Multi-center, Randomized, Placebo Controlled, Interventional Phase 2A Clinical Trial Evaluating the Safety and Potential Efficacy of Multiple Dosing of Mesenchymal Stromal Cells in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2)
Phase: PHASE2
Conditions: Acute Respiratory Distress Syndrome, ARDS (Moderate or Severe), COVID-19 Pneumonia
Sponsor: Masonic Cancer Center, University of Minnesota

University of Minnesota MT2020-12 
 
Phase 2A Trial of Mesenchymal Stromal Cells for COVID19 ARDS 
 
 
 
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MULTI-CENTER, RANDOMIZED, PLACEBO CONTROLLED, INTERVENTIONAL PHASE 
2A CLINICAL TRIAL EVALUATING THE SAFETY AND POTENTIAL EFFICACY OF 
MULTIPLE DOSING OF MESENCHYMAL STROMAL CELLS IN PATIENTS WITH SEVERE 
ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-Cov-2) 
 
Version 10-21-2020 
IND# 21779 
 
IND Sponsor:  
 
John E. Wagner, MD 
 
Principal Investigator: 
David H. Ingbar, MD, PhD 
 
University of Minnesota 
Co-Investigators: 
 
Maneesh Bhargava, MBBS, PhD, Pulmonary/Critical Care 
 
 
 
 
Yuka Furuya, MD, Pulmonary/Critical Care  
 
 
 
 
Joshua Rhein, MD, Infectious Diseases 
 
 
 
 
Marc Pritzker, MD, Cardiology  
 
 
 
 
Angela Panoskaltsis-Mortari, PhD*  
 
 
 
 
David H. McKenna, Jr., MD* 
*laboratory only, will not consent subjects 
 
University of Pittsburgh 
Co-Principal Investigator: Luis Ortiz, MD 
 
University of Pittsburgh  
Co-Investigators: 
 
Bryan McVerry, MD 
 
 
 
 
Peter Rubin, MD 
 
 
 
Study Biostatistician: 
Todd E. Defor, MS 
 
Development Phase: 
2A 
 
 
 
 
This document contains confidential information that is the property of the  
University of Minnesota and University of Pittsburgh 
Do not copy, disclose or circulate this protocol without written authorization from the Principal Investigators or Sponsor 

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Revision History 
Revision 
# 
Version 
Date 
Summary of Changes 
Consent 
Revision 
 
04/27/2020 
Original to CPRC 
 
V2 
5/20/2020 
Per CPRC stipulation: Clarified primary and secondary 
endpoints and statistical consideration.  
 
Administrative change – each institution will use their own 
IRBs. 
 
• Section 
2.3 
added 
background 
and 
additional 
references 
• Section 4: Updated inclusion and exclusion criteria 
• Section 5.5 Updated definition of high risk stratification 
• Section 9: Safety updates: added monitoring during 
infusion; added to definition of reportable events; added 
unblinding procedures; added medical monitor; updated 
monitoring guidelines  
• section 8.2 added arterial blood gasses  
• Appendix I and Appendix II added Apache II and Sofa 
Scoring, and Dyspnea Index Questionnaire  
• Updated study procedures to remove single IRB. 
 
Minor edits: 
Added IND number and additional investigators to cover 
page Synopsis, section 4.6 clarified HIV exclusion criteria 
Section 8.1 and section 8.2, clarified timing of follow up 
procedures, added clinical pulmonary follow up procedures 
 
 
 
N/A 
V3 
6/16/2020 
Revised after FDA Review: 
• 
Updated study title 
• 
Synopsis, section 1.3, section 12.1.1 – clarified 
primary endpoint 
• 
Synopsis, Section 4.1 – updated inclusion criteria to 
clarify definitions of ARDS and SARS-CoV-2, 
increased upper age limit to 80 
• 
Synopsis, Section 4.2 – updated exclusions to allow 
for use of other agents 
• 
Section 1.1, Section 3 – Clarified hypothesis and 
design to include efficacy 
• 
Section 5 – enrollment will be staggered so that 
patients cannot be enrolled until 48 hours after the 
last infusion in the most recently treated patient 
• 
Section 6.2 – Updated management of SAEs 
• 
Section 8.1 – clarified testing time points 
• 
Section 9.2.2 – Updated documentation of events 
to 
include 
supportive 
interventions, 
vitals, 
oxygenation, number of ventilator and ICU days 
• 
Section 9.6 – added more detail to stopping rule 
event monitoring 
• 
Section 12.4 – minor clarification to stopping rule 
language 
Minor administrative edits to contact information, section 5.4, 
section 8.1, and section 10.8 
N/A 

University of Minnesota MT2020-12 
 
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V4 
6/26/2020 
Section 6.2 added that if patient condition is deteriorating 
they will be permitted to enter another study 7 days after their 
last dose of MSCs 
NA 
V5 
10/21/2020 
Synopsis  – Clarified procedure for post-treatment consent; 
removed “in the supine position” from exclusion criteria 
Section 4.1 - Clarified procedure for post-treatment consent 
Section 4.2 – Clarified measures to determine cardiac 
inclusion 
Section 4.3 - removed “in the supine position” from exclusion 
criteria 
Section 6.1 – Clarifications to infusion procedures 
Section 8.1 – Updates to clinical care procedures to reflect 
current standard of care, expand window of procedures, 
remove redundancies, and allow for virtual visits 
Section 8.2 – Updated window around research related 
procedures, updated timing of baseline research blood draw 
Section 
9.2 
– 
Clarification 
of 
Adverse 
Event 
reporting/documentation 
Section 9.5 – Edited timing of DSMB review to match DSMB 
charter 
Section 11.5 – Clarified that Acute Lung Injury Score will not 
be calculated in the event of no chest imaging within 48 hours 
window. 
Throughout protocol – minor updates for formatting and 
clarity. 
No 
 
 
 

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Table of Contents 
 
Revision History ................................................................................................................................................. 2 
List of Abbreviations .......................................................................................................................................... 8 
Protocol Synopsis ............................................................................................................................................ 10 
Treatment Design and Plan ............................................................................................................................. 12 
1. 
Hypothesis and Objectives ....................................................................................................................... 13 
1.1 
Hypothesis ............................................................................................................................................... 13 
1.2 
Primary Objective .................................................................................................................................... 13 
1.3 
Primary Endpoint ..................................................................................................................................... 13 
1.4 
Secondary Endpoints ............................................................................................................................... 13 
1.5 
Exploratory Endpoints .............................................................................................................................. 13 
2 
Background .............................................................................................................................................. 14 
2.1 
ARDS: Pathophysiology and Treatment................................................................................................... 14 
2.2 
MSC for Treatment of ARDS ................................................................................................................... 14 
2.3 
SARS-CoV-2 Mediated ARDS ................................................................................................................. 15 
2.4 
Rationale for MSC in the Treatment of SARS-CoV-2 Associated ARDS .................................................. 16 
2.5 
Rationale for the Proposed Study ............................................................................................................ 17 
3 
Study Design ............................................................................................................................................ 17 
4 
Patient Selection ....................................................................................................................................... 18 
4.1 
Inclusion Criteria ...................................................................................................................................... 18 
4.2 
Organ Specific Inclusion Criteria .............................................................................................................. 18 
4.3 
Exclusion Criteria ..................................................................................................................................... 18 
5 
Patient Registration and Randomization ................................................................................................... 19 
5.1 
Registration with the University of Minnesota Masonic Cancer Center’s CTO-CGI .................................. 19 
5.2 
Study Enrollment with the University of Minnesota CTO-CGI ................................................................... 19 
5.3 
Enrolled Patients Not Receiving Study Treatment ................................................................................... 20 
5.4 
Randomization......................................................................................................................................... 20 
5.5 
Risk Group Assignment ........................................................................................................................... 20 
6 
Treatment Plan ......................................................................................................................................... 21 
6.1 
Investigational Intervention ...................................................................................................................... 21 
6.2 
Management of Adverse Events During Study Agent Infusion ................................................................. 22 
Concomitant Therapies ...................................................................................................................................... 22 
6.3 
Duration of Study Participation ................................................................................................................ 23 

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7 
Expected Treatment Related Toxicities ..................................................................................................... 23 
7.1 
Potential MSC and Vehicle Placebo Control Toxicities ............................................................................ 23 
8 
Schedule of Patient Activities .................................................................................................................... 24 
8.1 
Required Clinical Care Examinations ....................................................................................................... 25 
8.2 
Patient Research Related Examinations .................................................................................................. 28 
9 
Adverse Event Monitoring, Recording and Reporting ................................................................................ 30 
9.1 
Definitions ................................................................................................................................................ 30 
9.2 
Adverse Event Monitoring, Recording and Reporting............................................................................... 31 
9.2.1 
Event Monitoring ............................................................................................................................... 31 
9.2.2 
Event Recording/Documentation ...................................................................................................... 31 
9.2.3 
Site Investigator’s Reporting Requirements ...................................................................................... 32 
9.2.4 
Event Reporting to the Study Sponsor, IRB and FDA ....................................................................... 33 
9.2.5 
Institutional Event Reporting Table ................................................................................................... 34 
Sponsor Reporting: Notifying the DSMB............................................................................................................. 34 
9.3 
Unblinding Procedures ............................................................................................................................ 35 
9.4 
External Medical Monitoring ..................................................................................................................... 35 
9.5 
Monitoring for Stopping Rule Events ........................................................................................................ 35 
10 
Study Data Collection and Monitoring ................................................................................................... 37 
10.1 Data Management ................................................................................................................................... 37 
10.2 Case Report Forms ................................................................................................................................. 37 
10.3 Data and Safety Monitoring Board ........................................................................................................... 37 
10.4 IND Annual Reports ................................................................................................................................. 38 
10.5 Data Sharing with Participating Sites ....................................................................................................... 38 
10.6 Monitoring ................................................................................................................................................ 38 
10.7 Teleconferences – Lead Site and Participating Site ................................................................................. 38 
10.8 Participating Site Monitoring .................................................................................................................... 39 
10.9 Study Record Retention ........................................................................................................................... 39 
11 
Definition of Study Endpoints ................................................................................................................ 39 
11.1 Change in Oxygenation Indices ............................................................................................................... 39 
11.2 Ventilator Free Days ................................................................................................................................ 40 
11.3 ICU Free Days ......................................................................................................................................... 40 
11.4 Mortality ................................................................................................................................................... 40 
11.5 Acute Lung Injury Score .......................................................................................................................... 40 
12 
Statistical Considerations ...................................................................................................................... 41 

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12.1 Study Design, Objectives and Endpoints ................................................................................................. 41 
12.1.1 
Primary Endpoint .............................................................................................................................. 41 
12.1.2 
Secondary Endpoints........................................................................................................................ 41 
12.1.3 
Exploratory Endpoints....................................................................................................................... 41 
12.2 Statistical Analysis ................................................................................................................................... 41 
12.3 Rationale for Sample Size ....................................................................................................................... 42 
12.4 Monitoring Guidelines .............................................................................................................................. 42 
12.5 Gender and Ethnicities Statement ........................................................................................................... 43 
13 
Conduct of the Study ............................................................................................................................. 43 
13.1 Good Clinical Practice ............................................................................................................................. 43 
13.2 Ethical Considerations ............................................................................................................................. 43 
13.3 Informed Consent .................................................................................................................................... 43 
14 
References ............................................................................................................................................ 44 
Appendix I – Apache II and Sofa Scoring ......................................................................................................... 47 
Appendix II – Dyspnea Index Questionnaire .................................................................................................... 52 
 
 
 

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Sponsor 
John E. Wagner, MD 
Director, Institute for Cell, Gene and Immunotherapies  
Professor, Department of Pediatrics 
660 Cancer Research Building  
425 East River Road  
Minneapolis, MN 55455 
612-626-2961 (phone) 
612-210-7877 (mobile) 
612-626-4074 (fax) 
wagne002@umn.edu (email) 
 
University of Minnesota Principal 
Investigator/Contact Information:  
David Ingbar, MD 
Director, Division of Pulmonary, Allergy, 
Critical Care & Sleep Medicine 
Professor, Department of Medicine  
Mayo Mail Code 276 
420 Delaware Street SE Minneapolis, 
MN 55455 USA  
612-624-0999 (office phone) 
612-709-7987 (mobile) 
612 625-2174 (fax) 
ingba001@umn.edu (email) 
University of Pittsburgh Co- Principal 
Investigator/Contact Information:  
Luis Ortiz, MD 
130 De Soto Street  
Pittsburgh, PA 15261  
USA  
412-624-5269 (office phone) 
724-612-1436 (mobile)  
lao1@pitt.edu (email) 
University of Minnesota Multisite 
Program Manager 
Clinical Trials Office  
MMC 498 
420 Delaware Street SE  
Minneapolis, MN 55455 
Phone: 612 626-5174 
Email: affiliates@umn.edu  
Fax: 612 625-6145 
 
Refer to the Procedures Manual for 
Participating Sites for a complete list of 
study personnel and contact 
information. 
 
