A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial to Assess Efficacy and Safety of Allogeneic HB-adMSCs to Provide Immune Support Against COVID-19.
Phase: PHASE2
Conditions: COVID-19
Sponsor: Hope Biosciences Research Foundation

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
0  
 
Allogeneic HB-adMSCs to provide immune support against COVID-19.  
 
Clinical Study Protocol Board Action Date: 01/29/2021 
Protocol Number: HBCOVID02  
“A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial to Assess Efficacy and 
Safety of Allogeneic HB-adMSCs to Provide Immune Support Against COVID-19”  
IND Number:  
19708  
NCT Number  
NCT04348435  
Protocol Version  
1.5      
Protocol Version Date  
25-JAN-2021 
 
 
Ethics and Regulatory Compliance Statement  
  
The procedures set forth in this protocol are designed to ensure that the Hope Biosciences Stem  
Cell Foundation and principal investigator(s) abide by the International Conference on  
Harmonization (ICH) current Good Clinical Practice (cGCP) guidelines, current Good  
Laboratory Practice (cGLP) guidelines, the Declaration of Helsinki, and applicable local 
regulatory requirements and laws in the conduct, evaluation, and documentation of this study.  
  
 
-CONFIDENTIAL-  
  
This document and its contents are the property of and confidential to Hope Biosciences. Any 
unauthorized copying or use of this document is prohibited.  
 
 
 
 
 
 
 
Protocol Version 1.5  
Version Date: 25-JAN-2021 
 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
1  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
   
  
Synopsis   
  
Title of the Study:  
“A Randomized, Double-Blind, Placebo-Controlled, Clinical  
Trial to Assess Efficacy and Safety of Allogeneic HB-adMSCs to 
Provide Immune Support Against COVID-19”  
Protocol Number:  
HBCOVID02  
Investigators   
Principal Investigator: Thanh Cheng, MD Sub-
Investigator: Djamchid Lotfi, MD  
Study Site: Single site:  
Hope Biosciences Stem Cell Research Foundation 
16700 Creek Bend Dr.  
Sugar Land, TX 77478  
Phase of development   
II  
Objectives  
Primary:  
- 
To investigate the efficacy of HB-adMSCs in providing 
immune support against development of COVID-19 by 
decreasing the percentage of subjects that develop 
symptoms of COVID-19 infection.   
  
Secondary:   
- 
To investigate the efficacy of HB-adMSCs in the 
prevention of upper and lower respiratory infections 
requiring hospitalization.   
  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
2  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Study Design:  
This Phase 2, randomized, double-blind, single center, efficacy 
and safety study is designed to evaluate allogeneic HB-adMSCs 
to provide immune support against COVID-19 in subjects 
classified as high risk or very high risk.  
  
The screening period, up to 45 days long for each patient, will be 
used to assess eligibility. At baseline (Week 0), approximately 53 
patients who are eligible will be randomly assigned to one of 4 
groups (n=25 per group). Three groups will receive allogeneic 
HB-adMSCs infusions in different doses, and the fourth group of 
subjects will receive vehicle infusions (solution without cells).   
  
After the study is finished the investigators should know whether 
or not HB-adMSCs provides immune support against COVID-19 
and whether or not it is safe to give this medication to patients 
with an increased risk of infection by SARS-CoV-2. To ensure 
that the drug is safe, a Medical Monitor will oversee the entire 
study. Laboratory data, including complete blood counts, serum 
chemistry and adverse events will be reviewed.  
Planned Sample Size:   
Population: 53 patients.  
The sample size required assumes a 15% drop-out of patients.  
Treatment Duration:  
The approximate maximum duration of treatment for each patient 
is 14 weeks (Week 0 through 14), and the approximate duration of 
the study is 26 weeks.   
Criteria for Evaluation:   
  
Safety:   
  
Safety will be assessed by adverse event (AE) reporting, physical 
examinations, vital signs, and clinical laboratory values. Patient 
safety data will be closely monitored by the clinical team to 
ensure patient safety, as well as the Medical Monitor and DSMB.   
  
Clinical Efficacy:   
  
Efficacy will be evaluated through the analysis of Complete 
Blood Count with differential.  Exploratory measures will include 
changes from baseline inflammation, SF-36 and PHQ-9.  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
3  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Study Endpoints:   
  
Primary endpoints:   
  
- 
Incidence of hospitalization for COVID-19  
- 
Incidence of symptoms associated with COVID-19  
  
Secondary endpoints:   
  
- 
Absence of upper/lower respiratory infections up to 3 
months post infusions.  
- 
Change from baseline in leukocyte differential  
- 
Change from baseline in C-Reactive Protein, TN alpha, 
IL-6  
- 
Clinically significant changes in laboratory values, vital 
signs, weight and physical examination results.   
Incidence of AEs (AEs) and serious AEs (SAEs) related 
to the drug  
Statistical Methods and 
Planned Analyses:   
The statistical analysis plan is defined and enumerated.   
  
  
   
Introduction   
  
 
Background and Study Rationale    
  
In December 2019, several unexplained cases of pneumonia were reported in Wuhan, China. On 
January 12, 2020, the World Health Organization temporarily named this new virus the 2019 
novel coronavirus (2019-nCoV), which was later updated to include the disease caused by 
2019nCoV, Coronavirus Disease (COVID-19). The most common complications observed in 
patients with COVID-19 are acute respiratory distress syndrome (ARDS), anemia, acute heart 
injuries, and secondary infections.  Currently, there is no specific therapeutic intervention to 
effectively improve clinical outcomes in ARDS [1]. Pulmonary fibrosis risk is greatly increased 
in infected patients and may persist even after infection is resolved [2]. In addition to many 
pulmonary symptoms, it has been reported that there is evidence that coronaviruses are not 
confined to the respiratory tract [3]. COVID-19 could also affect the central nervous system 
(CNS), with symptoms like headache, nausea, vomiting, and potentially lead to neurological 
disease [4]. Currently, healthcare professionals are treating infected patients with antibiotics, 
antiviral therapy, and systemic corticosteroids, however these methods have no effect on 
transmission. A substantial proportion of the US is susceptible to COVID-19 infection, as most 
of the infected patients are older, with reports of median age ranging from 47 to 75 years [4-8], 
and had underlying disease, likely increasing their vulnerability [5]. As this pandemic continues 
to spread across the globe, researchers and clinicians are rapidly working to find effective 
treatment and methods for prevention. While the world awaits an effective vaccine, treatment 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
4  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
targets are focused on other methods to prevent infection and increasing immune support to 
lessen the effects, should infection occur.  
  
At least 14 trials have been reported claiming use of stem cells to treat COVID-19 patients in China. 
One study has reported significant functional improvement in 8 patients infected with Sars-CoV-2 
following treatment with umbilical cord-MSCs. The dose of MSCs used in this study is reported to be 
a single infusion of 1 million cells per kilogram, or approximately 60 million cells for an average 
60kg adult. Another patient in Baoshan was treated with UC-MSCs in 3 infusions of 50 million cells 
each. The large quantity of cells used in these patients is considered critical in achieving recovery. 
Four additional patients are reported to have been treated with stem cells and recovered, however 
there are very few details regarding their treatment. The stem cell community is supporting the use of 
MSCs to treat COVID-19, based upon the innate immunomodulatory and regenerative properties 
these cells convey. We suspect more reports of successful stem cell treatment of COVID-19 will 
appear daily, as this therapy appears to be an ideal candidate for treating these patients. Furthermore, 
MSC therapy does not result in negative side effects, unlike many pharmaceutical interventions. 
Given our increasing evidence of safety and efficacy, HB-adMSCs, in our opinion, would 
significantly impact these critically ill patients.  
  
