Phase I/IIA Study of Descartes-30 in Acute Respiratory Distress Syndrome
Phase: PHASE1
Conditions: Acute Respiratory Distress Syndrome, Covid19
Sponsor: Cartesian Therapeutics



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INVESTIGATOR’S AGREEMENT 
I have received and read the investigator’s brochure for Descartes-30. I have read the protocol and 
agree to conduct the study as outlined and in conformance with Good Clinical Practices (GCPs) 
and applicable regulatory requirements. I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
Printed Name of Investigator 
Signature of Investigator 
 
Date 

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TABLE OF CONTENTS 
Protocol Synopsis ........................................................................................................................9 
1 
Schedule of Activities (SOA) .......................................................................................... 12 
2 
Introduction and Rationale .............................................................................................. 14 
2.1 
Risk/Benefit Assessment ............................................................................................ 15 
3 
Objectives ....................................................................................................................... 16 
4 
Study Design................................................................................................................... 17 
4.1 
Schema....................................................................................................................... 17 
4.2 
Overall Study Design ................................................................................................. 18 
4.3 
Justification for Dose .................................................................................................. 18 
4.4 
Dose Escalation Rules ................................................................................................ 19 
4.5 
Dose Escalation Stopping Rules ................................................................................. 19 
5 
Study Population ............................................................................................................. 20 
5.1 
Inclusion Criteria ........................................................................................................ 20 
5.2 
Exclusion Criteria ....................................................................................................... 20 
5.3 
Screen Failures ........................................................................................................... 21 
5.4 
Strategies for Recruitment and Retention .................................................................... 21 
5.5 
Patient Identification .................................................................................................. 21 
6 
Study Procedures ............................................................................................................ 22 
6.1 
Screening ................................................................................................................... 22 
6.2 
Day 0,1,2 Descartes-30 Infusion ................................................................................. 23 
6.3 
Safety Monitoring Days 3-6 ....................................................................................... 24 
6.4 
Primary Safety Review (Day 7) .................................................................................. 25 
6.5 
Short-term Follow-up (Day 14, 21 and 28) ................................................................. 26 
6.6 
Long-term follow-up (Day 90+ 14) ............................................................................ 27 
7 
Study Intervention ........................................................................................................... 28 
7.1 
Study Intervention(s) Administration .......................................................................... 28 
7.1.1 
Study Intervention Description ...........................................................................28 
7.1.2 
Dosing and Administration .................................................................................28 
7.1.3 
Return or Destruction of Study Product ..............................................................31 
7.2 
Safety Monitoring Period ........................................................................................... 31 
7.2.1 
Concomitant Medications ...................................................................................31 
7.2.2 
Management of Toxicities ..................................................................................31 
8 
Safety Assessment and Procedures .................................................................................. 33 
8.1 
Definitions ................................................................................................................. 33 
8.1.1 
Adverse Events (AE) ..........................................................................................33 
8.1.2 
Dose Limiting Toxicity (DLT)............................................................................33 
8.1.3 
Serious Adverse Event (SAE) .............................................................................33 

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8.1.4 
Serious Unexpected Adverse Reaction (SUSAR) ................................................34 
8.2 
Recording of Adverse Events ..................................................................................... 34 
8.2.1 
Adverse Event Recording ...................................................................................34 
8.2.2 
Pregnancy ...........................................................................................................34 
8.3 
SAE and SUSAR Reporting ....................................................................................... 34 
8.3.1 
Study Sponsor Notification .................................................................................35 
8.3.2 
IRB Notification .................................................................................................35 
8.3.3 
FDA Notification ................................................................................................35 
8.4 
Criteria for Off-Study ................................................................................................. 36 
8.5 
Study Pausing and Stopping Rules ............................................................................. 36 
9 
Statistical Considerations ................................................................................................ 37 
9.1 
Sample Size................................................................................................................ 37 
9.2 
Safety ......................................................................................................................... 37 
9.3 
Efficacy ...................................................................................................................... 37 
9.4 
Exploratory ................................................................................................................ 37 
10 
Supporting Documentation and Procedures ..................................................................... 38 
10.1 
Informed Consent Process .......................................................................................... 38 
10.2 
Study Discontinuation and Closure ............................................................................. 38 
10.3 
Medical Monitor......................................................................................................... 38 
10.4 
Recording of Protocol Deviation ................................................................................ 38 
10.5 
Data Handling and Record Keeping ............................................................................ 39 
10.5.1 
Source Data ........................................................................................................39 
10.5.2 
Case Report Forms .............................................................................................39 
10.5.3 
Confidentiality....................................................................................................39 
11 
References ...................................................................................................................... 40 
12 
Appendix A .................................................................................................................... 44 
13 
Appendix B ..................................................................................................................... 46 
14 
Appendix C ..................................................................................................................... 47 
15 
Appendix D .................................................................................................................... 48 
16 
Appendix E ..................................................................................................................... 49 
16.1 
Study Design .............................................................................................................. 50 
16.1.1 
Schema ...............................................................................................................50 
16.2 
Overall Study Design ................................................................................................. 51 
16.3 
Schedule of Activities................................................................................................. 51 
16.4 
Study Procedures ........................................................................................................ 52 
16.4.1 
Screening ...........................................................................................................52 
16.4.2 
Day 1,2,3 ............................................................................................................53 
16.4.3 
Days 4-6 .............................................................................................................53 

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16.4.4 
Day 28 (or day of discharge)...............................................................................54 
16.5 
Biomarker Analysis and Statistical Considerations ..................................................... 54 
16.5.1 
Sample Size ........................................................................................................54 
16.5.2 
Clinical End-points .............................................................................................54 
16.5.3 
Biomarker Analysis ............................................................................................55 
 
 
LIST OF TABLES 
Table 1. 
Definition of Dose Levels ..................................................................................... 18 
 

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ABBREVIATIONS AND DICTIONARY OF TERMS 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartyl aminotransferase 
AUC 
Area Under the (time-concentration) Curve 
BiPAP 
Bilevel Positive Airway Pressure 
CBC 
Complete blood count 
CK 
Creatine Kinase 
CPAP 
Continuous Positive Airway Pressure 
CrCl 
Creatinine Clearance 
CRP 
C-Reactive Protein 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DMF 
Drug Master File 
DNA 
Deoxyribonucleic acid 
DVT 
Deep Venous Thrombosis 
ECG 
Electrocardiogram 
FiO2 
Fraction of inspired oxygen 
GMP 
Good Manufacturing Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus  
HIV 
Human immunodeficiency virus 
HR 
Hazard Ratio 
ICU 
Intensive Care Unit 
IFN-γ 
Interferon-gamma 
Ig 
Immunoglobulin 
IL 
Interleukin 
IND 
Investigational New Drug (application) 
IV 
Intravenous(ly) 
LOS 
Length of Stay 
MSC 
Mesenchymal Stem Cell 
MTD 
Maximal Tolerated Dose 
MRSD 
Maximum Recommended Starting Dose 
MSSD 
Maximum Safe Starting Dose 
NET 
Neutrophil Extracellular Trap 
NOAEL 
No Observed Adverse Effect Level 
NSAID 
Non-steroidal anti-inflammatory drug 
PaO2 
Arterial oxygen pressure 
PEEP 
Positive End Expiratory Pressure 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PNA 
Pneumonia 

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ABBREVIATIONS AND DICTIONARY OF TERMS 
SAE 
Serious Adverse Event 
SEM 
Standard Error of the Mean 
SM 
Starting Materials 
SOFA 
Sequential Organ Failure Assessment 
SUSAR 
Serious Unexpected Adverse Reaction 
TK  
Toxicokinetic(s)  
WHO 
World Health Organization 
 

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• 
Dose Level 4: 1200 million cells administered on Days 0, 1 and 2 
 
An additional 12 patients per cohort (ARDS or PNA) may be enrolled at a 
dose up to MTD. 
Study Duration: 
Participant Duration: 
30 months 
3 months 

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1 
SCHEDULE OF ACTIVITIES (SOA) 
Procedures 
Screening Visit j 
Study Product Infusion 
Day 0 
Study Product Infusion 
Day 1 
Study Product Infusion 
Day 2 
Safety Monitoring 
Day 3-6 k, l 
Primary safety review 
Day 7 or last day in 
administering unitw 
Short-term Follow-up 
Day 14 l  
Short-term Follow-up 
Day 21 l 
Short-term Follow-up m 
Day 28 or last day in 
hospital 
Long-term Follow-up 
Day 90+ 14 n 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical examinationa 
X 
X 
X 
X 
X 
X 
Xs,t 
Xs,t 
Xs,t 
X 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Descartes-30 Cell 
Infusion  
 