 
 
 
 

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List of Abbreviations 
ABBREVIATION 
DEFINITION 
ACE2 
ANGIOTENSIN CONVERTING ENZYME-2 
AE 
ADVERSE EVENT 
AHC-IS 
ACADEMIC HEALTH CENTER-INFORMATIONAL SYSTEMS 
ALT 
ALANINE AMINOTRANSFERASE 
APACHE 
ACUTE PHYSIOLOGY AND CHRONIC HEALTH EVALUATION SCORE 
AST 
ASPARTATE AMINOTRANSFERASE 
ARDS 
ACUTE RESPIRATORY DISTRESS SYNDROME 
BMT 
BLOOD AND MARROW TRANSPLANT 
BNP 
B-TYPE NATRIURETIC PEPTIDE 
BUN 
BLOOD UREA NITROGEN 
CFR 
CODE OF FEDERAL REGULATIONS 
CI 
CONFIDENCE INTERVAL 
CLIA 
CLINICAL LABORATORY IMPROVEMENT AMENDMENT 
COPD 
CHRONIC OBSTRUCTIVE LUNG DISEASE 
CRF 
CASE REPORT FORM 
CPRC 
CANCER PROTOCOL REVIEW COMMITTEE 
CT 
COMPUTED TOMOGRAPHY 
CTCAE 
COMMON TOXICITY CRITERIA ADVERSE EVENT 
CTO 
CLINICAL TRIALS OFFICE 
CTO-CGI 
CLINICAL TRIALS OFFICE FOR CELL, GENE AND IMMUNOTHERAPIES 
CTSI 
CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE 
DSMB 
DATA SAFETY MONITORING BOARD 
DMSO 
DIMETHYLSULFOXIDE 
ECG 
ELECTROCARDIOGRAM 
ECHO 
ECHOCARDIOGRAM 
ECMO 
EXTRACORPOREAL MEMBRANE OXYGENATION 
FACT 
FOUNDATION FOR THE ACCREDITATION OF CELLULAR THERAPY 
FDA 
FOOD AND DRUG ADMINISTRATION 
FIO2 
FRACTION OF INSPIRED OXYGEN 
GCP 
GOOD CLINICAL PRACTICE 
GVHD 
GRAFT VERSUS HOST DISEASE 
HIPAA 
HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT 
HIV 
HUMAN IMMUNODEFICIENCY VIRUS 
HLA 
HUMAN LEUKOCYTE ANTIGEN 
HTLV1/2 
HUMAN T CELL LYMPHOTROPIC VIRUS 1/2 
H2O 
WATER 
ICF 
INFORMED CONSENT FORM 
ICU 
INTENSIVE CARE UNIT 
IDMC 
IDEPENDENT DATA AND SAFETY MONITORING COMMITTEE 
INFγ 
INTERFERON GAMMA 
IQR 
INTER QUARTILE RANGE 
IND 
INVESTIGATIONAL NEW DRUG 
IRB 
INSTITUTIONAL REVIEW BOARD 
IV 
INTRAVENOUS 
LDH 
LACTATE DEHYDROGENASE 
LIMS 
LABORATORY INFORMATION MANAGEMENT SYSTEM 

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LFT 
LIVER FUNCTION TEST 
LVEF 
LEFT VENTRICULAR EJECTION FRACTION 
MAP 
MEAN ARTERIAL PRESSURE 
MCC 
[UNIVERSITY OF MINNESOTA] MASONIC CANCER CENTER 
MSC 
MESENCHYMAL STROMAL CELLS 
PAO2 
PARTIAL PRESSURE OF OXYGEN 
PCR 
POLYMERASE CHAIN REACTION 
PEEP 
POSITIVE END EXPIRATORY PRESSURE 
PFT 
PULMONARY FUNCTION TEST 
PHI 
PROTECTED HEALTH INFORMATION 
PCRC 
PRIMARY CLINICAL RESEARCH COORDINATOR 
PNTBNP 
PRO-N-TERMINAL B TYPE NATURIETIC PEPTIDE 
SAE 
SERIOUS ADVERSE EVENT 
SCRF 
SCREENING CRF 
SLE 
SYSTEMIC LUPUS ERYTHEMATOSIS 
SOBQ 
UNIVERSITY OF CALIFORNIA, SAN DIEGO SHORTNESS OF BREATH QUESTIONNAIRE  
SOP 
STANDARD OPERATING PROCEDURE 
TMPRSS2 
TRANSMEMBRANE PROTEASE, SERINE 2 
TNFΑ 
TUMOR NECROSIS FACTOR ALPHA 
ULN 
UPPER LIMIT OF NORMAL 
UMN 
UNIVERSITY OF MINNESOTA 
US 
UNITED STATES 
WHO 
WORLD HEALTH ORGANIZATION 
 
 
 

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Protocol Synopsis 
Study Design: 
This is a multi-center, randomized, placebo controlled, interventional phase 2A 
safety trial to evaluate the safety profile and potential efficacy of multi-dosing 
of mesenchymal stromal cells (MSC) for patients with SARS-CoV-2 associated 
ARDS. After informed consent, treatment assignment will be made by 
computer-generated randomization to administer either MSC or vehicle 
placebo control with a 2:1 allocation to the MSC: placebo arm. 
 
Investigational 
Agent: 
Three fixed doses of MSC (300 x 106 MSC) or vehicle control approximately 
48 hours apart. 
 
Key Eligibility 
Criteria: 
• Age 18-80 years 
• Meets ‘Berlin Criteria’ for diagnosis of moderate to severe ARDS for a 
minimum of 4 hours1 
• Less than 48 hours on a ventilator after meeting criteria for diagnosis of 
ARDS  
• SARS-CoV-2 (proven by RT-PCR assay) with radiographic infiltrates 
• PaO2/FiO2 < 250 
• Positive end-expiratory airway pressure (PEEP) >5 cm H20 
• Elevated C-reactive protein (above laboratory upper limit of normal) 
• Meets organ function requirements [detailed in protocol section 4.2] 
• Off other investigational agents directed against inflammatory cytokines at 
least 48 hours prior to enrollment; agents directed against the replication 
of SARS-CoV-2 [e.g., Remdesivir] are permitted. 
• Voluntary informed consent in person or virtually by the patient or patient 
surrogate considering the face to face limitations during the COVID-19 
pandemic and, given the nature of the study population, which frequently 
requires mechanical ventilation with sedation, surrogate consent will likely 
occur in a substantial proportion of the study population. This will remain a 
valid consent until the patient is fully alert and consistently competent at 
which point the patient will be provided a second consent to continue 
participation in the study. In addition, a summary information sheet about 
this protocol will be in the patient’s room and will be available for the patient 
and family member. 
 
Key Exclusion 
Criteria: 
• Ventilator support of FiO2 >0·8 or PEEP >20 cm H2O and ongoing use of 
more than two vasopressors for 2 or more hours with any agent at the 
doses shown below. 
o Norepinephrine >12 µg/min or 0.2 µg/kg per min 
o Phenylephrine >150 µg/min or  3 µg/kg per min 
o Epinephrine >10 ug/min or 0.2 µg/kg per min 
o Vasopressin >0.04 units/min 
• Concurrent use of other investigational agents specifically for treatment of 
ARDS or inflammatory cytokines (Note: Agents, currently under 
investigations, shown to be efficacious will be permitted as these data 
emerge). 
• Known ineligibility for use of a ventilator for a minimum of 7 days, as judged 
by the institution’s Triage Team 
• Known allergy to MSC components: fetal calf serum, human albumin or 
DMSO 

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• Active invasive malignant disease requiring chemotherapy/radiation 
• Other concurrent life-threatening disease (life expectancy <6 months) or 
eligible for hospice care 
• Known history of HIV infection on active treatment 
• Females who are pregnant or breastfeeding 
• Current mean arterial pressure (MAP) <60 mmHg while on 2 or more 
vasopressors at above doses for more than 2 hours 
• History of any significant cardiac (myocardial infarction within 12 months of 
screening visit or unstable angina), chronic ongoing hepatic, or renal 
disease (grade 3 or higher); diagnosis of congestive heart failure with 
hypoxemia primarily due to decompensated heart failure; diagnosis of 
severe chronic obstructive pulmonary disease (COPD) or interstitial lung 
disease requiring supplemental oxygen at home 
• Concurrent diagnosis of diffuse alveolar hemorrhage 
• Inability to temporarily discontinue dialysis (i.e. unable to stop dialysis 
immediately prior to during infusion for 2 hours thereafter) 
 
Primary 
Objective: 
 
Safety and feasibility of three sequential MSC infusions within a 7 day period 
Primary 
Endpoint: 
 
Incidence of grade 3-5 infusional toxicities and predefined hemodynamic or 
respiratory adverse events related to the infusion of MSC 
Secondary 
Endpoints: 
Relative to the first infused dose of study agent 
• Incidence of a reduction in one or more biomarkers of inflammation by day 7 
• Trend changes in PaO2:FiO2 ratio, oxygenation index, peak and plateau 
pressures, static compliance and PEEP from baseline on days 3, 7 and 14 
• Incidence of mortality by day 28 and 100 
• Number of ICU-free days alive by day 28 
• Number of days alive and ventilator free composite score3 by day 28 
• Change in acute lung injury score2 between baseline and day 28 
• Incidence and severity of serious adverse events by day 28 
• Number of days alive off supplemental oxygen by day 100 
• Number of hospital days by day 100  
• Description of lung function status over time to 1 year 
 
Exploratory 
Endpoints: 
• Characterize immunological changes over 28 days 
• Characterize inflammatory and alveolar epithelial function/injury biomarkers 
changes over 28 days 
Accrual 
Objective: 
30 patients (2:1 randomization MSC:placebo) in patients with SARS-CoV-2 
associated ARDS requiring ventilator support 
 
Endpoint Footnote 
 
1 Berlin Criteria for ARDS: [1] 
 
2 Acute Lung Injury Score: a composite 4 point scoring system validated by the NHLBI ARDS Network that considers PaO2/FiO2, the level of positive 
end-expiratory airway pressure, respiratory compliance, and the extent of pulmonary infiltrates on the chest radiograph. [2] 
 
3 Alive and ventilator free score: Novack V, Beitler JR, Yitshak-Sade M, Thompson BT, Schoenfeld DA, Rubenfeld G, Talmor D, Brown SM. Alive and 
Ventilator Free: A Hierarchical, Composite Outcome for Clinical Trials in the Acute Respiratory Distress Syndrome. Crit Care Med. 2020 Feb;48(2):158-
166.[3] 

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Treatment Design and Plan 
Patients will receive study agent (MSC or placebo) within 48 hours of enrollment and within 72 
hours of intubation. Three doses will be administered unless a severe infusion adverse event 
occurs that is related to the MSC infusion. Doses will be repeated approximately every 48 hours 
with the aim of completing 3 doses within 7 days of the first dose. All patients will receive standard 
of care treatments for ARDS.  Enrollment will be staggered such that each new patient will be 
enrolled only after the prior patient has been followed >48 hours after the final dose without grade 
3-5 infusional toxicities or predefined hemodynamic or respiratory adverse events.  
 
 
 
 

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1. 
Hypothesis and Objectives 
1.1 Hypothesis 
Three doses of mesenchymal stromal [stem] cells (MSC) with known immunomodulatory 
and broad anti-inflammatory properties can be safely administered and potentially 
effective in patients with moderate to severe COVID- 19 mediated acute respiratory 
distress syndrome (ARDS). If multiple doses are well-tolerated with improvements in 
efficacy measures (e.g. reduction in proinflammatory cytokines, ventilator days and/or 
acute lung injury scores), a phase 2B study will be developed with more reliable sample 
size estimates based on outcomes in this study. 
1.2 Primary Objective 
Determine safety and feasibility of three sequential MSC infusions within a 7 day period. 
1.3 Primary Endpoint 
Incidence of grade 3-5 infusional toxicities and hemodynamic or respiratory adverse 
events within 6 hours of the start of infusion probably related or related to the infusion of 
MSC. 
1.4 Secondary Endpoints 
• 
Incidence of a reduction in one or more biomarkers of inflammation by day 7 
• 
Trend changes in PaO2:FiO2 ratio, oxygenation index, peak and plateau pressures and 
PEEP from baseline on days 3, 7 and 14 
• 
Incidence of mortality by day 28 and 100 
• 
Number of ICU-free days alive by day 28 
• 
Number of days alive and ventilator free composite score3 by day 28 
• 
Change in acute lung injury (ALI) score2 between baseline and day 28 
• 
Incidence and severity of serious adverse events by day 28 
• 
Number of days alive off supplemental oxygen by day 100 
• 
Number of hospital days by day 100  
• 
Description of lung function status over time to 1 year 
 
1.5  Exploratory Endpoints 
Additional analyses will be performed that may be important for the design of future trials. 
These include: 
• 
Characterize the effects of study agent on host immunity over 28 days (e.g., quantitation 
of macrophage/monocyte, T, B, NK cell subsets, expression of interferon-γ [IFN-γ] by 
CD4+T, CD8+T and NK cells) 
• 
Characterize the effects of study agent on inflammatory biomarkers over 28 days (e.g., 
ferritin, C reactive protein (CRP), IL-1b, IL-2, IL-6, IL-8, IL-10, IL-18, sIL-2R, sIL-6R, 
sTNFR1, TNFα, IFN-γ, Ang-1, Ang-2, gp130) and biomarkers of alveolar function/injury. 

