield 20 participants 
on placebo and 10 in each of the hCT-MSC arms. The two hCT-MSC arms will be pooled for 
analyses comparing treated patients to placebo. 
 
Phase I, Safety 
 
 
 
 
 
 
Phase II Randomization, Efficacy 
 
Placebo 
 
 
 
 
 
hCT-MSCs 
 
 
 
 
 
 
 
 
10 patients 
1x10^6/kg patient weight 
(max 100x10^6) 
20 patients 
10 patients 
DUKE 
Fixed dose 100x10^6 
10 patients 
UNIVERSITY OF MIAMI 
Fixed dose 100x10^6 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 12 of 32 
 
3.3. OBJECTIVES 
The Primary Objective of this study is safety of the Investigational Product, hCT-MSCs. 
The primary endpoint is safety measured by:  
1. Incidence of infusion reactions 
2. Incidence of later reactions attributed to the investigational product Formation of new anti-
PRA antibodies 
 
The Secondary Objective of this study is to describe the potential for MSC therapy to favorably 
alter the course of COVID-ARDS. Endpoints are: 
1. Time to recovery, defined as discharge from the hospital (alive) or remaining in the hospital 
without the need for supplemental oxygen or other COVID-related medical care. 
2. Increase in PaO2/FiO2 ratio by 50% by Day 4 (96 hours after first infusion).  PaO2/FiO2 may be 
calculated from an arterial blood gas or imputed from the SpO2/FiO2 table (Brown, et al. Chest 
2016). 
3. Days to hospital discharge to home 
4. # of ventilator free days 
5. # of days requiring O2 support 
6. Feasibility of accrual to the randomized portion of this study 
 
3.4. ALLOGENEIC, HUMAN CORD TISSUE-DERIVED MSC - Duke 
The Marcus Center for Cellular Cures at Duke University, is manufacturing third party, allogeneic, 
human cord tissue-derived MSCs (hCT-MSC) in the Robertson GMP Cell Manufacturing Laboratory 
which are being utilized in clinical trials to treat pediatric patients with autism spectrum disorder 
(IND 17313), cerebral palsy (IND 17921), hypoxic ischemic encephalopathy (IND 17313) and adults 
with osteoarthritis of the knee (IND18414). Manufacturing is identical for all products used in these 
clinical trials. The final product is a cryopreserved P2 product that is thawed and diluted on the day 
of infusion. 
 
The MSCs are manufactured from cord tissue donated to the Carolinas Cord Blood Bank at Duke, a 
FDA licensed public cord blood bank (DUCORD), by mothers delivering healthy term male babies by 
Cesarean section, after full written informed consent from the newborn infant’s mother. Full donor 
screening and testing is performed in accordance with regulatory requirements. The cord tissue is 
harvested in the operating room and placed in a sterile container containing 200mL of sterile 
Plasmalyte-A solution without antibiotics. The tissue is transported in a validated container at room 
temperature by a dedicated and trained courier to the manufacturing lab on the same day of the 
baby’s delivery. In the GMP lab, in the clean room, it is cut into 2” sections and digested with 4 GMP 
grade enzymes (DNAase, collagenase, alpha hyaluronidase, and papain) on the Miltenyi Octo tissue 
dissociator. The resultant cell suspension is plated in a cell stack with SXFM media (Irving Scientific) 
supplemented with human platelet lysate in a 5-layer cell stack flask (Corning) and cultured for 7-10 
days. When confluent, the cells are harvested (P0) and replated in hyperstacks (Corning) for 7-8 days 
to confluence and harvested (P1) and then replated again and cultured to P2. The P2 harvest is 
washed and cryopreserved in a final concentration of 10% DMSO in dextran in 5 finger cryobags (Pall 
Medical), frozen in a controlled rate freezer and stored in the vapor phase of liquid nitrogen until 
use. A portion of the P0 and P1 cells are also cryopreserved and stored as part of a master (P0) and 
working (P1) cell bank during manufacturing. 
 
A representative P2 dose is thawed and tested for characterization (phenotype and differentiation), 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 13 of 32 
sterility (bacT-alert and adventitial virus testing), endotoxin, mycoplasma, P53 mutation, and 
functional assays (suppression of third party T-cell proliferation and suppression of microglial 
activation). All assays must pass specifications for release. Stability for the post thaw product is 4 
hours at room temperature. 
 
On the day of infusion, the product is thawed, diluted 1:1 with Plasmalyte-A with 5% Human Serum 
Albumin (HSA), and assessed for total nucleated cell count and viability on a Cellometer. The volume 
needed for the patient’s dose is then calculated, removed and diluted in additional Plasmalyte-A 
with 5% HSA to 20-40mL and taken to the bedside for infusion. The release specification for viability 
post thaw is >70%. 
 
3.5. ALLOGENEIC, HUMAN CORD TISSUE DERIVED MSC – University of Miami 
Clinical Research Cell Manufacturing Program (CRCMP) at the University of Miami has manufactured 
allogeneic hCT-MSCs from sourced cord tissue obtained from Carolinas Cord Blood Bank (CCBB) at 
Duke.  Screening of allogeneic donors will follow standard transplant practices and all allogeneic 
donors will meet allogeneic donor eligibility criteria as outlined in 21 CFR Part 1271 including FDA 
screening guidance on Zika and SAR CoV-2 The allogeneic hCT-MSCs will be derived from normal 
donors meeting criteria for allogeneic unrelated human cord tissue.  
 
Cell manufacturing is done at the Clinical Research Cell Manufacturing Program (CRCMP) laboratory, 
Interdisciplinary Stem Cell Institute (ISCI), Miller School of Medicine, University of Miami. Cells are 
manufactured in compliance with current Good Manufacturing Practice (cGMP) and current Good 
Tissue Practice (cGTP) regulations. CRCMP is accredited by Foundation for Accreditation of Cellular 
Therapy (FACT) and American Association of Blood Bank (AABB).  In brief, umbilical cord tissue will 
undergo the process to obtain MSCs. Cells obtained in initial passages are cultured and expanded in 
three passages. The expansion is performed in tissue culture flasks incubated in 37°C, 5% CO2 
humidified incubators.  At the final passage, MSCs are counted and cells viability are determined. 
Samples are collected for cell phenotypes assay, mycoplasma PCR testing, sterility testing, adventitial 
virus testing, and endotoxin assay. After harvest, cells are aliquoted into cryopreservation bags 
containing 120 to 130 million cells and cryopreserved using a control rate freezer. The bags are stored 
in the vapor phase liquid nitrogen storage cryogenic freezers at ≤ -120 °C.  
 
The cryogenic freezer is located in the secured storage area accessible only by authorized personnel. 
Laboratory Director and Quality Assurance Manager will review the production records and quality 
control testing results to release the product for clinical use. 
 
For cell manufacturing of hCT-MSC, cross-references to CMC sections of University of Miami is 
provided with this application. Please refer to cross reference letter to BB IND #17324 of University of 
Miami. 
 
