Clinical trial NCT04317040
Conditions: Coronavirus Disease 2019 (COVID-19)
Sponsor: Oncoimmune, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Start date: 2020-04-24; Completion date: 2020-10-20
Enrollment: 234 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the efficacy and safety of efprezimod alfa in hospitalized adult participants who are diagnosed with coronavirus disease 2019 (COVID-19) and receiving oxygen support.

The primary hypothesis of the study is clinical improvement in the experimental group versus the control group.

Detailed description:

Arms: arm 1: Participants receive single dose of 480 mg efprezimod alfa, diluted to 100 ml with normal saline, intravenous (IV) infusion in 60 minutes on Day 1. arm 2: Participants receive single dose of placebo as normal saline solution 100 ml, IV infusion in 60 minutes, on Day 1.
Interventions: intervention 1: Efprezimod alfa intervention 2: Placebo
Intervention descriptions: intervention 1: Efprezimod alfa is given on Day 1. intervention 2: Placebo is given on Day 1.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04317040 
Document Date: 
16-Aug-2020
A Randomized, Double-blind, Placebo-controlled, Multi-site, Phase 
III Study to Evaluate the Safety and Efficacy of CD24Fc in 
COVID-19 Treatment (SAC-COVID)


OncoImmune Inc. 
Clinical Trial Protocol (SAC-COVID) 
IND 148237 
CD24Fc-007-US 
 
CD24Fc for COVID-19 Treatment; v1.9:  August 16, 2020 
Page 1 of 89 
A Randomized, Double-blind, Placebo-controlled, Multi-site, Phase III Study to Evaluate 
the Safety and Efficacy of CD24Fc in COVID-19 Treatment 
 
Protocol Number: CD24Fc-007-US 
 
Posted on ClinicalTrials.gov as NCT04317040. 
 
Sponsor: 
OncoImmune, Inc.  
 
 
9430 Key West Ave, Suite 113  
 
 
Rockville, MD 20850 
 
IND NUMBER: 148237 
 
Protocol Version / Date:  
1.9 / August 16, 2020 
 
 
Study Principal Investigator, US: 
Shyam Kottilil, MD 
Director, Division of Clinical Care and Research 
Chief, Division of Infectious Diseases 
Institute of Human Virology 
University of Maryland Baltimore 
Study Statistician: 
R&G Inc. 
Multisite Coordinator: 
ClinSmart, LLC (CRO)  
32 Blacksmith Road 
Newtown, PA 18974   
Phone: 
 
Email:  
 
Fax:  
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of OncoImmune Inc. except to the extent that disclosure would be required by law and 
for the purpose of evaluating and/or conducting a clinical trial for OncoImmune Inc. You are 
allowed to disclose the contents of this document only to your Institutional Review Board or 
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 OncoImmune Inc. and that it may not be further disclosed to third parties. 
 
 
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Clinical Trial Protocol (SAC-COVID) 
IND 148237 
CD24Fc-007-US 
 
CD24Fc for COVID-19 Treatment; v1.9:  August 16, 2020 
Page 2 of 89 
STUDY SYNOPSIS 
 
Title of the Study: 
A Randomized, Double-blind, Placebo-controlled, Multi-site, Phase 
III Study to Evaluate the Safety and Efficacy of CD24Fc in COVID-
19 Treatment (SAC-COVID)  
Study Drug and Route:  
CD24Fc, IV infusion.  
Protocol Number: 
CD24Fc-007-US 
Principal Investigator: 
Shyam Kottilil, MD, PhD 
Study Design: 
The study is designed as a randomized, placebo-controlled, double blind, 
multicenter, Phase III trial to compare two COVID-19 treatment 
regimens in hospitalized adult subjects who are diagnosed with severe 
COVID-19. 
Arm A: CD24Fc/Best Available Treatment  
Arm B: placebo/ Best Available Treatment  
CD24Fc will be administered as single dose of 480 mg via IV infusion 
on Day 1. Total of 270 subjects will be enrolled and randomized in 1:1 
ratio to receive CD24Fc or placebo. All subjects will be treated with the 
best available treatment. The follow up period is 28 days.  
If the patient clinical status improves and is discharged to home care, the 
follow up visits can be carried out through telemedicine (phone or video 
interviews). The clinical investigators should make best effort to obtain 
the vital signs, clinical status evaluation, concomitant medicines and 
adverse events assessment. The laboratory tests, radiology study, ECG 
and research samples are optional.  
Primary Objective: 
The primary objective of the Phase III study is to evaluate the safety and 
efficacy of adding CD24Fc to COVID-19 best available treatment by 
comparing COVID disease status improvement time between CD24Fc 
and placebo arms in 28 days.  
Secondary Objectives: 
Secondary objectives are to compare, for each treatment arm, the 
proportion of patients who died or had respiratory failure (defined as the 
need for mechanical ventilation, ECMO, non-invasive ventilation, or 
high flow oxygen devices), the time to disease progression, the rate of all-
cause death, the proportion of death or respiratory failure, rates of 
hospital discharge time, rate of duration of mechanical ventilation, 
duration of mechanical ventilation, use of pressors, rate of duration of 
extracorporeal membrane oxygenation, rate of duration of supplemental 
oxygen, the length of hospital stay, and the changes in absolute 
lymphocyte count and markers of inflammation.  
Exploratory objectives:  
To explore the effect of CD24Fc treatment of COVID-19 on systemic 
steroid dosage, inflammatory cytokine changes, D-dimer level changes, 
lymphocyte subtype distribution and T lymphocyte activation and 
exhaustion markers.  
To explore the effect of CD24Fc in pulmonary function, inflammatory 
markers, coagulation markers, cardiac function, liver enzymes and renal 
function. 
 
 
 
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Clinical Trial Protocol (SAC-COVID) 
IND 148237 
CD24Fc-007-US 
 
CD24Fc for COVID-19 Treatment; v1.9:  August 16, 2020 
Page 3 of 89 
Study Endpoints:  
Primary Endpoint: 
Time to improvement in clinical status: the time (days) to the 
improvement of clinical status from “scale 2 to 4” to “scale 5 or above 
that is sustained without a drop to below 5” based on NIAID 8-point 
ordinal scales (Appendix A) within 28 days from randomization.  
Secondary Endpoints: 
• 
Proportion of patients who died or had respiratory failure, defined as 
the need for mechanical ventilation, ECMO, non-invasive 
ventilation, or high flow oxygen devices, at Day 29; 
• 
Time to disease progression in clinical status: the time (days) for 
progression from scale 3 or 4 to scale 1 or 2, or 2 to 1, based on 
NIAID ordinal scale with 28 days from randomization;  
• 
All-cause mortality at Day 15 and Day 29; 
• 
Proportion of clinical relapse, as defined by rate of return to oxygen 
support for more than 1 day within 28 days from randomization after 
initial recovery;  
• 
Conversion rate of clinical status on days 8 (proportion of subjects 
who changed from “scale 2 to 4” to “scale 5 or higher” on NIAID 
ordinal scale); 
• 
Conversion rate of clinical status on days 15 (proportion of subjects 
who changed from “scale 2 to 4” to “scale 5 or higher” on NIAID 
ordinal scale); 
• 
The discharge time  
• 
Duration of mechanical ventilation (IMV, NIV) (days); 
• 
Duration of pressors; 
• 
Duration of extracorporeal membrane oxygenation (days); 
• 
Duration of oxygen therapy (oxygen inhalation by nasal cannula or 
mask) (days); 
• 
Length of hospital stay (days); 
• 
Absolute lymphocyte count; 
• 
D-dimer concentration in the plasma. 
Exploratory endpoints: 
• 
Effect of CD24Fc on systemic steroid usage; 
• 
Effect of CD24Fc on cytokine levels; 
• 
Effect of CD24Fc on lymphocyte subtype distribution. 
Safety evaluation:  
• 
Adverse events, vital signs, laboratory tests (blood routine, blood 
biochemistry, coagulation function, urine routine),  ECG. 
Study Population: 
Hospitalized severe and critical COVID-19 adult patients. 
Eligibility Criteria: 
Inclusion criteria 
1) Should be at least 18 years of age. 
 
 
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Clinical Trial Protocol (SAC-COVID) 
IND 148237 
CD24Fc-007-US 
 
CD24Fc for COVID-19 Treatment; v1.9:  August 16, 2020 
Page 4 of 89 
2) Male or female, female should have negative pregnancy test. 
3) Diagnosed with COVID-19 and confirmed SARS-CoV-2 viral 
infection, prior positive viral results allowed. 
4) Informed consent form signed by the patient or by the legally 
authorized representative. 
5) Hospitalized and requiring oxygen support, NIAID 8-point ordinal 
score 2, 3 or 4, regardless of ARDS (Appendix A). The intubation 
for mechanical ventilation is within 7 days.  
6) Women of childbearing potential, under the age of 54 years, who use 
adequate contraception and who agree to use adequate contraception 
for the duration of the study. 
Exclusion criteria: 
1) Patients who are pregnant, breastfeeding, or have a positive 
pregnancy test result before enrollment. 
2) Patients who previously enrolled in CD24Fc clinical trial. 
3) Intubation for invasive mechanical ventilation is over 7 days. 
4) Documented acute renal or hepatic failure; 
5) The investigator believes that participating in the trial is not in the 
best interests of the patient, or the investigator considers unsuitable 
for enrollment (such as unpredictable risks or subject compliance 
issues). 
Treatment Description:  
The Phase III study will be a randomized double-blind placebo 
controlled study in 270 subjects. Patients will be randomized 1:1 to 
receive one of the following treatments: 
 
Arm A: CD24Fc, 480mg, diluted to 100ml with normal saline, IV 
infusion in 60 minutes. 
 
Arm B:  placebo, normal saline 100ml, IV infusion in 60 minutes.  
 
The best available treatment and supportive care will be given to all 
subjects according to local institutional guideline. Those who uses 
immune modulators such as IL-6/IL-6R antagonists or experimental 
antiviral drugs such as remdesivir or convalescent plasma are allowed to 
participate the trial. 
Accrual Objective: 
The study will enroll 270 patients, or 135 per arm. 
Accrual Period: 
The estimated accrual period is 5 months. 
Study Duration: 
Patients will be followed for 28 days. 
Interim Analysis: 
The Phase III study will include one interim analysis:  
 
 
 
The interim analysis will be at the time when the required number of 
events is at 70% for the purpose of sample size re-estimation only. 
Stopping Guidelines: 
Monitoring of the safety endpoint will be conducted by the CRO in a 
blinded fashion. The CRO will collect the data and share this with the 
DSMB at two safety reviews, respectively when 50% or 75% of enrolled 
patients reached D15.  DSMB may call a meeting with the DSMB at 
other times if needed.  DSMB may recommend early termination if it 
 
 
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Clinical Trial Protocol (SAC-COVID) 
IND 148237 
CD24Fc-007-US 
 
CD24Fc for COVID-19 Treatment; v1.9:  August 16, 2020 
Page 5 of 89 
find significantly higher SAE in the CD24Fc arm after considering the 
clinical benefit of the treatment.  The final decision will be made by the 
sponsor. 
 
 
Figure 1:  
Diagram of the study. 
 
 
 
 
 
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Clinical Trial Protocol (SAC-COVID) 
IND 148237 
CD24Fc-007-US 
CD24Fc for COVID-19 Treatment; v1.9:  August 16, 2020 
Page 6 of 89 
Table 1: 
Inclusion and Exclusion Criteria and NIAID 8-Point Scale for COVID-19. 
Inclusion Criteria 
Exclusion Criteria 
NIAID 8-point scale for COVID-19 
1)
Age ≥ 18 years
2)
Male or Female, Female pregnancy test 
negative 
3)
Diagnosed with COVID-19 and
confirmed SARS-CoV-2 infection. 
4) Informed consent form signed by patient 
or by a legally authorized representative. 
5) NIAID 8-point ordinal score 2 to 4
regardless of ARDS. The intubation for 
invasive mechanical ventilation should
be within 7 days. 
6) Women of childbearing potential who
use adequate contraception and who
agree to use adequate contraception for 
the duration of the study. 
1)
Patients who are pregnant, breastfeeding, 
or have a positive pregnancy test result 
before enrollment.
2)
Patients who previously enrolled in 
CD24Fc study. 
3)
The intubation for invasive mechanical 
ventilation is over 7 days. 
4)
Documented acute renal or hepatic 
failure; 
5) The investigator believes that 
participating in the trial is not in the best 
interests of the patient, or the investigator 
considers unsuitable for enrollment (such
as unpredictable risks or subject 
compliance issues). 
1)
Death; 
2)
Hospitalized, on invasive mechanical 
ventilation or extracorporeal membrane 
oxygenation (ECMO);
3)
Hospitalized, on non-invasive ventilation
or high flow oxygen devices; 
4)
Hospitalized, requiring supplemental 
oxygen; 
5)
Hospitalized, not requiring supplemental 
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; 
8)
Not hospitalized, no limitations on
activities. 
 
 
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Clinical Trial Protocol (SAC-COVID) 
IND 148237 
CD24Fc-007-US 
 
CD24Fc for COVID-19 Treatment; v1.9:  August 16, 2020 
Page 7 of 89 
Table 2:  
Phase III study schedule 
1. Monitor vital signs before study drug infusion and at 60±10 minutes after drug infusion started. ECG before study drug 
infusion and at 2 hours ± 15 min after drug infusion. Body temperature should be recorded daily when in hospital.  
2. The complete physical examination should be done during screening. The D15 visit should record any changes.  
3. The tests that have been done 72 hr prior to screening are allowed in lieu of screening. See Section 7.1.5 for details.  
4. Arterial Blood Gas (ABG) and Chest image study: Chest X-ray or CT scan frequency may be determined by local 
institutional guideline. The ABG and Chest Image Study at Screening is recommended but not required.  The ABG and chest 
image studies that have been done 72 hr prior to Screening are allowed in lieu of screening.  
5. The clinical status (NIAID ordinal scale) and respiratory treatment status should be evaluated and recorded daily while the 
patient is hospitalized. If the patient is discharged, these data should be captured for study visits through telemedicine. 
6. For specified clinical sites only: Blood samples should be collected before and after study drug infusion, and on D4, D8, D15 
to measure inflammatory cytokines (IL-1β, IL-6, TNF-α, MIPα, INF-γ, IP10, MCP, GCSF, IL-10) and DAMP molecules 
(HMGB-1, HSP70 / 90) in serum. The PBMC will be used to measure lymphocyte subtypes and lymphocyte activation and 
exhaustion markers (flow cytometry for: CD3 / CD4 / CD8 / PD1 / Tim3, etc.). 
7. When enrolled patient is in the hospital for the treatment, the study schedule should be followed. If the patient is improved 
and discharged from the hospital, the follow up visits (D4±2, D8±2, D15±2, D29±3) can be conducted via telephone or video 
interview for clinical status evaluation, concomitant medications and adverse events assessment. The scheduled laboratory 
and radiology studies are recommended but not required.  
 
 
Screening 
Treatment/Follow up7 
 
Observations 
 
D1 
D4 
D8 
D15 
D29 
Informed Consent 
x 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
Medical History 
x 
 
 
 
 
 
Collect demographic data 
x 
 
 
 
 
 
Confirm inclusion / exclusion criteria 
x 
x 
 
 
 
 
Vital Sign monitoring1 
x 
x1 
x 
x 
x 
x 
Physical Examination 
x 
 
 
 
x2 
 
Laboratory Testing3 
x 
x 
x 
x 
x 
 
Digital oxygen saturation 
x 
As needed 
 
Arterial blood gas analysis 
x4 
As needed 
 
Chest image study4  
x4 
As needed4 
 
Pregnancy test (if applicable) 
x 
 
 
 
 
 
ECG monitoring 
x 
x1 
 
x 
x 
 
COVID-19 test 
x 
 
 
 
 
 
CD24Fc (Study Agent） 
 
x 
 
 
 
 
Clinical status evaluation 
x 
x5,7 
x5,7 
IMV/NIV, ECMO, or supplement oxygen 
x 
x5 
x7 
Blood samples for cytokines and 
lymphocyte subtypes6 
x 
x 
x 
x 
x 
 
Concomitant Medications  
x 
x 
x7 
x7 
Adverse events assessment (NCI CTCAE 
V5.0) 
 
x7 
x7 
 
 
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Clinical Trial Protocol (SAC-COVID) 
IND 148237 
CD24Fc-007-US 
 
CD24Fc for COVID-19 Treatment; v1.9:  August 16, 2020 
Page 8 of 89 
CD24Fc-007-US PROTOCOL SIGNATURE PAGE 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practice, and the applicable laws and regulations of 
the federal government. I will promptly submit the protocol to the IRB for review and approval. 
Once the protocol has been approved by the IRB, I understand that any modifications made 
during the study must first be approved by the IRB prior to implementation except when such 
modification is made to remove an immediate hazard to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the study treatment, the conduct of the study, and the 
obligations of confidentiality. 
This document may be signed and dated electronically through submission and approval by the 
Principal Investigator at institutional IRB Electronic Research Integrity and Compliance 
Administration (ERICA) system or be signed and dated with a hand-written signature on this 
signature page. 
Instructions to multi-site Principal Investigators:   
Return the electronically signed and dated or scanned hand-written signed and dated copy to 
OncoImmune Research Compliance Office at 
. Retain a copy in the 
regulatory binder. 
 