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2 Background 
As of May 16, 2020, a total of 4,530,650 persons in 185 countries and regions were reported to be 
infected by SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), a disease that had 
led to more than 307,384 deaths [https://coronavirus.jhu.edu/map.html] Although the number of new 
cases appears to have sharply decreased in China, there are now more than 1.5 million confirmed 
cases in the United States with more than 88,000 confirmed death. While New York, New Jersey, 
Massachusetts, have been afflicted the most, Pennsylvania and Minnesota have been hit hard with 
65178 and 14249 cases confirmed respectively, and 4432 and 692 subjects confirmed death as a 
result of the disease to date [05/16/2020].  Mortality data discloses significant race disparities with 
the largest mortality identified among the black and Latino populations. 
SARS-CoV-2 is causing a pandemic [4,5] because it is a new virus to which there is no underlying 
immunity. Based on projections, a conservatively low estimate is that 5% of the population could 
become infected within 3 months [6]. Preliminary data from China and Italy regarding the distribution 
of case severity and fatality vary widely but a recent large-scale analysis from China suggests that 
80% of those infected either are asymptomatic or have mild symptoms [7]. If the 20% of the infected 
population requires medical services, about 15% have severe illness and 5% have critical illness. 
Overall mortality ranges from 0.25% to as high as 3.0% with higher case fatality rates in vulnerable 
populations. Similar rates and outcomes were reported from Seattle [8]. Death from the SARS-CoV-
2 virus is most often due to an acute respiratory distress syndrome (ARDS). To date, there are no 
proven treatments for COVID- 19 associated ARDS. A recent nonrandomized observational study 
suggests that glucocorticoids may be associated with improved clinical outcomes in patients with 
COVID-19 and ARDS [9]; however, additional studies are needed to verify this conclusion. Novel 
strategies are needed to prevent and treat replication of the SARS-CoV-2 virus and ameliorate the 
severity of COVID-19 mediated ARDS [10]. 
2.1 ARDS: Pathophysiology and Treatment 
Acute Respiratory Distress Syndrome (ARDS) is a form of acute respiratory failure with protein-
rich pulmonary edema characterized by acute inflammation and injury to the lung and epithelia 
[11]. The nature of the underlying clinical trigger is one important determinant of outcome, e.g., 
sepsis-associated ARDS has a higher mortality as compared to ARDS due to trauma or 
pancreatitis. ARDS due to pneumonia and/or aspiration has an intermediate mortality, 
respectively [12]. Mortality also is highly dependent on age and, to a lesser extent, race with 
African-Americans and Hispanics having a higher 60-day mortality rate (33%) compared to 
Caucasians (27%) [13] 
The acute lung injury of ARDS has rapid onset of acute inflammation with epithelial and 
entodothelial cell damage and disruption of the alveolar-capillary barrier. With loss of alveolar–
capillary membrane integrity, alveoli are filled with a neutrophilic proteinaceous procoagulant 
exudate with high levels of pro- inflammatory, cytotoxic mediators, proteases and oxidants 
[14,15]. Biomarkers found on the epithelium and endothelium and that are involved in the 
inflammatory and coagulation cascades predict morbidity and mortality. 
2.2 MSC for Treatment of ARDS 
MSCs secrete paracrine factors that may reduce the severity of acute lung injury, including 
growth factors, factors that regulate barrier permeability, and anti-inflammatory cytokines [16, 

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17, 18, 19]. Gupta and al. reported the anti-inflammatory properties of MSC both in vivo and in 
vitro. In a mouse model where Escherichia coli endotoxin was instilled into the distal airspaces 
of the lung, followed by direct intrapulmonary administration of MSC 4 hours later. MSC was 
associated with a decreased extravascular lung water, alveolar–capillary permeability and 
mortality. Furthermore, the pro- inflammatory response was downregulated, whereas the anti-
inflammatory response upregulated [20]. 
To date, several phase I and II clinical trials incorporating MSC in the treatment of acute lung 
injury and ARDS have been completed with mixed response. Two multicenter clinical trials 
[21,22] assessed the safety and potential efficacy of MSC in subjects afflicted by moderate to 
severe ARDS in whom a mortality greater than 40% was expected. The first of these was a multi-
center, open-label, dose- escalation phase 1 clinical trial of a single dose of intravenous MSC in 
patients with moderate-to-severe ARDS [clinicaltrials.gov number NCT01775774]. The first three 
patients were treated with low dose MSC (1 million cells/kg predicted body weight (PBW)); the 
next three patients received intermediate dose MSC (5 million cells/kg PBW); and the final three 
patients received high dose MSC (10 million cells/kg PBW). Primary outcomes included the 
incidence of pre-specified infusion associated events and serious adverse events. Secondary 
outcomes included standard respiratory and systemic endpoints, 28- and 60-day mortality, and 
measurement of biologic markers of inflammation and endothelial and epithelial injury. The trial 
completed enrollment in January 2014. The investigators reported that there were no pre-
specified infusion associated events or treatment-related adverse events in any of the nine 
patients in this trial. Serious adverse events (SAEs) were subsequently observed in three 
patients in the weeks following the infusion: two patients expired >7 days after the MSC infusion, 
and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and 
brain that were age- indeterminate but thought to have occurred prior the MSC infusion based 
on MRI results. None of these SAEs were thought to be MSC-related. The investigators 
concluded that a single IV infusion of allogeneic, bone marrow-derived human MSCs was well-
tolerated in 9 patients with moderate to severe ARDS [21]. 
Based on this phase I experience, a phase 2A START trial was initiated evaluating the safety of 
MSC (10 million/kg PBW) for moderate to severe ARDS [clinicaltrials.gov number 
NCT02097641]. Sixty patients were enrolled (1038 screened between 03/24/2014 and 
02/09/2017). No patient experienced predefined MSC-related hemodynamic or respiratory 
adverse events. One patient in the MSC group died within 24 hours of MSC infusion, but death 
was judged to be probably unrelated. Results showed that 28-day mortality did not differ between 
the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2·4, 95% CI 0·5-
15·1). However, at baseline, the MSC group had numerically higher mean scores than the 
placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 [SD 31] 
vs 89 [SD 33]), minute ventilation (11·1 [3·2] vs 9·6 [2·4] L/min), and PEEP (12·4 [3·7] vs 10·8 
[2·6] cm H2O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days 
was 1·43 (95% CI 0·40-5·12, p=0·58). Viability of MSC ranged from 36% to 85% and was 
suspected to be at least in part related to the post-thaw wash procedure. On the basis of these 
results investigators concluded that a single dose of IV MSC was safe in patients with moderate 
to severe ARDS, larger trials were needed to assess efficacy, and viability of MSC was 
inconsistent and should be improved [22]. 
2.3  SARS-CoV-2 Mediated ARDS 
Both clinical and epidemiological features of patients with COVID-19 have recently been 
reported, demonstrating that the SARS-CoV-2 infection can cause clusters of severe respiratory 
illness with clinical presentations of rapid progression of ARDS, leading to intensive care unit 
(ICU) admission and high mortality [23]. Clinical manifestations have included fever, fatigue, dry 

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cough, shortness of breath, and ARDS. Acute respiratory distress syndrome (ARDS) is defined 
as acute-onset hypoxemia (the ratio of the partial pressure of arterial oxygen to the fraction of 
inspired oxygen [Pao2:Fio2], <300) with bilateral pulmonary opacities on chest imaging that are 
not fully explained by congestive heart failure or other forms of volume overload. 
Using the Berlin Definition, mild, moderate, and severe ARDS were associated with increasing 
mortalities (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%-34%; and 45%; 95% CI, 42%-
48%,respectively; P < .001) and increasing median durations of mechanical ventilation in 
survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, 
respectively; P < .001). While these outcomes predate COVID-19 mediated ARDS, limited data 
suggest that outcomes may be similar, although some data suggest that COVID-10 ARDS 
patients who recover require long periods of ventilator support, with a mean of approximately 14 
days in the Wuhan, China experience [23]. 
Most patients with severe COVID-19 exhibit substantially elevated serum levels of pro-
inflammatory cytokines including IL-6 and IL-1β, as well as IL-2, IL-8, IL-17, G-CSF, GM-CSF, 
IP10, MCP1, MIP1α (also known as CCL3) and TNF, characterized as cytokine storm [23, 24, 
25, 26]. Also, C-reactive protein and D-dimer are found to be abnormally high. High levels of pro-
inflammatory cytokines may lead to shock and tissue damage in the heart, liver and kidney, as 
well as respiratory failure or multiple organ failure. They also mediate extensive pulmonary 
pathology, leading to massive infiltration of neutrophils and macrophages, diffuse alveolar 
damage with the formation of hyaline membranes and a diffuse thickening of the alveolar wall. 
Spleen atrophy and lymph node necrosis were also observed, indicative of immune-mediated 
damage in deceased patients.  In addition to the cytokine-based pathology in patients with severe 
COVID-19, complement activation has also been observed, indicating that complement 
inhibitors, if used at an early stage of the infection, may attenuate the inflammatory damage. 
Hopefully these approaches will be approved into clinical trials to benefit the patients. 
2.4 Rationale for MSC in the Treatment of SARS-CoV-2 Associated ARDS 
MSCs are adult, non-hematopoietic precursor cells derived from a variety of tissues (e.g., bone 
marrow, adipose tissue, and placenta) and have been used as therapy in multiple conditions, 
especially in immune-mediated inflammatory diseases, such as graft versus-host disease (GVHD) 
and systemic lupus erythematosus (SLE) with evidence of benefit. In preclinical models, MSC are 
effective in ameliorating acute lung injury due to their ability to secrete paracrine factors that 
regulate lung endothelial and epithelial permeability, including growth factors, anti-inflammatory 
cytokines, and antimicrobial peptides [27, 28, 29]. As infused MSC home to the areas of 
inflammation, it is possible that these cells will limit the severity and duration of ARDS and 
potentially improve survival. Even in the setting of ARDS, MSC infusions are safe [22]. Of 40 
patients treated with MSC in this study, no MSC- related hemodynamic or respiratory adverse 
events were observed. 
Multiple clinical trials using stem cell therapy to treat the SARS-CoV-2 from China have been 
registered at www.clinicaltrials.gov . Leng et al. reported on the results of MSC in 7 subjects with 
COVID-19 pneumonia treated at a single institution between 01/23/2020 and 02/16/2020 [30]. 
Signs and symptoms were severe in 5 and moderate in 2 with an additional 3 patients with severe 
disease treated with placebo. The pulmonary function and symptoms in all MSC treated patients 
significantly improved in 2 days after MSC infusion. No infusion related events were observed. 
After treatment, the peripheral lymphocytes increased, C-reactive protein decreased, with changes 

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in the cytokine profile suggesting a switch away from the underlying proinflammatory state. While 
not conclusive, these data support further study of MSC in the treatment of SARS-CoV-2 
associated pneumonia and ARDS. 
2.5 Rationale for the Proposed Study 
Currently, there is no pharmacologic agent or other approach, such as a cell therapy with proven 
impact on the risk of mortality of ARDS. Treatment remains primarily supportive, with lung-protective 
ventilation and a fluid conservative strategy, as well as prone positioning in more severe cases. 
Despite improved management, mortality of ARDS generally remains high between 30-40% in 
clinical studies. [31,32] 
Seven patients with COVID-19 pneumonia were treated with MSC with promising preliminary 
results [30]. The pulmonary function and symptoms significantly improved in 2 days after MSC 
transplantation, potentially improving resource allocations as well as survival. Furthermore, the 
gene expression profile demonstrated that MSC were ACE2neg and TMPRSS2neg which suggests 
that MSC should be free from COVID-19 infection. In summary, the intravenous infusion of MSC in 
patients with COVID-19 pneumonia was safe and potentially effective. 
In a prospective, double-blind, multicenter, randomized trial, Matthay et al. [22] compared a single 
dose of MSC compared to placebo in 60 patients with ARDS. No patient experienced any of the 
MSC-related hemodynamic or respiratory adverse events. While MSC were found to be safe in 
ARDS, 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the 
placebo group, odds ratio 2·4, 95% CI 0·5–15·1). While this outcome might be due to higher risk 
patients being assigned to the MSC arm, (i.e. higher baseline APACHE III score; minute ventilation 
and PEEP compared to the control arm) and variable MSC viability, the lack of an efficacy signal 
caused us to consider alternative approaches with MSC. 
Based on the promising preliminary data that MSC can block the expression of inflammatory 
induced lung injury in animal models, and intriguing results in patients with COVID19 associated 
pneumonia and ARDS as well as an established safety profile of MSC generally and in ARDS in 
particular, the proposed study will evaluate the safety of multiple doses of MSC rather than a single 
large dose and their efficacy and biological activity in suppressing proinflammatory cytokines, and 
utilizing  a uniform, optimized MSC thaw procedure to reduce the variability of MSC viability upon 
thawing. 
Additionally, since the phase 2A trial [22] the Cell Therapy Lab of the University of Minnesota, which 
supported MSC manufacture for all sites, optimized manufacturing and harvest to improve on both 
pre- and post-thaw viability. 
3 Study Design 
This is a multi-center, randomized, placebo controlled, interventional phase 2A safety trial to evaluate 
the safety profile of multidosing of MSC and the potential efficacy and biological activity  in patients 
with SARS-CoV-2 associated ARDS. There will be a 2:1 randomization for MSC and vehicle placebo 
control, respectively. 

