A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation, Multicenter Study to Evaluate the Efficacy and Safety of F-652 (IL-22:IgG2 Fusion Protein) in Patients With Moderate to Severe COVID-19
Phase: PHASE2
Conditions: Covid19
Sponsor: EVIVE Biotechnology

A Phase 2, Randomized, Double-Blind, Placebo-Controlled,
Dose-Escalation, Multicenter Study to Evaluate the Efficacy and
Safety of F-652 (IL-22:IgG2 Fusion Protein) in Patients with
Moderate to Severe COVID-19  
 
Investigational Product: F-652 
Protocol Number: GC-652-04  
NCT04498377
Original Protocol: 01 July 2020 
Amendment: Version 2.0, 08 January 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CLINICAL STUDY PROTOCOL
A Phase 2, Randomized, Double-Blind, Placebo-Controlled,
Dose-Escalation, Multicenter Study to Evaluate the Efficacy and 
Safety of F-652 (IL-22:IgG2 Fusion Protein) in Patients with 
Moderate to Severe COVID-19
Investigational Product: F-652
Protocol Number: GC-652-04
Sponsor:
Generon (Shanghai) Corporation
Building 9, 787 Kangqiao Road
Shanghai, China 201315
Telephone: 86-21-6176-0866
Fax: 86-21-6176-0865
Original Protocol: 01 July 2020
Amendment: Version 2.0, 08 January 2021 
Confidentiality Statement
The information in this document is confidential and is not to be disclosed without the written 
consent of Generon (Shanghai) Corporation, hereinafter Generon, except to the extent that 
disclosure would be required by law and for the purpose of evaluating and/or conducting a 
clinical study for Generon. You are allowed to disclose the contents of this document only to 
your Institutional Review Board/Independent Ethics Committee and study personnel directly 
involved with conducting this protocol. Persons to whom the information is disclosed must be 
informed that the information is confidential and proprietary to Generon and that it may not be 
further disclosed to third parties.

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INVESTIGATOR AGREEMENT
By signing below I agree that:
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Generon to study personnel under my supervision. I will discuss this material with them to 
ensure they are fully informed about the study product and study procedures. I will let them know 
that this information is confidential and proprietary to Generon and that it may not be further 
disclosed to third parties. I understand that the study may be terminated or enrollment suspended 
at any time by Generon, with or without cause, or by me if it becomes necessary to protect the best 
interests of the study patients.
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board Regulations, and International Council for Harmonisation Guidelines 
for Good Clinical Practices.
______________________________________________
____________________
Investigator’s Signature
Date
______________________________________________
Investigator’s Printed Name

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SYNOPSIS
TITLE:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation,
Multicenter Study to Evaluate the Efficacy and Safety of F-652 (IL-22:IgG2 Fusion Protein) in 
Patients with Moderate to Severe COVID-19 
PROTOCOL NUMBER: GC-652-04 
INVESTIGATIONAL PRODUCT: F-652 
PHASE: 2 
INDICATION: Treatment of moderate to severe coronavirus disease 2019 (COVID-19) 
OBJECTIVES:
The primary objective is to evaluate the safety and efficacy of F-652 when intravenously (IV) 
administered in hospitalized, confirmed COVID-19 adult patients with moderate to severe
symptoms.
The secondary objective is to evaluate the pharmacodynamics (PD) of F-652 when IV 
administered in hospitalized, confirmed COVID-19 adult patients with moderate to severe 
symptoms.
POPULATION:
Inclusion Criteria

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STUDY DESIGN AND DURATION:
This is an interventional, multicenter, 2-arm, parallel-group, randomized, double-blind, 
placebo-controlled, dose-escalation, safety and efficacy study of F-652 treatment versus placebo 
in patients aged 18 years or older with a COVID-19 diagnosis confirmed by PCR. Eligible patients 
will have moderate to severe COVID-19 symptoms and will be hospitalized. 

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The study plans to include 4 cohorts, with enrolled patients being randomized 1:1 in a blinded 
manner on Day 1, following screening, to F-652 or placebo as follows: 
x
Cohort 1 (sentinel cohort): Four patients will receive either 
or placebo. 
Two patients will receive F-652 and 2 patients will receive placebo. Upon completion of 
sentinel dosing (7 days after last patient last dose), the Data Monitoring Committee (DMC) 
will evaluate the safety and tolerability data of the sentinel patients and determine if it is 
acceptable to dose the remaining patients in this dosing group in Cohort 2. 
x
Cohort 2: Fourteen patients will receive either
or placebo. Seven patients will 
receive F-652 and 7 patients will receive placebo. Upon completion of Cohort 2, the DMC 
will convene and review all available safety data to determine if the study can proceed to the 
next dose level. 
x
Cohort 3 (sentinel cohort): Four patients will receive either 
or placebo. 
Two patients will receive F-652 and 2 patients will receive placebo. Upon completion of 
sentinel dosing (7 days after last patient last dose), the DMC will evaluate the safety and 
tolerability data of the sentinel patients and determine if it is acceptable to dose the remaining 
patients in this dosing group in Cohort 4. 
x
Cohort 4: Sixteen patients will receive 
or placebo. Eight patients will 
receive F-652 and 8 patients will receive placebo. 
Treatment will begin on Day 1 following randomization. Patients assigned to active drug will 
receive a total of 2 doses of F-652 (1 IV infusion on Day 1 and 1 IV infusion on Day 8). Patients 
assigned to placebo will receive identical IV infusions of placebo vehicle on Days 1 and 8. If the 
patient is discharged from the site prior to Day 8, they will return for an outpatient visit to receive 
the second IV infusion and remain at the site for an approximate 2-hour observation period. All 
patients will receive available supportive and antiviral therapies as standard of care. Efficacy will 
be assessed on Days 15 and 29. Patients will be followed for safety until Day 60. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION:
EFFICACY ENDPOINTS:
Primary Efficacy Endpoint
The primary efficacy endpoint is the time to achieve a t2-point increase in the National Institute
of Allergy and Infectious Diseases (NIAID) 8-point ordinal scale from baseline by Day 29.  
The NIAID 8-point ordinal scale includes the following grades:  
1. Death;
2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 

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3. Hospitalized, on non-invasive ventilation or high-flow oxygen devices;
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, not requiring supplementation oxygen – requiring ongoing medical care
(COVID-19 related or otherwise);
6. Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care; 
7. Not hospitalized, limitation on activities and/or requiring home oxygen; and
8. Not hospitalized, no limitations on activities.
Secondary Efficacy Endpoints
The secondary efficacy endpoints, listed in hierarchical order, include the following: 
x
Time to achieve a t2-point decrease in the NIAID 8-point ordinal scale; 
x
Length of hospital stay from first dosing (Day 1) and percentage of patients who have 
recovered and been discharged from the hospital by Days 15 and 29; 
x
Mortality rate by Days 15 and 29; 
x
Proportion of patients with a t2-point increase in the NIAID 8-point ordinal scale from 
baseline to Days 15 and 29; 
x
Alive and respiratory failure free days by Days 15 and 29; 
x
Percentage of patients progressed to severe/critical disease by Day 15; and 
x
Occurrence of any new infections during the study by Day 29. 
SAFETY ENDPOINTS: 
The safety endpoints include the following:
x
All cause treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs);
x
Change from screening (baseline) in clinical symptoms and abnormal vital signs, abnormal 
laboratory tests (e.g., complete blood count, serum chemistry, routine urinalysis, and 
coagulation function), and 12-lead electrocardiograms (ECGs); and 
x
Relationship of any observed adverse events (AEs) with F-652 treatment based on the 
Investigator’s judgement. 