 
____________________________________ 
_______________ 
Signature of Principal Investigator  
 
Date 
 
____________________________________ 
Principal Investigator Name (Print) 
 
____________________________________ 
Name of Institution 
 
 
__________________________________  
_______________ 
Signature of Chief Medical Officer  
 
Date 
 
  
Name  
 
 
 
 
 
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Clinical Trial Protocol (SAC-COVID) 
IND 148237 
CD24Fc-007-US 
Page 9 of 89 
TABLE OF CONTENTS 
CD24FC-007-US PROTOCOL SIGNATURE PAGE ....................................................................8 
TABLE OF CONTENTS .................................................................................................................9 
LIST OF FIGURES .......................................................................................................................13 
LIST OF TABLES .........................................................................................................................13 
1.
BACKGROUND AND SIGNIFICANCE ..................................................................14 
COVID-19 ..................................................................................................................14 
Rationale for Clinical Study of CD24Fc for COVID-19 Treatment ..........................15 
CD24Fc Overview ......................................................................................................19 
In vitro Efficacy Studies of CD24Fc ..........................................................................20 
CD24Fc protects animals against virus-induced T cell lymphopenia and 
immunotherapy- or SIV-induced pneumonitis ...........................................................21 
Pharmaceutical Information of Study Drug ................................................................25 
1.6.1. 
CD24Fc or CD24IgG (OncoImmune, Inc.), Study Agent ..........................................25 
1.6.2. 
Molecular Formula and Formulation ..........................................................................25 
1.6.3. 
Packaging, Ordering, and Inventory Management .....................................................26 
1.6.4. 
Availability, Storage and Stability ..............................................................................26 
1.6.5. 
Administration ............................................................................................................26 
Clinical Experience of CD24Fc in Humans ...............................................................26 
1.7.1. 
Phase I Summary: .......................................................................................................26 
1.7.2. 
Phase IIa Summary: ....................................................................................................27 
Safety in Humans ........................................................................................................29 
1.8.1. 
Phase I Safety Data .....................................................................................................29 
1.8.2. 
Phase IIa Safety Data ..................................................................................................29 
1.8.3. 
Treatment Emergent AEs (TEAEs) ............................................................................30 
Pharmacokinetics in Humans .....................................................................................32 
1.9.1. 
Phase I PK ...................................................................................................................32 
1.9.2. 
Phase IIa PK ...............................................................................................................33 
Immunogenicity in Humans .......................................................................................33 
1.10.1. 
Phase I ADA ...............................................................................................................33 
1.10.2. 
Phase IIa ADA ............................................................................................................35 
 
 
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Page 10 of 89 
 
Rationale for CD24Fc in COVID-19 treatment ..........................................................35 
 
Rationale for a Randomized, double blind, placebo-controlled Phase III Trial .........36 
 
Pharmacological study in dose selection ....................................................................36 
2. 
STUDY OBJECTIVES ..............................................................................................39 
 
Primary objective: .......................................................................................................39 
 
Secondary objectives: .................................................................................................39 
 
Exploratory objectives: ...............................................................................................39 
 
Primary Endpoints: .....................................................................................................39 
 
Secondary Endpoints: .................................................................................................39 
 
Exploratory endpoints .................................................................................................40 
 
Safety evaluation ........................................................................................................40 
3. 
STUDY DESIGN .......................................................................................................41 
 
Study Design Overview ..............................................................................................41 
 
Sample size .................................................................................................................41 
4. 
ELIGIBILITY CRITERIA .........................................................................................42 
 
Inclusion criteria .........................................................................................................42 
 
Exclusion criteria: .......................................................................................................42 
5. 
REMOVAL FROM STUDY ......................................................................................43 
6. 
STUDY DRUG ...........................................................................................................44 
 
Study drug CD24Fc ....................................................................................................44 
 
Placebo ........................................................................................................................44 
 
Study drug administration ...........................................................................................44 
 
Best available treatment ..............................................................................................44 
7. 
STUDY PROCEDURES ............................................................................................45 
 
Procedure and tests description ..................................................................................45 
7.1.1. 
Informed consent ........................................................................................................45 
7.1.2. 
Collect demographic data ...........................................................................................45 
7.1.3. 
Allergy history / medical history, previous / combined medication collection ..........45 
7.1.4. 
Vital signs and physical examination .........................................................................45 
7.1.5. 
Laboratory tests ..........................................................................................................46 
7.1.6. 
Analysis of oxygen saturation and arterial blood gas .................................................46 
 
 
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7.1.7. 
Pregnancy test .............................................................................................................46 
7.1.8. 
ECG ............................................................................................................................46 
7.1.9. 
Chest X-ray or CT scan ..............................................................................................47 
7.1.10. 
SARS-CoV-2 Viral nucleic acid check ......................................................................47 
7.1.11. 
Cytokine and lymphocyte subtype detection (For selected sites only) .......................47 
7.1.12. 
Evaluation of clinical status ........................................................................................47 
 
REQUIRED OBSERVATIONS (STUDY CALENDAR as in Synopsis) .................48 
7.2.1. 
Screening period .........................................................................................................48 
7.2.2. 
Treatment / follow-up observation period (D1 ~ D29)...............................................48 
8. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................51 
 
Adverse Events ...........................................................................................................51 
8.1.1. 
Definition of Adverse Events .....................................................................................51 
8.1.2. 
Definition of Serious Adverse Events (SAE) in COVID-19 ......................................51 
8.1.3. 
Criteria for Determining the Severity of Adverse Events ..........................................51 
8.1.4. 
Relationship to Study Drug ........................................................................................51 
8.1.5. 
Expectedness ...............................................................................................................52 
8.1.6. 
Follow-up of Adverse Events .....................................................................................52 
 
Adverse Event Reporting ............................................................................................53 
 
Serious Adverse Event Reporting ...............................................................................53 
 
Reporting of Pregnancy ..............................................................................................54 
 
Infusion Reaction Management ..................................................................................54 
9. 
DATA MANAGEMENT ...........................................................................................56 
 
Data Collection and Management Responsibilities ....................................................56 
 
Study Records Retention ............................................................................................56 
 
Protocol Deviations ....................................................................................................56 
 
Publication and Data Sharing Policy ..........................................................................57 
 
Conflict of Interest Policy ...........................................................................................57 
10. 
STATISTICAL ANALYSIS ......................................................................................58 
 
Sample size .................................................................................................................58 
 
Analysis Set ................................................................................................................58 
10.2.1. 
Intended-to-treat Set (ITT) .........................................................................................58 
 
 
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10.2.2. 
Per Protocol Set (PPS) ................................................................................................58 
10.2.3. 
Safety Data Set (SS) ...................................................................................................58 
Analysis methods ........................................................................................................58 
10.3.1. 
General principles .......................................................................................................58 
10.3.2. 
Distribution of subjects ...............................................................................................59 
10.3.3. 
Demographics, Medical History, and Baseline Characteristics ..................................59 
Efficacy Analysis ........................................................................................................59 
10.4.1. 
Primary efficacy endpoint ...........................................................................................59 
10.4.2. 
Secondary efficacy endpoints .....................................................................................60 
10.4.3. 
Exploratory Indicator Analysis ...................................................................................61 
10.4.4. 
Safety Analysis ...........................................................................................................62 
Interim Analysis and Stopping Rules .........................................................................62 
Missing Data Convention ...........................................................................................63 
11.
REGULATORY, ETHICAL, AND STUDY OVERSIGHT
CONSIDERATIONS ..................................................................................................64 
Informed Consent Process ..........................................................................................64 
11.1.1. 
Consent/assent and Other Informational Documents Provided to participants ..........64 
11.1.2. 
Consent Procedures and Documentation ....................................................................64 
11.1.3. 
Use of Legally Authorized Representative (Surrogate Consent) ...............................64 
Study Discontinuation and Closure ............................................................................66 
Confidentiality and Privacy ........................................................................................66 
Future Use of Stored Specimens and Data .................................................................67 
Clinical Monitoring ....................................................................................................67 
Quality Assurance and Quality Control ......................................................................69 
Trained and Certified Personnel .................................................................................69 
Independent Data and Safety Monitoring Board (DSMB) .........................................70 
Multi-center Coordination ..........................................................................................70 
11.9.1. 
Subject Screening and Registration Procedure ...........................................................70 
11.9.2. 
Contact Information ....................................................................................................71 
12.
REFERENCES ...........................................................................................................72 
13.
APPENDIX A .............................................................................................................76 
14.
APPENDIX B .............................................................................................................77 
 
 
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EVALUATION TO SIGN A CONSENT FORM FOR RESEARCH ..........................................77 
Evaluator  Date   Witness  Date ..................................................................................................78 
15. 
SUMMARY OF CHANGES ......................................................................................79 
 
LIST OF FIGURES 
Figure 1:  Diagram of the study. ...................................................................................................5 
Figure 2:  Radiological and histological presentation of COVID-19. .........................................16 
Figure 3:  The absolute lymphocyte numbers and subtype lymphocyte numbers in mild 
and severe COVID-19 patients. ..................................................................................17 
Figure 4:  Serum inflammatory cytokine changes in mild and severe COVID-19 
patients. .......................................................................................................................18 
Figure 5:  CD24Fc inhibits production of TNF-α and IFN-γ in activated human T cells. .........20 
Figure 6:  CD24 inhibits inflammatory cytokine production by human macrophages. ..............21 
Figure 7:  CD24Fc treatment reduces HIV-1 viral load and protects CD4+ T cells from 
depletion in the spleen of humanized mice with acute HIV infection. .......................22 
Figure 8:  CD24Fc protects SIV-infected monkeys from pneumonitis. .....................................23 
Figure 9:  CD24Fc reduces immunotherapy-induced pneumonitis. ...........................................23 
Figure 10:  CD24Fc reduces immunotherapy induced myocardiac inflammation and 
injuries. .......................................................................................................................24 
Figure 11:  The rationale for testing CD24Fc for the treatment of COVID-19. ...........................25 
Figure 12:  Plot of Mean (±SD) Plasma CD24Fc Concentration by Treatment – PK 
Evaluable Population. .................................................................................................32 
Figure 13:  Plot of Mean (±SD) Plasma CD24Fc Concentration by Treatment – PK 
Evaluable Population. .................................................................................................34 
 
LIST OF TABLES 
Table 1: 
Inclusion and Exclusion Criteria and NIAID 8-Point Scale for COVID-19. ...............6 
Table 2:  
Phase III study schedule ...............................................................................................7 
Table 3:  
Clinical syndromes associated with COVID-19 .........................................................15 
Table 4:  
Summary of the Pharmacokinetics data from Phase I and Phase IIa studies .............37 
 
 
 
 
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1. 
BACKGROUND AND SIGNIFICANCE  
 
COVID-19 
Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly 
emergent coronavirus, SARS-CoV-2, that was first recognized in Wuhan, China, in December 
2019, has now been detected in more than 100 locations internationally, including in the United 
States. On March 11, WHO characterized COVID-19 as a pandemic. As the unofficial data 
collected on April 8, 2020, there are approximate 1,530,000 confirmed cases and more than 
89,000 deaths due to COVID-19 worldwide. Genetic sequencing of the virus suggests that it is a 
betacoronavirus closely linked to the SARS virus (1).    
Although most people with COVID-19 have uncomplicated or mild illness (81%), some will 
develop severe illness requiring hospitalization and oxygen therapy (19%) and approximately 
5% will require admission to an intensive care unit (ICU). Of those critically ill, most will 
require mechanical ventilation (2, 3). The most common diagnosis in severe COVID-19 patients 
is severe pneumonia. Older patients and those with comorbidities, such as cardiovascular disease 
and diabetes mellitus, have increased risk of severe disease and mortality. They may present with 
mild symptoms but have high risk of deterioration and should be admitted to a designated unit 
for close monitoring. In severe cases, COVID-19 can be complicated by the acute respiratory 
distress syndrome (ARDS), sepsis and septic shock, multiorgan failure, including acute kidney 
injury and cardiac injury (3). A recent multivariable analysis confirmed older age, higher 
Sequential Organ Failure Assessment (SOFA) score and d-dimer > 1 μg/L on admission were 
associated with higher mortality. This study also observed a median duration of viral RNA 
detection of 20.0 days (IQR 17.0–24.0) in survivors, but COVID-19 virus was detectable until 
death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days 
(4, 5). 
WHO issued a second edition (version 1.2) of “The Interim Guidance on Clinical Management 
of Severe Acute Respiratory Infection (SARI) When COVID-19 Disease Is Suspected” on Mar 
13, 2020. This guidance will serve as a foundation for optimized supportive care to ensure the 
best possible chance for survival and to allow for reliable comparison of investigational 
therapeutic interventions as part of randomized controlled trials (6, 7). Table 3 listed the clinical 
syndromes associated with COVID-19 in adult patients. The appendix A has detailed description.  
 
 
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Table 3:  
Clinical syndromes associated with COVID-19 
Mild illness  
Patients may have non-specific symptoms such as fever, fatigue, cough (with or 
without sputum production), anorexia, malaise, muscle pain, sore throat, dyspnea, 
nasal congestion, or headache. Rarely, patients may also present with diarrhea, 
nausea, and vomiting (4, 8-10).  
 
Moderate 
Pneumonia  
Adult with pneumonia but no signs of severe pneumonia and no need for 
supplemental oxygen. Chest imaging may show increased bilateral interstitial 
changes. 
 
Severe pneumonia  Adolescent or adult: fever or suspected respiratory infection, plus one of the 
following: respiratory rate ≥ 24 breaths/min; severe respiratory distress; or SpO2 ≤ 
94% on room air. Requires oxygen therapy. 
While the diagnosis is made on clinical grounds; chest imaging may identify or 
exclude some pulmonary complications.  
 
Acute respiratory 
distress syndrome 
(ARDS) (11, 12) 
(Critical 
Condition) 
Required admission to ICU and mechanical ventilation. Referred to Appendix A for 
detailed description 
 
 
Rationale for Clinical Study of CD24Fc for COVID-19 Treatment 
As the newest global medical emergency (9), COVID-19 exhibits feature that are unlikely 
ameliorated solely by antiviral-based therapeutic approaches.   
First, although the new coronavirus (SARS-CoV-2) viral load was reduced around day 9 after 
appearance of clinical symptoms in upper respiratory samples (13), radiology studies based on 
CT scan suggest that lung damage peaked after day 9 and lasted well beyond 14 days (3) (Figure 
2a). The lung tissue in autopsy samples showed diffuse alveolar destruction and bronchiolar 
epithelial cell death. There are type II pneumocyte proliferation and interstitial infiltration of 
macrophages, some forming multi-nucleated giant cells similar to giant cell pneumonia. There 
are diffuse alveolar capillary congestion and alveolar disconnection and disintegration (14) 
(Figure 2b). This is reminiscent of findings in SARS-CoV infected patients where pneumonitis 
can peak after clearance of the virus (findings in SARS-CoV infected patients where 
pneumonitis can peak after clearance of the virus (15-17). Therefore, a successful counter 
measure must include amelioration of lung inflammation by non-antivirals. In this context, it is 
of important to note that, since steroid, the anti-inflammatory drug widely used in addressing 
severe inflammation, was not recommended for COVID-19 or SARS (18, 19), new approach is 
urgently needed. 
 
 
 
 
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Figure 2:  
Radiological and histological presentation of COVID-19. 
 
Second, patients with severe clinical symptoms show significant T cell lymphopenia that rivals 
human immunodeficiency virus (HIV) infection (Figure 3).  In contrast, patients with mild 
clinical symptoms have largely normal lymphocyte counts (20). The reduction of lymphocytes is 
due to loss of CD4 and CD8 T lymphocyte as B cell numbers are unaffected (20). In addition, 
functional exhaustion of T cells is suggested by high expression of T-cell exhaustion markers 
(8).  There were significant increase of several inflammatory cytokines in the serum (20) (Figure 
4).  The deletion and functional exhaustion of T cells prevent successful clearance of SARS-
CoV2, therefore further delaying clinical recovery. 
 
 
 
 
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Figure 3:  
The absolute lymphocyte numbers and subtype lymphocyte numbers in mild and 
severe COVID-19 patients.  
Severe COVID-19 patients have lymphopenia and reduced T lymphocyte numbers similar to HIV infection.  
 
 
 
 
 
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Figure 4:  
Serum inflammatory cytokine changes in mild and severe COVID-19 patients.  
 
Taken together, in addition to viral damage of lung epithelial cells, the cause of COVID-19 may 
well involve inflammation in response to cellular injuries caused by the virus, which is mediated 
by inflammatory factors referred to as damage-associated molecular patterns, or DAMPs.  The 
prototypical DAMPs such as HMGB1 and HSP70/90 are released when cells undergo either 
stress or necrosis, and trigger inflammation by interacting with TLR4 or RAGE.  Over 10 years 
ago, we have revealed that the CD24-Siglec 10/G interaction selectively regulates inflammation 
to DAMPs (21) (22) .  Numerous studies have confirmed the role of DAMPs in the pathogenesis 
of HIV (23, 24) and coronavirus (25, 26) infections.  Recent reports from our group in 
 
 
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collaboration with others have demonstrated a critical role for CD24 and Siglecs in inflammation 
associated with inflammation caused by human/simian immunodeficiency virus (HIV/SIV) (27).  
Based on this new understanding, treatment of COVID-19 likely requires a combination of both 
antiviral and non-antiviral-based approaches.  Antivirals can limit SARS-CoV2 replication; 
while immune modulators that ameliorate inflammation in the lung, preserve immune function 
by preventing T cell lymphopenia and functional T cell exhaustion, and prevent CRS.  Given the 
biology of the CD24-Siglec pathway in limiting inflammation to DAMPs, it is of great interest to 
test if this innate immune checkpoint can be fortified to address these challenges. Our 
preliminary studies suggest that our product, currently at Readiness Level 7, may fulfill all these 
roles. 
 
CD24Fc Overview 
CD24Fc comprises the non-polymorphic extracellular regions of CD24, which we have shown to 
be an innate checkpoint against the inflammatory response to tissue injuries or DAMPs (danger-
associated molecular patterns), attached to the Fc region of human IgG1.  Preclinical and clinical 
studies have demonstrated that CD24Fc effectively addresses the major challenges associated 
with COVID-19.  First, a Phase I clinical trial of heathy volunteers not only demonstrated safety 
of CD24Fc, but also demonstrated its biological activity in suppressing expression of multiple 
inflammatory cytokines  (28, 29).  Second, in a Phase II clinical trial in leukemia patients 
undergoing hematopoietic stem cell transplantation, three doses of CD24Fc effectively 
eliminated severe (Grade III-IV ) acute graft vs host disease (NCT02663622), which is caused by 
transplanted T cells attacking recipient target tissues (30, 31).  
 
 
 
 
 
  
As of this writing, OncoImmune has received Chinese Center for Drug Evaluation (CDE) 
approval for a Phase I/III clinical trial of CD24Fc for the treatment of severe COVID-19 patients 
in Wuhan, China.  Here we propose an independent Phase III clinical trial in the US testing the 
clinical efficacy of CD24Fc for treating severe COVID-19 patients using a new clinical protocol 
adapted based on US clinical practice.  The Phase III trial will involve 230 patients randomized 
into blinded placebo and CD24Fc arms, with time to clinical improvement from severe to mild 
symptoms as the primary endpoint.  It is anticipated that by reducing inflammation in the lung, 
CD24Fc could be a new generation of immune modifier that will enable repair of lung damage 
resulting from SARS-CoV2 infection.  At the same time, by rescuing T lymphocytes from 
deletion and functional exhaustion, CD24Fc will promote clearance of SARS-CoV2.  
Furthermore, by reducing cytokine storm, CD24Fc may further prevent multiple organ failures in 
COVID-19 patients.  
 
 
 
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Figure 5:  
CD24Fc inhibits production of TNF-α and IFN-γ in activated human T cells.  
 
 
 
 
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Figure 6:  
CD24 inhibits inflammatory cytokine production by human macrophages. 
 
 
 
 
 
  
 
 
CD24Fc protects animals against virus-induced T cell lymphopenia 
and immunotherapy- or SIV-induced pneumonitis 
Since T cell loss is associated with severe clinical symptoms in HIV patients, we established a 
mouse HIV model to study virally-induced T cell loss. 
We first investigated whether CD24Fc treatment influences HIV-1 replication and immune-
pathogenesis in acute HIV-1 infection with humanized mice. As shown in Figure 7a, in the 
vehicle-treated group, R3A replication rapidly increased to 1x106 copies/mL at 1 week post-
infection (wpi) and then it gradually increased to 108 copies/mL at 2-3 wpi. In the CD24Fc 
treated group, R3A increase in the first week was unaffected.  However, no further increase was 
observed at 2 and 3 wpi.  Nevertheless, CD24Fc treatment affected both CD4 and CD8 T cells 
equally as it did not reduce CD4 T cell frequency among CD3+ T cells (Figure 7b). Notably, 
 
 
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CD24Fc treatment significantly increased the numbers of CD4+ T cells in the spleen at the 
termination of the mice at 3 wpi (Figure 7c). This increase of CD4+ T cell number corresponded 
with an increase of the total human lymphocytes in the spleen of humanized mice (Figure 7d). 
These data indicate that CD24Fc has the potential to reduce HIV-1 viral load and protect T cells 
from depletion in the spleen of humanized mice with acute HIV infection.  Since the CD4 and 
CD8 ratio was not altered (Figure 7b), CD24Fc protected against loss of both CD4 and CD8 T 
cells. 
Figure 7: 
CD24Fc treatment reduces HIV-1 viral load and protects CD4+ T cells from 
depletion in the spleen of humanized mice with acute HIV infection.  
(a) The effect of CD24Fc treatment on plasma HIV-1 loads in of R3A infected mice with or without CD24Fc
administered by i.p. at 5 mg/kg on days1, 8 and 15 after infection. (b) Summary data of the percentages of CD4+ T
cells in the peripheral blood of R3A infected mice with or without CD24Fc. (c and d) Summary data of the absolute
number of CD4+ T cells (c) and total human lymphocytes (d) in the spleen of R3A infected mice with or without
CD24Fc at termination. Data shown are mean and s.e.m. *P < 0.05, ** P < 0.01 (analysis of two-tailed unpaired
Student’s t-test). Similar protection of CD8 T cells are achieved as the CD4% in T cells was unaffected by CD24Fc.
We have recently reported that CD24Fc protected Chinese rhesus monkey against SIV-induced 
AIDS and death, primarily by reducing organ damage caused by inflammation (18). To test 
whether CD24Fc protects monkeys against SIV-induced pneumonitis, we analyzed the histology 
of the lung from SIV-infected monkey that were treated with either vehicle (PBS) or CD24Fc at 
56 days after viral infection (Figure 8a).  As shown in Figure 8b, 5 out of 6 monkeys receiving 
vehicle developed severe pneumonitis and two monkeys expired in week 13 and week 19. There 
are only 2 out of 6 monkeys that received CD24Fc had pneumonitis when examined after pre-
specified euthanization. Thus, CD24Fc reduced the rate of viral pneumonitis from 83% to 33%.   
human cell number_SP
R3A
R3A+CD24
0
2.0×106
4.0×106
6.0×106
8.0×106
human cell number
CD3+CD4+ cell number_SP
R3A
R3A+CD24
0
20000
40000
60000
80000
100000
CD3+CD4+ cell number
viral load
1
2
3
1.0×100
1.0×101
1.0×102
1.0×103
1.0×104
1.0×105
1.0×106
1.0×107
R3A
R3A+CD24
wpi
HIV RNA copies/ml
CD3+CD4+% in BL
pre-inf
1 wpi
2 wpi
3 wpi
0
20
40
60
80
100
R3A
R3A+CD24
CD4 T cell% in CD3
a
b
c
d
 
 
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Figure 8:  
CD24Fc protects SIV-infected monkeys from pneumonitis.   
A.  Diagram of experimental design.  Note that monkeys received PBS or CD24Fc at 8 weeks after infection.  All 
monkeys had established SIV infections and were randomized into treatment groups based on plasma viral titer, 
immune activation of CD8 T cells and CD4 T cell numbers.  B.  Histopathology of monkeys receiving PBS (left 6 
panels) and CD24Fc (right panels).  Pneumonitis were diagnosed based on histology in double blind fashion by 2 
independent investigators.  
 