The homeostasis of the respiratory system is maintained by interactions between alveolar 
epithelial cells and resident immune cells which monitor the environment, induce tolerance, and 
regulate efficient immune reactions to pathogens [9]. In the case of viral infection, the host innate 
immune response is the first line of defense to prevent invasion or replication prior to adaptive 
immune response. Epithelial cells and mucosal macrophages are typically the first immune cells 
to encounter pathogens and are activated to initiate a cascade of inflammation. In the case of 
SARS-CoV-2 infection, the CoV spike (S) glycoprotein binds to host angiotensinconverting 
enzyme 2 (ACE2) receptor, which is normally expressed on alveolar epithelial cells. Pattern 
recognition receptors (PRR) engage to detect viral components and to induce type 1 interferons 
(IFNs) and pro-inflammatory cytokines. Type 1 interferons are produced by all cell types in 
response to viral infection. IFNs are known to exhibit pleiotropic functions, increasing 
expression of intrinsic proteins and inducing apoptosis of virus-infected cells, and induce cellular 
resistance to viral infection [10]. Much of the function of PRRs is to discriminate pathogen 
nucleic acids from host nucleic acids, often through toll-like receptors (TLRs). PRRs are also 
known to initiate recruitment and activation of immune cells to the site. SARS-CoV-2-associated 
damage to alveolar cells triggers a systemic immune response. Detected viral structures activate 
macrophages and dendritic cells (DCs) via TLRs to secrete pro-inflammatory cytokines, such as 
interleukins (ILs) and tumor necrosis factor (TNF) and induce proliferation of naïve T-cells. 
Macrophages, once activated, undergo polarization to either an M1 or M2 phenotype. M1 
macrophages exhibit pro-inflammatory functions, secreting pro-inflammatory cytokines such as 
IL-12, IL-23, TNF-α, IL-1β, and IL-6. Increased production of IL-1a, IL-6, TNF-α, and IFN-γ is 
known to contribute significantly to the development of acute lung injury [11]. M2 macrophages 
exhibit anti-inflammatory functions, secreting anti-inflammatory cytokines such as IL-10 and 
TGF-β. It has been reported that SARS-CoV-2 biophysically and structurally exhibits a binding 
ability 10-20 times stronger than that observed with SARS-CoV [12], which would likely elicit a 
significantly more robust response.  
  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
5  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Worldwide, stem cells have become a promising tool for the treatment of autoimmune disease, 
degenerative disease, and injury by protection from immune attack associated damage and 
reparative mechanisms. Donor-screened allogeneic stem cells present a safe option as they will 
not induce immune rejection. MSCs are known for their ability to regulate the immune system 
and reduce inflammation [13]. Tissue repair by MSCs has been shown to occur both directly and 
through the release paracrine factors [14]. MSCs have low immunogenicity due to low 
expression levels of major histocompatibility complex-I (MHC-I) and no expression of MHC-II 
molecules and costimulatory molecules including CD80, CD86 or CD40. MSCs also secrete 
soluble factors such as IL-6 and macrophage-colony stimulating factor (M-CSF), suppress the 
activation and proliferation of T and B lymphocytes, and interfere with differentiation, 
maturation and function of DCs. MSCs release anti-inflammatory and anti-apoptotic molecules 
and hence may protect damaged tissues [15]. In cases of infection, the activation of the innate 
immune system results in cytokines, adhesion molecules, and chemokines interacting to facilitate 
leukocyte migration to the lungs and recruitment of neutrophils. In this cascade, lung injury may 
be a direct consequence of inflammatory response. MSCs suppress lymphocyte proliferation and 
activation, reduce cytokine secretion and cytotoxicity, and induce peripheral tolerance and 
regulatory cell expansion [16-18]. MSCs have been effective in acute and chronic inflammatory 
lung conditions by suppressing the immune response and, possibly, by differentiating into type II 
alveolar epithelial cells in the repair process [19, 20].   
  
MSC therapy has been shown to be effective in many models, including models of ARDS, CNS 
and nerve injury, via mechanisms of immunomodulation, remodeling, and neuroprotection [1, 
21-29]. Inhibition of T cell proliferation is a key immunomodulatory feature of MSCs [30], along 
with their ability to dampen the immune response and attenuate secondary injury mechanisms 
[31, 32]. They suppress T cell-dependent inflammation by secretion of soluble factors such as  
IL-6, M-CSF, prostaglandin E2 (PGE2), transforming growth factor beta (TGF-β), indoleamine  
2,3-dioxygenase (IDO), and nitric oxide (NO) [33]. In addition to direct suppression of effector  
T cells, MSCs also suppress the generation of Th1, Th2, and Th17 cells via PGE2, IL-10, and 
IL6-dependent modulation of DCs [19]. MSCs have been shown to significantly reduce the total 
number of effector T cells in injured lungs, attenuating Th1-, Th2, and Th17-driven 
inflammation [19]. MSCs can exert potent immunomodulatory effects through many 
mechanisms which have not been completely elucidated, however the concept of ‘licensing’ is a 
well-accepted mechanistic component. MSCs are licensed when they encounter endogenous 
proinflammatory factors, such as TNF-α and IFN-γ [34], which upregulates the expression of 
regulatory factors and produces an anti-inflammatory response [34-36]. Stimulation of MSCs 
induces production of TNF-α-stimulated gene 6 protein (TSG-6), which has been shown to 
decrease inflammatory reactions in several animal models [37-39], in part by limiting invading 
neutrophil and monocyte/macrophage response and reducing stimulation of NF-κB signaling in 
resident macrophages [37]. This negative-feedback loop attenuates the pro-inflammatory cascade 
and subsequent neutrophil recruitment [40]. MSCs have also been shown to modulate 
macrophage differentiation and activation states, specifically prompting attenuation of 
proinflammatory M1 and enhancement of anti-inflammatory M2 [41-45]. This has been 
proposed as another possible mechanism through which adMSC exert anti-inflammatory effects, 
evident in treatment of immunological and inflammatory diseases [46-50]. In addition to 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
6  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
previously described immunomodulatory potential of MSCs, specifically in studies using MSCs 
to treat ARDS, MSCs have been shown to also increase antimicrobial peptide levels, increase 
phagocytic activity, increase T reg cell expansion, increase alveolar fluid clearance and increase 
microbial clearance [1]. Together, these effects resulted in increased recovery and decreased 
endothelial injury [51].  
  
The drug for this submission is Hope Biosciences’ allogeneic, adipose-derived culture-expanded 
mesenchymal stem cells (HB-adMSCs) to provide immune support and protection against 
developing COVID-19. We hypothesize that the immunomodulatory properties of MSCs will 
inhibit cell-mediated immune inflammatory responses and MSC endogenous regenerative 
properties will reduce pathological changes of lung associated with COVID-19. The population 
we are proposing to treat are at high-risk due to age, preexisting conditions, or high exposure to 
individuals infected with SARS-CoV-2 and/or diagnosed with COVID-19. We believe this 
patient population is high-risk and therefore, we must provide cells to give them the best chance 
against this virus. We have preclinical safety and efficacy data, as well as clinical evidence of the 
safety of HB-adMSCs in patients in ongoing phase I/IIa clinical trials for Rheumatoid Arthritis 
(NCT03691909), Traumatic Brain Injury and/or Hypoxic-Ischemic Encephalopathy 
(NCT04063215), and Alzheimer’s Disease (NCT04228666), as well as individual expanded 
access for Parkinson’s Disease (NCT04064983), Spinal Cord Injury (NCT04064957 and 
NCT03925649), and Cerebral Palsy (NCT04029896). We have experience with an individual 
expanded access for Pancreatic Cancer (NCT04087889) who received allogeneic HB-adMSCs, 
as well. All treatments have been well-tolerated, with no severe adverse events related to the 
study drug.   
  
 
Study Objectives and Endpoints   
  
Study Objectives  
  
Primary:  
- 
To investigate the efficacy of HB-adMSCs in providing immune support against 
development of Coronavirus Disease by incidence of hospitalization for COVID-19, 
incidence of symptoms associated with COVID-19 (ie., fever, shortness of 
breath/difficulty breathing, and/or cough), and severity of COVID-19 associated 
symptoms (fever 38C or higher, cough, shortness of breath/difficulty breathing).   
  
Secondary:   
- 
To investigate the efficacy of HB-adMSCs in the prevention of upper and lower 
respiratory infections in a high-risk population.  
  
   

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
7  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Study Endpoints   
  
Primary endpoints:   
- 
Incidence of hospitalization for COVID-19.   
- 
Incidence of symptoms associated with COVID-19.   
  
Secondary endpoints:   
- 
Absence of upper/lower respiratory infections (with hospitalization criteria) up to 3 
months post infusions.  
- 
Change from baseline in leukocyte differential  
- 
Change from baseline in C-Reactive Protein  
- 
Change from baseline in TNF-alpha  
- 
Change from baseline in IL-6  
- 
Change from baseline in IL-10  
- 
Clinically significant changes in laboratory values, vital signs, weight, X-rays, ECG, and 
physical examination results.   
- 
Incidence of AEs (AEs) and serious AEs (SAEs) related to the drug  
  
Investigational Plan  
  
This Phase 2, randomized, double-blind, single center, efficacy and safety study, is designed to 
evaluate allogeneic HB-adMSCs to provide immune support against COVID-19 in subjects 
classified as high risk. ‘High risk’, according to CDC at the time of protocol development, 
includes subjects age 65 or older, as well as subjects in high exposure environments such as 
healthcare professionals and law enforcement, or individuals with preexisting conditions, 
including but not limited to cardiopathies, diabetes mellitus, cancer, COPD, asthma or any other 
systemic autoimmune disease. The study will have 4 arms:   
Arm 1 (allogeneic HB-adMSCs 200MM)  
Subjects assigned to this arm will receive HB-adMSCs during the whole duration of the study.   
  
Arm 2 (allogeneic HB-adMSCs 100MM)  
Subjects assigned to this arm will receive HB-adMSCs during the whole duration of the study.   
  
Arm 3 (allogeneic HB-adMSCs 50MM)  
Subjects assigned to this arm will receive HB-adMSCs during the whole duration of the study.   
  
Arm 4 (Placebo)  
Subjects assigned to this arm will receive placebo injections throughout the entire duration of the 
study.  
  
The screening period, up to 45 days long for each patient, will be used to assess eligibility. At 
baseline (Week 0), approximately 53 patients who are eligible will be randomized in a 3:1 ratio 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
8  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
to the HB-adMSCs and Placebo groups, respectively. Safety assessments will be ongoing. 
Complete Blood Count, Comprehensive Metabolic Profile and Coagulation Panel will screen for 
hepatotoxicity, renal failure or alterations in the coagulation cascade that might entail a safety 
concern for the individual. Efficacy assessments will include PHQ-9, SF-36, TNF-a, IL-6, IL-10, 
and CRP.  
  
The trial is designed to be conducted over 3 periods or phases:  
  
● Phase 1 (screening): Our screening process starts with a telephone call to provide a 
general overview of the study and discuss eligibility requirements.  The study patient will 
receive the informed consent document by e-mail or in the pre-paid envelope provided. 
If, after reviewing this consent the study patient is still interested in participating in the 
study, he/she will need to sign and return the consent form to Hope Biosciences Stem 
Cell Research Foundation. This process can take up to 45 days.   
  