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4 Patient Selection 
Study entry is open to persons regardless of gender or ethnic background. There will be every effort 
to seek out and include females and minority patients. 
4.1  Inclusion Criteria 
• 
Age 18-80 years 
• 
Meets ‘Berlin Criteria’ for diagnosis of moderate orsevere ARDS for a minimum of 4 hours [1] 
• 
Less than 48 hours on a ventilator after meeting criteria for diagnosis of ARDS  
• 
SARS-CoV-2 (proven by RT-PCR assay) with radiographic infiltrates 
• 
PaO2/FiO2 ratio < 250 
• 
Positive end-expiratory airway pressure (PEEP) >5 cm H20 
• 
Elevated C-reactive protein (above laboratory upper limit of normal) 
• 
Meets organ function requirements[detailed in protocol section 4.2] 
• 
Off other investigational agents directed against inflammatory cytokines 48 hours prior to 
enrollment; agents directed against the replication of SARS-CoV-2 [e.g., Remdesivir] are 
permitted 
• 
Voluntary informed consent in person or virtually by the patient or patient surrogate considering 
the face to face limitations during the COVID-19 pandemic and, given the nature of the study 
population, which frequently requires mechanical ventilation with sedation, surrogate consent 
will likely occur in a substantial proportion of the study population (this will remain a valid 
consent until the patient is fully alert, and consistently competent, and can provide a second 
consent to continue participation in the study).  
 
4.2  Organ Specific Inclusion Criteria 
• 
Adequate organ function is defined as: 
o 
Renal: Calculated estimated glomerular filtration rate >30 mL/min/1.73 m2 (on chemistry 
panel) 
o 
Hepatic: Bilirubin <3x upper limit of normal (ULN) and AST, ALT and alkaline 
phosphatase <5x ULN 
o 
Cardiac: Absence of uncontrolled arrhythmia and heart failure (i.e., normal B-type natriuretic 
peptide [BNP] or LVEF >35% by echocardiogram)  
4.3 Exclusion Criteria 
• 
Ventilator support of FiO2 >0·8 or PEEP >20 cm H2O and ongoing use of more than 
two vasopressors for 2 or more hours with any agent at doses shown below. 
o Norepinephrine >12 µg/min or 0.2 µg/kg per min 
o Phenylephrine >150 µg/min or  3 µg/kg per min 
o Epinephrine >10 ug/min or 0.2 µg/kg per min 
o Vasopressin >0.04 units/min 
• 
Concurrent use of other investigational agents specifically for treatment of ARDS or 
inflammatory cytokines. (Note: Agents, currently under investigations, shown to be 
efficacious will be permitted as these data emerge). 

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• 
Known ineligibility for use of a ventilator for a minimum of 7 days, as judged by the 
institution’s Triage Team 
• 
Known allergy to MSC components: fetal calf serum, human albumin or DMSO 
• 
Active invasive malignant disease requiring chemotherapy/radiation 
• 
Other concurrent life-threatening disease (life expectancy <6 months) or eligible for 
hospice care 
• 
Known history of HIV infection on active treatment 
• 
Females who are pregnant or breastfeeding 
• 
Current mean arterial pressure (MAP) <60 mmHg while on 2 or more vasopressors 
at above doses for more than 2 hours 
• 
History of any significant cardiac (myocardial infarction within 12 months of 
screening visit or unstable angina), chronic ongoing hepatic, or renal disease (grade 
3 or higher); diagnosis of congestive heart failure with hypoxemia primarily due to 
decompensated heart failure; diagnosis of severe chronic obstructive pulmonary 
disease (COPD) or interstitial lung disease requiring supplemental oxygen at home 
• 
Concurrent diagnosis of diffuse alveolar hemorrhage 
• 
Requiring continuous dialysis (unable to stop dialysis during study agent infusion) 
5 Patient Registration and Randomization 
Enrollment will be staggered.  Specifically, patients potentially meeting eligibility cannot be enrolled until 
48 hours after the last infusion in the most recently treated patient. Registration will occur after the patient 
or patient’s surrogate has signed the subject consent but before any treatment has been administered. 
Patients who were not able to sign consent originally, will be re- consented if they are able to 
subsequently. To be eligible for registration to this study, the patient must meet each criterion listed on 
the eligibility checklist (found in ONCORE) based on the eligibility assessment documented in the 
patient’s medical record. 
5.1 Registration with the University of Minnesota Masonic Cancer Center’s CTO-
CGI 
Any patient who has been consented is to be registered in ONCORE by the Primary Study 
Coordinator or designee. If a patient is consented, but not enrolled, the patient’s record is updated 
in ONCORE as a screen failure and reason for exclusion recorded. Complete registration 
information is found in the study’s Procedures Manual for Participating Sites. 
Participating sites only: At the time of registration, the signed consents will be uploaded into 
ONCORE as an attachment under the appropriate record. 
Participating sites are responsible for fulfilling any local registration requirements. 
5.2  Study Enrollment with the University of Minnesota CTO-CGI 
To be eligible for study enrollment, the patient or patient’s surrogate must sign the treatment consent 
and the patient must meet each of the inclusion criteria and none of the exclusion on the eligibility 
checklist (ONCORE) based on the eligibility assessment documented in the patient’s medical 
record. 

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The PCRC or designee will assign the study treatment arm and add the on-treatment date to 
complete enrollment. Additional information can be found in the study’s Procedures Manual for 
Participating Sites. 
5.3  Enrolled Patients Not Receiving Study Treatment 
If a patient is enrolled onto the study and is subsequently not able to begin the planned study 
treatment for whatever reason, the patient will be removed from study and treated at the 
physician’s discretion. The study coordinator or designee will update ONCORE of the patient’s 
non-treatment status and notify the Principal Investigator. The reason for removal from study 
prior to starting study treatment will be clearly indicated in ONCORE. The patient may be 
replaced. 
5.4  Randomization 
Patients will be randomly assigned (2:1) to receive either 300 × 10^6 MSC or vehicle placebo 
control. Randomization will be stratified by risk (high versus standard risk detailed in Section 
5.5.), using permuted block sizes of 3. The allocation sequence will be accessed by each cell 
processing laboratory through ONCORE. Personnel in the cell processing laboratories are not 
masked to the treatment group, but patients, clinical staff, and investigators will be unaware of 
treatment assignment. To maintain masking of the investigators and clinicians, bags containing 
the study products and intravenous tubing had opaque coverings applied in the cell 
laboratories. 
5.5  Risk Group Assignment 
Presence of preexisting co-morbidities appears to be associated with risk of death from COVID- 
19 [30]. For this study patients will be stratified as high risk or standard risk (Table 1) based on 
the presence of specific co-morbidities based on the judgement of the care team. 
Table 1:Risk Definitions 
High Risk Definition 
Standard Risk Definition 
History of any of the following on medical history review: 
• 
Coronary artery disease or other chronic 
cardiovascular disease (h/o myocardial infarction 
(MI); heart failure; stent placement) 
• 
Hypertension (excluding well-controlled 
hypertension on a single agent) 
• 
Chronic pulmonary disease (moderate or severe as 
defined by either multiple exacerbations requiring 
treatment and/or outpatient FEV1  < 70% predicted 
when free of exacerbation) 
• 
Insulin dependent diabetes (type 1 or type 2) 
• 
Cerebrovascular disease (h/o ischemic or 
hemorrhagic stroke) 
• 
Chronic renal disease – GFR <30% 
• 
Age >65 years 
 
 
 
Absence 
of 
any 
high 
risk 
co-
morbidities 
Note: It is recognized that the standard of care for COVID-19 ARDS is rapidly changing.  In the event that drugs 

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like Tocilizumab are approved during the study period.   
6 Treatment Plan 
All patients with ARDS will be managed with standard of care treatments, including lung protective 
ventilation as implemented by the NIH ARDS Network (typically with a tidal volume <6 ml/kg/ideal body 
weight and a plateau airway pressure <30 cm H2O). Patients may be proned and, if necessary, may be 
placed on extracorporeal membrane oxygenation (ECMO). 
6.1  Investigational Intervention 
In addition to standard aggressive medical management, patients enrolled in this clinical trial will 
receive the investigational product, MSC-derived from allogeneic bone marrow, or vehicle placebo 
control based on a 2:1 randomization scheme. 
 
Table 2: Study Agents 
Agent 
Route 
and 
Time 
of 
Administration 
Preparation 
MSC 
IV, masked bag and tubing, 
delivered within 30 minutes of 
start of infusion 
Thawed product containing MSC in 
DMSO resuspended 1:1 with Dextran 
40 + 5% human serum albumin [total 
volume 60 mL] 
Vehicle Placebo 
Control 
IV, masked bag and tubing, 
delivered over 30 minutes 
Dextran 40 + 5% human serum 
albumin + [total volume 60 mL] 
Prior to each Infusion: Study agent may be infused (Table 2) after a patient is off hemodialysis 
(if applicable) and considered to be sufficiently stable, as defined by a transcutaneous oxygen 
saturation of >88% with ventilator support of FiO2 <0·8 or PEEP <20 cm H2O and use of no more 
than two vasopressors at doses shown below in the supine position. 
o Norepinephrine <12 µg/min or 0.2 µg/kg per min 
o Phenylephrine <150 µg/min or 3.0 µg/kg per min 
o Epinephrine <10 µg/kg per min or 0.2 µg/kg per min 
o Vasopressin <0.04 units/min 
Administration of Investigational Agent: MSC or the vehicle placebo control will be 
administered intravenously with a standard blood filter tubing set with a pore size of 170 µm. The 
study product will be infused by gravity over approximately 30 minutes. 
Pre-medications and hydration 30 minutes before administration of the investigational product will 
include: 
o Benadryl 25 mg IV 
o Tylenol 500 mg, PO or rectal 
The product before infusion will not be irradiated and in-line leukocyte filters will not be used for 
product infusion. In addition, no medications will be infused in the same line as investigational 
product during the product infusion. Potential toxicities of MSC and vehicle control are detailed in 
section 7.1. 