3.6. CLINICAL EXPERIENCE WITH HCT-MSC 
The current hCT-MSC product manufactured at Duke  has been used in >90 children given >160 doses 
of 12-6 million hCT-MSC/kg intravenously, in approximately 54 adults with OA of the knee at 10-20M 
cells/dose given directly into the knee joint, and in 1 adult with bronchiectasis under an IND at a dose 
of 100 million total cells. In the proposed Phase 1 pilot portion of this study, we capped the dose per 
infusion at 100 million cells (total absolute dose) to follow conventions in an ongoing trial where 
absolute doses of 200 million cells appeared less effective than 100 million cells.   

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 14 of 32 
 
The first 10 patients enrolled in this study were enrolled on the Phase 1, open label portion of this 
study.  That cohort was fully enrolled with 8 patients treated at DUMC and 2 patients treated at the 
Boca Raton Regional Hospital.   The median age of the patients was 61.5 years (29-79 years), 70% 
were female, 60% were Caucasian, and 30% were Hispanic. There were 4 SAEs reported in the trial, all 
resulting in death occurring on days 7, 27, 39, and 344 on study.  None were deemed related to the 
MSC product.  The MSC product infusions were well tolerated.  There were no infusion related AEs or 
SAEs.   
 
3.6.1 
SAFETY 
All patients will be pre-medicated before each dose of hCT-MSCs with a parenteral dose of 
diphenhydramine (12.5-25mg) and hydrocortisone 0.5 mg/kg IV approximately 30-60 minutes 
prior to infusion. Using this approach, infusion- associated reactions are uncommon (<1%) and 
mild. Observed reactions consist of, rash, bronchospasm and rarely, transient hypotension. If an 
adverse event occurs after the first or second dose, the subsequent doses will not be 
administered. 
 
The following adverse events, deemed not related to the MSC product have been reported in 
patients receiving BM-MSCs for treatment of graft versus host disease following a blood or 
marrow transplant where more than 1,000 adults have been treated: increased blood pressure, 
low blood pressure, difficulty breathing, pain in the abdomen or stomach, abdominal distension, 
bleeding in the gastrointestinal tract, swelling in legs or arms, nausea, vomiting, diarrhea, 
dizziness, itching, rash, fever, elevation of blood cells (eosinophils), increase in blood levels of 
various laboratory values (including alkaline phosphatase, creatinine, lactate dehydrogenase, 
alanine transaminase and glucose), hypocalcemia, ascites, kidney impairment, hepatomegaly, 
neutropenia, thrombocytopenia graft versus host disease, chest discomfort, chest pain, oral 
yeast infection, muscle weakness, joint pain, back pain, cold sweat, headache, and depression. 
 
Other theoretical risks include engraftment and differentiation of transplanted MSCs with 
ectopic tissue formation. In addition, MSCs in the paracrine and endocrine systems may promote 
tumor growth and metastasis by diminishing or suppressing the antitumor immunity and 
inducing neovascularization. 
 
Long term safety information of the use of MSCs is still unknown, but 10 year follow-up in 
hundreds of treated patients has not revealed any serious problems to date. 
 
Risks associated with the use of diphenhydramine include dizziness, sedation, dry mucous 
membranes, dryness of the nose and throat, and thick sputum. Allergic reaction can occur, 
which would, include swelling of the throat and trouble breathing. 
 
Possible side effects of corticosteroids include fluid retention and weight gain, muscle weakness, 
peptic ulcer; high blood pressure; permanent changes in the bones; increase in infection risk and 
hyperglycemia. 
 
 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 15 of 32 
 
3.7 TREATMENT PROTOCOL PROCEDURES RATIONALE  
3.7.1 
 CLINICAL DOSE SELECTION 
The dose for the first 10 patients will be 1 million cells/Kg (with a maximum dose of 100 million 
cells) with 70% viability post thaw. The dose for the subsequent randomized patients will be 
100 million cells (absolute fixed dose) daily x 3 days without adjustment for weight.  Analysis of 
total nucleated cell count and nucleated cell viability is determined in an automated device 
called a Cellometer (Nexcelom). This dose has been derived from previous clinical studies where 
hCT-MSCs have been infused at a dose of 2-6 million cells/Kg. 
3.7.2 
CELL SHIPMENT, PREPARATION FOR ADMINISTRATION AND INFUSION - Duke 
The hCT-MSC cells manufactured at Duke will be shipped prior to initiation of treatment from the 
Robertson GMP Cell Manufacturing Laboratory at Duke University to the outside treatment 
site(s) in a dry shipper validated to maintain temperatures <-150 degrees C for 8 days. The cells 
can be maintained in the dry shipper or transferred to a vapor phase liquid nitrogen freezer 
which is continuously monitored for temperature. On the day of infusion, the cells will be thawed 
in a cell therapy laboratory or in a room near the bedside at the infusion site, per standard 
operating procedure, and aspirated into a sterile syringe containing an equal volume of 
PlasmaLyte-A with 5% HSA. A TNCC and viability will be performed and cell dose adjusted to 1 
million cells/kg with a viability of >70% (maximum dose 100 million cells). After this initial 
dilution, the volume containing the dose for the patient will be further diluted into additional 
PlasmaLyte-A + 5% HSA to a total volume of 80mL placed into a transfer bag, and transported to 
the bedside. There they will be administered over approximately 30-60 minutes by gravity. Three 
daily infusions, 12-36 hours apart will be administered as long as the patient does not have a 
reaction or other adverse event after the first or second infusion. If an infusion reaction or 
adverse event related to the hCT-MSC infusion occurs, subsequent infusions will not be 
administered. For the first 3 consecutive patients on the phase 1 portion of the study there will 
be a 3 day staggering interval between consecutive patients before the next patient is treated. 
After the first 3 patients have no detected acute and/or subacute adverse events, the study will 
continue with open enrollment to complete 10 consecutive patients in phase 1.  For phase 2, 
patients will be randomized 2:1:1 against placebo with patients randomizing to MSCs will be 
further randomized to receive either Duke of Miami cells. 
After release, the labeled product will be delivered and issued to the appropriate medical staff in 
a validated temperature monitored cooler. Clinical coordinator or medical staff maintains 
custody of the product container to ensure that the product is kept in the proper temperature 
until it is ready to be removed for infusion.   
 
3.7.2.1 CELL SHIPMENT, PREPARATION FOR ADMINISTRATION – University of Miami 
The hCT-MSC cells manufactured at the University of Miami will be shipped prior to initiation of 
treatment from CRCMPlab at the University of Miami.  Upon receiving request for product, a 
product(s) bag with the appropriate dose is assigned. The preparation of the final product for 
administration will follow the Standard Operating Procedures maintaining under 
standardization of procedures. The principal investigator at clinical site will submit a signed 
request for the final product with date and time of product infusion to processing laboratory 
prior to the scheduled date. On the day of product infusion, the appropriate number of 
released frozen bags will be thawed in a 37±1°C water bath. In a biological safety cabinet, the 
cell suspension is transferred to conical tubes and slowly diluted with buffer containing 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 16 of 32 
PlasmaLyte A supplemented with 1% human serum albumin (HSA). The diluted suspension will 
be centrifuged and the cell pellet will be suspended in the dilution buffer. Viability and cell 
count will be measure on a cellometer (Nexcellom). The cells will be centrifuged and the cell 
pellet resuspended in the buffer to a required dose in a total volume of 80mL.  Cell dose will be 
loaded into an infusion bag. The prepared product will undergo a final inspection and release 
process.  
After release, the labeled product will be delivered and issued to the appropriate medical staff 
in a validated temperature monitored cooler. Clinical coordinator or medical staff maintains 
custody of the product container to ensure that the product is kept in the proper temperature 
until it is ready to be removed for infusion.   
 