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STATISTICAL ANALYSES:
All computations will be performed using SAS® Version 9.4 or higher. 
The following analysis populations will be defined for this study:
x
Intent-to-Treat (ITT) Population: All patients who are randomized;
x
Safety Population: All randomized patients who receive at least 1 dose of study drug; and
x
Per Protocol (PP) Population: All patients in the ITT Population who finish the study as 
designed and without major protocol deviations.
Efficacy and safety data will be summarized by treatment arm. Data from all enrolled cohorts will 
be pooled together for analysis and sequentially analyzed by subgroups. 
The ITT Population will be used to examine efficacy for both the primary and secondary 
endpoints, the Safety Population will be used to assess the safety endpoints, and the PP Population 
will be used as a secondary population for the analysis of the primary efficacy endpoint.
Efficacy Analyses
Primary efficacy endpoint
The time to achieve a t2-point increase in the NIAID 8-point ordinal scale from baseline by
Day 29 will be analyzed using the Cochran-Mantel-Haenszel (CMH) test adjusting for the baseline 
NIAID 8-point ordinal scale. The NIAID 8-point ordinal scale will be assessed daily while the 
patient is hospitalized. If the patient remains hospitalized, the scale will also be assessed on 
Days 15 and 29. Any patient in the ITT Population with a missing primary endpoint result will be 
considered as a non-responder. The point estimates of the time to achieve a t2-point increase will 
be presented by treatment arm together with their 95% confidence intervals. The CMH odds ratio, 
associated 95% confidence interval, and p-value will also be presented.
Secondary efficacy endpoints
The time to achieve a t2-point decrease in the NIAID 8-point ordinal scale, proportion of patients 
with a t2-point increase in the NIAID 8-point ordinal scale from baseline to Days 15 and 29,
mortality rate by Days 15 and 29, percentage of patients who have recovered and been discharged 
from the hospital by Days 15 and 29, and percentage of patients progressed to severe/critical 
disease by Day 15 will be analyzed using the same method as described for the primary efficacy 
endpoint.
The number of alive and respiratory failure free days by Days 15 and 29, the length of hospital 
stay from first dosing (Day 1) to discharge by Days 15 and 29, and occurrence of any new 
infections during the study by Day 29 will be summarized using descriptive statistics.
Exploratory Endpoints
The exploratory endpoints will be summarized using descriptive statistics.
Safety Analyses
All safety analyses will be performed on the Safety Population.
AEs will be coded using the Medical Dictionary for Regulatory Activities and summarized by 
system organ class, preferred term, and treatment arm as the number and percentage of patients 

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with an event. The following subsets will also be summarized by treatment arm: TEAEs, 
treatment-related AEs, treatment-related SAEs, and AEs leading to drug discontinuation.  
Changes from baseline in clinical laboratory data, ECGs, vital signs, and physical examination 
findings will be summarized with descriptive statistics by treatment arm.
All demographic data will be summarized using descriptive statistics (number of patients, mean, 
median, standard deviation, minimum, and maximum) for continuous variables and using 
frequencies and percentages for discrete variables.
A formal statistical analysis plan providing full technical details of the planned analyses will be 
finalized prior to database lock.
SAMPLE SIZE DETERMINATION:
The study plans to randomize 38 patients, with 4 patients in Cohort 1 (sentinel cohort), 14 patients 
in Cohort 2, 4 patients in Cohort 3 (sentinel cohort), and 16 patients in Cohort 4. The sample size 
is based on the purpose of the study and experience with similar proof-of-concept studies, and not 
based on statistical power calculation.
SITES: Approximately 10 sites in the United States and Russia  

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TABLE OF CONTENTS
Signature Page ................................................................................................................................ 2 
Investigator Agreement................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 11 
List of Tables ................................................................................................................................ 15 
List of Figures ............................................................................................................................... 16 
List of Abbreviations and Definition of Terms............................................................................. 17 
1 Introduction and Background Information ............................................................................. 19 
1.1 
Epidemiology ................................................................................................................ 19 
1.2 
Clinical Features ............................................................................................................ 19 
1.3 
Treatment ...................................................................................................................... 20 
1.4 
Summary of Clinical Development of F-652 ................................................................ 20 
1.5 
Rationale ........................................................................................................................ 22 
1.6 
Risk/Benefit ................................................................................................................... 22 
2 Study Objectives ..................................................................................................................... 23 
2.1 
Primary Objective ......................................................................................................... 23 
2.2 
Secondary Objective ..................................................................................................... 23 
3 Study Description.................................................................................................................... 24 
3.1 
Summary of Study Design ............................................................................................ 24 
3.2 
Data Monitoring Committee ......................................................................................... 25 
3.2.1 Criteria for Data Monitoring Committee Review ............................................. 25 
3.3 
Study Indication ............................................................................................................ 26 
4 Selection and Withdrawal of Patients ..................................................................................... 27 
4.1 
Inclusion Criteria ........................................................................................................... 27 
4.2 
Exclusion Criteria .......................................................................................................... 27 
4.3 
Stopping Criteria ........................................................................................................... 29 
4.3.1 Criteria for Discontinuation of Dosing in Individual Patients .......................... 29 
4.3.2 Criteria for Study Termination .......................................................................... 29 
4.4 
Withdrawal Criteria ....................................................................................................... 30 
5 Study Treatments .................................................................................................................... 31 

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5.1 
Treatment Groups .......................................................................................................... 31 
5.2 
Rationale for Dosing ..................................................................................................... 31 
5.3 
Randomization and Blinding ......................................................................................... 31 
5.4 
Breaking the Blind ........................................................................................................ 31 
5.5 
Drug Supplies ................................................................................................................ 32 
5.5.1 Formulation and Packaging ............................................................................... 32 
5.5.2 Study Drug Preparation and Dispensing ........................................................... 32 
5.5.3 Study Drug Administration ............................................................................... 33 
5.5.4 Treatment Compliance ...................................................................................... 33 
5.5.5 Storage and Accountability ............................................................................... 33 
5.6 
Prior and Concomitant Medications .............................................................................. 34 
5.6.1 Prohibited Medications During the Study ......................................................... 34 
5.6.2 Documentation of Prior and Concomitant Medication Use and/or Procedures 34 
6 Study Procedures .................................................................................................................... 35 
7 Efficacy Assessments.............................................................................................................. 36 
7.1 
Efficacy Endpoints ........................................................................................................ 36 
7.1.1 Primary Efficacy Endpoint ................................................................................ 36 
7.1.2 Secondary Efficacy Endpoints .......................................................................... 36 
7.2 
Exploratory Endpoints ................................................................................................... 36 
7.3 
Mortality ........................................................................................................................ 37 
7.4 
New Infections .............................................................................................................. 37 
7.5 
Pharmacodynamics ........................................................................................................ 37 
8 Safety Assessments ................................................................................................................. 38 
8.1 
Safety Endpoints ........................................................................................................... 38 
8.2 
Adverse Events .............................................................................................................. 38 
8.2.1 Adverse (Drug) Reaction .................................................................................. 39 
8.2.2 Unexpected Adverse Drug Reaction ................................................................. 39 
8.2.3 Assessment of Adverse Events by the Investigator .......................................... 39 
8.3 
Serious Adverse Events ................................................................................................. 40 
8.4 
Serious Adverse Event Reporting í Procedures for Investigators ................................ 41 
8.5 
Pregnancy Reporting ..................................................................................................... 42 
8.6 
Expedited Reporting ...................................................................................................... 42 

