Conditions: 2019 Novel Coronavirus Infection COVID-19 Virus Infection SARS Coronavirus 2 Infection SARS-CoV-2 Infection Respiratory Distress Syndrome, Adult Adult Respiratory Distress Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
This trial will study the use of USB002 given as an intravenous infusion in patients with respiratory distress due to infection with COVID-19.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: USB002 intervention 2: Placebo
Intervention descriptions: intervention 1: USB002 is pharmaceutically formulated Angiotensin 1-7 \[A(1-7)\], a non-hypertensive derivative of Angiotensin-II (A-II), and is suspended in a vehicle as a sterile solution of USB002. Depending upon cohort assignment, subjects in the USB002 group will receive one of four doses of USB002 administered intravenously (IV). intervention 2: The placebo formulation will be the USB002 formulated solution without the addition of A(1-7). The placebo will be administered intravenously (IV).

Protocol document:
Prot_000.pdf: 
Phase 2 Trial of USB002 in Patients with Resp Distress from COVID-19 
Version 6.0 
USB002-2020-001 
 
17 February 2022 
 
US Biotest, Inc.  
 
 
CONFIDENTIAL 
 
 
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A Phase 2 Trial to Evaluate the Safety, Tolerability, and Preliminary 
Efficacy of Intravenous USB002 to Treat Patients with Respiratory 
Distress due to COVID-19 Infection 
 
 
Protocol Identifying Number: USB002-2020-001 
 
IND Sponsor: US Biotest, Inc. 
 
Version Number: 6.0 
 
17 February 2022 
 
 
 
 
    
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................... 10 
1.  BACKGROUND INFORMATION .............................................................................. 13 
1.1.  Investigational Product:  USB002 ...................................................................... 13 
1.2.  Nonclinical Experience with A(1-7) .................................................................... 13 
1.3.  Clinical Experience with USB002 ...................................................................... 13 
1.4.  Known and Potential Risks and Benefits to Human Subjects ............................ 14 
1.4.1.  Potential Benefits to Human Subjects ......................................................... 14 
1.4.2. 
 Rationale for Clinical Trial ........................................................................ 15 
1.5.  Rationale for Dose Selection ............................................................................. 16 
2.  STUDY OBJECTIVES AND PURPOSE ................................................................... 17 
2.1.  Study Objectives and Endpoints ....................................................................... 17 
2.1.1 
Primary Objectives and Endpoints ............................................................ 17 
2.1.2 
Secondary Objectives and Endpoints ....................................................... 17 
2.1.3. Exploratory Endpoints .................................................................................. 18 
3.  STUDY DESIGN ...................................................................................................... 18 
3.1 
Study drug(s) and Control Description ............................................................. 20 
3.1.1.  Formulation and Appearance ...................................................................... 20 
3.1.2. 
Packaging and Labeling ............................................................................ 21 
3.1.3. 
Storage and Accountability Procedures .................................................... 21 
3.1.4. 
Dosage and Administration ....................................................................... 21 
3.1.5. 
 Route of Administration ............................................................................ 21 
3.2. 
 Dose Regimen and Escalation ..................................................................... 22 
3.3.  Randomization .................................................................................................. 22 
3.4 Treatment Period................................................................................................. 23 
3.5.  Study Participation Duration .............................................................................. 23 
3.6 Study Population ................................................................................................. 23 
4.  PATIENT SELECTION CRITERIA ........................................................................... 23 
4.1.  Inclusion Criteria................................................................................................ 23 
4.2.  Exclusion Criteria .............................................................................................. 24 
4.3.  Subject Withdrawal ............................................................................................ 24 
4.4. Study Withdrawal Criteria ................................................................................... 25 
5.  STUDY PROCEDURES AND VISIT SCHEDULE .................................................... 25 
5.1.  Standard of Care Procedures ............................................................................ 25 


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5.2. Clinical Laboratory Evaluations .......................................................................... 25 
5.3 Other Assays or Procedures ............................................................................... 26 
5.4 Visit Schedule ..................................................................................................... 27 
5.4.1.  Screening (Part 1 & Part 2) ......................................................................... 27 
5.4.2.  Visit Schedule Part 1 ................................................................................... 28 
5.4.3.  Visit Schedule Part 2 ................................................................................... 30 
5.4.4 End of Treatment or Early Termination of Treatment .................................... 31 
5.4.5 Hospital Discharge Prior to Day 28 ............................................................... 31 
5.5.  Concomitant Medication .................................................................................... 37 
5.6. Prohibited Medication ......................................................................................... 37 
6.  ASSESSMENT OF SAFETY .................................................................................... 37 
6.1.  Safety Parameters ............................................................................................. 37 
6.1.1.  Definition of Adverse Events (AE) ............................................................... 38 
6.1.2.  Definition of Serious Adverse Events (SAE) ................................................ 38 
6.2 Classification of an Adverse Event ...................................................................... 38 
6.2.1. Severity of Event .......................................................................................... 38 
6.2.2.  Relationship to Study Drug .......................................................................... 39 
6.2.3.  Expectedness ............................................................................................ 40 
6.3. 
Adverse Event Follow-Up ............................................................................. 40 
6.4. 
Reporting Procedures ................................................................................... 40 
6.4.1 Adverse Event Reporting .............................................................................. 40 
6.4.2 Serious Adverse Event Reporting ................................................................. 41 
6.4.3 
Reporting of Pregnancy ............................................................................ 42 
6.5 Study Halting Rules ............................................................................................. 42 
6.6.  Safety Oversight ................................................................................................ 43 
7. STATISTICAL CONSIDERATIONS .......................................................................... 43 
7.1 Statistical and Analytical Plans ............................................................................ 43 
7.2 Description of Statistical Methods ....................................................................... 44 
7.2.1  Analysis of the Efficacy Endpoint(s) ............................................................. 44 
7.2.2.  Extent of Exposure ...................................................................................... 45 
7.2.3 
Safety Analyses ........................................................................................ 46 
7.3. Sample Size ....................................................................................................... 48 
7.4. 
Measures to Minimize Bias ........................................................................... 48 
7.4.1 Enrollment/Randomization/Masking Procedures ........................................... 48 


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7.4.2 Evaluation of Success of Blinding ................................................................. 48 
7.4.3 Breaking the Study Blind/Participant Code.................................................... 48 
8.  CLINICAL MONITORING ......................................................................................... 48 
9.  QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 49 
9.1.  Electronic Data Capture .................................................................................... 49 
10. ETHICAL STANDARD ............................................................................................ 50 
10.1.  Institutional Review Board (IRB) ...................................................................... 50 
10.2 Informed Consent Process ................................................................................ 50 
10.2.1. Subject Information and Consent .............................................................. 50 
10.2.2. Consent Procedures and Documentation ................................................. 50 
10.3.  Confidentiality .................................................................................................. 51 
11.  DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ......................... 51 
11.1 Study Records Retention .................................................................................. 52 
11.2 Source Documents ............................................................................................ 52 
11.3 Protocol Deviations ........................................................................................... 53 
12.  PUBLICATION AND DATA SHARING POLICY ..................................................... 53 
13.  LIABILITY AND INSURANCE ................................................................................ 54 
14.  References ............................................................................................................. 55 
APPENDIX 1: Ordinal Scale for Clinical Improvement (OSCI) ...................................... 57 
APPENDIX 2: SPONTANEOUS BREATHING TRIAL (SBT) ........................................ 58 
 
LIST OF TABLES 
Table 1. USB002 Formulated Solution ....................................................................... 20 
Table 2. Schedule of Assessments: Part 1 ............................................................... 33 
Table 3. Schedule of Assessments: Part 2 ............................................................... 35 


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LIST OF ABBREVIATIONS 
A(1-7) 
Angiotensin 1-7 
A-II 
Angiotensin-II 
ABG 
Arterial blood gas 
ACE 
Angiotensin-converting Enzyme 
ACE2 
Angiotensin-converting Enzyme 2 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AT1R 
Angiotensin II receptor type 1 
AUC 
Area under the curve 
BiPap 
Bilevel positive airway pressure 
BP 
Blood pressure 
C 
Celsius 
Cmax 
Maximum concentration  
CK 
Creatinine kinase 
CPAP 
Continuous positive airway pressure 
CO2 
Carbon dioxide 
COVID-19 
Coronavirus disease - 2019 
C-RP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events  
DSMB 
Data Safety Monitoring Board  
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation  
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EPO 
Erythropoietin 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
HR 
Heart rate 


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ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
ICMJE 
International Committee of Medical Journal Editors 
ISF 
Investigator Site File 
IWRS 
Interactive Web Response System 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
µg 
Microgram 
MedDRA 
Medical Dictionary of Drug Regulatory Activities 
mg  
Milligrams 
mL  
Milliliter 
MM 
Medical Monitor  
mm 
Millimeters 
mM 
Millimolar 
mmHg 
Millimeters of mercury 
MTD 
Maximum tolerated dose 
MV 
Mechanical ventilation 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
NO 
Nitric oxide 
NOAEL 
No-observed adverse effect level 
OA 
Oleic acid 
OSCI 
Ordinal Scale for Clinical Improvement 
PaO2 
Arterial partial pressure of oxygen 
PBW 
Predicted body weight 
PEEP 
Positive end expiratory pressure 
pH 
Hydrogen ion concentration 


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PI 
Primary Investigator  
PK 
Pharmacokinetics 
QTc 
QT interval corrected for heart rate 
QTcB 
Correction of QT values using Bazett’s Formula 
QTcF 
Correction of QT values using Fredericia's Formula 
RAS 
Renin angiotensin system 
RBC 
Red blood cell 
RR 
Breaths per Minute 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan  
SARS 
Severe Acute Respiratory Syndrome 
SBT 
Spontaneous breathing trial 
SC 
Subcutaneous 
S-D 
Sprague-dawley rats  
SHR 
Spontaneously hypertensive  
SMP 
Safety Management Plan 
SOB 
Shortness of breath 
SOC 
Standard of care (system organ class also SOC) 
SpO2 
Peripheral capillary oxygen saturation 
TEAE 
Treatment-emergent adverse event 
TG+ 
Renin transgenic  
TTP 
Time to progression  
Vt 
Tidal volume 
USP 
United States Pharmacopeia 
WBC 
White blood cell 
WCG IRB 
Western IRB/Copernicus Group 
WHO 
World Health Organization 


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SPONSOR SIGNATURE PAGE  
 
Protocol Title: 
A Phase 2 Trial to Evaluate the Safety, Tolerability, and 
Preliminary Efficacy of Intravenous USB002 to Treat Patients 
with Respiratory Distress due to COVID-19 Infection 
Protocol Number: 
USB002-2020-001 
Version Number: 
6.0 
Date: 
17 February 2022 
IND Number:       
151166 
Investigational Product: 
USB002 
 
Sponsor: 
US Biotest, Inc. 
 
231 Bonetti Dr., Suite 240 
 
San Luis Obispo, CA 93401-7310 
 
805-595-1300 
 
 Name and Title: 
Gere diZerega, MD 
President and CEO, US Biotest. Inc. 
 
 
______________________________ 
 
 
_________________________ 
  
 
Date 
 
 


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INVESTIGATOR SIGNATURE PAGE 
I have read the attached protocol and agree to comply with the contents of this document. 
I agree to comply with applicable FDA regulations and guidelines set forth in 21 CFR 
Parts 11, 50, 54, 56, and 312. 
This document is a confidential communication of US Biotest, Inc. The recipient agrees 
that no unpublished information contained herein will be published or disclosed without 
prior written permission of US Biotest. However, this document may be disclosed to 
appropriate institutional review boards, or authorized representatives of the Investigator 
or to boards of health under the condition that they are requested to respect the 
confidentiality of the document. 
The signature of the Principal Investigator below constitutes agreement. 
 
Principal Investigator: 
_______________________________  
Institution Address:  
________________________________ 
 
 
 
 
________________________________ 
 
 
 
 
________________________________ 
 
 
 
 
________________________________ 
 
___________________________________ 
           _____________________ 
Signature of Principal Investigator 
 
 
Date 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
 
Title: 
A Phase 2 Trial to Evaluate the Safety, Tolerability, and 
Preliminary Efficacy of Intravenous USB002 to Treat Patients 
with Respiratory Distress due to COVID-19 Infection 
Sponsor: 
US Biotest, Inc. 
Study number: 
USB002-2020-001 
Phase: 
Phase 2 
Study objectives: 
Parts 1 and Part 2: 
 
• To determine the safety and tolerability of USB002 in 
treatment of respiratory distress from coronavirus 
disease – 2019 (COVID-19) infection;  
• To identify an early efficacy signal of USB002. 
 
Part 1: 
 
• To determine the maximum tolerated dose (MTD) of 
USB002 (up to 900 ug/kg/day). 
 
Part 2: 
 
• To determine preliminary efficacy of the USB002 MTD 
following up to 14 days of continuous infusion.  
Study Endpoints: 
 
Safety of USB002 will be evaluated by: 
 
The rate of occurrence and severity of Adverse Events (AEs) 
resulting from clinical changes (Day/Visit 1 to Day 28):  
 
• Cardiovascular parameters, to include blood pressure 
(BP), heart rate (HR), 12-lead electrocardiogram (ECG), 
and requirements for inotropes and vasopressors; 
• Laboratory parameters, to include kidney and liver 
function. 
 
Preliminary efficacy of USB002 will be determined from start of 
treatment (Day/Visit 1) by time to peripheral capillary oxygen 
saturation (SpO2) ≥ 94% on room air, sustained for at least 48 
hours, through Day 28. 
 