X 
X 
X 
 
 
 
 
 
 
Clinical Endpoint 
Assessment b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs c  
X 
X 
X 
X 
X 
X 
Xs 
Xs 
Xs 
X 
CBC with differential d 
X 
Xv 
Xv 
Xv 
Xv 
Xv 
Xs 
Xs 
Xs 
 
Serum chemistry d, e 
X 
Xv 
Xv 
Xv 
Xv 
Xv 
Xs 
Xs 
Xs 
 
CRP, ferritin, D-Dimerd 
 
X 
X 
X 
X 
X 
 
 
 
 
Blood and/or sputum 
culturex 
X 
 
 
 
 
 
 
 
 
 
COVID-19 nucleic acid 
testf 
X 
 
 
 
 
 
 
 
 
 
Urinalysis d 
X 
Xv 
Xv 
Xv 
Xv 
Xv 
Xs 
Xs 
Xs 
 
Pregnancy test g 
X 
 
 
 
 
 
 
 
 
 
ECG 
Xs 
Xs 
Xs 
 
 
 
 
 
 
Research Blood 
Collection h 
X 
Xr 
X 
Xr 
Xp 
X 
Xs,t 
Xs,t 
Xs,t 
Xn 
PT/INR, PTT 
 
Xr 
X 
Xr 
Xp 
 
 
 
 
 
Exploratory BAL h,o 
X 
 
 
 
Xp 
 
 
 
 
Chest X-Ray or Chest 
CT 
Xp 
Xp 
Xq,u 
Xs 
Xs 
Xs,q 
 
AE review and 
evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
APACHE II score 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 

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a  See Section 6 for details of physical exam at each visit.  
b  Clinical End-Point Assessments include: Survival (Y/N), On mechanical ventilation (Y/N), In ICU (Y/N), In Hospital (Y/N), Use of 
anticoagulation (drug, dose, intent: prophylaxis vs therapeutic), WHO Ordinal Score. Following parameters to be collected only if patient is 
still in ICU: Sequential Organ Failure Assessment (SOFA), PaO2/FiO2, ventilation variables (See Section 6 for details), recording of vasoactive 
drugs and renal support, recording of supportive interventions that can impact clinical endpoints (i.e., use of prone ventilation, use of paralytics, 
use of pulmonary vasodilators, use of corticosteroids, use of oral decontamination and raising the head of the patient to at least 30º to prevent 
ventilator-associated pneumonia.  
c  Vital signs include core temperature, mean arterial pressure (mmHg), pulse (beats/min), respiratory rate (breaths/min). 
d  Samples should be taken in the morning between 04:00 and 10:00 using the values closest to 10:00. 
e  Serum Chemistry includes Glucose, Ca, Mg, Phos, ALP, Albumin, Total Protein, Total Bilirubin, K, Na, Cl, HCO3, BUN, Cr, ALT, AST, 
LDH, Amylase. 
f  
Only if there is clinical suspicion for COVID-19. 
g  Blood or urine test, only in women of childbearing potential. 
h  See Laboratory Manual for details of sample collection for exploratory assays.  
i  
See Appendix A for APACHE II score system.  
j  
Patient should continue to have respiratory failure as defined in Section 5.1 and moderate/severe ARDS status at least for 24 hours prior to 
signing consent. Screen visit and Day 0 infusion can be on the same day.  
k  Assessments below should be done once a day unless stated otherwise. 
l  
If patient is discharged from the hospital these assessments can be omitted.  
m  These assessments will be done on the day the patient leaves the administering unit or on Day 28, whichever comes earlier.  
n  In-person or telemedicine. Omit Research Blood collection if telemedicine.  
o    Optional based on PI discretion. If not possible, use tracheal aspirates for intubated patients and induced (preferred) or expectorated sputum for 
patients who are not intubated. 
p  At least one time only during this period 
q  If possible, CT scan is preferred. 
r  
Collection is done one-time pre-infusion and one-time post-infusion. See Laboratory Manual for details (for Research blood collections). 
s  
Should be done only if patient is in the hospital and procedure is Standard of Care as per PI discretion. 
t  
If patient is still in the administering unit. 
u  Imaging within 24h before or after visit will be accepted. 
v  Mandatory in Arm 1 and done only if SOC at institution in Arm 2. 
w  Administering unit is ICU in Arm 1 (Dose Escalation) and ARDS Cohort of Arm 2 (Dose Expansion), and ICU, IMC, or acute care floor in 
the PNA Cohort of Arm 2. 
x  Blood and/or sputum culture should be collected prior to administration of antibiotics.  Cultures collected during admission prior to screening 
are accepted.

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2 
INTRODUCTION AND RATIONALE 
Descartes-30 is a cell therapy product consisting of allogeneic human Mesenchymal Stem Cells 
(MSCs) engineered with mRNA to transiently secrete recombinant human Dnase1 and 
recombinant human Dnase1L3.  These enzymes are naturally secreted by human cells and are an 
important homeostatic tool to break down extracellular DNA and chromatin to control 
inflammation.23,24  Both enzymes have potent activity in breaking down neutrophil extracellular 
traps (NETs), long strands of DNA and chromatin generated by neutrophils during acute 
inflammation in a programmed cell death process known as NETosis.9  NETs exacerbate 
inflammation by trapping immune cells, and NET breakdown inhibits inflammation.9  NETs are 
present in acute respiratory distress syndrome (ARDS) and play a key role in the disease 
process.14,22 
 
Clinical data strongly suggests that allogeneic human MSCs can home to the lungs, inhibit 
inflammation, and improve symptoms in patients with ARDS.39-42  Breakdown of NETs by Dnases 
is also expected to reduce inflammation and improve symptoms in ARDS.9  Descartes-30 
combines the inherent immunosuppressive capacity of MSCs with the potent and synergistic 
capacity of Dnase1 and Dnase1L3 to break down NETs and promote healing of tissue damage.  
The enzymes are expected to work quickly and synergistically within the diseased tissue.  The 
benefit: risk ratio is enhanced by transient and local secretion of the enzymes for this acute 
condition. 
 
There are no FDA-approved treatments for ARDS, and its management is based entirely on 
supportive care and treatment of the underlying clinical insult.  Because ARDS is a host reaction 
to the insult, such treatments do not address ARDS mechanisms per se, and there is a need for 
treatments that do.  Neutrophil activation is critical to the  pathogenesis of ARDS, and ample 
evidence exists to implicate NETosis10,15,31, leading to generation of thick, viscous NETs that 
directly propagate inflammation. Pulmonary parenchyma NET levels correlate with disease 
severity.18-20 An ideal treatment for ARDS would reduce neutrophil activation while removing 
excess NETs. Descartes-30 can potentially achieve both objectives as MSCs are known to exhibit 
anti-inflammatory properties in the context of ARDS, and the MSCs have been specifically 
modified to secrete Dnases to degrade NETs.  Therefore Descartes-30 is expected to dramatically 
improve outcomes in ARDS without eliciting significant adverse events.  
 
Increased NET production has also been implicated in severe pneumonia of both bacterial and 
viral etiology. In bacterial pneumonia, NETs may assist dissemination of Streptococcus 
pneumoniae through cleavage of host immune proteins and inducing lung injury,23 and foster 
formation of Staphylococcus aureus and Pseudomonas aeruginosa biofilms.23–25 Neutrophil 
dysfunction and NETosis have also been demonstrated in viral pneumonia, in both animal models 
and clinical samples of patients with influenza, varicella, and SARS-CoV-2 pneumonia.26–29 
Neutrophils of patients with COVID-19 and influenza pneumonia produce higher levels of NETs 
inducing lung epithelial cell death,28,29 while in varicella-zoster virus infection the release of NETs 
caused by the virus was associated with dysregulated expression of alveolar epithelial cell tight 
junction proteins, contributing to disease severity.27 Treatment of severe pneumonia has so far 
been limited to pathogen-targeting antimicrobials, without addressing host factors such as 
increased NETosis.24 Notably, targeting NETs directly is not expected to interfere with other 
neutrophil functions important for controlling pathogens, thereby limiting risk for worsening 
infection.30 
 

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4 
STUDY DESIGN  
4.1 SCHEMA 
 
 
 
          
 
 
 
 
 
 
 
 
 
         
                                                                                                    Within 7/14 days of PNA/ARDS diagnosis  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
* If not discharged from the administering unit (ICU or IMC for ARDS Cohort; ICU, IMC, or acute care 
floor for PNA Cohort) 
# Day 7 or Day of discharge from the administering unit, whichever comes first 
** If not discharged from the hospital 
*** Day 28 or Day of discharge from hospital, whichever comes first 
$ In-person or telephone visit 
 
Informed Consent/Screening 
Short-term Follow-up (Day 14**, Day 21**, Day 28***) 
Cell Infusion (Day 0,1,2) 
Safety Monitoring and Exploratory studies (Day 3-6)* 
Safety Review (Day 7#) 
Long-term Follow-up (Day 90$) 
Diagnosis of Moderate/Severe ARDS or PNA 

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Semi-log dose escalation between dose levels is customary for ascending dose studies, including 
studies with MSCs.   
 