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8.7 
Clinical Laboratory Evaluations .................................................................................... 43 
8.8 
Viral Testing .................................................................................................................. 43 
8.9 
Vital Signs ..................................................................................................................... 43 
8.10 Electrocardiograms ........................................................................................................ 43 
8.11 Physical Examinations .................................................................................................. 44 
8.12 Lung Function Assessments .......................................................................................... 44 
8.13 Echocardiogram ............................................................................................................ 44 
9 Statistics .................................................................................................................................. 45 
9.1 
Analysis Populations ..................................................................................................... 45 
9.2 
Statistical Methods ........................................................................................................ 45 
9.2.1 Analysis of Efficacy .......................................................................................... 45 
9.2.1.1 Primary efficacy endpoint ................................................................... 45 
9.2.1.2 Secondary efficacy endpoints ............................................................. 45 
9.2.2 Exploratory Endpoints ....................................................................................... 46 
9.2.3 Analysis of Safety ............................................................................................. 46 
9.2.4 Interim Analysis ................................................................................................ 46 
9.2.5 Sample Size Determination ............................................................................... 46 
10 Data Management and Record Keeping ................................................................................. 47 
10.1 Data Management ......................................................................................................... 47 
10.1.1 Data Handling ................................................................................................... 47 
10.1.2 Computer Systems ............................................................................................. 47 
10.1.3 Data Entry ......................................................................................................... 47 
10.1.4 Medical Information Coding ............................................................................. 47 
10.1.5 Data Validation ................................................................................................. 47 
10.2 Record Keeping ............................................................................................................. 47 
10.3 End of Study .................................................................................................................. 48 
11 Investigator Requirements and Quality Control ..................................................................... 49 
11.1 Ethical Conduct of the Study ........................................................................................ 49 
11.2 Ethics Review ................................................................................................................ 49 
11.3 Informed Consent .......................................................................................................... 49 
11.4 Study Monitoring Requirements ................................................................................... 49 
11.5 Disclosure of Data ......................................................................................................... 50 

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11.6 Retention of Records ..................................................................................................... 50 
11.7 Publication Policy ......................................................................................................... 50 
11.8 Financial Disclosure ...................................................................................................... 51 
12 Study Administrative Information .......................................................................................... 52 
12.1 Protocol Amendments ................................................................................................... 52 
13 References ............................................................................................................................... 53 
Appendix A: Schedule of Procedures ........................................................................................... 55 
Appendix B: Clinical Laboratory Analytes .................................................................................. 58 
Appendix C: Definitions and Management of Infusion-Related Reactions ................................. 60 

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LIST OF TABLES
Table 1. 
Dosing Strategy ........................................................................................................... 25 
Table 2. 
Composition of the Study Drug .................................................................................. 32 

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LIST OF FIGURES
Figure 1. Study Design ............................................................................................................... 24 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation
Definition
ACE2
Angiotensin converting enzyme 2
AE
Adverse event
aGVHD
Acute graft versus host disease
AH
Alcoholic hepatitis
CBC
Complete blood count
CFR
Code of Federal Regulations
CMH
Cochran-Mantel-Haenszel
CoV
Coronavirus(es)
COVID-19
Coronavirus disease 2019
CRA
Clinical research associate
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EIU
Exposure In Utero
EOS
End of study 
EV
Extracellular vesicle
FCBP
Female(s) of childbearing potential
FDA
Food and Drug Administration
FiO2
Fraction of inspired oxygen
GCP
Good Clinical Practice
GI
Gastrointestinal
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC 
Independent Ethics Committee 
IL
Interleukin
IRB
Institutional Review Board
ITT
Intent-to-Treat
IV
Intravenous(ly)
JAK
Janus kinase
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-Stage Liver Disease

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Abbreviation
Definition
MERS
Middle East Respiratory Syndrome
NIAID
National Institute of Allergy and Infectious Diseases
PaO2
Partial pressure of oxygen
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PP
Per Protocol
QTcF
Heart rate-corrected QT interval using Fridericia’s formula
Reg3
Regenerating islet-derived 3
RNA
Ribonucleic acid
SAE
Serious adverse event
SARS
Severe acute respiratory syndrome
SpO2
Peripheral capillary oxygen saturation
STAT3
Transcription 3
SUSAR
Suspected Unexpected Serious Adverse Reactions
SWFI
Sterile water for injection
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
TNF
Tumor necrosis factor

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1
INTRODUCTION AND BACKGROUND INFORMATION 
1.1
Epidemiology 
Coronaviruses (CoV) are widely found in nature and possess the largest single-stranded 
positive-sense RNA genome known. 7KH\DUHGLYLGHGLQWRJHQHUDĮȕȖDQGį$OODUHwell 
known causes of respiratory, enteric, and systemic infections in many species of mammals, birds, 
and fish.1 Since 1960, 7 strains of community-DFTXLUHGKXPDQȕ&R9 have also been identified. 
Four of these are mildly pathogenic and cause cold-like upper respiratory infections in adults and 
children, while 2 of these (severe acute respiratory syndrome [SARS]-CoV-1 and Middle East 
Respiratory Syndrome [MERS]-CoV) cause severe viral pneumonia. SARS-CoV-1 emerged in 
2002 in China and MERS-CoV emerged in 2012 in Saudi Arabia. The SARS-CoV-1 epidemic 
included about 8439 cases with 812 deaths (9.6% mortality), while the MERS-CoV epidemic 
claimed about 919 lives out of a total of 2521 cases (35% mortality).2,3 Both SARS-CoV-1 and 
MERS-CoV showed wide areas of global emergence, high risk of human-to-human transmission, 
and presented as acute respiratory distress syndrome.  
In December 2019, in Wuhan, China, the third highly pathogenic CoV, SARS-CoV-2, emerged in 
the human population.4 It was identified as the causal pathogen in a cluster of 8 viral pneumonia 
cases of unknown etiology. SARS-CoV-2, officially named CoV disease 2019 (COVID-19),
spread rapidly throughout China despite delayed quarantine, mandatory protective measures, and 
social distancing. On 30 January 2020, the World Health Organization declared the pandemic as a 
public health emergency of international concern.5 As of 30 May 2020, there were 
5,817,385 confirmed cases globally, with 362,705 deaths (6.2% mortality). In the United States, 
there have been 1,694,864 confirmed cases of COVID-19 with 100,304 deaths (5.9% mortality).6
The virus is zoonotic. Bats are believed to serve as the original reservoir of human pathogenic 
CoV, including SARS-CoV-1 and SARS-CoV-2, although other animals, such as camels in the 
case of MERS-CoV, may serve as an intermediate host from which the virus crosses the species 
barrier into humans.7 The human host receptor to which SARS-CoV-2 binds is believed to be 
angiotensin converting enzyme 2 (ACE2).7
1.2
Clinical Features
Symptoms of COVID-19 appear from 2 to 14 days after exposure, with a median of 5 to 7 days, 
and range from mild to severe illness and death, although approximately 8% of infected humans 
develop no symptoms. Primary symptoms and their prevalence in order of frequency consist of 
fever >100.4°F (83% to 98% of patients); dry, hacking cough (76% to 82% of patients); fatigue 
and/or myalgia (11% to 44% of patients); and dyspnea (31% of patients).8 Abnormal laboratory 
findings include lymphopenia (70% of patients), prolonged prothrombin time (58% of patients), 
and elevated lactate dehydrogenase (40% of patients).9 The majority of infected healthy adults 
appear to develop mild symptoms. Adults who are immunocompromised (e.g., human 
immunodeficiency virus [HIV] infection) or over 65 years of age, particularly those with 
comorbidities such as hypertension, chronic obstructive pulmonary disease, moderate to severe 
asthma, diabetes, cardiovascular disease, chronic kidney disease undergoing dialysis, liver disease,
or severe obesity (body mass index of 40 kg/m2 or higher), are more susceptible to severe 
respiratory complications and pneumonia.10