To confirm if CD24Fc protects pneumonitis by virus-independent mechanisms, we tested its 
activity in mice that received combined immunotherapy of anti-PD-1 and anti-CTLA-4 
antibodies, which can lead to immune-related adverse events (irAE) in the lung.  As shown in 
Figure 9, CD24Fc significantly reduced inflammation in the lung.   
Figure 9:  
CD24Fc reduces immunotherapy-induced pneumonitis.   
The left and middle panels show histopathology staining, while the right panel shows the summary of double 
blinded pathology scores. 
 
Lung inflammation scores
B
 
 
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Major cardiac complications have been reported to develop in a considerable number of patients 
with COVID-19 pneumonia, and people with underlying cardiovascular diseases are among the 
highest risk individuals for severe disease and death. Cardiac troponin I values are significantly 
increased in patients with severe SARS-CoV-2 infection compared to those with milder forms of 
disease (4, 10, 20, 35). To confirm if CD24Fc protects myocardiac injuries by virus-independent 
mechanisms, we tested its activity in mice that received combined immunotherapy of anti-PD-1 
and anti-CTLA-4 antibodies, which can lead to immune-related adverse events (irAE) in the 
heart.  As shown in Figure 10, CD24Fc significantly reduced inflammation in the heart.  
Figure 10:  
CD24Fc reduces immunotherapy induced myocardiac inflammation and injuries. 
(A)The histopathology of the aorta base and left ventricle of the heart; (B) The histopathology of the right atrium of 
the heart; (C) The summary of double blinded pathology scores.   
 
 
Taken together, our preclinical studies revealed that CD24Fc can effectively control 
inflammatory cytokines, rescue T cells from virus-induced depletion, and prevent lung 
inflammation.  In addition, we also observed that CD24Fc significantly reduced exhaustion of 
human T cells in HIV-infected humanized mice (data not shown).  Given the critical roles of 
these features in the pathogenesis of COVID-19, our data provided strong rationale for the 
clinical evaluation of CD24Fc as an immune modifier for COVID-19 (Figure 11). 
 
 
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Figure 11:  
The rationale for testing CD24Fc for the treatment of COVID-19.  
SARS-CoV2 infected caused damage in the pneumocytes, resulting in release of DAMPs, which triggers production 
of inflammatory cytokines and a vicious cycle of tissue damage.  Inflammation also cause T cell overdrive, resulting 
in functional T cell exhaustion and IFNγ-mediated activation-induced cell death (32-34), leading to T cell 
lymphopenia.  CD24Fc blocks these key steps in COVID-19 pathogenesis, and thus represent a unique immune 
modifier that provides a new therapeutic approach for COVID. 
 
 
Pharmaceutical Information of Study Drug 
1.6.1. 
CD24Fc or CD24IgG (OncoImmune, Inc.), Study Agent 
CD24Fc (CD24 Ig) is a fusion protein consisting of the extracellular domain of mature human 
CD24 linked to the human immunoglobulin G1 (IgG1) Fc domain. 
1.6.2. 
Molecular Formula and Formulation 
The complete molecular formula of CD24Fc has not been determined at this time.  The mature 
 
 
 
 
   
CD24Fc has been formulated as single dose injection solution, at a concentration of 10 mg/mL in 
phosphate buffered saline at pH 7.2.  Each 20 mL CD24Fc Drug Product vial 120 mg of CD24Fc 
in a volume that allows for extractable 12 ml. Each vial will be labeled according to Title 21 of 
the U.S. Code of Federal Regulations with “Caution: New Drug – Limited by Federal (or United 
States) Law to Investigational Use. The label should have Product Name CD24Fc and Lot 
number: 0118-002.  
CD24Fc abrogates multiple steps of 
COVID-19 pathogenesis
1. Inhibition of expression of multiple 
inflammatory cytokines
2. Prevent expression of T lymphocyte 
exhaustion markers
3. Prevention lymphopenia by inhibiting 
IFNγ production: an underlying cause of T 
cell death during viral infection.
 
 
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1.6.3. 
Packaging, Ordering, and Inventory Management 
CD24Fc Drug Product is supplied in clear borosilicate glass vials with chlorobutyl rubber 
stoppers and aluminum flip off seals. Vials of Lot 0118-002 are further packaged into 8 vial 
patient kit boxes comprising labeled paperboard boxes outfitted with cardstock box dividers and 
tamper evident seals.  Drug product vials are stored at OncoImmune’s clinical distribution site, 
Almac Clinical Services, at 25 Fretz Road, Souderton, PA. On site inventory will be managed by 
the CRO and additional drug will be ordered by OncoImmune or the CRO and shipped directly 
to the drug site from Almac. 
1.6.4. 
Availability, Storage and Stability 
CD24Fc is supplied as a sterile, clear, colorless, preservative-free aqueous solution for parenteral 
administration. CD24Fc is stored at -20° C until use.  CD24Fc should be thawed and equilibrated 
to room temperature prior to administration.  CD24Fc Drug Product used in the Phase I and 
Phase IIa trials (Lot 09MM-036) is stable for at least 66 months at -20oC, for 6 months at 5°C 
and 3 months at 25oC. New CD24Fc Drug Product has been manufactured as “Lot 0118-002”. 
The new Drug Product has been administered 58 times in the Phase II expansion cohort study. 
Stability studies for Lot 0118-002 are ongoing and it has demonstrated to be stable for 24 months 
at the intended storage temperature, -20oC, for 6 months at 5oC and 1 month at 25°C. 
1.6.5. 
Administration 
CD24Fc at doses up to 480 mg will be prepared in a diluent comprising 0.9% Sodium Chloride 
in a volume of 100 ml and be administrated by intravenous infusion over a minimum of 60 
minutes.  
 
Clinical Experience of CD24Fc in Humans 
1.7.1. 
Phase I Summary: 
OncoImmune Inc. has developed and manufactured clinical grade CD24Fc for use in humans. 
CD24Fc has been tested in a Phase I clinical trial in healthy human subjects, and this study 
showed preliminary safety of single dose CD24Fc by IV administration. A total of 40 subjects 
were randomized in 5 cohorts of 8 subjects, and 39 subjects completed the study. CD24Fc was 
administered via IV infusion over 1 hour at doses ranging from 10 to 240 mg, and the subjects 
were followed over a six-week period. A MTD was not encountered.  
In general, adverse events were mild to moderate in severity. The most common AEs were 
headache (6 [15.0%] subjects), accidental burns second degree (3 [7.5%] subjects), non-
sustained ventricular tachycardia (2 [5.0%] subjects), and upper respiratory tract infection (2 
[5.0%] subjects). The rates of the AEs were similar in the placebo control group. The SAE of 
ventricular tachycardia was considered mild in severity by the investigator and did not lead to 
discontinuation of the subject from the study. This SAE was considered to be drug related due to 
its close temporal proximity to dosing, though similar short, isolated episodes of non-sustained 
ventricular tachycardia may be seen in up to 4% of normal, healthy populations. No deaths or 
adverse events leading to discontinuation occurred during the study.  
 
 
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1.7.2. 
Phase IIa Summary: 
A Phase IIa prospective randomized double-blind clinical trial of CD24Fc for acute GVHD 
prophylaxis in myeloablative matched unrelated donor HCT was initiated in July 2016. The first 
patient was enrolled in Sept 2016. A total of 24 patients were enrolled in three cohorts, 240mg 
single dose given at day -1, 480mg single dose at day -1, 480-240-240mg multi-dose given on 
day -1, day 14 and day 28, with 6 patients receiving CD24Fc and 2 patients receiving placebo in 
each cohort. The last patient was enrolled in Dec 2017. The last patient reached one year 
post-HCT in December 2018. Data was locked and the final clinical study report (CSR) was 
submitted to FDA in April 2019. In total there are 18 patients in the CD24Fc group and 
6 patients in the placebo group (3:1 randomization).  All planned dosages were delivered on 
schedule.   
1.7.2.1. 
Phase IIa Clinical Study Overview 
The primary objectives of the Phase IIa are to assess the safety and tolerability of CD24Fc in 
combination with methotrexate and tacrolimus prophylaxis in subjects undergoing matched 
unrelated donor HCT following myeloablative conditioning, and to define the recommended 
Phase II dose (RP2D) or maximum tolerated dose (MTD). In addition, secondary efficacy 
objectives in the Phase IIa include: 
• assessing grade II – IV aGVHD free survival (GFS) at day 180 after HCT,  
• assessing the incidence of chronic GVHD (cGVHD) at one year following HCT 
• assessing the incidence of relapse one year following HCT 
• assessing the incidence of transplant-related mortality (TRM) one year following 
HCT 
• assessing infection rates at day 100 following HCT 
• evaluating overall survival (OS), absence of grade III-IV GVHD, and relapse-free 
survival one year following HCT 
• evaluating conditioning toxicity including oral mucositis and organ failure 
Other exploratory objectives include assessment of the pharmacokinetic (PK) profile of CD24Fc, 
examining the immune cell profile and functional responses of APCs and T cells after HCT in 
the CD24Fc and placebo groups, and assessing pharmacodynamics (PD) biomarkers such as the 
plasma concentrations of pro-inflammatory cytokines, DAMPs, lipids, and GVHD biomarkers in 
the CD24Fc and placebo groups. 
Subjects between the ages of 18-70 years old undergoing matched unrelated donor allogeneic 
HCT for a malignant hematologic condition (AML, ALL, CML, CMML, MDS) with a 
Karnofsky performance score ≥ 70% were eligible for the trial. An 8/8 HLA allelic match 
between the unrelated donor and the recipient at HLA-A, HLA-B, HLA-C, and HLA-DRB1 was 
required. All subjects received myeloablative conditioning and standard of care GVHD 
prophylaxis with methotrexate and tacrolimus per the Phase IIa protocol. Patients received a 
myeloablative conditioning regimen consisting of either fludarabine and busulfan (Flu/Bu) or 
 
 
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cyclophosphamide and total body irradiation (Cy/TBI), as decided by the treating physician, 
followed by an infusion of stem cells on day 0. The source of donor stem cells was either 
peripheral blood stem cells (PBSC) or bone marrow (BM). GVHD prophylaxis was administered 
to all subjects and consisted of tacrolimus (initiated Day -3 before transplant) and methotrexate 
(initiated Day +1 after transplant) in combination with CD24Fc in the treatment arms, and 
tacrolimus/methotrexate plus saline solution in the placebo arm. In the absence of GVHD, 
tacrolimus tapering started on day +100.  
1.7.2.2. 
Phase IIa Clinical Study Summary 
Overall, CD24Fc was well tolerated in the Phase IIa study. There were no infusion-related 
toxicities. There was one possible drug related treatment emergent adverse event (TEAE) of 
≥ grade III-IV hyperglycemia in the 480 mg CD24Fc group, which was managed with insulin. 
One dose-limiting toxicity (DLT) was observed in the placebo group, and no DLTs were 
observed in the CD24Fc group. There were no adverse events leading to death in subjects 
administered CD24Fc within the 180 days. There was one adverse event of pneumonia that led to 
the death of a subject at Day 48 in the placebo group. The development of anti-drug antibodies 
(ADA) were not detected in any of the 24 subjects at any point out to day 100 after HCT. 
The most common TEAEs ≥ grade III (> 10%) included a decrease in platelet counts (83.3% 
placebo and 94.4% CD24Fc), decrease in WBC counts (66.7% placebo and 88.9% CD24Fc), 
decrease in neutrophil counts (50% placebo and 83.3% CD24Fc), decrease in lymphocyte counts 
(50% placebo and 77.8% CD24Fc), anemia (50% placebo and 66.7% CD24Fc), stomatitis 
(83.3% placebo and 50% CD24Fc), and nausea (0% placebo and 11.1% CD24Fc). These are 
expected SAEs were anticipated as they were hematologic in nature and were otherwise 
considered related to the myeloablative conditioning regimen of HCT. 
In the Phase IIa study, compared to treatment with placebo, treatment with CD24Fc resulted in 
trends toward:  
1. Higher Grade III to IV acute GFS rate at Day 180 (94.4% in CD24Fc treatment group, 
50.0% in placebo) (hazard ratio = 0.1),  
2. Higher DFS rate at 1 year (83.3% in CD24Fc treatment group, 50.0% in placebo) (hazard 
ratio = 0.2),  
3. Higher OS rate at 1 year (83.3% in CD24Fc treatment group, 50.0% in placebo) (hazard 
ratio = 0.2),  
4. Higher Grade III to IV acute GRFS rate at Day 180 (83.3% in CD24Fc treatment group, 
33.3% in placebo) (hazard ratio = 0.2), 
5. Lower incidence of Grade III-IV acute GVHD by Day 180 (5.6% in CD24Fc treatment 
group, 33.3% in placebo) (hazard ratio = 0.1),  
6. Lower cumulative incidence of leukemia relapse at 1 year (11.1% in CD24Fc treatment 
group, 33.3% in placebo) (hazard ratio = 0.3), 
7. Lower incidence of non-relapse mortality at 1 year (5.6% in CD24Fc treatment group, 
16.7% in placebo) (hazard ratio = 0.3), 
 
 
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8. Similar cumulative incidence of Grade II to IV acute GVHD by Day 180 (38.9% in 
CD24Fc treatment group, 33.3% in placebo) (hazard ratio = 2.6),  
9. Similar 1 year GRFS (Grade III-IV acute GVHD / chronic GVHD requiring systemic 
immunosuppressive treatment /relapse free survival) (32.4% in CD24Fc treatment group, 
33.3% in placebo) (hazard ratio = 0.7), 
10. Higher cumulative incidence of all grade chronic GVHD at 1 year (63.3% in CD24Fc 
treatment group, 33.3% in placebo) (hazard ratio = 2.1).  
 
Safety in Humans  
1.8.1. 
Phase I Safety Data 
A Phase I, randomized, double-blind, placebo-controlled, single ascending dose study to assess 
the safety, tolerability, and PK of CD24Fc in healthy male and female adult subjects was 
conducted. Details are also provided in section 3.8 A total of 40 subjects were randomized in 
5 cohorts of 8 subjects each, and 39 subjects completed the study. CD24Fc was administered via 
IV infusion over 1 hour. In total, 18 (45.0%) subjects had a treatment-emergent adverse event 
(TEAE) during the study: 6 (60.0%) subjects in the placebo group, 2 (33.3%) subjects in the 
CD24Fc 10 mg group, 3 (50.0%) subjects in the CD24Fc 30 mg group, 2 (33.3%) subjects in the 
CD24Fc 60 mg group, 3 (50.0%) subjects in the CD24Fc 120 mg group, and 2 (33.3%) subjects 
in the CD24Fc 240 mg group. 
All TEAEs in the study were considered mild to moderate in severity by the Investigator except 
for 1 subject in the placebo group who experienced a severe headache. The most common 
TEAEs were headache (6 [15.0%] subjects), burns second degree (3 [7.5%] subjects), non-
sustained ventricular tachycardia (2 [5.0%] subjects), and upper respiratory tract infection (2 
[5.0%] subjects). 
Overall, 5 (12.5%) subjects had a study drug-related TEAE: 1 (10.0%) subject in the placebo 
group, 2 (33.3%) subjects in the CD24Fc 10 mg group, 1 (16.7%) subject in the CD24Fc 30 mg 
group, and 1 (16.7%) subject in the CD24Fc 60 mg group. The study drug-related TEAEs during 
the study were headache (4 [10.0%] subjects) and ventricular tachycardia (1 [2.5%] subject). A 
drug-related SAE of ventricular tachycardia was experienced by 1 subject in the CD24Fc 60 mg 
group. This SAE occurred at a rate comparable with normal populations, was considered mild by 
the Investigator, and did not lead to discontinuation from the study. No subjects died during the 
study and no subjects discontinued from the study due to an adverse event. There were no 
clinically meaningful changes from baseline in laboratory parameters, vital signs, ECGs, or 
physical exams during the study. 
1.8.2. 
Phase IIa Safety Data 
The number of subjects with TEAEs from Day -1 to 30 or 60 days after the last dosing was the 
same between all treatment groups: 6 (100.0%) patients in the 240 mg CD24Fc single dose 
cohort, 6 (100.0%) patients in the 480 mg CD24Fc single dose cohort, 6 (100.0%) patients in the 
480/240/240 mg multiple dose cohort, and 6 (100.0%) patients who received placebo 
experienced TEAEs.  
 