3.7.2.2 PLACEBO 
The placebo for this study will be comprised of 40-80 mL of Plasmalyte-A + 1% Human Serum 
Albumin (HAS) prepared in an identical container to the one used for cell administration. The 
placebo product will undergo the same process of sterility testing including release inspection, 
transport and product custodian. 
 
3.7.2.3  INFUSION FLOW RATE 
Prior clinical trials have used flow rates up to 30×106 hMSC/min where no infusion related 
toxicity was observed. In the proposed study, the rate of infusion will be conservatively 
assessed based on patient-specific tolerance of infusion observed by real time assessment by 
the treating physician. The infusion will be targeted to infuse between 30-60 minutes but 
definitely before the expiry of the thawed cells (4 hours).  
SHOULD THE PATIENT DEVELOP SYMPTOMS SUGGESTIVE OF INTOLERANCE OF THE 
MAINTENANCE FLOW RATE, THE RATE OF INFUSION MAY BE REDUCED OR THE INFUSION 
STOPPED AND RESTARTED AT THE DISCRETION OF THE TREATING PHYSICIAN. IF A SERIOUS 
HYPERSENSITIVITY REACTION OCCURS (HYPOXIA, HYPOTENSION), THE INFUSION MAY BE 
TERMINATED. 
 
4. 
ENROLLMENT AND WITHDRAWAL 
 
 
All patients will receive standard ICU monitoring and all available supportive care for their condition, 
including oxygen, antibiotics, bronchodilators, mechanical ventilation, antibiotics, etc., and any other 
FDA approved treatment for COVID-19 infection as per treating physician. 
 
4.1. INCLUSION CRITERIA 
1. The patient or legally authorized representative (LAR) must have the ability to understand 
and the willingness to provide a signed and dated informed consent form. 
2. Age 18 years and over 
3. The patient agrees to use adequate contraception for the duration of the treatment 
protocol and for 6 months post treatment. 
4. Positive RT- PCR testing for COVID-19 nucleic acid using nasopharyngeal swabbing or any 
other site 
5. Patient meets ARDS criteria and is on non-invasive or mechanical ventilation or high flow 
nasal cannula 
a. 
bilateral opacities on chest imaging consistent with pulmonary edema 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 17 of 32 
b. 
A need for positive pressure ventilation or high flow nasal cannula 
c. 
PaO2/FiO2 ratio ≤ 300 mmHg by arterial blood gas or SpO2/FiO2 imputation. 
d. 
Infiltrates not fully explained by cardiac failure or fluid overload in the 
physician’s  best clinical judgement 
6. Subjects requiring dialysis as a result of a COVID-19 infection will not be excluded. 
 
4.2. EXCLUSION CRITERIA 
1. Evidence of multiorgan failure involving one or more organs, excluding the lungs as 
defined below: 
a. 
Presence of shock, defined as MAP < 65 mmHg with signs of peripheral 
hypoperfusion, or continuous infusion of 2 or more vasopressor or inotrope 
agents to maintain MAP ≥ 65 mmHg. 
b. 
Serum bilirubin > 10 mg/dl 
c. 
Platelet count < 50,000/ml 
d. 
Subjects requiring dialysis as a result of anything other than a COVID-19 
infection will be excluded 
2. Evidence of acquired or congenital immunodeficiency (due to immunosuppressive 
therapy excluding steroid use for treatment of COVID-19 acute respiratory failure, HIV, 
previous treatment for cancer, etc.) 
3. History of metastatic cancer diagnosis or treatment in the past 1 year 
4. History of previous treatments with MSCs or other cell therapies 
5. Patient is co-enrolled in any other IND-sponsored clinical trials for COVID-19 or ARDs. 
Drugs that are administered under emergency use authorizations (EUA) by the FDA are 
permitted.  
6. Evidence of pregnancy or lactation 
7. Moribund patient not expected to survive >24 hours 
8. Unable/unwilling to deliver lung protective ventilation 
9. Patient is receiving Extracorporeal Membrane Oxygenation (ECMO) 
 
4.3. PATIENT WITHDRAWAL OR TERMINATION 
The patient is free to withdraw from this treatment protocol at any time upon request. The 
reason(s) for discontinuation of treatment should be recorded. 
 
The treating physician may terminate the treatment protocol if any clinical adverse event (AE) or 
other medical condition or situation occurs such that continued treatment would not be in the best 
interest of the patient. The patient will be followed by the treating physician for disease 
assessments unless the patient withdraws consent for follow up. 
 
5. 
TREATMENT PLAN 
 
 
5.1. STUDY SCHEMA 
This is a 50 patient study in two phases. Phase 1 is an open label safety pilot in 10 patients. Phase 2 is 
a small exploratory randomized placebo controlled study. The first 10 patients will be consecutively 
enrolled on an open label phase 1 trial giving 3 doses of hCT-MSCs once a day for 3 days. There will 
be a hold of 3 days, between each of the first 3 patients on the phase 1 open-labelled portion of the 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 18 of 32 
study, to observe for any early toxicity associated with the MSC infusions.  If there is not toxicity, the 
next 7 patients in the phase 1 portion of the study will proceed without any holds between patients. 
 
An interim analysis, for safety will be conducted and reviewed by the Data Safety and Monitoring 
Board (DSMB) after the first 10 patients have completed treatment and reached the 28 day 
endpoint. If there are no safety concerns, the trial will proceed with enrollment on the phase 2 
portion of the study where the subsequent 40 patients will be randomized in a 1:1 fashion between 
treatment with MSCs or placebo in a blinded fashion. 
 
 
 
 
 
 
 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 19 of 32 
5.2. DOSE 
The hCT-MSC infusion, 1 million cells/kg (maximum 100 million cells) with >70% viability (based on 
Cellometer), is infused over approximately 30-60 minutes for the first 10 patients. Subsequent 
patients, randomizing to treatment, will receive 100 million cells/dose per infusion without an 
adjustment for weight.  A second and third infusion of the same number of cells will be given 24 
hours (+/- 6 hours) and 48 hours (+/- 6 hours) later, respectively. 
5.2.1  DOSE ADMINISTRATION 
• 
Treatment will start within 72 hours from enrollment or when clinically indicated and the 
subject meets eligibility  
• 
IV placement 
• 
Premedication with each of the following given approximately 30-60 minutes prior to the 
hCT- MSC infusion: 
o 12.5-25 mg diphenhydramine IV; 
o 0.5mg/kg hydrocortisone IV 
o Note: if subjects are currently receiving decadron treatment, hydrocortisone may 
be omitted at the discretion of the PI. 
• 
hCT-MSC infusion, maximum 100 million cells, infused over approximately 30-60 minutes 
• 
Patient monitoring:  
o Vital signs including BP and respiratory rate will be taken every 15 minutes 
during the infusion and every 30 minutes for one hour after the infusion 
o Pulse oximetry monitoring during and for 1 hour after the infusion  
o 
Daily monitoring of pulse oximetry and vital signs in between infusions for a 
minimum of 4 days following the first infusion. 
 