Additional preliminary efficacy assessments include the 
following, from start of treatment (Day/Visit 1) through Day 28: 


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• All-cause mortality at 60 days; 
• Number of ventilator-free days; 
• Number and proportion of subjects progressing from 
non-invasive to mechanical ventilation; 
• Time of progression from non-invasive to mechanical 
ventilation; 
• Proportion of subjects weaned from mechanical 
ventilation; 
• Number of days of vasoactive agent usage;  
• Time (days) to hospital discharge; 
• Changes in clinical status, as defined by the 7-point 
ordinal scale. 
 
Study design: 
This randomized, double-blinded, placebo-controlled study will 
be conducted in two parts:  
 
Part 1 will escalate through four sequential doses of USB002 to 
determine the MTD. Part 2 will determine preliminary efficacy of 
the USB002 MTD dose identified in Part 1.   
 
In Part 1, subjects will be randomized to receive Standard of 
Care (SOC) plus USB002 in up to 4 escalating doses (n=3) or 
SOC plus placebo (n=3) via continuous intravenous (IV) 
infusion, for up to 96 hours. 
 
Dose escalation, assessment of progress and safety will be 
determined by a Data Safety Monitoring Board (DSMB) after 
review of the 96-hour clinical data. If toxicity is identified 
[evaluated according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), 
version 5.0 criteria] at the lowest cohort level (90 ug/kg/day), 
DSMB may determine to de-escalate or halt the study. 
Escalation will continue until Part 1 enrollment is completed and 
the MTD is determined. 
 
In Part 2, subjects will be randomized 1:1 to receive either SOC 
plus USB002 at the MTD established in Part 1 or SOC plus 
placebo infusion for up to 14-days. 
 
For both Groups, when infusion is stopped/completed, whether 
prior to 96 hours, at the end of infusion (96 hours in Part 1, 
Day 14 in Part 2), or earlier, there will be a 24-hour 
observation period. If a subject stops treatment for any reason 
after the Visit 1 infusion begins, all attempts will be made to 
conduct the End of Treatment (Visit 5 in Part 1 and Day 16 in 


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Part 2 ) procedures (See Tables 2 and 3). End of Treatment 
(Visit 5 or Day 16) procedures may be conducted during the 
24-hour observation period.  
 
Infusion of USB002/placebo will be discontinued at any time if 
SpO2 is > 94%, sustained for at least 48 hours, on room air. 
Visits will continue up to Day 28, if subject is still hospitalized. 
The Day 28 and Day 60 follow-up visits will be conducted by 
phone (Telemed) if discharged.  
Population: 
• 18 years of age or older; shortness of breath (SOB) and 
respiratory distress requiring oxygen due to COVID-19 
infection; 
• Up to 10 sites in the United States. 
Sample size: 
Part 1, up to 48 subjects. 
 
Part 2, 30 subjects.   
 
 
 


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1.  BACKGROUND INFORMATION 
 
1.1.  Investigational Product:  USB002 
 
USB002 is pharmaceutically formulated Angiotensin 1-7 [A(1-7)], a non-hypertensive 
derivative of Angiotensin-II (A-II) and is suspended in a vehicle as a sterile solution of 
USB002 (22.5 mg/ml) which is stable at room temperature for 90 days.  
 
1.2.  Nonclinical Experience with A(1-7) 
 
The proposed treatment of patients with COVID-19-induced respiratory distress with 
USB002 is supported by animal models of Acute Respiratory Distress Syndrome (ARDS) 
(ventilator, oleic acid [OA] and sepsis induced), pulmonary hypertension, and ﬁbrosis 
(Fleming 2005, Ishiyama 2004, Donoghue 2003, Imai 2005, Shenoy 2010, Walther 2011, 
Yamazato 2009, Zambelli 2015), which demonstrated that an imbalance between the 
angiotensin converting enzyme (ACE)/Ang-II/angiotensin II type 1 and the angiotensin 
converting enzyme 2 (ACE2)/Ang-(1–7)/Mas axis of the renin-angiotensin system (RAS) 
occurs in animals with lung disease.  
 
Imai et al. (2005) showed that ACE2, which converts A-II to A(1-7) by cleavage of one 
amino acid, protects mice from ARDS induced by acid aspiration or sepsis. Shenoy et al. 
(2010) in rats showed positive effects in a pulmonary fibrosis model using lentiviral 
packaged A(1-7)-fusion genes or ACE2 cDNA. Overexpression of A(1-7) significantly 
prevented the associated negative effects of pulmonary fibrosis. Blockade of the Mas 
receptor abolished the beneficial effects of A(1-7), confirming the role of the Mas receptor 
and A(1-7) in protection of the lung. A(1-7) protects against ventilator induced ARDS in 
mice. A(1-7) attenuated the development of ARDS, as demonstrated by a normalization 
of the lung wet-to-dry weight ratio and a significant improvement in PaO2. A(1-7) also 
protects against OA-induced acute lung injury/ARDS in Sprague-Dawley rats as shown 
by changes in lung wet-to-dry weight ratio and reduced pulmonary vascular resistance 
(Yamazato 2009). Importantly, A(1-7) infusion was shown to improve pulmonary function, 
including prolonged improvement in oxygenation, reduction in inflammatory cells 
recruitment and reduction in lung fibrosis long term in an animal model of ARDS involving 
two insults, acid instillation and prolonged injurious ventilation. A(1-7) was effective even 
after delayed administration (Zambelli 2015).  
 
1.3.  Clinical Experience with USB002 
 
The safety of USB002 has been demonstrated in seven clinical trials whose indications 
include breast cancer and chronic kidney disease. USB002 has also been studied in 
healthy volunteers. To date, 107 subjects have been treated with USB002 (referred to in 
studies as TXA127). Doses administered ranged from 2.5 µg/kg/day to 300 µg/kg/day 
administered as a subcutaneous (SC) dose for up to 28 days. USB002 has been well 
tolerated with no drug-related serious adverse events (SAEs) noted. A Phase 1/2 
randomized, double-blinded, placebo-controlled study of intravenous (IV) USB002 given 
alone and with erythropoietin (EPO) was conducted in subjects with anemia associated 


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with end-stage renal disease. The trial had two arms: EPO plus USB002 at one of three 
(10, 25, or 50 µg/kg) IV doses, and EPO plus placebo three times weekly, administered 
following each hemodialysis session. No dose limiting toxicity (DLT) was observed in any 
dosing group. There were no differences between USB002 and EPO in adverse events 
(AEs) by body system.  
 
1.4.  Known and Potential Risks and Benefits to Human Subjects 
 
A favorable safety profile has been demonstrated with USB002 in preclinical toxicology 
studies. Single-dose and repeat-dose (4-week) toxicity studies were conducted in rats 
and dogs utilizing IV USB002 administration. The daily parenteral administration of 
USB002 to rats and dogs for one month at doses up to 1000 µg/kg/day did not affect 
clinical condition, body weight, or food intake. No changes in hematology parameters, 
serum chemistry values, or urinalysis were noted. In addition, there were no treatment-
related histopathologic changes in any of the tissues or organs examined. Thus, the 
maximum no-observed adverse effect level (NOAEL) in rats and dogs following repeat-
dosing was 1000 µg/kg/day. An acute IV study evaluated five male and five female mice 
that were injected with 100 mg/kg USB002. Clinical observations were recorded for 14 
days. No treatment-related changes in clinical condition occurred. An acute IV irritation 
study was performed in 5 groups of three female rats each. The USB002 dose levels 
were 0.01, 0.1, 1.0, 10, and 100 mg/kg. A concurrent control group of three female rats 
received placebo. There were no deaths or gross necropsy findings, and no test article-
related changes in body weight or clinical findings. An IV one-month study was conducted 
in rats (Crl:CD(SD)BR VAF/Plus) administered placebo or USB002 by slow bolus injection 
into a tail vein once daily for 4 weeks at doses of 0 (placebo), 0.01, 0.1, or 1.0 mg/kg. No 
test article-related effects were found for any toxicological parameter at any dose level. 
An IV one-month study of USB002 was conducted in beagle dogs by slow bolus IV 
injection once daily for 4 weeks at doses of 0 (placebo), 0.01, 0.1, or 1.0 mg/kg. No test 
article-related effects were found for any toxicological parameter at any dose level. 
 
1.4.1.  Potential Benefits to Human Subjects 
 
The RAS can be thought of as a hormonal system with 2 axes – the ACE/Ang-
II/angiotensin II receptor type 1 (AT1R) axis (pathological arm) and the counter-regulatory 
ACE2/A(1-7)/Mas receptor axis (protective arm). The ACE/Ang-II/AT1R axis has now 
been implicated in the pathophysiology of the cardiovascular, renal, pulmonary, and 
central nervous systems (Nehme 2019). In vivo, Mas acts as a functional antagonist of 
the AT1R, thereby inhibiting these actions of Ang-II (Kostenis 2005). A(1-7) is the 
endogenous ligand of the Mas receptor and a member of the protective RAS.  
 
COVID-19, like severe acute respiratory syndrome (SARS), binds to the cell surface 
protein receptor, ACE2, a member of the ACE2/A(1-7)/Mas axis. SARS pathology 
emerges, in part, due to the reduced ability of ACE2 to cleave A-II, a pro-inflammatory, 
fibrotic peptide, to A(1-7) (Zhou 2020). Ang-II is a potent vasoconstrictor that can increase 
lung injury and lung edema (Flemming 2005). A(1-7) counteracts the effects of Ang-II and 
mobilizes endogenous regenerative processes. Patients in intensive care for ARDS that 


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do not survive have reduced levels of A(1-7) compared to those that do survive. IV 
treatment with A(1-7) would not only reduce inflammation and oxidative stress but 
rebalance the RAS.  
 
In a recent study of intensive care unit (ICU) patients with ARDS, increased serum levels 
of A(1-10) and reduced serum levels of A(1-7) at the time of admission in patients with 
this degree of dysregulation of angiotensin peptide metabolism did not survive, despite 
aggressive ventilator-assisted pulmonary therapy (Reddy 2019). Further, a recent 
publication showed that circulating Ang-II levels increased with increased COVID 19 viral 
load and reduced PaO2/FiO2 levels (Lui 2020). In SARS-infected animals, increased 
levels of Ang-II were observed due to reduced ACE2 activity. In this study ACE2 cleaves 
Ang-II to A(1-7), thereby reducing the pathological activities of Ang-II and increasing the 
protective arm of the RAS through the ACE2/A(1-7)/Mas axis (Imai 2008).  
 
In a bacterial model of pneumonia, treatment with A(1-7) reduced lung congestion 24 
hours after infection (Soto 2020). Finally, in an unpublished study of bone marrow 
transplant following lethal irradiation, mice began to die due to an unplanned norovirus 
infection at day 3 after transplant. In mice that received donor cells from the saline treated 
animals and saline treatment after transplant, there was only 20% survival. In A(1-7) 
treated mice (both donor and recipient), there was 100% survival. This data show that 
A(1-7) not only improved sequelae secondary to infection but also prevented multiple 
organ system failure and death. 
 
1.4.2.  Rationale for Clinical Trial 
 
COVID-19 may lead to respiratory distress which progresses from shortness of breath 
(SOB) requiring hospitalization and supplemental oxygen by nasal cannula, high flow 
oxygen delivered by a mask with <15 liters/minute of oxygen, bilevel positive airway 
pressure (BiPAP) with a mask that delivers high pressure 100% oxygen at 5 mmHg peak 
inspiratory pressure, and ultimately to intubation and assisted ventilation with a respirator. 
With an increasing number of hospitalized COVID-19 cases in the United States since 
January of 2020, COVID-19 presents an acute and urgent threat to global health security. 
Therapeutic interventions capable of reducing pulmonary distress would reduce the 
fatality rate, improve long-term outcomes, and free up scarce ICU resources. 
 
Respiratory distress in untreated COVID-19 infected patients presents as a progressive 
continuum from SOB to cardiopulmonary collapse and death. It is diagnosed in 
symptomatic patients with bilateral lung infiltrates with confirmed positive tests for COVID-
19. Without supportive therapy, pulmonary distress rapidly progresses to hospitalization 
where supplemental oxygen can be given by nasal cannula, high-flow mask, BiPAP mask, 
and eventually intubation and assisted ventilation. Overall, the physiological damage to 
cells and structures of the lung can begin within hours of exposure and progress within 
days (Fahy 2012). The pathologic hallmarks of COVID-19-induced pulmonary distress 
include neutrophilic alveolitis, hyaline membrane disease secondary to protein 
transudation and precipitation in the airspace, microthrombi secondary to the generation 
of procoagulant mediators as well as endothelial and epithelial injury. For these reasons, 


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there is considerable interest in the use of a A(1-7) to treat patients who have developed 
respiratory distress from COVID-19 infection (Soto 2020, Piero 2020, NCT 04332666). 
 
1.5.  Rationale for Dose Selection 
 
Sponsor US Biotest, Inc. was given permission to proceed with a clinical trial of USB002 
(referred to as TXA127) to treat subjects with sepsis-induced ARDS under IND 110550. 
The study was closed with no enrollment. The doses of USB002 and treatment durations 
in Parts 1 and 2 of this protocol are the same as those approved by the U.S. Food and 
Drug Administration (FDA) to treat sepsis induced ARDS. 
 
IV single and repeat-dose (4-week) toxicity studies were conducted in rats, mice, and 
dogs. The NOAEL in rats and dogs following repeat dosing was 1000 µg/kg/d or higher. 
Much higher doses of up to 100 mg/kg (100,000 µg/kg) of A(1-7) in mice, produced only 
reduced body weight gain. 
 
