Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles Infusion Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Phase II Clinical Trial
Phase: PHASE2
Conditions: COVID-19, ARDS
Sponsor: Direct Biologics, LLC

CLINICAL STUDY PROTOCOL 
 
 
 
 
NCT Number: 
NCT04493242 
 
 
Study Title: 
Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Infusion Treatment for COVID-19 Associated Acute Respiratory Distress 
Syndrome (ARDS): A Phase II Clinical Trial 
 
 
 
Study Number: 
DB-EF-PHASEII-001 
 
 
Protocol Version and Date: 
Amendment 6: 
08 Feb 2021 

 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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CONFIDENTIAL 
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by you, your staff, and 
Ethics Committee/Institutional Review Board (EC/IRB). The information contained in this document is regarded as 
 
 
 
 
 
 
Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles Infusion Treatment for COVID-19 
Associated Acute Respiratory Distress Syndrome (ARDS): A Phase II Clinical Trial 
 
Protocol Number: 
DB-EF-PHASEII-001 
 
Investigational New Drug (IND) Number: 
21669 
 
Study Phase: 
II 
 
Study Type: 
Double-Blinded, Placebo-controlled, Randomized Controlled Trial 
 
Study Investigational Product: 
Bone Marrow Mesenchymal Stem Cell (bmMSC)-Derived 
Extracellular Vesicles (via Intravenous Administration) 
 
Administrative Amendment: 
Date & Document Version: 
6 
8 February 2021 
| 
7.0 
 
 
Administrative Amendment: 
Date & Document Version: 
5 
31 December 2020 
| 
6.0 
 
 
Administrative Amendment: 
Date & Document Version: 
4 
2 November 2020 
| 
5.0 
 
 
Administrative Amendment: 
Date & Document Version: 
 
3 
7 October 2020 
| 
4.0 
 
 
Administrative Amendment: 
Date & Document Version 
 
2 
31 August 2020 
| 
3.0 
 
 
Administrative Amendment: 
Date & Document Version 
 
1 
7 August 2020 
| 
2.0 
 
 
Original Protocol: 
Date & Document Version 
 
- 
24 July 2020 
| 
1.0 
 
Sponsor: 
Direct Biologics, LLC 
13492 Research Blvd, Ste 120-758 
Austin, TX 78750 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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confidential and, except to the extent necessary to obtain informed consent, may not be disclosed to another party unless such 
disclosure is required by law or regulations. Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
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PROTOCOL AUTHORIZATION 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
6 
 
 
 
 
INVESTIGATOR’S AGREEMENT 
 
 
Title: Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles Infusion Treatment 
for COVID-19 Associated ARDS: A Phase II Clinical Trial 
Protocol Number: DB-EF-PHASEII-001 
 
 
Signature of Investigator 
dd/mm/yy 
Printed Name of Investigator and Title 
Site Number(s): 
By my signature, I agree to supervise and oversee the conduct of this study and to ensure its 
conduct is in compliance with the protocol, informed consent, IRB/EC procedures, 
instructions from Direct Biologics representatives, the Declaration of Helsinki, International 
Conference on Harmonisation (ICH) Good Clinical Practices (GCP) guidelines, and the 
applicable parts of the United States (US) Code of Federal Regulations (CFR) and local 
regulations governing the conduct of clinical studies. 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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TABLE OF CONTENTS 
 
 
 
 
 
1. 
PROTOCOL SUMMARY ........................................................................................................................... 16 
1.1 
Synopsis ................................................................................................................................................ 16 
1.2 
Schema ................................................................................................................................................. 18 
1.3 
Schedule of Activities* ......................................................................................................................... 19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5. 
STUDY POPULATION ............................................................................................................................... 40 
5.1 
Inclusion Criteria .................................................................................................................................. 40 
5.2 
Exclusion Criteria ................................................................................................................................. 41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF IN-TEXT TABLES 
Table 1. Schedule of Activities .................................................................................................................. 19 
 
 