5.3. INTERRUPTION OR DISCONTINUATION OF INFUSION 
At the time of the infusion, emergency medications will be located in close proximity to the bedside 
for use if a hypersensitivity reaction were to occur. The medications will include at a minimum 
epinephrine, solumedrol and diphenhydramine, albuterol (inhaled), and automated external 
defibrillator (AED) equipment will also be available. The personnel at the infusion site are trained in 
resuscitating procedures.  
In the event of an infusion-related reaction, e.g. generalized urticaria, cough, dyspnea, wheezing, 
hypoxia (pulse ox <90), the infusion will be stopped immediately. If medically indicated the patient 
will be treated with a second dose of diphenhydramine (up to 50mg IV), a second dose of steroids 
(e.g. solumedrol) (up to 60mg IV). If these signs or symptoms develop, the infusion will not be 
restarted and the therapy will be aborted. If this occurs after the first or second infusion, the 
subsequent infusions will not be administered. 
 
If the patient experiences a clinically significant Grade 3 or 4 adverse event (AE) considered by the 
treating physician to be related to the investigational product or due to the infusion procedure, the 
infusion will be stopped. Infusion may be restarted at the treating physician’s discretion if the AE 
responds to medical management; otherwise, the infusion should be discontinued permanently. 
 
 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 20 of 32 
6. 
TREATMENT PROCEDURES AND OBSERVATIONS 
 
6.1. SAFETY EVALUATION 
Safety will be evaluated through adverse event monitoring, clinical evaluations (i.e., vital signs, 
physical examinations), laboratory tests (i.e., hematology, serum chemistries, and urinalysis), lung 
injury severity (Murray lung injury score), oxygenation (PaO2/FiO2 ratio and oxygenation index), and 
microbiology (i.e. sputum cultures), chest imaging (i.e. chest CT) from the signing of informed 
consent and throughout the patient’s participation in this treatment protocol. 
6.1.1. LABORATORY AND CLINICAL EVALUATIONS 
• 
Baseline is at enrollment (within 3 days- excluding COVID-19 PCR test which can obtained 
within 90 days to avoid repeat testing). Days post infusion are calculated from the first 
infusion. The “*” signifies that the test results from standard of care testing will be used 
however, they do not need to be obtained specifically for the study  
• 
Height and weight with baseline physical examination 
• 
Hematology: hemoglobin, hematocrit, platelet count, white blood cell (WBC) count, and WBC 
differential at baseline, day of infusion, Day 4, Day 7*, and Day 28* 
• 
Coagulation: prothrombin time (PT)/aPTT/INR, D-dimer at baseline, Day 4*, and Day 28* 
• 
Serum chemistry: CRP, ESR, AST, ALT, LDH, total bilirubin, alkaline phosphatase, total protein, 
albumin, sodium, potassium, chloride, carbon dioxide, calcium, blood urea nitrogen (BUN), 
creatinine, creatinine clearance and glucose at baseline, day of infusion*, Day 4* , Day 7*, and 
Day 28*  
• 
Urinalysis*: pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and 
nitrite at baseline. Microscopy required only to follow-up clinically significant abnormal 
findings 
• 
Chest x-ray* at baseline, Day 4*, Day 7*, and Day 28* 
• 
ABGs prior, 1-4 hours after, Day 4*, Day 7*, and Day 28* 
• 
COVID-19 PCR at baseline (do not repeat testing if obtained within 90 days of enrollment), day 
4*, 7*, and 28* post treatment 
• 
Donor referral panel at baseline 
• 
HLA typing (high resolution class I and class II) at baseline 
• 
PRA (Anti-HLA antibodies) at baseline and day 28 
• 
PaO2/FiO2 and oxygenation index endpoints (based on invasive or non-invasive mechanical 
ventilation or high flow nasal cannula use). To be done at Baseline, Day 1, Day 2, Day 4, and if 
on continued ventilation - Day 7, and Day 14. PaO2/FiO2 may be calculated from an arterial 
blood gas or imputed from the SpO2/FiO2 table (Brown, et al. Chest 2016) 
• 
Day 28 mortality 
• 
Hospital discharge 
• 
Invasive or non-invasive mechanical ventilation-free days and oxygen-free days 
• 
Lung injury severity score (Murray) at Baseline, Day 1, Day 2, Day 4, Day 7, and Day 14. The 
most recent chest x-ray will be used to calculate the Murray score. For patients on pressure 
support mode ventilation, the peak pressure will be used in place of the plateau pressure to 
calculate compliance 
• 
Any laboratory or imaging can be repeated outside the protocol requirements at the discretion 
of the treating physicians 
 
 
 
 

Version: 7.0 / Date: 16 MAR2021 
 
Confidential 
 
 
Page 21 of 32 
 
 
Please see table of events for details and time windows for each of the tests. 
In addition, clinical data will be collected on other interventions that would be expected 
to affect oxygenation: 
 
a. 
Use and duration of prone ventilation 
b. 
Use and duration of neuromuscular blocker administration 
c. 
Use and duration of inhaled nitric oxide 
d. 
Use and duration of inhaled epoprostenol 
e. 
Use and duration of corticosteroids (methylprednisolone, prednisone, 
hydrocortisone, dexamethasone 
 
The treating physician will review all clinical laboratory results, and clinically significant findings 
will be reported as AEs and followed or treated according to institutional guidelines or the 
treating physician’s medical judgment. 
6.1.2. OTHER SAFETY CONSIDERATIONS 
Physical examinations (by PI, sub-I or clinical team) will be performed at baseline, following IV 
infusion (as clinically indicated by the clinical team), and daily during hospitalization. Patient 
will have a follow-up visit at Day 28 (+/-2 days) and 90 days after Day 1 of investigational 
product administration. Data analysis will commence at 28 days. Follow up at 90 days will be 
to assess for any delayed SAEs. Please see table of events for details. The baseline and end of 
treatment (or termination) examination will be a complete physical examination; other 
examinations should be focused, at the discretion of the treating physician, to assess changes 
from the previous examination. 
 
Other safety assessments will include vital signs and oxygen requirement. The treating 
physician will review all vital sign results and oxygenation parameters, and clinically 
significant findings will be reported as AEs and followed or treated according to institutional 
guidelines or the treating physician’s medical judgment. 
 
Any immediate hypersensitivity reaction after infusion will result in discontinuation of treatment. 
 