The pharmacokinetics (PK) of 250 µg/kg A(1-7) explored in normal Sprague-Dawley (S-
D) spontaneously hypertensive (SHR), and renin transgenic (TG+) rats (Yamada 1998) 
demonstrated different kinetics depending on the model used. The reported half-life was 
approximately 10 seconds. Plasma A(1-7) clearance was significantly reduced (39-60%) 
in the SHR and TG+ rats compared to S-D rats. After four weeks of dosing, the area under 
the curve (AUC) increased 6-fold and the maximum concentration (Cmax) increased 10-
fold.  
 
In the dog, SC administration of 10 mg/kg/day resulted in a half-life of 30.86 ± 12.59 
minutes on Day 0, and a 15% reduction to 27.7 ± 4.02 minutes by Day 28. The AUC and 
Cmax decreased by similar amounts. 
 
Preliminary PK data on single doses of SC USB002 at 100 µg/kg body weight are 
available for 15 breast cancer patients. The mean baseline concentration of A(1-7) was 
20.7 pg/mL (range: 6.3-84.5 pg/mL). The mean and standard deviation (SD) of total body 
weight (used as the dosing weight in this study) were 75.8 and 13.6 kg, respectively, with 
a range between 55.4 and 301.2 kg. The highest concentration of A(1-7) was observed 
in the 0.5-hour sample, with an average value (corrected for baseline level) of 1,577 
pg/mL (range: 260 - 5086 pg/mL). By 3-6 hours post-dosing, plasma A(1-7) 
concentrations were at or below baseline levels. The Cmax and area under the curve for 
0-3 hours (AUC0-3) (both corrected for baseline measurements) correlated with dose, but 
there was variability among patients. Assuming linear kinetics and that 5 half-lives are 
required to return A(1-7) to baseline, the return to baseline within 3-6 hours would suggest 
an average half-life of about one hour. 
 
From the above, the initial dose will be 1/10th the NOAEL in rats and dogs, and 1/1000th 
the maximum dose administered to mice, i.e., 90 µg/kg/day. 
 


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2.  STUDY OBJECTIVES AND PURPOSE 
 
2.1.  Study Objectives and Endpoints 
 
The objectives of the study are twofold: 
 
• To determine the safety and tolerability of USB002 in treatment of respiratory 
distress from COVID-19 infection; and 
• To identify an early efficacy signal of USB002. 
 
2.1.1 Primary Objectives and Endpoints 
 
The primary objectives of safety and tolerability of USB002 will be evaluated for rate of 
occurrence and severity of AEs resulting from clinical changes (Visit 1/Day 1 to Day 28): 
cardiovascular parameters, to include blood pressure (BP), heart rate (HR), 12-lead 
electrocardiogram (ECG), and requirements for inotropes and vasopressors; laboratory 
parameters, to include kidney and liver function.    
 
The primary endpoint of preliminary efficacy will be demonstrating the difference 
between USB002 and placebo groups in time to peripheral capillary oxygen saturation 
(SpO2) ≥ 94%, sustained for at least 48 hours, on room air through Day 28.  
 
2.1.2 Secondary Objectives and Endpoints 
 
Secondary objectives and endpoints will be assessed from time of start of USB002 or 
placebo infusion (Visit 1/Day 1) to Day 28.  
 
Secondary endpoints include:   
• All-cause mortality at Day 60. 
• Number of ventilator-free days (defined as the number of days between Visit 
1/Day 1 and Day 28 that subjects are both alive and free of mechanical 
ventilation [MV]; freedom from MV is further defined as free from MV for at least 
48 hours after extubation).  
o In the case of repeated MV, duration of MV will be summed for the 
purposes of calculation. In the case of tracheostomy, the same criteria 
apply.  
• Proportion of subjects weaned from mechanical ventilation through Day 28 
(defined as free from MV for at least 48 hours after extubation. In the case of 
tracheostomy, the same criteria will apply). This applies only to subjects on 
mechanical ventilation at baseline. 
• Proportion of subjects progressing from non-invasive (at baseline) to mechanical 
ventilation. This applies only to subjects not on mechanical ventilation at 
baseline. 
• Time to progression (TTP) from non-invasive to mechanical ventilation.  


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o In the case of repeat admission to hospital and/or ICU within the first 28-
days, the time from first treatment with study medication will be used to 
calculate TTP to MV;  
• Number of days of vasoactive agent usage (defined as use of a vasoactive agent 
for 6 hours or more within any 24-hour period); 
• Time (days) to hospital discharge; 
• Changes in Ordinal Scale for Clinical Improvement (OSCI) status (see Appendix 
1) from Visit 1/Day 1 to Day 28, defined as 1) time to change and 2) proportions 
of subjects, with 1-point and 2-point clinical status changes utilizing a time-to-
event analysis from time of start of infusion (Visit 1/Day 1) of study medication to 
Day 28 for the time to change analysis between active and placebo groups. 
 
2.1.3. Exploratory Endpoints 
 
For any subject that is taken off assisted ventilation and study treatment is terminated 
earlier than planned (96 hours in Part 1 and Day 14 in Part 2), the re-initiation of assisted 
ventilation will be assessed as an exploratory endpoint. In the event of re-initiation of 
assisted ventilation, subjects who continued receiving USB002/placebo infusion will be 
assessed separately to those who discontinued treatment. 
 
3.  STUDY DESIGN  
 
The study is designed as a randomized double-blind study.  All staff at the site will be 
blinded to the treatment allocation, including Pharmacy staff, and all Sponsor personnel 
will also be blinded.  The randomization and allocation of kits will be managed by the data 
management group via an interactive web randomization system (IWRS). 
  
Part 1 
 
Dose escalation will be randomized, double-blinded and placebo-controlled in 24 subjects 
(up to 48 if DLT occurs). Up to six subjects will receive either SOC plus USB002 (n=3) or 
SOC plus placebo (n=3) in up to 4 escalating doses. 
 
COVID-19 diagnosed patients in pulmonary distress requiring supplemental oxygen will 
be eligible for enrollment once consent has been obtained from the subject or legal 
representative and eligibility has been confirmed. Screening assessments obtained prior 
to consent and within 72 hours of infusion start will be used to assess eligibility and will 
not require repeating, unless determined by the Investigator as needed.   
 
Study registration (subject number assignment) will be conducted through the IWRS upon 
enrollment. The Investigator will confirm eligibility and notify the pharmacy so designated 
study pharmacy staff can request cohort assignment and a drug kit identification 
randomization number through IWRS system. The pharmacy will receive dosage 
instructions directly from the IWRS system.  
 
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placebo for up to 96-hours. Safety will be assessed by changes in physical examination 
findings, changes in vitals and laboratory parameters. AEs will be collected from the 
time of informed consent; those occurring between informed consent and start of 
infusion will be designated as medical history, and those occurring after start of infusion 
will be designated as AEs. Baseline assessments are defined as those conducted on 
Visit 1, prior to start of infusion. 
Visit 5 will serve as the End of Treatment visit for Part 1. Additional visits will be 
conducted on Days 7, 9, 12, 14, 16, 18, 21, 24 and 28 (if/while still hospitalized). The 
follow-up visits on Days 28 and 60 will be conducted by phone (Telemed) upon 
discharge. If the subject is discharged earlier than Day 28, Telemed visits will be 
conducted once a week until Day 28, with the first occurring 7 days after discharge. The 
Day 28 Telemed visit and Day 60 Telemed visit will occur on Days 28 and 60, 
respectively, regardless of when the subject is discharged from hospital and the timing 
of their previous weekly Telemed visits.     
 
The decision to dose-escalate, de-escalate, or increase the number of subjects in any 
group will be made by a Data Safety Monitoring Board (DSMB) as described in Section 
6.6. Dose escalation will use the traditional 3+3 design to assess dose-response as 
described in Section 3.2. Assessment of progress and safety will be conducted by the 
DSMB, per the Safety Management Plan (SMP). If the DSMB determines there is a 
reasonable safety concern, enrollment may be delayed or halted. If toxicity is identified 
(graded according to NCI-CTCAE v5.0) at the lowest cohort level (90 ug/kg/day), DSMB 
may determine to de-escalate or halt the study. Escalation will continue until Part 1 
enrollment is completed and the MTD is determined. 
 
Part 2 
 
30 subjects will be randomized at the MTD, as determined in Part 1, to either SOC plus 
USB002 (n=15) or SOC plus placebo (n=15). Subjects will be treated on a continuous 
infusion for up to 14 days. Infusion will be discontinued at any time if SpO2 ≥ 94% on room 
air is sustained for at least 48 hours. Additional visits will be conducted on Days 16 (End 
of Treatment visit), 18, 21, 24 and 28 (if still hospitalized). The follow-up visit on Days 28 
and 60 will be conducted by phone (Telemed) upon discharge. If the subject is discharged 
earlier than Day 28, Telemed visits will be conducted once a week until Day 28, with the 
first occurring 7 days after discharge. The Day 28 Telemed visit and Day 60 Telemed visit 
will occur on Days 28 and 60, respectively, regardless of when the subject is discharged 
from hospital and the timing of their previous weekly Telemed visits.   
 
Parts 1 and 2 
 
For both groups, there will be a 24-hour observation period, after infusion stop time, 
regardless of when this occurs and regardless of reason.  
 
If a subject’s treatment is terminated after the Visit 1/Day 1 infusion begins, for any 
reason, all attempts will be made to conduct all remaining study visits and assessments, 


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as applicable (See Tables 2 and 3). End of Treatment (Part 1 – Visit 5; Part 2 – Day 16) 
procedures may be conducted during the 24-hour observation period. Missed End of 
Treatment assessments due to disease progression or early discharge, will be 
considered deviations.  
 
Respiratory evaluations will be determined by recovery landmarks of time to acceptable 
spontaneous breathing efforts (up to 30 minutes), termination for the need of oxygen (see 
Spontaneous Breathing Trial [SBT]: Appendix 2), and time to discontinuation of ventilatory 
assistance, if applicable. Clinical status will be evaluated using the OSCI and physical 
examination findings.  
 
Follow-up for AEs with a start prior to Day 28 will be followed to resolution, stabilization, 
or to Day 60. Survival will be captured during the follow-up period through to Day 60, 
regardless of treatment or hospitalization status. AEs with a start date after Day 28 will 
not be captured. Any SAE that occurs at any time, through to Day 60, will be collected.   
 
Participation will terminate for all subjects on Day 60 or at early termination due to death, 
consent withdrawal or lost to follow-up.  
 
3.1 
Study drug(s) and Control Description 
 
3.1.1.  Formulation and Appearance 
 
USB002 is formulated as a sterile, preservative-free, non-pyrogenic solution for injection. 
Formulated solution for injection consists of (Table 1):  
 
Table 1. USB002 Formulated Solution 
Angiotensin 1-7 
 
22.5 mg/mL 
Glacial Acetic Acid, USP3 
0.90 mg/mL (15 mM1) 
Sodium Acetate Trihydrate, USP3 
4.76 mg/mL (35 mM) 
Mannitol, USP3 
40.0 mg/mL (4%) 
Sterile Water for Injection, USP3 
quantity sufficient to 100% 
Sodium Hydroxide, NF2 
to pH 5 
Glacial Acetic Acid, USP3  
to pH 5 
1Millimolar[mM] 2National Formulary 3 United States Pharmacopeia 
 
The parenteral formulation is produced as a hydrogen ion concentration (pH) buffered 
solution, adjusted for the proper osmolality with the addition of 4% mannitol to provide a 
final osmolality of 295-415 milliosmole for the dosing concentrations of A(1-7). 
Sterilization of USB002 is achieved via 0.22-micron filtration of the final bulk solution into 
the appropriate number of vials filled under aseptic conditions.  
 
The placebo formulation will be the USB002 formulated solutions (see Table 1) without 
the addition of A(1-7). 
 


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3.1.2. Packaging and Labeling 
 
USB002 is packaged in a 22.5 mg/ml, single-use, stoppered 2.0 mL vial with a 2.1-mL fill. 
 
USB002 and placebo vials will be identically labelled as ‘For Investigational Use Only,’ 
volume, kit #, and sponsor address.  
 
3.1.3. Storage and Accountability Procedures  
 
The Investigator (or delegate) will maintain adequate records showing the receipt, 
dispensing, return, or other disposition of USB002/placebo, including the date, quantity, 
kit number, vial number and identification of subjects (number, initials as allowed) 
receiving study medication.  
 
USB002/placebo will be stored securely in the institution pharmacy, where it will be 
prepared and provided to the study staff for infusion. USB002/placebo will be labeled with 
the date of preparation, subject ID#, and final dose concentration in addition to institution-
required labelling.  
 
Used vials and empty kit boxes will not be kept for accountability purposes; they will be 
disposed of according to the institution destruction procedures. 
 
3.1.4. Dosage and Administration 
 
A new, unused vial will be used for each dose. The total dose administered will be 
dispensed per kg of body weight. USB002 or placebo will be diluted (see pharmacy 
manual) in saline and infused continuously by a dedicated line.  
 
Pharmacy will prepare USB002 or placebo and provide the final product for infusion to 
the study team in a 100 mL sodium chloride (0.9%) Injection, USP bag(s). USB002 or 
placebo should not be administered with other medications in the same IV line and require 
a dedicated line. The infusion of study medication (USB002/placebo) may be piggy-
backed on a 0.9% saline infusion if it is being used specifically and solely for the purpose 
of keeping vascular access open i.e. TKVO. 
 
If possible, no other procedures should be performed within 90 minutes of the start of 
infusion; procedures or medication which may induce hypotension (BP decrease by 20% 
mmHg systolic) should be avoided during the same period.  
 