 
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The most common TEAEs were stomatitis (6 [100.0%] patients in the 240 mg CD24Fc single 
dose cohort, 6 [100.0%] patients in the 480 mg CD24Fc single dose cohort, 5 [83.3%] patients in 
the 480/240/240 mg CD24Fc multiple dose cohort, and 6 [100.0%] patients who received 
placebo); platelet count decreased (6 [100.0%] patients in the 240 mg CD24Fc single dose 
cohort, 6 [100.0%] patients in the 480 mg CD24Fc single dose cohort, 5 [83.3%] patients in the 
480/240/240 mg CD24Fc multiple dose cohort, and 5 [83.3%] patients who received placebo); 
white blood cell count decreased (6 [100.0%] patients in the 240 mg CD24Fc single dose cohort, 
6 [100.0%] patients in the 480 mg CD24Fc single dose cohort, 5 [83.3%] patients in the 
480/240/240 mg CD24Fc multiple dose cohort, and 4 [66.7%] patients who received placebo). 
Severe stomatitis (≥ Grade 3) occurred in 3 (50.0%) patients in the 240 mg CD24Fc single dose 
cohort, 4 (66.7%) patients in the 480 mg CD24Fc single dose cohort, 2 (33.3%) patients in the 
480/240/240 mg CD24Fc multiple dose cohort, and 5 (83.3%) patients who received placebo, 
with a clear inverse correlation between CD24Fc doses and duration of severe stomatitis. 
One (16.7%) patient in the 480 mg CD24Fc single dose cohort and 2 (33.3%) patients who 
received placebo experienced a study drug-related TEAE. The most common study drug-related 
TEAE was diarrhea (1 [16.7%] patient in the 480 mg CD24Fc single dose cohort and 
2 [33.3%] patients who received placebo). No patients in other cohorts experienced a study 
drug-related TEAE. 
The incidence of Grade 3/4/5 TEAEs was the same between all treatments: 6 (100.0%) patients 
in the 240 mg CD24Fc single dose cohort, 6 (100.0%) patients in the 480 mg single dose cohort, 
6 (100.0%) patients in the 480/240/240 mg multiple dose cohort, and 6 (100.0%) patients who 
received placebo. One (16.7%) patient in the 480 mg CD24Fc single dose cohort experienced 
hyperglycemia that was considered a study drug-related Grade 3/4/5 TEAE. 
No patients receiving CD24Fc experienced a DLT during the study.  One dose-limiting toxicity 
(DLT) was observed in the placebo group 
In total, 1 (4.2%) patient died during the study. Patient 
 received placebo and 
experienced Grade 4 pneumomediastinum and Grade 5 pneumonia TEAEs that resulted in death. 
Per the Investigator, it was considered unlikely that these TEAEs were related to study drug. 
1.8.3. 
Treatment Emergent AEs (TEAEs) 
In total, 9 (37.5%) patients experienced TESAEs from Day -1 to 30/60 days after the last dosing: 
2 (33.3%) patients in the 240 mg CD24Fc single dose cohort (30 days), 1 (16.7%) patient in the 
480 mg CD24Fc single dose cohort (30 days), 4 (66.7%) patients in the 480/240/240 mg 
CD24Fc multiple dose cohort (60 days), and 2 (33.3%) patients who received placebo (30, 30, 
60 days). Treatment-emergent SAEs reported for patients who received CD24Fc (some patients 
had more than one condition) were nausea (2), stomatitis (1), abdominal pain (1), dehydration(1), 
decreased appetite (1), device related infection (1), pain (1), weight decreased (1), arthritis (1), 
cognitive disorder (1), and embolism (1).  
In total, 1 patient experienced a TEAE that led to discontinuation of study drug: this patient 
received placebo. Patient 
 experienced a Grade 4 pneumonia TEAE that led to 
discontinuation of study drug (ie, placebo). Per the Investigator, it was considered unlikely that 
this TEAE was related to study drug. 
 
 
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In Chemistry laboratory tests, the incidence of TEAEs of alanine aminotransferase increased or 
blood alkaline phosphatase increased were similar between patients who received CD24Fc and 
patients who received placebo (ALT: 44% vs 50%; ALP 22% vs 17%). The incidence of TEAEs 
of aspartate aminotransferase increased was higher for patients who received CD24Fc compared 
to patients who received placebo (28% vs 18%). Treatment-emergent adverse events of blood 
creatinine increased were only reported by patients who received placebo (33.3%). A TEAE of 
blood bilirubin increased was reported by 1 (16.7%) patient who received placebo. In general, 
TEAEs were consistent with toxicities normally associated with HCT conditioning and did not 
appear associated with investigational therapy or placebo.   
Hematologic Effects: 
In total, the incidence of TEAEs of white blood cell count decreased, lymphocyte count 
decreased, and neutrophil count decreased were higher in patients who received CD24Fc 
compared to patients who received placebo (white blood cells decrease 94% vs 67%, lymphocyte 
decrease 83% vs 50%, neutrophil decrease 89% vs 50%). The incidence of TEAEs of platelet 
count decreased was similar between patients who received CD24Fc and patients who received 
placebo (94% vs 83%). 
No patient had a laboratory abnormality that was considered an SAE or resulted in 
discontinuation of study drug.  
No patients who received either single or multiple dosing of CD24Fc had positive ADA results 
at any time point sampled pre- or post-infusion. 
A TEAE of weight increased was reported by 1 (16.7%) patient who received placebo and A 
TEAE of weight decreased was reported by 3 (16.7%) patients who received CD24Fc. A TEAE 
of ECG QT prolonged was reported by 1 (16.7%) patient who received placebo. 
Donor Cell Engraftment and Chimerism: 
In total, 18 (100.0%) patients who received CD24Fc and 6 (100.0%) patients who received 
placebo experienced neutrophil engraftment. The median time to neutrophil engraftment was 
13.5 days for patients in the 240 mg CD24Fc single dose cohort, 13.5 days for patients in the 480 
mg CD24Fc single dose cohort, 13.0 days for patients in the 480/240/240 mg CD24Fc 
multi-dose cohort, and 15.5 days for patients who received placebo.  
In total, 18 (100.0%) patients who received CD24Fc and 5 (83.3%) patients who received 
placebo experienced platelet engraftment. The median time to platelet engraftment was 15.5 days 
for patients in the 240 mg CD24Fc single dose cohort, 13.0 days for patients in the 480 mg 
CD24Fc single dose cohort, 12.0 days for patients in 480/240/240 mg CD24Fc multiple dose 
cohort, and 15.0 days for patients who received placebo. No patients experienced primary 
engraftment failure. 
The mean CD3 cell chimerism on Day 28/Day 30 was 73.0% donor cells for patients who 
received CD24Fc and 77.4% donor cells for patients who received placebo. The mean CD3 cell 
chimerism on Day 100 was 80.9% donor cells for patients who received CD24Fc and 73.8% 
donor cells for patients who received placebo. 
 
 
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The mean CD33 cell chimerism on Day 28/Day 30 was 100.0% donor cells for patients who 
received CD24Fc and 100.0% donor cells for patients who received placebo. The mean CD33 
cell chimerism on Day 100 was 99.4% donor cells for patients who received CD24Fc and 96.6% 
donor cells for patients who received placebo.  
 
Pharmacokinetics in Humans 
1.9.1. 
Phase I PK 
The PK of CD24Fc in healthy human subjects was determined from the single dose Phase I 
study. The mean plasma concentration of CD24Fc increased proportionally to the dose of 
CD24Fc administered (Figure 12). For all dose groups except 120 mg, the maximum mean 
plasma concentration of CD24Fc was reached at 1 hour post-dose. The maximum mean plasma 
concentration of CD24Fc for the 120 mg group was reached at 2 hours post-dose. By Day 42 
(984 hours), the mean plasma concentration of CD24Fc for all groups had decreased to between 
2% and 4% of the maximum mean plasma concentration. CD24Fc reached Tmax at 1.34 hours. 
The t½ of plasma CD24Fc range was 280.83 to 327.10 hours.  
Figure 12:  
Plot of Mean (±SD) Plasma CD24Fc Concentration by Treatment – PK Evaluable 
Population.   
PK = pharmacokinetic; SD = standard deviation. 
Source: Investigators Brochure.  
 
 
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1.9.2. 
Phase IIa PK 
The PK of CD24Fc in human subjects undergoing HCT has been determined from the Phase IIa 
study from the two single dose cohorts and one multi-dose cohort (Figure 13). With the 240 mg 
single dose, the mean plasma concentration of CD24Fc is similar to the 120 mg single dose in 
Phase I human volunteers. The 480 mg dose shows a proportional increase of CD24Fc at all time 
points. The 480/240/240 mg multi-dose maintains the CD24Fc plasma concentration over 
10,000 ng/ml over the period of Day-1 to Day 42 post-HCT.  
Following a single IV administration of CD24Fc (240 and 480 mg CD24Fc single dose cohorts), 
the geometric mean plasma exposure (Cmax,-1d, AUC0-42d, and AUC0-inf) increased with increasing 
CD24Fc doses. The mean t½ and λz were similar between the 240 and 480 mg doses of CD24Fc. 
The mean values of t½ were 414.739 and 406.648 h and the mean values of λz were 0.0018 and 
0.0017 h-1 for the 240 and 480 mg CD24Fc single dose cohorts, respectively. Additionally, there 
was an increase in the mean Vz and CL between the 240 and 480 mg doses of CD24Fc. 
Following multiple IV administrations of CD24Fc (480/240/240 mg CD24Fc multi-dose cohort), 
the exposure of CD24Fc was sustained over time. Additionally, the mean plasma CD24Fc 
concentration on Day 100 was higher for the 480/240/240 mg CD24Fc multi-dose cohort (850.84 
ng/mL) compared to the single dose cohorts (216.38 ng/mL and 330.96 ng/mL for the 240 and 
480 mg CD24Fc single dose cohorts, respectively). Furthermore, the geometric mean 
AUC0-last,overall value was higher for the 480/240/240 mg CD24Fc multi-dose cohort 
(37,363,953.5 ng⋅h/mL) compared to the single dose cohorts (10,156,549.9 ng⋅h/mL and 
15,522,686.2 ng⋅h/mL for the 240 and 480 mg CD24Fc single dose cohorts, respectively). 
The median tmax,-1d (2.10 h for both the 240 and 480 mg CD24Fc single dose cohorts and 2.13 h 
for the 480/240/240 mg CD24Fc multiple dose cohort) remained consistent across all of the 
CD24Fc doses. For the 480/240/240 mg CD24Fc cohort, the median tmax,-1d and tmax,28d were 
similar (2.13 and 2.52 h, respectively). 
 
Immunogenicity in Humans 
1.10.1. 
Phase I ADA 
Serum samples in the Phase I study were screened for anti-drug antibodies. Anti-CD24Fc 
antibodies were detectable at Day 28 and Day 42 in 1 subject in each of the 5 dose cohorts; 
however, for the subject in the CD24Fc 120 mg group and the subject in the CD24Fc 240 mg 
group, anti-CD24Fc antibodies were also detectable pre-dose at levels higher than post-dose 
levels. Except for those subjects with significant pre-dose anti-CD24Fc antibody levels, all post-
dose anti-CD24Fc antibody levels were modest. No deviations in PK were found in any subjects 
with detectable anti-CD24Fc antibody levels. 
 
 
 
 
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Figure 13:  
Plot of Mean (±SD) Plasma CD24Fc Concentration by Treatment – PK 
Evaluable Population.  
Upper Panel: PK in linear scale. Lower Panel: PK in semi-log scale. Single dose cohorts, 240mg (n=6); 480mg 
(n=6); multi-dose cohort, 480-240-240mg (n=6). 
 
 
 
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1.10.2. 
Phase IIa ADA 
In the Phase IIa allogeneic HCT context, given the immunoablation and immunosuppression of 
host immunity at time of CD24Fc administration, ADA responses were monitored but unlikely to 
be elicited.  
For the two single dose cohorts, the samples were collected at 7 time points from Day-1 to Day 
100. For the multi-dose cohort, the samples were collected at 13 time points from Day-1 to Day 
100. As expected, all samples are negative for ADA in the Phase IIa study. 
 
Rationale for CD24Fc in COVID-19 treatment 
Early clinical trials of CD24Fc in the prevention of acute GVHD are based on the following 
principles: 1) Early tissue damage occurs during conditioning regimen before HCT. Early tissue 
damage leads to the release of DAMP inflammatory mediators, which triggers acute GVHD; 
2) CD24Fc can significantly inhibit the DAMP inflammatory response that triggers acute GVHD 
by directly binding to DAMP molecules or by enhancing the interaction between CD24Fc and 
Siglec-10; and 3) studies from multiple pre-clinical models of acute GVHD demonstrate that 
early administration of exogenous human CD24Fc before infusion of donor cells can alleviate 
acute GVHD and improve survival after HCT. The results of the 2a clinical trial of CD24Fc 
provided the proof of concept in safety and efficacy in CD24Fc for the prevention of acute 
GVHD.  
In non-human primates, CD24Fc effectively reduced the inflammatory response and AIDS 
caused by the monkey immunodeficiency virus (SIV). In a humanized mouse model, CD24Fc 
effectively inhibits the production of multiple inflammatory cytokines and prevents the HIV 
induced T cell depletion and T cell exhaustion.  
Coronavirus SARS-CoV-2 infection involves lower respiratory tract and alveolar pneumocytes 
where the virus replicates. Early coronavirus infection triggers the body's innate immunity. 
Activated innate immune cells will release interferon type cytokines to limit the viral replication. 
A few days later, the adaptive immune system (adaptive immunity) joins the process of 
eliminating viral infected cells until the virus is cleared. However, the over-activated innate 
immunity and adaptive immunity may over reactive to cause damage to host tissues. ACE2, the 
receptor for SARS-CoV-2, is highly expressed on the epithelial cells of the lower respiratory 
tract and alveolar pneumocytes (36). Therefore, the host response induced by viral infection and 
specific inflammatory mediators may lead to bystander damage to lung tissues. This is 
considered to be the major mechanism for acute lung injury (ALI) and acute respiratory distress 
syndrome (ARDS) in COVID-19. Thus, the COVID-19 treatment should be the anti-viral drugs 
to inhibit viral replication in combination with non-anti-viral immunomodulators to protect lung 
tissue injury. Current clinical anti-inflammatory therapy consists of systemic corticosteroid and 
non-steroidal anti-inflammatory drugs. In this context, it is of important to note that, 
corticosteroid, the anti-inflammatory drug widely used in addressing severe inflammation, was 
not recommended for COVID-19 or SARS (18, 19). 
CD24Fc plays a dual role in the innate immune response triggered by the release of DAMPs 
from necrotic cells. CD24Fc directly binds multiple DAMP molecules such as HMGB1 and 
HSP70 / 90 to neutralize DAMPs. CD24Fc also bind to Siglec 10 to activate the CD24-Siglec 
 
 
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signaling pathway on antigen presenting cells to suppress the NFkB activation and to reduce the 
biosynthesis of multiple inflammatory cytokines, including IL-6, IL-1β, TNF-α and INF-γ. 
CD24Fc will be an important immunomodulator in COVID-19 treatment.  
Here we provided the strong evidence from pre-clinical data from in vitro cell culture, 
humanized mouse HIV model, and nonhuman primate model of SIV viral pneumonitis, the 
safety and efficacy in clinical proof-of-concept studies, and the pathogenesis of COVID-19 to 
support the clinical study in testing the safety and efficacy of CD24Fc as an immunomodulator 
in COVID-19 treatment. Based on the clinical experience and pharmacokinetic data of CD24Fc, 
we plan to give a single dose of 480 mg CD24Fc to eligible patients with confirmed COVID-19 
and severe pneumonia. This dose is deemed safe as 32 HCT patients have been exposed to this or 
higher doses.  The only drug-related SAE is a transient hyperglycemia in 1 patient that responded 
well to insulin treatment. Furthermore, based on in vitro effect of IFNγ inhibition and PK in HCT 
patients, a single dose should be sufficient to provide adequate drug concentration during the 
study period of two weeks. 
All patients should have best available treatment according to local institutional guideline in US. 
It is recommended to follow the WHO Interim Guidance on Clinical Management of Severe 
Acute Respiratory Infection (SARI) When COVID-19 is Suspected (version 1.2, Mar. 13, 2020). 
 
Rationale for a Randomized, double blind, placebo-controlled Phase 
III Trial 
The Phase 1, Phase IIa and Phase II expansion cohort studies suggest that CD24Fc is safe and 
well tolerized in healthy people and in patients with hematological malignancies heavily treated 
with chemotherapy and radiation.  
This multicenter Phase III clinical trial will evaluate adding CD24Fc to best available treatment 
for the efficacy in increase the proportion of patients from severe COVID-19 to convert to mild 
or moderate COVID-19. The randomized, double blind and placebo-controlled study will 
provide the most rigorous analysis to assess the efficacy of the novel biological agent CD24Fc in 
COVID-19 treatment.  
 
Pharmacological study in dose selection 
Inflammatory response in COVID-2019 induces lymphopenia and T cell depletion in critically 
status patients.  Increased levels of inflammatory cytokines can be detected in the severely 
pneumonia patients in early stage of disease. CD24Fc can block the viral infection associated 
activation induced cell death in T cells, reduce the T cell depletion, and reduce the inflammation 
caused by viral induced cell necrosis. IFN-γ is a valuable biomarker that can best reflect the 
effect of CD24Fc on inhibition of T cell activation and death. 
In an in vitro pharmacodynamic experiment completed in March 2019, IFN-γ was used as an 
indicator to evaluate the in vitro inhibitory effect of different batches of CD24Fc products on 
human peripheral blood mononuclear leukocytes (PBML) activation. In the study, T cells in 
human PBML were activated with widely used T cell receptor agonist anti-CD3 antibodies and 
recombinant human IL-2. T cell activation was assessed by measuring IFN-γ production in cell 
 
 
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culture supernatants, and the biological activity of CD24Fc was determined by measuring the 
extent to which CD24Fc inhibited IFN-γ production. This study includes a batch of BF0222 
CD24Fc preparations produced under GMP conditions (produced in February 2018 and has been 
applied to 20 subjects in Phase II expansion cohort clinical trial in GVHD prevention. The 
product is safe and well tolerized. This batch will be used in this COVID-19 study) and 
09MM-036 (produced in December 2009, has been used in the US phase I and IIa GVHD 
prevention trials with good safety profile). 
The results showed that CD24Fc from 4 batches of production significantly reduced IFN-γ 
produced by human activated PBML in a dose-dependent manner. For IFN-γ inhibition, the 
concentration at which the test product produced 50% inhibition (IC50) was used as the 
evaluation index. The IC50 of batch 09MM-036 was 5.860 ug / mL, and the IC50 of batch 
BF0222 was 9.455 ug / mL. 
Based on the IC50 data of the BF0222 batch, the blood concentration of CD24Fc in existing 
clinical trials is compared, and the Pharmacological Activity (PA) of CD24Fc at different blood 
concentrations is calculated using the Hill equation, as shown in Table 4. 
𝐏𝐏𝐏𝐏=
𝐂𝐂𝜸𝜸
𝐈𝐈𝐈𝐈𝟓𝟓𝟓𝟓+ 𝐂𝐂𝜸𝜸 
Note: PA represents the pharmacological activity level, IC50 represents the half inhibitory 
concentration obtained in the in vitro experiment of this pharmacological activity, C represents 
the drug concentration at this pharmacological activity level, and the Hill coefficient γ used in 
the formula is set to 1. 
Table 4:  
Summary of the Pharmacokinetics data from Phase I and Phase IIa studies 
 
 
CD24Fc 240mg 
CD24Fc 480mg 
CD24Fc 960mg1 
D1 
Cmax average (ug/mL, PA%) 
52.3（84.7%） 
86.3（90.1%） 
102.8（91.6%） 
D14 
Cmin average (ug/mL, PA%) 
7.95（45.7%） 
10.4（52.4%） 
14.4（60.4%） 
D14 
Cmin (ug/mL, PA%) 
4.95（34.4%） 
7.05（42.7%） 
11.4（54.7%） 
D14 
Cmax (ug/mL, PA%) 
18.3（65.9%） 
12.5（56.9%） 
18.2（65.8%） 
1. Cumulative doses with first dose of 480mg.  
 
The above data demonstrated that at a dose of 480 mg of CD24Fc, the concentration level of the 
drug can be maintained at more than 50% of the pharmacological activity of the drug after 14 
days, and it should be expected to have a corresponding efficacy effect. The 480mg dose group 
also has good safety data. Additional dose escalation will be further explored in the Chinese 
population in the Phase I part of the study.  
In addition, data from previous clinical trials have shown that with the increase in drug dose and 
exposure, the safety performance of CD24Fc observed in clinical trials has not changed 
significantly. Therefore, it is considered that the safety of CD24Fc is within the acceptable range 
even if the exposure is slightly increased in lower body-weight people. 
 
 
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Based on the above factors, we intend to apply a fixed dose of 480 mg in single administration 
on Day 1 for this COVID-19 study.  
 
 
 
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2. 
STUDY OBJECTIVES 
 
Primary objective:  
• To evaluate the safety and efficacy of adding CD24Fc to COVID-19 best available 
treatment by comparing COVID-19 disease status improvement time between 
CD24Fc and placebo arms within 28 days. 
 
Secondary objectives:  
• Secondary objectives are to compare, for each treatment arm, proportion of patients 
who died or had respiratory failure (defined as the need for mechanical ventilation, 
ECMO, non-invasive ventilation, or high flow oxygen devices), the time to disease 
progression, rate of all-cause death, proportion of death or respiratory failure, rates of 
hospital discharge time, rate of duration of mechanical ventilation, duration of 
mechanical ventilation, use of pressors, rate of duration of extracorporeal membrane 
oxygenation, rate of duration of supplemental oxygen, the length of hospital stay, and 
the changes in absolute lymphocyte count and markers of inflammation.  
 
