Safety, Tolerability and Efficacy and Dose Response of GLS-1027 in the Prevention of Severe Pneumonitis Caused by SARS-CoV-2 Infection
Phase: PHASE2
Conditions: Pneumonitis, SARS-CoV Infection
Sponsor: GeneOne Life Science, Inc.

 
 
GLS27-005 
GeneOne Life Science, Inc. 
 
Clinical Protocol 
 
 
 
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Brief protocol title 
GLS27-005 
 
 
Formal protocol title 
Safety, Tolerability, Efficacy and Dose Response of GLS-
1027 in the Prevention of Severe Pneumonitis caused by 
SARS-CoV-2 Infection  
 
 
 
Regulatory Sponsor: 
GeneOne Life Science Inc.  
535 Pennsylvania Ave., Suite 200 
Fort Washington, PA 19034 
(610) 707-5671 
 
 
IND Protocol Number: 
150401 
 
 
Clinical Trials.gov #: 
NCT04590547 
 
 
 
Version Summary 
Initial version:  
Version 3.0 
11 Dec 2020 
Amendment:  
 
 
 
 

 
 
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Clinical Protocol 
 
 
 
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CONFIDENTIAL 
The information in this document is considered privileged and confidential by GeneOne 
Life Science, Inc. and may not be disclosed to others except to the extent necessary to 
obtain Institutional Review Board/Ethics committee approval and informed consent, or as 
required by local regulatory authorities. Persons to whom this information is disclosed 
must be informed that this information is privileged and confidential and that it must not 
be further disclosed without the written permission of GeneOne Life Science, Inc. Any 
supplemental information added to this document is also confidential and proprietary 
information of GeneOne Life Science, Inc. and must be kept in confidence in the same 
manner as the contents of this document. 
 
 
 
  
 
 

 
 
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Clinical Protocol 
 
 
 
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PROTOCOL ACKNOWLEDGEMENT 
 
 
I have read this Protocol and agree that it contains all necessary details for carrying out the study 
described. I understand that it must be reviewed by the Institutional Review Board or Independent 
Ethics Committee overseeing the conduct of the study and receive approval or a favorable opinion 
before implementation. 
 
The signature of the Principal Investigator and Sponsor below constitute their approval of this 
protocol and provide the necessary assurances that this study will be conducted according to the 
Declaration of Helsinki, GCP, ICH guidelines, local legal and regulatory regulations as well as to 
all stipulations of the protocol in both the clinical and administrative sections, including statements 
regarding confidentiality. 
 
 
 
 
_________________________________ 
 
 
_________________ 
Investigator’s printed name and signature 
 
 
Date 
 
 
 
 
11 Dec 2020 
_________________________________ 
 
 
_________________ 
Medical Monitor 
 
 
 
 
 
Date 
 
 
 
Protocol Number: GLS27-005 
Version Number: 3.0 / Version Date: 11 Dec 2020 
 
 
 
  
 
 
 
 

 
 
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GeneOne Life Science, Inc. 
 
Clinical Protocol 
 
 
 
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TABLE OF CONTENTS 
 
PROTOCOL ACKNOWLEDGEMENT ................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................................... 4 
CLINICAL PROTOCOL SYNOPSIS ....................................................................................................... 8 
1. 
INTRODUCTION .............................................................................................................................. 13 
1.1 
Background and Rationale .................................................................................................. 13 
1.1.1 
Pre-clinical experience with GLS-1027 ..................................................................... 14 
1.1.2 
Human experience with GLS-1027............................................................................. 20 
1.2 
Investigational Agent ............................................................................................................ 21 
1.4 
Risk/Benefit Assessment ..................................................................................................... 22 
2. 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................................ 23 
2.1 
Hypothesis ............................................................................................................................... 23 
2.2 
Primary Objectives and Outcome Variables ................................................................... 23 
2.3 
Exploratory Objectives ......................................................................................................... 23 
3. 
STUDY DESIGN ............................................................................................................................... 23 
3.1 
Safety Monitoring ................................................................................................................... 24 
3.2 
Data and Safety Monitoring Board (DSMB) ..................................................................... 24 
4. 
SELECTION AND ENROLLMENT OF PARTICIPANTS .......................................................... 24 
4.1 
Recruitment of Participants ................................................................................................ 24 
4.2 
Inclusion Criteria for enrollment ........................................................................................ 24 
4.3 
Exclusion Criteria for enrollment ....................................................................................... 25 
4.4 
Discontinuation/Withdrawal of Study Participants ....................................................... 25 
4.5 
Treatment with dexamethasone post-enrollment .......................................................... 26 
5. 
STUDY PRODUCT .......................................................................................................................... 26 
5.1 
Investigational Product ........................................................................................................ 26 
5.2 
Packaging and Labeling ....................................................................................................... 27 
5.3 
Handling of Study Drug ........................................................................................................ 27 
5.4 
Dispensing of Study Drug.................................................................................................... 27 
5.6 
Preparation of Investigational Product ............................................................................ 27 
5.7 
Record of Investigational Product Disposition at Site ................................................. 28 
5.8 
Return and Destruction of Investigational Product ...................................................... 28 

 
 
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6. 
STUDY PROCEDURES AND TREATMENTS ............................................................................ 28 
6.1 
Procedures by Visit (also see Table S2) .......................................................................... 28 
6.1.1 
Day 1: Review Study and Eligibility Criteria; Obtain Informed Consent, 
Enrollment ........................................................................................................................................ 28 
6.1.2 
Day 2 (PK sub-study participants ONLY) ................................................................. 28 
6.1.3 
Day 2 through 29 (or until discharge or death) ...................................................... 28 
6.1.4 
Day 56 ................................................................................................................................ 29 
6.2 
Timing and Evaluations ........................................................................................................ 29 
6.2.1 
Informed Consent (Day 1) ............................................................................................ 29 
6.2.2 
Enrollment (Day 1) ......................................................................................................... 29 
6.2.3 
Safety Assessments ...................................................................................................... 30 
6.3 
Assessment of Laboratory Abnormalities....................................................................... 31 
6.4 
Assessment of Clinical Adverse Events .......................................................................... 31 
6.5 
Plasma for PK sub-study and/or trough level determination of GLS-1027 ............ 31 
6.6 
Serum and PBMCs for immunology assessments ....................................................... 31 
7. 
EVALUATION OF SAFTY AND MANAGEMENT OF TOXICITY ............................................ 31 
7.1 
Safety Parameters .................................................................................................................. 31 
7.1.1 
Adverse Events (AEs) ................................................................................................... 31 
7.1.2 
Serious Adverse Events (SAEs) ................................................................................. 32 
7.1.3 
Suspected Unexpected Serious Adverse Drug Reactions (SUSARs) .............. 33 
7.1.4 
Assessing Severity (Intensity) .................................................................................... 33 
7.1.5 
Causal Relationship of Investigational Product to Adverse Events ................ 33 
7.1.6 
Abnormal Laboratory Values ...................................................................................... 34 
7.1.7 
Pregnancy During Study .............................................................................................. 34 
7.1.8 
Decreases in renal function during study ............................................................... 34 
7.1.9 
Post-study Reporting Requirements ........................................................................ 34 
7.2 
Methods and Timing for Collection and Recording of Safety Data .......................... 34 
7.3 
Safety and Toxicity Management ....................................................................................... 35 
7.3.1 
Events Requiring Expedited Reporting .................................................................... 35 
7.3.2 
Reasons to Discontinue Treatment ........................................................................... 35 
7.3.3 
Unblinding ........................................................................................................................ 37 
8. 
STATISTICAL METHODS and CONSIDERATIONS ................................................................ 37 
8.1 
Data Sets to be Analyzed ..................................................................................................... 37 

 
 
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8.2 
Sample Size ............................................................................................................................. 37 
8.3 
Randomization ........................................................................................................................ 38 
8.4 
Demographic and Other Baseline Characteristics ........................................................ 38 
8.5 
Safety Analysis ....................................................................................................................... 38 
8.5.1 
Adverse events ............................................................................................................... 38 
8.5.2 
Laboratory Data .............................................................................................................. 38 
8.6 
Efficacy Analysis .................................................................................................................... 39 
8.7 
Other Analysis ........................................................................................................................ 39 
8.8 
Interim Analysis ...................................................................................................................... 40 
8.9 
Missing Values ........................................................................................................................ 40 
9. 
DATA COLLECTION, MONITORING, AND AE REPORTING ................................................ 41 
9.1 
Confidentiality ......................................................................................................................... 41 
9.2 
Source Documents ................................................................................................................ 41 
9.3 
Data Collection ....................................................................................................................... 41 
9.4 
Record Retention ................................................................................................................... 41 
9.5 
Safety and Quality Monitoring and Record Availability ............................................... 41 
9.6 
Adverse event (AE) Reporting ............................................................................................ 42 
9.6.1 
Study Reporting Period of Adverse Events ............................................................ 42 
9.6.2 
Study Reporting Period for Serious Adverse Events ........................................... 42 
9.6.3 
Notification of Serious Adverse Events ................................................................... 43 
9.7 
Study Termination ................................................................................................................. 43 
10. 
PUBLICATION OF RESEARCH FINDINGS ........................................................................... 44 
11. 
LIST OF ABBREVIATIONS ....................................................................................................... 44 
12. 
REFERENCES ............................................................................................................................. 45 
13. 
APPENDICES ............................................................................................................................... 47 
 