3.1.5.  Route of Administration 
 
USB002 or placebo will be administered by IV. The infusion rate of the reconstituted study 
medication/solution supplied by the pharmacist is fixed at 4.167 ml/hour (0.069 ml/min) 
for all dose levels and all subjects when a 100 ml infusion bag is used. The daily dose 
required for each subject is calculated and dispensed according to the instructions in the 
pharmacy manual. 


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3.2. 
 Dose Regimen and Escalation 
  
Part 1: Dose Escalation 
 
During dose escalation, the study will follow a traditional “3+3” design with three subjects 
in each cohort receiving SOC plus USB002 and three subjects in each cohort receiving 
SOC plus placebo. Cohorts will be enrolled sequentially for USB002 dose, with subjects 
receiving active drug at four sequential cohort doses of 90, 300, 600 and 900 ug/kg/day.  
 
DSMB escalation decisions will be conducted on unblinded data. In Part 1, data review 
to determine dose escalation, de-escalation and study stop will be conducted by the 
DSMB after the last subject in each cohort has completed infusion (96-hour timepoint). 
Recruitment will be halted during DSMB data review for dose escalation decisions. 
Notification of changes in dose concentrations (escalation or de-escalation) will be issued 
through the IWRS. 
 
The first 6 subjects (3 SOC plus USB002 subjects and 3 SOC plus placebo subjects) will 
be treated at the lowest dose. If one subject experiences an AE that is determined by the 
DSMB to be a potential DLT, an additional 6 subjects (3 SOC plus USB002 and 3 SOC 
plus placebo) will be treated at the same cohort dose.  If DLTs are experienced in the 
new cohort at the same dose, the study may be stopped, or dose de-escalated.  
 
DLT of hypotension (systolic BP < 90 mmHg) is a possibility, which may require the 
administration of fluid boluses or IV pressor agents.  
 
At the time of a DSMB safety review, if no DLTs are identified in the first cohort, approval 
will be issued to treat the next 6 subjects (3 SOC plus USB002 and 3 SOC plus placebo) 
at the next dose. The DSMB safety reviews will be repeated between cohorts until the 
MTD or top dose of 900 µg/kg/day is reached.  
 
Part 2: Dose Expansion 
 
30 subjects will be randomized to either SOC plus USB002 at the MTD established in 
Part 1 (n=15) or SOC plus placebo (n=15). Subjects will be treated on a continuous 
infusion for up to 14 days.  
 
3.3.  Randomization  
 
Randomization codes will be generated based on a central randomization schema, and 
the appropriate code assigned to the study kit will be issued to the Pharmacy via IWRS. 
Subjects will be randomized in a 1:1 ratio to receive either SOC plus USB002 or SOC 
plus placebo. Detailed instructions for the IWRS (enrollment/randomization/unblinding) 
will be provided separately. 
 


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3.4 Treatment Period  
 
Part 1 
 
Treatment will start during Visit 1/hour 0 and continue for up to 96 hours.  
 
Part 2 
 
MTD treatment will start at Day 1 and continue for up to 14 days. 
 
3.5.  Study Participation Duration  
 
Part 1 and Part 2 subjects completing all study assessments will be on study for up to 
70 days.  
 
3.6 Study Population 
 
Subjects over the age of 18 with COVID-19 infections and SOB requiring supplemental 
oxygen to maintain SpO2 ≥ 94% will be enrolled.  
 
4.  PATIENT SELECTION CRITERIA  
 
4.1.  Inclusion Criteria  
 
1. Signed informed consent from patient or legal representative;  
2. Age 18 or greater; 
3. Positive reverse transcription polymerase chain reaction (RT-PCR) for SARS-
CoV-2 (<10 days of start of infusion); 
4. Respiratory rate > 20 RR; 
5. SpO2 < 94% on room air, requiring supplemental oxygen, on mechanical 
ventilation for <72 hours (at time of informed consent); 
 
If screening and infusion occur on the same day, the first SpO2 taken at the time 
of screening needs to be <94% to satisfy eligibility (patient will be put onto 
oxygen immediately); if screening and infusion occur on separate days, confirm 
sustained SpO2 <94% on room air prior to infusion –if on supplemental oxygen 
just prior to infusion and SpO2 < 94% then patient automatically meets the 
criteria. 
 
6. Chest X-ray confirming bilateral pulmonary infiltrates; 
7. Body mass index of < 40 units/kg/m2;  
8. Adequate method of birth control for subjects of child-bearing potential.* 
 
* Note: A female patient is considered to be of childbearing potential unless she has had 
a hysterectomy, is at least one year postmenopausal or has undergone tubal ligation. For 
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approved and highly effective method of birth control, defined as those which result in a 
low failure rate (i.e., < 1% per year) when used consistently and correctly, such as 
implants, injectables and oral contraceptives combined with the use of double condoms. 
Only male patients whose vasectomy has been confirmed by semen analysis at least 3 
months after the vasectomy are allowed not to use acceptable contraceptive methods. 
 
4.2.  Exclusion Criteria 
 
1. Terminally ill patients due to underlying cardiac, cancer or severe debilitating 
neurological disease including coma; 
2. Hospitalization expected to be < 96 hours due to medical improvement; 
3. Interstitial lung disease; 
4. Patients receiving vasopressors at time of starting infusion; 
5. Correction of QTc values obtained by 12 lead EKG using Fridericia’s formula 
(QTcF) > 450 ms; 
6. History of hypotension (mean arterial blood pressure < 65 mmHg), unrelated to 
CoVID-19 infection;  
7. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times 
upper limit of normal; 
8. Creatinine >115umol/L (Part 2 only); 
9. BUN > 8.3 mmol/L (Part 2 only); 
10. Participating concurrently on another clinical trial for the experimental treatment of 
COVID-19; 
11. Patients who appear to be showing clinical improvement, in the investigator’s 
opinion (and documented in the source), between screening and baseline 
(infusion); 
12. Active chemotherapy use; 
13. Pregnant and/or lactating women. 
 
4.3.  Subject Withdrawal 
 
Subjects may withdraw from the study at any time without stating a reason and without 
prejudice to further treatment. Incapacitated subjects may be withdrawn by the legally- 
authorized representative. The reason for withdrawal will be documented in the source 
notes and in the Electronic Data Capture system (EDC). Any potential or confirmed drug-
related event (clinical AE, laboratory abnormality, or other medical condition/situation) 
occurring, and/or DSMB determination which may be attributed to the withdrawal, must 
be documented and followed for the safety of the subject. 
 
Withdrawal of a subject from the study applies to subjects who withdraw their consent; 
otherwise, all subjects will be followed through Day 60.  Subjects who are lost to follow-
up (attempts to reach subjects will be documented) will be noted as such, at Day 60, but 
will not be deemed to have been withdrawn; subjects who do not survive to Day 60 will 
be noted as such but will not be considered to have been withdrawn. 
 


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The sponsor should be notified immediately when a subject withdraws consent from the 
study after any treatment, as every attempt should be made to capture as much 
information following treatment as possible.  If a subject withdraws consent after the 
start of infusion, for any reason, all attempts will be made to conduct the End of 
Treatment (Day 5 or Day 16) procedures (See Tables 2 and 3). End of Treatment (Day 
5 or Day 16) procedures may be conducted during the 24-hour observation period.  
 
Following discharge, reasonable and diligent attempts to contact the subject should be 
documented (dates, phone discussions, emails and registered mail) in the subject’s 
record. 
 
4.4. Study Withdrawal Criteria 
 
The study may be suspended or prematurely terminated at any site if there is sufficient 
reasonable cause.  
 
Written notification, documenting the reason for the study suspension or termination, will 
be provided by the suspending or terminating party. If the study is prematurely terminated 
or suspended, the Investigator(s) will promptly inform the Institutional Review Boards 
(IRBs) and will provide the reasons for the termination or suspension. The study may 
resume once concerns about safety, protocol compliance, and data quality are addressed 
and satisfy the sponsor, IRB, and/or FDA. 
 
Circumstances that may warrant termination include, but are not limited to: 
 
• DSMB determination of unexpected, significant, or unacceptable risk to subjects 
based on safety evaluations and DLTs;   
• Insufficient compliance with protocol requirements; 
• Data that are not sufficiently complete and/or evaluable; 
• Determination of futility. 
 
5.  STUDY PROCEDURES AND VISIT SCHEDULE  
 
5.1.  Standard of Care Procedures 
 
SOC testing obtained prior to consent and within 72 hours of USB002/placebo infusion 
start can be used to assess eligibility and will not require repeating, unless determined by 
the Investigator. SOC tests done on hospital admission may be used to determine patient 
eligibility. 
 
5.2. Clinical Laboratory Evaluations  
 
Clinical laboratory assessments will be conducted at the local Clinical Laboratory 
Improvement Amendments certified laboratory routinely used by the Investigator. 
Laboratory samples will be collected and processed per institution requirements and 
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Laboratory Assessments include:  
(Part 1, Screening, Visit 1, 5 and Days 14, 21 and 28) 
(Part 2, Screening, Day 1, Days 7, 16 and 28) 
 
• Chemistry: Sodium, potassium, chloride, carbon dioxide (CO2), calcium, 
phosphorus, glucose, blood urea nitrogen (BUN), serum creatinine, serum lipase, 
serum amylase, alkaline phosphatase (ALP), total bilirubin, AST, ALT, lactate 
dehydrogenase (LDH), LDH isoenzymes, total protein, albumin, triglycerides, uric 
acid, C-reactive protein (C-RP), creatinine kinase (CK), CK isoenzymes, thyroid 
stimulating hormone (TSH);  
• Hematology: Complete blood count (CBC) to include: Red blood cells (RBC), 
white blood cells (WBC), complete differential, hemoglobin (Hgb), hematocrit 
(Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), and platelet count (Plt); 
• Urinalysis: Specific gravity, hydrogen ion concentration (pH), RBC, WBC, protein, 
and glucose;  
(Urinalysis for Part 1 only at Screening, Visit 5 and Day 28) 
(Urinalysis for Part 2 only at Screening and Day 16) 
• Coagulation: Activated partial thromboplastin time (aPTT), prothrombin time (PT) 
and international normalized ratio (INR) and fibrinogen assay. 
 
Laboratory Assessments include:  
(Part 1: 24, 48, 72 and 96 hours)  
(Part 2: Days 2, 3, 4, 5, 9, 12, 14, 18, 21 and 24) 
 
• Chemistry: Sodium, potassium, chloride, carbon dioxide (CO2), calcium, glucose, 
blood urea nitrogen (BUN), serum creatinine, alkaline phosphatase (ALP), total 
bilirubin, AST, ALT, total protein, albumin;  
• Hematology: Complete blood count (CBC) to include: Red blood cells (RBC), 
white blood cells (WBC), complete differential, hemoglobin (Hgb), hematocrit 
(Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), and platelet count (Plt);  
• Coagulation: Activated partial thromboplastin time (aPTT), prothrombin time (PT) 
and international normalized ratio (INR) and fibrinogen assay. 
 
5.3 Other Assays or Procedures 
 
Other assays or procedures include:  
 
• Pregnancy test (for females of childbearing potential). 
• OSCI (Appendix 1); 
• In addition to study required OSCI status collection, any additional OSCI 
assessments conducted during the study will also be collected. 
• SBT (Appendix 2);  
• Chest X-ray (required at screening only); 


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• 12-lead ECG to include HR and QRS intervals, QT/QTcF/QTcB; Correlation of QT 
values using Fridericia’s formula;  
• Vitals to be captured daily; and during the infusion period at a minimum of every 8 
hours. Vitals to include systolic and diastolic BP, HR, RR and temperature; 
• If BP changes significantly post start of infusion, mean arterial pressure will 
be collected at 15-minute intervals, until resolution;  
• Weight measured at screening only;  
• Study–required respiratory assessments (first and last assessments can be based 
on 24 hour clock or from infusion time): 
 Arterial Blood Gas (ABG): If multiple assessments are conducted daily, the first 
and last assessment of the day will be collected; missed ABGs do not qualify 
as deviations,  
• FiO2 (%) – The highest value in a 24-hour period to be recorded in the event of 
multiple daily assessments, 
• PaO2/FiO2 ratio, the PaO2 value to be obtained from the ABG when performed, 
• Respiratory rate (breaths/min) – The highest value in a 24-hour period to be 
recorded in the event of multiple daily assessments, 
• SpO2 (%) – The lowest value in a 24-hour period to be recorded in the event of 
multiple daily assessments. 
 
5.4 Visit Schedule  
 
5.4.1.  Screening (Part 1 & Part 2) 
 
The following procedures and assessments must be completed, documented and 
reviewed by the Investigator within the 72-hour screening period, prior to the first 
treatment dose (see Tables 2 and 3) unless otherwise indicated: 
 
• Written informed consent, including comprehensive discussion of the study 
schedule, procedures and protocol requirements with the patient or legal 
representative; 
• Review of demographic data, including date of birth, sex, weight and race; 
• Complete medical and surgical history. Any AEs occurring prior to the first 
USB002/placebo dose will be considered history; 
• Medical history to include dates of vaccinations, booster and prior COVID-19 
infection(s), if applicable; 
• Medical history to include ICU admission date, if applicable;  
• Positive RT-PCR for SARS-CoV-2 (<10 days of start of infusion); 
• Chest X-ray; 
• Comprehensive physical examination (to include lung auscultation to determine 
presence or absence of lung crackles (rales), wheezing, dullness to percussion);  
• 12-lead ECG; 


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• Sample collection and processing for clinical laboratory assessments (Section 
5.2); 
• Urinalysis collection (if patient is producing urine) (Section 5.2); 
• Vitals assessments (Section 5.3); 
• Respiratory assessments (Section 5.3); 
• Pregnancy test for females of childbearing potential; 
• OSCI; 
• Review and documentation of all concomitant prescription and non-prescription 
medication. 
 