4.4 DOSE ESCALATION RULES 
A minimum of three patients will be dosed at each dose level. In the dose escalation arm, there 
will be a minimum of 7 days between each patient’s first cell infusion. At the time a patient is 
diagnosed with ARDS, the clinic will contact the sponsor who, by default, will assign the patient 
to the next slot in the active dose level. Patients will receive three doses of Descartes-30 cells on 
Days 0,1 and 2. On Day 7 or last day in ICU, whichever comes earlier, the Principal Investigator 
will review the clinical data with the Medical Monitor and authorize the next patient’s infusion if 
there is no safety concern. The selection of Day 7 for safety review is based upon preclinical data 
demonstrating that Dnase expression wanes over 7 days.  Furthermore, the study will not proceed 
to the next dose level until: 1) at least 3 patients in the previous dose level have been observed 
through Primary Safety Review; 2) no study stopping rules have been triggered; and 3) the medical 
safety monitor has reviewed the cumulative safety data and concluded and documented that the 
next Dose Level may be initiated.  
 
4.5 DOSE ESCALATION STOPPING RULES 
The Medical Monitor will apply the following rules to determine if it is safe to proceed to the next 
Dose Level, or if dose escalation should stop. Pre-specified rules for pausing or stopping the whole 
study are described in Section 8.5 and rules for individual patient withdrawal are described in 
Section 8.4. 
 
Should one of three patients in a Dose Level experience dose-limiting toxicity (DLT, see 
Section 8.1.2 for definition) within 7 days after receiving the first dose of the cells that is 
considered probably or definitely related to Descartes-30, 3 more patients will be enrolled and 
treated at that Dose Level. If only 1/6 of patients at that Dose Level has a DLT, and if the medical 
monitor agrees, treatment will proceed to the next higher Dose Level. If 2 or more out of 3 to 6 
patients develop a DLT, no further patients will be dosed at that dose level. The MTD will be 
defined as the highest dose at which a maximum of 1 of 6 patients has a DLT. In Arm 2, up to 12 
more patients who meet the eligibility criteria may be treated in each cohort (ARDS and PNA) at 
a dose up to MTD, provided that the medical monitor approves the enrollment of each such patient 
based on ongoing review of the cumulative safety data.  

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5 
STUDY POPULATION 
The study will enroll subjects who meet all inclusion and none of the exclusion criteria and those 
subjects who are expected to comply with the protocol.  The study is expected to enroll about 
21 subjects, and possibly more based on pre-specified dose escalation criteria. 
 
5.1 INCLUSION CRITERIA 
ARDS Cohort only: 
1. Patient maintains a diagnosis of ARDS according to the Berlin definition of ARDS (See 
Appendix C).5 All four components of Berlin criteria must be satisfied at Screening: 
a. Acute onset of respiratory failure within 1 week of a known clinical insult or new 
or worsening respiratory symptoms   
b. Respiratory failure associated with known ARDS risk factors and not fully 
explained by either cardiac failure or fluid overload (an objective assessment of 
cardiac failure or fluid overload is needed if no risk factors for ARDS are present)  
c. Radiological abnormalities on chest X-ray or on computed tomography (CT) scan, 
i.e., bilateral opacities that are not fully explained by effusions, nodules, masses, or 
lobar/lung collapse 
d. Hypoxemia with PaO2/FiO2 ≤300 mmHg (40 kPa) and positive end expiratory 
pressure (PEEP) ≥5 cm H2O (the PaO2/FiO2 may be estimated from pulse 
oximetry or determined by arterial blood gas; PEEP requirement may also be 
established by noninvasive ventilation, or high-flow nasal canula at ≥30L/min)  
2. The radiological and hypoxemia criteria (1c and 1d) must occur within the same 24-hour 
period. The time of onset of ARDS is when the last of the two specified ARDS criteria is 
met. 
3. Administration of the first dose of study product must be planned to take place within 
14 days of ARDS diagnosis. 
 
PNA Cohort only: 
4. Patient is diagnosed with pneumonia based on defined as pulmonary infiltrate on chest 
radiography not seen previously plus at least 1 symptom compatible with pneumonia, such 
as cough, fever, dyspnea, and/or chest pain. 
5. Pneumonia is severe per 2019 ATS/IDSA criteria (See Appendix C)6 . 
6. Patient is on appropriate antibiotic therapy, in the opinion of the investigator. 
 
Both cohorts: 
7. An informed consent from the patient or the patient’s legal representative must be 
available. 
8. Patient is aged ≥18 years. 
 
5.2 EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Patient is in moribund state with expected survival <24 hours. 
2. Patient is pregnant. 
3. Patient has baseline clinical morbidity that, in the opinion of the Investigator, would 
prevent patient from coming off ventilation, e.g., motor neuron disease, Duchenne 
muscular dystrophy, or rapidly progressive interstitial pulmonary fibrosis. 

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6 
STUDY PROCEDURES 
This section explains the clinical and laboratory tests that will be performed in each study visit. 
See Section 1 for study visit schedule.  Please contact Sponsor for clarification in the event of 
conflict between Section 6 and Section 1. If applicable, study procedures can be completed 
remotely.  
 
6.1 SCREENING 
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee at 
the Screening Visit to ensure that the subject qualifies for the study. All inclusion criteria must be 
met and none of the exclusion criteria may apply. Subjects found ineligible during review of 
inclusion/exclusion will not proceed through the remaining screening process.  
• Informed consent 
• Demographics, Medical History 
• Physical Exams: At minimum should include examination of eyes, mouth, throat, 
cardiovascular, respiratory, skin, and brief neurological exam.  
• Height and weight will be measured and recorded at Screening only, if possible. 
• Concomitant medications 
• Vital Signs: include core temperature, mean arterial pressure (mmHg), pulse (beats/min), 
respiratory rate (breaths/min). 
o The same method for assessing temperature should be used at all visits until patient 
is discharged from the administering unit, if possible. 
• CBC with differential: Samples should be taken in the morning between 04:00 and 10:00 
using the values closest to 10:00. 
• Serum chemistry:  
o Samples should be taken in the morning between 04:00 and 10:00 using the values 
closest to 10:00.  
o Chemistry includes Glucose, Ca, Mg, Phos, ALP, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, HCO3, BUN, Cr, ALT, AST, LDH, Amylase. 
• Blood and/or sputum culture prior to initiation of antibiotics (required for patients in the 
PNA Cohort, optional for patients in the ARDS Cohort). If patient is already on antibiotics 
at the time of screening, blood and/or sputum cultures collected prior to initiation of the 
antibiotics are acceptable. 
• COVID-19 nucleic acid test: A local qualitative sample (e.g., nasopharyngeal swab) if there 
is clinical suspicion of COVID-19.  
• Urinalysis: Samples should be taken in the morning between 04:00 and 10:00 using the 
values closest to 10:00.  
• Pregnancy test: Blood or urine test, only in women with child-bearing potential. 
• ECG: Electrocardiogram may be performed as standard of care, at the discretion of the 
Investigator. 
• Research blood collection: All protocol required research blood collection assessments 
must be conducted in accordance with Laboratory Manual, and the Schedule of Activities. 
Laboratory requisition forms must be completed, and samples must be clearly labelled with 
the subject number, protocol number, site number, and visit date. Details for the preparation 
and shipment of samples will be provided by the laboratory and are detailed in the 
Laboratory Manual. Reference ranges for all safety parameters will be provided to the site 
by the laboratory responsible for the assessments. 
• Exploratory Bronchoalveolar lavage, Tracheal Aspirate or sputum (induced or 
expectorated): Optional based on PI’s discretion. See Schedule of Activities (Section 1) 

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and Laboratory Manual for more details. Should be done per institute’s standards of 
operations (alternatively it can be done on Day 0 before infusion) 
• Chest Imaging: CT scan or Chest X-Ray (alternatively it can be done on Day 0 before 
infusion) 
• AE review and evaluation: AE collection starts after consent is signed.  
• APACHE II Score: See Appendix A for APACHE II score. 
• Clinical End-point Assessment includes: Survival (Y/N), On mechanical ventilation (Y/N), 
In ICU (Y/N), In Hospital (Y/N), Use of anti-coagulation (drug, dose, intent: prophylaxis 
vs therapeutic), WHO Ordinal Score (See Appendix D for scale). If patient is in ICU then 
the following assessment will be completed: Sequential Organ Failure Assessment (SOFA, 
See Appendix B for template form), PaO2/FiO2, following ventilation parameters (as 
applicable): type of ventilation (CPAP, BiPAP, or intubation)/ ventilation rate/ pulse/ tidal 
volume/ positive end-expiratory pressure (PEEP), recording of vasoactive drugs and renal 
support, recording of supportive interventions that can impact clinical endpoints (use of 
prone ventilation, use of paralytics, use of pulmonary vasodilators, use of corticosteroids, 
use of oral decontamination and raising the head of the patient to at least 30º to prevent 
ventilator-associated pneumonia. 
 