Exploratory objectives:  
• To explore the effect of CD24Fc treatment of COVID-19 on systemic steroid dosage, 
inflammatory cytokine changes, D-dimer level changes, lymphocyte subtype 
distribution and T lymphocyte activation and exhaustion markers.  
• To explore the effect of CD24Fc in pulmonary function, inflammatory markers, 
cardiac function, liver enzymes and renal function.   
 
Primary Endpoints:  
• Time to improvement in clinical status: the time (days) required for improvement 
from scale 2 - 4 to scale ≥ 5 or above that is sustained without a drop to below 5 
based on NIAID ordinal scales (Appendix A) within 28 days from randomization. 
 
Secondary Endpoints: 
• Proportion of patients who died or had respiratory failure, defined as the need for 
mechanical ventilation, ECMO, non-invasive ventilation, or high flow oxygen 
devices, at Day 29 
• Time to disease progression in clinical status: the time (days) for progression from 
scale 3 or 4 to scale 1 or 2 based on the NIAID ordinal scale within 28 days from 
randomization.  
• All cause mortality at Day 15 and Day 29 
• Proportion of clinical relapse, as defined by rate of return to oxygen support for more 
than 1 day within 28 days from randomization after initial recovery 
 
 
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• Conversion rate of clinical status on Day 8 (proportion of subjects who changed from 
“scale 2, 3 or 4” to “scale 5 or higher” in the NIAID ordinal scale) 
• Conversion rate of clinical status on Day 15 (proportion of subjects who changed 
from “scale 2, 3 or 4” to “scale 5 or higher” in the NIAID ordinal scale) 
• The discharge from hospital time 
• Duration of mechanical ventilation (IMV, NIV) (days) 
• Duration of pressors (days) 
• Duration of extracorporeal membrane oxygenation (days) 
• Duration of oxygen therapy (oxygen inhalation by nasal cannula or mask) (days) 
• Length of hospital stay (days) 
• Absolute lymphocyte count 
• D-dimer concentration in the plasma 
 
Exploratory endpoints 
• Effect of CD24Fc on systemic steroid usage. 
• Effect of CD24Fc on cytokine levels. 
• Effect of CD24Fc on lymphocyte subtype distribution. 
 
Safety evaluation 
• Adverse events, vital signs, physical examination, laboratory tests (blood routine, 
blood biochemistry, coagulation function, urine routine),  ECG. 
 
 
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3. 
STUDY DESIGN  
 
Study Design Overview 
This is a Phase III randomized double-blind placebo controlled multi-site study to compare two 
COVID-19 treatment regimens in hospitalized adult subjects who are diagnosed with severe 
COVID-19. 
Arm A: CD24Fc/Best Available Treatment;  
Arm B: placebo/Best Available Treatment.  
CD24Fc will be administered as single dose of 480mg via IV infusion on Day 1. Total of 270 
subjects will be enrolled and randomized in 1:1 ratio to receive CD24Fc or placebo. All subjects 
will be treated with the best available treatment. The follow up period is 28 days. Those who 
uses immune modulators such as IL-6/IL-6R antagonists or experimental antiviral drugs are 
allowed to participate the trial. 
Phase III study consists of screening period and treatment/follow up period. Each subject should 
have 6 visits. Visit 1 (D-3 to D-1); Visit 2 (D1); Visit 3 (D4); Visit 4 (D8±1d); Visit 5 (D15±2d), 
Visit 6 (D29±4d).  
If the patient’s clinical status improves and is discharged to home care, the follow up visits can 
be carried out through telemedicine (phone or video interviews). The clinical investigators 
should make best efforts to obtain the vital signs, clinical status evaluation, concomitant 
medicines and adverse events assessment. The laboratory tests, radiology study, ECG and 
research samples are optional if the patient is discharged.  
 
Sample size 
In Phase III study, a total of 270 subjects will be enrolled in 1:1 ratio for study drug arm and 
placebo arm (135 subjects per arm). For the calculation method of sample size, please refer to 
Section 10.1.  
 
 
 
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4. 
ELIGIBILITY CRITERIA 
 
Inclusion criteria 
1) 
Should be at least 18 years of age,  
2) 
Male or female, female should have negative pregnancy test, 
3) 
Diagnosed with COVID-19 and confirmed SARS-CoV-2 viral infection, prior positive viral 
results allowed,  
4) 
Informed consent form signed by patient or by a legally authorized representative, 
5) 
Hospitalized and requiring oxygen support, NIAID 8-point ordinal score 2, 3, 4, regardless of 
ARDS (Appendix A), intubation for invasive mechanical ventilation should be within 7 days, 
6) 
Women of childbearing potential, under the age of 54 years, who use adequate contraception and 
who agree to use adequate contraception for the duration of the study. 
 
Exclusion criteria: 
1) 
Patients who are pregnant, breastfeeding, or have a positive pregnancy test result before 
enrollment, 
2) 
Patients previously enrolled in the CD24Fc study, 
3) 
Intubation for invasive mechanical ventilation is over 7 days,  
4) 
Documented acute renal or hepatic failure,  
5) 
The investigator believes that participating in the trial is not in the best interests of the patient, or 
the investigator considers unsuitable for enrollment (such as unpredictable risks or subject 
compliance issues). 
 
 
 
 
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5. 
REMOVAL FROM STUDY 
Patients have the right to withdraw from the study at any time for any reason. The clinical site PI 
also has the right to withdraw patients from the study in the event of intercurrent illness, adverse 
events, treatment failure, protocol violation, or other reasons. Should a patient (or a patient’s 
legally authorized guardian or representative) decide to withdraw, all efforts will be made to 
complete and report the observations as thoroughly as possible. A complete final evaluation 
should be made at the time of the patient’s withdrawal with an explanation of why the patient is 
withdrawing and every effort should be made to perform follow-up evaluations. Patients may be 
removed from the study treatment if one or more of the following events occur: 
• Significant protocol violation or noncompliance, either on the part of the patient or 
the clinical site PI. 
• Refusal of the patient to continue treatment and / or observations. 
• Unacceptable or dose-limiting toxicity. 
• Decision by the clinical site PI that removal from the study is in the patient’s medical 
interest. 
• Unrelated medical illness or complication. 
• Lost to follow-up. 
 
 
 
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6. 
STUDY DRUG 
 
Study drug CD24Fc 
Name 
CD24Fc for IV infusion. 
Vial content 
120mg/12mL 
Formulation 
Liquid formulation for IV infusion. 
Route 
IV Infusion 
Storage 
-20℃, avoid light.  
Manufacturer 
Catalent, Inc. 
Provider 
OncoImmune, Inc 
 
 
Placebo 
The placebo is 0.9% Sodium Chloride Solution for IV infusion.  
 
Study drug administration 
CD24Fc will be administered intravenously on day 1 in single dose.   
Arm A:  480 mg CD24Fc diluted with normal saline to 100 ml, IV infusion in 60 min. 
Arm B:  Normal saline 100ml, IV infusion in 60 min. 
 
Best available treatment 
The best available treatment and supportive care will be given to all subjects according to local 
institutional guideline. Those who uses immune modulators such as IL-6/IL-6R antagonists or 
experimental antiviral drugs such as remdesivir are allowed to participate the trial. 
 
 
 
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7.
STUDY PROCEDURES
Procedure and tests description
7.1.1. 
Informed consent
The researchers explain all the research procedures to the subjects before the screening, 
including information about the nature of the research, and obtain informed consent signed by 
the patient or by a legally authorized representative.  
Before the process to obtain informed consent from the legal authorized representative, 
investigators should use the EVALUATION TO SIGN A CONSENT FORM FOR 
RESEARCH in Appendix B to assess the understanding of the consent process of person who 
may have cognitive impairments, or may elicit the information using clinical interview 
procedures.  
7.1.2. 
Collect demographic data 
Obtain the demographic data of the subjects during the screening period, including information 
such as date of birth, height, weight, gender, ethnicity, and race. 
7.1.3. 
Allergy history / medical history, previous / combined medication collection 
Obtain subjects' past medical history, especially chronic diseases (such as chronic obstructive 
pulmonary disease, angina pectoris, hypertension, cerebral thrombosis, diabetes, etc.) during the 
screening period and other major diseases and drug treatment history, surgery history, allergy 
history, and comorbidities judged by the investigator.  
It is important to obtain the number of days of onset of the symptoms, the history of exposure to 
confirmed cases within 14 days before the onset of the symptoms, recent temperature, and the 
treatment status (antiviral drugs, antibacterial drugs, oxygen therapy, duration of treatment, etc.). 
Concomitant medications: from the beginning of the screening period to the end of the treatment 
/ follow-up observation period.  
7.1.4. 
Vital signs and physical examination 
Vital signs include body temperature (° C), blood pressure (mmHg), heart rate (beats / min), 
respiratory rate (beats / min), which need to be performed at each visit.   
On the D1 for treatment, vital signs for body temperature, blood pressure, heart rate, respiratory 
rate should be recorded before (0 min) and after IV infusion (60 min). The data from monitor are 
allowed. During the IV infusion, the data from the remote monitoring can be recorded without 
entering the room at 60±10 min after the start of infusion.  
Physical examination will be performed during the screening period. Any changes should be 
recorded at D15. Check the general body surface, skin, head and neck, chest (heart, lung, breast), 
abdomen (gastrointestinal and liver), musculoskeletal, nervous system including taste and smell 
changes, lymph nodes, etc. 
 
 
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If the patient clinical status improves and is discharged to home care, the follow up visits can be 
carried out through telemedicine (phone or video interviews). The clinical investigators should 
make best effort to obtain the vital signs, clinical status evaluation, concomitant medicines and 
adverse events assessment. The laboratory tests, radiology study and research samples are 
optional.  
7.1.5. 
Laboratory tests 
Blood tests: red blood cell count (RBC), hemoglobin concentration (HGB), white blood cell 
count (WBC), platelet count (PLT), neutrophil count (ANC), lymphocyte count (LY), monocyte 
count (MO), Eosinophil count (EO), basophil count (BA). 
Blood biochemical tests: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), albumin (ALB), total bilirubin 
(TBIL), direct bilirubin (DBIL), lactate dehydrogenase (LDH), urea nitrogen (BUN) / urea 
(Urea), creatinine (Cr), creatine kinase (CK), creatine kinase isoenzyme (CK -MB), fasting blood 
glucose and cardiac Troponin I.  
C-reactive protein (CRP), ESR. 
Urine routine examination: urine pH, urine red blood cells, urine white blood cells, urine protein, 
urine glucose, urine ketone body. 
Examination of coagulation function: D-dimer, prothrombin time (PT), activated partial 
thromboplastin time (aPTT), thrombin time (TT), plasma fibrinogen (Fbg).  
Laboratory tests should include CBC, blood biochemistry, CRP, coagulation function and urine 
test during the screening period and the treatment / follow-up observation period (D1, D4, D8 
and D15).  
Laboratory tests done at Day 1 should be done prior to the infusion.  
If the patient clinical status improves and is discharged to home care, the follow up visits can be 
carried out through telemedicine (phone or video interviews). The laboratory tests, radiology 
study, ECG and research samples are optional.  
7.1.6. 
Analysis of oxygen saturation and arterial blood gas 
It is recommended but not required to conduct arterial blood gas analysis at screening, and 
during the treatment / follow-up observation periods according to clinical needs.  
7.1.7. 
Pregnancy test 
Only for women of childbearing age, under 54 years old, during the screening period. 
7.1.8. 
ECG 
During the screening period (up to 72 hr prior to screening is allowed), treatment / follow-up 
observation period.  On the drug administration day (Day 1), ECG should be done before drug 
infusion and 2 hrs after drug infusion. ECG should be done in visit D8 and D15, if patient is still 
in hospital.  
 
 
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7.1.9. 
 Chest X-ray or CT scan 
It is recommended but not required to have Chest X-ray or CT scan during the screening period. 
Imaging study that has been done up to 72 hr prior to screening is allowed in lieu of screening.  
During the treatment / follow-up observation period, the doctor can determine the number and 
time of chest image study. 
7.1.10. 
SARS-CoV-2 Viral nucleic acid check 
Positive viral tests that have been done prior to screening are allowed in lieu of screening. If the 
investigator conducts an unscheduled visit to the viral nucleic acid test, the data results must be 
recorded in the CRF. The follow up viral nucleic acid tests are optional.  
7.1.11. 
Cytokine and lymphocyte subtype detection (For selected sites only) 
If conditions permit, a 5 ml blood sample should be collected and separated into plasma and 
PBMC. The samples can be frozen and stored for research purposes. Plasma samples are for 
testing of inflammatory cytokines (IL-1β, IL-6, TNF-α, MIPα, INF-γ, IP10, MCP, GCSF, IL-10). 
The PBMC are for testing lymphocyte subtypes and activation/exhaustion markers (flow 
cytometry detection analysis: CD3 / CD4 / CD8 / PD1 / Tim3, etc.) at D1 before IV infusion, D4, 
D8 and D15.  
7.1.12. 
Evaluation of clinical status 
Clinical status should be evaluated and recorded daily when the patient is hospitalized. The 
screening period must assess the clinical status and recorded as baseline.   
If the patient clinical status improves and is discharged to home care, the follow up visits should 
follow the study schedule (Table 2), and the visits can be carried out through telemedicine 
(phone or video interviews). The clinical investigators should make best effort to obtain the vital 
signs, clinical status evaluation, concomitant medicines and adverse events assessment. The 
laboratory tests, radiology study, ECG and research samples are optional.  
 
 
 
 
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REQUIRED OBSERVATIONS (STUDY CALENDAR as in 
Synopsis) 
7.2.1. 
Screening period 
Visit 1 
• Sign the informed consent by patient or by a legally authorized representative; 
• Record the past medical history; 
• Collect demographic data; 
• Record vital signs and physical examination; 
• Laboratory tests should be done according to Section 7.1.5. Tests done 72 hrs prior to 
screening are allowed;  
• Record digital oxygen saturation; 
• Arterial blood gas analysis (optional, tests done 72 hrs prior to screening are 
allowed); 
• Pregnancy check (women only, under 54 years old); 
• ECG. Tests done 72 hrs prior to screening are allowed; 
• Chest CT scan or X-ray. Tests done 72 hrs prior to screening are allowed;  
• Detection of SARS-CoV-2 viral nucleic acids. Prior positive viral results are allowed;  
• Clinical status assessment; 
• Collect blood samples for serum cytokines and lymphocyte subtypes (selected sites 
only); 
• Confirm the inclusion / exclusion criteria; 
• Record concomitant medications. 
7.2.2. 
Treatment / follow-up observation period (D1 ~ D29) 
Visit 2 (D1) 
• Record vital signs before study drug infusion and at 60±10 minutes after the start of 
drug infusion;  
• Confirm the inclusion / exclusion criteria; 
• Subject is randomized; 
• Chest CT examination (optional); 
• Record digital oxygen saturation; 
• Arterial blood gas analysis (optional); 
 
 
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• Laboratory tests according to Section 7.1.5;  
• ECG before drug infusion, and at 2 hrs (120 ± 15 min) after drug infusion; 
• Study drug administration; 
• Clinical status assessment; 
• Record IMV / NIV, ECMO, or oxygen therapy; 
• Collect blood samples for serum cytokines and lymphocyte subtypes (selected sites 
only); 
• Record adverse events and concomitant medications. 
Visit 3 (D4 ± 2d) 
• Record vital signs; 
• Clinical status assessment; 
• Chest CT scan (optional); 
• Record digital oxygen saturation; 
• Arterial blood gas analysis (optional); 
• Laboratory tests: CBC, blood biochemistry, C-reactive protein; 
• Collect blood samples for serum cytokines and lymphocyte subtypes (selected sites 
only); 
• Record adverse events and concomitant medications. 
Visit 4 (D8 ± 2d) 
• Record vital signs; 
• Laboratory tests: CBC, blood biochemistry, C-reactive protein, coagulation tests; 
• Chest CT scan (optional); 
• Record digital oxygen saturation; 
• Arterial blood gas analysis (optional); 
• ECG; 
• Clinical status assessment; 
• Record IMV / NIV, ECMO, or oxygen therapy; 
• Collect blood samples for serum cytokines and lymphocyte subtypes (selected sites 
only); 
• Record adverse events and concomitant medications. 
 
 
 
 
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Visit 5 (D15 ± 2d) 
• Record vital signs; 
• Laboratory tests: CBC, blood biochemistry, C-reactive protein; coagulation tests;  
• Chest CT scan (optional); 
• Record digital oxygen saturation; 
• Arterial blood gas analysis (optional); 
• ECG; 
• Clinical status assessment; 
• Record IMV / NIV, ECMO, or oxygen therapy; 
• Collect blood samples for serum cytokines and lymphocyte subtypes (selected sites 
only); 
• Record adverse events and concomitant medications. 
Visit 6 (D29 ± 3d) 
• Record vital signs; 
• Detection of SARS-CoV-2 viral nucleic acids if the D15 test is positive; 
• Clinical status assessment; 
• Record IMV / NIV, ECMO, or oxygen therapy; 
• Record adverse events and concomitant medications. 
If the patient clinical status improves and is discharged to home care, the follow up visits can be 
carried out through telemedicine (phone or video interviews). The clinical investigators should 
make best effort to obtain the vital signs, clinical status evaluation, concomitant medicines and 
adverse events assessment. The laboratory tests, radiology study, ECG and research samples are 
optional.  
 
 
 
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8. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
Adverse Events 
8.1.1. 
Definition of Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related. Since the clinical study 
has the target population as hospitalized patients with COVID-19 diagnosis and requiring oxygen 
support, the Grade III to V adverse events will be collected and reported in this study.  
8.1.2. 
Definition of Serious Adverse Events (SAE) in COVID-19 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor in this COVID-19 clinical trial, it results in any of the 
following outcomes: death, or a life-threatening adverse event other than COVID-19 progression 
that requires admission to the ICU, or organ failures in addition to COVID-19 respiratory failure.  
8.1.3. 
Criteria for Determining the Severity of Adverse Events 
AEs not listed in the CTCAE 5.0 version table can be classified into grades 1-5 with reference to 
the following table.  
Grade 
CTCAE 
1 
Asymptomatic or mild; only clinical or diagnostic observations; no intervention required 
2 
Moderate: Small, local, or non-invasive measures are required; age-related instrumental daily life 
activities (ADL) are limited *. 
3 
Serious or medically significant but not immediately life-threatening: hospitalization or 
lengthening of hospital stay required; disability, limited autonomic ADL **. 
4 
Life-threatening: urgent measures are needed. Intervention indicated to prevent permanent 
impairment, persistent disability or death. 
5 
deaths related to adverse events 
 
8.1.4. 
Relationship to Study Drug  
All Grade III-V adverse events (AEs) must have their relationship to study intervention assessed 
by the clinician who examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below.  
• Related – There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and 
 
 
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cannot be explained by concurrent disease or other drugs or chemicals. The event 
must be pharmacologically or phenomenologically definitive. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to study intervention administration makes a 
causal relationship improbable (e.g., the event did not occur within a reasonable time 
after administration of the study intervention) 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 – The AE is completely independent of study intervention 
administration, and/or evidence exists that the event is definitely related to another 
etiology. There must be an alternative, definitive etiology documented by the 
clinician. 
8.1.5. 
Expectedness 
The PI will be responsible for determining whether a Grade III to V adverse event (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 intervention. 
8.1.6. 
Follow-up of Adverse Events 
Grade III to V AEs including local and systemic reactions not meeting the criteria for SAEs will 
be captured in the study record. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those 
with the training and authority to make a diagnosis), and time of resolution/stabilization of the 
event. Grade III to V AEs occurring while on study must be documented appropriately regardless 
of relationship. All Grade III to V AEs will be followed to adequate resolution. Grade III to V 
AEs and SAEs will be collected between Day 1 and Day 29 (completion of study).  
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
The PI or study coordinator will record all reportable Grade III or V events with start dates 
occurring after IP treatment is initiated until the last day of study participation.  At each study 
visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
All enrolled subjects who have received CD24Fc or placebo will be evaluated for safety with the 
laboratory assays done at each visit as outlined in section 7.2. Safety will be assessed by vital 
signs, hematology, and chemistries. Vital signs will include pulse, blood pressure, respiratory 
rate, and oxygen saturation. The severity of signs, symptoms, and AEs will be determined by 
using CTCAE V5.0. The CD24Fc infusion will be administered over a minimum of 1 hour. 
 