If a randomized subject eligible to proceed to Visit 1 infusion, suffers an AE and/or if the 
Investigator deems the subject cannot start the infusion, infusion may be delayed up to 
72 hours. If the decision to start infusion is > 72 hours, the subject is considered a screen 
fail and screening procedures must be repeated. In this situation, a new screening 
number will be used and a new randomization number provided.  
 
5.4.2.  Visit Schedule Part 1 
 
AEs and concomitant medications will be reviewed and documented every day of 
hospitalization.  
 
Visit 1 
Prior to infusion start:  
• Conduct final determination of eligibility prior to the start of USB002/placebo 
infusion;  
• If not done in previous 72 hours, repeat within 24 hours prior to start of 
USB002/placebo infusion: 
o Physical exam (for eligibility only, does not need repeating); 
o Laboratory sample collection per Section 5.2; 
o Respiratory assessments per Section 5.3; 
o Vitals; 
o 12 lead-ECG; 
o Chest X-ray (for eligibility only, does not need repeating); 
o Pregnancy test; 
o OSCI assessment. 
  
Visit 1 – 0 hours 
• Infusion start: as soon as possible once deemed eligible.  
 
Visits 1 – 4 (4, 8, 12, 24, 32, 40, 48, 72 and 96 hours) 
• Blinded Dosing 
• Vitals (If no continuous vitals monitoring, collect vital signs per Section 5.3 during 
the infusion period); 
• Respiratory assessments per Section 5.3; 


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• Laboratory (chemistry, hematology and coagulation per Section 5.2) at 
approximately 24, 48, 72, 96 hours; 
• 12 lead-ECG at approximately 48, 72, 96 hours; 
• For mechanically ventilated subjects, SBT at approximately 24, 48, 72, and 96 
hours, if weaning criteria met; 
• AEs; 
• Concomitant medications. 
 
Visit 5 (End of Treatment or Early Termination of Treatment) 
• Laboratory (chemistry, hematology, coagulation and urinalysis per Section 5.2);  
• 12 lead-ECG;  
• Vitals; 
• Respiratory assessments per Section 5.3;  
• SBT and at any time that weaning criteria is met;  
• OSCI assessment; 
• AEs; 
• Concomitant medications. 
 
Days 7, 9, 12 and 14  
• Laboratory (chemistry, hematology and coagulation per Section 5.2) (Day 14); 
• 12 lead-ECG (Days 7, 9, 14); 
• Vitals; 
• Respiratory assessments per Section 5.3;  
• SBT at Days 7, 9 and 14 and at any time that weaning criteria is met; 
• AEs; 
• Concomitant medications. 
 
Day 16  
• Vitals; 
• Respiratory assessments per Section 5.3;  
• SBT and at any time that weaning criteria is met;  
• OSCI assessment; 
• AEs; 
• Concomitant medications. 
 
Days 18, 21, 24, 28 
• OSCI assessment (Day 28); 
• AEs; 
• Laboratory (chemistry, hematology, coagulation and urinalysis per Section 5.2) 
(Day 21 and Day 28 with urinalysis at Day 28) 
• Concomitant medications; 
• Follow-Up (Telemed) (Day 28). 


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Day 60 
• AEs 
• Follow-Up (Telemed).  
 
5.4.3.  Visit Schedule Part 2 
 
AEs and concomitant medications will be reviewed and documented every day of 
hospitalization. Monitoring is to be conducted daily if no continuous monitoring is 
available, unless specified below. 
 
Day 1 
Prior to infusion start  
• Conduct final determination of eligibility prior to the start of USB002/placebo  
infusion.  
• If not done in previous 72 hours, repeat within 24 hours of start of infusion: 
o Physical exam (for eligibility only, does not need repeating); 
o Laboratory sample collection per Section 5.2; 
o Respiratory assessments per Section 5.3; 
o Vitals; 
o 12 lead-ECG; 
o Chest X-ray (for eligibility only, does not need repeating); 
o Pregnancy test; 
o OSCI assessment. 
  
Day 1 - 0 hours 
• Infusion start: As soon as possible once deemed eligible.  
 
Days 1-14 
• Blinded Dosing 
• Vitals;  
• If no continuous vitals monitoring, collect vital signs per Section 5.3 during 
the infusion period. 
• Respiratory assessments per Section 5.3;  
• Laboratory (chemistry, hematology, coagulation and urinalysis [Day 1 only] per 
Section 5.2); 
• 12 lead-ECG (Day 1); 
• SBT and at any time that weaning criteria is met; 
• OSCI (Day 7); 
• AEs; 
• Concomitant medications. 
 


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Day 16 (End of Treatment or Early Termination of Treatment) 
• Laboratory assessments (chemistry, hematology, coagulation and urinalysis per 
Section 5.2);  
• 12 lead-ECG;  
• Vitals; 
• Respiratory assessments per Section 5.3;  
• SBT and at any time that weaning criteria is met;  
• OSCI assessment; 
• AEs; 
• Concomitant medications. 
 
Days 18, 21, 24, 28 
• Laboratory (chemistry, hematology, coagulation per Section 5.2);  
• OSCI assessment (Day 28); 
• AEs; 
• Concomitant medications; 
• Follow-Up (Telemed) (Day 28). 
Day 60 
• AEs; 
• Follow-Up (Telemed).  
 
5.4.4 End of Treatment or Early Termination of Treatment 
 
Subjects completing the study up to Visit 5 (in Part 1) or Day 16 (in Part 2)  will have 
End of Treatment procedures completed at Visit 5 (in Part 1) or Day 16 (in Part 2). For 
subjects discharged prior to Visit 5 (in Part 1) or Day 16 (in Part 2) or where treatment is 
terminated early, for any reason, all attempts will be made to conduct the End of 
Treatment (Visit 5 or Day16) procedures (See Tables 2 and 3). End of Treatment (Visit 
5 or Day16) procedures may be conducted during the 24-hour observation period.  
 
See Section 5.4.2 Visit 5 (Part 1) and Section 5.4.3 Day 16 (Part 2).  
 
5.4.5 Hospital Discharge Prior to Day 28 
 
If a subject is discharged from hospital earlier than Day 28, Telemed visits will be 
conducted once a week until Day 28, with the first occurring approximately 7 days after 
discharge. The Day 28 and Day 60 Telemed visits will occur on Days 28 and 60, 
respectively, regardless of when the subject is discharged from hospital and the timing of 
their previous weekly Telemed visits. Part 1 subjects discharged prior to Day 28 will not 
return to the site for visits (may apply to any of Days 7, 9, 12, 14, 16, 18, 21, or 24, 
depending on day of discharge) or undergo the procedures regularly scheduled for those 
visits. Part 2 subjects discharged prior to Day 28 will not return to the site for visits (may 
apply to Days 18, 21, or 24, depending on day of discharge) or undergo the procedures 
regularly scheduled for those visits. 


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Data from the Telemed visits post-discharge will be captured in the EDC. 


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Table 2. Schedule of Assessments: Part 1 
 
Timepoint  
Assessments 
Screening 
(72 hours) 
 
 
 
 
Visit 5 
Day 
75 
95 
125 
145 
165 
185 
215 
245 
285,6 
+/- 7 
days 
Visit 1  
Visit 2  
Visit 
3 
Visit 
4 
End of 
Treatment4 
0 
hrs2 
4 
hrs 
8 
hrs 
12 
hrs 
24 
hrs 
32 
hrs 
40 
hrs 
48 
hrs 
72 
hrs 
96 
hrs 
 
60 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
Surgical 
History1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
exam3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry  
X 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
Hematology 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
Coagulation 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
Chest X-ray 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
SBT 
Assessment 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
Respiratory 
assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Blinded Dosing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
OSCI Status  
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Adverse 
Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Follow-
Up5,6(Telemed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 


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1. 
History to include but not limited to any significant, ongoing, or controlled with treatment, medical condition; date of hospital admission; date of ICU 
admission; start time of supplemental oxygen therapy; start time of nasal high-flow oxygen therapy; start time of non-invasive mechanical ventilation or 
mechanical ventilator via intubation.  
2. 
If screening assessments are not completed prior to start of infusion, conduct within 24 hours of infusion start. If performed as part of screening and within 
72 hours, do not repeat unless required by the Investigator. Chext X-ray and Physical Exam do not need repeating within 24 hours. 
3. 
Physical exam to include lung auscultation. 
4. 
Visit 5 is also End of Treatment – all End of Treatment assessments are to be conducted at Visit 5 for all subjects or for any discharge prior to Visit 5. 
5. 
If subject is discharged from hospital, Telemed visits will be conducted once a week until Day 28, with the first occurring approximately 7 days after 
discharge. Day 28 and Day 60 Telemed visits will occur on Days 28 and 60, respectively, regardless of discharge date and timing of previous Telemed 
visits. Discharged subjects will not attend the site for visits (Days 7, 9, 12, 14, 16, 18, 21, or 24, as applicable to discharge day) or undergo procedures 
scheduled for those visits.  
6. 
Telephone follow-up, if discharged. Day 28 phone call window = +/- 3 days; window not applicable if still hospitalized. 
 
 


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Table 3. Schedule of Assessments: Part 2 
Assessments 
Timepoint (Days) 
Screening 
(72 hours) 
12 
2 
3 
4 
5 
7 
9 
12 
14 
165 
186 
216 
246 
286,7 
 
+/- 7 
days 
End of 
Treatment 
60 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical 
History1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Chest X-ray 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
SBT Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Respiratory 
assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Blinded Dosing4  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
OSCI Status  
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Follow-
Up6,7(Telemed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


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1. 
History to include but not limited to any significant, ongoing, or controlled with treatment medical condition; date of hospital admission; date of ICU admission; 
start time of supplemental oxygen therapy; start time of nasal high-flow oxygen therapy; start time of non-invasive mechanical ventilation or mechanical 
ventilator via intubation. 
2. 
If screening assessments are not completed prior to start of infusion, conduct on Day 1, prior to infusion. If performed as part of screening and within 72 hours, 
do not repeat unless required by the Investigator. Chest X-ray and Physical Exam do not need repeating within 24 hours.  
3. 
Physical exam to include lung auscultation.  
4. 
Continuous infusion of USB002 or placebo for up to 14 days. 
5. 
Day 16 is also End of Treatment – all End of Treatment assessments are to be conducted at Day 16 or for any discharge prior to Day 16. 
6. 
If subject is discharged from hospital, Telemed visits will be conducted once a week until Day 28, with the first occurring approximately 7 days after discharge. 
Day 28 and Day 60 Telemed visits will occur on Days 28 and 60, respectively, regardless of discharge date and timing of previous Telemed visits. Discharged 
subjects will not attend the site for visits (Days 18, 21, or 24, as applicable to discharge day) or undergo procedures regularly scheduled for those visits. 
7. 
Telephone follow-up, if discharged. Day 28 phone call window = +/- 3 days; window not applicable if still hospitalized. 


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5.5.  Concomitant Medication 
 
Any treatment or medication for respiratory distress associated with COVID-19 infection, 
underlying medical conditions, or prophylaxis, to include, but not limited to prescribed 
medication, anticoagulants, corticosteroids, convalescent plasma, or VEKLURY® 
(remdesivir) is allowed on this study. For this study, a prescription medication is defined 
as a medication that can be prescribed only by a properly authorized/licensed clinician. 
 
All concomitant medications will be recorded on the case report forms (eCRFs), to 
include concomitant prescription medications, over-the-counter medications, and non-
prescription medications taken by, or administered to the subject while on study 
(ongoing at baseline, changed from baseline (frequency and/or dose), started after 
baseline) until discharge. Medication started after discharge will be collected only if 
administered for the treatment of a Serious Adverse event. Any medication continuing 
after discharge will be recorded as ongoing in the eCRF. 
 
Medications that are needed for the purpose of mechanical ventilation i.e. any induction 
agents, muscle relaxants, or sedative agents are not needed to be captured. Medication 
administered for other procedures that might be performed while in ICU e.g. 
opiates/analgesics for tracheostomy, local anesthetics for chest tubes or other 
procedures, oral hygiene care, etc. are not needed to be captured. Anything that is 
administered for the treatment of COVID should be captured, as well as any 
vasopressors that might be required post infusion, (since there is the potential BP affect 
with USB002). Medication for complications of COVID e.g. prophylactic anticoagulation, 
DVTs, strokes, MIs, AKI, stroke, hemorrhage, etc. are captured. In addition, antibiotics 
used prophylactically or as treatment for any infection, and use of nephrotoxic agents, 
including any imaging agents, should be captured. 
 
5.6. Prohibited Medication 
 
Ongoing treatment of cancer with chemotherapy is not allowed while enrolled in the study.  
Use of vasopressors at time of infusion is not permitted. 
 
6.  ASSESSMENT OF SAFETY  
 
6.1.  Safety Parameters 
 
Safety assessments to be conducted in this study include: 
 
• AEs collected at all study visits from the time of first study drug dose; 
• Changes in concomitant medications;  
• Findings from physical examinations; 
• Changes in laboratory parameters; 
• Changes in respiratory and cardiovascular assessments. 
 
Safety and tolerability will be assessed by the DSMB (see Section 6.6). 


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Any AE that is considered definitely, probably, or possibly related to USB002 is potentially 
a DLT. DLT will be defined per the DSMB SMP. 
 