● Phase 2 (Treatments): Includes Infusion 1 (Week 0), Infusion 2 (Week 2), Infusion 3 
(Week 6), Infusion 4 (Week 10) and Infusion 5 (Week 14). Subjects will be monitored at 
the clinical site for 1 hours following HB-adMSCs administration.   
  
● Phase 3 (follow-up): Includes Follow Up Week 18, 22 and End of Study at Week 26.   
  
  
Selection and Withdrawal of Patients  
  
Inclusion Criteria   
  
Inclusion Criteria:  
  
1. Men, and women 18 years of age or older  
2. Participant works in a capacity that is characterized as high-risk or very high-risk  
a. High-Risk Exposure jobs are those with high potential for exposure to known or suspected 
sources of COVID-19.   
- 
First responders, health care delivery and support staff (e.g., law enforcement, fire 
fighters, paramedics, doctors, nurses, and other hospital staff who must enter patients' 
rooms) exposed to individuals potentially having COVID-19.  
- 
Mortuary workers involved in preparing (e.g., for burial or cremation) the bodies of 
people who are known to have, or suspected of having, COVID-19 at the time of their 
death  
b. Very High-Risk Exposure jobs are those with high potential for exposure to known or 
suspected sources of COVID-19 during specific medical, postmortem or laboratory 
procedures.  
- 
Health care workers (e.g., doctors, nurses, dentists, paramedics, emergency medical 
technicians) performing aerosol-generating procedures (e.g., intubation, cough induction 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
9  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
procedures, bronchoscopies, some dental procedures and exams or invasive specimen 
collection) on known or suspected COVID-19 patients  
- 
Health care or laboratory personnel collecting or handling specimens from known or 
suspected COVID-19 patients (e.g., manipulating cultures from known or suspected 
COVID-19 patients)  
- 
Morgue workers performing autopsies, which generally involve aerosol-generating 
procedures, on the bodies of people who are known to have, or suspected of having, 
COVID-19 at the time of their death  
3. No signs or symptoms of infection, including but not limited to, body temperature >100 F 
and pulse rate > 100 BPM.   
4. Subject provides written informed consent prior to initiation of any study procedures.  
5. Agrees to the collection of venous blood per protocol.  
6. Agrees to conformational testing for SARS-CoV-2 before end of study.  
  
Exclusion Criteria   
  
1. Women who are pregnant or lactating, or those who are not pregnant but do not take 
effective contraceptive measures  
2. Patients who are participating in other clinical trials or have intake of investigational drug 
within the previous 30 days;  
3. Inability to provide informed consent or to comply with test requirements;  
4. Any medical disease or condition that, in the opinion of the site PI or sub-investigator, 
precludes study participation. Including acute, subacute, intermittent or chronic medical 
disease or condition that would place the subject at an unacceptable risk of injury, render  
the subject unable to meet the requirements of the protocol, or may interfere with the 
evaluation of responses or the subject's successful completion of this trial.  
5. Patients who have received a stem cell treatment within one year.  
6. Receipt of any other SARS-CoV-2 or other experimental coronavirus vaccine at any time 
prior to or during the study.  
7. Patient currently or recently symptomatic for COVID-19 or anyone with COVID-19 
associated symptoms within the past 30-days  
  
Withdrawal, Removal, and Replacement of Patients  
  
Patients will be considered to have completed the study if they complete treatment and 
assessments through Week 26. A patient’s investigational treatment should be discontinued if 
any of the following situations occurs:  
  
● The Investigator believes that for safety reasons, it is in the best interest of the patient to 
stop treatment.  
● The patient is non-compliant with the study visit schedule or other protocol requirements.  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
10  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
● The patient develops a severe allergic reaction that occurs following investigational 
product administration.  
  
A patient may voluntarily withdraw or be withdrawn from the study at any time for reasons 
including, but not limited to, the following:  
  
● Patient withdrawal of consent: At any time, a patient's participation in the study may 
terminate at his/her request. The specific reason for patient withdrawal will be noted on 
the case report form (CRF).  
● Lost to follow-up: The patient stops coming for visits, and study personnel is unable to 
contact the patient after repeated attempts (e.g., mail, or email).  
● This study may be terminated at the discretion of the Sponsor or any regulatory agency.   
  
If a patient’s infusions are discontinued at any point during the trial and the patient maintains 
consent to contribute additional outcome information, the patient should continue to be followed 
through Week 26 for all safety and efficacy assessments. Investigators will be trained about the 
importance of retention and steps to prevent missing data.   
  
The date and reason for withdrawal are to be documented in the CRF. The study site must 
immediately notify the medical monitor. The patients who withdraw prematurely must attend an 
early discontinuation visit if possible, at which time they will complete all assessments described 
in Table 2 under the Week 24 visit.   
  
In the event that a patient discontinues prematurely from the study due to an Adverse Event (AE) 
or serious AE, the event will be followed until it resolves (returns to normal or baseline values) 
or stabilizes, or until it is judged by the Investigator to be no longer clinically significant.   
Once a patient is withdrawn from the study, the patient may not re-enter the study.   
If the subject develops symptoms associated with COVID-19 during the conduct of this study, 
they will be asked to consult their personal physician and be tested for COVID-19, and to 
selfquarantine for at least 14 days. Quarantine must occur while waiting for COVID-19 test 
results. Once asymptomatic, subject may resume site visits. If the test results are positive, the 
subject will be asked to quarantine and may continue to receive infusions at the quarantine site. If 
the subject develops severe symptoms (i.e., shortness of breath/difficulty breathing) they should 
go to the ER instead of personal physician.  
  
 
 
 
 
Treatments  
  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
11  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Details of the investigational product  
  
Allogeneic HB-adMSCs is to be administered as an IV infusion with a syringe containing 5 x 107 
cells. Each syringe will be provided by Hope Biosciences on the day of the infusion after all 
quality control assays have been performed and the results are within normal range.  
   
Instructions for Administration   
  
The designated study staff will administer the investigational product in the following manner:   
● Prior to administration, visually inspect the infusion solution for particulates. If foreign 
particles are present, do not use the solution.  
● Emergency equipment, such as epinephrine, antihistamines, and corticosteroids must be 
available in the event of infusion-related reactions.  
● Start IV administration after dilution.   
● Administer the infusion solution over a period of 1h. Observe the patient for at least 2 
hours post-infusion for acute infusion-related reactions, including anaphylaxis. See 
Appendix 1 for guidelines on diagnosing anaphylaxis.  
● Do not store or reuse any unused portion of the infusion solution. Any unused product or 
waste material should be disposed.   
● Volume of study drug infused, start times, and stop times will be recorded. If any portion 
of the infusion (cell solution) is discarded, the reason will be recorded in the CRF.  
● The patient will be monitored for a total of 3 hours from drug exposure to discharge.  
a. During the Investigational product administration (1 hour) vital signs will be measured 
at minute 0, 15, 30 and 45.  
b. Post infusion, vital signs will be measured at minute 0, 30 and 60.   
  
Investigational Product Assignment and Infusion Schedule (Randomization and 
Staggering)  
  
Randomization  
A total of 53 eligible subjects will be randomized to either placebo or treatment group within the 
associated study arm at baseline. Randomization will determine whether the subject receives 
placebo or HB-adMSCs.   
A neutral, third-party personnel will be responsible for assigning the participants’ treatment 
group. This role will be referred to as ‘randomizer’. The designated personnel from the drug 
manufacturer will be responsible in labeling and packaging the investigational product for each 
participant. This role will be referred to as ‘mixer’. Participants’ names are not disclosed to the 
mixer and the unblinded information will only be known to the randomizer.   
       
Staggering  
  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
12  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Each patient will be allocated a unique subject number at screening and will retain this number 
throughout the study. The first 4 patients (1 for each group) will receive their first infusions on 
weeks 0 and 2. Upon successful completion of infusion 2 for the first 4 patients, the DSMB will 
meet at least 48hrs after the last second infusion, to review safety. If permitted by DSMB, the 
rest of the patients can receive their infusions as long as all inclusion criteria have been met and 
none exclusion criteria is.   
  
The Investigational Product is to be administered to eligible, enrolled patients by intravenous 
infusion at a dose that will depend on the group they have been randomized to:  
  
● Group 1→2 x108 cells at weeks 0, 2, 6, 10 and 14.   
● Group 2→1 x108 cells at weeks 0, 2, 6, 10 and 14.  
● Group 3→5 x107 cells at weeks 0, 2, 6, 10 and 14.  
● Group 4→Placebo infusions at weeks 0, 2, 6, 10 and 14.  
  
  
Every effort should be made to adhere to the dosing schedule. However, a scheduled infusion 
should not be administered if a patient has an ongoing AE that, in the Investigator’s opinion, 
warrants holding the infusion.  
  
Blinding  
  
Blinding for Dose Administration  
  
All patients, investigators, mixer, and site staff will be blinded to treatment assigned.  
  
Amber bags covering the saline will be used for product infusion. Only subject ID, DOB and 
expiration date will be on the bag label, to ensure proper distribution. Mixer will inject product 
into the bag before handing off to the clinical team.   
  
Blinding for Clinical Evaluators  
  
To minimize assessment bias, clinical evaluators (data analysts and physicians) will be trained on 
how to maintain blinding to treatment as best as possible. “Best as possible” means that blinding 
will be maintained unless an adverse event occurs that requires unblinding the physician, which 
is determined by the medical monitor or DSMB. Training includes review of the process of 
blinding, describing who will be responsible for assigning product for the appropriate group, 
labels that will be used to identify subjects but not treatment group, and the process that should 
be followed if an adverse event occurs, triggering review by medical monitor and/or DSMB.   
  