List of Figures 
FIGURE 1.1.1.1-1: PULMONARY LPS-INDUCED INFLAMMATION IS INHIBITED BY GLS-1027 ......... 15 
FIGURE 1.1.1.1-2: PULMONARY LPS-INDUCED INFLAMMATION IS INHIBITED BY GLS-1027 ......... 16 
FIGURE 1.1.1.2-2: GLS-1027 LOWERS PM2.5 INDUCED LUNG INFLAMMATION AND AIRWAY 
RESISTANCE .................................................................................................................................................. 18 
FIGURE 1.1.1.3-1: SARS-COV CASE-FATALITY RELATIVE TO PROVINCIAL AIR POLLUTION 
INDEX  .............................................................................................................................................................. 19 
FIGURE 1.2-1: STRUCTURE OF GLS-1027 ....................................................................................................... 21 
FIGURE 1.2-2: STRUCTURE OF MICROCRYSTALLINE CELLULOSE ....................................................... 22 
 

 
 
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List of Tables 
TABLE 5.2-1. GLS-1027 AND PLACEBO DRUG PRODUCT VIAL LABELS .............................................. 27 

 
 
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CLINICAL PROTOCOL SYNOPSIS 
Title of study: Safety, Tolerability, Efficacy and Dose Response of GLS-1027 in the Prevention of 
Severe Pneumonitis caused by SARS-CoV-2 Infection 
Number of study participants: 132 
Study Phase: II 
Study Type: Randomized, double-blind, placebo-controlled  
Research Hypothesis: GLS-1027 will be safe, well tolerated and reduce the incidence of treatment 
failure as characterized by 1) advancing to WHO COVID-19 Classification level ≥6 which includes the 
need for intubation with mechanical ventilation, initiation of extracorporeal mechanical oxygenation 
(ECMO), or death, in SARS-CoV-2 infected hospitalized patients, 2) need for institution of salvage 
therapy 72 hours after study entry with either an IL-6 monoclonal antibody or dexamethasone (≥6 
mg/day), 3) withdrawing consent from the study, 4) becoming lost to follow-up, or 5) discontinuation 
of treatment for any reason other than decrease in renal function or pregnancy. 
Primary study objectives and outcome variables:  
 Incidence of serious adverse events relative to treatment group 
 Incidence of treatment failure within 28 days from enrollment 
Exploratory study objectives and outcome variables: 
 Assess the number of days requiring ICU care relative to treatment group 
 Assess the number of days of mechanical ventilation relative to treatment group 
 Assess incidence of WHO COVID-19 Classification levels relative to baseline serum IL-6 level 
 Assess incidence of WHO COVID-19 Classification levels relative to baseline serum ferritin level 
 Assess incidence of WHO COVID-19 Classification levels relative to baseline CRP  
 Assess trough level of GLS-1027 relative to serum creatinine 
 Assess the maximal level of Positive End-Expiratory Pressure (PEEP) for subjects who are 
intubated relative to treatment group.  
 Assess the number of days of PEEP > 5 cm H2O for subjects who are intubated relative to 
treatment group 
 Incidence of progression to  WHO COVID-19 Classification level 6, or 7, or 8 (individually) 
 Assess SARS-CoV-2 IgM antibody responses relative to treatment group 
Table S1: Dosing arms and treatment regimen 
Group 
N 
Treatment assignment 
Study drug 
dose 
Treatment 
schedule 
1 
44 
Placebo + SOC 
0 mg 
Daily 
2 
44 
GLS-1027 + SOC 
120 mg 
Daily 
3 
44 
GLS-1027 + SOC 
360 mg 
Daily 
 
Study design: 
Phase II randomized, double-blind, placebo-controlled, study to assess 2 different doses of GLS-
1027 in the prevention of treatment failure among participants admitted to hospital with PCR 
confirmed infection with SARS-CoV-2 (WHO classification 3 or 4). The enrollment period will extend 
to 72 hours from hospital admission. Participants will be randomized at a 1:1:1 ratio to either SOC 
plus placebo, or SOC plus GLS-1027 at either 120 mg or 360 mg daily. Participants will be 
administered drug until discharge or death for a maximum treatment period of 28 days. Clinical status 
will be monitored through 56 days from the initiation of treatment.  

 
 
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Sample Size: 
Based early literature reports [1], it is anticipated that approximately 50% of subjects hospitalized with 
PCR-positive SARS-CoV-2 infections (WHO COVID-19 Classification level 3 or 4) will progress to 
WHO COVID-19 classification level of 6 or greater as defined by one or more of the following: the need 
for intubation or mechanical ventilation (level 6), the need for ECMO (level 7), or any cause death (level 
8). The sample size estimate for this proof of concept is based on Fisher’s Exact two-sided test for 2 
proportions using NQuery 8 (www.statsols.com).  
 
Although the interim analysis will utilize masked treatment assignments, the O’Brien Fleming group 
sequential sample size estimation confirms that a single interim look would retain a cumulative exit 
probability of 70% with a cumulative alpha =0.05 after the final analysis using the target enrollment of 
132 (44 per group) to detect a reduction of those reaching the endpoint of treatment failure, which 
includes advancing to WHO COVID-19 Classification level ≥6 from 50% (SOC treated) to 25% in either 
treatment group of SOC plus GLS-1027. Other conditions also qualify a subject as treatment failure 
include: need for salvage therapy with IL-6 monoclonal antibody; or institution of salvage therapy with 
dexamethasone (≥ 6 mg/day), withdrawing consent from the study, becoming lost to follow-up, or 
discontinuation of treatment for any reason other than renal function or pregnancy.  This study is not 
powered to assess statistically significant differences between GLS-1027 doses.  
Study assessments: 
Adverse events will be monitored and recorded throughout hospitalization from the point of enrollment. 
Daily assessments of vital signs and clinical laboratory parameters will be reviewed and recorded. 
Follow-up clinical status will be assessed to Day 56.  The first 15 persons enrolled will be included in a 
pharmacokinetic sub-study assessment to determine elimination of GLS-1027, while trough levels will 
be monitored throughout the study.  
Efficacy will be assessed by evaluating the difference in the proportion of treatment failures by group.  
Treatment failure will be defined as any of the following:  
1) progression to WHO COVID-19 classification level of 6 or greater within the 28 days of treatment 
initiation,  
2) need for salvage therapy with IL-6 monoclonal antibody; or institution of salvage therapy with 
dexamethasone (≥ 6 mg/day),   
3) withdrawing consent from the study,  
4) becoming lost to follow-up, or  
5) discontinuation of treatment for any reason other than renal function or pregnancy. 
A masked interim analysis will be performed when 22 subjects in each group have been assessed for 
the primary endpoint of treatment failure.  The interim analysis is intended for blinded safety assessment. 
Unless safety is of concern, the study will not be stopped for futility and enrollment will continue to the 
targeted sample size of 132. 
Study population: 
Inclusion criteria for enrollment: 
1. Age 18 years or older 
2. Able to provide consent  
3. Able and willing to comply with study procedures 
4. Enrollment within 72 hrs of hospitalization with a diagnosis of PCR confirmed SARS-CoV-2  
5. WHO COVID-19 classification level 3 or 4 
Exclusion criteria for enrollment: 
1. Pregnant or lactating 
2. SpO2 less than 90% on room air or less than 95% if on supplemental oxygen 
3. Calculated GFR < 60 (Cockcroft-Gault)  

 
 
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4. Meets hospital COVID-19 treatment algorithm for treatment with dexamethasone at a dose of 6 
mg/day for a 10-day course. A single bolus dose of 6 mg of dexamethasone given in the 
Emergency Department and continued at a dose of ≤ 3.5 mg/day or less is allowed. 
5. Meets treatment algorithm criteria for treatment with toclizumab or other anti-IL-6 agent 
6. Treatment with an anti-IL-6 inhibitor, anti-IL-1 inhibitor, anti-TNF monoclonal antibody, or anti-
JAK inhibitor (see Appendix A exclusionary period for specific drugs)  
7. Participation in a COVID-19 clinical trial that includes prescription of a drug with anti-cytokine 
activity 
8. Treatment within the past 60 days with a chemotherapeutic agent 
9. Current treatment with systemic corticosteroids at a dose equivalent of 20 mg/day or greater of 
prednisone or prednisolone, 16 mg/day or greater of methylprednisolone, or 4 mg/day or 
greater of dexamethasone  
10. Diagnosis of leukemia or lymphoma  
11. WHO COVID-19 classification level of 5 or greater (use of high-flow oxygen, non-mechanical 
ventilation such as CPAP, mechanical ventilation)  