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6.2  Management of Adverse Events During Study Agent Infusion 
During the infusion of study agent, patients will have monitoring of continuous arterial blood 
pressure, heart rate, rhythm as well as oxygen saturation. Study personnel will be available for the 
duration of the infusion to monitor the patient. Body temperature will be monitored at a minimum 
at the start, midway through, and at the end of the infusion. During study agent infusion, patients 
will be monitored closely for signs of allergic reactions, e.g. rash, urticarial, angioedema, wheezing 
as well as worsening hypotension or new arrhythmias. Emergency drugs for hypersensitivity 
reactions, worsening hypotension or arrhythmias will be available and administered according to 
institutional guidelines. If there are any signs of a transfusion related reactions, the infusion will be 
stopped immediately. The infusion can also be stopped at the discretion of the study investigator 
or care team if there is concern about the patient’s status.   If a patient is deteriorating or not 
improving after the third MSC infusion, they may enter another study 7 days after last infusion. 
Appropriate medical care should be instituted as per standard institutional practices. If possible, 
additional systemic corticosteroids should be avoided unless absolutely required for management 
of acute allergic/infusion reactions (Table 3), as determined by the Investigator. Study agent 
infusion may be interrupted temporarily upon resolution of the event at the discretion of the care 
team and Investigator, based on the management guidelines below. 
Table 3 CTCAE Term: Infusion Related Reaction 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines,  
suctioning, IV Fluids or 
other supportive care 
measure typical in the 
management of COVID-
19 related ARDS 
Prolonged (e.g., 
not rapidly 
responsive to 
symptomatic 
medication and/or 
brief interruption). 
Life- 
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Common Toxicity Criteria for Adverse Events version 5.0 (CTCAE v5) are detailed at:  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_QuickReference
_5x7.pdf for documenting severity of observed events 
 
The study agent infusion may be reinitiated if the reaction is grade 2 as defined in Table 3. If the 
grade 2 event recurs after infusion re-initiation or if the event is considered to be grade 3 or greater, 
the infusion will be stopped and the uninfused product will be retained for further evaluation (a 
Transfusion Medicine consultation will be obtained and the product will be evaluated for sterility).  
Antihistamines, such as diphenhydramine 50 mg IV, should be considered for treatment of allergic 
reactions, any grade reaction.  Systemic corticosteroids may be used for grade 3-4 allergic 
reactions but should be avoided for grade 1 and 2 reactions.  Fluids and.or increases in dose or 
addition of vasopressors will be used for treatment of hypotension.  Anti-arrhythmia agents will be 
used to treat new arrhythmias. 
 Concomitant Therapies 
All patients will be treated with standard of care based on Society or CDC guidelines. All other 
pharmacologic agents used in the conventional treatment of ARDS will be recorded. Patients may 
be treated with anti-viral agents; however, all concomitant drugs with potential immunomodulatory 

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activities should be reviewed by the PI or co-investigators prior to enrollment. Chloroquine or 
hydroxychloroquine is permitted. 
Note: Every effort should be made not to initiate glucocorticoids if the patient is not receiving 
glucocorticoids after treatment or increase the dose of steroids if the patient is receiving low to 
moderate dose steroids on study initiation. If the treating physician feels it is in the best interest to 
initiate high dose steroids, e.g. due to new onset of diffuse alveolar hemorrhage, lack of response 
after 7 days or worsening respiratory status after 4 days from the first infusion of the investigational 
product (MSC vs vehicle placebo control), the reason should be documented in the medical record. 
6.3 Duration of Study Participation 
Patients will be followed for 1 year after treatment. 
7 Expected Treatment Related Toxicities 
7.1  Potential MSC and Vehicle Placebo Control Toxicities 
MSC, like other blood products, may cause infusional reactions, including hemodynamic effects or 
acute hypersensitivity reactions. Furthermore, the cryoprotectant, DMSO, can cause side effects 
as shown below (Table 4). 
Table 4: Side Effects of MSC 
Relatively Common 
Less Common 
Unknown Risks in MSC 
Group 
• DMSO toxicities (e.g., 
headache, hypertension, 
cardiac toxicity, nausea 
and vomiting) 
• Allergic reaction (including 
itching, hives, flushing [red 
face], skin rash, fever, 
chills, wheezing, stiff 
muscles. 
 
While shortness of breath 
and 
chest tightness 
are 
common symptoms in those 
who are not on the ventilator, 
these symptoms might not 
be obvious. Rapid increase 
in FIO2 requirement and 
other ventilator settings may 
occur. 
• Hemodynamic 
instability 
• Increased pulmonary 
vascular resistance 
 
DMSO side effects and symptoms are generally associated with histamine release and include 
coughing, flushing, rash, chest tightness and wheezing, nausea and vomiting, and cardiovascular 
instability [33]. However, due to the small MSC cryobag volume (~30 ml), a reaction to DMSO is 
not expected. Signs of allergic reaction and any changes in hemodynamic stability or respiratory 
changes will be treated with appropriate medications per institutional practice for the signs and 
symptoms observed. 
Note: Vehicle placebo control will not contain DMSO.  While the MSC product will contain DMSO, 
for sedated, ventilated patients, caregivers will not be able to detect the associated DMSO odor 

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(e.g. cabbage or wild radish odor), important for maintaining the blinding of caregivers and 
investigators.   
Emergency drugs should be available and administered per institutional guidelines. 
8 Schedule of Patient Activities 
Scheduled evaluations after screening and until day 100 are shown in Table 5A (clinical) and Table 5B 
(research). For assessments after discharge from the hospital, evaluations may be performed +/-3 days 
from the listed target date through day 28 and +/-7 days for the month 2 and month 3 evaluations and +/-
1 month for the one year evaluation.  

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8.1 Required Clinical Care Examinations 
Table 5A: Clinical Care 
Study Phase 
Screening 
First 
MSC or 
Placebo 
Infusion7 
Follow up Days [unless otherwise noted] relative to first Study Agent (MSC/placebo) Infusion 
Study Time 
Interval 
Days -2 to 
Day 0 prior 
to infusion 
0 
1 
2 
3 
4 
5 
6 
7 
14 
2111 
Day 2811, month 
211, month 311, 
Month 611 and 1 
year11 
Informed* 
Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Current medical 
conditions# 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Body weight 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs# 
X 
X
8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination# 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X12 
BNP 
X10 
 
 
 
 
 
 
 
 
 
 
Day 28
9,10 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
Day 28
9 
Chest x-ray or 
chest CT 
 
X 
 
 
 
 
 
 
 
 
 
 
Day 28 chest 
imaging X 
Lung function 
status1 
 
 
 
 
 
 
 
 
 
 
 
Month 2, Month 3, 
Month 6 and 1 year 
Dyspnea Index 
Questionnaire1 
 
 
 
 
 
 
 
 
 
 
 
Day 28, month 2, 
month 3, month 6 and 
1 year 
Full PFTs 
Including Lung 
Volumes & 
DLCO1 
 
 
 
 
 
 
 
 
 
 
 
3 month, 6 month, 1 
year 
6 minute walk 
test (O2 
assessment)1, 
unless clinically 
contraindicated 
 
 
 
 
 
 
 
 
 
 
 
Day 28, month 2, 
month 3, month 6 and 
1 year 
Non-contrast 
High Resolution 
Chest CT with 
 
 
 
 
 
 
 
 
 
 
 
3 month, 1 year 

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Table 5A: Clinical Care 
Study Phase 
Screening 
First 
MSC or 
Placebo 
Infusion7 
Follow up Days [unless otherwise noted] relative to first Study Agent (MSC/placebo) Infusion 
Study Time 
Interval 
Days -2 to 
Day 0 prior 
to infusion 
0 
1 
2 
3 
4 
5 
6 
7 
14 
2111 
Day 2811, month 
211, month 311, 
Month 611 and 1 
year11 
inspiratory & 
expiratory 
views1 
SARS-CoV-2 
pcr 
 
X 
 
 
 
 
 
 
 
 
 
 
Day 28 only 
Chemistries2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immuno- 
globulin levels 
(IgG, IgA, IgM) 
 
X 
 
 
 
 
 
 
 
 
 
 
Day 289  
Coagulation 
panel4 
X 
 
 
 
 
 
 
 
X 
 
 
 
Clinical Covid 
Cytokine 
Panel5 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Pregnancy test 
(females) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
SOFA and 
APACHE II 
Score6 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Abbreviations: ECHO=echocardiogram; ECG=electrocardiogram; PFT=pulmonary function tests; SOFA=sequential organ failure assessment; 
APACHE=acute physiology and chronic health evaluation; AE=adverse event; ICRF=result recorded in infusion case report form; pcr=polymerase 
chain reaction; HLA=histocompatibility locus antigens. 
*Consent should be re-obtained when the patient’s condition permits, if the patient’s surrogate provided the original consent.  
#Medical monitoring will be conducted daily at least for 7 days but will continue daily during the length of the hospitalization.  e-Visits using iPads 
and visualization are permitted to reduce infectious disease risks and minimize PPE use.’ 
1. Recommended pulmonary clinic follow up visits (virtual only if patient is unable to return to clinic) 
2. Chemistries include: Na, K, Cl, CO2, BUN, Cr, glucose, Ca, P, ALT, AST, Alk P, TB, Alb, TP, LDH, C-reactive protein (CRP). 
3. Hematology includes: white count with differential, hemoglobin, MCV, platelets. 
4. Coagulation panel: PT, PTT, fibrinogen, protein C, D-dimer (add lupus anticoagulant, if PTT elevated [34]) 
5. Clinical COVID-19 cytokine panel: IL-1, IL-6, TNFa, and IL-8.  

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6. SOFA and APACHE II scores (Appendix I) are done only for patients remaining in the ICU. 
7. MSC or vehicle placebo control will be administered three times within 7 days of the first infusion, aiming for 48 hour intervals. Vital signs will be checked before and 
every 15 minutes during the infusion, at the completion of the infusion, and one, 3 and 6 hours post study agent infusion. More frequent vital signs may be required 
depending on reactions to the product infusion. 
8. Vital signs include body weight, body temperature, blood pressure, pulse, and pulse oximetry. The highest temperature recorded within 24 hr period will be reported. 
9. If abnormal on d28, additional tests will be done until normal at 2, 3 and 12 months 
10 Echocardiogram is only required if BNP is abnormal 
11. If patient cannot return to clinic for a follow-up visit; every attempt will be made to obtain laboratory tests along with a virtual clinic visit 
12. 21 day, 28 day and 2 month assessments can include either virtual visit and/or use of data from clinical provider visits. 
 
 
 

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8.2 Patient Research Related Examinations 
Table 5B: Research Related Examinations 
Study Phase 
Screening 
First 
MSC or 
Placebo 
Infusion5 
Follow up Days [unless otherwise noted] relative to first Study Agent (MSC/placebo) Infusion 
Study Time 
Interval 
Days -2 to 
Day 0 prior 
to infusion 
0 
1 
2 
3 
4 
5 
6 
7 
14 
21 
Day 28, month 2, 
month 3, Month 6 
and 1 year 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
MSC or 
Placebo 
Infusion 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Arterial blood 
gas 
 
X           
[30 min 
before and 
once 1-4 
hours post 
infusion] 
 
 
 
 
 
 
 
 
 
 
Immune profile1 
10 ml green top 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Cytokine 
profile2 
5 ml red top 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum, plasma, 
cell storage3 
5 ml red top 
10 ml green top 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Arterial blood 
gasses4 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
ICRF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. All samples are collected and handled per current University of Minnesota guidelines for SARS-CoV-2 infected patients. All research samples (unless otherwise 
noted) are transferred to the BSL-2 Lab on the 2nd floor of Microbiology Research Facility for processing and storage. This lab is certified for COVID-19 samples. 
Immune profile (green top) includes: T, B, NK, macrophage, dendritic cell subsets and expression of interferon-γ [IFN-γ] by CD4+T, CD8+T and NK cells (samples 
will be cryopreserved, stored in liquid nitrogen or -120oC freezers and evaluated retrospectively). All samples collected and handled at the University of Minnesota 
will follow local guidelines for SARS- CoV-2 infected patients. All research samples (unless otherwise noted), including those from University of Pittsburgh shipped 
after cryopreservation, are transferred to the BSL-2 Lab on the 2nd floor of Microbiology Research Facility for processing stored following Institutional guidelines.   
2. Extended cytokine profile (red top) includes: IL-2, IL-10, IL-18, sIL-2R, sIL-6R, sTNFR1, IFN-γ, Ang-1, Ang-2, gp130. Samples will be processed and stored following 
Institutional guidelines. Serum will be stored at - 80oC for planned batch analysis of all samples at the end of study. Evaluations will be performed at the University of 
Minnesota Cytokine Laboratory a BSL2 Laboratory. 
3. Serum (red top) and mononuclear cell preps (green top) will be stored in liquid nitrogen at each site for planned batch analysis of all samples at the end of study (e.g., 

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research will include development of antibodies to SARS-CoV-2). All samples collected and handled at the University of Minnesota will follow local guidelines for 
SARS-CoV-2 infected patients. All research samples (unless otherwise noted) are transferred to the BSL-2 Lab on the 2nd floor of Microbiology Research Facility for 
processing and storage. This lab is certified for COVID-19 samples. 
4. Prior to and sometime between 1 and 4 hours after the first study agent infusion 
5. MSC or vehicle placebo control will be administered three times within 7 days of the first infusion, aiming for 48 hour intervals. Vital signs will be checked before and 
every 15 minutes during the infusion, at the completion of the infusion, and one, 3 and 6 hours post study agent infusion. More frequent vital signs may be required 
depending on reactions to the product infusion.  An arterial blood gas will be obtained within 30 minutes prior and once between 1 and 4 hours after the first study 
agent infusion. 