Planned Unblinding  
  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
13  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Unblinding of patient and researcher will occur in the case of adverse event suspected to be 
related to the investigational product, per the medical monitor and DSMB.   
  
Regulatory authorities and/or the IRB may request the unblinding of data from one or more 
patients at any time.   
  
Prior and concomitant conditions  
  
The investigators should document all prior significant medical history. Additional conditions 
present at the time when informed consent is given and up to the time of first infusion (Week 0) 
are to be regarded as concomitant conditions. Illnesses first occurring or detected during the 
study and/or worsening of a concomitant condition during the study should be documented as 
AEs in the CRF.   
  
 
Prior and concomitant medications   
  
All medications, including over-the-counter treatments and preventative vaccines taken by the 
patient during the study, including those treatments initiated prior to the start of the study, must 
be recorded in the CRF. The entry must include the dose, regimen, route, indication, and dates of 
use.   
Study Procedures  
  
Table 2 outlines the timing of procedures, and assessments to be performed throughout the study.  
 
      Table 2. Schedule of Assessments  
  
Visit Number   
1  
2  
3  
4  
5  
6  
7  
8  
9  
Weeks   
N/A  
Week 0  
Week 2  
Week 6  
Week 10  
Week 14  
Week 
18  
Week 
22  
Week 
26  
Visit Name   
Screening  
(Phone 
call)  
Infusion- 
1  
/Baseline  
Infusion 
2  
Infusion 
3  
Infusion 
4  
Infusion 
5  
Follow 
Up  
Follow 
Up  
EOS  
Window Period  
Up to 45 
days  
+4 days  
+4 days  
+4 days  
+4 days  
+4 days  
+4 
days  
+3 
days  
+3 days  
STUDY PROCEDURES  
 
 
 
 
 
 
 
 
Informed Consent   
X  
X  
  
  
  
  
  
  
  
Inclusion and Exclusion  
Criteria   
X  
X  
  
  
  
  
  
  
  
Pre-infusion assessment  
  
X  
X  
X  
X  
X  
  
  
  
Review of Medical History   
X  
X  
X  
X  
X  
X  
X  
X  
X  
Concomitant Medication 
Review  
X  
X  
X  
X  
X  
X  
X  
X  
X  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
14  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Vital Signs  
  
X  
X  
X  
X  
X  
X  
X  
X  
Weight and Height1   
  
X  
X  
X  
X  
X  
X  
X  
X  
Physical Examination   
  
X  
X  
X  
X  
X  
X  
X  
X  
SF-36 Questionnaire   
  
X  
X  
X  
X  
X  
X  
X  
X  
PHQ-9   
  
X  
X  
X  
X  
X  
X  
X  
X  
Rapid antibody COVID-19  
  
X  
  
  
  
  
  
  
X  
CBC with differential  
  
X  
  
X  
  
X  
  
  
X  
Chemistry  
  
X  
  
X  
  
X  
  
  
X  
Coagulation Panel  
  
X  
  
X  
  
X  
  
  
X  
CRP  
  
X  
  
X  
  
X  
  
  
X  
IL-6  
  
X  
  
X  
  
X  
  
  
X  
IL-10  
  
X  
  
X  
  
X  
  
  
X  
TNF alpha  
  
X  
  
X  
  
X  
  
  
X  
HB-adMSCs Administration  
  
X  
X  
X  
X  
X  
  
  
  
24-hour telephone encounter  
  
X  
X  
X  
X  
X  
  
  
  
Adverse Event Monitoring   
  
X  
X  
X  
X  
X  
X  
X  
X  
1. Height will only be measured at baseline  
 
 
 
 
 
 
 
 
  
Informed Consent (ICF)  
  
Prior to commencement of any trial related activity, the investigator or designated staff will 
obtain written informed consent from the patient.   
  
Patient Re-Screening  
  
If a patient is screened and fails to meet any study entry criteria may be re-screened only once. 
Such patient must be fully consented a second time before the second set of screening 
assessments take place and shall be assigned a new subject number. Investigator discretion 
should be exercised in determining who may be re-screened.  
  
In case of doubt about the accuracy of screening laboratory value(s), the laboratory test(s) may 
be repeated provided that this can be done within the 45-day screening period without the need to 
repeat all other screening procedures (i.e., no re-screening).   
  
If a patient is enrolled after they have been re-screened, such subject shall be assigned a new 
subject ID number, different from the previous attempt to enroll.  
  
Assessments by Week  
  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
15  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Assessments will occur as outlined in the following subsections. For visits at Weeks 0 through 
26, there will be a window of ±4 days.   
  
Screening  
  
The Screening visit will last up to 45 days. These are the procedures to be performed during this 
visit:  
  
● Demographic Information will be obtained.  
● Medical History and Current conditions will be obtained,   
● Concomitant Medications will be obtained. Every medication listed should match a 
condition in the medical history.   
● Ascertain patient eligibility by evaluating patient results against the inclusion/exclusion 
criteria.  
  
Upon completion of all Screening procedures, the Principal Investigator must confirm and 
document the patient eligibility in the “Screening Result” CRF and notify the Sponsor via Fax or 
e-mail.   
  
Infusion Visits (Baseline/Week 0, Week 2, Week 6, Week 10, and Week 14)   
  
Generally, these are the procedures to be performed at every infusion visit. For details, please 
refer to the schedule of assessments.   
Baseline assessments will be taken before the administration of the first infusion.  A second 
assessment of informed consent shall be obtained prior to the first infusion.  
  
● Pre-infusion assessment will be made by telephone call in the morning prior to all 
infusion visits to assess any occurrence of symptoms.  In the event a subject is exhibiting 
symptoms, the subject will be asked to remain home.  ● Weight will be measured  
● Vital Signs will be measured.   
● Concomitant medications will be reviewed and updated if necessary.   
● Medical History will be reviewed and updated if necessary. If the patient reported a 
medication which does not match the current medical history, further investigation will 
be required to determine whether it was an Adverse Event, or the patient just forgot to 
mention it before. If it is found to be an AE, it should be recorded in the appropriate CRF. 
If the patient forgot to mention it before, a note to file (NTF) should be made to clarify 
the case.  
● Blood samples will be collected for laboratory assessments at weeks 0, 2, 6, 10, 14, and  
26.   

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
16  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
● Pre-infusion medications: Prior to IP administration the subject will be administered: 
Aspirin 81 mg per mouth, and Loratadine 10 mg per mouth  
● Physical examination performed by principal investigator or sub-investigator.   
● Patient will complete SF-36 and PHQ-9 assessments.  
● Administer investigational product.  
● Monitor for AEs. Observe the patient for at least 1 hour after infusion for symptoms of 
infusion-related reactions and allergic reactions, including anaphylaxis (See Appendix 1).   
● Instruct the patient on recognition of delayed serious allergic reactions, including 
anaphylaxis and seeking for medical assistance.   
● Telephone encounter 24 hours after the infusion will be performed to assess the 
occurrence of AEs.   
 
 
Follow Up Weeks 18, and 22.   
  
●  Weight will be measured  
●  Vital Signs will be measured.   
●  Concomitant medications will be reviewed and updated if necessary.   
●  Medical History will be reviewed and updated if necessary. If the patient reported a 
medication which does not match the current medical history, further investigation will be 
required to determine whether it was an Adverse Event, or the patient just forgot to 
mention it before. If it is found to be an AE, it should be recorded in the appropriate CRF. 
If the patient forgot to mention it before, a note to file (NTF) should be made to clarify 
the case.  
●  Physical examination performed by principal investigator or sub-investigator.   
●  Patient will complete SF-36 and PHQ-9 assessments.  
●  Instruct the patient on recognition of delayed serious allergic reactions, including 
anaphylaxis and seeking for medical assistance.   
● Telephone encounter 24 hours after the infusion will be performed to assess the 
occurrence of AEs.   
  
Weeks 26 (End of the Study or Early Discontinuation Visit)  
 
●  Weight will be measured  
●  Vital Signs will be measured.   
●  Concomitant medications will be reviewed and updated if necessary.   
●  Medical History will be reviewed and updated if necessary. If the patient reported a 
medication which does not match the current medical history, further investigation will 
be required to determine whether it was an Adverse Event, or the patient just forgot to 
mention it before. If it is found to be an AE, it should be recorded in the appropriate CRF. 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
17  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
If the patient forgot to mention it before, a note to file (NTF) should be made to clarify 
the case.  
●  Blood samples will be collected.  
●  Physical examination performed by principal investigator or sub-investigator  
●  Patient will complete SF-36 and PHQ-9 assessments.  
  
If a patient prematurely withdraws from the study for any reason, the early discontinuation visit 
requirements should be completed. If the early discontinuation visit is not done, the reason(s) 
will be recorded in the CRF.   
  
Unscheduled Visits  
  
The Investigator may at his/her discretion arrange for a patient to have an unscheduled 
assessment, especially in the case of adverse events (AEs) that require follow-up, or an AE 
considered by the Investigator to be possibly related to the use of the investigational product. The 
unscheduled visit page in the CRF must be completed.   
Efficacy Assessments  
  
Complete Blood Count with Differential  
The evaluation of the Complete Blood count with differential will help suspect the presence of a 
bacterial or viral infection with the predominance of either the neutrophils or lymphocytes. 
Generally, a healthy person’s blood count would not show out of range values in the differential 
in the absence of a pathological condition.  
  