6.2 DAY 0,1,2 DESCARTES-30 INFUSION  
Three equal doses will be administered once a day over 3 consecutive days.  A minimum of 
12 hours should elapse between infusions.  Study treatment will be infused intravenously over a 
period of 30-90 minutes. Further details, including criteria for delaying cell infusion, are available 
in Section 7 and the Descartes-30 Handling and Storage Manual. Before administration of the 
product on each infusion day, the following assessments should be completed:  
 
• Physical Exams: At minimum should include examination of eyes, mouth, throat, 
cardiovascular, respiratory, skin, and brief neurological exam.  
• Concomitant medications 
• Clinical End-point Assessment includes: Survival (Y/N), On mechanical ventilation (Y/N), 
In ICU (Y/N), In Hospital (Y/N), Use of anti-coagulation (drug, dose, intent: prophylaxis 
vs therapeutic), WHO Ordinal Score (See Appendix D for scale). If patient is in ICU then 
the following assessment will be completed: Sequential Organ Failure Assessment (SOFA, 
See Appendix B for template form), PaO2/FiO2, following ventilation parameters (as 
applicable): type of ventilation (CPAP, BiPAP, or intubation)/ ventilation rate/ pulse/ tidal 
volume/ positive end-expiratory pressure (PEEP), recording of vasoactive drugs and renal 
support, recording of supportive interventions that can impact clinical endpoints (use of 
prone ventilation, use of paralytics, use of pulmonary vasodilators, use of corticosteroids, 
use of oral decontamination and raising the head of the patient to at least 30º to prevent 
ventilator-associated pneumonia). 
• Vital Signs: include core temperature, mean arterial pressure (mmHg), pulse (beats/min), 
respiratory rate (breaths/min). 
o The same method for assessing temperature should be used at all visits for each 
individual subject, if possible. 
• CBC with differential: Samples should be taken in the morning between 04:00 and 10:00 
using the values closest to 10:00. (mandatory for Arm 1, only if done as part of standard of 
care at institution for Arm 2) 
• Serum chemistry (mandatory for Arm 1, only if done as part of standard of care at 
institution for Arm 2):  

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o Samples should be taken in the morning between 04:00 and 10:00 using the values 
closest to 10:00.  
o Chemistry includes Glucose, Ca, Mg, Phos, ALP, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, HCO3, BUN, Cr, ALT, AST, LDH, Amylase. 
• CRP, ferritin, D-Dimer (mandatory for both Arms) 
• Urinalysis: Samples should be taken in the morning between 04:00 and 10:00 using the 
values closest to 10:00. (mandatory for Arm 1, only if done as part of standard of care at 
institution for Arm 2) 
• ECG: Electrocardiogram may be performed as standard of care, at the discretion of the 
Investigator.  
• Research blood collection: All protocol required research blood collection assessments 
must be conducted in accordance with Laboratory Manual. 
• Chest Imaging: CT scan or Chest X-Ray (Once before first infusion and once between 
Days 1-6) 
• AE review and evaluation 
• PT/INR, PTT (mandatory for both Arms) 
 
After completion of Descartes-30 infusion: 
      1. On Day(s) 0 and 2, Research Blood Collection at 30min (+10 min). Please See Laboratory 
Manual for more details.    
      2. On Day(s) 0 and 2, PT/INR, PTT at 30min (+10 min).    
      3. For details of post-infusion clinical monitoring for 4 hours  (Arm 1) or 1 hour (Arm 2) after 
completing infusion, please see Section 7.1.2.3.  
 
6.3 SAFETY MONITORING DAYS 3-6 
The following assessments will be completed daily during the safety monitoring period until the 
primary Safety Review on Day 7 if patient is still in the administering unit.  
 
• Physical Exams: Abbreviated, targeted physical examinations (i.e., assessments of the skin, 
respiratory, cardiovascular system, and abdomen (liver and spleen), will be performed at 
time points specified in the Schedule of Activities (Section 1) and will be based on the 
subject’s clinical status and what the clinic staff deem is appropriate. 
• Concomitant medications 
• Clinical End-point Assessment includes: Survival (Y/N), On mechanical ventilation (Y/N), 
In ICU (Y/N), In Hospital (Y/N), Use of anti-coagulation (drug, dose, intent: prophylaxis 
vs therapeutic), WHO Ordinal Score (See Appendix D for scale). If patient is in ICU then 
the following assessment will be completed: Sequential Organ Failure Assessment 
(SOFA), PaO2/FiO2, following ventilation parameters (as applicable): type of ventilation 
(CPAP, BiPAP, or intubation)/ ventilation rate/ pulse/ tidal volume/ positive end-
expiratory pressure (PEEP), recording of vasoactive drugs and renal support, recording of 
supportive interventions that can impact clinical endpoints (use of prone ventilation, use of 
paralytics, use of pulmonary vasodilators, use of corticosteroids, use of oral 
decontamination and raising the head of the patient to at least 30º to prevent ventilator-
associated pneumonia) 
• Vital Signs: include core temperature, mean arterial pressure (mmHg), pulse (beats/min), 
respiratory rate (breaths/min). 
o The same method for assessing temperature should be used at all visits until 
patient is discharged from the administering unit, if possible. 

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• CBC with differential: Samples should be taken in the morning between 04:00 and 10:00 
using the values closest to 10:00. (mandatory for Arm 1, only if done as part of standard of 
care for Arm 2) 
• Serum chemistry  (mandatory for Arm 1, only if done as part of standard of care for Arm 2):  
 Samples should be taken in the morning between 04:00 and 10:00 using the values 
closest to 10:00.  
 Chemistry includes Glucose, Ca, Mg, Phos, ALP, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, HCO3, BUN, Cr, ALT, AST, LDH, Amylase. 
• CRP, ferritin, D-Dimer (mandatory for both Arms). 
• Urinalysis: Samples should be taken in the morning between 04:00 and 10:00 using the 
values closest to 10:00. (mandatory for Arm 1, only if done as part of standard of care for 
Arm 2) 
• Research blood collection: At least once between Day 3 and Day 6. All protocol required 
research blood collection assessments must be conducted in accordance with Laboratory 
Manual. 
• Exploratory Bronchoalveolar lavage: Should be done at least once during this period if 
it was performed prior to administration of cells. If BAL is not performed then tracheal 
aspirate or sputum (induced or expectorated). 
• Chest Imaging: CT scan or Chest X-Ray. Once between Days 1-6. 
• AE review and evaluation  
• PT/INR, PTT (Should be done at least once during this period, for patients in both Arms). 
 
6.4 PRIMARY SAFETY REVIEW (DAY 7) 
Primary Safety Review is on Day 7 or on last day of stay in the administering unit, whichever 
comes earlier. In Arm 1, upon completion of Primary Safety Review assessments, the Principal 
Investigator and the Medical Monitor will review the data. 
 
• Physical Exams: Abbreviated, targeted physical examinations (i.e., assessments of the skin, 
respiratory, cardiovascular system, and abdomen (liver and spleen), will be performed at 
time points specified in the Schedule of Activities (Section 1) and will be based on the 
subject’s clinical status and what the clinic staff deem is appropriate. 
• Concomitant medications 
• Clinical End-point Assessment includes: Survival (Y/N), On mechanical ventilation (Y/N), 
In ICU (Y/N), In Hospital (Y/N), Use of anti-coagulation (drug, dose, intent: prophylaxis 
vs therapeutic), WHO Ordinal Score (See Appendix D for scale). If patient is in ICU then 
the following assessment will be completed: Sequential Organ Failure Assessment 
(SOFA), PaO2/FiO2, following ventilation parameters (as applicable): type of ventilation 
(CPAP, BiPAP, or intubation)/ ventilation rate/ pulse/ tidal volume/ positive end-
expiratory pressure (PEEP), recording of vasoactive drugs and renal support, recording of 
supportive interventions that can impact clinical endpoints (use of prone ventilation, use of 
paralytics, use of pulmonary vasodilators, use of corticosteroids, use of oral 
decontamination and raising the head of the patient to at least 30º to prevent ventilator-
associated pneumonia) 
• Vital Signs: include core temperature, mean arterial pressure (mmHg), pulse (beats/min), 
respiratory rate (breaths/min). 
o The same method for assessing temperature should be used at all visits until 
patient is discharged from the administering unit, if possible. 