 
 
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Table S2: Schedule of Events per Study Day 
Tests and Observations 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
56m 
Clinical Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain written Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review Medical Record 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WHO COVID-19 Classification (Appendix B) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Vital Signs a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Hematology b 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Record Basic Metabolic Panel, LFTs c 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Record other labs d (for days available) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record Procalcitonin (baseline value) e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record admission CXR  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record if care given in ICU setting  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record whether nasal O2 prescribed and dose 
level (L/min) f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record whether CPAP prescribed and 
expiratory pressure g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record if mechanically ventilated and level of 
PEEP, % FiO2 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record if treated by ECMO 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record admission ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Related Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer assigned study drug i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
 
Perform urine pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform ECG (12-lead) j 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect serum for CPK, GGT k 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect blood for plasma for PK assessment l 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect blood for plasma for trough drug 
measurement (AM blood draw) 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 

 
 
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Collect blood for serum (10mL red top,3 tubes) 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Collect blood for PBMCs (10mL ACD; 3 tubes) 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Blood volume for serum, PBMCs 
60 
 
 
60 
 
 
5 
 
60 
 
 
 
 
 
 
60 
 
 
 
 
 
 
60 
 
 
 
 
60 
 
 
 
a Vital signs to be recorded daily to include maximal and minimal: temperature, respiratory rate, heart rate, systolic and diastolic blood pressure 
b Hematology labs to be collected as necessary and recorded: Hemoglobin, hematocrit, platelets, neutrophils, band forms, lymphocytes, eosinophils 
c Basic metabolic panel labs to be collected as necessary and recorded: Sodium, potassium, CO2 (bicarbonate), creatinine, BUN, glucose, liver function tests 
(LFTs) that should be recorded include AST, ALT, bilirubin (direct), alkaline phosphatase, LDH, albumin . These labs are performed daily per the hospital COVID 
algorithm. 
d Other labs to be recorded as available: Ferritin, CRP, IL-6, troponin, D-dimer 
e Procalcitonin: record only initial measurement or within 48 hours of admission and/or SARS-CoV-2 diagnosis (may be performed prior to date of enrollment) 
f Record maximal daily level of O2 by nasal cannula prescribed, if applicable 
g Record maximal daily level of end expiratory pressure delivered by CPAP prescribed, if applicable 
h Record maximal daily level of PEEP and delivered FiO2 by mechanical ventilation, if applicable 
i Study drug administration will commence on the day of enrollment if treatment can be administered before 10 pm and then with AM medications thereafter, If, 
study drug cannot be administered prior to 10 pm on the day of enrollment, then the 1st day of treatment will occur on the day after enrollment.  
j Perform a 12-lead ECG on the 2nd day of treatment with study drug between 75 and 90 minutes post-administration on day 2; and on day 15 (± 2 days) 
k Serum is collected for CPK and GGT on day 1 and day 7, and weekly thereafter, if values on day 7 are abnormal until return to normal 
l PK assessment will be performed for the initial 15 subjects enrolled. Blood (5 ml) will be collected for plasma collection at baseline (pre-treatment), and then at 1, 
2, 4, and 8 hr. Trough measurements will be obtained as indicated for all study participants  
m The clinical record should be reviewed through to Day 56 as relevant to denote date of discharge, date of death, or clinical status (WHO COVID-19 Classification 
Level) at Day 56  
 
 
 

 
 
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1. 
INTRODUCTION 
This study will examine whether GLS-1027 is safe, tolerated and can reduce the risk 
treatment failure among patients admitted to hospital with confirmed Severe Acute 
Respiratory Syndrome coronavirus type 2 (SARS-CoV-2) infection and who require 
supplemental oxygen and assess if there appears to be a dose dependent response. 
1.1 
Background and Rationale 
SARS-CoV-2 is a novel coronavirus first recognized in November 2019. Since discovery, 
greater than 60 million confirmed cases and greater than 1 million deaths have been 
documented globally, and greater than 13 million cases and greater than 250,000 deaths 
in the US, as of 30 November, 2020. Although coronaviruses typically cause a self-limited 
upper respiratory infection in the winter months, SARS-CoV-2 represents the third highly 
pathogenic coronavirus to emerge over the past 2 decades. SARS-CoV similarly was first 
recognized in 2002 and over the two-year period between 2002-2003 there were 
approximately 8,000 cases with a mortality rate of 10% and resulted in outbreaks and 
cases worldwide. The Middle East Respiratory Syndrome coronavirus (MERS-CoV) has 
resulted in fewer than 3,000 cases but with a mortality rate of 36-38%. Cases of MERS-
CoV have been largely restricted to inhabitants of or travelers to the Arabian peninsula or 
neighboring countries.  
Clinically, each of the pathogenic coronaviruses cause lower respiratory tract illness. For 
SARS-CoV-2, clinical illness typically starts with a viral prodrome characterized by 
malaise, muscle aches, and headache that can progress to a febrile illness with 
diaphoresis. Less usual, but pathognomonic signs are anosmia, ageusia, conjunctivitis, 
and perniosis. While most individuals will recover, progression to increasing respiratory 
compromise requiring oxygenation, high-flow oxygenation, intubation and mechanical 
ventilation, extracorporeal mechanical oxygenation (ECMO), or death may occur. Other 
complications of severe disease include renal failure and arterial thrombosis that may 
present as stroke, myocardial infarction, or peripheral arterial obstruction. Early studies 
reported that approximately 50% of those who require supplemental oxygenation after 
admission to hospital progress to needing mechanical ventilation at some time during 
hospitalization [1]. It is generally considered that as the level of acuity of admitted patients 
has increased, this percentage of those progressing to severe disease is likely higher. 
The mortality rate of those requiring mechanical ventilation has been reported as 50-80% 
[1] including recent data reported from New York City. Risk factors for severe disease and 
death include older age, diabetes mellitus, hypertension, cardiac disease, and chronic 
obstructive pulmonary disease. As was reported for both SARS-CoV and MERS-CoV, the 
fatality rate in men exceeds that for women.  
Pulmonary disease associated with SARS-CoV-2 infection is characterized by a marked 
inflammatory component that was not described for either SARS-CoV or MERS-CoV. In 
fact, at presentation, minimally symptomatic patients may present with marked interstitial 
inflammatory changes on chest radiography presenting as “white-out” as described by 
colleagues treating infected patients in Seoul, Korea. Of interest, a similar presentation 
of severe pulmonary inflammatory disease despite a relatively low level of virus has been 
observed in ferrets). This inflammatory pneumonitis has been ascribed inflammatory 

 
 
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cytokine release. related to the release of multiple cytokines including TNFα, IL-1β, IL-6 
and can lead to capillary leakage, hypotension, and myocardial dysfunction.  
Treatment with anti-IL-6 monoclonal antibodies (mAb) such as tocilizumab or siltuximab 
for severe SARS-CoV-2 infection. Although anti-IL-6 mAbs appeared to be potentially 
beneficial, later studies did not bear this out. Moreover, anti-IL-6 mAbs are parenterally 
administered, difficult and expensive to manufacture, and are associated with potential 
serious adverse events including severe hypersensitivity and risk for opportunistic 
infection. A recent report provides critical insights as to why treatment directed against a 
single cytokine may be insufficient finding that the inflammatory effects were related to 
combinations of cytokines, especially TNFα plus IFNγ, whereas individual cytokines were 
not pathogenic [2].  
GLS-1027 is an oral medication with high bioavailability that has inhibitory activity against 
multiple inflammatory cytokines including IL-6, IL-1β, TNFα, IL-17, and IL-23 and 
decreases Th17 T cell activity. As reviewed below, in pre-clinical studies, GLS-1027 is as 
potent in preventing inflammatory changes as dexamethasone. GLS-1027 is being 
assessed for the prevention of progression of severe respiratory disease among patients 
admitted to the hospital with documented SARS-CoV-2 infection and who require 
supplemental oxygen. The hypothesis being tested is whether daily oral treatment of 
GLS-1027 for those admitted to hospital at WHO COVID-19 Classification level of 3 or 4 
will significantly reduce the number of SARS-CoV-2 infected patients who fail treatment. 
Pre-clinical and clinical experience with GLS-1027 are presented in the sections below.  
1.1.1 Pre-clinical experience with GLS-1027 
There is extensive literature regarding the use of GLS-1027 in either in vitro or in vivo 
animal models of inflammatory and autoimmune diseases with greater than 25 papers 
published by more than 15 groups of investigators. In the scientific literature, the GLS-
1027 molecule is also known as VGX-1027 or GIT-27. For simplicity, the summaries 
below will only use the designation of GLS-1027. Those papers relevant to this study are 
presented in detail below. 
In vitro, GLS-1027 was shown to prevent development of carragenen-induced pleuritis in 
mice with treatment effects similar to a monoclonal antibody against TNFα [3] and was 
equal to dexamethasone to prevent the development of collagen-induced arthritis [3] in 
mice and to prevent LPS-induced uveitis in rats [4]. The therapeutic effect of GLS-1027 
correlated with inhibition of IL-1β, IL-6, and TNFα.  
Unpublished data have also shown that GLS-1027 can successfully treat dogs with 
steroid-resistant autoimmune uveitis.  
Of note, dexamethasone is the only treatment that has prevented progression of COVID-
19 disease that has borne the test of time.  
 