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1. PROTOCOL SUMMARY 
 
1.1 
Synopsis 
 
Title: Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles Infusion 
Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome 
(ARDS): A Phase II Clinical Trial 
Study 
Description: 
ExoFloTM Infusion Treatment for COVID-19 Associated ARDS (EXIT 
COVID-19), a multicenter, double-blinded, placebo-controlled, randomized 
control trial to evaluate the efficacy and safety in COVID-19 associated 
moderate to severe ARDS. 
Objectives: To evaluate the safety and efficacy of intravenous (IV) administration of bone 
marrow mesenchymal stem cell derived extracellular vesicles (EVs), ExoFlo, 
versus placebo as treatment for COVID-19 associated moderate-to-severe 
Acute Respiratory Distress Syndrome (ARDS). 
Endpoints: Primary Endpoint: 
1) Improvement in partial pressure of arterial oxygen to fraction of inspired 
oxygen (PaO2/FiO2) ratio from pre-infusion baseline (Day 0) to Day 7. 
PaO2 may be calculated from arterial blood gas (ABG) or imputed from the 
SpO2 daily (                        ). 
Note: Day 0 is designated as Day of Screening and Day 1 as Day of the First 
Study Intervention. Patients may be screened and treated within the same 24 
hours—in this scenario, Day 1 will be synonymous with Day 0 & the pre- 
infusion value used will be from Day 1. 
Secondary Endpoints: 
2) Time to recovery as defined by the number of days from the first study 
treatment until return of oxygenation saturation (SpO2) ≥ 93% on room air 
(or PaO2/FiO2 ≥ 300 mmHg). If patient has chronic lung disease, recovery 
is defined as pre-COVID-19 SpO2 and O2 support. 
3) Incidence of serious adverse events. 
All-cause mortality. 
Exploratory Endpoints: 
5) Viremia: qualitative serum severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) ribonucleic acid (RNA) load on Days 0 or 1, 15, 29, and 61. 
6) Acute phase reactants: C-reactive protein (CRP), D-dimer, Ferritin, 
interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) on Days 1, 4, 7, 
10, 15, 29. CRP, D-dimer, & Ferritin also on Day 0. 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
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7) Immune cell counts: Absolute neutrophil count (ANC); CD3+, CD4+, 
CD8+ thymus cells also known as T lymphocytes (T cells); natural killer 
(NK) cells on Days 1, 4, 7, 10, 15, 29. 
8) Sequential Organ Failure Assessment (SOFA) Score on Days 1, 15, 29 for 
patients who are still hospitalized. 
9) Quality of life (QOL) assessment for patients who are discharged. EQ-5D- 
5L on Days 29 and 61. See Appendix 11.2 for sample EQ-5D-5L, which 
includes dimensions of mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression. 
Study 
Population: 
Up to 120 adult male and female patients between 18 and 85 years of age 
hospitalized with COVID-19 associated ARDS. 
Phase: Phase II 
Site Number: 2-15 
Description of 
Intervention: 
Patients will be randomized to one of the following: 
Treatment Arm 1: PLACEBO Normal saline 100 mL 
Treatment Arm 2: IP (Exoflo) 10ml dose in Normal saline 90 mL, which is 
approximately 800 billion EVs (Lot# P-441-1901-E5, P-441-2004-C5). 
Treatment Arm 3: IP (Exoflo) 15ml dose in Normal saline 85 mL, which is 
approximately 1.2 trillion EVs (Lot# P-441-1901-E5, P-441-2004-C5). 
The intervention will be infused over 60 minutes on Day 1 and repeated on Day 
4 provided that the patient has not recovered as defined by SpO2 ≥ 93% on RA 
or PaO2/FiO2 ≥ 300 mmHg. If patient has chronic lung disease, recovery is 
defined as baseline SpO2 and O2 support. 
Allocation of 
Intervention: 
Patients will be randomized 1:1:1 to each of the three treatment arms initially. 
The Interactive Response Technology will notify the DSMB such that a safety 
and interim analysis can be held following day 7 of the 60th patient randomized. 
Duration: Each patient will be enrolled in the study for an estimated 60 days. 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
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Perform basic evaluation, respiratory evaluation, standard labs, acute phase 
reactants, flow cytometry labs, SOFA score, adverse event review per section 1.3. 
Repeat the same treatment received on day =1, provided that the patient has not 
recovered as defined by SpO2 ≥ 93% on RA (or P/F ratio ≥ 300 mmHg) or pre- 
COVID-19 O2 support & SpO2 if patient has chronic lung disease. 
Perform basic evaluation, respiratory evaluation (includes SARS-CoV-2 RT PCR & O2 
support recording), standard labs (BMP, CBC differential, LFTs, PT/INR), acute phase 
reactants, flow cytometry labs, SOFA score, microbiology & rule out labs, adverse 
event review per section 1.3 Schedule of Activities. 
Administer the randomly assigned treatment. 
Perform basic evaluation, respiratory evaluation, standard labs, acute phase 
reactants, flow cytometry labs, SOFA score, adverse event review per section 1.3 if 
still hospitalized. 
Randomize 
Arm 1 
100 mL NS + SOC 
N=40* 
Arm 2 
10 mL IP & 90 mL 
NS + SOC N=40* 
N Up To 120: Obtain written informed consent. Screen potential participants by 
inclusion and exclusion criteria; obtain history and lab values. 
 