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9 Adverse Event Monitoring, Recording and Reporting 
Toxicity and adverse events will be classified according to NCI's Common Terminology Criteria for 
Adverse Events V 5.0 (CTCAE) and reported on the schedule below. A copy of the CTCAE events can 
be downloaded from http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
9.1  Definitions 
The following definitions are based on the Code of Federal Regulations Title 21 Part 312.32 
(21CFR312.32(a)). 
Adverse Event: Any untoward medical occurrence associated with the use of a study agent in 
humans, whether or not considered study agent related. 
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that 
the study agent caused the adverse event. 
Treatment-Emergent Adverse Event: Any event not present prior to the initiation of the treatment 
or any event already present that worsens in either intensity or frequency following exposure to the 
treatment. A treatment emergent AE refers to an event temporally related to the study agent 
regardless of the causality assessment by the investigator. 
Life-Threatening Adverse Event or Life-Threatening Suspected Adverse Reaction: An adverse 
event or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. Note: 
a life-threatening event does not necessarily equate to a CTCAE grade 4. 
Serious Adverse Event or Serious Suspected Adverse Reaction: An adverse event or suspected 
adverse reaction to the study agent is considered “serious” if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered "unexpected" if it is not listed in the investigator brochure 
or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is 
not required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended. Thus, as defined by the FDA 
adverse events that occur as part of the disease process or underlying medical conditions are 
considered unexpected; however, for the purposes of this study they will not be documented or 
reported. 
 

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Major Deviation: A deviation or violation that impacts the risks and benefits of the research; may 
impact subject safety, affect the integrity of research data and/or affect a subject’s willingness to 
participate in the research. Deviations that place a subject at risk, but do not result in harm are 
considered to be major deviations. 
Minor Deviation: A deviation or violation that does not impact subject safety, compromise the 
integrity of research data and/or affect a subject’s willingness to participate in the research. 
9.2 Adverse Event Monitoring, Recording and Reporting 
9.2.1 Event Monitoring 
Monitoring for adverse events will begin on the day of the first study agent infusion and 
continue through 28 days. 
9.2.2 Event Recording/Documentation 
Due to the seriousness of SARS-CoV-2 mediated ARDS, numerous adverse events are 
anticipated in this patient population regardless of the infusion of the study agent.  
Use of specific supportive interventions, including prone positioning (days of proning), use of 
paralytics, pulmonary vasodilators, tocilizumab, steroids, and use of alternative modes of 
ventilation (APRV, HFOV, etc.) and ECMO will be collected. 
Other events to be documented will include: 
1) Changes in heart rate, systolic and diastolic blood pressure, temperature, oxygen 
saturation, ventilator parameters, urine output, and vasopressor dose at baseline and 
every 15 minutes during the one hour of study agent infusion, then hourly for six hours. 
every 8 hours until the next study agent infusion. 
2) Oxygenation Indices including: PaO2:FiO2 ratio, peak and plateau pressures, PEEP 
at baseline, day of study agent infusion and each day thereafter while ventilated.  In 
addition, at specified time points (see Table 5A), lung function status, dyspnea index, 
pulmonary function tests, 6 minute walk test, high resolution chest CT, will be 
assessed to determine the short and long term effects on COVID-19 ARDS and the 
impact of treatment. 
3) Number of ventilator days 
4) Number of ICU Days 
For this trial, a reportable adverse event is defined as: 
1) Sustained decline (>1 hour) in cardiorespiratory status within 6 hours from the start of 
study product infusion as defined by: 
• 
An increase in vasopressor requirement such that the for any agent doses are: 
o Norepinephrine >12 µg/min or 0.2 µg/kg per min 
o Phenylephrine >150 µg/min or 3.0 µg/kg per min 
o Epinephrine >10 µg/kg per min or 0.2 µg/kg per min 
o Vasopressin >0.04 units/min 
• 
Addition of a third vasopressor 

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• 
New cardiac arrhythmia requiring cardioversion or ventricular tachycardia, ventricular 
fibrillation or asystole 
• 
Hypoxemia requiring an increase in FiO2 of 0.2 or more and an increase in PEEP of 5 
or more to maintain Sp02 in the target range of 88-95% 
• 
Clinical scenario consistent with transfusion incompatibility or transfusion-related 
infection (e.g., urticaria, new bronchospasm) 
2) Any cardiac arrest or death occurs within 24 hours from the start of study product will be 
reported as a pre-specified infusion-associated significant event. Any cardiac arrest or 
death occurs during the study period will be a reportable event that will be reviewed in 
detail. 
As patient safety is an essential component of this protocol, each participating investigator has 
primary responsibility for the safety of study participants under his or her care. The Principal 
Investigator will evaluate all clinically important adverse events.  
Expected events for ARDS are untoward clinical occurrences that are perceived by the 
investigator to occur with reasonable frequency in the day to day care of patients with ARDS 
treated in an ICU with mechanical ventilation. Examples of adverse events that are expected 
in the course of ARDS include transient hypoxemia, agitation, delirium, nosocomial infections, 
skin breakdown, and gastrointestinal bleeding. Such events, which are often the focus of 
prevention efforts as part of usual ICU care, will not be considered reportable adverse events 
unless the event is considered by the investigator to be associated with the study cell product 
or procedures, or unexpectedly severe or frequent for an individual patient with ARDS. 
Examples of unexpectedly frequent adverse events would be repeated episodes of 
unexplained hypoxemia.  This would be in contrast to an isolated episode of transient 
hypoxemia (e.g., Sp02 ~85%), related to positioning or suctioning. This latter event would not 
be considered unexpected by nature, severity or frequency. 
Organ failure related to ARDS or the patient’s underlying condition will be systematically 
captured by the protocol but should not be reported as adverse events unless they are 
considered to be study related. 
All adverse events occurring during the study period must be recorded in the patient’s case 
report forms (CRFs). The clinical course of each event should be followed until resolution, 
stabilization, or until it has been determined that the study treatment or participation is not the 
cause. SAEs that are still ongoing at the end of the study period must be followed up to 
determine the final outcome. Any SAE that occurs after the study period and is considered to 
be possibly related to the study treatment or study participation should be recorded and 
reported immediately to the study sponsor (see Section 9.2.3.). 
9.2.3 Site Investigator’s Reporting Requirements 
Investigators will report all serious AND unexpected, AND study-related adverse events to the 
study sponsor and CTO-CGI at the University of Minnesota within 24 hours by fax, phone or 
email. 
Investigators must also report Unanticipated Problems, regardless of severity, associated with 
the study drug or study procedures within 24 hours. 

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The IRB must also be notified in a timely manner, as per the IRB‟s requirement. The 
investigator will then submit a detailed written report to the study sponsor and the IRB (as 
required) no later than 5 calendar days after the investigator discovers the event. 
The minimum necessary information (Table 6) to be provided at the time of the initial written 
report includes: 
Table 6: Essential Information 
o Study identifier 
o Study Center 
o Subject number 
o Date of event onset 
o A description of the event 
o Whether study treatment was discontinued 
o The reason why the event is classified as 
serious 
o Investigator assessment of the association 
between the event and study treatment 
o Current status 
 
9.2.4 Event Reporting to the Study Sponsor, IRB and FDA 
 
The University of Minnesota has the following expedited reporting responsibilities (Table 7): 
Table 7: Expedited Reporting 
Agency 
reporting to 
 
Criteria for reporting 
 
Timeframe 
Form to 
Use 
Submission 
address/email 
address 
 
 
 
 
 
University of 
Minnesota 
IRB 
Events requiring prompt reporting 
include, but are not limited to 
unanticipated death of a locally 
enrolled subject(s); new or increased 
risk, any adverse event that requires a 
change to the protocol or consent 
form, or any protocol deviation that 
results in harm.  
 
Deviations from the protocol that do 
not result in harm may also need to be 
reported to the IRB, per the IRB’s 
current reporting requirements.  
 
For a complete list, refer to 
http://www.research.umn.edu/irb/guida
nce/ae.html#.VC7xraI0-sh.  
Within 5 business days 
of event discovery 
RNI form 
 
http://www.ethos.um
n.edu 
FDA 
Unexpected and fatal or unexpected 
and life threatening suspected adverse 
reaction 
no later than 7 
Calendar Days 
SAE Report 
Form 
Submit to FDA as 
an amendment to 
IND, with a copy 
to each 
participating site 
1) Serious and unexpected suspected 
adverse reaction or 
2) increased occurrence of serious 
suspected adverse reactions over that 
listed in the protocol or investigator 
brochure or 
3) findings from other sources (other 
studies, animal or in vitro testing) 
no later than 15 
Calendar-Days 
Note: Events due to the disease under treatment or an preexisting medical condition will not 
require expedited reporting to the FDA for the purposes of this study 

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The MCC SAE Coordinator or designee is responsible for reviewing each report and 
determines if the event is reported in real time to the Independent Data Safety Monitoring 
Board (DSMB) in real time or as part of quarterly summary reports required for any high risk 
trial. 
At the time of continuing review/IND annual report, relevant events recorded in ONCORE will 
be reported in summary format by those persons responsible for such reporting. 
9.2.5 Institutional Event Reporting Table 
Individual institutional sites will be responsible for reporting any event meeting local reporting 
requirements to their institutional IRB and/or other research oversight committees. 
Institutional sites will be responsible for reporting events within the following time frames to 
the MCC Multisite Program Manager. 
Table 8: Institutional Reporting 
Event Type 
Reporting 
Timeframe 
Form to Use 
Report to 
Any event meeting the 
definition of an SAE 
Within 24 hours of 
knowledge 
For UMN: 
ONCORE SAE 
Report Form 
 
For Participating 
Sites: Paper SAE 
Report Form 
For Participating Sites: Masonic 
Cancer Center (MCC) Multisite 
Program Manager 
affilates@umn.edu 
 
Local institutional IRB or other 
entities per institutional policies 
and guidelines 
 
Independent DSMB 
Stopping Rule Events as 
per section 9.2.2 and 
section 12.4 
Within 24 hours of 
knowledge 
Stopping Rule 
Event Form in 
ONCORE 
Major Deviations, as 
defined in Section 9.1. 
Within 5 working 
days of knowledge 
Deviation Report 
Form in 
ONCORE 
Minor Deviations, as 
defined in Section 9.1. 
Per Institutional 
Policy 
n/a (record in 
Deviations Tab) 
For UMN MCC: Report to the 
study’s regulatory specialist 
 
For Participating Sites: minor 
deviations are not reportable to 
the MCC Multisite Manager. 
Report to local institutional IRB 
or other entities per institutional 
policies and guidelines. 
 
 Sponsor Reporting: Notifying the DSMB 
The study sponsor will report all serious, unexpected, and study-related adverse events to the 
DSMB, by email, or telephone, within 7 calendar days of the study sponsor being notified of the 
event. A written report will be sent to the DSMB within 15 calendar days, and these reports will 
be sent to investigators for submission to their respective IRBs, as required. The DSMB will also 
review all adverse events during scheduled interim analyses. Sponsor Reporting: Notifying All 
Participating Investigators. 
It is the responsibility of the study sponsor to notify all participating investigators, in a written IND 
safety report, of any adverse event associated with the use of the drug that is both serious and 

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unexpected. Additionally, sponsors are also required to identify in IND safety reports all previous 
reports concerning similar adverse events and to analyze the significance of the current event in 
light of the previous reports. IND safety reports will be sent to the participating investigators 
immediately after submission to the IND. 
The study sponsor will distribute the written summary of the DSMB‟s periodic review of adverse 
events to investigators for submission to their respective IRBs in accordance with NIH guidelines. 
9.3 Unblinding Procedures 
The study will have an external Medical Monitor separate from the Investigator/Sponsor and who 
will not be affiliated with any of the study sites or participate in any study procedures (e.g., 
screening of subjects, consenting of subjects or surrogates, administration of MSCs or study 
follow-up). If unblinding the study therapy is necessary to ensure a subject’s safety, this will be 
done by the external medical monitor after review of the clinical events. If this is done in 
conjunction with the site Principal Investigator, the study sponsor must be informed within 24 
hours by phone, fax or email of the unblinding event, followed by a detailed written narrative within 
48 hours of the event by the Principal Investigator at the study site. 
In other circumstances, the medical monitor may choose to unblind him/herself if there is concern 
based on the safety data that a type of adverse event may be associated with MSCs treatment; 
in this case, the medical monitor will inform the study sponsor that he/she has unblended 
him/herself, but not of the treatment assignments. 
9.4 External Medical Monitoring 
An external expert in pulmonary medicine and critical care will serve as the Medical Monitor. The 
Medical monitoring will include a regular assessment of each adverse event, as well as the 
number and type of SAEs. The Medical Monitor will be blinded to the treatment but will provide 
an assessment of the relationship to study agent. If an SAE is considered to be related to the 
study agent infusion, the DSMB will be notified. 
9.5 Monitoring for Stopping Rule Events 
Early stopping rules will be in place for infusion related toxicity in recipients of MSC. The stopping 
rules are generated using an adaptation of Pocock stopping boundaries [35]. In the event that a 
stopping boundary is triggered, study enrollment will be suspended and the PI, IRB, DSMB will 
be notified. 
For this study, excess grade 3-5 infusional toxicities (using Common Toxicity Criteria for Adverse 
Events version 5.0 (CTCAE v5, section 6.2, Table 3) or predefined hemodynamic or respiratory 
AEs within 6 and 24 hours of the start of infusion of study agent will be used for triggering early 
stopping. As patients must have been had a transcutaneous oxygen saturation 88–95% without 
the need for an FiO2 >0.8 or PEEP >20 cm H2O) or use of more than two vasopressors in the 
supine position, worsening as defined in table 9 below within 6 hours after MSC infusion will be 
considered an adverse event(s) that contributes to the cumulative stopping boundary.  
It is expected that the rate of events will be <10%. The goal is to construct a boundary based on 
toxicity such that the probability of early stopping is at most 10% if the rate is equal to 9.5%and 
our sample size is 20. With these stipulations, the trial will be stopped and reviewed if 2 events 
out of 3 patients, 3 events out of 9 patients, 4 events out of 15 patients or 5 events occur. The 
probability of hitting the stopping boundary if the rate is 30% is 82%. 