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• CBC with differential: Samples should be taken in the morning between 04:00 and 10:00 
using the values closest to 10:00 (mandatory for Arm 1, only if done as part of standard of 
care for Arm 2). 
• Serum chemistry (mandatory for Arm 1, only if done as part of standard of care for Arm 2):  
 Samples should be taken in the morning between 04:00 and 10:00 using the values 
closest to 10:00.  
 Chemistry includes Glucose, Ca, Mg, Phos, ALP, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, HCO3, BUN, Cr, ALT, AST, LDH, Amylase. 
• CRP, ferritin, D-Dimer (mandatory for both Arms). 
• Urinalysis: Samples should be taken in the morning between 04:00 and 10:00 using the 
values closest to 10:00 (mandatory for Arm 1, only if done as part of standard of care for 
Arm 2).  
• Research blood collection: All protocol required research blood collection assessments 
must be conducted in accordance with Laboratory Manual. 
• Exploratory Bronchoalveolar lavage: Should be done only if not performed at least once 
after administration of cells while a sample was collected prior to treatment with cells. 
If BAL is not performed then tracheal aspirate or sputum (induced or expectorated). 
• Chest Imaging: CT scan (preferred) or Chest X-Ray. Imaging done on Day 6 or Day 8 will 
be accepted.   
• AE review and evaluation. 
 
6.5 SHORT-TERM FOLLOW-UP (DAY 14, 21 AND 28)  
If patient is discharged from the hospital, Day 14 and 21 visits can be omitted. Day 28 visit can be 
the day of discharge from the hospital if it is earlier. 
 
• Physical Exams: Only if patient is in the the administering unit, abbreviated, targeted 
physical examinations (i.e., assessments of the skin, respiratory, cardiovascular system, 
and abdomen (liver and spleen)), will be performed at time points specified in the Schedule 
of Activities (Section 1) and will be based on the subject’s clinical status and what the 
clinic staff deem is appropriate. 
• Concomitant medications 
• Clinical End-point Assessment includes: Survival (Y/N), On mechanical ventilation (Y/N), 
In ICU (Y/N), In Hospital (Y/N), Use of anti-coagulation (drug, dose, intent: prophylaxis 
vs therapeutic), WHO Ordinal Score (See Appendix D for scale). If patient is in ICU then 
the following assessment will be completed: Sequential Organ Failure Assessment 
(SOFA), PaO2/FiO2, following ventilation parameters (as applicable): type of ventilation 
(CPAP, BiPAP, or intubation)/ ventilation rate/ pulse/ tidal volume/ positive end-
expiratory pressure (PEEP), recording of vasoactive drugs and renal support, recording of 
supportive interventions that can impact clinical endpoints (use of prone ventilation, use of 
paralytics, use of pulmonary vasodilators, use of corticosteroids, use of oral 
decontamination and raising the head of the patient at least 30º to prevent ventilator-
associated pneumonia) 
• Vital Signs: include core temperature, mean arterial pressure (mmHg), pulse (beats/min), 
respiratory rate (breaths/min). 
 The same method for assessing temperature should be used at all visits for each 
individual subject, if possible. 
• CBC with differential. Only if performed as Standard of Care. 
• Serum chemistry. Only if performed as Standard of Care:  

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 Chemistry includes Glucose, Ca, Mg, Phos, ALP, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, HCO3, BUN, Cr, ALT, AST, LDH, Amylase.  
• Chest Imaging: CT scan (preferred on Day 28) or Chest X-Ray. Only if performed as 
Standard of Care. 
• AE review and evaluation  
• Research blood collection: Only if patient is in the administering unit. All protocol 
required research blood collection assessments must be conducted in accordance with 
Laboratory Manual.  
 
6.6 LONG-TERM FOLLOW-UP (DAY 90+ 14) 
On Day 90+ 14 days, an in-person visit, or telemedicine will be arranged to complete the 
assessments listed below. If any of the laboratory assessments cannot be performed due to inability 
to arrange a blood collection, it will not be considered as protocol deviation.  
 
• Physical Exams: Abbreviated, targeted physical examinations (i.e., assessments of the 
skin, respiratory, cardiovascular system, and abdomen [liver and spleen]), will be 
performed at time points specified in the Schedule of Activities (Section 1) and will be 
based on the subject’s clinical status and what the clinic staff deem is appropriate. 
• Concomitant medications 
• Clinical End-point Assessment includes: Survival (Y/N), On mechanical ventilation 
(Y/N), In ICU (Y/N), In Hospital (Y/N), Use of anti-coagulation (drug, dose, intent: 
prophylaxis vs therapeutic), WHO Ordinal Score (See Appendix D for scale). If patient 
is in ICU then the following assessment will be completed: Sequential Organ Failure 
Assessment (SOFA), PaO2/FiO2, following ventilation parameters (as applicable): 
type of ventilation (CPAP, BiPAP, or intubation)/ ventilation rate/ pulse/ tidal volume/ 
positive end-expiratory pressure (PEEP), recording of vasoactive drugs and renal 
support, recording of supportive interventions that can impact clinical endpoints (use 
of prone ventilation, use of paralytics, use of pulmonary vasodilators, use of 
corticosteroids, use of oral decontamination and raising the head of the patient at least 
30º to prevent ventilator-associated pneumonia) 
• Vital Signs: include core temperature, mean arterial pressure (mmHg), pulse 
(beats/min), respiratory rate (breaths/min). 
• Research blood collection: Can be omitted if visit is telemedicine. All protocol required 
research blood collection assessments must be conducted in accordance with 
Laboratory Manual 
• AE review and evaluation 
 

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If these criteria are met, a spontaneous breathing trial (SBT) procedure and assessment for 
unassisted breathing should be performed. The SBT will take place for up to 120 minutes of 
spontaneous breathing with FiO2 <0.5 using any of the following approaches: 
• Pressure support (PS) <5 cmH2O, PEEP <5 cmH2O 
• Continuous positive airway pressure (CPAP) <5 cmH2O 
• T-piece 
• Tracheotomy mask 
 
If all criteria below are met for the last 30 minutes of the trial, the SBT will be reported as 
“successful” and ventilation support will be removed: 
• SpO2 ≥90% and/or PaO2 ≥60 mmHg 
• Respiratory rate ≤35/min 
• No respiratory distress (defined as ≥2 of the following): 
o Heart rate ≥120% of the rate at 06:00 (≤5 min at ≥120% may be tolerated) 
o Marked use of accessory muscles 
o Abdominal paradox 
o Diaphoresis 
o Marked subjective dyspnea 
 
If above criteria are not met, the SBT will be reported as “unsuccessful” and previous ventilator 
settings will be initiated. The patient should be reassessed for weaning the following day.  
 
Patients will be reported as “ventilator free” after two consecutive calendar days of “unassisted 
breathing”. “Unassisted breathing” will be defined as any of the following: 
• Spontaneously breathing with face mask, nasal cannula or room air 
• T-piece breathing 
• Tracheostomy mask breathing 
• CPAP ≤5 without Pressure Support or intermittent mandatory ventilation assistance 
• Use of CPAP or bi-level positive airway pressure solely for sleep apnea management 
 
Please discuss with Sponsor if institutional ventilator weaning policy conflicts significantly with 
the above criteria. 
7.1.2.5 CRITERIA FOR COMING OFF-TREATMENT 
Off-treatment criteria mainly apply to eligibility for repeat Descartes-30 treatments. Patients will 
be taken off treatment for the following: 
• 
DLT as defined in Section 8.1.2 directly attributable to Descartes-30 cells. 
• 
General or specific changes in the patient's condition rendering the patient ineligible for further 
treatment in the judgment of the investigator. 
 