CRP  
C-reactive protein is considered to be an "acute phase protein," an early indicator of infectious or 
inflammatory conditions. CRP must be interpreted in the clinical context; no single value will be 
used to rule in or rule out a specific diagnosis.  
  
SF-36  
The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health. The  
SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their 
section. Each scale is directly transformed into a 0-100 scale on the assumption that each 
question carries equal weight. The lower the score the more disability.   
  
PHQ-9  
The PHQ-9 is the depression module, which scores each of the nine DSM-IV criteria as "0" (not 
at all) to "3" (nearly every day). It is not a screening tool for depression, but it is used to monitor 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
18  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
the severity of depression. In addition to making criteria-based diagnoses of depressive disorders, 
the PHQ-9 is also a reliable and valid measure of depression severity.   
  
TNF-a  
The primary role of TNF is in the regulation of immune cells. TNF, being an endogenous 
pyrogen, is able to induce fever, apoptotic cell death, cachexia, inflammation and to inhibit 
tumorigenesis and viral replication and respond to sepsis via IL1- & IL6-producing cells.  
  
IL-10  
IL-10 is a cytokine with multiple effects in immunoregulation and inflammation. It 
downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory 
molecules on macrophages. It also enhances B cell survival, proliferation, and antibody 
production.  
  
IL-6   
Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an 
antiinflammatory myokine. In humans, it is encoded by the IL6 gene.   
  
Safety Assessments  
  
Safety assessments (vital signs, weight, physical examinations, AEs, routine clinical laboratory 
tests (CBC, CMP, PT and PTT/INR) will be performed at the visits specified in the schedule of 
assessments in Table 2.  
  
Vital Signs, Height, and Weight   
  
Vital signs (body temperature, pulse, oxygen saturation, systolic and diastolic blood pressure 
measurements) will be evaluated at the visits indicated in the schedule of assessments. It is 
important that all vital signs be measured after the patient has been resting in a sitting position 
for at least 5 minutes. Blood pressure measurements are to be taken in the same arm for the 
duration of the study. Body weight (without coats and shoes) will be recorded whenever vital 
signs are recorded, and height (without shoes) will be recorded at Infusion 1 (baseline) only.   
  
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range blood pressure and pulse measurements will be repeated at the Investigator’s 
discretion. Any confirmed, clinically significant vital sign measurements will be recorded as AEs 
and followed up as such.   
  
Physical Examination   
  
A complete physical examination (head, eyes, ears, nose, throat, heart, lungs, abdomen, skin, 
cervical and axillary lymph nodes, neurological, and musculoskeletal systems) will be performed 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
19  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
at baseline visit. In addition, medical history (including smoking history) will be recorded at 
baseline.   
  
A limited physical examination to verify continued patient eligibility and to follow up any 
change in medical history will be performed at the visits indicated in the schedule of 
assessments. Symptom-driven physical examinations will be performed as clinically indicated at 
any study visit. All changes not present at baseline or described in the past medical history and 
identified as clinically noteworthy will be recorded as AEs.   
  
Clinical Laboratory Parameters   
  
The Investigator must review all laboratory reports and document the review. Any laboratory test 
result or change considered by the Investigator to be clinically significant should be considered 
an AE and recorded in the AE CRF. Clinically significant abnormal values occurring during the 
study will be followed until repeat test results return to normal, stabilize, or are no longer 
clinically significant.   
  
Laboratory tests to be performed during the study:  
  
Complete Blood Count with Differential  
IL-6  
Chemistry  
Il-10  
Coagulation study (PTT/PT/INR)     
Tumor Necrosis Factor alpha   
C Reactive Protein   
Rapid Antibody Test for COVID-19  
  
Adverse Events  
  
An AE is any symptom, physical sign or disease that either emerges during the study or, if 
present at screening, worsens during the study, regardless of the suspected cause of the event. All 
medical and psychiatric conditions (except those related to the indication under study) present at 
screening will be documented in the medical history CRF. Changes in these conditions and new 
symptoms, physical signs, or diseases should be noted on the AE CRF during the rest of the 
study.   
  
Clinically significant laboratory abnormalities should also be recorded as AEs. Surgical 
procedures that were planned before the patient enrolled in the study are not considered AEs if 
the conditions were known before study inclusion; the medical condition should be reported in 
the patient’s medical history.   
  
Serious Adverse Events (SAE)  
  
A serious adverse event (SAE) is any AE that is:   

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
20  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
- 
fatal  
- 
life-threatening  
- 
requires or prolongs hospital stay  
- 
results in persistent or significant disability or incapacity  
- 
Important Medical Events (IME): those events that may not result in death, be 
immediately life threatening, or require hospitalization. They may be considered a SAE 
when, based upon medical judgement, they may jeopardize the subject and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, 
drug overdose or abuse, a seizure that did not result in in-patient hospitalization, or 
intensive treatment of bronchospasm in an emergency department would typically be 
considered serious. (FDA, 21CFR312.32; ICH E2A and ICH E6)  
  
All SAEs must be reported to Hope Biosciences immediately after the Investigator becomes 
aware of the event, along with a determination as to whether it is associated with the study drug.  
Patients will be instructed to report AEs at each study visit. All AEs are to be followed until 
resolution or until a stable clinical endpoint is reached.   
  
Each AE is to be documented in the CRF with reference to onset date, duration, frequency, 
severity, relationship to study drug, treatment of event, and outcome. Furthermore, each AE is to 
be classified as being serious or non-serious. Changes in AEs and resolution dates are to be 
documented in the CRF.   
  
For the purposes of this study, the period of observation for collection of AEs extends from the 
time the patient gives informed consent through Week 26 (or early discontinuation visit). 
Follow-up of the AE is required until the event resolves or stabilizes at a level acceptable to the 
Investigator.  
  
Intensity of Adverse Event  
  
The intensity of the AE will be judged based on the following:  
• Mild:          Awareness of sign(s) or symptom(s) which is/are easily tolerated  
• Moderate:  Enough discomfort to cause interference with usual activity  
• Severe:       Incapacitating or causing inability to work or to perform usual activities  
  
Causal Relationship of Adverse Events  
  
Medical judgement will be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge and confounding factors such 
as concomitant medication, concomitant disease and relevant history. Assessment of causal 
relationship will be recorded in the CRF.  
  
● Definitely Related:  The adverse event is clearly related to the investigational product –  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
21  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
i.e. an event that follows a reasonable temporal sequence from administration of the study 
intervention, follows a known or expected response pattern to the suspected intervention, 
that is confirmed by improvement on stopping and reappearance of the event on repeated 
exposure and that could not be reasonably explained by the known characteristics of the 
subject’s clinical state.  
  
● Possibly Related:  An adverse event that follows a reasonable temporal sequence from 
administration of the study intervention follows a known or expected response pattern to 
the suspected intervention, but that could readily have been produced by a number of 
other factors.  
  
● Not Related:  The adverse event is clearly not related to the investigational product. -   
i.e. another cause of the event is most plausible; and/or a clinically plausible temporal 
sequence is inconsistent with the onset of the event and the study intervention and/or a 
causal relationship is considered biologically implausible.   
  
Investigator Reporting: Notifying the Study Sponsor  
  
Any study-related unanticipated problem posing risk to subjects or others, and any type of 
serious adverse event, will be reported to Hope Biosciences (Sponsor) by telephone within 24 
hours of the event.  To report such events, a Serious Adverse Event (SAE) form will be 
completed by the investigator and electronically faxed to the sponsor within 24 hours to fax 
number: (855) 700-6838.  The investigator will keep a copy of this SAE form on file at the study 
site.    
  
Within the following 48 hours, the investigator will provide further information on the Serious 
Adverse Event or unanticipated problem in the form of a written narrative.  This should include a 
copy of the completed Serious Adverse Event form, and any other diagnostic information that 
will assist the understanding of the event.  Significant new information on ongoing Serious 
Adverse Events should be provided promptly to Hope Biosciences.  
  
Routine Study Close-out   
  
The study will end when Hope Biosciences has obtained all data necessary to complete its studies 
of the investigational product. Standard procedures may include, but is not limited to, review of 
regulatory documents, collection of completed case report forms, reconciliation of study records, 
removal or destruction of ancillary study supplies, and informing the Investigator of remaining 
obligations (e.g., record retention, final report submission to the IRB, financial disclosure 
updates, etc.).  
  
Infusion Stopping Rules  
  
Infusion will be stopped when:  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
22  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
  
• 
Allergic reaction is aroused after the product has been administered intravenously.  
• 
Patient verbally decline the treatment at any moment prior, or during the infusion.   
• 
Hyperpyrexia develops after infusion administration begins (core body temperature 
greater than or equal to 40°C) [57].  
• 
PI may stop the study at any time, based upon PI’s discretion  
• 
Malignant Hypertension (180/120 mm/Hg)  
• 
Sudden Severe Hypotension (30-40 mm/Hg drop from pre-infusion level)  
  
Study Alteration Rules  
  
If any of the following events listed below occur, administration of the study drug will be 
immediately suspended. The Internal Monitoring Committee (IMC), presided by the Medical 
Monitor will meet to review the incident and its etiology. The committee determine if it is likely 
related to the drug, the infusion or unrelated. If the IMC along with the Medical Monitor agree 
that the SAE is unlikely or unrelated to the drug, the study will be continued. If the SAE appears 
to be definitely drug-related, the study will be stopped. If the SAE is probably or possibly linked 
to the drug, the IMC will determine the risk to future patients and decide if the study should 
proceed or be stopped.   
  