6.1.1.  Definition of Adverse Events (AE) 
 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
change in structure, function, sign, or symptom temporally associated with the use of a 
medicinal product, whether related to the product. Undesirable changes in laboratory 
values should not be considered AEs unless they are considered symptomatic of a clinical 
condition or diagnosis, are evaluated as clinically significant, or require therapy. 
Worsening of a pre-existing condition is also considered an AE, as is the discovery of an 
abnormal finding during a physical exam (done per SOC) that was not included in the 
medical history. Clinical conditions attributable to disease progression will be considered 
AEs. 
 
6.1.2.  Definition of Serious Adverse Events (SAE) 
 
An SAE is any AE that meets at least one of following criteria: 
 
• Is fatal; 
• Is life-threatening; in the opinion of the Investigator, the subject was at 
substantial risk of dying at the time of the adverse event, or use or continued use 
of the medical product might have resulted in the death of the patient; 
• Is a persistent or significant disability or incapacity; 
• Requires hospitalization or prolongs an existing hospitalization. Hospitalization 
will be defined as such if > 24 hours, or a hospitalization that requires an 
intervention to treat emergent symptomatology (non-diagnostic); 
• Exposure prior to conception or during pregnancy may have resulted in a 
congenital anomaly or birth defect in the child; 
• Other important medical events not noted in events above, but may be 
considered a serious experience when, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes as listed in #1-5 in this definition. 
 
6.2 Classification of an Adverse Event 
 
6.2.1. Severity of Event 
 
Signs and symptoms will be graded by the Investigator as mild, moderate, severe, life-
threatening, or fatal according to the following definitions: 
 
• Mild:  The AE is transient and does not interfere significantly with the subject’s 
normal functioning level. The AE resolves spontaneously or may require minimal 


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therapeutic intervention; 
• Moderate:  The AE produces limited functional impairment and may require 
therapeutic intervention. The AE produces no sequelae; 
• Severe:  The AE results in significant impairment of function and may lead to 
temporary inability to resume the subject’s normal life pattern. The AE produces 
sequelae which require prolonged therapeutic intervention; 
• Life-Threatening:  The AE results in life-threatening consequences, urgent 
intervention is indicated, urgent operative intervention is indicated, or the patient 
is at risk of death at the time of the event if immediate intervention is not 
undertaken; 
• Fatal:  The AE results in death. 
 
Further, toxicities should be evaluated according to the NCI-CTCAE v5.0 criteria.  
 
6.2.2.  Relationship to Study Drug  
 
The following five-point scale will be used by the Investigator to rate the relationship of 
the AE to the study drug: 
 
• Definitely related: A clinical event (including laboratory test abnormality) 
occurring in a plausible time relationship to drug administration, and which cannot 
be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (de-challenge) should be clinically plausible. The event must 
be definitively associated pharmacologically, using a satisfactory re-challenge 
procedure, if necessary;  
• Probably related: A clinical event (including laboratory test abnormality) with a 
reasonable time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a clinically 
reasonable response on withdrawal (de-challenge). Re-challenge information is 
not required to fulfill this definition; 
• Possibly related: A clinical event (including laboratory test abnormality) with a 
reasonable time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear; 
• Unlikely to be related: A clinical event (including laboratory test abnormality) 
whose temporal relationship to drug administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after 
administration of the trial medication) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments); 
• Not related: An event for which sufficient information exists to conclude that the 
etiology of the event is unrelated to the study drug. An alternative definitive etiology 
should be documented by the Investigator. 
 


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6.2.3.  Expectedness  
 
Expectedness determination will be related to the study drug specifically. An event may 
be unexpected in the subject but that in itself does not qualify as unexpected; review 
against information available and provided for the study drug is what will determine 
expectedness. 
 
Sponsor will be responsible for determining whether an AE is expected or unexpected. 
An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study drug, in the 
protocol and within the Investigator Brochure. 
 
6.3. 
Adverse Event Follow-Up 
 
AEs will be recorded throughout the study and will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). AEs ongoing at the final study visit or early 
termination, must be followed until resolution or until the Investigator determines them to 
be stable and/or adequately managed.  
 
Date and time of onset and resolution (if applicable) of all AEs will be documented. 
 
All SAEs must be followed until the event resolves or, in the opinion of the Investigator, 
become stable.  
 
The Sponsor will report any serious, unexpected and drug-related AE to applicable 
regulatory agencies and provide these reports to the clinical trial sites. The Investigator 
must promptly inform the IRB of such events and retain a copy of the notification in the 
Investigator Site File (ISF). 
 
6.4. 
Reporting Procedures 
 
6.4.1 Adverse Event Reporting 
 
AEs will be captured from the start of USB002/placebo infusion until Day 28 or hospital 
discharge, whichever occurs last. Any AEs ongoing at Day 28 (or discharge) will be 
followed/assessed up to the Day 60 Telemed visit.  No new AEs will be collected following 
discharge.  SAEs (new or ongoing) will be followed and/or collected until Day 60. 
 
All AEs (whether attributable to the study drug) occurring during the study observed by 
the Investigator or reported by the subject will be recorded on the eCRF. The following 
information will be recorded for all AEs: 
 
• 
Event: name/condition/diagnosis/description; 
• 
Onset and resolution time and/or date; 
• 
Severity; 
• 
Relationship to study drug (assessment by staff trained and authorized to 


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diagnose); 
• 
Action taken; 
• 
Seriousness.  
6.4.2 Serious Adverse Event Reporting  
 
All SAEs are to be marked in EDC as an SAE.  However, sites are not expected to 
complete the SAE forms if the event occurs while subject is in the ICU.  If an event is 
serious while not in the ICU, regular reporting of SAEs will occur (SAE forms completed 
and forwarded to MM immediately). 
 
Dr. Antony Verco 
Medical Monitor 
E-mail: tony.verco@usbiotest.com 
Phone: 805-235-9193 
Fax: 805-980-4897 
 
24-hour Emergency Contacts: 
 
 
 
Medical Monitor Tony Verco, MD 805-235-9193 or Medical Director Gere 
diZerega, MD 805-630-2800  
 
 
   
 
SAEs occurring during the study period, from the initiation of USB002/placebo infusion 
up to Day 60, will be recorded. 
 
SAEs experienced by subjects enrolled into the study, who are not transferred to the 
ICU, will be reported according to standard regulatory requirements and guidelines.  
 
For all patients enrolled outside ICU but progress and end up in ICU: all SAEs that 
occur prior to ICU admission should be recorded and reported per usual requirements, 
any SAE that occurs after ICU admission will be recorded as an SAE in the EDC but no 
SAE form will be required to be submitted.  Should the Medical Monitor require further 
information that will be requested directly. 
 
For all patients enrolled when already in ICU, all events are to be recorded as an SAE in 
the EDC but will not require reporting on an SAE form unless the Investigator feels the 
event was not a consequence/progression of COVID, in which case the event should be 
reported on an SAE form per standard practice. 
 
For all those patients discharged from ICU, all SAEs that occur after discharge are to be 
recorded and reported per standard practice. 
 
The Sponsor will request additional information or documentation as required. As 
applicable, the Investigator should provide the following documentation at the time of 
notification if available: 
 


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• 
SAE Report Form; 
• 
Concomitant medication (supporting documents); 
• 
Relevant diagnostic reports; 
• 
Relevant laboratory reports; 
• 
Hospitalization notes; 
• 
Hospital discharge summary (if available). 
 
Due to the high rate of expected clinical deterioration in the ICU group of patients, the 
following anticipated adverse events/interventions associated with COVID-19 infection 
will be reported to the Sponsor immediately via email: 
 
• Abnormal pathology results from presentation (including inflammatory markers 
related to a hyperinflammatory response) 
• Secondary infection 
• Renal failure 
• Cardiac disease e.g., arrythmias, right heart failure 
• Intubation and ventilation 
• Venous thromboembolism/arterial thrombosis 
• Other clinically significant end organ damage, either biochemical e.g., acute 
kidney injury, liver impairment, or clinical e.g., stroke 
• Death from COVID-19 
 
6.4.3 Reporting of Pregnancy  
 
A female patient is of childbearing potential unless she has had a hysterectomy, is at least 
one year postmenopausal, or has undergone tubal ligation. All sexually active patients 
must use a reliable method of birth control until Day 60. Any pregnancy occurring in a 
subject or a subject’s sexual partner during the study must be reported to US Biotest as 
soon as the Investigator is aware of it. The pregnancy will not be considered an SAE; 
however, information on the event will be collected and the outcome followed to birth or 
termination of pregnancy. 
 
Any pregnancy complication or premature terminations including miscarriage, 
spontaneous abortion, or elective termination of a pregnancy for medical reasons will be 
reported as an SAE, as described in Section 6.4.2. Should the pregnancy result in a 
congenital anomaly or birth defect, a separate SAE report must be submitted. 
Furthermore, all neonatal deaths that occur within 30 days of the birth should be reported 
as SAEs, without regard to causality. In addition, any infant death that occurs after the 
30-day reporting period that the Investigator suspects is related to the in-utero exposure 
to the study treatment should also be reported. 
 
6.5 Study Halting Rules 
 
This study is a Phase 2 dose escalation study. Dose escalation will be determined 
following review of the safety and tolerability data in a cohort by the DSMB (see Section 
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all subjects who have received treatment will be followed for safety up to Day 60.  The 
Sponsor is responsible for notifying FDA of any temporary halt to the study or when the 
study is terminated. The Investigator will be required to notify the IRB accordingly. 
 
6.6.  Safety Oversight 
 
Safety will be overseen by the MM and the DSMB. The DSMB will be comprised of three 
medical experts, at least one of whom is an infectious disease specialist, and will be 
supported by a Statistician, who will not be a voting member. The DSMB will be 
independent and external to the Sponsor and study personnel. DSMB meetings will be 
conducted per the DSMB charter.   
 
All subject study data will be captured in an EDC system, allowing real-time access to 
safety and tolerability data and prior to proceeding to dose escalation.  
 
Prior to dose escalation, the DSMB will convene to review the cohort data, and generate 
a report outlining safety concerns from the subjects’ EDC data. This review will be 
conducted prior to proceeding with either addition of more subjects to a current cohort or 
proceeding to dose escalation in the next cohort. Assessment of progress and safety, as 
well and decision to dose-escalate, de-escalate, or increase the number of subjects in 
any group will be made by a DSMB and recorded in the DSMB meeting minutes as 
described in the SMP.  
 
The DSMB will evaluate data for each cohort after all 6 subjects in the cohort have 
completed 96-hours of the USB002/placebo infusion.  During the safety review, DSMB 
members will review all EDC safety data available; provided as reports generated directly 
from the EDC system and by the Data Management group. Emphasis will be placed on 
emerging safety trends or events which may constitute DLT (See Section 6.1). 
 
 
Enrollment will be halted during the cohort data review.  If the DSMB determines there is 
a reasonable safety concern, further enrollment and dose escalation may be delayed or 
halted. Escalation will continue until Part 1 enrollment is completed and the MTD is 
determined for Part 2.  
 
In Part 2, DSMB safety reviews will be conducted every 6 weeks.  As with Part 1, the 
DSMB may decide to halt or delay enrollment at any time during Part 2. 
 
7. STATISTICAL CONSIDERATIONS  
 
7.1 Statistical and Analytical Plans 
 
Formal Statistical Analysis Plans (SAP) will be prepared for each part (1 and 2) of this 
trial and will be signed off prior to study database lock and prior to any unblinding 
procedures. Part 1 will detail parameters and interpretation of safety and efficacy signals 
for dose escalation randomization groups (SOC plus USB002 and SOC plus placebo). 
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randomized groups. Any deviations to the planned analyses specified within the SAP will 
be justified in writing and presented in the final clinical study report.  
 
In Part 1, the data summaries, which will be supported with by-subject listings, will focus 
on the dose group for SOC plus USB002 as compared to the SOC plus placebo as well 
as time in trial.  
 
In Part 2, preliminary efficacy assessments will compare the endpoints for the two 
treatment groups for a signal of efficacy including: time without mechanical ventilation, 
all-cause mortality, survival at discharge, absence of respiratory failure, responders 
according to OSCI (see Appendix 1).  Data relating to efficacy response will be listed and 
summarized by dose cohort and time point, as appropriate. On each measurement day, 
the worst OSCI score will be recorded. Since the efficacy objective of this study is to 
assess the preliminary efficacy signals, statistical inference (e.g. p value) from the efficacy 
analyses will be used to assess the strength of the efficacy signals, and will not be 
adjusted for multiple comparisons. Unless specified in the analyses of efficacy endpoints 
(see Section 7.2.1), missing data will not be imputed.  
 
7.2 Description of Statistical Methods  
 
7.2.1  Analysis of the Efficacy Endpoint(s) 
 
Efficacy assessments will be based on the safety analysis set, which is defined as all 
subjects who have received at least one dose of study medication. Data relating to 
efficacy response will be listed and summarized by treatment group and time point, as 
appropriate. Any efficacy related outcomes in Part 1 will be present descriptively and will 
be detailed in the SAP. 
 
Summary statistics (mean, median, standard deviation, minimum, and maximum) and 
change from baseline to each scheduled study assessment for ventilator readings will be 
presented by treatment group. Baseline is defined as the latest non-missing assessment 
prior to the first study drug infusion.  
 
The primary efficacy outcome, time to peripheral capillary oxygen saturation (SpO2) ≥ 
94% on room air, sustained for at least 48 hours, through Day 28, will be estimated and 
compared between the two treatment groups using Kaplan-Meier (KM) analysis.  Subjects 
who do not achieve SpO2 ≥ 94%,  sustained for at least 48 hours, or die by Day 28 will be 
censored at Day 28.  As a supplemental analysis, an analysis using a Cox proportional 
hazards model incorporating the baseline covariates: age, baseline severity, and 
comorbidity,  will be performed. 
 