1.1.1.1. GLS-1027 protects mice from LPS-induced acute lung injury 
Zhang et al. studied a model of lipopolysaccharide (LPS) induced acute lung injury in 
mice [5]. Following intranasal infusion of 10 μg of LPS mice were treated intraperitoneally 
an hour later with either atractylenolide I at doses of 5, 10, or 20 mg/kg or GLS-1027 at 
0.5 mg/mouse (approximately 20 mg/kg).  

 
 
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Figure 1.1.1.1-1: Pulmonary LPS-induced inflammation is inhibited by GLS-1027 
Effects of AO-I on histopathological changes in lung tissues in LPS-induced ALI mice. Mice were given an 
intraperitoneal injection of AO-I (5,10 and 20 mg/kg) 1h after administration of LPS. Lungs tissues from each 
experimental group were processed for histological evaluation at 6h after LPS challenge. Representative histological 
changes of lung obtained from mice of different groups. A:Control group, B:LPS group, C:LPS + AO-I (5mg/kg) group, 
D:LPS +A O-I (10mg/kg) group, E:LPS + AO-I (20mg/kg) group, F: LPS + VGX-1027 (0.5mg/mouse) (Hematoxylin and 
eosin staining, magnification 200). 
As shown in Figure 1.1.1.1-1 (Fig 1 from paper), compared to control untreated mice 
(Panel A), LPS induced significant inflammatory changes with thickened interstitial 
membranes and small alveolar spaces. Whereas atractylenolide showed a dose-related 
effect with near-normal lung histology at the highest dose (Panel E), animals treated with 
GLS-1027 had normal lung histology (Panel F). GLS-1027 treatment was also associated 
with significant decreases in neutrophil and macrophage influx into the lungs relative to 
LPS. Importantly, the anti-inflammatory effect of GLS-1027 was associated with 
significantly lower levels of IL-6, IL-13, TNFα, and IL-1β (Figure 1.1.1.1-2 panels A-D 
respectively, called VGX-1027 in Fig 5 from paper). The inflammatory changes related to 

 
 
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SARS-CoV-2 infection are expected to mirror the pathogenesis of LPS induced lung injury 
demonstrating a potential benefit of GLS-1027 treatment.  
 
 
 
 
 
Figure 1.1.1.1-2: Pulmonary LPS-induced inflammation is inhibited by GLS-1027 Effects of AO-I and GLS(VGX)-
1027 on TNF-α, IL-6, IL-1β, IL-10, IL-13, and MIF production in the BALF of LPS-induced ALI mice. BALF was collected 
a t 6 h following LPS challenge to analyze the inflammatory cytokines TNF-α, IL-6, IL-1β, IL-10, IL-13 and MIF. The 
values presented are mean +- S.D. (n = 12 in each analysis) of three independent experiments. P# <0.01 vs control 
group, P* < 0.05, P** < 0.01 vs LPS group. 
 
1.1.1.2. Lung inflammation induced by PM2.5 particulates is prevented by GLS-1027; 
Potential role for particulate enhancement of SARS-CoV and SARS-CoV-2 
related disease 
Xu et al. examined whether GLS-1027 could prevent PM2.5 particulate induced lung 
inflammation [6]. The deleterious pulmonary effects of air pollution are associated with fine 
particular matter of a size less than 2.5 μm, referred to as PM2.5, which leads to multiple 
respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), 
and lung cancer.  
A 
B 
C 
D 

 
 
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Mice pretreated with GLS-1027 (25 mg/kg given intraperitoneally) were exposed to PM2.5 
particulates (7.8 mg/kg) over two consecutive days. Whereas PM2.5 exposed, untreated 
mice developed significant inflammatory changes in the lungs and bronchi consisting of 
infiltration of mononuclear cells and thickened alveoli, PM2.5 exposed, GLS-1027 treated 
animals did not akin to PBS treated controls. Bronchoalveolar lavage fluid demonstrated 
that alveolar inflammation was associated with marked increases in TNFα, IL-1β, and IL-
6; increases blocked by GLS-1027 as correlated with mRNA transcriptional reductions 
(Figure 1.1.1.2-1, Fig 3 from paper).  
 
Figure 1.1.1.2-1: GLS-1027 inhibits PM2.5 induced inflammatory cytokine expression Effect of PM 2.5 (7.8 mg/kg) 
exposure and of VGX-1027 (25 mg/kg) pretreatment on individual and mean levels of TNF-α (A), IL-1β (B) and IL-6 (C) 
in bronchoalveolar lavage (BAL) fluid. *P < 0.05, **P < 0.01, ***P < 0.001 compared with PBS-pretreated PM2.5-instilled 
mice 
The therapeutic effect of GLS-1027 in PM2.5 exposed mice yielded lower pulmonary 
inflammation scores (Figure 1.1.1.2-2, panel A; VGX-1027 in Fig 4E from paper). 
Moreover, GLS-1027 treatment lowers PM2.5 induced airway resistance (Figure 1.1.1.2-
2, panel B; VGX-1027 in Fig 1C from paper) – a factor that is a critical determinant in 
being able to effectively oxygenate persons after airway intubation. GLS-1027 also 
reduced levels of IL-18, caspase-1 and NLRP3 inflammasome mRNA.  
A.
B.
C

 
 
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Figure 1.1.1.2-2: GLS-1027 lowers PM2.5 induced lung inflammation and airway resistance Effect of PM2.5 (7.8 
mg/kg) exposure and of VGX-1027 (25 mg/kg) pretreatment on lung inflammation (A) and airway resistance (B). A. 
Individual and mean values of inflammation scores measured from H&E-stained sections. *P<0.05, **P<0.01, 
***P<0.001 compared with PBS-pretreated PM2.5-instilled mice. B. Individual and mean airway resistance at 256 mg/mL. 
*P<0.05, **P<0.01, ***P<0.001 compared with PBS-pretreated PM2.5-instilled mice. 
 
1.1.1.3. Particulate exposure is associated with increased mortality SARS-CoV and 
SARS-CoV-2 
Lung pollution has also been associated with greater morbidity and mortality with severe 
coronavirus infection. Cui et al. examined the mortality during the 2002-2003 SARS-CoV 
epidemic in China [7]. They found a 2-fold increase in mortality between regions 
experiencing either short-term or long-term exposure to environmental particulates 
yielding an air pollution index > 100 relative to an index < 75. Moreover, analysis of 
Chinese provinces reveals a near linear relationship (R2 = 0.86) between air pollution 
index and SARS-CoV case fatality rate (Figure 1.1.1.3-1; Fig. 1 from paper). A similar 
association is being anecdotally reported for SARS-CoV-2 infection and has been 
postulated by many as a risk factor for greater mortality.  
A.
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Figure 1.1.1.3-1: SARS-CoV case-fatality relative to provincial air pollution index The correlation and 
association between short-term exposure to ambient air pollution and case fatality of SARS in People's Republic of 
China.  
The data showing that GLS-1027 reduces airway inflammation related to PM2.5 air 
pollution provides a potential second important anti-inflammatory effect of GLS-1027 that 
may be associated with lower progression to severe pulmonary disease. Moreover, the 
fact that PM2.5 exposure was associated with greater airway resistance, an effect blocked 
by GLS-1027 in mice, raises the possibility that, for those individuals who progress to 
requiring mechanical ventilation, continued GLS-1027 treatment may increase ventilatory 
effectiveness and possibly reduce the level of positive end-expiratory pressure (PEEP) 
required to maintain oxygenation status. Note, that in general, higher levels of PEEP are 
considered as a negative prognostic factor for survival. Thus, an additional exploratory 
goal of this study will be to determine whether those patients who do progress to 
intubation and mechanical ventilation differ in the level of PEEP required relative to 
treatment group. 
  