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Eighty percent of fatalities related to COVID-19 reported in the United States have been in adults 
t65 years of age. Of these, 10% to 27% of adults t85 years and 4% to 11% of adults 65 to 84 years 
of age have died. Hospitalization has been required in the United States for 31% to 70% of adults 
>85 years of age and 31% to 59% of adults 65 to 84 years of age.6
In those who develop severe lower respiratory symptoms, pulmonary infection is typically 
accompanied by a sustained extreme inflammatory response or cytokine storm, which can lead to 
severe complications such as respiratory distress syndrome and subsequent pulmonary edema, 
systemic hypoxia, septic shock, metabolic acidosis, and multiple organ failure.6
1.3
Treatment 
No effective antiviral agents against COVID-19 have yet been confirmed. Current treatment 
focuses on standard of care symptomatic and respiratory support for viral pneumonia, including 
oxygen therapy, extracorporeal membrane oxygenation to patients with refractory hypoxemia, and 
mechanical ventilation if needed.5
Potential drug candidates include lopinavir/ritonavir (Kaletra®), nucleoside analogs, neuramidase 
inhibitors, remdesivir, umifenovir (Arbidol®), DNA (deoxyribonucleic acid) synthesis inhibitors
(tenofovir disoproxil and lamivudine), chloroquine, ACE2-based peptides, 3C-like protease 
inhibitors, novel vinyl sulfone protease inhibitors, teicoplanin, and Chinese traditional medicine 
(ShuFengJieDu or Lianhuaqingwen capsules).5,7,11,12
1.4
Summary of Clinical Development of F-652 
F-652 is a recombinant fusion protein consisting of human IL-22 and human immunoglobulin 
G2 Fc fragments. F-652 is produced in Chinese Hamster Ovary cells, with an immunoglobulin-like 
structure with 2 IL-22 molecules (recombinant human IL-22 dimer) at the N-terminal. 
Similar to endogenous IL-22, F-652 was able to activate the STAT3 pathway. F-652 has been 
evaluated in vitro and in vivo in models of influenza and pneumococcal pneumonia lung infection 
and reported in the published literature.16,18 Administration of F-652 following influenza infection 
promoted tight junction formation, reducing fluid buildup and inflammation. In a murine 

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pneumonia model, F-652 administration showed decreased lung, liver, and spleen bacterial 
burdens post-infection. Taken together, F-652 has the potential to be effective in promoting a 
protective response in the lungs following infection with COVID-19. 

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1.5
Rationale 
F-652 has been postulated as a potential therapeutic candidate for treatment of patients with
COVID-19, particularly in patients with moderate to severe symptoms. The overall aim of this 
exploratory study is to evaluate the safety and efficacy of F-652 when IV administered in 
hospitalized, confirmed COVID-19 adult patients with moderate to severe symptoms. 
1.6
Risk/Benefit 
The participation of patients with COVID-19 in this study can involve significant risks but there 
are expectations of medical benefits for the patients as well. The study population will include 
patients with moderate to severe COVID-19 who meet all the inclusion and none of the exclusion 
criteria that were developed based on safety and ethical considerations. Based on previous 
experience and understanding of F-652 and its demonstrated safety margin, the protocol will 
ensure the safety of enrolled patients. 

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2
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective is to evaluate the safety and efficacy of F-652 when IV administered in 
hospitalized, confirmed COVID-19 adult patients with moderate to severe symptoms.
2.2
Secondary Objective
The secondary objective is to evaluate the PD of F-652 when IV administered in hospitalized, 
confirmed COVID-19 adult patients with moderate to severe symptoms.

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3
STUDY DESCRIPTION
3.1
Summary of Study Design 
This is an interventional, multicenter, 2-arm, parallel-group, randomized, double-blind, 
placebo-controlled, dose-escalation, safety and efficacy study of F-652 treatment versus placebo 
in patients aged 18 years or older with a COVID-19 diagnosis confirmed by polymerase chain 
reaction (PCR). Eligible patients will have moderate to severe COVID-19 symptoms and will be 
hospitalized. Figure 1 provides an overview of the study design. 
AE = adverse event; COVID-19 = coronavirus disease 2019; ECG = electrocardiogram; NIAID = National Institute of Allergy and 
Infectious Diseases; PCR = polymerase chain reaction; PD = pharmacodynamic(s); SAE = serious adverse event; 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TEAE = treatment-emergent adverse event.
The study plans to include 4 cohorts (see Table 1), with enrolled patients being randomized 1:1 in 
a blinded manner on Day 1, following screening, to F-652 or placebo as follows: 
x
Cohort 1 (sentinel cohort): Four patients will receive either 
or placebo. 
Two patients will receive F-652 and 2 patients will receive placebo. Upon completion of 
sentinel dosing (7 days after last patient last dose), the Data Monitoring Committee (DMC) 
will evaluate the safety and tolerability data of the sentinel patients and determine if it is 
acceptable to dose the remaining patients in this dosing group in Cohort 2. 
x
Cohort 2: Fourteen patients will receive eithe
 or placebo. Seven patients will 
receive F-652 and 7 patients will receive placebo. Upon completion of Cohort 2, the DMC will 
convene and review all available safety data to determine if the study can proceed to the next 
dose level.

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x
Cohort 3 (sentinel cohort): Four patients will receive either 
or placebo. 
Two patients will receive F-652 and 2 patients will receive 
mpletion of 
sentinel dosing (7 days after last patient last dose), the DMC will evaluate the safety and 
tolerability data of the sentinel patients and determine if it is acceptable to dose the remaining 
patients in this dosing group in Cohort 4. 
x
Cohort 4: Sixteen patients will receive eith
r placebo. Eight patients will 
receive F-652 and 8 patients will receive placebo. 
Table 1. Dosing Strategy 
Cohort
Number of Patients
Dosing
1 (sentinel)
4
2
14
3 (sentinel)
4
4
16
Treatment will begin on Day 1 following randomization. Patients assigned to active drug will 
receive a total of 2 doses of F-652 (1 IV infusion on Day 1 and 1 IV infusion on Day 8). Patients 
assigned to placebo will receive identical IV infusions of placebo vehicle on Days 1 and 8. If the 
patient is discharged from the site prior to Day 8, they will return for an outpatient visit to receive 
the second IV infusion and remain at the site for an approximate 2-hour observation period. All 
patients will receive available supportive and antiviral therapies as standard of care. Efficacy will 
be assessed on Days 15 and 29. Patients will be followed for safety until Day 60. 

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3.3
Study Indication
The indication for this study is the treatment of moderate to severe COVID-19.  