Study Stopping Rules  
  
The stopping rules listed below will trigger cessation of enrollment and potential study closure 
pending a comprehensive DSMB safety review.   
  
1. Any infusion related death deemed by PI to be associated or possibly associated with 
study drug.   
2. Three or more of the same Grade 3 or higher AEs (judged by the investigator, medical 
monitor or sponsor), including infusion site reactions.  
3. Any event which, in the opinion of the investigator, medical monitor or sponsor, 
contraindicates further dosing of additional subjects.  
4. An infusion related, sustained (over 1 minute) episode of hypoxia (SaO2 of less than 
80%).  
5. Any Grade 4-5 Adverse Event as defined in the NCI CTCAE v4.0 and determined to be  
temporally related to the HB-adMSCs infusion by the Medical Safety Monitor and/or 
DSMB.   
  
After such review, resumption of dosing may be considered, including consideration for any 
prophylactic interventions (e.g. antihistamines or corticosteroids for injection site reactions).   
  
Medical Monitoring  
  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
23  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site. This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above. At Hope Biosciences, Dr. Rajiv Thakur, MD (832) 435-2906 will be 
responsible for reviewing any reported AEs and SAEs to determine if changes to the study need 
to be made or if the study should be stopped for the protection of patients. DSMB will review all 
deaths (to assure non-attribution), cases of anaphylaxis or suspected anaphylaxis,  
thromboembolic events, new malignancy/tumor, infections/hospitalizations (including unrelated 
to COVID-19 but due to underlying condition). After 15 subjects diagnosed with COVID-19, 5 
subjects are hospitalized, or 3 subjects in the ICU, DSMB will review. DSMB will also review 
safety data at mid-point of the study.  
  
Risks    
  
Potential Risks of the Investigational Product and Clinical Investigation   
  
Risks Associated with HB-adMSCs   
  
Respiratory Risks:  
A potential risk is that the infusion could initiate a VTE event with subsequent cardiopulmonary 
sequelae of respiratory failure and/or right heart strain/failure. We plan to monitor oxygen 
saturation, and respiratory rate/work of breathing for the first 2 hours post- infusion. The patient 
will be examined for VTE events (clinical exam, oxygen saturation) during each infusion visit 
and at each follow-up visit.  
Hepatic Risks:  
The reticuloendothelial system can sequester immature blood elements, theoretically resulting in 
hepatic injury. An acute elevation of the AST/ALT hepatic enzymes > 900 U/dl post-infusions 
will be considered an infusion related adverse event. This level is based upon the organ system 
scoring definitions for moderate hepatic failure and corresponds to the CTCAE v4.03 Grade 4 
adverse event. It is unlikely that "end vessel" micro-thrombosis would occur in the liver due to 
the dual blood supply of the liver and the lung is the first pass organ. A CMP will be obtained at 
follow-up visits.   
Coagulation Cascade:  
A coagulation panel will be obtained at screening, baseline, infusion and the follow-up 
visits. The patient will be monitored for the development of venous thromboembolic events 
(see pulmonary monitoring above) as well as for the development of clinical deep vein 
thrombosis (limb swelling, tenderness, discoloration).  
  
The risks associated with this cellular product are currently unknown and have not been studied 
in this population, to date. There is a potential risk of increased vulnerability to COVID-19, 
worsening of the disease, and/or complications from the disease. Although currently not 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
24  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
observed in HB-adMSCs, risks of infusion with MSCs include infusionrelated reactions, 
thrombogenesis or malignancy.  
  
The types of risk associated with HB-adMSCs are also stated in the Informed Consent Form (See 
ICF)   
  
Minimization of Risks   
  
Although the risk to subjects participating in the study is anticipated to be minimal, the clinician, 
at his/her discretion, will not collect data from those individuals for whom collection is judged to 
pose an unusually high risk of physical or mental harm or discomfort.   
  
Participation in this study poses moderate risk to study personnel related to potential pathogens 
that may be present in the subject’s specimens which are then expanded during the culture 
process. These risks will be minimized by adherence to the principles of universal precautions 
and by conducting the planned testing on blood from the subject at screening for particular 
pathogens of concern.   
  
Personnel should wear appropriate personal protective equipment to avoid contact of the eyes or 
skin with hazardous materials or products derived from biological sources.   
  
Subjects will be advised to follow current federal guidelines regarding COVID-19 such as the 
following:  
  
- 
Use hand sanitizer that contains at least 60% alcohol  
- 
Avoid touching your eyes, nose, and mouth with unwashed hands  
- 
Avoid close contact  
- 
Adhere to social distancing guidelines and maintain at least 6’ of distance with others  
  
  
General procedures for personnel include:  
  
- 
Hands must be washed with soap and water for at least 20 seconds, if soap and running 
water are unavailable, an alcohol-based hand rub with at least 60% alcohol will suffice 
this action. Always wash hands that are visibly soiled.  
- 
Avoid touching their eyes, nose or mouth.  
- 
Healthcare workers will wear:  
o 
Gowns o Gloves o Disposable surgical masks.   
o 
Eye/face protection (e.g., goggles, face shield)  
- 
Surfaces where subjects have been in contact will be disinfected 70% Isopropyl Alcohol, 
hydrogen peroxide, or Clorox disinfectant.  
  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
25  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Potential Benefits   
  
Subjects may benefit from their participation in the study by experiencing an overall feeling of 
well-being.  Subjects enrolled in the study will be contributing to the advancement of science and 
to future investigations regarding stem cells and possible therapeutic applications, including 
treatment and prevention of respiratory diseases, specifically COVID-19.   
  
Statistical Analysis  
  
Determination of Sample Size  
  
Sample size calculation was determined based upon the number of patients currently banked at 
our facility and those who are already registered to bank. Sample size for this study is not to 
exceed 53 patients.   
  
Null hypothesis- Efficacy  
Treatment with HB-adMSCs does not cause changes in primary and secondary endpoints (listed 
below) for providing immune support against Coronavirus Disease.  
   
Alternative hypothesis-Efficacy  
The alternative hypothesis for this study is that HB-adMSCs treatment does result in changes 
from baseline values of primary and secondary endpoints in patients.  
  
Null hypothesis-Safety  
Treatment with HB-adMSCs results in adverse or serious adverse events and/or detrimental 
changes in laboratory values, vital signs, weight, X-rays, ECG, or physical examination 
determined to be related to the study drug.  
   
Alternative hypothesis-Safety  
HB-adMSCs treatment for COVID-19 does not result in adverse or serious adverse events and/or 
detrimental changes in laboratory values, vital signs, weight, X-rays, ECG, or physical 
examination determined to be related to the study drug.  
  
Endpoints  
The endpoints measured in this study are safety and clinical efficacy.  
   
Safety is assessed by incidence of adverse and serious adverse events, incidence of specific 
adverse events including serious infections, infusion-related reactions, hepatotoxicity, heart 
failure, and cytopenia. Clinically significant changes in laboratory values, vital signs, weight, and 
physical examination results will also be measured.  
   

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
26  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Clinical efficacy is assessed by primary and secondary endpoints. Primary endpoints include 
incidence of hospitalization for COVID-19, incidence of symptoms associated with COVID-19, 
and severity of symptoms associated with COVID-19. Secondary endpoints include absence of 
upper/lower respiratory tract infections, change from baseline in inflammation, SF-36 and PHQ9 
questionnaires.  
  
Analysis Population  
  
Men, and women, age 65 or older OR high exposure risk individuals (healthcare professionals 
and law enforcement), OR individuals considered to be high risk due to preexisting conditions.   
  
Safety: all subjects that receive at least one HB-adMSCs infusion will be included in safety 
analysis  
  
Efficacy: all subjects that receive all 5 infusions of HB-adMSCs will be included in efficacy 
analysis  
  
Demographic and Baseline Characteristics  
  
Information describing subjects’ gender, race/ethnicity, and age will be displayed in tables 
similar to the ones included below. The number and percent of the total sample population will 
be calculated for each demographic category.   
  
Demographics  
Female  
Male  
Both 
Genders  
Race/Ethnicity   
N  
%  
N  
%  
Total  
%  
White   
  
  
  
  
  
  
Black or African American   
  
  
  
  
  
  
Hispanic or Latino  
  
  
  
  
  
  
Other (Specify)  
  
  
  
  
  
  
Total   
  
  
  
  
  
  
  
  
The mean, minimum, and maximum age at enrollment will be determined using standard 
calculations. The number and percent of total subjects in each age group will be calculated and 
reported.   
  
Age at Enrollment  
  
 
Mean  
  
Minimum  
  
Maximum  
  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
27  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
  
N  
%  
18-21 years  
  
  
22 – 29 years   
  
  
30 - 39 years  
  
  
40 - 49 years  
  
  
50 - 59 years  
  
  
60 – 69 years  
  
  
70 – 79 years  
  
  
80 – 89 years  
  
  
90 – 99 years  
  
  
100 – 109 years  
  
  
Total   
100  
100%  
  
Safety Analysis  
  
The number, type, and description of all AEs and SAEs will be recorded and reported. Clinical 
laboratory values will also be recorded and reported.  
  
Efficacy Analysis  
  
Efficacy will be measured by incidence of hospitalization for COVID-19, incidence of symptoms 
associated with COVID-19, and severity of symptoms associated with COVID-19. We will also 
record and reported inflammatory markers and SF-36, PHQ-9 questionnaires.  
  
Interim Analysis  
  
Interim analysis of all safety and efficacy data may be performed at any time deemed appropriate 
by the Sponsor. Data will be analyzed for internal informational purposes, reports, presentations, 
and manuscripts.   
  