1.1.1.4. Biomaterial induced thrombosis is TLR2/4 mediated  
Langadec et al. investigated the pathogenesis of biomaterial induced thrombosis [8]. 
Some observations from this study have relevance to the use of GLS-1027 in SARS-CoV-
2 disease. The study showed that pathogenesis of thrombogenesis was initiated through 
a classic inflammatory response involving NF-κB translocation resulting in induction of 
TNFα and pro-IL-1β release, the latter then cleaved to IL-1β through caspase-1 cleavage. 
In addition, there is formation of the NLRP3 inflammasome that together with the 
inflammatory cytokines IL-1β, IL-6, and IL-18 serves as the initial triggering mechanism 
to start a thrombotic response. The investigators demonstrated the critical role of IL-6 in 
this process and demonstrated that GLS-1027 was able to effectively block the initiating 
inflammatory cytokine IL-1B and IL-6 activation pathways.  
It is of interest that there have been a large number of recent reports of relatively healthy, 
young patients presenting with SARS-CoV-2 infection complicated by intracerebral and 

 
 
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peripheral arterial thromboses resulting in stroke (including fatal strokes) and vascular 
compromise leading to amputation of legs and myocardial infarction.  
Whether the thrombotic complications associated with SARS-CoV-2 infection are related 
to an inflammatory priming event is, as yet, unknown. However, should such a 
mechanism ultimately be proven, it provides yet another inflammatory complication of 
SARS-CoV-2 infection that may be benefitted by GLS-1027. Thus, this study as an 
exploratory goal will additionally determine whether thrombotic complications differ 
relative to treatment group.   
1.1.1.5. GLS-1027 inhibits IL-6 mediated neuroinflammation in TBI and autism 
models  
Additional studies documented the ability of GLS-1027 to inhibit IL-6, IL-1β, and TNFα in 
neuroinflammatory models.  
The study by Laird et al. investigated the role of GLS-1027 to reduce cerebral edema and 
neuroinflammation following traumatic brain injury (TBI) [9]. In this study, the investigators 
found that high mobility group box protein-1 (HMGB1) is released from damaged neurons 
following traumatic brain injury in mice. HMGB1 in turn activates TLR4 on microglial cells 
and induces release of aquaporin-4, a water channel, that results in cerebral edema. This 
pathway is IL-6 mediated and was blocked by pharmacologic treatment of mice with GLS-
1027. Thus, a common secondary complication of increased cerebral edema that can 
occur following cerebral thrombosis and stroke may additionally be benefitted by 
treatment with GLS-1027. Since vascular complications are considered to be seen in a 
minority of study subjects, with stroke representing only a subset of patients, any potential 
treatment effects of GLS-1027 in preventing or ameliorating cerebral edema will be 
observed and catalogued but will not be included as an exploratory aim of the study. 
Should such complications be observed then they will be catalogued as part of the Clinical 
Study Report (CSR) and published with clinical trial results.  
Ahmad et al. studied the effect of GLS-1027 on neuroinflammation in BTPR Itpr3tf/J mice, 
a model of human autism [10]. As with other studies, GLS-1027 was observed to down-
regulate inflammatory cytokines IL-1β, IL-6, and TNFα in peripheral mononuclear cells. 
Of note, GLS-1027 was also able to down regulate the same inflammatory response in 
neural tissue, confirming that the drug was able to penetrate the blood brain barrier and 
limit neuroinflammation.  
1.1.2 Human experience with GLS-1027 
GLS-1027 has completed two Phase I safety and pharmacodynamic studies: CAT-001 
(NCT00627120) and CAT-002 (NCT00760396). The compound was then called VGX-
1027. Both human clinical studies, as well as pre-clinical pharmacokinetic (PK) studies, 
were published together in 2016 by Lee et al. [11]. More detailed information regarding 
these clinical trials is presented in the GLS-1027 Investigator’s Brochure.  
CAT-001 was a single-ascending dose study of GLS-1027. Six subjects each received 
single doses of drug at 0, 1, 10, 100, 200, 400, and 800 mg in a fasted state with 72-96 
hours between administration of successive doses. An additional sub-study was 
conducted to determine PK of a 100 mg dose given in a fasted or fed state. CAT-002 was 
a multiple-ascending dose study of GLS-1027 administered at doses of either 0, 40, 100, 

 
 
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200 mg daily, or 200 mg twice daily over a 5-day period. Adverse events and PK were 
assessed during the trial.  
Overall, in the multiple ascending dose study, 15 of the 40 subjects experienced one or 
more adverse events. Among those receiving study drug, grade 1 hypertension was 
observed in 4 subjects at each of the three highest doses of 100, 200, and 200 mg BID. 
Each of these subjects had borderline elevations in systolic blood pressure (>145). 
Additionally, two subjects in the single ascending dose study (100, 200 mg) experienced 
neutropenia. Both subjects were of African American ethnicity and had low baseline 
neutrophil counts. Headache was observed in two individuals in the multiple dose study 
(200, 200 mg BID). Hypersomnia was observed in two individuals in the single dose study 
who received 10 mg of GLS-1027, however, it was also observed in two placebo subjects 
in the single dose study.  
The pharmacokinetic profile of GLS-1027 showed proportionate increases in peak serum 
concentration and AUC relative to dose with normalized Cmax of approximately 60 μg/L/mg 
and normalized AUC of 450-500 μg-hr/L/mg. Serum Cmax and AUC was increased by a 
factor of approximately 1.4-1.5 in the fed state. The serum half-life was approximately 7 
hours with no drug accumulation observed over the 5-day period at any dose level. Drug 
was highly bioavailable with 90% excreted unchanged in the urine. Separate pre-clinical 
toxicology studies showed no evidence of hepatic metabolism or interaction with the 
cytochrome P450 enzymes.   
GLS-1027 was safe and well-tolerated in these two Phase I studies with a PK profile that 
demonstrated high bioavailability, renal excretion, and pharmacodynamics that support 
daily dosing.  
1.2 
Investigational Agent 
GLS-1027, the therapeutic agent in this study, is an isoxazole compound. The structure 
of GLS-1027, [S,R]-3-phenyl-4,5-dihydro-isoxazoleacetic acid, is shown below (Figure 
1.2-1). 
Microcrystalline cellulose will be used as the placebo in this study. The structure of 
microcrystalline cellulose is shown below (Figure 1.2-2). 
                                          
 
   
 
Figure 1.2-1: Structure of GLS-1027 
 

 
 
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Figure 1.2-2: Structure of microcrystalline cellulose 
 
1.3 
Dose and Regimen Rationale  
The doses of GLS-1027 used in this clinical trial are 120 mg or 360 mg given orally once 
daily. Pre-clinical studies have found that the effective dose in mice of 20 mg/kg would 
correlate to a human dose of 1.626 mg/kg, or 113 mg for a 70 kg person. This study will 
assess doses of 120 mg and 360 mg given in the fasting state to determine whether there 
is a dose effect. Treatment will commence on the day of enrollment (or the following day 
if drug administration would be after 10 pm) and then once daily, given with daily AM 
medications through the period of hospitalization to a maximum treatment period of 28 
days.  
1.4 
Risk/Benefit Assessment 
In accordance with the International Conference on Harmonization (ICH), this study has 
been designed to minimize the risk to study participants. The potential benefit of treatment 
is to reduce the incidence of progression to severe disease is consistent with the known 
risks and adverse events known to occur with GLS-1027. Since patients will be monitored 
in an in-patient setting, daily changes in clinical status can be assessed and changes to 
drug regimens made as clinically indicated.  
GLS-1027 has been well tolerated in Phase I clinical studies. The doses chosen conform 
to those already studied and known to be tolerated. The maximal dose level is below the 
800 mg/day maximal dose in the single ascending dose study (CAT-001) or the 400 
mg/day maximal dose in the multiple ascending dose study (CAT-002).  
An initial PK assessment of GLS-1027 will be conducted for the initial 15 enrollees. For 
all subjects, trough dosing will be assessed throughout the study. Modifications to drug 
dosing will be made based on changes in renal function as warranted, as described in 
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2. 
HYPOTHESIS AND STUDY OBJECTIVES 
2.1 
Hypothesis 
GLS-1027 will be safe, well tolerated and, for those admitted to hospital with PCR 
confirmed SARS-CoV-2 infection at WHO COVID-19 classification level of 3 or 4, will 
reduce likelihood for progression to WHO COVID-19 classification level of 6 or greater 
(defined as severe pneumonitis characterized by the need for intubation with mechanical 
ventilation, initiation of ECMO, or death) or need for salvage treatment started 72 hours 
after study entry with either an IL-6 monoclonal antibody or dexamethasone at a dose of 
≥ 6 mg/day. 
2.2 
Primary Objectives and Outcome Variables 
 Incidence of serious adverse events relative to treatment group 
 Incidence of treatment failure within 28 days from enrollment 
2.3 
Exploratory Objectives 
 Assess the number of days requiring ICU care relative to treatment group 
 Assess the number of days of mechanical ventilation relative to treatment group 
 Assess incidence of WHO COVID-19 Classification levels relative to baseline 
serum IL-6 level 
 Assess incidence of WHO COVID-19 Classification levels relative to baseline 
serum ferritin level 
 Assess incidence of WHO COVID-19 Classification levels relative to baseline 
CRP  
 Assess trough level of GLS-1027 relative to serum creatinine 
 Assess the maximal level of Positive End-Expiratory Pressure (PEEP) for 
subjects who are intubated relative to treatment group.  
 Assess the number of days of PEEP > 5 cm H2O for subjects who are intubated 
relative to treatment group 
 Incidence of progression to  WHO COVID-19 Classification level 6, or 7, or 8 
(individually) 
 
Assess SARS-CoV-2 IgM antibody responses relative to treatment group 
3. 
STUDY DESIGN 
This is a Phase II, randomized, double-blind, placebo-controlled study to assess 2 dose 
levels of GLS-1027 for the prevention of treatment failure among participants admitted to 
hospital with PCR confirmed infection with SARS-CoV-2 (WHO classification 3 or 4). The 
enrollment period will extend to 72 hours from hospital admission. 
 