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4
SELECTION AND WITHDRAWAL OF PATIENTS  
4.2
Exclusion Criteria

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22
4.3
Stopping Criteria
All AEs should be considered related to study drug unless clearly unrelated or if there is a clear 
etiology other than study drug such as a pre-existing medical condition, underlying disease, or 
concomitant medication.  
4.3.1
Criteria for Discontinuation of Dosing in Individual Patients 
Patients will be discontinued from dosing but will continue to be followed in the study if they 
experience any of the following: 
x
tGrade 3 (CTCAE v5.0) AE or clinically significant laboratory abnormality considered related 
to study drug; 
x
tGrade 3 (CTCAE v5.0) infusion reaction in the first 24 hours post-infusion; 
x
tGrade 2 (CTCAE v5.0) cytokine release syndrome; 
x
tGrade 2 skin-related AEs;
x
Severe anaphylactic reaction, including bronchospasm; and/or 
x
Progression to acute respiratory distress syndrome.
For any patient who prematurely discontinues from study treatment, the reason and date of 
discontinuation will be documented in the electronic case report form (eCRF) and the patient 
should continue study visits and procedures as outlined in the Schedules of Procedures 
(Appendix A).
4.3.2
Criteria for Study Termination
In the event that any of the following are encountered, the DMC will convene as soon as possible 
to determine if the study must stop enrollment:
x
SAE considered related to study drug; 
x
tGrade 3 (CTCAE v5.0) reaction considered related to study drug; 
x
t2 patients are discontinued from treatment for safety reasons pertaining to study drug per 
DMC decision; 

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x
t2 patients experience similar SAEs or Grade 3 (CTCAE v5.0) AEs related to study drug per 
DMC decision; and/or
x
t2 patients experience worsening of cytokine release syndrome related to study drug per DMC 
decision.
The following will not be considered as criteria for study termination:
x
Grade 3 to 4 fever if present at study entry;
x
Grade 3 nausea if it resolves to dGrade 1 within 72 hours;
x
Grade 3 fatigue, malaise, or insomnia if it resolves to dGrade 1 within 72 hours; and/or
x
dGrade 4 isolated electrolyte abnormalities that resolve with or without intervention to 
dGrade 2 within 72 hours.
4.4
Withdrawal Criteria
Participation of a patient in this study may be discontinued for any of the following reasons:
x
Withdrawal of consent or request for discontinuation from the study for any reason;
x
Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol;
x
Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or 
other medical condition which indicates to the Investigator that continued participation is not 
in the best interest of the patient;
x
Pregnancy;
x
Use of prohibited concomitant medication;
x
Patient failure to comply with protocol requirements or study-related procedures; or
x
Termination of the study by the Sponsor or the regulatory authority.
For patients who discontinue early from the study, the Investigator is responsible to ensure all 
safety assessments and final follow-up assessments scheduled for the end of study (EOS) visit, 
including follow-up for unresolved AEs (including SAEs), are completed prior to patient
discontinuation. If the patient does not return for a scheduled visit, the Investigator must make 
every effort (documented telephone calls and registered letter, as allowed) to contact the patient.
Patients will be deemed as lost-to-follow-up once the Investigator has completed a minimum of 
3 telephone calls followed by a certified letter (as allowed) to the last known address of the patient
or next of kin, as appropriate, with no response obtained. Attempts to contact the patient must be 
made and documented in the patient’s medical records.
Patients who are consented but do not meet eligibility criteria will be considered screen failures.
Patients withdrawn for safety reasons will not be replaced.

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5
STUDY TREATMENTS
5.1
Treatment Groups
The study drug will be administered only to patients who have given informed consent.  
The patients will be randomly assigned to F-652 or placebo treatment in a 1:1 ratio in a blinded 
manner. Treatment will begin on Day 1 following randomization. All patients will receive 
available supportive and antiviral therapies as standard of care.
5.3
Randomization and Blinding
Patients will be randomized in a 1:1 ratio in a double-blind manner to receive F-652 or placebo. 
An independent statistician from Medpace Inc., hereinafter Medpace, will generate the 
randomization schedule. Patients meeting eligibility criteria will be randomized on Day 1,
following screening, in a 1:1 ratio to F-652 or placebo, respectively. Patients will be assigned a 
randomization number and treatment assignment according to the randomization schedule. This 
randomization schedule will be maintained by the investigative site pharmacist until it is 
appropriate to break the blind. The Investigator, investigative site personnel (except 
site-designated pharmacist and dedicated assistant), study monitors, vendors, Sponsor, and 
Medpace will remain blinded to treatment assignment.
Details of the emergency unblinding procedures are given in Section 5.4.
5.4
Breaking the Blind
Individual treatment assignments may be unblinded when immediate knowledge of the treatment 
assignment is needed to optimize the clinical management of the patient. The Investigator should 
contact the Medical Monitor to discuss the event prior to unblinding. In the event this is not 
possible, the Investigator should contact the Medical Monitor as soon as possible to discuss the 
event.
Randomization assignments will be prepared by the independent statistician and provided to the 
investigative site pharmacist to enable emergency code break procedures for individual patients 
without compromising the blind of the study. Documentation of the blind break, including the 
patient’s identification, reason for breaking the blind, and the date and time of breaking the blind, 
must be retained in the patient’s source documents at the sites in such a way as to avoid unblinding 
the treatment assignment to other site or Sponsor blinded personnel. 

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5.5
Drug Supplies
5.5.1
Formulation and Packaging 
The lyophilized formulation of F-652 (5 mg/vial) will be provided to the investigative sites for 
patients' use. It is presented as a white or yellowish cake in a sterile 3 mL glass vial. The 
composition of the study drug is listed in Table 2. 

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5.5.3
Study Drug Administration 
F-652 will be administered, based on the patient’s most recent weight, at a dose
IV on Days 1 and 8. Placebo vehicle will be identical in appearance to the study drug and will be 
administered IV on Days 1 and 8. If the patient is discharged from the site prior to Day 8, they will 
return for an outpatient visit to receive the second IV infusion and remain at the site for an 
approximate 2-hour observation period.
The definitions and management of infusion related reactions are described in Appendix C.
5.5.4
Treatment Compliance
Administration of the study drug will be performed by the investigative site staff and supervised 
by the Investigator or Sub-Investigator.  
Details of the date and time when the study drug is administered, along with any deviation from 
the procedure described in this protocol, will be recorded in the patient’s source documents and 
the eCRF.
Product technical complaints should be reported to the Sponsor. A product complaint is any report 
or complaint about a potential or alleged failure of the Sponsor’s product to meet any of its quality 
specifications. These complaints may or may not represent a potential risk to the patient.
Product technical complaints may include: 
x
Quality defects as described in Section 5.5.2 and temperature excursions;
x
Defects of containers and external wrappings; or 
x
Defects of labeling and packaging leaflets.

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6
STUDY PROCEDURES
Study procedures will follow the Schedule of Procedures (Appendix A). 

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7
EFFICACY ASSESSMENTS
7.1
Efficacy Endpoints
7.1.1
Primary Efficacy Endpoint 
The primary efficacy endpoint is the time to achieve a t2-point increase in the National Institute 
of Allergy and Infectious Diseases (NIAID) 8-point ordinal scale from baseline by Day 29.  
The NIAID 8-point ordinal scale includes the following grades:  
1. Death;
2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 
3. Hospitalized, on non-invasive ventilation or high-flow oxygen devices; 
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, not requiring supplementation oxygen – requiring ongoing medical care 
(COVID-19 related or otherwise);
6. Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care; 
7. Not hospitalized, limitation on activities and/or requiring home oxygen; and 
8. Not hospitalized, no limitations on activities.
7.1.2
Secondary Efficacy Endpoints 
The secondary efficacy endpoints, listed in hierarchical order, include the following: 
x
Time to achieve a t2-point decrease in the NIAID 8-point ordinal scale; 
x
Length of hospital stay from first dosing (Day 1) and percentage of patients who have 
recovered and been discharged from the hospital by Days 15 and 29; 
x
Mortality rate by Days 15 and 29; 
x
Proportion of patients with a t2-point increase in the NIAID 8-point ordinal scale from 
baseline to Days 15 and 29; 
x
Alive and respiratory failure free days by Days 15 and 29; 
x
Percentage of patients progressed to severe/critical disease by Day 15; and
x
Occurrence of any new infections during the study by Day 29. 

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7.3
Mortality
Data collected for patient deaths will include whether the death occurred after withdrawal of care 
and, if so, the reason for withdrawal of care. 
7.4
New Infections
Any new infections, regardless of the organism (e.g., viral or nonviral), should be captured on the 
eCRF. The site of infection and source of culture (e.g., sputum, blood, urine) should also be
recorded. 