The secondary efficacy outcome of proportion of subjects with all-cause mortality within 
60 days from start of treatment, will be compared between the two treatment groups using 
Fisher’s exact test. In addition, as a supplemental analysis, a logistic regression analysis 
will also be performed to adjust for the same baseline covariates in the primary efficacy 
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The secondary efficacy outcomes that are binary, e.g., subjects weaned from mechanical 
ventilation within the 28-day, subjects progressing from non-invasive (at baseline) to 
mechanical ventilation, the proportions will be compared using Fisher’s exact test.  Death 
will be considered unfavorable outcome for these analyses, i.e. death prior to Day 28 will 
be considered as on mechanical ventilation.  In addition, analysis of subjects weaned 
from mechanical ventilation will be conducted on those who were on mechanical 
ventilation at baseline, and analysis of subjects progressing from non-invasive to 
mechanical ventilation will be conducted on those who were not on mechanical ventilation 
at baseline.  Time to hospital discharge will be analyzed using Kaplan-Meier method.  
Subjects who are not discharged by Day 28 or die will be censored at Day 28 for the 
analysis.    
 
All other secondary outcomes will be presented descriptively.  
  
7.2.1.1. 
Sub-Group Analyses 
 
The primary efficacy outcome and key secondary outcome will be analyzed for the Per 
Protocol population.  Subjects who withdrew prior to completing 48 hours in the treatment 
period will be excluded from the PP population.  Details will be described in the SAP. 
 
7.2.1.2.  Baseline Descriptive Statistics 
 
Complete demographic and baseline data will be tabulated. The medical history, which 
will be coded in MedDRA, will be presented. The disease history data, with a focus on the 
previous treatment and current staging, and the information collected on the procedure 
to apply the treatment will also be summarized.  
 
7.2.1.3. Concomitant Medication 
 
All medication taken during the trial will be, at a minimum, listed with the start and stop 
dates. Concomitant medications will be coded using the World Health Organization 
(WHO) drug dictionary and summarized by anatomical therapeutic chemical (ATC) level 
2 (pharmacological or therapeutic sub-group) and ATC level 4 (chemical sub-group). 
 
7.2.1.4.   Interim Analyses  
 
There are no formal interim analyses planned. Safety and tolerability review will be 
conducted by the DSMB. 
 
7.2.2.  Extent of Exposure 
 
A summary of exposure to study drug including the total exposure to USB002 and the 
duration of exposure, will be provided. 
 


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7.2.3 Safety Analyses 
 
All subjects who are enrolled and infusion dose of study drug/placebo was started will be 
included in the descriptive analysis. All safety and tolerability assessments will be based 
on the safety analysis set, which is defined as all subjects who have been randomized 
into the study. All subjects will be included in the analyses irrespective of protocol 
deviations or discontinuation from the study. No formal statistical analysis will be 
performed on safety data. Part 1 and Part 2 will be presented separately.  
 
7.2.3.1.  Adverse Events 
 
The number of subjects reporting, and number of events reported will be presented in 
frequency tables (overall, by intensity, by relationship and by outcome) for each dose 
cohort in each group. AEs of special interest will be presented separately. No specific 
AEs of interest are prospectively defined for the purposes of this study. AEs will be coded 
according to MedDRA (Vn. 23.1). All AE and abnormal laboratory variables will be 
assessed according to the CTCAE v5.0 grading system. Treatment-emergent adverse 
events (TEAEs) (events not present at baseline and worsened in severity following the 
start of treatment) will be presented. The following summaries will be provided at a 
minimum (the SAP will provide further details of summaries that will be provided): 
 
• A summary of the number and percentage of patients reporting any TEAE/SAE; 
• A summary of the number and percentage of patients reporting TEAEs according 
to severity; 
• A summary of the number and percentage of patients reporting related 
TEAEs/SAE; 
• A summary of the number and percentage of patients reporting TEAE/SAE by 
treatment group, preferred term, and system organ class; 
• A summary of the number and percentage of patients reporting TEAE/SAE by 
treatment group, severity, and system organ class; 
• A summary of the number and percentage of patients reporting TEAE/SAE by 
treatment group, by relationship to study drug, and system organ class; and 
• A summary of the number and percentage of patients reporting a TEAE leading to 
withdrawal from study treatment by treatment group, preferred term, and system 
organ class. 
 
Listings of the above will also be presented for the DSMB reviews on an ongoing basis; 
for each subject and for each TEAE, the worst severity recorded will be attributed and 
used in the by-severity summaries.  
 
7.2.3.2.  Laboratory Analytes 
 
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change from baseline to each scheduled study assessment will be presented for all 


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continuous laboratory parameters. Baseline is defined as the latest non-missing 
laboratory assessment prior to the first study drug infusion.  
 
For continuous laboratory parameters, shift tables of the number and percentage of 
patients with normal, low, or high results (as defined by the normal ranges) will be 
presented from baseline to the most extreme post baseline value by group and treatment 
group. For categorical urinalysis parameters, shift tables of the number and percentage 
of patients by classification at baseline and each post baseline visit will be presented. 
Abnormal laboratory values will be graded according to the latest version of the CTCAE 
(v5.0). All laboratory assessments will be listed. 
 
7.2.3.3.  Vital Signs 
 
Summary statistics (mean, median, standard deviation, minimum, and maximum) and 
change from baseline to each scheduled study assessment for systolic and diastolic BP, 
HR, RR, SpO2, and body temperature will be presented by treatment group. Baseline is 
defined as the latest non-missing vital sign value prior to the first study drug infusion. By-
patient listings of all vital signs will be presented flagging the notable values. 
 
7.2.3.4.  ECG Evaluation 
 
Summary statistics (mean, median, standard deviation, minimum, and maximum) and 
change from baseline to each scheduled study assessment for all ECG parameters will 
be presented by treatment group. Baseline is defined as the latest non-missing value prior 
to the start of the first treatment infusion.   
 
A shift table from baseline to maximum post baseline ECG result of the number and 
percentage of subjects with normal, clinically insignificant abnormalities and clinically 
significant abnormalities will be presented. The number and percentage of subjects 
meeting threshold criteria for QTcF and QTcB will be presented by treatment group. The 
threshold criteria for QTcF and QTcB interval prolongation are as follows: [International 
Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) E14]: >450 ms, >480 ms, >500 ms, and interval 
increases from baseline of >30 ms and >60 ms. 
 
By-patient listings of notable abnormal changes in ECG parameters will be presented 
along with the overall interpretation of ECGs for Part 1 at visits 1 (0, 48, 72, 96 hrs), 5, 7, 
9 and 14 and Part 2 at Days 1 and 16. 
 
7.2.3.5.  Physical Examination 
 
Results from the physical examinations (to include lung auscultation) will be summarized, 
as available, based on categories “normal” and “abnormal”. Baseline is defined as the 
latest non-missing PE value prior to the first study drug infusion. By-patient listings of 
physical examination data will be listed. 
 


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7.3. Sample Size  
 
Given the dose escalation nature of this study, no specific sample size calculations were 
performed for Part 1. The number of subjects for each escalation was chosen to provide 
reasonable confidence in safety to inform the dose for Part 2.  For Part 2, sample size is 
determined not based on statistical power; 15 subjects per group are planned to be 
enrolled, which is expected to provide sufficient data to evaluate the efficacy signals for 
this study. 
 
7.4. 
Measures to Minimize Bias 
 
7.4.1 Enrollment/Randomization/Masking Procedures 
 
Study registration (subject number assignment) will be conducted through an IWRS 
system upon enrollment. The Sponsor, Investigator, pharmacy, and all study staff will be 
blinded.    
 
7.4.2 Evaluation of Success of Blinding 
 
Not Applicable 
 
7.4.3 Breaking the Study Blind/Participant Code 
 
The requirements for unblinding (to include emergency unblinding) will be controlled with 
immediate notifications transmitted to key stakeholders and recorded in the audit trail. All 
procedures will be detailed in the IWRS Procedure Manual. 
 
8.  CLINICAL MONITORING  
 
US Biotest monitors, or delegates, will conduct scheduled site visits to the investigational 
centers or remotely, for the purposes of monitoring the study. The Investigator agrees to 
allow monitors and other authorized sponsor personnel or designees, access to the 
subject’s complete and comprehensive medical and research study records, ISF, 
pharmacy document and any other applicable documents as needed to assure that the 
conduct of the study and the safety of the study subject is maintained and within 
compliance. In addition, FDA or other government agencies may request an inspection, 
following notification to the site. In such an event, the Investigator agrees to notify the 
Sponsor immediately, or at the earliest possible opportunity of the request. The clinical 
trial site will allow access to the inspectors to review requested records. 
 
US Biotest will conduct the site initiation visit to provide the Investigator and study staff 
with a comprehensive overview of the protocol and study procedures and to review 
mutual obligations and requirements of regulatory authorities. The ISF (may be identified 
as regulatory file or binder) containing required documentation will be up to date 
throughout the life of the study and maintained at the site for reference and inspection. 
 


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Routine monitoring visits will be conducted on-site or remotely to assure compliance with 
the study protocol and regulatory requirements, to review and verify the subject’s eCRF 
by comparing with source documents, to ensure adequate records of clinical supplies are 
maintained, and to assess the continued suitability of the investigational site. On 
completion of the study, the monitor will conduct a final visit to assess the conduct of the 
study, inform the Investigator of ongoing and final regulatory obligations and perform a 
final inventory of all clinical supplies to be either returned to US Biotest, destroyed or 
retained at the site. 
 
9.  QUALITY CONTROL AND QUALITY ASSURANCE  
 
9.1.  Electronic Data Capture 
 
Data required by the protocol will be collected and entered into a validated data 
management system that is compliant with all regulatory requirements. The eCRF is an 
electronic document designed to record all protocol-required information to be reported 
to the Sponsor on each study subject. 
 
Data recording must follow the instructions described in the CRF Completion Guidelines. 
The Primary Investigator (PI) has ultimate responsibility for the collection and reporting of 
all clinical data entered in the eCRF. The PI or designee, as identified on form FDA 1572, 
must electronically sign the completed eCRF for each participating subject to attest to its 
accuracy, authenticity, and completeness. 
 
The EDC application being used in this study will be TrialMaster® version 5.0 from Anju 
Life Sciences software. TrialMaster studies are hosted from a state-of-the-art data center 
with rigorous physical and electronic security. All data is backed up daily to Iron Mountain, 
in Ohio and is also backed up to a hurricane-proof bunker in Fort Lauderdale, Florida. 
Anju Life Sciences is certificated with European “Safe Harbor” regulations (all necessary 
measures are in place to protect patient confidentiality even with the data being stored in 
a US data center). The data management and statistical CRO, McDougall Scientific Ltd., 
ensures that the development of the eCRF follows their SOPs which are based on the 
Systems Development Life Cycle methodology. Access to the system is restricted by 
username and password; these are controlled by the Data Management CRO. All 
personnel using the system will be trained and the training documented. All changes to 
the database are recorded in an audit trail. The database will be locked when all 
outstanding queries have been addressed, all agreed-to data is marked as source-
verified, and the PI has signed off on the eCRF contents.  
 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements. 
 


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10. ETHICAL STANDARD  
 
The study will be conducted in accordance with the ethical principles of the Declaration 
of Helsinki. Sponsor and Investigator will comply with their responsibilities as defined in 
21 CFR 312.50-312.70. 
 
10.1.  Institutional Review Board (IRB) 
 
Regulatory oversight will be conducted by Western IRB/Copernicus Group (WCG IRB) 
services. Before the start of the study, the sponsor will be responsible to submit the study 
protocol, informed consent form, and/or other appropriate documents to WCG IRB in 
accordance with local legal requirements. It is the responsibility of the Sponsor and 
Investigator to assure that all aspects of the IRB review are conducted in accordance with 
current regulations. The Sponsor and the Investigator must inform each other in writing 
that all ethical and legal requirements have been met before the first subject is enrolled 
in the study. Amendments to the protocol will be subject to the same requirements as the 
original protocol. All changes to the consent form will be IRB-approved; a determination 
will be made regarding whether previously consented participants need to be re-
consented by the IRB. 
 
10.2 Informed Consent Process  
 
10.2.1. 
Subject Information and Consent 
 
Subjects being considered for participation in this study will be provided an informed 
consent form (ICF) to read and sign before being permitted to participate, by the subject 
or by legal representative if subject is incapacitated and unable to consent. The ICF will 
describe the study drug and any prior findings from previous studies; study procedures 
including the timing of study clinic visits and responsibility to adhere to those timelines; 
any risks which may be associated with the study drug or the procedures being carried 
out in the study; and all other items required under 21 CFR Part 50.25.  
 
10.2.2. 
Consent Procedures and Documentation 
 
The Investigator will obtain informed consent from each subject enrolled in the study, in 
accordance with the FDA regulations 21 CFR 50.20 - 50.27 and the laws and regulations 
of the states and countries in which the investigation is being conducted. The IRB must 
approve the ICF to be used at the study site. Written IRB approval must be provided to 
the Investigator, before permitting subject enrollment into the study. 
 
It is the responsibility of the Investigator to ensure that informed consent is obtained from 
the subject or legal representative before any activity or treatment is undertaken which is 
not part of routine care; consent will be obtained prior to participation in Part 1 or Part 2 
of the study. This includes, but is not limited to, the performance of diagnostic or 
therapeutic procedures and the administration  of the first dose of study drug.  
 


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In the event a protocol is amended, the consent form may be revised to reflect those 
changes; in which case, it is the responsibility of the Investigator to ensure that an 
amended consent is approved by the IRB and signed by all subjects currently on study, 
as well as those subsequently entered in the study, if required by the IRB. The terms of 
the consent and when it was obtained must also be documented in the eCRF. The 
original, signed informed consent document must be maintained on file at the study site 
and be made available for review during monitoring visits and site audits. 
 