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this study. The management is supportive care as reactions are expected to quickly subside 
spontaneously.  
7.2.2.3 THROMBOEMBOLIC EVENTS 
Recent pre-clinical and clinical data demonstrate that MSCs can express or increase secretion of 
proteins associated with coagulation signals.49,50 However, these incident events are rare (17 events 
in 1112 patients in the meta-analysis39), and were reported in both treatment and control groups 
with no significant difference associated with administration of MSCs. Thus, these events will 
likely be rare and as such investigators should evaluate embolic events in their differential 
diagnosis while managing clinical changes within 24 hours following Descartes-30 infusion.  
7.2.2.4 MALIGNANCY/ECTOPIC TISSUE FORMATION 
In the pooled analysis of 19 RCTs that reported on malignant transformation and/or ectopic tissue 
formation, there was no significant increase in the risk of these serious adverse events. However, 
investigators should instruct the patients to contact the Investigator and/or the Sponsor that there 
is a theoretical risk of malignancy and therefore patients should report these events if they are 
diagnosed even after coming off-study.  

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8 
SAFETY ASSESSMENT AND PROCEDURES 
8.1 DEFINITIONS  
8.1.1 ADVERSE EVENTS (AE) 
An adverse event (AE) is defined as any reaction, side effect, or untoward event that occurs during 
the clinical trial associated with the use of a test article in humans, whether or not the event is 
considered related to the treatment or clinically significant. For this study, AEs will include events 
reported by the patient, as well as clinically significant abnormal findings on physical examination 
or laboratory evaluation. A new illness, symptom, sign or worsening of a pre-existing condition or 
abnormality is considered an AE. An abnormal laboratory value will be considered an AE if the 
laboratory abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study.  
• 
Is associated with clinical signs or symptoms.  
• 
Requires treatment or any other therapeutic intervention.  
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until satisfactory resolution.  
8.1.2 DOSE LIMITING TOXICITY (DLT) 
Following reactions within 4 hours of Descartes-30 infusion will be considered as DLT: 
1. Addition of a third vasopressor 
2. Increase in vasopressor dose over baseline greater than or equal to the following: 
a. Norepinephrine: 1.5 µg/kg per min 
b. Phenylephrine: 100 μg/kg per min 
c. Dopamine: 10 μg/kg per min 
d. Epinephrine: 1 μg/kg per min 
e. Vasopressin: 0.04 IU/min 
3.  Hypoxemia requiring an increase over baseline in FiO2 of ≥0.2 and/or increase in 
positive end-expiratory airway pressure level of 5 cm H2O or more to maintain 
transcutaneous oxygen saturations in an acceptable range based on PI’s discretion 
4. New cardiac arrhythmia requiring cardioversion (chemical or electrical) 
5. New ventricular tachycardia, ventricular fibrillation, or asystole 
6. Death 
 
Also, any Grade 3-5 toxicity probably or definitely attributed to Descartes-30 will be a DLT.  
8.1.3 SERIOUS ADVERSE EVENT (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
Investigator or the Sponsor it results in any of the following: 
• 
Death  
• 
Infusion reaction defined in Section 8.1.2 
• 
Prolongation of existing hospitalization  
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a SAE experience 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. 

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8.1.4 SERIOUS UNEXPECTED ADVERSE REACTION (SUSAR) 
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.  
"Unexpected" also refers to adverse events or suspected adverse reactions that are mentioned in 
the Investigator Brochure as occurring with a class of the test article or as anticipated from the 
pharmacological properties of the drug but are not specifically mentioned as occurring with the 
test article under investigation. 
8.2 RECORDING OF ADVERSE EVENTS 
8.2.1 ADVERSE EVENT RECORDING 
The adverse event recording period for this study starts after patient or legal representative signs 
consent and ends at Day 90 visit or when patient comes off-study based on criteria in Section 8.4. 
For SAE and SUSAR, reporting period starts with first Descartes-30 infusion and ends 7 days after 
last infusion. After 7 days, an AE (only in Arm 2), SAE (both Arms) or SUSAR (both Arms) is 
only reported if it is probably or definitely attributed to Descartes-30 infusion. At each contact 
with the subject during the adverse event recording period, the Investigator or his/her designee 
must seek information on adverse events by specific questioning and, as appropriate, by 
examination. Information on all adverse events should be recorded immediately in the source 
document, and in the appropriate adverse event module of the case report form (CRF). All clearly 
related signs, symptoms, and abnormal diagnostic procedures results should be recorded in the 
source document, though it should be grouped under one diagnosis. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. Adverse events should 
be entered into the e-CRF system within 3 working days from the knowledge of the event took 
place. Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
8.2.2 PREGNANCY 
Monitoring of pregnancies is not applicable to this study because pregnancy is an exclusion 
criterion and a pregnancy test is performed in all women of childbearing potential at screening. 
Owing to the nature of the study involving short (3-day) treatment with the study product in an 
inpatient setting, it is not possible for women to become pregnant during treatment and for there 
to be any fetal exposure to the study product.   
8.3 SAE AND SUSAR REPORTING 
To ensure patient safety, every SAE and SUSAR, regardless of suspected causality, occurring 
during the adverse event reporting period defined in Section 8.2.1 must be reported to the Sponsor 
within 24 hours of learning of its occurrence. Recurrent episodes, complications, or progression of 
the initial SAE must be reported as follow-up information is received. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event. 

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8.3.1 STUDY SPONSOR NOTIFICATION 
Any SUSAR and SAE as defined in Section 8.1.3 and Section 8.1.4 must be reported to the 
Sponsor by fax within 24 hours of knowledge of the event. SUSARs and SAEs should also be 
discussed via email or telephone contact with the Sponsor Medical Monitor. To the extent possible, 
adverse events should be recorded as a diagnosis. Do not list symptoms if a diagnosis can be 
assigned. At the time of the initial notification, a serious adverse event (SAE) report form should 
be filled. The following information will be collected in the form: 
• subject identifying information; 
• a description of the event (if there is a diagnosis, it should be included); 
• date of onset; 
• current status;  
• whether study treatment was discontinued; 
• reason why the event is classified as serious; 
• investigator assessment of the association between the event and study treatment; 
• concomitant medications when the event happened; and 
• narrative summary of the event. 
 
Follow-up information on this event should be reported when received. The follow-up information 
should describe 1) whether the event has resolved (with or without sequelae) or continues; 2) if 
and how it was treated; and 3) whether the patient continued or withdrew from study participation. 
8.3.2 IRB NOTIFICATION 
Information that indicates a change to the patient risks or potential benefits of the research, in terms 
of severity or frequency, should be communicated to the IRB in the following scenarios: 
• safety monitoring indicates that a particular side effect is more severe, or more frequent 
than initially expected; 
• change in FDA safety labeling or withdrawal from the marketing of a drug, device, or 
biologic used in a research protocol;  
• breach of confidentiality; 
• change to the protocol taken without prior IRB review to eliminate an apparent immediate 
hazard to a research participant; 
• complaint by a participant when the complaint indicates unexpected risks, or the complaint 
cannot be resolved by the research team; or  
• protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more participants 
at increased risk or affects the rights or welfare of subjects. 
 
Deaths that occur during the study should be reported within the IRB-specified time frame. 
For reportable deaths, the initial submission to the IRB may be made by contacting the IRB 
Director or Associate Director. The AE/Unanticipated Problem Form is required as a follow up to 
the initial submission. 
8.3.3 FDA NOTIFICATION 
The Sponsor is required to report certain study events in an expedited fashion to the FDA. These 
written notifications of adverse events are referred to as IND safety reports. The sponsor must 
report an IND safety reports as described in: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM227351.pdf 

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The following describes the safety reporting requirements by timeline for reporting and associated 
type of event: 
• within 7 Calendar Days any study event that is unexpected, fatal or life-threatening 
suspected adverse reaction; or 
• within 15 Calendar Days any study event that is unexpected, suspected adverse reaction 
that is serious, but not fatal or life-threatening -or- a previous adverse event that was not 
initially deemed reportable but is later found to fit the criteria for reporting, any finding 
from tests in laboratory animals that suggest a significant risk for human subjects including 
reports of mutagenicity, teratogenicity, or carcinogenicity or reports of significant organ 
toxicity at or near the expected human exposure. 
 
8.4 CRITERIA FOR OFF-STUDY 
Patients will be taken off study for the following: 
• 
The patient voluntarily withdraws  
• 
Death  
Patients must be followed until all adverse events attributed to Descartes-30 have resolved to 
Grade 2. If an adverse event is not expected to resolve to Grade 2 or less, this will be noted in the 
patient medical record and the patient will be taken off-study. 
8.5 STUDY PAUSING AND STOPPING RULES 
Premature termination of the clinical trial may occur because of a regulatory authority decision, 
change in opinion of the IRB or Medical Monitor. Additionally, recruitment may be stopped for 
reasons of particularly low recruitment, protocol violations, or inadequate data recording. 
Specifically, study will be stopped if: 
• 
Study Sponsor or a Regulatory Body decides for any reason that subject safety may be 
compromised by continuing the study.  
• 
The Sponsor decides to discontinue the development of the intervention to be used in this 
study.  
 