 

Version: 7.0 / Date: 16MAR2021 
Confidential 
Page 22 of 33 
 
 
 
7 
TREATMENT VISIT SCHEDULE 
 
 
 
Evaluation 
Baseline 
(within 3 days) 
Infusion Daysi 
Day 4 
Day 7 
( + 1 day) 
Day 14 
(+ 2 days) 
Day 28 
(+2 days) 
Day 90 
(+ 5 days) 
Informed Consent 
X 
Medical History, 
height, weight, and 
Demographics 
X 
Physical Exam 
X 
Xj 
X 
X 
 
Vital Signs a 
X 
Xbj 
Hematology c 
X 
X 
X* 
X* 
Serum Chemistry d 
X 
X* 
X* 
X* 
X* 
Coagulation e 
X 
X* 
X* 
Pregnancy Test f 
X 
EKG 
X* 
Urinalysis 
X* 
HLA Typing 
X 
PRA 
X 
X 
Donor screening 
panel 
X 
COVID PCR 
X 
X* 
X* 
X* 
Chest x-ray 
X* 
X* 
X* 
X* 
ABG 
X 
Xgj 
X* 
X* 
X* 
Pre-medications 
Xj 
Concomitant 
Meds 
X 
X 
X 
X 
X 
Adverse Events 
Assessment 
X 
X 
X 
X 
Lung Injury 
Severity Score 
(Murray) 
X 
XJ 
X 
X 
X 
X 
 
 
LAR 

Version: 7.0 / Date: 16MAR2021 
Confidential 
Page 23 of 33 
 
 
hCT-MSC Infusion 
 
Xh  
 
 
 
PaO2/FiO2 
X 
Xj 
X 
X 
X 
Prone Ventilationk 
X 
X 
X 
X 
Neuromuscular 
blockerk 
X 
X 
X 
X 
Inhaled nitric acidk 
X 
X 
X 
X 
Inhaled 
epoprostenaolk 
X 
X 
X 
X 
Corticosteroidsk 
X 
X 
X 
X 
Survival 
X 
X 
Oxygen use 
Xm 
 
a. Blood Pressure, Heart Rate, Respiratory Rate, Temperature, and 02 Saturation 
b. Vitals are taken prior to pre-medications, prior to infusion, every 15 minutes during infusion, every 30 minutes post infusion X 2, then 
hourly X 4. 
c. Hematology: Hemoglobin, Hematocrit, platelet count, White Blood Cells, and differential 
d. Chemistry: CRP, ESR, AST, ALT, LDH, total bilirubin, alkaline phosphatase, total protein, albumin, sodium, potassium, chloride, 
carbon dioxide, calcium, blood urea nitrogen, creatinine, creatinine clearance, glucose 
e. Coagulation: Prothrombin Time (PT)/aPTT/INR, D-dimer 
f. 
Pregnancy Test (WOCBP) Women of Child Bearing Potential. If done prior to baseline as part of hospitalization, this does not need to be 
repeated. 
g. ABGs to be done prior to infusion, and 1-4 hours after each infusion 
h. Three infusions will be given on days 1, 2 and 3. 
i. 
All Days will be calculated from the first infusion, or Day 1. 
j. 
These elements will be done on Day 1, Day 2, and Day 3. Premedications, and vital signs will also be done at each infusion. Physical 
exams will be done daily during hospitalization and data will be pulled from those clinical notes. 
k. Monitor the use, duration, and if applicable, the dose during hospitalization 
l. 
Only SAEs are gathered at Day 90 
m. If use of oxygen is required at Day 90 will be documented 
n. Day 28 is the time the primary endpoint will be evaluated. 
o. Day 90 is assessing survival, SAEs, and if oxygen is still required. This may be a face time interview via the telephone. 
p. Demographics will include Date of Birth, Sex, and Race. 
 
* The “*” signifies that the test results from standard of care testing will be used; however, they do not need to be obtained specifically for the study.

Version: 7.0 / Date: 16MAR2021 
 
Page 24 of 32 
 
8 
ASSESSMENT OF SAFETY 
 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS  
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
For the purposes of this treatment protocol, an adverse event (AE) is any untoward medical 
occurrence associated with the use of an intervention in humans, whether or not considered 
intervention-related (21 CFR 312.32 (a)). 
Progression of the patient’s lung disease, or events which are unequivocally due to disease 
progression, should not be reported as an AE (unless it is considered to be related to the 
investigational product by the treating physician). 
8.1.2. DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
For the purposes of this treatment protocol, a “serious” adverse event is defined in regulatory 
terminology as any untoward medical occurrence that: 
1. Results in death. 
2. Is life-threatening. 
The patient was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe. 
3. Requires in-patient hospitalization or prolongation of existing hospitalization. 
Note: Hospitalization (including hospitalization for an elective procedure) for a 
pre-existing condition which has not worsened does not constitute a serious 
adverse event. 
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
Any event that does not meet the above criteria, but that in the judgment of the 
treating physician jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of “Serious Adverse Event“. 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT  
8.2.1 GRADING OF ADVERSE EVENT 
For the purposes of this treatment protocol, all adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The CTCAE v5.0 is available 
at https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40 
8.2.2 RELATIONSHIP TO INVESTIGATIONAL AGENT 
For all collected AEs, the treating physician will evaluate the patient to determine the AE’s 
causality based on temporal relationship and his/her clinical judgment using the following 
categories: 
• 
Definite – The AE is clearly related to the treatment protocol. 
• 
Probable – The AE is likely related to the treatment protocol. 
• 
Possible – The AE may be related to the treatment protocol. 
• 
Unlikely – The AE is doubtfully related to the treatment protocol. 
• 
Unrelated – The AE is clearly NOT related to the treatment protocol. 

Version: 7.0 / Date: 16MAR2021 
 
Page 25 of 32 
 
8.2.3 EXPECTEDNESS 
Expected events are those that have been previously identified as resulting from administration of 
the investigational agent. An adverse event is considered unexpected, for expedited reporting 
purposes only, when either the type of event or the severity of the event is not listed in the 
current Product Label. 
8.3 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of the treating physician during patient 
visits or any other times the patient requires medical care. Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, relationship to investigational 
product (assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs will be followed to adequate resolution. 
Any condition present before the first treatment/infusion, including pre-existing conditions and pre- 
treatment protocol AEs, will be considered medical history and will not be reported as a treatment- 
emergent AE unless the condition worsens during or after infusion. Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a preexisting condition, which is 
temporally associated with the use of the investigational agent, is also an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Patients will be followed daily while in hospital and for 7 days after administration of infusion. In 
addition, patients will be followed up to 90 days after administration for severe adverse events 
and survival. However, data analysis will be conducted at 30 days for purposes of publication 
and dissemination of information. 
 
8.3.1 ADVERSE EVENT REPORTING 
The Institutional Review Board (IRB) of record must be notified of AE’s according to its policies. 
8.3.2 SERIOUS ADVERSE EVENT REPORTING 
Unexpected serious suspected adverse reactions will be reported to FDA on an expedited basis as 
per 21 CFR 312.32. 
8.4 STOPPING RULES 
The safety monitoring committee will consider stopping the trial if any one of the following events 
occur: 
1. Three deaths occur within 24 hours of MSC infusion (related or unrelated to study 
product) 
2. One Severe or Life-Threatening infusion-related reaction 
3. One death related to study product 
4. One case of graft versus host disease 
 
9 
STATISTICAL CONSIDERATIONS 
 
 
9.1 SAMPLE SIZE JUSTIFICATION 
This study will enroll and treat 10 patients with MSCs for the first, open label portion of the study. 