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8
SAFETY ASSESSMENTS
8.1
Safety Endpoints
The safety endpoints include the following:
x
All cause TEAEs and SAEs; 
x
Change from screening (baseline) in clinical symptoms and abnormal vital signs, abnormal 
laboratory tests (e.g., complete blood count [CBC], serum chemistry, routine urinalysis, and 
coagulation function), and 12-lead electrocardiograms (ECGs); and 
x
Relationship of any observed AEs with F-652 treatment based on the Investigator’s judgement.
8.2
Adverse Events
An AE is defined as any untoward medical occurrence in a clinical investigation patient
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational therapeutic product, whether or not related to the investigational therapeutic
product. All AEs, including observed or volunteered problems, complaints, or symptoms, are to 
be recorded on the appropriate eCRF.
AEs, which include clinical laboratory test variables, will be monitored and documented from the 
time of informed consent to Day 60 or until all drug-related toxicities have resolved, whichever is 
later. Patients should be instructed to report any AE that they experience to the Investigator,
whether or not they think the event is due to study treatment. Beginning at screening, Investigators 
should make an assessment for AEs at each visit and record the event on the appropriate AE eCRF.
Wherever possible, a specific disease or syndrome rather than the individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, 
or transfusion) should be recorded as an AE, not the procedure itself.
Any medical condition already present at screening should be recorded as medical history and not 
be reported as an AE unless the medical condition or signs or symptoms present at baseline changes 
in severity, frequency, or seriousness at any time during the study. In this case, it should be reported 
as an AE.
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that are 
detected during the study or are present at screening and significantly worsen during the study 
should be reported as AEs, as described below. The Investigator will exercise his or her medical 
and scientific judgement in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. Clinically significant abnormal laboratory values occurring 
during the clinical study will be followed until repeat tests return to normal, stabilize, or are no 
longer clinically significant. Abnormal test results that are determined to be an error should not be 

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reported as an AE. Laboratory abnormalities or other abnormal clinical findings (e.g., ECG
abnormalities) should be reported as an AE if any of the following are applicable:
x
If an intervention is required as a result of the abnormality;
x
If action taken with the study drug is required as a result of the abnormality; or
x
Based on the clinical judgement of the Investigator.
8.2.1
Adverse (Drug) Reaction
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an AE is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out.
8.2.2
Unexpected Adverse Drug Reaction
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. 
8.2.3
Assessment of Adverse Events by the Investigator
The Investigator will assess the severity (intensity) of each AE according to the CTCAE grading 
system. The Investigator will also categorize each AE as to its potential relationship to study drug 
using the categories of yes or no.
The severity of all AEs should be graded according to the CTCAE v5.0. For those AE terms not 
listed in the CTCAE, the following grading system should be used:
x
CTCAE Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated;
x
CTCAE Grade 2: Moderate; minimal local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living;
x
CTCAE Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living;
x
CTCAE Grade 4: Life-threatening consequences; urgent intervention indicated; or
x
CTCAE Grade 5: Death related to the AE.
Causality assessment
The relationship of an AE to the administration of the study drug is to be assessed according to the 
following definitions:
No (unrelated, not related, unlikely to be related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc.) is suspected.

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Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE is consistent with a causal relationship and 
no other cause (concomitant drugs, therapies, complications, etc.) can be identified.
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship.
The following factors should also be considered:
x
The temporal sequence from study drug administration-
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event.
x
Underlying, concomitant, intercurrent diseases-
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the patient may have.
x
Concomitant drug-
The other drugs the patient is taking or the treatment the patient receives should be examined 
to determine whether any of them might be recognized to cause the event in question.
x
Known response pattern for this class of study drug-
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect.
x
Exposure to physical and/or mental stresses-
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event.
x
The pharmacology and PK of the study drug-
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered.
8.3
Serious Adverse Events
An AE or adverse reaction is considered serious if, in the view of either the Investigator or Sponsor, 
it results in any of the following outcomes:
x
Death;
x
A life-threatening AE;
Note: An AE or adverse reaction is considered “life-threatening” if, in view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death. It does 
not include an event that, had it occurred in a more severe form, might have caused death.
x
Requires hospitalization or prolongation of existing hospitalizations;
Note: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will not 
be recorded as an SAE under this criterion, nor will hospitalization for a procedure scheduled 

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or planned before signing of informed consent, or elective treatment of a pre-existing condition 
that did not worsen from baseline. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as AEs and assessed for 
seriousness. Admission to the hospital for social or situational reasons (i.e., no place to stay, 
live too far away to come for hospital visits, respite care) will not be considered inpatient 
hospitalizations. 
x
A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions;
x
A congenital anomaly/birth defect; or
x
An important medical event.
Note: Important medical events that do not meet any of the above criteria may be considered 
an SAE when, based upon appropriate medical judgement, they may jeopardize the patient and 
may require medical or surgical intervention to prevent 1 of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency.
Events of progression of the patient’s underlying COVID-19 diagnosis will be captured as efficacy 
endpoints; therefore, events clearly related to progression of the patient’s underlying COVID-19 
(signs/symptoms of progression) should not be reported as an SAE unless considered related to 
the study drug or the outcome is fatal during the study or within the safety reporting period. If the 
event has a fatal outcome during that timeframe, the event of “Progression of COVID-19” must 
be recorded as an SAE with a fatal outcome.
8.4
Serious Adverse Event Reporting í Procedures for Investigators
Initial reports
All SAEs occurring from the time of informed consent must be reported to Medpace Clinical 
Safety within 24 hours of the knowledge of the occurrence. After Day 60, any SAE that the 
Investigator considers related to study drug must be reported to Medpace Clinical Safety or the 
Sponsor/designee.
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria and 
it is not possible to access the EDC system, send an email to Medpace Safety at 
medpace-safetynotification@medpace.com or call the Medpace SAE reporting line (phone 
number listed below), and fax/email the completed paper SAE form to Medpace within 24 hours 
of awareness. When the EDC system becomes available, the SAE information must be entered 
within 24 hours of the system becoming available.
Follow-up reports
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient
dies.

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Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(e.g., patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or email. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs. 
8.5
Pregnancy Reporting
If a patient becomes pregnant during the study, the Investigator is to stop dosing with study drug(s) 
immediately and the patient should be withdrawn from the study. Early termination procedures 
should be implemented at that time. 
A pregnancy is not considered to be an AE or SAE; however, it must be reported to Medpace 
Clinical Safety within 24 hours of knowledge of the event. Medpace Clinical Safety will then 
provide the Investigator/site the Exposure In Utero (EIU) form for completion. The 
Investigator/site must complete the EIU form and fax/email it back to Medpace Clinical Safety. 
If the female partner of a male patient becomes pregnant while the patient is receiving study drug, 
the Investigator should notify Medpace Clinical Safety as described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the EIU form should be completed and faxed/emailed to 
Medpace Clinical Safety. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE.
8.6
Expedited Reporting
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSARs) that are fatal or life-threatening as soon as possible to the Food and 
Drug Administration (FDA) and in any case no later than 7 days after knowledge by the 
Sponsor/designee of such a case. Relevant follow-up information will subsequently be 
communicated within an additional 8 days.  
All other SUSARs will be reported to the FDA as soon as possible but within a maximum of 
15 days of first knowledge by the Sponsor/designee.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation. 
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to investigational therapeutic product. 