The study will be paused if: 
• 
There is death that is reasonably attributed to study product before Day 4. 
• 
Two subjects with Grade 3 or 4 adverse events to vital organs that are assessed as probably or 
definitely related to study product within the first 7 days after first infusion. 
 
If the study is paused for the reasons above, the PI and members of the study team will meet in 
person or by teleconference within 24 hours of the event to have a thorough discussion of the 
event. Meeting minutes capturing the review of any ongoing investigations, including next steps 
in the management of the subject and any proposed changes to the protocol will be forwarded to 
the Medical Monitor. If all parties agree as to the event resolution, then the pause will be lifted. If 
the study is paused for manufacturing reasons, the Sponsor will make recommendations for 
process improvements to be implemented. Pending successful completion of a process validation 
run, the manufacturing pause will be lifted. 

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10 SUPPORTING DOCUMENTATION AND PROCEDURES 
10.1 INFORMED CONSENT PROCESS 
The Investigator at each investigational site is responsible for ensuring that informed consent for 
study participation is given by each patient or their legal representative prior to collection of study 
data and administration of the study product. The Investigator will not undertake any intervention 
specifically required only for the clinical study until valid consent has been obtained. If consent 
has not been obtained, a patient cannot be enrolled into the study.  
 
Consent will be sought directly from patients if possible. However, given that most patients in ICU 
will not be able to give written informed consent themselves due to alteration in their level of 
consciousness caused by therapeutic sedation, informed consent will be sought from a qualified 
representative. Consent can be obtained electronically if applicable.  
 
If a protocol amendment is required, the informed consent form (ICF) may need to be revised to 
reflect those changes. If the ICF is revised, it must be reviewed and approved by the appropriate 
ethics committee and signed by all patients (or their representatives) subsequently enrolled in the 
study as well as those currently enrolled in the study.  
 
10.2 STUDY DISCONTINUATION AND CLOSURE 
Premature termination of the clinical trial may occur because of a regulatory authority decision, 
change in opinion of the IRB or medical monitor. Additionally, recruitment may be stopped for 
reasons of particularly low recruitment, protocol violations, or inadequate data recording. 
Specifically, the study will be stopped if: 
 
• study Sponsor or a regulatory body decides for any reason that subject safety may be 
compromised by continuing the study; or 
• the Sponsor decides to discontinue the development of the intervention to be used in this 
study.  
 
10.3 MEDICAL MONITOR 
The medical monitor will be a Sponsor physician or Sponsor-appointed physician with appropriate 
experience to oversee study conduct on the Sponsor’s behalf, consult with site investigators, 
review and synthesize safety information from the various clinical sites, and to apply study-
stopping criteria. All decisions by the medical monitor affecting study conduct, including the 
application of study-stopping or dose-escalation rules, will be documented in the study record. 
 
10.4 RECORDING OF PROTOCOL DEVIATION 
If the impact of the protocol deviation disrupts the study design, may affect the outcome 
(objectives), or compromises the safety and welfare of the subjects, the deviation must be reported 
to the medical monitor within three business days. Include the following information on the 
Sponsor-supplied exception/deviation form: protocol number, subject study number, description 
of the exception/deviation from protocol and rationale. Ensure all completed exception/deviation 
forms are signed by the Site Investigator and submitted to the Study Sponsor and medical monitor 
for review. Once approval of the exception request or acknowledgment of the deviation has been 
granted by the Sponsor and medical monitor, the exception or deviation will be submitted to IRB 
and all other applicable committees. 
 

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10.5 DATA HANDLING AND RECORD KEEPING  
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harmonization (ICH) region and until there are no 
pending or contemplated marketing applications in an ICH region or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the study intervention. These 
documents should be retained for a longer period, however, if required by local regulations. No 
records will be destroyed without the written consent of the sponsor, if applicable. It is the 
responsibility of the sponsor to inform the investigator when these documents no longer need to 
be retained. 
 
10.5.1 SOURCE DATA 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents. Examples of these original documents and data records include 
hospital records, clinical and office charts, laboratory notes, memoranda, subject diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
 
10.5.2 CASE REPORT FORMS 
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded. All entries will be entered into an electronic data capture 
system (e-CRF). The Principal Investigator is responsible for assuring that the data entered into 
e-CRF is complete, accurate, and that entry and updates are performed in a timely manner. 
 
10.5.3 CONFIDENTIALITY 
The investigator must ensure the anonymity of the patients; patients must not be identified by 
names in any documents submitted to the sponsor. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
 
• what protected health information (PHI) will be collected from subjects in this study; 
• who will have access to that information and why; 
• who will use or disclose that information; and 
• the rights of a research subject to revoke their authorization for the use of their PHI. 
 
If a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization. For subjects 
that have revoked authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (i.e., that the subject is alive) at the end of their scheduled study 
period. 

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23. Block, H, and Zarbock A. A Fragile Balance: Does Neutrophil Extracellular Trap Formation 
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Acute Lung Injury of Influenza Pneumonitis. The American Journal of Pathology 2011; 179: 
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Dysfunction at the Extremes of Age. Thorax 2020; 75:2;164–71.  
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36. Pottecher J, Noll E, Borel M, et al. Protocol for TRAUMADORNASE: a prospective, 
randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized 
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patients. Trials 2020;21:274. 
37. Davis JC, Jr., Manzi S, Yarboro C, et al. Recombinant human Dnase I (rhDNase) in patients 
with lupus nephritis. Lupus 1999;8:68-76. 
38. 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;179:1855-63. 
39. Lee JW, Fang X, Gupta N, Serikov V, Matthay MA. Allogeneic human mesenchymal stem 
cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human 
lung. Proc Natl Acad Sci U S A 2009;106:16357-62. 
40. Fang X, Neyrinck AP, Matthay MA, Lee JW. Allogeneic human mesenchymal stem cells 
restore epithelial protein permeability in cultured human alveolar type II cells by secretion of 
angiopoietin-1. J Biol Chem 2010;285:26211-22. 
41. Krasnodembskaya A, Samarani G, Song Y, et al. Human mesenchymal stem cells reduce 
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42. Mei SH, Haitsma JJ, Dos Santos CC, 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. 
43. Nemeth K, Leelahavanichkul A, Yuen PS, et al. Bone marrow stromal cells attenuate sepsis 
via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their 
interleukin-10 production. Nat Med 2009;15:42-9. 
44. Krasnodembskaya A, Song Y, Fang X, et al. Antibacterial effect of human mesenchymal stem 
cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells 
2010;28:2229-38. 
45. Curley GF, Hayes M, Ansari B, et al. Mesenchymal stem cells enhance recovery and repair 
following ventilator-induced lung injury in the rat. Thorax 2012;67:496-501. 
46. McAuley DF, Curley GF, Hamid UI, et al. Clinical grade allogeneic human mesenchymal stem 
cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am J Physiol 
Lung Cell Mol Physiol 2014;306:L809-15. 
47. Asmussen S, Ito H, Traber DL, et al. Human mesenchymal stem cells reduce the severity of 
acute lung injury in a sheep model of bacterial pneumonia. Thorax 2014;69:819-25. 
48. Thompson M, Mei SHJ, Wolfe D, et al. Cell therapy with intravascular administration of 
mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-
analysis. EClinicalMedicine 2020;19:100249. 
49. Zheng G, Huang L, Tong H, et al. Treatment of acute respiratory distress syndrome with 
allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot 
study. Respir Res 2014;15:39. 
50. Wilson JG, Liu KD, Zhuo H, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: 
a phase 1 clinical trial. The Lancet Respiratory medicine 2015;3:24-32. 
51. Simonson OE, Mougiakakos D, Heldring N, et al. In Vivo Effects of Mesenchymal Stromal 
Cells in Two Patients With Severe Acute Respiratory Distress Syndrome. Stem cells 
translational medicine 2015;4:1199-213. 
52. Jacono F, Bannard-Smith J, Brealey D, et al. Primary Analysis of a Phase 1/2 Study to Assess 
MultiStem® Cell Therapy, a Regenerative Advanced Therapy Medicinal Product (ATMP), in 
Acute Respiratory Distress Syndrome (MUST-ARDS).  B14 LATE BREAKING CLINICAL 
TRIALS:A7353-A. 
53. Matthay MA, Calfee CS, Zhuo H, et al. Treatment with allogeneic mesenchymal stromal cells 
for moderate-to-severe acute respiratory distress syndrome (START study): a randomised 
phase 2a safety trial. The Lancet Respiratory medicine 2019;7:154-62. 
54. Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2(-) Mesenchymal Stem Cells Improves 
the Outcome of Patients with COVID-19 Pneumonia. Aging Dis 2020;11:216-28. 
55. Walter J, Ware LB, Matthay MA. Mesenchymal stem cells: mechanisms of potential 
therapeutic benefit in ARDS and sepsis. The Lancet Respiratory medicine 2014;2:1016-26. 
56. Glassberg MK, Minkiewicz J, Toonkel RL, et al. Allogeneic Human Mesenchymal Stem Cells 
in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase 
I Safety Clinical Trial. Chest 2017;151:971-81. 
57. Butler J, Epstein SE, Greene SJ, et al. Intravenous Allogeneic Mesenchymal Stem Cells for 
Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial. 
Circulation research 2017;120:332-40. 
58. Moll G, Rasmusson-Duprez I, von Bahr L, et al. Are therapeutic human mesenchymal stromal 
cells compatible with human blood? Stem Cells 2012;30:1565-74. 
59. Hoogduijn MJ, de Witte SF, Luk F, et al. Effects of Freeze-Thawing and Intravenous Infusion 
on Mesenchymal Stromal Cell Gene Expression. Stem cells and development 2016;25:586-97. 