Version: 7.0 / Date: 16MAR2021 
 
Page 26 of 32 
 
The primary objective is to evaluate safety of this treatment in COVID-19 related ARDS. If safety is 
demonstrated, an additional 40 patients will be enrolled and randomized to hCT-MSC or placebo for 
the purpose of evaluating the potential benefit of hCT-MSC in COVID-19 related ARDS. 
9.1.1 PHASE I 
The first phase of the study is uncontrolled and the sample size is intended to support evaluation 
of safety. Therefore, as an alternative to power calculation we provide the following estimates of 
the probability of observing different types of product-related adverse reactions among the first 
10 enrolled patients based on binomial probabilities. 
 
With 10 patients enrolled and treated our study will have the following probability of identifying 
product-related adverse reactions that happen in 10%, 25% and 33% of infusions. These 
calculations show that even with 10 patients our study is likely to identify the most commonly 
occurring product- related adverse reactions. 
 
Background Rate of Product-Related 
Reaction 
Probability of Observing >= 1 Reaction 
in 10 Patients 
0.10 
0.65 
0.25 
0.94 
.33 
0.98 
 
9.1.2 PHASE II 
The second phase of the study will randomize 20 patients to placebo and 20 to hCT-MSC. The 
primary utility of the randomized phase of the trial is to evaluate the feasibility of conducting a 
larger, randomized trial comparing hCT-MSC to placebo, and to conduct descriptive analyses of 
efficacy outcomes. To enroll and randomize 90% of the eligible patients screened is a positive 
indicator of feasibility. The primary efficacy outcome of interest is time to recovery, defined as 
discharge from the hospital (alive) or remaining in the hospital without the need for supplemental 
oxygen or other COVID-related medical care. We expect based on previous research that 30% of 
patients in the placebo arm will recover at Day 28. This study is not powered to detect differences 
between arms except when those differences are large. Therefore, the approach to analysis will 
be descriptive. For example, with 20 patients per arm and no losses to follow-up, a 365-day 
accrual period and 28 days of follow-up per patient, the study would have 54% power to detect a 
doubling in the hazard of recovery with treatment (hazard ratio = 2.0) and 76% power to detect a 
hazard ratio of 2.5 using a log-rank test with 2-sided Type I error of 5%.  
 
9.2 RANDOMIZATION PLAN 
In Phase II of this study, a total of 40 participants will be randomized in a ratio of 2:1:1 to placebo, 
hCT-MSC manufactured at Duke, or hCT-MSC manufactured at Miami. This randomization plan will 
yield 20 participants on placebo and 10 in each of the hCT-MSC arms. The two hCT-MSC arms will be 
pooled for analyses comparing treated patients to placebo (see below). The infusion will be blinded 
so that the medical teams and the patients/LARs will not know which product (placebo, Duke MSC or 
Miami MSC) the patient receives.   There will be unblinded technicians in the laboratories preparing 
the cells and placebo for infusion, but the final product configuration will be the same for all 
infusions. 
 

Version: 7.0 / Date: 16MAR2021 
 
Page 27 of 32 
 
 
Phase I, Safety 
 
 
 
 
 
 
Phase II Randomization, Efficacy 
 
Placebo 
 
 
 
 
 
hCT-MSCs 
 
 
 
 
 
 
 
 
 
 
 
 
9.3 ANALYSIS POPULATIONS 
Given the differences in design, Phases I and II of the trial will be analyzed separately. All patients 
who are treated will be analyzed in Phase I. In Phase II the intention-to-treat principle will be 
adhered to such that participants are analyzed as assigned regardless of whether they receive the 
assigned treatment or otherwise deviate from the protocol. 
9.4 ANALYSIS PLAN 
Baseline characteristics of the participants will be summarized by study phase. The proportion of 
patients with infusion-related reactions and other unexpected product- related adverse reactions 
will be tabulated descriptively using CTCAE terminology. For Phase II, the time to recovery will be 
described using Kaplan-Meier plots comparing cumulative incidence in participants randomized to 
hCT-MSC with placebo. Results will be analyzed two ways: combining the two hCT-MSC arms vs. 
placebo, and each hCT-MSC arm separately vs. placebo. Other continuous, ordinal and binary 
outcomes will be analyzed in a similar fashion using appropriate descriptive statistics. 
 
10 ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
 
10.1 ETHICAL CONDUCT OF TREATMENT PLAN 
The treating physician is responsible for the conduct of this treatment plan in accordance with of the 
U.S. Code of Federal Regulations Title 21 Parts 50, 56, and 312, and the ethical principles originating 
from the Declaration of Helsinki. The treating physician is responsible for personally overseeing the 
treatment of the patient. The treating physician must assure that all clinical staff members, adhere 
to the treatment plan protocol and all FDA/GCP/NCI regulations and guidelines regarding single 
patient use/expanded access for an investigational agent. 
10 patients 
1x10^6/kg patient weight 
(max 100x10^6) 
20 patients 
10 patients 
DUKE 
Fixed dose 100x10^6 
10 patients 
UNIVERSITY OF MIAMI 
Fixed dose 100x10^6 

Version: 7.0 / Date: 16MAR2021 
 
Page 28 of 32 
 
10.2 INSTITUTIONAL REVIEW BOARD 
This treatment protocol is being reviewed by the Western Institutional Review Board (IRB) and will 
be the IRB of record. 
The protocol, informed consent form, and any patient materials will be submitted to the Institutional 
Review Board (IRB) of record for review before the patient is treated. 
10.3 DATA AND SAFETY MONITORING BOARD 
Safety will be overseen by a Data and Safety Monitoring Board (DSMB) throughout the duration of 
study conduct. At any time, the DSMB may recommend that dosing be modified or enrollment 
stopped due to safety concerns. The DSMB may also request to receive additional data unblinded to 
the subject level in response to identified safety concerns. Routine meetings are to be scheduled as 
determined by the DSMB. Ad hoc meetings will be convened if needed in response to safety 
concerns. The DSMB Charter will describe the composition of the DSMB and safety monitoring 
details, as well as the frequency of meetings needed as the study progresses. 
Members of Board 
Joe G. N. Garcia, MD 
The University of Arizona Health Sciences 
<skipgarcia@email.arizona.edu> 
520-626-1197 
 
Elizabeth J. Shpall, MD 
University of Texas MD Anderson Cancer Center 
<eshpall@mdanderson.org> 
713-745-2161 
 
Jennifer G. Le-Rademacher, PhD  
Mayo Clinic 
<Le-Rademacher.Jennifer@mayo.edu 
507-284-2511 
 
10.4 INFORMED CONSENT PROCESS 
10.4.1 CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PATIENTS 
A consent form describing in detail the investigational agent, treatment procedures, and risks are 
given to the patient or their legally authorized representative (LAR) and written documentation of 
informed consent is required prior to starting this treatment protocol. The consent form will 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the treating 
physician is assured that the patient understands the implications of participating in this 
treatment protocol, the patient will be asked to give consent to participate in the treatment plan 
by signing the consent form. Prior to the patient’s participation, the written informed consent 
form should be signed and personally dated by the patient, or the legally authorized 
representative (LAR), and by the person who conducted the informed consent discussion. 
 