Participants will be randomized to placebo or GLS-1027 at either 120 mg or 360 mg daily 
in a 1:1:1 ratio as adjunctive to standard of care based on the hospital COVID-19 
treatment algorithm and/or local COVID-19 treatment practices. Participants will be 
administered study drug for a maximum treatment period of 28 days or until discharge or 

 
 
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death, whichever comes first. Follow-up will continue through to Day 56 to document AEs 
and outcome as to discharge, death, or WHO COVID-19 classification level if subject 
remains hospitalized.  
3.1 
Safety Monitoring 
Participants will be monitored by hospital personnel as per protocol. Clinical adverse 
events (AEs) will be reviewed daily through to discharge or the end of the treatment 
period. Safety monitoring will also include laboratory assessment of hematology, 
chemistry and ECG as per the Schedule of Events. Serum trough levels of GLS-1027 will 
be assessed at select times throughout the trial as per the Schedule of Events. 
Participants will also be followed for up to 56 days post-enrollments for health status and 
adverse events. 
3.2 
Data and Safety Monitoring Board (DSMB) 
In addition to internal monitoring of safety data by the site PI and medical monitor, an 
independent data and safety monitoring board (DSMB), consisting of expert members not 
related to the clinical trial or sponsor staff will provide safety oversight. The DSMB will 
include at a minimum three members: a physician specializing in either Infectious Disease 
or Pulmonary / Critical Care, a second health-care practitioner who may be a physician, 
and someone with statistical experience (physician or non-physician).  
The DSMB will meet at the start of the clinical trial to review and finalize the DSMB charter. 
At a minimum, the DSMB will meet to review interim data when 50% of the target enrollees 
(66 subjects) have completed the primary observation period to discharge, death, 
discontinuation or 28 days of treatment. The DSMB will review safety data and outcomes 
for enrolled subjects in a blinded manner. Unless a safety signal has been encountered, 
enrollment will continue through to at least 44 per group (total N=132).  
A summary of all AEs and SAEs will be provided to the DSMB as masked treatment 
groups by an independent statistician together with a summary rates of retention in the 
study, and other relevant events. Reports will include a summary of participants’ baseline 
characteristics, early study discontinuations, and a summary of participants who reach 
primary endpoint and/or end of study follow-up. The DSMB may recommend corrective 
measures, up to termination of the study for safety concerns. Study termination can be 
implemented by the Project PI, FDA, Sponsor, or site-specific or other supervising IRBs. 
Conference call or video conference meetings are allowed as necessary.  
Additional details can be found in the DSMB Charter. 
4. 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
4.1 
Recruitment of Participants 
4.2 
Inclusion Criteria for enrollment 
1. Age 18 years or older 
2. Able to provide informed consent  
3. Able and willing to comply with study procedures 
4. Enrollment within 72 hrs of hospitalization with a diagnosis of PCR confirmed SARS-
CoV-2 infection 
5. WHO COVID-19 classification level of 3 or 4  

 
 
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4.3 
Exclusion Criteria for enrollment 
1. Pregnant or lactating 
2. SpO2 less than 90% on room air or less than 95% on supplemental oxygen 
3. Calculated GFR < 60 (Cockcroft-Gault)  
4. Meets hospital treatment algorithm for treatment with dexamethasone at a dose of 6 
mg/day for a 10 day course. A single bolus dose of 6 mg of dexamethasone given in the 
Emergency Department and continued at a dose of ≤ 3.5 mg/day or less is allowed. 
5. Meets treatment algorithm criteria for treatment with toclizumab or other anti-IL-6 agent 
6. Treatment with an anti-IL-6 inhibitor, anti-IL-1 inhibitor, anti-TNF monoclonal antibody, or 
anti-JAK inhibitor (see Appendix A for exclusionary period for individual drugs)  
7. Participation in a COVID-19 clinical trial that includes prescription of a drug with anti-
cytokine activity 
8. Treatment within the past 60 days with a chemotherapeutic agent 
9. Current outpatient treatment with systemic corticosteroids at a dose equivalent of 20 
mg/day or greater of prednisone or prednisolone, 16 mg/day or greater of 
methylprednisolone 
10. Diagnosis of leukemia or lymphoma  
11. WHO COVID-19 classification level of 5 or greater (use of high-flow oxygen, non-
mechanical ventilation such as CPAP, mechanical ventilation)  
4.4 
Discontinuation/Withdrawal of Study Participants 
The Informed Consent will require that subjects allow follow-up for the primary outcome 
and safety through to 56 days post-enrollment or death. A subject may withdraw from the 
study by withdrawing consent to continue participation.  If a subject withdraws consent 
from participating in the study at any time after enrollment, but prior to the final scheduled 
study visit, the investigator will make every effort to have the participant complete all 
assessments at the time of withdrawal. All data collected up to the time of withdrawal will 
be used for data analyses. The request to withdraw consent must be documented.   
 
Discontinuing treatment is not a reason for withdrawing from participating in the study.  
Subjects who discontinue treatment for any reason should be followed until 56 days post-
enrollment or death, whichever comes first. 
 
Reasons for treatment discontinuation are defined below.  
 The PI or Medical Monitor consider that continuation of treatment may pose a 
safety risk to the subject.  Treatment discontinuation will be considered a treatment 
failure, unless the subject discontinues treatment due to pregnancy or renal 
insufficiency. The subject should however continue to be monitored as per protocol 
for outcome measures through to study end (Day 56). 
 Adverse event (Adverse Reaction): clinical or laboratory events that in the medical 
judgement of the investigator are grounds for discontinuation of treatment. This will 
be considered as a treatment failure. Subjects should however continue to be 
monitored as per protocol for outcome measures through to study end (Day 56).  
 Lost to follow-up: for subjects who are discharged from the hospital within 28 days 
of treatment initiation who cannot be contacted after multiple attempts, will be 

 
 
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considered as Lost to Follow-up for purposes of Long-term outcomes (56 days). 
Otherwise, without relapse of COVID-19 symptoms, discharge within 28 days of 
enrollment is considered a treatment success. For subjects who are discharged 
from the hospital, every effort should be made to contact the subject to determine 
clinical status and adverse events post-discharge. 
 
Transfer of subject to another hospital.  All transfers will be considered treatment 
failures. 
 
 
4.5 
Treatment with dexamethasone post-enrollment  
Treatment with dexamethasone at a dose of 6 mg/day for 10 days is currently considered 
as part of the standard of care for COVID-19 at many institutions, however, the specifics 
of treatment and whether such treatment is formally algorithm based varies between 
institutions. Moreover, it is recognized that dexamethasone treatment may be ordered as 
part of clinical care for some subjects after enrollment into the study.    
Enrollment into the study is allowed for individuals who have not been treated with 
dexamethasone since hospital admission. Enrollment into the study is also allowed for 
those have received a single bolus dose of 6 mg of dexamethasone at presentation to the 
hospital with or without continuation of dexamethasone at a dose of 3.5 mg/day or less.  
Enrolled subjects for whom dexamethasone is initiated within 72 hours of the time of 1st 
dose of study drug will be considered to have required dexamethasone at the time of 
presentation to hospital and will be treated the same as those who received a single bolus 
dose of 6 mg at presentation to the hospital. Unless dexamethasone is prescribed for 10 
days at 6 mg, sSuch subjects will not be considered to have met the definition of the need 
for salvage therapy, and will not be considered as meeting a study endpoint for failure.  
Enrolled subjects for whom dexamethasone is ordered at a dose of ≥ 6 mg per day and 
is initiated 72 hours or later after the 1st dose of study drug will be considered to have met 
the definition of need for salvage therapy and thus have met a study endpoint for failure. 
Initiation of treatment with dexamethasone at a dose of less than 6 mg/day after 
enrollment in the study will not be considered as treatment failure.  
 
Subjects will be subgrouped for summary by concomitant bolus dexamethasone within 
72 hours of enrollment versus no concomitant dexamethasone with 72 hours of 
enrollment.  
5. 
STUDY PRODUCT 
5.1 
Investigational Product 
GLS-1027 is a small molecule with a chemical structure as shown in Figure 1.2-1 and has 
a molecular weight of 205.21 g/mol. GLS-1027 will be formulated in capsules at a dose 
of 120 mg per capsule. 