 
1.2 
Schema 
 
Prior to 
Enrollment 
 
 
 
 
 
 
Arm 3 
15 mL IP & 85 mL 
NS + SOC N=40* 
 
 
 
 
Day = 1 
 
 
 
 
 
 
Day = 4 
 
 
 
 
 
 
Day = 7, 10, 15, 29 
 
 
 
 
Day = 15, 29, 61 
 
 
Abbreviations: AE=adverse event; BMP=basic metabolic profile; CBC=complete blood count; EQ-5D-5L=quality of life 
assessment; IP=investigational product; IV=intravenous; LFT-liver function test; NK cells=natural killer cells; 
NS=normal saline; P/F ratio = partial pressure of arterial oxygen to fraction of inspired oxygen ratio; PT/INR= 
prothrombin time/international normalized ratio; RNA=ribonucleic acid; SOC=standard of care; SOFA=sequential 
organ failure assessment score; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. 
Perform basic evaluation, respiratory evaluation, standard labs, acute phase 
reactants, SOFA score per section 1.3 if still hospitalized. Follow-up call with EQ-5D- 
5L if patient is discharged. Interim adverse event review is performed. 

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1.1 
Schedule of Activities* 
 
NOTE: If eligibility criteria are met, patients may receive the first study intervention on the 
same day as screening, such that Day 1 is synonymous with Day 0 and the pre-infusion value 
from Day 1 may be used in place of the value from Day 0. See table footnotes A-J for answers 
to other common site questions. 
 
Table 1. Schedule of Activities. 
 
Screen 
Day 
PROCEDURES 
0 or 1 
1 
4 
7 
10 
15 
29 
61 
Visit 
0 
1 
2 
3 
4 
5 
6 
7 
BASIC EVALUATION 
Informed consent 
X 
Inclusion/Exclusion 
X 
X 
Demographics 
X 
Medical history 
X 
Days of Illness Before Admission 
XA 
Concomitant Meds 
X 
X 
XB 
XB 
XB 
XB 
XB 
XB 
Vital SignsC 
X 
X 
XB 
XB 
XB 
XB 
XB 
XB 
Height & WeightI 
XI 
Physical examination 
X 
X 
XB 
XB 
XB 
XB 
XB 
XB 
Glasgow Coma Score 
X 
X 
XB 
XB 
XB 
XB 
XB 
XB 
Pregnancy TestD 
XD 
XD 
EKGI 
XI 
PRN AS INDICATED; N/A AFTER D/C 
Randomization 
X 
Administer IV Study Intervention 
X 
XE 
RESPIRATORY EVAL 
SARS-CoV-2 RT-PCRF 
X 
XJ 
XB 
XB 
XB 
Record Prone Posn (Y/N, Freq) 
X 
XJ 
XB 
XB 
XB 
XB 
XB 
XB 
PaO2/FiO2 ratio 
X 
CALCULATE DAILY UNTIL D/C; SEE SECTION 11.1 
Record O2 Support 
X 
DAILY UNTIL D/C; NOTE NC (LPM), FM (LPM), NRB, BiPAP (FiO2), 
HFNC O2 (FiO2), MV (FiO2, PEEP), HFOV (FiO2). 
CXR or CT chest 
X 
PRN AS INDICATED; N/A AFTER D/C 

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STANDARD LABS 
BMP 
X 
XJ 
XB 
XB 
XB 
XB 
XB 
XB 
CBC with differential 
X 
XJ 
XB 
XB 
XB 
XB 
XB 
XB 
LFTS (including Bilirubin) 
X 
XJ 
XB 
XB 
XB 
XB 
XB 
XB 
PT/INR 
X 
XJ 
XB 
XB 
XB 
XB 
XB 
XB 
PTT 
X 
XJ 
XB 
XB 
XB 
XB 
XB 
XB 
ACUTE-PHASE REACTANTS 
CRP 
X 
XJ 
XB 
XB 
XB 
XB 
XB 
D-dimer 
X 
XJ 
XB 
XB 
XB 
XB 
XB 
Ferritin 
X 
XJ 
XB 
XB 
XB 
XB 
XB 
Il-6 
XJ 
XB 
XB 
XB 
XB 
XB 
TNF-α 
XJ 
XB 
XB 
XB 
XB 
XB 
FLOW CYTOMETRY 
T-lymphocyte panel (stain CD3+, 
CD4+, CD8+) 
XJ 
XB 
XB 
XB 
XB 
XB 
NK cells count (CD3- CD56+ subset 
of lymphocyte gate) 
XJ 
XB 
XB 
XB 
XB 
XB 
METRIC 
SOFA Score 
XJ 
XG 
XG 
EQ-5D-5L (Call Survey) 
XH 
XH 
MICROBIOLOGY 
UrinalysisI 
XI 
PRN AS INDICATED; N/A AFTER D/C 
Urine cultureI 
XI 
PRN AS INDICATED; N/A AFTER D/C 
Blood culture x 2I 
XI 
PRN AS INDICATED; N/A AFTER D/C 
Sputum cultureI 
XI 
PRN AS INDICATED; N/A AFTER D/C 
RULE OUT TESTS 
Mycoplasma IgMI 
XI 
QuantiFERON GoldI 
XI 
Legionella AgI 
XI 
Strep. Pneumoniae AgI 
XI 
Influenza A/B PCRI 
XI 
Adverse Events Review 
X 
DAILY UNTIL D/C; CALL F/U ON DAY 15, 29, 61 