If a subject or LRA is unable to connect in person with study personnel, the following methods can be 
used to obtain informed consent that meets the requirements of local regulations, ICH guidelines, 

Version: 7.0 / Date: 16MAR2021 
 
Page 29 of 32 
 
and the IRB/EC or study center, where applicable:  
 
• 
Review of the informed consent process will be provided via telehealth, phone, and/or 
videoconference (zoom health) in alignment with local regulatory guidance. During the 
remote informed consent process the subject, a witness, and someone from the study team 
will be present. 
  
Signatures of the informed consent can be obtained in any of the following ways:  
• 
Electronically (Docusign or Adobe Certificate); OR  
• 
Secure email or picture of the signed informed consent. This does not preclude a site from 
obtaining consent via paper, if such arrangements can be made, e.g. fax, mail.  
 
The following consent materials are submitted with this protocol:  
• 
Adult Informed Consent Form. 
10.4.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the patient’s agreement to participate in 
the treatment protocol and continues throughout the patient’s participation. Extensive discussion 
of risks and possible benefits of participation will be provided to the patient. Consent forms will 
be IRB- reviewed and the patient will be asked to read and review the document. The treating 
physician, or designee, will explain the treatment plan to the patient and answer any questions 
that may arise. The patient will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the treatment and of their 
rights as a patient. He will have the opportunity to carefully review the written consent form and 
ask questions prior to signing. The patient should have the opportunity to discuss the treatment 
with his surrogates or think about it prior to agreeing to participate. The patient will sign the 
informed consent document prior to any procedures being done specifically for the treatment 
plan. The patient may withdraw consent at any time throughout the course of the treatment.  
A copy of the informed consent document will be given to the patient for their records. The rights 
and welfare of the patient will be protected by emphasizing to him that the quality of their 
medical care will not be adversely affected if they decline to participate in this treatment protocol. 
 
10.5 PATIENT AND DATA CONFIDENTIALITY 
In accordance with the Health Information Portability and Accountability Act (HIPAA), if the patient 
has provided written informed consent, the patient must also allow the clinical staff, a regulatory 
authority, or Institutional Review Board access to patient’s medical information relevant to this 
treatment protocol. 
Patient confidentiality is strictly held in trust by the treating physician and their staff. This 
confidentiality is extended to cover testing of biological samples and genetic tests in addition to the 
clinical information relating to patients. Therefore, the treatment protocol, documentation, data, 
and all other information generated will be held in strict confidence. No information concerning this 
treatment protocol or the data will be released to any unauthorized third party without prior written 
approval of the patient. 
The patient’s contact information will be securely stored for internal use during this treatment 
protocol. At the end of the treatment, all records will continue to be kept in a secure location for as 
long a period as dictated by IRB of record and Institutional regulations. 

Version: 7.0 / Date: 16MAR2021 
 
Page 30 of 32 
 
11 LITERATURE REFERENCES 
 
 
1. Sohrabi C, Alsafi Z, O'Neill N, et al. World Health Organization declares global emergency: A 
review of the 2019 novel coronavirus (COVID-19) [published correction appears in Int J Surg. 
2020 Apr 15;:]. Int J Surg. 2020;76:71‐76. doi:10.1016/j.ijsu.2020.02.034 
2. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID- 
19) outbreak. J Autoimmun. 2020;109:102433. doi:10.1016/j.jaut.2020.102433 
3. Matthay MA, Aldrich JM, Gotts JE. Treatment for severe acute respiratory distress syndrome 
from COVID-19. Lancet Respir Med. 2020;8(5):433‐434. doi:10.1016/S2213-2600(20)30127-2 
4. ICNARC. “ICNARC report on COVID-19 in critical care 24 April 2020.” ICNARC Case Mix 
Programme Database, 24 April 2020. 
5. Aghasafari P, George U, Pidaparti R. A review of inflammatory mechanism in airway 
diseases. Inflamm Res. 2019;68(1):59‐74. doi:10.1007/s00011-018-1191-2 
6. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J 
Antimicrob Agents. 2020;55(3):105924. doi:10.1016/j.ijantimicag.2020.105924 
7. O'Dwyer DN, Gurczynski SJ, Moore BB. Pulmonary immunity and extracellular matrix 
interactions. Matrix Biol. 2018;73:122‐134. doi:10.1016/j.matbio.2018.04.003 
8. Moldoveanu B, Otmishi P, Jani P, Walker J, Sarmiento X, Guardiola J, Saad M, Yu J. Inflammatory 
mechanisms in the lung. J Inflamm Res. 2009;2:1-11 
https://doi.org/10.2147/JIR.S4385 
9. Fagon JY, Chastre J, Novara A, Medioni P, Gibert C. Characterization of intensive care unit 
patients using a model based on the presence or absence of organ dysfunctions and/or 
infection: the ODIN model. Intensive Care Med. 1993;19(3):137‐144. doi:10.1007/BF01720528 
10. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 
2000;342(18):1334‐1349. doi:10.1056/NEJM200005043421806 
11. Khoury M, Cuenca J, Cruz FF, Figueroa FE, Rocco PRM, Weiss DJ. Current Status of Cell-Based 
Therapies for Respiratory Virus Infections: Applicability to COVID-19 [published online ahead 
of print, 2020 Apr 7]. Eur Respir J. 2020;2000858. doi:10.1183/13993003.00858-2020 
12. Bing Liang,Junhui Chen,Tao Li,Haiying Wu,Wenjie Yang,Yanjiao Li,Jianchun Li,Congtao 
Yu,Fangang Nie,Zhaoxia Ma,Mingxi Yang,Panrong Nie,Yanfeng Gao,Chuanyun Qian,Min 
Hu.(2020).Clinical remission of a critically ill COVID-19 patient treated by human umbilical 
cord mesenchymal stem cells.[ChinaXiv:202002.00084] 
13. Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2- Mesenchymal Stem Cells Improves the 
Outcome of Patients with COVID-19 Pneumonia. Aging Dis. 2020;11(2):216‐228. Published 
2020 Mar 9. doi:10.14336/AD.2020.0228 
14. Wenchun, Qu, et al. “Cell-based Therapy to Reduce Mortality from COVID-19: Systematic 
review and meta-analysis of human studies on Acute Respiratory Distress Syndrome.” In 
press. 
15. Glassberg MK, Minkiewicz J, Toonkel RL, et al. Allogeneic Human Mesenchymal Stem Cells in 
Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I 
Safety Clinical Trial. Chest. 2017;151(5):971‐981. doi:10.1016/j.chest.2016.10.061 
16. Purdon S, Patete CL, Glassberg MK. Multipotent Mesenchymal Stromal Cells for Pulmonary 
Fibrosis?. Am J Med Sci. 2019;357(5):390‐393. doi:10.1016/j.amjms.2019.02.007 
17. Tzouvelekis A, Toonkel R, Karampitsakos T, et al. Mesenchymal Stem Cells for the Treatment 