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Predefined hemodynamic and respiratory SAEs (based on the START Study parameters [22]): 
Table 9: Hemodynamic and Respiratory SAEs 
Event within 6 hours of study agent infusion 
Definition of 
hemodynamic 
deterioration at 6 
hours 
Sustained decline (>1 hour) in cardiorespiratory status within 6 hours 
from the start of study product infusion as defined by: 
 
1. An increase in vasopressor requirement such that the doses are: 
• 
Norepinephrine >12 µg/min or 0.2 µg/kg per min 
• 
Phenylephrine >150 µg/min or 3.0 µg/kg per min 
• 
Epinephrine >10 µg/kg per min or 0.2 µg/kg per min 
• 
Vasopressin >0.04 units/min 
2. Addition of a third vasopressor 
3. New cardiac arrhythmia requiring cardioversion or ventricular 
tachycardia, ventricular fibrillation or asystole 
4. Hypoxemia requiring an increase in FiO2 of 0.2 or more and an 
increase in PEEP of 5 or more to maintain Sp02 in the target range 
of 88-95% 
Event within 24 hours of study agent infusion 
Definition of 
cardiopulmonary 
deterioration at 24 
hours 
) Cardiac arrest or death 
 
For this study, a DSMB will review day 28 safety data after 5 and 15 patients have been enrolled 
and received study agent.  Enrollment will not be suspended pending DSMB review.  All pre-
specified and other clinically important events and unexpected SAEs, including death, will be 
reported to the DSMB on an ongoing basis.  The study will be stopped for a safety evaluation by 
the DSMB if the DSMB members have any concerns or if three subjects have pre-specified 
clinically important events or unexpected SAEs except death since death will be common in this 
critically ill population due to the nature of the underlying illness, COVID-19 ARDS.   
ONCORE 
For participating sites, a copy of the completed Event Form must be sent to the MCC Multisite 
Program Manager at the time it is submitted to the study statistician. 
As these events are outcomes of the treatment, not toxicity as found in CTCAE, they should only 
be recorded/reported as an AE, if they meet the criteria found in section 9.2. 
 
 

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10 Study Data Collection and Monitoring 
10.1 
Data Management 
This study will collect regulatory and clinical data using University of Minnesota CTSI’s 
ONCORE® (Online Enterprise Research Management Environment). 
The ONCORE database resides on dedicated secure and PHI compliant hardware consisting of 
3 physical servers: dev, DR, and production. The dev server is located in the University of 
Minnesota datacenter and houses six database instances (test, train, sandbox, mcc reports, 
oncdm, and vendor) that are backed up locally because the data is refreshed from ONCORE 
production data. The production server is located in the UMN datacenter. All the data servers are 
managed by the Academic Health Center – Information Systems (AHC-IS) virtual servers which 
utilize clustered infrastructure to provide real-time failover of virtual servers. This real- time 
clustering is physically limited to the UMN data center. All relevant AHC IS procedures related for 
PHI compliant servers (as required by the Center of Excellence for HIPAA Data) apply to 
ONCORE databases. 
The integrated data will be stored in PHI compliant servers managed by AHC IS with access given 
to those authorized users in the Clinical and Translation Science Institute Informatics team. The 
data will be integrated and extracted to researchers through the CTSI Informatics team and will 
be delivered through secure and compliant mechanisms (e.g. AHC IE data shelter, BOX, sftp, 
etc). If data de-identification is needed, then compliant AHC IE data de- identification tools will be 
used. The informatics team will grant the IRB approved study team members access to data. 
10.2 
Case Report Forms 
Participant data will be collected using protocol specific CRFs developed within ONCORE, based 
on its library of standardized forms. The CRFs will be approved by the study’s Principal 
Investigator and the Biostatistician prior to release for use. There is a screening case report form 
(SCRF) which the Study Coordinator or designee will use to register the patient into ONCORE at 
time of study entry. An infusion case report form (ICRF) will be used to document adverse events 
during the infusion of study agent (MSC or vehicle placebo control) and outcomes case report 
form (CRF) will record specific outcomes data for submission to the BMT Database. As 
medications, blood product administration, provider examinations and laboratory/radiographic 
data are accessible to the BMT / Cell Therapy Database through a Data Sharing Agreement, 
CRFs will only be needed for specific data collection. 
10.3 
Data and Safety Monitoring Board 
This Phase 2A study will be monitored by an independent DSMB. The DSMB will contain at least 
3 members, 2 intensivists familiar with the care of patients with ARDS, expert in cell therapies. A 
DSMB Charter will define the DSMB’s responsibilities, summarized below. 
The DSMB will meet by teleconference prior to the start of the trial, and at the planned interim 
safety analyses after 5 and 15 patients. At these meetings, the DSMB will review post infusion 
safety data through day 28, all pre-specified clinically important events and unexpected serious 

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adverse events, including deaths.  All safety data will be reviewed in aggregate and will include 
individual adverse event narratives. During the Phase 2A trial, the DSMB will review the safety 
data in an unblinded fashion. 
SAEs and deaths will be reported to the DSMB on an ongoing basis; the study will be stopped for 
a safety evaluation by the DSMB if they have any concerns, or if a stopping rule is activated.    
The external Medical Monitor will serve as the liaison between the DSMB and the study sponsor 
and Principal Investigators. The actual analyses will be conducted by the Study Biostatistician 
who will ensure that the unblinded analyses are not available to study investigators. 
The DSMB chair will be responsible for recording the summary of its various meetings and for 
reporting findings and/or recommendations to the study sponsor and to the funding agency. 
10.4 
IND Annual Reports 
In accordance with regulation 21 CFR § 312.33, the sponsor-investigator with assistance from the 
University of Minnesota Masonic Cancer Center’s Clinical Trials Office for Cell, Gene and 
Immunotherapies (CTO-CGI) will submit a progress report annually. The report will be submitted 
within 60 days of the anniversary date that the IND went into effect. 
10.5 
Data Sharing with Participating Sites 
All data including identifiers will be submitted to the University of Minnesota BMT / Cell Therapy 
Database. Only the study sponsor and MCC investigators will have access to the complete data 
set including identifiers. 
10.6 
Monitoring 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
government regulatory bodies, and University of Minnesota compliance groups. The investigator 
will make available all study related documents (e.g. source documents, regulatory documents, 
data collection instruments, study data, etc.). The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.) will 
be available for trial related monitoring, audits, or regulatory inspections. 
10.7 
Teleconferences – Lead Site and Participating Site 
Regular teleconferences to facilitate communication between participating sites regarding the 
study’s progress, patient updates, summary of safety reports, case report form completion, and 
other issues for discussion. The University of Minnesota Multisite Program Manager will be 
responsible for arranging these teleconferences and preparing the agenda. Teleconferences will 
be scheduled at a regular interval determined by the lead institution. Participation of a minimum 
of one representative from each participating site will be required. These teleconferences are in 
addition to other previously described site interactions including centralized patient registration, 
institutional and MCC required reporting of safety related issues, case report form completion in 
the study’s central database (ONCORE) and participating site oversight through self-monitoring 
in compliance with the Masonic Cancer Center’s Data and Safety Monitoring plan. 

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10.8 
Participating Site Monitoring 
The Sponsor (Dr. Wagner) with the CTO has oversight responsibility for trial monitoring at 
participating sites. Participating sites must self-monitor following the University of Minnesota 
Cancer Center Data and Safety Monitoring Plan (DSMP - http://z.umn.edu/dmsp) and the CTO 
Affiliate and Satellite Site Monitoring SOPs. Alternately, participating sites that are an NCI 
designated Cancer Center may self-monitor using their NCI approved Data and Safety Monitoring 
Plan. 
See section 10.6 for additional information. 
10.9 
Study Record Retention 
The sponsor and principal investigators will retain study records including source data, copies of 
case report form, consent forms, HIPAA authorizations, and all study correspondence in a 
secured facility for at 6 years after the study file is closed with the IRB and FDA. 
In addition, the CTO-CGI will keep a master log of all patients participating in the study with 
sufficient information to allow retrieval of the medical records for that patient. 
Please contact the CTO-CGI before destroying any study related records. 
11 Definition of Study Endpoints 
This phase 2A clinical trial is intended to study the safety and effectiveness of three doses of 
MSCs on inflammatory biomarkers commonly observed in patients with COVID-19 ARDS. Safety 
will be measured by the absence of severe adverse pulmonary and hemodynamic changes 
related to MSC infusion. Efficacy will be measured by a trend toward greater reduction in 
inflammatory cytokines, CRP or ferritin during the first 7 days after the initial MSC infusion as 
compared to the vehicle placebo control.  For assessing the safety outcome, systematically 
collected hemodynamic, respiratory, and laboratory data along with physical findings during and 
after MSC administration versus vehicle placebo control will be compared. Safety parameters will 
include changes in heart rate, systolic and diastolic blood pressure, temperature, oxygen 
saturation, ventilator parameters, urine output, and vasopressor dose will be recorded at baseline 
and every 15 minutes during the one hour of MSC or placebo infusion, then hourly for three hours, 
then every 8 hours until the next MSC/Placebo infusion. 
Secondary endpoints include the following that require further definition: 
11.1 
Change in Oxygenation Indices 
All patients on a ventilator will have daily evaluations including: PaO2:FiO2 ratio, peak and plateau 
pressures, PEEP. The peak values for baseline, day of study agent infusion and each day 
thereafter will be recorded. 
 

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11.2 
Ventilator Free Days 
Days alive off the ventilator during the first 28 days after the initial dose of study agent was infused. 
11.3 
ICU Free Days 
Days alive discharged from the ICU during the first 28 days after the initial dose of study agent 
was infused 
11.4 
Mortality 
Mortality is death from any cause. Primary, secondary and tertiary causes of death will be 
recorded. Pulmonary failure and hypotension may be the proximate causes of death but only the 
underlying etiology will be recorded as the primary cause of death. 
11.5 
Acute Lung Injury Score 
The Acute Lung Injury Score (adapted from Murray et al. [2] erratum 1989:139:1065) is based on 
the maximum score at baseline and day 28 focusing on PaO2/FiO2, the level of positive end-
expiratory airway pressure, respiratory compliance, and the extent of pulmonary infiltrates on the 
chest radiograph, using the scoring below.  Note: If no chest imaging is available from within 48 
hours of the specified time, then the Acute Lung Injury Score for that time cannot be calculated 
and 
this 
will 
be 
a 
‘missing’ 
data 
point. 
 