 
 
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Microcrystalline cellulose, the placebo used in this study, has a chemical structure as 
shown in Figure 1.2-2 and has a molecular weight of 658.7 g/mol. Microcrystalline 
cellulose will be formulated in capsules at a dose of 105 mg per capsule. 
5.2 
Packaging and Labeling  
GLS-1027 will be supplied to the investigational pharmacy in bottles of 50 capsules, while 
the placebo will be supplied in bottles of 100 capsules. Drug will be dispensed by 
pharmacy personnel to study participants as part of daily medication dispensing to 
maintain blinding of other study personnel.  
Drug product vial label is shown below in Table 5.2-1.  
 
Table 5.2-1. GLS-1027 and Placebo drug product vial labels 
GLS-1027 
PLACEBO 
GLS-1027 Capsules, 120 mg   
Protocol No. GLS27-005 
Lot No. xxxx 
Quantity: 50 capsules 
(Caution New Drug Limited by Federal (United States) 
Law to Investigational Use 
Keep out of reach from children: Take as directed 
Store at 25ºC (77°F) excursion permitted to 15°-30°C 
(56° - 86°F) 
Sponsor: GeneOne Life Science 
Mfd by CoreRx Inc., 14205 Myerlake Circle, 
Clearwater FL 33760 
 
 
Placebo Capsules, 105 mg   
Protocol No. GLS27-005 
Lot No. xxxx 
Quantity: 100 capsules 
(Caution New Drug Limited by Federal (United States) 
Law to Investigational Use 
Keep out of reach from children: Take as directed 
Store at 25ºC (77°F) excursion permitted to 15°-30°C 
(56° - 86°F) 
Sponsor: GeneOne Life Science 
Mfd by CoreRx Inc., 14205 Myerlake Circle, 
Clearwater FL 33760 
 
 
5.3 
Handling of Study Drug 
Study drug will be stored at 25°C (ambient temperature, range  15°C to 30°C) in the 
hospital Investigational Drug Service. Investigational product must be stored in a secure 
area according to local regulations.  
5.4 
Dispensing of Study Drug 
Pharmacy service will provide 3 capsules per day (GLS-1027 or matching placebo) based 
on randomization assignment. The randomization treatment code will be provided to the 
site pharmacists from a web-based system. How to access the randomization system is 
covered in a separate Pharmacy Manual. It is the responsibility of the Investigators that 
study drug is dispensed only to study participants by hospital nursing personnel. 
Authorized personnel are the only ones to dispense product according to local regulation 
and study specific Delegation Log. Study drug administration is to be discontinued for 
periods when subject either has an eGFR < 60 mL/min/1.73 m2, is unable to take 
medications orally, or reaches a study endpoint (WHO COVID-19 classification of 6 or 
greater).  
5.5 
Precautions with Investigational Medicinal Product 
Medication should not be taken by children or anyone outside of the current clinical trial.  
5.6 
Preparation of Investigational Product 
No preparation of Investigational Product is required.   

 
 
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5.7 
Record of Investigational Product Disposition at Site 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product disposition is maintained at each study site where investigational product is 
inventoried and disposed. Investigational Pharmacy and/or Hospital Pharmacy records or 
logs must comply with applicable regulations and guidelines. 
5.8 
Return and Destruction of Investigational Product 
Remaining study drug at the hospital investigational drug service will be returned to 
GeneOne Life Science accompanied with relevant return log(s).  
6. 
STUDY PROCEDURES AND TREATMENTS 
6.1 
Procedures by Visit (also see Table S2) 
6.1.1 Day 1: Review Study and Eligibility Criteria; Obtain Informed Consent, Enrollment  
Subjects will be recruited and Study staff will review the protocol with the prospective 
participant and obtain written informed consent. One copy of the informed consent form 
(ICF) will be maintained with the investigative team, and the other given to the participant. 
Study procedures that will be completed include:  
 Document review of ICF process and that copy was provided to participant 
 Review and record medical history, demographics  
 Review concomitant medications 
 Record physical exam, height, weight, vital signs from medical record 
 Record baseline ECG 
 Record COVID-19 PCR result 
 Record baseline CBC and Basic Metabolic Profile (BMP), liver function tests 
(LFTs), CRP, IL-6, troponin, D-dimer, procalcitonin, admission CXR  
 Determine and record baseline WHO COVID-19 Classification (Appendix B)  
 Record whether participant is prescribed supplemental nasal O2 and flow rate or 
O2 via facemask and Fi O2 
 Perform urine pregnancy test if person is of child-bearing potential 
 Collect blood for CPK and GGT 
 Alert Pharmacy to enrollment to direct administration of study drug per 
randomization (if drug administration would occur after 10 pm, then start study drug 
on Day 2) 
 Collect serum and PBMCs as indicated in the Schedule of Events 
6.1.2 Day 2 (PK sub-study participants ONLY) 
 For the 15 persons enrolled, additional blood samples (5 ml) will be collected as 
follows  
o Pre-Dose 
o Post-Dose 1, 2, 4, 8 hr 
6.1.3 Day 2 through 29 (or until discharge or death) 
 
Administer study drug with AM medications if calculated creatinine clearance is ≥ 60.  
 
Determine and record WHO COVID-19 classification level (Appendix B) 

 
 
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 
Review new concomitant medications 
 
Record past 24 hour maximal and minimal temperature (°C), respiratory rate, heart rate, 
systolic and diastolic BP  
 
Record potential co-morbid complications of SARS-CoV-2 infection to include shortness 
of breath, arterial thrombosis (myocardial infarction, stroke, peripheral blood clot), mental 
confusion, death 
 
Record adverse effects 
 
Collect and Record labs as indicated in the Schedule of Events: CBC, BMP, LFTs, CRP, 
ferritin, D-dimer, CPK, IL-6 
 
Record if care given in ICU setting 
 
Record ventilatory status: O2 use, CPAP use, ventilator, ECMO 
 
Record O2 flow rate, FiO2 % (if intubated), CPAP pressure (as relevant), PEEP setting (as 
relevant) 
 
Perform ECG (12 lead) on day 2 at 75-90 minutes post dose, and on day 15 ± 2 days 
 
Collect serum for CPK and GGT (Day 7) and, if abnormal, then weekly until values 
normalize  
 
Collect blood for plasma for GLS-1027 trough measurement as indicated in the Schedule 
of Events 
 
Collect blood for serum and PBMCs as indicated in the Schedule of Events 
 
Pharmacy to review patient creatinine and calculated creatinine clearance daily.  
6.1.4 Day 56  
 
Review medical record to document date of discharge or death, as relevant 
 
Determine and record WHO COVID-19 classification level (Day 56) 
 
If hospitalized, review chart to document intercurrent AEs 
 
If not hospitalized, query participant to document intercurrent AE’s from the end of the 
primary study period 
6.2 
Timing and Evaluations 
6.2.1 Informed Consent (Day 1) 
Study personnel will meet with prospective study participants, explain the study, and 
provide them with an informed consent form (ICF) that describes the eligibility criteria for 
entering the study, study treatments, randomization, and follow-up procedures. An 
informed consent must be signed prior to any study related procedures being performed. 
A copy of the signed and dated consent form will be given to the participant.  
6.2.2 Enrollment (Day 1) 
Participants who consent to be in the study will be assigned a unique participant 
identification designation number (PID#). PID#’s consist of a 3 digit site code followed by 
a 3-digit subject number. Subject numbers are assigned in numerical order of enrollment 
(i.e., 1st subject is assigned XXX-001, 2nd subject is assigned XXX-002 with XXX a 
placeholder for the site number). Once assigned, PID numbers cannot be reused for any 
reason. Information regarding participant’s PID# will also be documented on a screening 
log. Study personnel will alert pharmacy to enrollment for drug administration and review 
medical record for study related procedures.  
Medical History 

 
 