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Abbreviations: Ag=antigen; ANC=absolute neutrophil count; BiPAP=bilevel positive airway pressure; BMP=basic 
metabolic profile; CRP=C-reactive protein; CBC=complete blood count; char=characteristics; CT=computed 
tomography; CXR=chest x-ray; D/C=discharge; EKG=electrocardiogram; EQ-5D-5L=5-dimentional quality of life 
assessment; FiO2=fraction of inspired oxygen; FM=face mask; Freq=frequency; HF NC O2=high flow nasal cannula 
oxygen support; HFOV=high frequency oscillatory ventilation; IgM=immunoglobulin M; IP=investigational 
product; IV=intravenous; LFT-liver function test; LPM=liters per minute; Meds=medications; MV=mechanical 
ventilation; N/A=not applicable; NC=nasal cannula; NK cells=natural killer cells; NRB=nonrebreather; 
PCR=polymerase chain reaction; PEEP=positive end expiratory pressure; POS=positioning; PT/INR= prothrombin 
time/international normalized ratio; PTT=partial prothrombin time; Quant=quantitative; RT-PCR=reverse 
transcriptase polymerase chain reaction; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; 
SOFA=sequential organ failure assessment score; T cells=thymus cells also known as T lymphocytes; TNF- 
α=tumor necrosis factor alpha. 
A: The number of COVID-19 symptomatic days prior to the current admission is recorded along with the number 
of days from admission to first study administration. 
B: Patients will be monitored for 72 hours as inpatients following each study intervention. Recovery will be defined 
in the study as SpO2 reaching ≥ 93% on RA (or P/F ≥ 300 mm Hg) or pre-COVID-19 SpO2 or O2 support if patient has 
chronic lung disease. 
• Following the first treatment on Day 1, the patient may be discharged on Day 4 or later. 
• Following the second treatment on Day 4, the patient may be discharged on Day 7 or later. 
• If a patient received the first but not the second treatment, he/she may be discharged prior to Day 7. 
• Following patient’s discharge, no labs will be drawn. Follow-up via phone-call only on Days 29 and 61. 
C: During the infusion, measurements +/- 2 minutes of specified times for q5min vitals and +/- 5 minutes of 
specified times for q15min vitals are considered permissible; following the infusion, vital sign measurements are 
permissible +/-15 minutes of the specified times. Temperature is required only 5 minutes prior and q15min 
during the course of the infusion. 
D: Serum pregnancy test (in women of childbearing potential) will be obtained on Day 0. Urine dipstick obtained 
on Day 1 at 4 hours prior to the first study treatment if >24 hours passed since the serum pregnancy test. 
E: Not all patients who recovered will receive a repeat study intervention. Patients who recovered by Day 4 do 
not receive a repeat study intervention. 
F: Qualitative SARS-CoV-2 RT PCR will be used for Day 0 or 1 (prior to the first dose), 15, 29, 61. If there is a 
shortage of tests, documentation of positive test within 14 days prior to admission suffices for Day 0 or 1. 
G: SOFA Score will be administered only if patient is still hospitalized. 
H: ED-5D-5L score will be administered over the phone only if patient is discharged. Note: This is not a meaningful 
measure for patients who are still hospitalized due to common use of IV sedatives or PO antipsychotics for 
delirium. A baseline prior to study infusion is not obtained because the patient is hypoxic, and the hospital staff 
needs to prioritize diagnostics and treatment rather than time-consuming quality of life metric. 
I: The Screen column refers to tests obtained prior to the first study treatment, usually obtained on Day 0, i.e., 24 
hours prior to the first study treatment. However, height & weight, EKG, microbiology, and rule out tests do not 
have to be repeated on Day 0 if obtained once following the current hospital admission. 
J: All lab tests including SARS-CoV-2 viremia, standard tests, acute phase reactants, flow cytometry will be 
obtained around 1-2 hours prior to the first study treatment on Day 1. On Day 1, SOFA score will be calculated on 
the morning values prior to the study treatment. 
 