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8.7
Clinical Laboratory Evaluations 
CBC with differential will be performed at screening, Days 1, 3, 5, 7, 8, 10, 12, and 14. If the 
patient remains hospitalized, will also be performed on Days 15 and 29. If the screening assessment 
was obtained within 24 hours of Day 1 dosing, it is not necessary to repeat the CBC prior to Day 1
dosing. 
Metabolic panel/chemistry assessments will be performed at screening, Days 1 and 8 (within 
24 hours prior to dosing) and as clinically indicated. If the patient remains hospitalized, will also 
be performed on Days 15 and 29. If the screening assessment was obtained within 24 hours of 
Day 1 dosing, it is not necessary to repeat the chemistries prior to Day 1 dosing. Lactate 
dehydrogenase test should be repeated daily if elevated above the upper limit of normal. 
Hemoglobin A1c will only be obtained at screening if the patient does not have a value within 
90 days prior to screening.
Urine dipstick is acceptable and microscopic analyses can be performed if clinically indicated. If 
t2+ protein on urine dipstick, then a spot urine sample should be collected in order to calculate 
the urine protein to creatinine ratio or a 24-hour urine should be collected. 
Clinical laboratory analytes are listed in Appendix B.
8.8
Viral Testing
A SARS-CoV-2 test will be performed on Day 1 (pre-dose), Day 4 (±1 day), Day 8 (pre-dose), 
Day 11 (±1 day), Day 14 (±1 day), and prior to discharge on Days 15 and 29. Patients will have a 
naso-pharyngeal swab collected at screening and analyzed using PCR. If possible, a central 
laboratory should be used to confirm local laboratory results.
8.9
Vital Signs
Vital signs will include systolic and diastolic blood pressure, respiration, pulse, and oral
temperature, and should be taken prior to study drug infusion, every 15 minutes during the 
infusion, at the end of the infusion, and hourly post-infusion, for a minimum of 4 hours after each 
infusion within a window of r5 minutes. Vital signs should be collected on a daily basis and may 
be collected more frequently if clinically indicated. Patients should be in a sitting position for at
least 5 minutes prior to collection.
8.10
Electrocardiograms
Twelve-lead ECGs will be obtained at screening, Days 1 and 8 (pre-dose and 30 r10 minutes after
the end of infusion) and as clinically indicated within a window of r10 minutes. If the patient 
remains hospitalized, will also be performed on Days 15 and 29. Whenever ECG and blood 
samples are specified to be collected at the same time, ECG will be obtained before the blood 
samples. ECGs should be obtained in digital format when possible and archived.  
Patients should be in a supine position for at least 10 minutes prior to the ECG measurement. The 
ECG measurements will include heart rate, RR-interval, PR-interval, QT-interval, QRS-complex, 
and QTcF. 

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8.11
Physical Examinations
A physical examination will be performed at screening, Days 1 and 8. If the patient remains 
hospitalized, will also be performed on Days 15 and 29. A complete physical examination will be 
performed at screening and Day 29 if the patient is hospitalized, while a symptom-directed
physical examination will be conducted on Days 1 and 8, and Day 15 if the patient is hospitalized.
The physical examination will consist of assessments of general condition, skin, 
eyes/ears/nose/mouth/throat, neck/thyroid, chest/lungs, heart, vascular system, lymph nodes, 
abdomen, extremities, nervous systems/reflexes, musculoskeletal, and spine.
The patient’s weight will be measured within 12 hours prior to dosing on each day of study drug 
administration. 
8.12
Lung Function Assessments
Lung function will be assessed daily by peripheral capillary oxygen saturation (SpO2) in ambient 
air (if possible), SpO2 with oxygen supplementation (if applicable), documentation of oxygen 
delivery method, highest oxygen delivery flow rate (if receiving noninvasive oxygen), highest 
fraction of inspired oxygen (% FiO2) (if on positive pressure ventilation), highest positive 
end-expiratory pressure (if on positive pressure ventilation), and lowest partial pressure of oxygen
(PaO2):fraction of inspired air (FiO2) ratio if arterial blood gas is obtained and the patient is on 
positive pressure ventilation.
8.13
Echocardiogram
An echocardiogram (ECHO) is not necessary unless otherwise indicated. An up-trending 
troponin-I with hemodynamic compromise or other concerning cardiovascular symptoms/signs 
should prompt consideration of obtaining an ECHO.

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9
STATISTICS
9.1
Analysis Populations
All computations will be performed using SAS® Version 9.4 or higher.
The following analysis populations will be defined for this study:
x
Intent-to-Treat (ITT) Population: All patients who are randomized;
x
Safety Population: All randomized patients who receive at least 1 dose of study drug; and
x
Per Protocol (PP) Population: All patients in the ITT Population who finish the study as
designed and without major protocol deviations.
Efficacy and safety data will be summarized by treatment arm. Data from all enrolled cohorts will 
be pooled together for analysis and sequentially analyzed in subgroups. 
The ITT Population will be used to examine efficacy for both the primary and secondary endpoints,
the Safety Population will be used to assess safety endpoints, and the PP Population will be used 
as a secondary population for the analysis of the primary efficacy endpoint. A list of patients with 
major protocol deviations leading to exclusion from the PP Population will be finalized prior to 
unblinding the randomized treatment assignments. All timepoints for analysis purposes will be 
collected from the day of randomization. 
9.2
Statistical Methods
9.2.1
Analysis of Efficacy
9.2.1.1
Primary efficacy endpoint
The time to achieve a t2-point increase in the NIAID 8-point ordinal scale from baseline by
Day 29 will be analyzed using the Cochran-Mantel-Haenszel (CMH) test adjusting for the baseline 
NIAID 8-point ordinal scale. The NIAID 8-point ordinal scale will be assessed daily while the 
patient is hospitalized. If the patient remains hospitalized, the scale will also be assessed on 
Days 15 and 29. Any patient in the ITT Population with a missing primary endpoint result will be 
considered as a non-responder. The point estimates of the time to achieve a t2-point increase will 
be presented by treatment arm together with their 95% confidence intervals. The CMH odds ratio, 
associated 95% confidence interval, and p-value will also be presented.
9.2.1.2
Secondary efficacy endpoints
The time to achieve a t2-point decrease in the NIAID 8-point ordinal scale, proportion of patients 
with a t2-point increase in the NIAID 8-point ordinal scale from baseline to Days 15 and 29,
mortality rate by Days 15 and 29, percentage of patients who have recovered and been discharged 
from the hospital by Days 15 and 29, and percentage of patients progressed to severe/critical 
disease by Day 15 will be analyzed using the same method as described for the primary efficacy 
endpoint in Section 9.2.1.1.
The number of alive and respiratory failure free days by Days 15 and 29, the length of hospital 
stay from first dosing (Day 1) to discharge by Days 15 and 29, and occurrence of any new 
infections during the study by Day 29 will be summarized using descriptive statistics.

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9.2.2
Exploratory Endpoints
The exploratory endpoints will be summarized using descriptive statistics.
9.2.3
Analysis of Safety
All safety analyses will be performed on the Safety Population.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized by system organ class, preferred term, and treatment arm as the number and 
percentage of patients with an event. The following subsets will also be summarized by treatment 
arm: TEAEs, treatment-related AEs, treatment-related SAEs, and AEs leading to drug 
discontinuation. 
Changes from baseline in clinical laboratory data, ECGs, vital signs, and physical examination 
findings will be summarized with descriptive statistics by treatment arm.
All demographic data will be summarized using descriptive statistics (number of patients, mean, 
median, standard deviation, minimum, and maximum) for continuous variables and using 
frequencies and percentages for discrete variables.
A formal statistical analysis plan providing full technical details of the planned analyses will be 
finalized prior to database lock.
9.2.4
Interim Analysis
Interim analysis is not planned for this study.
9.2.5
Sample Size Determination
The study plans to randomize 38 patients, with 4 patients in Cohort 1 (sentinel cohort), 14 patients 
in Cohort 2, 4 patients in Cohort 3 (sentinel cohort), and 16 patients in Cohort 4. The sample size 
is based on the purpose of the study and experience with similar proof-of-concept studies, and not 
based on statistical power calculation.