  
 
Study Management  
  
Institutional Review Board and Informed Consent  
  
Hope Biosciences is required to obtain IRB oversight of the research study. The IRB must be 
provided with Hope Biosciences-approved study protocol. Performance of the study may not 
begin until written evidence of IRB approval has been provided to Hope Biosciences. The 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
28  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
conduct and performance of this study will be in accordance with applicable Hope Biosciences 
and Investigator responsibilities as described in Title 21 CFR 312, subpart D and other Good 
Clinical Practice guidance.   
  
For each study patient, written informed consent will be obtained prior to any protocol-related 
activities. As part of this procedure, the Investigator or designated study staff must explain orally 
and in writing the nature, duration, and purpose of the study, and the action of the drug in such a 
manner that the patient is aware of the potential risks, inconveniences, or adverse effects that 
may occur. The patient should be informed that he/she may withdraw from the study at any time, 
and the patient will receive all information that is required by local regulations and ICH 
guidelines. The Investigator will provide the Sponsor or its representative with a copy of the 
IRB-approved ICF prior to the start of the study.  
  
Investigator Responsibility  
  
The PI is responsible for general administration of the study.   
  
Before the study, the PI must:  
  
● Sign the Protocol Signature Page him/herself and have all sub-investigators sign the 
Protocol Signature Page and return it to Hope Biosciences.  
● Provide financial disclosures to Hope Biosciences for themselves and all subinvestigators 
participating in study conduct, per Title 21CFR 54   
  
During the study, the PI must ensure that:  
  
● The study is conducted ethically   
● Case report forms (CRFs), including Subject ICFs, are provided with each transfer of 
data requiring informed consent.  
● All other study forms are completed as instructed by Hope Biosciences.  
  
In the case of completion or termination of the study or an Investigator's role in the study, or at 
Hope Biosciences request, all study materials must be returned to Hope Biosciences.  
  
  
  
Case Report Forms/Electronic Data Records  
  
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method(s) used.  
  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
29  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Reports received by the site, or from the central laboratory should be printed, retained as source 
documentation and signed by the principal investigator, indicating which values are considered 
clinically significant and to be reported as AEs.  
  
At all times, is it the PI’s personal responsibility the completion, review, and approval of all  
CRFs, so as the accuracy and authenticity of all clinical and laboratory data entered on these 
CRFs. His/her signature will be required to attest that the information contained on the CRFs is 
true. Original CRFs should not be made available in any form to third parties, except for 
authorized representatives of Hope Biosciences or appropriate regulatory authorities, without 
written permission from Hope Biosciences.   
  
Source Documents   
  
Source documents are considered to be all information in the original records and certified copies 
of original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study.  
  
Record retention   
  
To maintain confidentiality, all laboratory specimens, evaluation forms, reports, and other 
records transmitted outside the clinical site will be identified by a patient’s identification number. 
All study records, source medical records, and logs linking a patient’s name to an identification 
number will be kept in a secure location. Clinical information will not be released without 
written permission of the patient/legal representative, except as specified in the ICF (e.g., 
necessary for monitoring by regulatory authorities or the Sponsor of the clinical study). The 
Investigator must also comply with all applicable privacy regulations (e.g., US Health Insurance 
Portability Accountability Act of 1996). The investigator and the study site will retain the 
essential documents (e.g., source documents such as medical records, signed ICF).  Essential 
documents should be retained at the study site for at least 15 years following completion of the 
study, or per regulatory obligations if longer, and thereafter destroyed only after agreement with 
the Sponsor. The Sponsor should notify the head of the study site in writing when the study-
related records are no longer needed. The records should be managed by a responsible person 
appointed by the head of the study site.  
  
 
Monitoring   
  
The study will be monitored according to a Study Monitoring Plan (to be developed by Hope 
Biosciences Stem Cell Research Foundation) to ensure that all procedures are conducted and 
documented properly according to the protocol, GCP, and all applicable regulatory requirements. 
On-site monitoring visits will be made at appropriate times during the study. Monitors must have 
direct access to source documentation in order to check the completeness, clarity, and 
consistency of the data recorded in the CRF for each subject. The Investigator will make 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
30  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
available to the monitor source documents and medical records necessary to complete CRFs. In 
addition, the Investigator will work closely with the clinical monitor and, as needed, provide 
them appropriate evidence that the conduct of the study is being done in accordance with 
applicable regulations GCP guidelines.  
  
Clinical Research Associate  
  
A clinical research associate (CRA) will be continuously overseeing the conduct of the trial and 
ensuring it is at all times compliant with all authorities regulating the investigation including 
IRB, and FDA.  The CRA will perform monitoring site visits on a monthly basis.  The personnel 
will be qualified by education, training, and experience to assume responsibility for the proper 
monitoring of the research study.   
  
Audits  
  
The investigator will allow study-related monitoring, audits, and inspections by the IRB, the 
Sponsor, or FDA, of all study related documents (e.g. source documents, regulatory documents, 
data collection instruments, study data etc.). Participation as an investigator in this study implies 
acceptance of potential inspection by government regulatory authorities and applicable Hope 
Biosciences compliance and quality assurance offices.  
  
Protocol Deviations  
  
An Investigator may not knowingly deviate from the study protocol without prior approval by 
Hope Biosciences and/or the IRB unless the deviations are necessary under emergency 
circumstances to protect the rights, safety, or well-being of human subjects or the scientific 
integrity of the clinical investigation. Deviations must be documented and promptly reported to 
Hope Biosciences and, if applicable, to the IRB providing oversight of the study.   
  
Subject Stipends or Payments  
  
Payment to research subjects for participation in studies is not considered a benefit that would be 
part of the weighing of benefits or risks.   
  
Funding Source  
  
Privately funded.  
  
    
 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
31  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
Appendix 1: Clinical Criteria for Diagnosing Anaphylaxis  
  
Anaphylaxis is defined as a serious allergic reaction that is rapid in onset and may cause death.  
The following criteria were outlined by Sampson et al from the Second Symposium on the 
Definition and Management of Anaphylaxis (a 2005 meeting of the National Institute of Allergy 
and Infectious Disease and Food Allergy and Anaphylaxis Network).  
  
Anaphylaxis is highly likely when any 1 of the following 3 criteria are met:  
   
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND 
at least 1 of the following:   
  
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia)   
b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence)   
  
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):   
  
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen 
lipstongue-uvula)   
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia)   
c. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia 
[collapse], syncope, incontinence)   
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)   
  
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):   
  
a. Infants and children: low systolic BP (age-specific) or greater than 30% decrease in 
systolic BP. Low systolic BP for children is defined as less than 70 mmHg from 1 month 
to 1 year, less than (70 mmHg + [2 x age]) from 1 to 10 years, and less than 90 mmHg 
from 11 to 17 years.  
b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that 
person’s baseline  
  
 
 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
32  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
References  
  