 

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5. STUDY POPULATION 
 
5.1 
Inclusion Criteria 
 
Eligibility for study enrollment includes meeting all of the following criteria: 
1. Provision of signed and dated informed consent form (either by the individual or by the 
individual’s healthcare proxy). 
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study 
3. Male or female aged 18-85. 
4. COVID-19 positive as defined by positive Reverse Transcriptase Polymerase Chain 
Reaction (RT-PCR) SARS-CoV-2. 
5. Moderate to severe ARDS as defined by modified Berlin definition, * which includes 
timing within 1 week of known clinical insult or new or worsening respiratory symptoms; 
bilateral opacities not fully explained by effusions, or lung collapse; respiratory failure not 
fully explained by cardiac failure or fluid overload; PaO2/FiO2 ≤ 200 mm Hg. 
6. Hypoxia requiring noninvasive oxygen support such as Nasal Cannula (NC), 
Nonrebreather (NRB), Bilevel Positive Airway Pressure (BIPAP), Continuous Positive 
Airway Pressure (CPAP), high flow nasal cannula oxygen (HFNC O2) or mechanical 
ventilation (MV) despite initiating standard of care. 
7. If the candidate is either a male or female of reproductive potential, he or she must agree 
to use of double barrier method of highly effective birth control contraception such as 
condoms with oral contraceptive pill or choose to remain abstinent if already practicing 
abstinence during the screening period. The required duration of usage of double barrier 
method OR maintenance of abstinence must include the time from the beginning of the 
screening period until 90 days following the last dose of the study treatment. 
*Modified Berlin definition used in this study is the full Berlin definition, albeit without the PEEP 
specification, which implies mechanical ventilation. 
 
**To ensure flexible adaptation of products approved by the FDA for the treatment of severe 
COVID-19, standard of care is defined as the NIH Current COVID-19 Treatment Guidelines 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
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5.2 
Exclusion Criteria 
 
Exclusion from study enrollment includes meeting one or more of the following criteria: 
1. Vulnerable populations such as pregnant patients, children, individuals with severe 
physical or mental disabilities who cannot provide meaningful consent. 
2. Active malignancy requiring treatment within the last five years. 
3. Major physical trauma in the last 5 days, including motor vehicle accidents, assaults, 
mechanical falls with sequalae of significant bleeding or craniofacial bruising, and 
surgeries. 
4. Active tuberculosis or cystic fibrosis. 
5. Severe chronic respiratory disease including chronic obstructive pulmonary disease or 
pulmonary fibrosis requiring home oxygen > 5L/min. 
6. Use of extracorporeal membrane oxygenation (ECMO) during the current hospitalization. 
7. Pre-existing pulmonary hypertension. 
8. Severe pre-existing hepatic impairment (presence of cirrhosis, liver function tests (LFTs) 
≥ 6x baseline, INR ≥ 2.0). 
9. Pre-existing Chronic Kidney Disease (CKD) stage IIIb or End Stage Renal Disease (ESRD) 
prior to onset of COVID-19 (stage I, II, and IIIa are acceptable) 
10. Irreversible 
coagulopathy 
(e.g., 
frequently 
occluded 
vascular 
access 
despite 
anticoagulation, precipitous platelet drops concurrent with end-organ damage suggesting 
consumptive process) or irreversible bleeding disorder (e.g., frequent bleeding from 
vascular access, endotracheal tubes, and foley). 
11. Pneumonia clearly attributable to a non-COVID-19 related process, including aspiration 
pneumonia or pneumonia that is exclusively bacterial, or originating from a diagnosed 
alternative virus (e.g., influenza). 
12. Patients who are not full code. 
13. Endotracheal intubation duration ≤ 24 hours. 
14. Moribund—expected survival < 24 hours. 
15. Severe metabolic disturbances on presentation (e.g., ketoacidosis, pH < 7.3) 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
43 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
44 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
45 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
49 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
50 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
51 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
55 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
56 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
57 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
58 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
59 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
60 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
61 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
62 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
63 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
64 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
65 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
66 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
67 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
68 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
69 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
70 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
71 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
72 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
73 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
75 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
76 
 
 
 
 
 
 
 
 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
78 
 
 
 

Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles 
Protocol Number: DB-EF-PHASEII-001 
Direct Biologics, LLC 
 
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