 
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Subjects will be monitored after infusion is completed for 2 hours, and repeat vital signs and 
laboratory results will be ascertained as needed based on reported symptoms.  
 
Adverse Event Reporting 
Grade III to V AEs occurring from the time of treatment through the end of study will be 
documented, recorded, and reported.  The Investigator will evaluate Grade III to V AEs with 
respect to Severity (intensity or grade) and Causality (relationship to study agent and 
relationship to research). The investigator will record nonserious adverse events and report them 
to the sponsor in a timely manner.  
Grade III or V laboratory abnormalities that are gradable per the CTCAE v5.0 will be recorded 
as AEs or SAEs. All other laboratory abnormalities without clinical significance will not be 
recorded as AEs or SAEs. Grade III to V laboratory abnormalities that require medical or 
surgical intervention must be recorded as an AE or SAE if applicable. Laboratory assessments 
that are associated with signs and/or symptoms must be recorded as an AE or SAE if they meet 
the definition. If a diagnosis is clinically evident, the diagnosis, rather than the individual signs 
and symptoms or lab abnormalities will be recorded as the AE. 
Grade I or II adverse events that worsen to grade III or V during the study will be captured. Their 
start date will be the day the adverse events worsen to grade III or V. 
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any new or worsening adverse event that begins on or after the 
date of treatment until study completion. Summaries (number and percentage of subjects) of 
treatment-emergent adverse events will be provided at study completion.  
At each contact with the subject as outlined above in the study activities table, information 
regarding Grade III or V AEs will be elicited by appropriate questioning and examinations and 
will be immediately documented in the subject’s medical record. Medical records will be 
reviewed in a timely manner by the research team. The onset date, the end date, the severity of 
each reportable Grade III to V event, and the Investigator’s judgment of the AEs relationship to 
CD24Fc will also be recorded. 
 
Serious Adverse Event Reporting 
The study clinician will immediately report to the sponsor any serious adverse event, whether or 
not considered study intervention related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a reasonable possibility that the 
study intervention caused the event. Study endpoints that are serious adverse events (e.g., 
all-cause mortality) must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the study intervention and the event (e.g., death from 
anaphylaxis). In that case, the investigator must immediately report the event to the sponsor. 
All Grade V event (death) should be reported as SAE to CRO and sponsor in a timely manner.  
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting 
 
 
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documentation of the event may be requested by the study sponsor and should be provided as 
soon as possible. 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of 
any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no 
case later than 7 calendar days after the sponsor's initial receipt of the information.  In addition, 
the sponsor must notify the FDA and all participating investigators in an Investigational New 
Drug (IND) safety report of potential serious risks, from clinical trials or any other source, as 
soon as possible, but in no case later than 15 calendar days after the sponsor determines that the 
information qualifies for reporting. 
The Medical Monitor will advise the Sponsor regarding the safety of the study participants as 
well as the continuing safety and scientific validity of the trial.  The Medical Monitor may also 
review the results of any planned analysis, if applicable. If the data analysis shows significant 
findings with regards to safety, the Medical Monitor may recommend modification of the 
protocol, Informed Consent, and/or monitoring of the study.  In these cases, the regulatory 
authorities and local review committees may be notified. The Medical Monitor may also stop the 
study for reasons of safety.  
 
Reporting of Pregnancy 
Pregnancy itself is not an AE. However, complications of pregnancies are AEs and may be 
SAEs.  Pertinent obstetrical information of all pregnancies will be reported to the MM. The 
participant will be advised to notify her obstetrician of study agent exposure.  
Pregnancy outcome data (e.g., delivery outcome, spontaneous, or elective termination of the 
pregnancy, presence of absence of birth defects, congenital abnormalities, or other 
complications) will be reported to the MM. 
 
Infusion Reaction Management   
No infusion reactions were observed in Phase I, Phase IIa, and Phase II expansion cohort clinical 
trials. However, administration of any recombinant protein may induce infusion reactions. 
CD24Fc includes the Fc portion of human IgG1. After targeted binding, CD24Fc can induce 
FcγR cross-linking, which is related to infusion reactions that may occur during some treatments. 
Possible infusion reactions during or 2 hours after the infusion include, for example, changes in 
vital signs, fever, dyspnea, hypotension, systemic or facial edema, nausea, chills, changes in 
mental state, urticaria, or vomiting. 
The following procedures are designed to closely monitor, manage and mitigate any possible 
infusion reactions: 
• In this study, CD24Fc must be administered in hospital. During the administration of 
CD24Fc, the clinical condition of the subject must be closely monitored.  
• The infusion time is at least 60 minutes. Researchers are allowed to reduce the IV rate 
and extend the infusion time based on the infusion response. If severe infusion 
 
 
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reactions occur, such as severe hypotension and hypoxemia, the infusion should be 
stopped. 
• Provide supportive treatment based on clinical indications and the intensity of the 
infusion reaction, including oxygen supplementation, diphenhydramine, 
acetaminophen, ibuprofen, IV corticosteroids (ie, hydrocortisone), and intravenous 
fluid replacement. 
• During CD24Fc administration, bedside first aid equipment, cardiopulmonary 
resuscitation life support equipment and drugs (eg, epinephrine) must be prepared in 
order to cope with possible hypersensitivity reactions, severe infusion reactions and / 
or cytokine release. 
 
 
 
 
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9. 
DATA MANAGEMENT 
 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
Data will be recorded in an electronic case report form (eCRF) using the secure electronic 
database. The data system includes password protection. The data entered will include but not be 
limited to clinical findings and observations, laboratory and test data, hospital medical records, 
physician or office charts, physician or nursing notes, recorded data from automated instruments, 
x-rays, etc. 
 
Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harminosation (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the study 
intervention. These documents should be retained for a longer period, however, if required by 
local regulations. No records will be destroyed without the written consent of the sponsor, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these documents 
no longer need to be retained. 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 5.1 Quality Assurance and Quality Control, section 5.1.1  
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
Anticipated deviations in the conduct of the protocol will not be reported to the IRB unless they 
occur at a rate greater than anticipated by the study team, in accordance with findings from 
previous trials as outlined in the IB. If the rate of these events exceeds the rate expected by the 
study team, the events will be classified and reported as though they are unanticipated problems. 
Deaths related to the natural history of COVID-19 will be reported at the time of continuing 
review.  
 
 
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It is the responsibility of the site investigator to use continuous vigilance to identify and report 
unanticipated deviations within 7 working days of identification of the protocol deviation, or 
within 7 working days of the scheduled protocol-required activity.  
 
Publication and Data Sharing Policy   
The PI and study team share de-identified or identified data generated in this study with all 
collaborators and will have access to all data collected from all sites.   
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
This study will comply with the Clinical Trials Registration and Results Information Submission 
rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from this 
trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish 
results in peer-reviewed journals.  Data from this study may be requested from other researchers 
2 years after the completion of the primary endpoint by contacting the study Sponsor. 
At the conclusion of the study, the Sponsor will support the writing and publication of scientific 
reports, journal papers and oral presentations by the study principal investigator and others 
making scientific contribution to the research effort. Any reports, papers, and/or presentations 
must be reviewed and approved by prior to submitting for publication.  All reports generated by 
this study will be in accordance with the ethical standards of the responsible committee on 
human experimentation and the Helsinki Declaration of 1975, as revised in 1983.   
All publications relating to the study will comply with the guidelines set forth by the Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals drawn up by the International 
Committee of Medical Journal Editors.  
 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence is critical.  Therefore, any 
actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, 
or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a 
perceived conflict of interest will be required to have such conflicts managed in a way that is 
appropriate to their participation in the design and conduct of this trial.   
 
 
 
 
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10. 
STATISTICAL ANALYSIS 
 
Sample size 
In the phase III trial, the patients will be randomized at 1: 1 ratio into CD24Fc or placebo arms. 
It was assumed that the time to improvement the clinical status of the patients obeyed the 
exponential distribution, and the improvement hazard ratio (HR) was 1.54. The median time to 
improvement in the control group is presumed 11 days, and the median time to improvement in 
the treatment group is projected as 7.14 days. An interim analysis for efficacy will be performed 
when 70% of the required events are reached. The O'Brien-Fleming type consumption function 
of the Lan-DeMets algorithm is used to control the overall class I error rate α = 0.025 (one-
sided), at least 80% of the degree of confidence. At least 208 events are required to achieve 80% 
power. Assuming 28 days of patient follow up, the estimated number of 208 events will be 
reached for the final analysis approximately 28 days after the last subject is enrolled. Assuming 
78% recovery rate, 270 participants will be enrolled in this trial. 
The sample size was calculated on SAS 9.4 PROC SEQDESIGN. 
 
Analysis Set 
10.2.1. 
Intended-to-treat Set (ITT) 
Defined as all subjects who are enrolled in the randomized trial. The ITT population will be the 
main analysis population for the efficacy analysis of this study. Subjects will be analyzed based 
on the treatment group they are assigned. 
10.2.2. 
Per Protocol Set (PPS) 
PPS is a subset of the ITT. Refers to all randomized subjects who have received the protocol-
specified single-dose treatment without significant protocol deviations that significantly affect 
the main efficacy. PPS-based analysis will complement ITT-based analysis as a supporting 
analysis. Subjects will be analyzed based on the treatment arm they plan to assign. 
10.2.3. 
Safety Data Set (SS) 
SS is defined as all subjects who received at least one test drug. The safety analysis population is 
the main analysis population for safety data. Subjects will be analyzed based on their actual 
assigned treatment arm. 
 
Analysis methods 
10.3.1. 
General principles 
The statistical analysis uses SAS9.2 (or above) version of statistical analysis software, and the 
analysis process is all programmed. For continuous variables, the descriptive statistics will 
include the mean, median, standard deviation, maximal and minimal values (mean and median 
will be accurate to one more digit decimal point than the original data, and standard deviation 
will be accurate to two more digit decimal points than the original data, and the decimal points of 
 
 
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the maximum and minimum values will be the same as the original data, usually up to four 
decimal points are kept in the statistics table). Qualitative or grade indicators are summarized 
using descriptive statistics including the number of subjects, percentages, and / or number of 
events. The detailed statistical analysis plan and method will be described in detail in the 
statistical analysis plan. 
10.3.2. 
Distribution of subjects 
Descriptive statistics will be used to summarize the number of subjects screened, the number of 
screening failures, enrollment, entry into each analysis set (and reasons for excluding each 
analysis set), termination of treatment, withdrawal from the study, and follow-up. The number 
and percentage of subjects who entered each analysis set, discontinued treatment and study will 
be summarized by treatment arms. 
10.3.3. 
Demographics, Medical History, and Baseline Characteristics 
Demographic information and baseline characteristics, case history, and concomitant 
medications for all randomized subjects will be summarized using descriptive statistical methods 
based on randomization. 
 
Efficacy Analysis 
10.4.1. 
Primary efficacy endpoint 
The primary endpoint “Time to Clinical Improvement” (TTCI) will be the time (days) from the 
randomization in which the patient's clinical status improved from baseline (scale 2-4, NIAID 
ordinal scale, Appendix A) to 5 or above that is sustained without a drop to below 5 within 28 
days. Hospital discharge date (NIAID scale 7 or 8) is an important event time point. The date 
that clinical status evaluation ≥ 5 or the date of hospital discharge, whichever comes first will be 
used as the TTCI date.     
The record of re-hospitalization with oxygen therapy is required to modify the TTCI date. The 
new TTCI date should be the time from randomization to the latest clinical status evaluation ≥ 5 
or the date of the latest hospital discharge, whichever comes first.  
Time to clinical improvement (days) is calculated as:  
Time to Improvement = Date of (First Clinical Improvement/hospital discharge) – Date of 
Randomization 
The discharge to home due to clinical improvement is scored as NIAID scale ≥ 7.  The date that 
clinical status evaluation ≥ 5 or the date of hospital discharge, whichever comes first will be used 
as the clinical improvement date.  All subjects without clinical improvement within 28 days will 
be censored on the Day 29 visit. 
The Log-Rank Test will be used to compare the following two sets of curves to test the following 
hypotheses: 
H0: St(t) = Sp(t)  vs. H1: St(t) > Sp(t) for improvement;  
 
 
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St(t) represents the improvement probability function of the experimental group, and Sp(t) 
represents the improvement probability function of the control group. 
The probability function of clinical improvement will be estimated by Kaplan-Meier method. 
The median time and its 95% confidence interval for each group will be reported. The 95% 
confidence interval for the median time will be estimated using the Brookmeyer-Crowley 
method with log-log function conversion to achieve a normal approximation. The improvement 
rate will be estimated by the layered Cox-Model. Cumulative improvement rates estimated by 
the KM method for days 4, 8 and 15 and/or 29 their 95% confidence intervals will also be 
reported. 
Time-event efficacy endpoints / censorship rules  
For the primary endpoint, during the observation period, an improvement from NIAID scale 2, 3 
or 4 to scale 5 or above, if sustained without a drop below 5, is considered as an event. The days 
from the randomization to the first time point of such improvement will be defined as time of 
improvement. Additional follow-up can be used to determine clinical improvement events.  
Subjects who do not withdraw or do not experience improvement will be censored on the actual 
date of the D29 visit. 
Subjects without improvement but lost to follow-up will be censored on the last date of follow-
up. 
Subjects with death within 28 days will be censored on D29.   
Sensitivity analysis: 
(1) Imbalances in age, baseline score, use of antiviral drugs such as remdesivir, or IL-6/IL-6R 
antagonist, or related factors that may affect the results will be investigated with sensitivity 
analyses and these factors will be evaluated separately in the Cox-Model to assess their potential 
impact on the primary efficacy endpoint. 
(2) Use only data from planned visits to analyze time to improvement in the main analysis. 
(3) The days from randomization to the first clinical improvement will be analyzed. 
Since there are no available best supportive case (BSC) for this disease, controlling BSC use 
between two arms is difficult, and consequently there may be imbalance for some particular 
BSCs between two arms. To evaluate whether there may be some potential bias caused by such 
imbalance, we will evaluate the percentage of the largest and second largest BSC used in the trial 
if the difference of such BSC between two arms are significant. Further analyses will be 
performed to study whether the efficacy results are indeed caused by such differential BSC use 
between two arms. 
10.4.2. 
Secondary efficacy endpoints 
Proportion of death or respiratory failure, defined as the need for mechanical ventilation, ECMO, 
non-invasive ventilation, or high flow oxygen devices at D29. Cumulative number of subjects 
reaching the composite endpoint vs number of people in the ITT population. Chi-square test will 
be used to compare the difference between the two arms.  
 
 
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For the disease progression, during the observation period, a progression from scale 3 or 4 to 
scale 2 or 1, or from 2 to 1, is considered as an event. The days from the randomization to the 
first time point of progression will be defined as time of progression. The probability function of 
clinical progression will be estimated by Kaplan-Meier method. The median time and its 95% 
confidence interval for each group will be reported. The 95% confidence interval for the median 
time will be estimated using the Brookmeyer-Crowley method with log-log function conversion 
to achieve a normal approximation. The progression rate will be estimated by the layered Cox-
Model. Cumulative progression rates estimated by the KM method for day 29 and the 95% 
confidence intervals will be reported. 
All-cause mortality at Day 15 and Day 29: the Mantel-Haenszel stratum-weighted estimator of 
the risk difference will be used to compare the treatments. 
Rate of clinical relapse, defined as proportion of patients who have initially reached score 5 
(hospitalized, without oxygen therapy) for more than one day but subsequently become 
dependent on oxygen support. Since responders are not based on the randomization, a descriptive 
statistic will be reported and an exploratory analysis using a Chi-square test will be performed. 
Improvement rate of clinical status on Days 8 and 15 (proportion of subjects with clinical 
improvement): percentage of subjects with clinical improvement on Day 8 or 15 in the ITT 
population. Chi-square test will be used to compare the difference between the two arms. 
The discharge time starts from randomization to discharge. T-tests will be used to compare the 
differences between the two groups in completers. 
Duration of each major treatment (days): Descriptive statistics will be analyzed for mechanical 
ventilation (IMV, NIV), extracorporeal membrane oxygenation, duration of oxygen therapy, and 
length of hospital stay. 
Absolute Lymphocyte Count: patients' dynamic changes in absolute lymphocyte count during the 
treatment / observation period will be monitored to assess the possible correlation between 
lymphocyte levels and disease outcome and prognosis. 
D-dimer levels: patients' dynamic changes in D-dimer levels during the treatment / observation 
period will be monitored to assess the possible correlation between lymphocyte levels and 
disease outcome and prognosis. 
10.4.3. 
Exploratory Indicator Analysis 
Effect of CD24Fc on systemic steroid dosage: The frequency and dosage of glucocorticoids in all 
treatment groups will be collected to evaluate the potential impact of CD24Fc on steroid dosage. 
Effect of CD24Fc on cytokine levels: monitoring during the treatment / observation period 
including C-reactive protein, IL-6, IL-1β, IFN-γ, TNF-α, IP10, MCP, GCSF, IL10 and other 
cytokines and their risks The level of dynamic changes of related model molecules (HMGB-1, 
HSP70 / 90), to assess the possible correlation between the levels of various cytokines and 
disease outcome and prognosis. 
Effect of CD24Fc on the distribution of lymphocyte subtypes: monitor the dynamic changes of 
the proportion of CD4 and CD8 T cell subtypes in lymphocytes during the treatment / 
 
 
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observation period and analyze the state of T cell depletion, and evaluate the lymphocyte level 
and disease outcome and prognosis may be relevant. 
10.4.4. 
Safety Analysis 
Adverse events will be summarized according to the system organ classification (SOC) and 
preferred term (PT) coded by the MedDra thesaurus. The number of AE, TEAE, SAE, and ADR 
cases, incidence and number of cases were summarized in each arm. 
The results of specific laboratory tests, electrocardiograms, vital signs, and physical 
examinations will be summarized and their relative baseline changes will be reviewed. Where 
applicable, the baseline value and the value at each time point after the baseline are presented in 
the form of a crosstab. 
 
Interim Analysis and Stopping Rules 
This study will establish an independent Data and Safety Monitoring Board (DSMB) for interim 
analysis. The composition, task responsibilities and implementation details of DSMB will be 
specified in the DSMB charter. 
Two blinded safety reviews will be performed, respectively, when 50% and 75% of the planned 
enrollment has occurred with follow-up time reaching D15 and mortality data are available.   
The study will also include an interim analysis at 70% of the required 146 events. The final 
analysis will be carried out after all 270 subjects have been randomized, dosed and completed the 
study.  
In the interim analysis, the DSMB will re-estimate the sample size to determine whether it 
supports increasing the number of clinical improvement event targets. Chen's method will be 
used to re-estimate the sample size (37). 
Safety reviews and stopping rules 
The study have two blinded safety reviews respectively, when 50% and 75% of the planned 
enrollment has occurred with follow-up time reaching Day 15 and SAE data are available. 
DSMB will be provided with list of SAE including mortality and may unblind the data at its 
discretion to evaluate the balance of SAE in the two study arms. 
Stopping rules 
If the DSMB found that SAE is significantly higher in the CD24Fc arm, it may recommend 
termination of the trial after review of potential benefit of the study drug by unblinding all study 
subjects. Sponsor will make final decision based on the recommendation of DSMB. 
Sample Size Re-Estimation 
The interim analysis for the primary endpoint only will be performed after reaching 146 events 
(70% of information). A sample size reassessment of efficacy will be performed.  
There sample size re-estimation 146 events will be based on preliminary data that are not 100% 
source-verified.  The method will be based on Chen et al as stated in the protocol. If the 
conditional power is < 50% or >85%, the trial will continue without a sample size increase; 
whereas if the conditional power is between 50% to 85%, the sample size will be re-calculated to 
 
 
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have 85%. To maintain trial integrity, the DSMB will pick a sample size in a nearest interval 
with 5 patients. For example, if the re-estimated sample size is 287, the DSMB could pick any 
number in the interval of 285 to 289. Also, the maximum increased sample size will not be more 
than 70 patients above what is needed to observe 208 events. 
The final analysis will be performed when 270 randomized and dosed patients have completed 
28 days of follow up, and the p-value cutoff is 0.05 (two-sided) based on the O'Brien-Fleming 
function of the Lan-DeMets algorithm. 
 