1. 
Lopes-Pacheco, M., et al., Current understanding of the therapeutic benefits of 
mesenchymal stem cells in acute respiratory distress syndrome. Cell biology and 
toxicology, 2019: p. 1-20.  
2. 
Sun, P., et al., Understanding of COVID-19 based on current evidence [published online 
ahead of print, 2020 Feb 25]. Journal of Medical Virology, 2020.  
3. 
Clinical Pharmacology. 2019, Elsevier: Tampa, FL.  
4. 
Li, Y.C., W.Z. Bai, and T. Hashikawa, The neuroinvasive potential of SARS‐CoV2 may 
be at least partially responsible for the respiratory failure of COVID‐19 patients. Journal 
of Medical Virology.  
5. 
Huang, C., et al., Clinical features of patients infected with 2019 novel coronavirus in 
Wuhan, China. The Lancet, 2020. 395(10223): p. 497-506.  
6. 
Tian, S., et al., Characteristics of COVID-19 infection in Beijing. Journal of Infection, 
2020.  
7. 
Zhang, J.j., et al., Clinical characteristics of 140 patients infected by SARS‐CoV‐2 in 
Wuhan, China. Allergy, 2020.  
8. 
Xu, X., et al., Imaging and clinical features of patients with 2019 novel coronavirus 
SARS-CoV-2. European Journal of Nuclear Medicine and Molecular Imaging, 2020: p. 1- 
6.  
9. 
O'Dwyer, D.N., S.J. Gurczynski, and B.B. Moore, Pulmonary immunity and extracellular 
matrix interactions. Matrix Biology, 2018. 73: p. 122-134.  
10. 
Samuel, C.E., Antiviral actions of interferons. Clinical microbiology reviews, 2001. 
14(4): p. 778-809.  
11. 
Puneet, P., S. Moochhala, and M. Bhatia, Chemokines in acute respiratory distress 
syndrome. Am J Physiol Lung Cell Mol Physiol, 2005. 288: p. L3-L15.  
12. 
Wrapp, D., et al., Cryo-EM structure of the 2019-nCoV spike in the prefusion 
conformation. Science, 2020.  
13. 
DiMarino, A.M., A.I. Caplan, and T.L. Bonfield, Mesenchymal stem cells in tissue repair. 
Frontiers in immunology, 2013. 4: p. 201.  
14. 
Meirelles Lda, S., et al., Mechanisms involved in the therapeutic properties of 
mesenchymal stem cells. Cytokine Growth Factor Rev, 2009. 20: p. 419-427.  
15. 
Machado, C.d.V., P.D.d.S. Telles, and I.L.O. Nascimento, Immunological characteristics 
of mesenchymal stem cells. Revista brasileira de hematologia e hemoterapia, 2013. 35(1): 
p. 62-67.  
16. 
Di Nicola, M., et al., Human bone marrow stromal cells suppress T-lymphocyte 
proliferation induced by cellular or nonspecific mitogenic stimuli. Blood, 2002. 99(10): p. 
3838-3843.  
17. 
Le Blanc, K., et al., Mesenchymal stem cells inhibit and stimulate mixed lymphocyte 
cultures and mitogenic responses independently of the major histocompatibility complex. 
Scandinavian journal of immunology, 2003. 57(1): p. 11-20.  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
33  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
18. 
Zhao, Q., H. Ren, and Z. Han, Mesenchymal stem cells: Immunomodulatory capability 
and clinical potential in immune diseases. Journal of Cellular Immunotherapy, 2016. 
2(1): p. 3-20.  
19. 
Gazdic, M., et al., Mesenchymal stem cells: a friend or foe in immune-mediated diseases. 
Stem Cell Reviews and Reports, 2015. 11(2): p. 280-287.  
20. 
Xu, T., et al., Mesenchymal stem cell-based therapy for radiation-induced lung injury. 
Stem cell research & therapy, 2018. 9(1): p. 18.  
21. 
Oliveri, R.S., S. Bello, and F. Biering-Sørensen, Mesenchymal stem cells improve 
locomotor recovery in traumatic spinal cord injury: systematic review with metaanalyses 
of rat models. Neurobiology of disease, 2014. 62: p. 338-353.  
22. 
Hagmann, S., et al., FGF‐2 addition during expansion of human bone marrow‐derived 
stromal cells alters MSC surface marker distribution and chondrogenic differentiation 
potential. Cell proliferation, 2013. 46(4): p. 396-407.  
23. 
Kim, J.-W., et al., Bone marrow–derived mesenchymal stem cell transplantation for 
chronic spinal cord injury in rats: comparative study between intralesional and 
intravenous transplantation. Spine, 2013. 38(17): p. E1065-E1074.  
24. 
Torres-Espín, A., et al., Neuroprotection and axonal regeneration after lumbar ventral 
root avulsion by re-implantation and mesenchymal stem cells transplant combined 
therapy. Neurotherapeutics, 2013. 10(2): p. 354-368.  
25. 
Quertainmont, R., et al., Mesenchymal stem cell graft improves recovery after spinal cord 
injury in adult rats through neurotrophic and pro-angiogenic actions. PloS one, 2012. 
7(6): p. e39500.  
26. 
Walker, P.A., et al., Intravenous multipotent adult progenitor cell therapy for traumatic 
brain injury: preserving the blood brain barrier via an interaction with splenocytes. 
Experimental neurology, 2010. 225(2): p. 341-352.  
27. 
Menge, T., et al., Mesenchymal stem cells regulate blood-brain barrier integrity through 
TIMP3 release after traumatic brain injury. Science translational medicine, 2012. 4(161): 
p. 161ra150-161ra150.  
28. 
Cox Jr, C.S., et al., Treatment of severe adult traumatic brain injury using bone marrow 
mononuclear cells. Stem Cells, 2017. 35(4): p. 1065-1079.  
29. 
Walker, P.A., et al., Progenitor cells as remote" bioreactors": Neuroprotection via 
modulation of the systemic inflammatory response. World journal of stem cells, 2011. 
3(2): p. 9.  
30. 
Glennie, S., et al., Bone marrow mesenchymal stem cells induce division arrest anergy of 
activated T cells. Blood, 2005. 105: p. 2821-2827.  
31. 
Ankeny, D.P., D.M. McTigue, and L.B. Jakeman, Bone marrow transplants provide 
tissue protection and directional guidance for axons after contusive spinal cord injury in 
rats. Experimental neurology, 2004. 190(1): p. 17-31.  
32. 
Singer, N.G. and A.I. Caplan, Mesenchymal stem cells: mechanisms of inflammation. 
Annual Review of Pathology: Mechanisms of Disease, 2011. 6: p. 457-478.  
33. 
Volarevic, V., et al., Mesenchymal stem cell‐derived factors: Immuno‐modulatory effects 
and therapeutic potential. Biofactors, 2017. 43(5): p. 633-644.  
34. 
Krampera, M., et al., Role for interferon‐γ in the immunomodulatory activity of human 
bone marrow mesenchymal stem cells. Stem cells, 2006. 24(2): p. 386-398.  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
34  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
35. 
Ren, G., et al., Mesenchymal stem cell-mediated immunosuppression occurs via 
concerted action of chemokines and nitric oxide. Cell stem cell, 2008. 2(2): p. 141-150.  
36. 
Ren, G., et al., Species variation in the mechanisms of mesenchymal stem cell‐mediated 
immunosuppression. Stem cells, 2009. 27(8): p. 1954-1962.  
37. 
Choi, H., et al., Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates 
zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident 
macrophages. Blood, 2011. 118(2): p. 330-338.  
38. 
Milner, C., V. Higman, and A. Day, TSG-6: a pluipotent inflammatory mediator? 
Biochem Soc Trans, 2006. 3: p. 446-450.  
39. 
Wisniewski, H. and J. Vilcek, Cytokine-induced gene expression at the crossroads of 
innate immunity, inflammation and fertility: TSG-6 and PTX3/TSG-14. Cytokine Growth 
Factor Rev, 2004. 15(2-3): p. 129-146.  
40. 
Yung, S. and T. Chan, Intrinsic cells: mesothelial cells -- central players in regulating 
inflammation and resolution. Perit Dial Int, 2009. 29(Suppl 2): p. S21-S27.  
41. 
Cho, D.-I., et al., Mesenchymal stem cells reciprocally regulate the M1/M2 balance in 
mouse bone marrow-derived macrophages. Experimental & molecular medicine, 2014. 
46(1): p. e70.  
42. 
Geng, Y., et al., Mesenchymal stem cells ameliorate rhabdomyolysis-induced acute 
kidney injury via the activation of M2 macrophages. Stem cell research & therapy, 2014. 
5(3): p. 80.  
43. 
Nakajima, H., et al., Transplantation of mesenchymal stem cells promotes an alternative 
pathway of macrophage activation and functional recovery after spinal cord injury. 
Journal of neurotrauma, 2012. 29(8): p. 1614-1625.  
44. 
Kim, J. and P. Hematti, Mesenchymal stem cell–educated macrophages: A novel type of 
alternatively activated macrophages. Experimental hematology, 2009. 37(12): p. 
14451453.  
45. 
Prockop, D.J. and J.Y. Oh, Mesenchymal stem/stromal cells (MSCs): role as guardians of 
inflammation. Molecular therapy, 2012. 20(1): p. 14-20.  
46. 
Cho, K., et al., IFATS collection: Immunomodulatory effects of adipose tissue-derived 
stem cells in an allergic rhinitis mouse model. Stem Cells, 2009. 27(1): p. 259-265.  
47. 
Zhou, B., et al., Administering human adipose-derived mesenchymal stem cells to prevent 
and treat experimental arthritis. Clin Immunol, 2011. 141(3): p. 328-337.  
48. 
Gonzalez-Rey, E., et al., Human adipose-derived mesenchymal stem cells reduce 
inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid 
arthritis. Ann Rheum Dis, 2010. 69(1): p. 241-248.  
49. 
Kawata, Y., et al., Early injection of human adipose tissue-derived mesenchymal stem cell 
after inflammation ameliorates dextran sulfate sodium-induced colitis in mice through the 
induction of M2 macrophages and regulatory T cells. Cell Tissue Res, 2019. 376(2): p. 
257-271.  
50. 
Song, W., et al., TSG-6 Secreted by Human Adipose Tissue-derived Mesenchymal Stem 
Cells Ameliorates DSS-induced colitis by Inducing M2 Macrophage Polarization in Mice. 
Scientific Reports, 2017. 7: p. 5187.  

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411 
Allogeneic HB-adMSCs to provide immune support against COVID-19.                                                           
  
35  
Protocol Version 1.5  
Version Date: 25-JAN-2021  
         
51. 
Matthay, M.A., 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(2): p. 154-162.  
52. 
Mannelli, L.D.C., et al., Adipose-derived stem cells decrease pain in a rat model of 
oxaliplatin-induced neuropathy: Role of VEGF-A modulation. Neuropharmacology, 
2018. 131: p. 166-175.  
53. 
Ohta, Y., et al., Intravenous infusion of adipose-derived stem/stromal cells improves 
functional recovery of rats with spinal cord injury. Cytotherapy, 2017. 19(7): p. 839-848.  
54. 
Xie, M., et al., Adipose-derived mesenchymal stem cells ameliorate hyperglycemia 
through regulating hepatic glucose metabolism in type 2 diabetic rats. Biochemical and 
biophysical research communications, 2017. 483(1): p. 435-441.  
55. 
Aggarwal, A. and D.P. Misra, Enthesitis-related arthritis. Clinical rheumatology, 2015. 
34(11): p. 1839-1846.  
56. 
Ricciotti, E. and G.A. FitzGerald, Prostaglandins and inflammation. Arteriosclerosis, 
thrombosis, and vascular biology, 2011. 31(5): p. 986-1000.  
57. 
Walker, H.K., W.D. Hall, and J.W. Hurst, Temperature, in Clinical Methods: The 
History, Physical, and Laboratory Examinations, V. Del Bene, Editor. 1990, 
Butterworths: Boston. 

DocuSign Envelope ID: 2F360A02-B77C-446F-A719-A19A6B611411