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10
DATA MANAGEMENT AND RECORD KEEPING
10.1
Data Management
10.1.1
Data Handling
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. 
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data have
been accounted for.
10.1.2
Computer Systems
Data will be processed using a validated computer system conforming to regulatory requirements.
10.1.3
Data Entry
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations (CFR)
Part 11 and other appropriate international regulations. All passwords will be strictly confidential.
10.1.4
Medical Information Coding
For medical information, the following thesauri will be used:
x
MedDRA (latest) for medical history and AEs; and
x
World Health Organization Drug Dictionary for prior and concomitant medications.
10.1.5
Data Validation
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous or data that are missing will be 
referred to the investigative site for resolution through data queries.
The eCRFs must be reviewed and electronically signed by the Investigator.
10.2
Record Keeping
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study drug,
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records. 

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10.3
End of Study
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last patient in the study. Patients alive at the 
end of the study who require further follow-up may be entered into a separate long-term follow-up
study.

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11
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
11.1
Ethical Conduct of the Study
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human patients. Compliance 
with this standard provides public assurance that the rights, safety, and wellbeing of study patients
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible.
11.2
Ethics Review 
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will review all 
appropriate study documentation in order to safeguard the rights, safety, and well-being of patients. 
The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, 
Investigator’s Brochure, informed consent form (ICF), advertisements (if applicable), written 
information given to the patients, safety updates, annual progress reports, and any revisions to 
these documents will be provided to the IRB/IEC by the Investigator.
Federal regulations and International Council for Harmonisation (ICH) Guidelines require that 
approval be obtained from an IRB/IEC prior to participation of patients in research studies. Prior 
to study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for patient
recruitment, and any other written information regarding this study to be provided to a patient or 
a patient’s legal guardian must be approved by the IRB/IEC.
No study drug will be released to the site for dosing until written IRB/IEC authorization has been 
received by the Sponsor.
11.3
Informed Consent
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB/IEC prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements.
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB/IEC, and/or regulatory 
agencies. A copy of the signed ICF will be given to the patient.
11.4
Study Monitoring Requirements
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs.
To achieve this objective, the CRA’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized, and easily retrievable data. 
Before the enrollment of any patient in this study, the Sponsor or their designee will review with 

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the Investigator and site personnel the following documents: protocol, Investigator’s Brochure, 
eCRFs and procedures for their completion, informed consent process, and the procedure for 
reporting SAEs.
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data are
entered by the site, the CRA will review the data for safety information, completeness, accuracy, 
and logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to the 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible.
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log.
11.5
Disclosure of Data
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB/IEC as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal physician or 
other appropriate medical personnel responsible for their welfare.
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited.
11.6
Retention of Records
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE
forms, source documents, and detailed records of treatment disposition. The records should be 
retained by the Investigator according to specifications in the ICH guidelines, local regulations, or 
as specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met.
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.
11.7
Publication Policy
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved.

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11.8
Financial Disclosure
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study.

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12
STUDY ADMINISTRATIVE INFORMATION
12.1
Protocol Amendments
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB/IEC, unless immediate implementation of the change is necessary for patient safety. In this 
case, the situation must be documented and reported to the IRB/IEC within 5 working days.

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13
REFERENCES
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APPENDIX A: SCHEDULE OF PROCEDURES

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APPENDIX B: CLINICAL LABORATORY ANALYTES
Standard Safety Chemistry Panel
Alanine aminotransferase
Albumin
Alkaline phosphatase
Amylase
Aspartate aminotransferase
Blood urea nitrogen or urea
Calcium
Chloride
Creatine kinase
Creatinine
Estimated glomerular filtration rate (eGFR)
Glucose
Lactate dehydrogenase
Lipase
Magnesium
Phosphorus or phosphate
Potassium
Sodium
Total bilirubin
Uric acid
Additional Chemistry Parameters
Arterial blood gas [1]
Hemoglobin A1c [2]
1. Only if clinically indicated.
2. Obtained only if the patient does not have a value within 90 days prior to screening.
Endocrinology
Beta human chorionic gonadotropin (E-HCG) [1]
1. Serum E-HCG pregnancy test for females of childbearing potential.
Hematology
Absolute neutrophils [1]
Basophils
Eosinophils
Hematocrit 
Hemoglobin
Lymphocytes
Monocytes
Platelets
White blood cell count and differential [2]
1. Neutrophils plus bands.
2. Manual microscopic review will be performed only if white blood cell count and/or differential values are out of reference range.
Additional Hematology
Erythrocyte sedimentation rate (ESR)

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Urinalysis
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Microscopy [1]
Nitrite
pH
Protein
Specific gravity
Urobilinogen
1. Microscopy is performed only as needed based on positive urine dipstick test results. 

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APPENDIX C: DEFINITIONS AND MANAGEMENT OF 
INFUSION-RELATED REACTIONS
In the event of infusion-related reactions, Investigators should institute treatment measures
according to best medical practice. Any event of infusion-related reaction, generally defined as
clinically significant deviations in blood pressure, heart rate, respiratory rate, and oxygen
saturation, will be recorded. 
In the event of infusion-related allergic reaction, and if flushing, sudden rash, or difficulty 
breathing occur, the infusion will be stopped immediately and affected patients will be monitored 
until the infusion-related allergic reaction has resolved. 
The following treatment guidelines may be employed at the discretion of the treating physician: 
x
Grade 1 infusion-related reaction (Common Terminology Criteria for Adverse Events
[CTCAE] v5.0): Mild transient reaction; infusion interruption not indicated; intervention not
indicated;
x
Grade 2 infusion-related reaction (CTCAE v5.0): Therapy or infusion interruption indicated, 
but responds promptly to symptomatic treatment (e.g., antihistamines, non-steroidal 
anti-inflammatory drugs, narcotics, intravenous [IV] fluids); prophylactic medications 
indicated for d24 hours;
Treatment of Grade 1 or Grade 2 infusion-related reactions:
1. Decrease infusion rate by 50%, administer antihistamines, corticosteroids, etc., as 
medically indicated and monitor for worsening condition;
2. Stop infusion if infusion-related symptoms continue despite number 1;
3. Administer bronchodilators, oxygen, antihistamines, corticosteroids, etc., as medically
indicated;
4. Resume infusion at 50% of previous rate once reaction has decreased to Grade 1 in severity.
Monitor closely for any worsening; and
5. If the reaction reoccurs, stop infusion. Study treatment will be discontinued;
x
Grade 3 infusion-related reaction (CTCAE v5.0): Characterized as prolonged (e.g., not rapidly
responsive to symptomatic medication and/or brief interruption of infusion); recurrence of
symptoms following initial improvement; hospitalization indicated for clinical sequelae; or
x
Grade 4 infusion-related reaction (CTCAE
v5.0): Characterized as life-threatening 
consequences; urgent intervention indicated;
Treatment of Grade 3 or Grade 4 infusion-related reactions: 
1. Stop the infusion immediately and disconnect infusion tubing from the patient;
2. Administer epinephrine, bronchodilators, antihistamines, glucocorticoids, IV fluids,
vasopressor agents, oxygen, etc., as medically indicated;
3. Immediately contact Medical Monitor and report serious adverse event; and
4. Study treatment will be discontinued.