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60. Marshall JC, Murthy S, Diaz J, et al. A minimal common outcome measure set for COVID-19 
clinical research. The Lancet Infectious Diseases 2020;20:e192-e7. 
 
 
 

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15 APPENDIX D 
 
WHO Ordinal Score 
The World Health Organization has endorsed the use of an ordinal scale as an outcome measure 
in clinical trials to capture the trajectory of patients’ clinical progression and of healthcare 
resource use.51  
 
Score 
Descriptor 
1 
Discharged (alive) 
2 
Hospital admission, not requiring supplemental oxygen, no longer requiring medical 
care (hospitalisation extended for infection control or other nonmedical reasons e.g. 
social care. Sometimes documented as “medically fit for discharge” or “medically 
stable for discharge”) 
3 
Hospital admission, not requiring supplemental oxygen, but requiring ongoing 
medical care 
4 
Hospital admission, requiring supplemental oxygen  
(by face mask or nasal prongs) 
5 
Hospital admission, requiring high flow nasal oxygen, continuous positive airways 
pressure or non-invasive ventilation 
6 
Hospital admission, requiring invasive mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO) 
7 
Death 
 
 
 
 

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16.1 STUDY DESIGN  
16.1.1 SCHEMA 
 
 
 
          
 
 
 
 
 
 
 
 
 
         
                                                                                                    Within 14 days of ARDS diagnosis  
 
 
 
 
 
 
  
 
 
 
 
 
* If not discharged from the ICU 
** Day 28 or last day of hospital, which ever comes first. 
 
 
 
 
 
 
Informed Consent/Screening 
Day 1 clinical assessment & biospecimen collection 
Days 2-6 clinical assessment & biospecimen collection* 
Day 28 Final Clinical Assessment** 
Diagnosis of Moderate/Severe ARDS 

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16.4 STUDY PROCEDURES 
This section explains the clinical and laboratory tests that will be performed in each study visit. 
See Section 16.3 for the study visit schedule.  
 
16.4.1 SCREENING 
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee at 
the Screening Visit to ensure that the subject qualifies for the study. All inclusion criteria must be 
met, and none of the exclusion criteria may apply. Subjects found ineligible during the review of 
inclusion/exclusion will not proceed through the remaining screening process.  
• Informed consent 
• Demographics, Medical History 
• Concomitant medications 
• Research blood collection: All protocol required research blood collection assessments 
must be conducted in accordance with the Laboratory Manual and the Schedule of 
Activities. Laboratory requisition forms must be completed, and samples must be clearly 
labeled with the subject number, protocol number, site number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are detailed 
in the Laboratory Manual.  
• Exploratory Bronchoalveolar lavage: See Laboratory Manual for more details. Should be 
done per 'institute's standards of operations. If BAL can not be performed then tracheal 
aspirate. 
• Clinical End-point Assessment includes: Survival (Y/N), On mechanical ventilation (Y/N), 
In ICU (Y/N), In Hospital (Y/N), Use of anti-coagulation (drug, dose, intent: prophylaxis 
vs therapeutic), WHO Ordinal Score (See Appendix D for scale). If patient is in ICU then 
the following assessment will be completed: Sequential Organ Failure Assessment (SOFA, 
See Appendix B for template form), PaO2/FiO2, following ventilation parameters (as 
applicable): type of ventilation (CPAP, BiPAP, or intubation)/ ventilation rate/ pulse/ tidal 
volume/ positive end-expiratory pressure (PEEP), recording of vasoactive drugs and renal 
support, recording of supportive interventions that can impact clinical end-points (use of 
prone ventilation, use of paralytics, use of pulmonary vasodilators, use of corticosteroids, 
use of oral decontamination and raising the head of the patient to at least 30º to prevent 
ventilator-associated pneumonia). 
• CBC with differential: Only if performed as Standard of Care. 
• Serum chemistry: Only if performed as Standard of Care. Chemistry includes: Glucose, 
Ca, Mg, Phos, ALP, Albumin, Total Protein, Total Bilirubin, K, Na, Cl, HCO3, BUN, Cr, 
ALT, AST, LDH, Amylase. 
• CRP, ferritin, D-Dimer:  
• PT/INR, PTT: If performed as Standard of Care. 
• Chest Imaging: CT scan (preferred) or Chest X-Ray.  
 

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16.4.2 DAY 1,2,3  
On each day, the following assessments should be completed. There should be at least 12 hours 
between each assessment. Assessments after Day 1 are omitted if the patient is discharged from 
ICU. 
• Concomitant medications 
• Clinical End-point Assessment includes: Survival (Y/N), On mechanical ventilation (Y/N), 
In ICU (Y/N), In Hospital (Y/N), Use of anti-coagulation (drug, dose, intent: prophylaxis 
vs therapeutic), WHO Ordinal Score (See Appendix D for scale). If patient is in ICU then 
the following assessment will be completed: Sequential Organ Failure Assessment (SOFA, 
See Appendix B for template form), PaO2/FiO2, following ventilation parameters (as 
applicable): type of ventilation (CPAP, BiPAP, or intubation)/ ventilation rate/ pulse/ tidal 
volume/ positive end-expiratory pressure (PEEP), recording of vasoactive drugs and renal 
support, recording of supportive interventions that can impact clinical end-points (use of 
prone ventilation, use of paralytics, use of pulmonary vasodilators, use of corticosteroids, 
use of oral decontamination and raising the head of the patient to at least 30º to prevent 
ventilator-associated pneumonia). 
• Research blood collection: All protocol required research blood collection assessments 
must be conducted in accordance with Laboratory Manual. 
• Exploratory Bronchoalveolar lavage: This should be done only once during this period. 
There should be at least 48h passed since the collection for Screening Visit (Section 
16.4.1). If BAL can not be performed, then tracheal aspirate. 
• CBC with differential: Only if performed as Standard of Care. 
• Serum chemistry: Only if performed as Standard of Care. Chemistry includes: Glucose, 
Ca, Mg, Phos, ALP, Albumin, Total Protein, Total Bilirubin, K, Na, Cl, HCO3, BUN, Cr, 
ALT, AST, LDH, Amylase. 
• CRP, ferritin, D-Dimer. 
• PT/INR, PTT: If performed as Standard of Care. 
 
 
16.4.3 DAYS 4-6  
If the patient is still in ICU, the following assessments should be completed. There should be at 
least 12 hours between each assessment.  
 
• Concomitant medications: Should be done daily.  
• Clinical End-point Should be done daily. Assessment includes: Survival (Y/N), On 
mechanical ventilation (Y/N), In ICU (Y/N), In Hospital (Y/N), Use of anti-coagulation 
(drug, dose, intent: prophylaxis vs therapeutic), WHO Ordinal Score (See Appendix D for 
scale). If patient is in ICU then the following assessment will be completed: Sequential 
Organ Failure Assessment (SOFA), PaO2/FiO2, following ventilation parameters (as 
applicable): type of ventilation (CPAP, BiPAP, or intubation)/ ventilation rate/ pulse/ tidal 
volume/ positive end-expiratory pressure (PEEP), recording of vasoactive drugs and renal 
support, recording of supportive interventions that can impact clinical end-points (use of 
prone ventilation, use of paralytics, use of pulmonary vasodilators, use of corticosteroids, 
use of oral decontamination and raising the head of the patient to at least 30º to prevent 
ventilator-associated pneumonia)  
• Research blood collection: Only once during this period. All protocol required research 
blood collection assessments must be conducted in accordance with Laboratory Manual.