 
Missing Data Convention 
We will use the following rules to deal with missing data: 
Participants who have not been lost to follow up or experienced the event will be censored at 
Day 29.  Participants without an event but lost to follow-up will be censored at the last date of 
follow-up. 
We will perform two more analyses on the following data sets for the purpose of sensitivity 
analysis: 
First: Participants who have not dropped out or experienced an event are censored at Day 29. 
Participants not receiving study drug will be excluded from the analysis. Participants without an 
event but lost to follow-up will be censored at the last date of follow-up. When the event is 
documented, the time to the event is the length of time from the randomization to the event 
observed if at least one disease assessment before the event is documented.   
Second: Participants who have not been lost to follow up or experienced an event and are 
followed at the end of the trial will be included. Participants not receiving study drug will be 
excluded. Participants who have documented the event and have at least one disease 
assessment(s) will be included. 
We will compare the results of the primary analysis with the results from the analyses on the first 
and second sets, respectively. The impact of missing data and robustness of the primary analysis 
will be evaluated.  
 
 
 
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11. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
 
Informed Consent Process 
11.1.1. 
Consent/assent and Other Informational Documents Provided to participants 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given 
to the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.    
11.1.2. 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review 
the document. The investigator will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants.  Participants will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing 
to participate. The participant will sign the informed consent document prior to any procedures 
being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of 
the informed consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document (including the date), 
and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study.  
11.1.3. 
Use of Legally Authorized Representative (Surrogate Consent) 
Federal regulations permit investigators to obtain consent from a legally authorized 
representative. State laws define the categories of individuals who are allowed to provide 
surrogate consent for research. The following specific category applies to this study in end stage 
COVID-19 patient who is in ICU with mechanical ventilation.  
“Individuals whose medical condition may render them temporarily unable to provide informed 
consent as a consequence of severe pain, confusion, or impaired consciousness due to events 
such as life-threatening illness or trauma.”  
 
Definitions 
1. Legally Authorized Representative (LAR): An individual or judicial, or other body 
authorized under applicable law to grant permission on behalf of a prospective participant for 
their participation in research activities.  
 
 
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2. Surrogate Consent: The use of a legally authorized representative with reasonable knowledge
of the research participant.
3. Advance Directive: Documents written in advance of serious illness in which a person states
their choices for healthcare or names someone to make those choices. When a person is
selected to make the medical decisions, the document is called a Durable Power of Attorney
and the designated person is called an Agent. The Agent can serve as a LAR to provide
surrogate consent.
4. Capacity to Consent: The ability of the individual to understand the choices presented, to
appreciate the implications of choosing one alternative or another, and to make and
communicate a decision (e.g., whether or not to participate in a study).
Determining Capacity of Consent 
Whenever possible, investigators should attempt to obtain informed consent directly from the 
research participant. 
While there are no standardized measures for determining capacity to consent, participant should 
be assessed on the abilities to understand and to express a reasoned choice concerning the:  
•
Nature of the research and the information relevant to his/her participation;
•
Consequences of participation for their own situation, especially concerning their
health condition;
•
Consequences of the alternatives to participation.
Investigators may use the EVALUATION TO SIGN A CONSENT FORM FOR 
RESEARCH (Appendix B) to assess the understanding of the consent process of person who 
may have cognitive impairments, or may elicit the information using clinical interview 
procedures.  
Identifying an Appropriate Surrogate for End Stage COVID-19 Patient in ICU with 
Mechanical Ventilation  
In an emergency room setting or COVID-19 patient in ICU with mechanical ventilation, the 
order of priority does not apply, not does the surrogate have to show reasonable knowledge of 
the research participant. Surrogate consent may be obtained from any of the following:  
•
The person’s agent designated by an advance health care directive.
•
He conservators or guardian of the person having the authority to make heath care
decisions for the person.
•
The spouse of the person.
•
The domestic partner of the person as defined in Section 297 of the California Family
Code
 
 
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• An adult son or daughter of the person.  
• A custodial parent of the person.  
• Any adult brother or sister of the person.  
Important Note: In an emergency room or ICU environment, no surrogate may be utilized if 
there is a disagreement whether to consent among any available surrogates. 
 
 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, the 
principal investigator, the Investigational New Drug (IND) sponsor and regulatory authorities.  If 
the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study participants, the Institutional Review Board (IRB), and sponsor and will provide 
the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
 
Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
 
 
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study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the Institute of Human Virology and the 
Department of Epidemiology (University of Maryland School of Medicine). This will not 
include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites and by research staff will be secured 
and password protected. The PI and study team will have access to the password-protected 
database. At the end of the study, all study databases will be de-identified and archived at the 
University of Maryland School of Medicine.  
 
 
Future Use of Stored Specimens and Data 
Data collected for this study will be analyzed and stored at the Institute of Human Virology 
(University of Maryland). After the study is completed, the de-identified, archived data will be 
retained at the Institute of Human Virology (IHV) for use by other researchers including those 
outside of the study. Permission to retain the data at the IHV will be included in the informed 
consent.  
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), 
de-identified biological samples will be stored at the IHV. These samples could be used to 
research the causes of cardiovascular disease in HIV, its complications and other conditions for 
which individuals with HIV are at increased risk, and to improve treatment. IHV researchers will 
be provided with a code-link that will allow linking the biological specimens with the phenotypic 
data from each participant, maintaining the blinding of the identity of the participant. Genetic 
testing will not be performed.  
When the study is completed, access to study data and/or samples will be provided through the 
IHV. 
 
 
Clinical Monitoring 
Clinical studies must be conducted in accordance with the ethical principles that are consistent 
with Good Clinical Practices and in compliance with other applicable regulatory requirements. 
The following measures have been taken to ensure the safe conduct of this clinical trial: 
 
 
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Weekly teleconferences will be conducted among investigators from participating study sites, the 
principal investigator (PI), the Sponsor representatives and Medical Monitor from and other 
representatives from the CRO. At these meetings safety events, withdrawals, subjects’ progress 
and other relevant events on trial will be reviewed and appropriate actions will be taken 
including amending or suspending the trial. Safety reports generated by the CRO will also be 
submitted to the DSMB. The Medical Monitor and the Sponsor will both be responsible for 
reviewing these reports monthly and if necessary taking appropriate steps to ensure the safety of 
subjects and compliance with this protocol (i.e. inquiries, suspension, or termination of trial).  
Finally, whenever an unanticipated data, safety and monitoring board meeting takes place or 
when a new development occurs the Medical Monitor from the Sponsor and/or its designee (i.e. 
CRO) and IRB will be notified of the occurrence.   
This study will be continuously monitored by a clinical monitor, and the Medical Monitor from 
the CRO. Monitoring visits will be made during the conduct of the study and at study close-out. 
Remote monitoring will be carried out to minimize the travel and in person contact.  
Prior to subject recruitment, a site initiation meeting will be conducted by the Sponsor or the 
CRO. This meeting may take place by teleconference. The PI and the study staff should make 
every effort to attend the site initiation meeting. Study-related questions or issues identified 
during the site initiation meeting will be followed by the appropriate personnel until they have 
been answered and resolved. 
The monitoring visits should be carried out through remote monitoring. The purpose is to verify: 
a. Adherence to the protocol 
b. Completeness and accuracy of study data and samples collected 
c. Proper storage, dispensing, and inventory of study medication 
d. Compliance with regulations 
Monitoring may be in the form of a document review. During a monitoring visit, remote access 
to relevant hospital and clinical records must be given by the clinical site PI to the clinical 
monitor conducting the remote monitoring visit to verify consistency of data collected on the 
CRFs with the original source data.  While most patient cases will be selected from patients 
accrued since the previous monitoring visit, any patient case has the potential for review. At least 
one or more unannounced cases will be reviewed, if the total accruals warrant selection of 
unannounced cases. 
The clinical monitor expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues 
identified during these visits will be communicated and are expected to be resolved in a time 
manner. 
At close-out upon completion, termination, or cancellation of a study to ensure fulfillment of 
study obligations during the conduct of the study will occur, and the clinical site PI will be 
informed of his / her ongoing responsibilities. In general, close-out is conducted during a formal 
remote site visit. However, a site close-out can occur without a site visit.  
 
 
 
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Quality Assurance and Quality Control 
Data quality control (QC) checks will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
The Medical Monitor will verify that the clinical trial is conducted and data are generated and 
biological specimens are collected, documented (recorded), and reported in compliance with the 
protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 
applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP)). To ensure compliance with Good Clinical Practices and all applicable 
regulatory requirements, the Sponsor may conduct a quality assurance audit.   
During the study, the Sponsor or designee will conduct periodic remote monitoring visits to 
ensure that the protocol and ICH GCP guidelines are being followed.  The monitors may review 
source documents to confirm that the data recorded is accurate.  The Investigator and institution 
will allow the Sponsor monitor or designee and appropriate regulatory authorities direct access to 
source documents to perform this verification. 
The study site may be participant to review by the IRB, and/or quality assurance audits 
performed by the Sponsor, or companies working with or on behalf of the Sponsor, and/or 
inspection by appropriate regulatory authorities. 
 
 
Trained and Certified Personnel 
All of the research protocol personnel who will work with study subjects, study subject data or 
subjects’ research samples have completed training in the protection of human research 
participants per guidelines issued by the U. S. Department of Health and Human Services, Office 
of Human Research Protections. The documentation of completion of the certification is 
maintained by the CRO. The investigator and designated associates have attended an IRB 
sponsored HIPAA research presentation in accordance with the policy of the study site. Each 
participant in this research trial will be listed by study specific numbers, without initials or date 
of birth; however, the date of transplant may be included when corresponding with the IRB or 
outside agencies. 
Designation of Responsibilities: The Clinical Principal Investigator(s) are solely responsible for 
the implementation, conduct and safety of human subjects enrolled in this trial. The Clinical 
Principal Investigator has however, designated associates to assist with the protocol 
implementation which includes but is not limited to the following: 
1. 
Physicians – have been designated to assist with participant education, informed consent 
process, study implementation and compliance, recording of primary source 
documentation, AE assessment and reporting, adherence to all regulations. 
2. 
Research Nurse(s) - have been designated to assist with participant education, informed 
consent process, study implementation and compliance, recording of primary source 
documentation and adherence to all regulations. 
 
 
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3. 
Data Manager(s) - have been designated to assist with patient enrollment/eligibility, 
verification of protocol compliance, all data collection and recording from primary 
source, AE reporting, DSM reports and adherence to all regulations. 
4. 
Clinical Team - The members of the clinical team that have been designated to assist the 
investigator in any aspect of this protocol will be listed on the protocol specific 
designation log. 
 
 
Independent Data and Safety Monitoring Board (DSMB) 
An independent Data and Safety Monitoring Board (DSMB) will be convened for the Phase II/III 
study. The purpose of the DSMB will be to safeguard the interests of study participants, assess 
the safety of the interventions, and monitor the overall conduct of the study. The DSMB will act 
as an advisory to the clinical study leadership team of OncoImmune. The clinical study 
leadership will have responsibility for overall conduct of the study including managing the 
communication of study data. The leadership team will be responsible for promptly reviewing 
the DSMB recommendations, for providing guidance regarding the continuation or termination 
of the trial, and for determining whether amendments to the protocol or changes to the study 
conduct are required. 
 
 
Multi-center Coordination 
The Phase III randomized, double blind, placebo controlled, multi-center study will be 
coordinated by the CRO.  
11.9.1. 
Subject Screening and Registration Procedure 
Patient registration for this trial will be centrally coordinated by the CRO as described below: 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log. It is the responsibility of the clinical site PI to determine patient eligibility prior 
to submitting patient registration request to site pharmacy.   
Each subject will be given a randomization number. This number will be assigned in the order of 
the inclusion of subjects by onsite blind pharmacy. A computer-generated randomization list will 
be prepared by CRO statistician not directly involved in the conduct of the study and 
investigational study medication. It will be provided to the unblinded pharmacy team for study 
treatments preparation. All study personnel at the research site will be blinded to treatment 
identity during the conduct of the study until database lock. Subjects will be randomized such 
that both the investigators and the subjects will be blinded to the study medication they will 
receive on each visit. Identification code for randomized subjects has been prepared and 
validated according to the SOP. Only the unblinded statistician and the pharmacy staff have 
access to the unblinded randomization list. 
 
 
 
 
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11.9.2. 
Contact Information 
Sponsor 
OncoImmune Inc. 
9430 Key West Avenue 
Suite 125  
Rockville, MD 20850 
Tel. 
 
 
Contract Research Organization  
ClinSmart, LLC 
32 Blacksmith Road 
Newtown, PA 18974   
Tel: 
 
Fax: 
 
 
Project Management  
ClinSmart, LLC 
32 Blacksmith Road 
Newtown, PA 18974   
Tel: 
 
Fax: 
 
 
Drug Safety  
ClinSmart, LLC 
32 Blacksmith Road 
Newtown, PA 18974   
Tel: 
 
Fax: 
 
 
 
 
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13. 
APPENDIX A  
NIAID 8-point Ordinal Scale for COVID-19 (NCT04280705) 
The ordinal scale is an assessment of the clinical status at the first assessment of a given study 
day. The scale is as follows:  
1) Death;  
2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO);  
3) Hospitalized, on non-invasive ventilation or high flow oxygen devices;  
4) Hospitalized, requiring supplemental oxygen;  
5) Hospitalized, not requiring supplemental 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;  
8) Not hospitalized, no limitations on activities.  
 
 
 
 
 
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14.
APPENDIX B
EVALUATION TO SIGN A CONSENT 
Protocol: 
CD24Fc-007-US  
PI: 
Name:  _____________________________ 
Date of birth: _____________________ 
Directions: 
Make a subjective judgment regarding item 1 below.  Ask the patient questions 2 through 5.  The 
evaluator may select the appropriate language to use in formulating the questions in order to 
assist the subject’s understanding. 
1) Is the patient alert and able to communicate with the examiner? ___ Yes ___ No
2) Ask the patient to name at least two (2) potential risks incurred as a result of participating
in the study.
3) Ask the patient to name at least two things that will be expected of him/her in terms of
patient cooperation during the study.
4) Ask the patient to explain what he/she would do if he/she decides that they no longer
wish to participate.
5) Ask the patient to explain what he/she would do if he/she is experiencing distress,
discomfort or pain.
EVALUATION TO SIGN A CONSENT FORM FOR RESEARCH 
 
 
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6) Ask the patient if being in the study is voluntary or required. 
________________________________________________________________________ 
 
 
I hereby certify that the above patient is alert, able to communicate and able to give 
acceptable answers to items 2, 3, 4, 5 and 6 above. 
 
 
 
Evaluator  
Date  
 
Witness 
 
Date 
 
 
 
 
 
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15. 
SUMMARY OF CHANGES 
Substantive changes to the Protocol are outlined in the Table below. In cases where the change 
involves the insertion or deletion of one or a few words, the text may be underlined for ease of 
reviewing. Additional typographical corrections or edits may also be made throughout the 
Protocol but not detailed in the Table.  
 
Section of the 
document 
Revision and Justification 
Title page and 
footer (all pages) 
Protocol version number updated to 1.9, dated August 16, 2020 
Study Synopsis: 
Study Design 
(Page 2) 
Study Design changed from: 
CD24Fc will be administered as single dose of 480 mg via IV infusion on Day 1. 
Total of 230 subjects will be enrolled and randomized in 1:1 ratio to receive 
CD24Fc or placebo. All subjects will be treated with the best available treatment. 
The follow up period is 28 days.  
To: 
CD24Fc will be administered as single dose of 480 mg via IV infusion on Day 1. 
Total of 270 subjects will be enrolled and randomized in 1:1 ratio to receive 
CD24Fc or placebo. All subjects will be treated with the best available treatment. 
The follow up period is 28 days.  
Study Synopsis: 
Study Endpoints: 
(Page 3) 
Section 2.4 
Primary Endpoints: 
(Page 39) 
Primary Endpoint changed from: 
Time to improvement in clinical status: the time (days) to the improvement of 
clinical status from “scale 3 or 4” to “scale 5 or above that is sustained without a 
drop to below 5” based on NIAID 8-point ordinal scales (Appendix A) within 28 
days from randomization.  
To: 
Time to improvement in clinical status: the time (days) to the improvement of 
clinical status from “scale 2 to 4” to “scale 5 or above that is sustained without a 
drop to below 5” based on NIAID 8-point ordinal scales (Appendix A) within 28 
days from randomization.  
Study Synopsis: 
Study Endpoints: 
(Page 3) 
Section 2.5 
Secondary 
Endpoints: 
(Page 40) 
Secondary Endpoints changed from: 
Time to disease progression in clinical status: the time (days) for progression 
from scale 3 or 4 to scale 1 or 2 based on NIAID ordinal scale with 28 days from 
randomization;  
To: 
Time to disease progression in clinical status: the time (days) for progression 
from scale 3 or 4 to scale 1 or 2, or 2 to 1, based on NIAID ordinal scale with 28 
days from randomization;  
 
Secondary Endpoints changed from: 
Conversion rate of clinical status on days 8 (proportion of subjects who changed 
from “scale 3 or 4” to “scale 5 or higher” on NIAID ordinal scale); 
To: 
Conversion rate of clinical status on days 8 (proportion of subjects who changed 
from “scale 2 to 4” to “scale 5 or higher” on NIAID ordinal scale); 
 
 
 
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Secondary Endpoints changed from: 
Conversion rate of clinical status on days 15 (proportion of subjects who changed 
from “scale 3 or 4” to “scale 5 or higher” on NIAID ordinal scale); 
To: 
Conversion rate of clinical status on days 15 (proportion of subjects who changed 
from “scale 2 to 4” to “scale 5 or higher” on NIAID ordinal scale); 
Study Synopsis: 
Study Endpoints: 
(Page 3) 
Section 2.7 Safety 
evaluation (Page 
40) 
Safety evaluation changed from: 
Adverse events, vital signs, laboratory tests (blood routine, blood biochemistry, 
coagulation function, urine routine), 12 lead ECG. 
To: 
Adverse events, vital signs, laboratory tests (blood routine, blood biochemistry, 
coagulation function, urine routine), ECG. 
Study Synopsis: 
Study Population: 
(Page 3) 
Language changed from: 
Hospitalized severe COVID-19 adult patients.  
To: 
Hospitalized severe and critical COVID-19 adult patients. 
Study Synopsis: 
Eligibility Criteria: 
(Page 3-4) 
Table 1 (Page 6) 
Section 4.1 
Inclusion criteria 
(Page 42) 
Inclusion criteria changed from: 
1) Should be at least 18 years of age.
2) Male or female, female should have negative pregnancy test.
3) Diagnosed with COVID-19 and confirmed SARS-CoV-2 viral infection,
prior positive viral results allowed.
4) Able to sign the consent form.
5) Hospitalized and requiring oxygen support, NIAID 8-point ordinal score 3
to 4, regardless of ARDS (Appendix A).
6) Women of childbearing potential, under the age of 54 years, who use
adequate contraception and who agree to use adequate contraception for
the duration of the study.
To: 
1)
Should be at least 18 years of age.
2)
Male or female, female should have negative pregnancy test.
3)
Diagnosed with COVID-19 and confirmed SARS-CoV-2 viral infection, prior
positive viral results allowed.
4)
Informed consent form signed by the patient or by the legally authorized
representative.
5)
Hospitalized and requiring oxygen support, NIAID 8-point ordinal score 2, 3
or 4, regardless of ARDS (Appendix A). The intubation for mechanical
ventilation is within 7 days.
6)
Women of childbearing potential, under the age of 54 years, who use
adequate contraception and who agree to use adequate contraception for
the duration of the study.
Study Synopsis: 
Eligibility Criteria: 
(Page 4) 
Table 1 (Page 6) 
Section 4.1 
Exclusion criteria 
(Page 42) 
Exclusion criteria changed from: 
1) Patients with COVID-19 in critical condition (Appendix A) or NIAID 8-point
ordinal score 2 (Hospitalized, on invasive mechanical ventilation or
extracorporeal membrane oxygenation (ECMO)).
2) Patients with documented bacterial / fungal infections.
3) Patients with sepsis or septic shock.
 