10.3.  Confidentiality 
 
All local legal requirements regarding data protection will be enforced. All study findings 
and documents will be regarded as confidential. The Investigator and members of the 
research team must not disclose such information without prior written approval from the 
Sponsor. The anonymity of participating subjects must be maintained to the extent 
required by law. Throughout documentation and evaluation, the subjects will be identified 
in the eCRFs and other documents submitted to the Sponsor by their initials (if allowed 
by institution, local and/or state requirements), birth date, and subject number. 
Documents are not to be submitted to the Sponsor which identify the subject and must 
be maintained in confidence by the Investigator. The subjects will be informed that all 
study findings will be stored and handled in the strictest confidence, according to local 
requirements, and that authorized research Investigators and agents of the FDA, the NCI, 
and authorized personnel or delegates of the Sponsor have the right to inspect their 
medical records. 
 
11.  DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial site staff under the supervision of 
the site PI. The Investigator is responsible for ensuring the data is attributable, legible, 
contemporaneous, original, accurate, and complete (ALCOA+) compliant.  
  
For electronic source, the institution must provide a secure, validated electronic medical 
record (EMR) data management system that is 21 CFR Part 11 compliant and meets all 
regulatory requirements, regulations and quality standards. 
 
For paper source, documentation is expected to be completed in a neat, legible manner 
to ensure accurate interpretation of data. Black or blue ink is required to ensure clarity of 
reproduced copies.  
 
Source documents will be maintained for recording data for each participant enrolled in 
the study. Data reported in the eCRF derived from source documents should be 
consistent with the source documents. Any discrepancies should be explained and 
captured in a progress note and maintained in the subject’s official electronic study 
record. 
 


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11.1 Study Records Retention 
 
The Investigator must retain a copy of all study documents in accordance with FDA or 
local regulations, whichever are the more stringent. 
 
The Investigator must maintain study documents: 
 
• 
For a minimum of two years following the date the marketing application (NDA) 
is approved for the indication for which the drug was investigated;  
• 
For a minimum of two years following the release date of the final report, if no 
marketing application is to be filed, or if the marketing application is not 
approved for the indication of which the drug was investigated or is 
discontinued, and FDA has been notified. 
 
If the Investigator relocates, retires, or withdraws from the study for any reason, the study 
records may be transferred to an acceptable designee, such as another Investigator, 
another institution, or the Sponsor. The Investigator must obtain the Sponsor’s written 
permission before transferring or disposing of any records. 
 
11.2 Source Documents  
 
An eCRF is required and must be completed for each consenting and enrolled subject by 
qualified and authorized personnel. Any correction to eCRF entries must be reflected in 
a validated audit trail. Only data required by the protocol for the purposes of the study 
should be collected within the EDC. The Investigator must maintain adequate and 
accurate source documents on which the eCRFs for each subject are based. They will be 
separate and distinct from the eCRFs. These records should include detailed notes on: 
 
• The medical history prior to the subject’s involvement in the study; 
• Date of informed consent; 
• Basic identifying information that links the subject medical record with the 
eCRFs; 
• Screening, enrollment, treatment visits, End of Treatment and follow-up visit 
details including dates and reasons for early termination; 
• Results of all diagnostic tests performed, diagnoses made, therapy provided, 
and any other data on the condition of the subject; 
• All AEs; 
• The subject’s exposure to the study medication; 
• The subject’s exposure to any concomitant therapy; 
• All relevant observations and data on the condition of the subject throughout 
the trial; 
• Justification for all entries in the subject’s eCRF. 
 


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11.3 Protocol Deviations  
 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical 
Practice, or FDA or IRB requirements. The noncompliance may be on the part of the 
participant, the Investigator, or the study site staff. As a result of deviations, corrective 
actions are required and expected to be implemented promptly by the site. 
 
These practices are consistent with ICH E6(R2):  
 
• 4.5:  Compliance with Protocol, Sections 4.5.1, 4.5.2, 4.5.3 and 4.5.4;  
• 5.1:  Quality Assurance and Quality Control, Section 5.1.1;  
• 5.20:  Noncompliance, Sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site to use continuous vigilance to identify and report 
deviations as soon as possible after occurrence. All deviations must be addressed in 
study source documents, and reported to the Sponsor, the Data Management group and 
to the local IRB, per guidelines. The site PI/study staff is responsible to adhere to any IRB 
reporting requirements.  
 
Serious site non-compliance and an inability of the Sponsor to bring the site back into 
compliance, will be reported to FDA in accordance with their requirements.  
 
12.  PUBLICATION AND DATA SHARING POLICY 
 
By signing the study protocol, the Investigator agrees with the use of results of the study 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals. If necessary, the authorities will be notified of 
the Investigator's name, address, qualifications, and extent of involvement. The Sponsor 
will prepare an integrated clinical/statistical report. Publication/presentation of data is not 
allowed without explicit permission from The Sponsor. Submission of data for 
publication/presentation will be coordinated and approved by The Sponsor in 
collaboration with the Investigator. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have 
adopted a clinical trials registration policy as a condition for publication. The ICMJE 
defines a clinical trial as any research project that prospectively assigns human subjects 
to intervention or concurrent comparison or control groups to study the cause-and-effect 
relationship between a medical intervention and a health outcome. Medical interventions 
include drugs, surgical procedures, devices, behavioral treatments, process-of-care 
changes, and the like. Health outcomes include any biomedical or health-related 
measures obtained in subjects, including AE. The ICMJE policy, and the Section 801 of 
the FDA Amendments Act of 2007, requires that all clinical trials be registered in a public 
trials registry such as ClinicalTrials.gov, which is sponsored by the National Library of 
Medicine. Data entered to the ClinicalTrials.gov website will be in accordance with FDA 
requirements for this registration and for publication of study results on that site. 
 


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13.  LIABILITY AND INSURANCE  
 
The Sponsor will take out reasonable third-party liability insurance coverage in 
accordance with all local legal requirements. This insurance will cover all parties involved 
in the trial including, but not necessarily limited to, the PI, clinical trial site, and subjects.  
As a precautionary measure, the Investigator, the persons instructed by him and the 
hospital, practice or institute are included in such coverage in regard to work done by 
them in carrying out this study, to the extent that the claims are not covered by their own 
professional indemnity insurance. 
 
 


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14.  REFERENCES 
 
1. Donoghue M. Heart block, ventricular tachycardia, and sudden death in ACE2 
transgenic mice with downregulated connexins. Journal of Molecular and Cellular 
Cardiology. Academic Press; 2003 Sep 1;35(9):1043–53.  
2. Fahy RJ, Lichtenberger F, McKeegan CB, Nuovo GJ, Marsh CB, Wewers MD. The 
Acute Respiratory Distress Syndrome. American Journal of Respiratory Cell and 
Molecular Biology. American Thoracic Society; 2012 Dec 20; 28(4):499–503.  
3. Fleming I, Kohlstedt K, Busse R. New fACEs to the Renin-Angiotensin System. 
Physiology; 2005 Apr 1; 20(2):91–5.  
4. Flemming A. Unravelling SARS lethality. Nat Rev Drug Discov. Nature Publishing 
Group; 2005 Sep 1; 4(9):718–8.  
5. Freihaut F, Boer B, Johnson D. COVID-19 ARDS Ventilator PEEP Titration Protocol. 
2020. 
6. Imai Y, Kuba K, Penninger JM. The discovery of angiotensin converting enzyme 2 and 
its role in acute lung injury in mice. Exp Physiol; 2008 May; 93(5):543-548. 
7. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe 
acute lung failure. Nature. Nature Publishing Group; 2005 Jul 7; 436(7047):112–6.  
8. Ishiyama Y, Gallagher PE, Averill DB, et al. Upregulation of Angiotensin-Converting 
Enzyme 2 After Myocardial Infarction by Blockade of Angiotensin II Receptors. 
Hypertension. Lippincott Williams & Wilkins; 2004 May 1; 43(5):970–6.  
9. Kostenis E, Milligan G, Christopoulos A, et al. G-Protein–Coupled Receptor Mas Is a 
Physiological Antagonist of the Angiotensin II Type 1 Receptor. Circulation. Lippincott 
Williams & Wilkins; 2005 Apr 12; 111(14):1806–13. 
10. Lui Y, Yang Y, Zhang C et al. Clinical and biochemical indexes from 2019-nCoV 
infected patients linked to viral loads and lung injury. Science China Life Sciences 
2020 Mar; 63(3); 364-374. 
11. NCT 04332666 Angiotensin-(1,7) Treatment in COVID-19: the ATCO Trial. 
12. Nehme A, Zouein FA, et al. An update on the tissue renin angiotensin system and its 
role in physiology and pathophysiology. J. Cardiovas Dev Dis 2019; 6:14-30. 
13. NIH NHLBI Clinical Network, Mechanical Ventilation Protocol Summary. 2008 July.  
14. Reddy R, Asante I, Liu P, Liebler J, Borok Z, Rodgers, et al. Circulating angiotensin 
peptide levels in Acute Respiratory Distress Syndrome correlate with clinical 
outcomes: A pilot study. PLoS ONE; 2019; 14(3): e0213096. 
15. Shenoy V, Ferreira AJ, Qi Y, et al. The angiotensin-converting enzyme 
2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung 
fibrosis and pulmonary hypertension. American Journal of Respiratory and Critical 
Care Medicine. American Thoracic Society; 2010 Oct 15; 182(8):1065–72.  
16. Soto M, diZerega G, Rodgers KE. Countermeasure & therapeutic: A(1-7) to Treat 
Acute Respiratory Distress Syndrome due to COVID-19 Infection. Journal of the 
Renin-Angiotensin-Aldosterone System; 2020 Oct; 1-5. 
17. Walther T, Kuebler W, Berlin CU. Use of an ang-(1-7) receptor agonist in acute lung 
injury. 2011 Nov 17.  
18. WHO R&D Blueprint novel Coronavirus: COVID-19 therapeutic trial synopsis. 2020 
Feb 18. 


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19. Yamada K, Iyer SN, Chappell MC, Ganten D, & Ferrario CM. Converting enzyme 
determines plasma clearance of angiotensin-(1-7). Hypertension; 1997 Sep; 32(3): 
496-502. 
20. Yamazato Y, Ferreira AJ, Hong K-H, Sriramula S, Francis J, Yamazato M, et al. 
Prevention of Pulmonary Hypertension by Angiotensin-Converting Enzyme 2 Gene 
Transfer. Hypertension. Lippincott Williams & Wilkins; 2009 Aug 1; 54(2):365–71.  
21. Zambelli V, Bellani G, Borsa R, Pozzi F, Grassi A, Scanziani M, et al. Angiotensin-(1-
7) improves oxygenation, while reducing cellular infiltrate and fibrosis in experimental 
Acute Respiratory Distress Syndrome. ICMx. SpringerOpen; 2015 Dec 1; 3(1):1–17. 
22. Zhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak associated with a new 
coronavirus of probable bat origin. Nature. Nature Publishing Group; 2020 Mar; 
579(7798):270–3.  
 
 
 
 


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APPENDIX 1: ORDINAL SCALE FOR CLINICAL IMPROVEMENT (OSCI)  
 
Score Patient State 
Descriptor  
0 
Uninfected 
No clinical or virological evidence of infection 
1 
Ambulatory 
No limitation of activities 
2 
Limitation of activities 
3 
Hospitalized; Mild Disease 
Hospitalized, no oxygen therapy  
4 
Oxygen by mask or nasal prongs 
5 
Hospitalized; Severe Disease 
Non-invasive ventilation or high-flow oxygen  
6 
Intubation and mechanical ventilation  
7 
Ventilation + additional organ support – pressors, renal 
replacement therapy, ECMO 
8 
Dead 
Death  
 
WHO R&D Blueprint novel Coronavirus: COVID-19 therapeutic trial synopsis. 2020 Feb 18. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version 6.0 
USB002-2020-001 
 
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APPENDIX 2: SPONTANEOUS BREATHING TRIAL (SBT) 
 
Daily SBT will be conducted (as appropriate) to determine terminating oxygen needs. 
Daily monitoring of weaning criteria will be performed as per institutional standard and 
recorded.  
 
Weaning Criteria for initiating SBT: 
 
• SpO2 ≥ 0.88 with FiO2 ≤ 0.40 and PEEP ≤ 8 cm H2O; 
• PEEP and FiO2 ≤ values of previous day; 
• Acceptable spontaneous breathing efforts. (May decrease vent rate by 50% for 
5 minutes to detect effort); 
• BP ≥ 90/60 mmHg without vasopressor support. 
 
If all above criteria are met, initiate trial with up to 30 minutes of spontaneous breathing 
with FiO2 < 0.5 and PEEP < 5, as follows:  
 
1. Place on T-piece, tracheostomy collar, or CPAP ≤ 5 cm H2O with Pressure 
Support < 5 cm H2O  
2. Assess for tolerance for up to 30 minutes:  
a. SpO2 ≥ 90;  
b. Spontaneous Vt ≥ 4 mL/kg predicted body weight (PBW);  
c. Respiratory rate ≤ 35/min;  
d. pH ≥ 7.3;  
e. No respiratory distress (distress = 2 or more).  
• HR > 120% of baseline  
• Marked accessory muscle use  
• Abdominal paradox  
• Diaphoresis  
• Marked dyspnea  
3. If tolerated for at least 30 minutes, consider removal of endotracheal tube.  
4. If not tolerated, resume pre-weaning settings. 
 
 
 
 

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