Version: 7.0 / Date: 16MAR2021 
 
Page 31 of 32 
 
of Idiopathic Pulmonary Fibrosis. Front Med (Lausanne). 2018;5:142. Published 2018 May 15. 
doi:10.3389/fmed.2018.00142 
18. Matthay MA, Calfee CS, Zhuo H, et al. Treatment with allogeneic mesenchymal stromal cells 
for moderate to severe acute respiratory distress syndrome (START study): a randomised 
phase 2a safety trial. Lancet Respir Med. 2019;7(2):154‐162. doi:10.1016/S2213-
2600(18)30418-1 
19. Atluri S, Manchikanti L, Hirsch JA. Expanded Umbilical Cord Mesenchymal Stem Cells (UC-
MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for 
Compassionate Use. Pain Physician. 2020;23(2):E71‐E83. 
20. Matthay MA. Extracellular Vesicle Transfer from Mesenchymal Stromal Cells Modulates 
Macrophage Function in Acute Lung Injury. Basic Science and Clinical Implications. Am J 
Respir Crit Care Med. 2017;196(10):1234‐1236. doi:10.1164/rccm.201706-1122ED 
21. Schwede M, Wilfong EM, Zemans RL, et al. Effects of bone marrow-derived mesenchymal 
stromal cells on gene expression in human alveolar type II cells exposed to TNF-α, IL-1β, and 
IFN-γ. Physiol Rep. 2018;6(16):e13831. doi:10.14814/phy2.13831 
22. Volarevic V, Ljujic B, Stojkovic P, Lukic A, Arsenijevic N, Stojkovic M. Human stem cell 
research and regenerative medicine--present and future. Br Med Bull. 2011;99:155‐168. 
doi:10.1093/bmb/ldr027 
23. Volarevic V, Gazdic M, Simovic Markovic B, Jovicic N, Djonov V, Arsenijevic N. Mesenchymal 
stem cell-derived factors: Immuno-modulatory effects and therapeutic potential. Biofactors. 
2017;43(5):633‐644. doi:10.1002/biof.1374 
24. Xu T, Zhang Y, Chang P, Gong S, Shao L, Dong L. Mesenchymal stem cell-based therapy for 
radiation-induced lung injury. Stem Cell Res Ther. 2018;9(1):18. Published 2018 Jan 31. 
doi:10.1186/s13287-018-0776-6 
25. Kotas ME, Matthay MA. Mesenchymal stromal cells and macrophages in sepsis: new insights. 
Eur Respir J. 2018;51(4):1800510. Published 2018 Apr 26. doi:10.1183/13993003.00510-2018 
26. Tashiro J, Elliot SJ, Gerth DJ, et al. Therapeutic benefits of young, but not old, adipose-derived 
mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary 
27. fibrosis. Transl Res. 2015;166(6):554‐567. doi:10.1016/j.trsl.2015.09.004 
28. Chan MC, Kuok DI, Leung CY, et al. Human mesenchymal stromal cells reduce influenza A 
H5N1- associated acute lung injury in vitro and in vivo. Proc Natl Acad Sci U S A. 
2016;113(13):3621‐ 3626. doi:10.1073/pnas.1601911113 
29. Simonson OE, Mougiakakos D, Heldring N, et al. In Vivo Effects of Mesenchymal Stromal Cells 
in Two Patients With Severe Acute Respiratory Distress Syndrome [published correction 
appears in Stem Cells Transl Med. 2016 Jun;5(6):845]. Stem Cells Transl Med. 
2015;4(10):1199‐1213. 
30. Chen J, Hu C, Chen L, et al. Clinical study of mesenchymal stem cell treating acute respiratory 
distress syndrome induced by epidemic Influenza A (H7N9) infection, a hint for COVID-19 
treatment [published online ahead of print, 2020 Feb 28]. Engineering (Beijing). 2020;. 
doi:10.1016/j.eng.2020.02.006 
31. Harrell CR, Sadikot R, Pascual J, et al. Mesenchymal Stem Cell-Based Therapy of Inflammatory 
Lung Diseases: Current Understanding and Future Perspectives. Stem Cells Int. 
2019;2019:4236973. Published 2019 May 2. doi:10.1155/2019/4236973 
32. Abreu SC, Rolandsson Enes S, Dearborn J, et al. Lung inflammatory environments 
differentially alter mesenchymal stromal cell behavior. Am J Physiol Lung Cell Mol Physiol. 
2019;317(6):L823‐ L831. doi:10.1152/ajplung.00263.2019 

Version: 7.0 / Date: 16MAR2021 
 
Page 32 of 32 
 
33. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell 
responses. Blood. 2005;105(4):1815‐1822. doi:10.1182/blood-2004-04-1559 
34. Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen-
presenting cell maturation and induce T-cell unresponsiveness. Blood. 2005;105(5):2214‐
2219. doi:10.1182/blood-2004-07-2921 
35. Eggenhofer E, Hoogduijn MJ. Mesenchymal stem cell-educated macrophages. Transplant Res. 
2012;1(1):12. Published 2012 Sep 28. doi:10.1186/2047-1440-1-12 
36. Gazdic M, Volarevic V, Arsenijevic N, Stojkovic M. Mesenchymal stem cells: a friend or foe in 
immune-mediated diseases. Stem Cell Rev Rep. 2015;11(2):280‐287. doi:10.1007/s12015-
014- 9583-3 
37. Lu H, Poirier C, Cook T, et al. Conditioned media from adipose stromal cells limit 
lipopolysaccharide-induced lung injury, endothelial hyperpermeability and apoptosis. J Transl 
Med. 2015;13:67. Published 2015 Feb 21. doi:10.1186/s12967-015-0422-3 
38. Melief SM, Schrama E, Brugman MH, et al. Multipotent stromal cells induce human 
regulatory T cells through a novel pathway involving skewing of monocytes toward anti-
inflammatory macrophages. Stem Cells. 2013;31(9):1980‐1991. doi:10.1002/stem.1432 
39. Min, Hyunjung, et al. Mesenchymal Stromal Cells Reprogram Macrophages with Processing 
Bodies. Manuscript in preparation, 2020. 
40. Nenasheva T, Nikolaev A, Diykanov D, et al. The introduction of mesenchymal stromal cells 
induces different immunological responses in the lungs of healthy and M. tuberculosis 
infected mice. PLoS One. 2017;12(6):e0178983. Published 2017 Jun 8. 
doi:10.1371/journal.pone.0178983 
41. Prockop DJ. Concise review: two negative feedback loops place mesenchymal stem/stromal 
cells at the center of early regulators of inflammation. Stem Cells. 2013;31(10):2042‐2046. 
doi:10.1002/stem.1400 
42. Van Pham, P, et al. Umbilical cord-derived stem cells (MODULATIST TM) show strong 
immunomodulation capacity compared to adipose tissue-derived or bone marrow-derived 
mesenchymal stem cells. Biomedical Research and Therapy 2016, 3(6). doi:10.7603/s40730-
016- 0029-1. 
43. Sun, J, et al. Infusion of Human Umbilical Cord Tissue Mesenchymal Stromal Cells in Children 
with Autism Spectrum Disorder. STEM CELLS Translational Medicine. In press. 
doi:10.1002/sctm.19-0434