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12  
Statistical Considerations 
12.1 
Study Design, Objectives and Endpoints 
This is a Phase 2A safety study that will verify safety of and help guide estimates of efficacy for 
the design of future larger scale study for both efficacy and safety. Patients will be randomized in 
a 2:1 fashion (MSC: placebo). 
12.1.1 Primary Endpoint 
• Incidence of predefined grade 3-5 infusional toxicities and hemodynamic or respiratory 
adverse events related to the infusion of MSC. 
12.1.2 Secondary Endpoints 
• Incidence of a reduction in one or more biomarkers of inflammation by day 7 
• Trend changes in PaO2:FiO2 ratio, oxygenation index, peak and plateau pressures and 
PEEP from baseline on days 3, 7 and 14Incidence of mortality by day 28 and 100 
• Number of ICU-free days alive by day 28 
• Number of days alive and ventilator free composite score3 by day 28 
• Change in acute lung injury (ALI) score2 between baseline and day 28 
• Incidence and severity of serious adverse events by day 28 
• Number of days alive off supplemental oxygen by day 100 
• Number of hospital days by day 100  
• Description of lung function status over time to 1 year 
12.1.3 Exploratory Endpoints 
• Characterization of immunological changes over 28 days 
• Characterization of inflammatory and alveolar epithelial function/injury biomarker changes 
over 28 days 
12.2 
Statistical Analysis 
Our primary hypothesis is that 3 doses of MSC with known immunomodulatory and broad anti- 
inflammatory properties can be safely administered to patients with moderate to severe COVID-
19 mediated ARDS. If multiple doses are well-tolerated with improvements in efficacy measures 
(e.g. in terms of trends in mortality rates, ventilator days and/or acute lung injury scores), a phase 
2B study will be developed with more reliable sample size estimates based on outcomes in this 
study. The analysis will primarily be descriptive. The primary endpoint will be estimated with a 
simple proportion and a 95% confidence interval along with its standard deviation at day 28. 

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Comparison of groups may be performed by a Chi-square test or Fisher’s exact test. Other 
categorical endpoints will be measured in a similar manner. Overall survival at 100 days post MSC 
infusion will be estimated by Kaplan-Meier curves. Comparison of groups may be performed by a 
log-rank test. Continuous endpoints such as days on oxygen will be estimated with means and 
standard deviations or if skewed, then medians and ranges. A t-test, Wilcoxon may be used to 
compare continuous measures. Feasibility will simply be assessed by the ability to run a smooth 
study without missing data and providing estimates of the proportion of patients able to receive 3 
MSC doses. Descriptive endpoints may also be summarized with boxplots and dot plots. 
12.3 
Rationale for Sample Size 
Due to the nature of the early phase safety study, the study accrual will stop when a total of 20 
treated patients and 10 control patients have been enrolled. In general, however, the MSC and 
control arms will be used to help determine safety and whether there is a signal of benefit in each 
arm as well as to help us develop more accurate projections of the numbers needed to prove that 
the infusion of MSC is associated with improved survival. 
12.4 
Monitoring Guidelines 
Early stopping rules will be in place for infusion related toxicity in recipients of MSC. The stopping 
rules are generated using an adaptation of Pocock stopping boundaries [35]. In the event that a 
stopping boundary is triggered, study enrollment will be suspended and the PI, IRB, DSMB will be 
notified. 
For this study, predefined hemodynamic or respiratory AEs within 6 and 24 hours of the start of 
infusion of study agent will be used for triggering early stopping. As patients must have been had 
a transcutaneous oxygen saturation 88–95% without the need for an FiO2 >0.8 or PEEP >20 cm 
H2O) or use of more than two vasopressors in the supine position, worsening as defined in table 
9 below within 6 hours after MSC infusion will be considered an adverse event(s) that contributes 
to the cumulative stopping boundary.  
It is expected that the rate of events will be <10%. The goal is to construct a boundary based on 
toxicity such that the probability of early stopping is at most 10% if the rate is equal to 9.5%and 
our sample size is 20. With these stipulations, the trial will be stopped and reviewed if 2 events 
out of 3 patients, 3 events out of 9 patients, 4 events out of 15 patients or 5 events occur. The 
probability of hitting the stopping boundary if the rate is 30% is 82%. 
Predefined hemodynamic and respiratory SAEs (based on the START Study parameters [22]): 
Table 9: Hemodynamic and Respiratory SAEs 
Event within 6 hours of study agent infusion 
Definition of 
hemodynamic 
deterioration 
at 6 hours 
Sustained decline (>1 hour) in cardiorespiratory status within 6 hours 
from the start of study product infusion as defined by: 
1) An increase in vasopressor requirement such that the doses are: 
o Norepinephrine >12 µg/min or 0.2 µg/kg per min 
o Phenylephrine >150 µg/min or 3.0 µg/kg per min 
o Epinephrine >10 µg/kg per min or 0.2 µg/kg per min 
o Vasopressin >0.04 units/min 
2) Addition of a third vasopressor 

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3) New cardiac arrhythmia requiring cardioversion or ventricular 
tachycardia, ventricular fibrillation or asystole 
4) Hypoxemia requiring an increase in FiO2 of 0.2 or more and an 
increase in PEEP of 5 or more to maintain Sp02 in the target range 
of 88-95% 
Event within 24 hours of study agent infusion 
Definition of 
cardiopulmonary 
deterioration at 24 
hours 
Cardiac arrest or death 
Causality: Adverse events with a reasonable possibility of a causal relationship will be considered 
“related”. Causality will be assigned by the blinded independent Medical Monitor who is expert in 
critical care medicine.  The unblinded DSMB will provide the final assessment and determine 
whether the study can continue based on the defined stopping rules.   
12.5 
Gender and Ethnicities Statement 
This study is open to both males and females and to all racial/ethnic groups. It is not anticipated 
that the outcome will be affected by either race or gender. The study will not have separate accrual 
targets for different subgroups. 
13 Conduct of the Study 
13.1 
Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory requirement(s). 
Essential clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected. Master files will be established at the beginning of the study, 
maintained for the duration of the study and retained in a centralized file within the Clinical Trials 
Office of the Masonic Cancer Center according to the appropriate regulations. 
13.2 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB will review all appropriate study documentation in order to safeguard the rights, 
safety and well-being of the patients. The study will only be conducted at sites where IRB approval 
has been obtained. The protocol, consent, written information given to the patients, safety 
updates, annual progress reports, and any revisions to these documents will be provided to the 
IRB by the investigator. 
13.3 
Informed Consent 
All potential study participants or their surrogates will be given a copy of the IRB-approved consent 
to review. The investigator or designee will explain all aspects of the study in lay language and 
answer all questions regarding the study either in person or by virtual or telephone meeting. If the 
participant or surrogate decides to participate or allow participation in the study, he/she will be 
asked to sign and date the consent document. Patients who refuse to participate or who withdraw 

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from the study will be treated without prejudice and will receive standard medical care. 
14 References 
1) 
Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin 
Definition. JAMA 2012;307:2526-2533. 
2) 
Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory 
distress syndrome. Am Rev Respir Dis. 1988;4:720–723. 
3) 
Novack V, Beitler JR, Yitshak-Sade M, et al. Alive and Ventilator Free: A Hierarchical, Composite 
Outcome for Clinical Trials in the Acute Respiratory Distress Syndrome. Crit Care Med 
2020;48:158-166 
4) 
World Health Organization. WHO Director-General’s opening remarks at the media briefing on 
COVID-19—11 March 2020. Geneva, Switzerland: World Health Organization; 2020. 
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briefing-on-covid-19 
11-march-2020 
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World Health Organization. Coronavirus disease 2019 (COVID-19) situation report – 68. 
Geneva, Switzerland: World Health Organization; 2020. https://www.who.int/docs/default- 
source/coronaviruse/situation-reports/20200328-sitrep-68-covid-19.pdf?sfvrsn=384bc 
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CDC COVID-19 Response Team. Preliminary Estimates of the Prevalence of Selected 
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2600(20)30079-5 
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Pavan K, Ghassemieh BJ, Michelle Nichols, et al. COVID-19 in Critically Ill Patients in the Seattle 
Region — Case Series. March 30, 2020 DOI: 10.1056/NEJMoa2004500 
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Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome 
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10) Center for Systems Science and Engineering. Coronavirus COVID-19 global cases. 2019 
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67b4 8e9ecf6. 
11) Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med 2017; 
377: 562–72. 
12) Eisner MD, Thompson T, Hudson LD, el al. Acute Respiratory Distress Syndrome Network: 
Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung 
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13) Erickson SE, Shlipak MG, Martin GS, et al. National Institutes of Health National Heart, Lung, 

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and Blood Institute, and Acute Respiratory Distress Syndrome Network: Racial and ethnic 
disparities in mortality from acute lung injury. Crit Care Med. 2009;37:1–6. 
14) Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–
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15) Matthay MA, Zimmerman GA. Acute lung injury and the acute respiratory distress syndrome: 
four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol. 
2005; 33: 319–27. 
16) Ortiz LA, Gambelli F, McBride C, et al. Mesenchymal stem cell engraftment in lung is enhanced 
in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA. 
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17) Ortiz LA, Dutreil M, Fattman C, et al. Interleukin 1 receptor antagonist mediates the 
antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl 
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18) Rojas M, Xu J, Woods CR, et al. Bone marrow-derived mesenchymal stem cells in repair of the 
injured lung. Am J Respir Cell Mol Biol. 2005;33:145–152. 
19) Xu J, Woods CR, Mora AL, et al. Prevention of endotoxin-induced systemic response by bone 
marrow-derived mesenchymal stem cells in mice. Am J Physiol Lung Cell Mol Physiol. 
2007;293:L131–L141. 
20) Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA. Intrapulmonary delivery of bone 
marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced 
acute lung injury in mice. J Immunol. 2007;179:1855–1863. 
21) Wilson JG, Liu KD, Zhuo H, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a 
phase 1 clinical trial. Lancet Respir Med 2015; 3: 24–32. 
22) Matthay MA, Clfee CS, Shuo H, et al. Treatment with allogeneic mesenchymal stromal cells for 
moderate to severe acute respiratory distress syndrome (START study): a randomized phase 
2a safety trial. Lancet Respir Med 2019; 7:154-62. 
23) Huang C, Wang Y, Li X, Ren L, et al. Clinical features of patients infected with 2019 novel 
coronavirus in Wuhan, China. The Lancet, 2020;395:497-506. 
24) Xu, Z. et al. Pathological findings of COVID-19 associated with acute respiratory distress 
syndrome. Lancet Respir. Med. 8, 420–422 (2020). 
25) Qin, C. et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. 
Clin. Infect. Dis. https:// doi.org/10.1093/cid/ciaa248 (2020).  
26) Shi, Y. et al. Immunopathological characteristics of coronavirus disease 2019 cases in 
Guangzhou, China. Preprint at medRxiv https://doi.org/10.1101/2020.03.12.20034736 (2020).  
27) Nemeth K, Leelahavanichkul A, Yuen PS, et al. Mesenchymal stem cells reduce inflammation 
while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care 
Med. 2010; 182:1047–57. 
28) Maron-Gutierrez T, Silva JD, Asensi KD, et al. Effects of mesenchymal stem cell therapy on the 

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time course of pulmonary remodeling depend on the etiology of lung injury in mice. Crit Care 
Med. 2013; 41:e319–33 
29) Lee JW, Krasnodembskaya A, McKenna DH, Song Y, Abbott J, Matthay MA. Therapeutic effects 
of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am J Respir 
Crit Care Med. 2013; 187:751–60. 
30) Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2- Mesenchymal Stem Cells Improves the 
Outcome of Patients with COVID-19 Pneumonia. Aging Disease 2020; 11:216-228. 
31) Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. 
2012;122:2731–40. 
32) The ARDS Definition Task Force. Acute Respiratory Distress Syndrome: The Berlin Definition. 
JAMA. 2012;307:8 
33) Martín-Henao GA, Resano PM, Villegas JM, et al. Adverse reactions during transfusion of 
thawed haematopoietic progenitor cells from apheresis are closely related to the number of 
granulocyte cells in the leukapheresis product. Vox Sang. 2010; 99: 267-73 
34) Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor 
prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-847 
35) Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in oncology. 
Biometrics. 2005; 61: 540-5. 
 
 

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Appendix I – Apache II and Sofa Scoring 
MULTI-CENTER, RANDOMIZED, PLACEBO CONTROLLED, INTERVENTIONAL PHASE 
2A CLINICAL TRIAL EVALUATING THE SAFETY OF MULTIPLE DOSING OF 
MESENCHYMAL STROMAL CELLS IN PATIENTS WITH SEVERE ACUTE RESPIRATORY 
SYNDROME CORONAVIRUS 2 (SARS-Cov-2) 
APACHE II SCALE 
 
 

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MULTI-CENTER, RANDOMIZED, PLACEBO CONTROLLED, INTERVENTIONAL PHASE 
2A CLINICAL TRIAL EVALUATING THE SAFETY OF MULTIPLE DOSING OF 
MESENCHYMAL STROMAL CELLS IN PATIENTS WITH SEVERE ACUTE RESPIRATORY 
SYNDROME CORONAVIRUS 2 (SARS-Cov-2) 
SOFA SCORE 
 

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Appendix II – Dyspnea Index Questionnaire 
 
Below are the questions used in the University of California, San Diego Shortness of Breath Questionnaire 
(SOBQ). 
 

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