 
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Patients who are pregnant, breastfeeding, or have a positive pregnancy test 
result before enrollment.
Severe liver damage (Child-Pugh score ≥ C, AST> 5 times the upper limit), the 
tests can be done 72 hr prior to screening.
Patients with known severe renal impairment (creatinine clearance ≤ 30 mL /
min) or patients receiving continuous renal replacement therapy, hemodialysis, 
or peritoneal dialysis, the tests can be done 72 hr prior to screening.
The investigator believes that participating in the trial is not in the best interests 
of the patient, or the investigator considers unsuitable for enrollment (such as 
unpredictable risks or subject compliance issues).
To: 
1)
Patients who are pregnant, breastfeeding, or have a positive pregnancy test
result before enrollment.
2)
Patients who previously enrolled in CD24Fc clinical trial.
3)
Intubation for invasive mechanical ventilation is over 7 days.
4)
Documented acute renal or hepatic failure;
5)
The investigator believes that participating in the trial is not in the best
interests of the patient, or the investigator considers unsuitable for
enrollment (such as unpredictable risks or subject compliance issues).
Study Synopsis: 
Treatment 
Description: 
(Page 4) 
Language changed from: 
The Phase III study will be a randomized double-blind placebo controlled study in 
230 subjects. Patients will be randomized 1:1 to receive one of the following 
treatments: 
 Arm A: CD24Fc, 480mg, diluted to 100ml with normal saline, IV infusion in 60 
minutes. 
 Arm B:  placebo, normal saline 100ml, IV infusion in 60 minutes. 
 The best available treatment and supportive care will be given to all subjects 
according to local institutional guideline. Those who uses immune modulators 
such as IL-6/IL-6R antagonists or experimental antiviral drugs such as remdesivir 
are allowed to participate the trial. 
To: 
The Phase III study will be a randomized double-blind placebo controlled study in 
270 subjects. Patients will be randomized 1:1 to receive one of the following 
treatments: 
 Arm A: CD24Fc, 480mg, diluted to 100ml with normal saline, IV infusion in 60 
minutes. 
 Arm B:  placebo, normal saline 100ml, IV infusion in 60 minutes. 
 The best available treatment and supportive care will be given to all subjects 
according to local institutional guideline. Those who uses immune modulators 
such as IL-6/IL-6R antagonists or experimental antiviral drugs such as remdesivir 
or convalescent plasma are allowed to participate the trial. 
Study Synopsis: 
Interim Analysis: 
(Page 5) 
Language changed from: 
The Phase III study will include two interim analyses:  
-The first interim analysis will occur after 70 subjects are enrolled without a pause 
in enrollment. This will be a futility study with a requirement for positive 
4)
5)
6)
7)
 
 
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therapeutic activity of CD24Fc (HR≥1.14 based on TTCI; or HR≤0.88 based on 
the proportion of patients who died or had respiratory failure. 
-The second interim analysis will be for efficacy analysis for the primary 
endpoint, at the time when the required number of events is at 70%. A sample 
size re-estimation will be conducted on these two interim analyses. 
To: 
The Phase III study will include one interim analysis: 
-The interim analysis will be at the time when the required number of events is 
at 70% for the purpose of sample size re-estimation only. 
Study Synopsis: 
Stopping 
Guidelines: 
(Page 4) 
Language changed from: 
Monitoring of the safety endpoint will be conducted by the CRO in a blinded 
fashion. The CRO will collect the data and share this with the DSMB at the 
planned two interim analyses or call a meeting with the DSMB at other times if 
needed. 
To: 
Monitoring of the safety endpoint will be conducted by the CRO in a blinded 
fashion. The CRO will collect the data and share this with the DSMB at two safety 
reviews, respectively when 50% or 75% of enrolled patients reached D15.  DSMB 
may call a meeting with the DSMB at other times if needed.  DSMB may 
recommend early termination if it find significantly higher SAE in the CD24Fc arm 
after considering the clinical benefit of the treatment.  The final decision will be 
made by the sponsor. 
Section 3.1 Study 
Design Overview 
(Page 41) 
Language changed from: 
CD24Fc will be administered as single dose of 480mg via IV infusion on Day 1. 
Total of 230 subjects will be enrolled and randomized in 1:1 ratio to receive 
CD24Fc or placebo. All subjects will be treated with the best available treatment. 
The follow up period is 28 days. Those who uses immune modulators such as IL-
6/IL-6R antagonists or experimental antiviral drugs are allowed to participate the 
trial. 
To: 
CD24Fc will be administered as single dose of 480mg via IV infusion on Day 1. 
Total of 270 subjects will be enrolled and randomized in 1:1 ratio to receive 
CD24Fc or placebo. All subjects will be treated with the best available treatment. 
The follow up period is 28 days. Those who uses immune modulators such as IL-
6/IL-6R antagonists or experimental antiviral drugs are allowed to participate the 
trial. 
Section 6.4 Dose 
modification based 
on laboratory 
values 
Section 6.4.1 
Renal Function 
Section 6.4.2 
Hepatic Function  
Dose modification sections deleted to reflect that there will be no dose 
modifications based on laboratory values. 
 
 
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Section 7.1.1. 
Informed consent 
(Page 45) 
Language changed from: 
The researchers explain all the research procedures to the subjects before the 
screening, including information about the nature of the research, and obtain 
informed consent signed by the subject themselves. 
To: 
The researchers explain all the research procedures to the subjects before the 
screening, including information about the nature of the research, and obtain 
informed consent signed by the patient or by a legally authorized representative. 
Before the process to obtain informed consent from the legal authorized 
representative, investigators should use the EVALUATION TO SIGN A 
CONSENT FORM FOR RESEARCH in Appendix B to assess the understanding 
of the consent process of person who may have cognitive impairments, or may 
elicit the information using clinical interview procedures. 
Section 7.2.1. 
Screen period Visit 
1 (Page 48) 
Language changed from: 
•
Sign the informed consent;
To: 
•
Sign the informed consent by patient or by a legally authorized
representative;
Section 8.1.6 
Follow up of 
Adverse Events 
(Page 52) 
Language changed to indicate that Grade III-V AEs will be captured, rather than 
Grade III-IV AEs. 
Section 8.2 
Adverse Event 
Reporting (Page 
53) 
Language changed to indicate that Grade III-V AEs will be recorded, rather than 
Grade III-IV AEs. 
Section 10.2.2. 
Per Protocol Set 
(PPS) (Page 58) 
Language changed from: 
PPS is a subset of the ITT. Refers to all subjects who are randomized to receive 
the protocol-specified treatment without significant protocol deviations that 
significantly affect the main efficacy. PPS-based analysis will complement ITT-
based analysis as a supporting analysis. Subjects will be analyzed based on the 
treatment arm they plan to assign. 
To: 
PPS is a subset of the ITT. Refers to all randomized subjects who have received 
the protocol-specified single-dose treatment without significant protocol 
deviations that significantly affect the main efficacy. PPS-based analysis will 
complement ITT-based analysis as a supporting analysis. Subjects will be 
analyzed based on the treatment arm they plan to assign. 
Section 10.4.1 
Primary efficacy 
Language changed from: 
 
 
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endpoint (Page 
59) 
The primary endpoint will be the time (days) from the randomization in which the 
patient's clinical diagnosis improved from baseline (scale 3 or 4, NIAID ordinal 
scale) to 5 or above that is sustained without a drop to below 5 within 28 days.  
To: 
The primary endpoint “Time to Clinical Improvement:” (TTCI) will be the time 
(days) from the randomization in which the patient's clinical status improved from 
baseline (scale 2-4, NIAID ordinal scale, Appendix A) to 5 or above that is 
sustained without a drop to below 5 within 28 days. Hospital discharge date 
(NIAID scale 7 or 8) is an important event time point. The date that clinical status 
evaluation ≥ 5 or the date of hospital discharge, whichever comes first will be 
used as the TTCI date.     
The record of re-hospitalization with oxygen therapy is required to modify the 
TTCI date. The new TTCI date should be the time from randomization to the 
latest clinical status evaluation ≥ 5 or the date of the latest hospital discharge, 
whichever comes first.  
Time to clinical improvement (days) is calculated as:  
Time to Improvement = Date of (First Clinical Improvement/hospital discharge) – 
Date of Randomization 
The discharge to home due to clinical improvement is scored as NIAID scale ≥ 7.  
The date that clinical status evaluation ≥ 5 or the date of hospital discharge, 
whichever comes first will be used as the clinical improvement date.  All subjects 
without clinical improvement within 28 days will be censored on the Day 29 visit. 
 
Time-event efficacy endpoints / censorship rules changed from: 
For the primary endpoint, during the observation period, an improvement from 
NIAID scale 3 or 4 to scale 5 or above, if sustained without a drop below 5, is 
considered as an event. The days from the randomization to the first time point of 
such improvement will be defined as time of improvement. Additional follow-up 
can be used to determine clinical improvement events.  
To: 
For the primary endpoint, during the observation period, an improvement from 
NIAID scale 2, 3 or 4 to scale 5 or above, if sustained without a drop below 5, is 
considered as an event. The days from the randomization to the first time point of 
such improvement will be defined as time of improvement. Additional follow-up 
can be used to determine clinical improvement events.  
 
Section 10.4.2 
Secondary efficacy 
endpoint (Page 
59) 
Language changed from: 
For the disease progression, during the observation period, a progression from 
scale 3 or 4 to scale 2 or 1, is considered as an event. The days from the 
randomization to the first time point of progression will be defined as time of 
progression. The probability function of clinical progression will be estimated by 
Kaplan-Meier method. The median time and its 95% confidence interval for each 
 
 
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group will be reported. The 95% confidence interval for the median time will be 
estimated using the Brookmeyer-Crowley method with log-log function conversion 
to achieve a normal approximation. The progression rate will be estimated by the 
layered Cox-Model. Cumulative progression rates estimated by the KM method 
for day 29 and the 95% confidence intervals will be reported. 
To: 
For the disease progression, during the observation period, a progression from 
scale 3 or 4 to scale 2 or 1, or from 2 to 1, is considered as an event. The days 
from the randomization to the first time point of progression will be defined as 
time of progression. The probability function of clinical progression will be 
estimated by Kaplan-Meier method. The median time and its 95% confidence 
interval for each group will be reported. The 95% confidence interval for the 
median time will be estimated using the Brookmeyer-Crowley method with log-log 
function conversion to achieve a normal approximation. The progression rate will 
be estimated by the layered Cox-Model. Cumulative progression rates estimated 
by the KM method for day 29 and the 95% confidence intervals will be reported. 
Section 10.5 
Interim Analysis 
and Stopping 
Rules (Page 62) 
Language changed from: 
The study will also include an interim efficacy analysis at 70% events, which is 
146 events. The final analysis will be carried out after all 270 subjects have been 
randomized, dosed and completed the study.  
In the interim analysis, the DSMB will determine whether the trial demonstrates 
the efficacy and also re-estimate the sample size to determine whether it 
supports increasing the number of clinical improvement event targets. Chen's 
method will be used to re-estimate the sample size. 
To: 
The study will also include an interim analysis at 70% of the required 146 events. 
The final analysis will be carried out after all 270 subjects have been randomized, 
dosed and completed the study.  
In the interim analysis, the DSMB will re-estimate the sample size to determine 
whether it supports increasing the number of clinical improvement event targets. 
Chen's method will be used to re-estimate the sample size. 
 
 
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Section 10.5 
Interim Analysis 
and Stopping 
Rules (Page 62) 
Safety reviews and stopping rules language deleted and replaced with: 
The study have two blinded safety reviews respectively, when 50% and 75% of 
the planned enrollment has occurred with follow-up time reaching Day 15 and 
SAE data are available. DSMB will be provided with list of SAE including mortality 
and may unblind the data at its discretion to evaluate the balance of SAE in the 
two study arms. 
Stopping rules 
If the DSMB found that SAE is significantly higher in the CD24Fc arm, it may 
recommend termination of the trial after review of potential benefit of the study 
drug by unblinding all study subjects. Sponsor will make final decision based on 
the recommendation of DSMB. 
Section 10.5 
Interim Analysis 
and Stopping 
Rules (Page 63) 
 
Interim Efficacy Analysis section deleted 
Section 10.5 
Interim Analysis 
and Stopping 
Rules (Pages 63 
and 64) 
Sample Size Re-estimation changed form: 
The sample size re-estimation (at 70% of patients completing 28 days follow-up) 
will be based on Chen et al (37).  If the conditional power is < 50% or >85%, the 
trial will continue without a sample size increase; whereas if the conditional power 
is between 50% and 85%, the sample size will be re-calculated to have 85%. To 
maintain trial integrity, the DSMB will pick a sample size in a nearest interval with 
5 patients. For example, if the re-estimated sample size is 287, the DSMB could 
pick any number in the interval of 285 to 289. Also, the maximum increased 
sample size will not be more than 70 patients above what is needed to observe 
208 events. 
The final analysis will be performed when 270 randomized and dosed patients 
have completed 28 days of follow up, and the p-value cutoff is  0.0455 (two-
sided) based on the O'Brien-Fleming function of the Lan-DeMets algorithm. 
To: 
The interim analysis for the primary endpoint only will be performed after reaching 
146 events (70% of information). A sample size reassessment of efficacy will be 
performed.  
There sample size re-estimation 146 events will be based on preliminary data 
that are not 100% source-verified.  The method will be based on Chen et al as 
stated in the protocol. If the conditional power is < 50% or >85%, the trial will 
continue without a sample size increase; whereas if the conditional power is 
between 50% to 85%, the sample size will be re-calculated to have 85%. To 
maintain trial integrity, the DSMB will pick a sample size in a nearest interval with 
5 patients. For example, if the re-estimated sample size is 287, the DSMB could 
pick any number in the interval of 285 to 289. Also, the maximum increased 
sample size will not be more than 70 patients above what is needed to observe 
208 events. 
The final analysis will be performed when 270 randomized and dosed patients 
have completed 28 days of follow up, and the p-value cutoff is 0.05 (two-sided) 
based on the O'Brien-Fleming function of the Lan-DeMets algorithm. 
 
 
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Section 10.6. 
Missing Data 
Convention (Page 
64) 
Language changed from:  
Participants who have not been lost to follow up or experienced the event will be 
censored at Day 29.  Participants who received no CD24Fc or placebo will be 
excluded from analysis. Participants without an event but lost to follow-up will be 
censored at the last date of follow-up. 
We will perform two more analyses on the following data sets for the purpose of 
sensitivity analysis: 
First: Participants who have not dropped out or experienced an event are 
censored at Day 29. Participants not receiving study drug will be excluded from 
the analysis. Participants without an event but lost to follow-up will be censored at 
the last date of follow-up. When the event is documented, the time to the event is 
the length of time from the randomization to the event observed if at most one 
missed disease assessment before the event is documented.  If more than one 
clinical status assessment is missing before the event is documented, it censors 
at the last disease assessment without the event. 
Second: Participants who have not been lost to follow up or experienced an event 
and are followed at the end of the trial will be included. Participants not receiving 
study drug will be excluded. Participants who have documented the event and no 
missing disease assessment(s) will be included. 
To: 
Participants who have not been lost to follow up or experienced the event will be 
censored at Day 29.  Participants without an event but lost to follow-up will be 
censored at the last date of follow-up. 
We will perform two more analyses on the following data sets for the purpose of 
sensitivity analysis: 
First: Participants who have not dropped out or experienced an event are 
censored at Day 29. Participants not receiving study drug will be excluded from 
the analysis. Participants without an event but lost to follow-up will be censored at 
the last date of follow-up. When the event is documented, the time to the event is 
the length of time from the randomization to the event observed if at least one 
disease assessment before the event is documented.   
Second: Participants who have not been lost to follow up or experienced an event 
and are followed at the end of the trial will be included. Participants not receiving 
study drug will be excluded. Participants who have documented the event and 
have at least one disease assessment(s) will be included. 
11.1.3 Use of 
Legally Authorized 
Representative 
(Surrogate 
Consent) 
(Page 64-66) 
Section added: 
Federal regulations permit investigators to obtain consent from a legally 
authorized representative. State laws define the categories of individuals who are 
allowed to provide surrogate consent for research. The following specific category 
applies to this study in end stage COVID-19 patient who is in ICU with 
mechanical ventilation.  
“Individuals whose medical condition may render them temporarily unable to 
provide informed consent as a consequence of severe pain, confusion, or 
impaired consciousness due to events such as life-threatening illness or trauma.”  
 
Definitions 
 
 
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a.
Legally Authorized Representative (LAR): An individual or judicial, or other
body authorized under applicable law to grant permission on behalf of a
prospective participant for their participation in research activities.
b.
Surrogate Consent: The use of a legally authorized representative with
reasonable knowledge of the research participant.
c.
Advance Directive: Documents written in advance of serious illness in which a
person states their choices for healthcare or names someone to make those
choices. When a person is selected to make the medical decisions, the
document is called a Durable Power of Attorney and the designated person is
called an Agent. The Agent can serve as a LAR to provide surrogate consent.
d.
Capacity to Consent: The ability of the individual to understand the choices
presented, to appreciate the implications of choosing one alternative or
another, and to make and communicate a decision (e.g., whether or not to
participate in a study).
Determining Capacity of Consent 
Whenever possible, investigators should attempt to obtain informed consent 
directly from the research participant. 
While there are no standardized measures for determining capacity to consent, 
participant should be assessed on the abilities to understand and to express a 
reasoned choice concerning the: 
•
Nature of the research and the information relevant to his/her
participation;
•
Consequences of participation for their own situation, especially
concerning their health condition;
•
Consequences of the alternatives to participation.
Investigators may use the EVALUATION TO SIGN A CONSENT FORM FOR 
RESEARCH (Appendix B) to assess the understanding of the consent process of 
person who may have cognitive impairments, or may elicit the information using 
clinical interview procedures. 
Identifying an Appropriate Surrogate for End Stage COVID-19 Patient in ICU 
with Mechanical Ventilation 
In an emergency room setting or COVID-19 patient in ICU with mechanical 
ventilation, the order of priority does not apply, not does the surrogate have to 
show reasonable knowledge of the research participant. Surrogate consent may 
be obtained from any of the following: 
•
The person’s agent designated by an advance health care directive.
•
He conservators or guardian of the person having the authority to
make heath care decisions for the person.
•
The spouse of the person.
•
The domestic partner of the person as defined in Section 297 of the
California Family Code
 
 
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• 
An adult son or daughter of the person.  
• 
A custodial parent of the person.  
• 
Any adult brother or sister of the person.  
Important Note: In an emergency room or ICU environment, no surrogate may 
be utilized if there is a disagreement whether to consent among any available 
surrogates. 
 
 
 
 
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