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Investigators should document all significant illnesses that the participant has 
experienced as Medical History in the last 6 months. Illnesses’ first occurring or detected 
during the study and/or worsening of an existing illness that occurs after the first 
administration of study drug are documented as AEs on the electronic case report form 
(eCRF).  
Prior and Concomitant medications 
Prior treatments, defined as administered up to 4 months prior to the time of enrollment 
with designation as to whether the drug was prescribed as an outpatient or only since 
admission, will be recorded in the eCRF as prior medications. Concomitant treatments, 
defined as continuing or new treatments taken at or after the signing of the informed 
consent, will be recorded in the eCRF as concomitant medications. 
Review and record baseline labs 
The medical record will be reviewed and labs from the day of enrollment recorded. Labs 
and evaluations such as procalcitonin, CXR, D-dimer, troponin will be recorded from the 
1st recorded instance in the medical record if not repeated through to the time of or on the 
day of enrollment.  
Determine and record WHO COVID-19 classification level 
Determine from the clinical record the WHO COVID-19 classification level (Appendix B) 
and record. This will be determined and recorded on a daily basis. 
Review and record oxygenation status 
Document that participant is prescribed nasal O2 and the flow rate.  
If mechanically ventilated, record level of PEEP and %FiO2 
Record if CPAP prescribed and expiratory pressure 
Record if given ECMO treatment 
Contact pharmacy for study drug administration 
Contact the investigational pharmacy regarding study recruitment for assignment of 
randomization code and to dispense study drug to inpatient ward.  
6.2.3 Safety Assessments 
6.2.3.1  
SARS-CoV-2 associated events 
The medical record will be reviewed daily for the occurrence of SARS-CoV-2 associated 
events, which include shortness of breath and arterial thrombosis (myocardial infarction, 
stroke, peripheral blood clot).  
6.2.3.2  
Adverse events 
The medical record will be reviewed daily for the occurrence of any adverse events, 
change in clinical status, or death. These will be graded as per the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0. 
6.2.3.3  
Vital Signs 
Vital signs will be recorded from the medical record daily to include maximal and minimal 
temperature (°C), respiratory rate, heart rate, and systolic and diastolic blood pressure.  
6.2.3.4  
Weight and Height 
Height and as listed in the medical record at the time of admission will be recorded at the 
time of enrollment.  

 
 
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6.2.3.5  
12-lead ECG 
The results of the participant’s baseline or first 12-lead ECG from the admission will be 
recorded. A repeat ECG will be performed on Day 2 at 75-90 minutes post-dose and Day 
15 of the study (± 2 days). 
6.2.3.6  
Laboratory Evaluations 
Laboratory evaluations to include CXR, CBC, biochemistries, CPK; and ferritin, CRP, IL-
6 (if ordered at site), D-dimer, and procalcitonin as available; are recorded as per the 
Schedule of Events.   
6.3 
Assessment of Laboratory Abnormalities 
Serum chemistries (complete metabolic panel) and complete blood count with differential 
blood count will be graded as noted in Section 7.1.  
6.4 
Assessment of Clinical Adverse Events 
The Investigator will grade clinical AEs (based on discussions with study participants) 
using the CTCAE v5.0.  
6.5 
Plasma for PK sub-study and/or trough level determination of GLS-1027  
Blood will be collected for plasma as per the Schedule of Events for measurement of 
trough concentrations of GLS-1027. The first 15 subjects are to be enrolled into a sub-
study to determine drug elimination of GLS-1027 in SARS-CoV-2 infected patients. 
6.6 
Serum and PBMCs for immunology assessments 
Serum and PBMCs are collected per the Schedule of Events to assess the effect of 
treatment on cytokine expression and serum levels, and STAT3 activation in PBMCs 
relative to treatment group.  
7. 
EVALUATION OF SAFTY AND MANAGEMENT OF TOXICITY 
7.1 
Safety Parameters 
7.1.1 Adverse Events (AEs) 
An AE (also referred to as an adverse experience) is defined as any unfavorable and 
unintended sign, symptom, or laboratory abnormality that is temporarily associated with 
the use of a drug or treatment and does not imply any judgement about causality. An 
adverse event can arise with any use of a drug or treatment regardless of route of 
administration, dose, and may be delayed after a drug or treatment has been 
discontinued. An adverse event is not the same as an “overdose”; an overdose is a dose-
related event specifically caused by exposure to an increased amount of drug.  
An unexpected AE is:  
• 
Not identified in the Investigator’s Brochure (IB) or otherwise not expected from the 
characteristics of the clinical material 
• 
Not listed at the specificity or severity that has been previously observed 
• 
Not specifically mentioned in the IB as known to occur with the particular drug under 
investigation, even though the adverse event may be known to occur with other drugs 
in the same pharmacologic class or with drugs that share pharmacologic properties 
with the study drug. 
Treatment emergent AEs (TEAE) include the following: 
• 
Post-treatment complications that occur as a result of protocol mandated procedure  

 
 
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• 
Any pre-existing condition that increases in severity, or changes in nature during or as 
a consequence of the study drug phase of a human clinical trial, will also be 
considered an AE 
• 
Complications and termination of pregnancy; see Section 7.1.8 for additional 
information.  
• 
Non-elective medical or surgical procedures  
Study related AEs do not include the following: 
• 
Expected complications or clinical consequences due to elective medical or surgical 
procedures 
• 
Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before study enrollment or prior to the first administration of study drug that do not 
worsen 
• 
Overdose of non-study drug  
• 
Incorrect or increased dose administration of study drug without adverse clinical 
sequelae 
• 
Any laboratory abnormality that is considered as non-significant  
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
7.1.2 Serious Adverse Events (SAEs) 
A SAE is any AE that meets one of the following conditions: 
 
Is immediately life-threatening (e.g., participant was, in the view of the Investigator, 
at immediate risk of death from the event as it occurred).  
 
Requires or prolongs hospitalization; 
 
Results in congenital anomaly or birth defect; 
 
Results in persistent or significant disability/incapacity; 
 
Is an important medical event that may not result in death or be life threatening, but 
based upon appropriate medical judgment, may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed above.  
 
Results in death 
Important medical events that do not result in death, are life-threatening, or require 
hospitalization may be considered as an SAE when, in the judgement of the Investigator, 
potentially jeopardize the study participant and may require medical or surgical 
intervention. 
SAE’s occurring up to and including the final study visit will be collected regardless of the 
Investigator’s opinion of causation.  
If an Investigator becomes aware of an SAE that has occurred after a participant has 
completed the study, the Investigator should report the SAE to the sponsor regardless of 
the Investigator’s opinion of causation. 
SAEs should be followed until resolution. The reporting period for SAEs is described in 
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7.1.3 Suspected Unexpected Serious Adverse Drug Reactions (SUSARs) 
A SUSAR is a serious adverse event not listed in the IB and that the PI identifies as 
related to study drug or procedure. 
7.1.4 Assessing Severity (Intensity) 
The Investigator will grade laboratory AEs and clinical AEs (based on discussions with 
study participants) using the NCI Common Terminology Criteria for Adverse Events v5.0: 
 Mild (Grade 1) 
 Moderate (Grade 2) 
 Severe (Grade 3) 
 Life-threatening consequences (Grade 4) 
 Death related to AE (Grade 5) 
Adverse events will be recorded on the eCRF at the severity reported by the investigator. 
If an ongoing AE worsens or increases in its severity or its relationship to the study drug 
changes, a new AE entry for the event should be entered on the eCRF. 
The following is a link to the grading scale: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf 
7.1.5 Causal Relationship of Investigational Product to Adverse Events 
A causally related AE is one judged to have a suspected relationship to the administration 
of the investigational agent. Conversely, an AE may also be assessed as not related to 
the investigational product. The Investigator is responsible for reporting adverse events 
and judging the relationship between the administration of the investigational product and 
an AE because the investigator is knowledgeable about the participant (e.g., medical 
history, concomitant medications), administers the investigational product, and monitors 
the participant’s response to the investigational product. The Sponsor will assess the 
overall safety of the investigational product and determine whether expedited reporting to 
regulatory agencies is indicated. 
Investigators should use their knowledge of the Study Participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to determine 
whether or not an adverse event is considered to be related to the study drug by the 
following criteria: 
• 
Related – the investigator considers that there is a causal relationship between the 
event and study drug; 
o Probably related – the Investigator considers that there is a probability of a causal 
relationship of the event to the study drug. Such events should be entered as 
“related” in the database  
o Possibly related – the investigator considers that there is a possible causal 
relationship of the event to the study drug. Such events should be entered as 
“related” in the database 
• 
Not related – the investigator considers that the event has no relationship to 
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The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to initiation of study drug; 
• 
Course of the event, discontinuation of study drug, or reintroduction of study drug 
(when applicable); 
• 
Known association of the event with the study drug or with similar treatments; 
• 
Known association of the event with the disease under study; 
• 
Presence of risk factors in the Study Participant or use of concomitant medications 
known to increase the occurrence of the event 
7.1.6 Abnormal Laboratory Values 
Laboratory abnormalities will be classified according to the CTCAE v5: 
7.1.7 Pregnancy During Study 
Pregnancy is an exclusion criterium for the study. If a participant is found to be pregnant 
at any time during the study after enrollment, then study medication will be immediately 
discontinued. Such participants are requested to remain in the study for continued 
observation and will be analyzed with regard to assigned study treatment.  Data on fetal 
outcome will be collected for regulatory reporting. Pregnant subjects will be assessed for 
efficacy endpoints in the same manner as all other subjects. 
7.1.8 Decreases in renal function during study 
Pharmacy will monitor patient’s renal function during the study. Study drug will be 
administered as per the assigned group for a calculated creatinine clearance ≥ 60. If the 
calculated creatinine clearance decreases below 60 then study drug will be discontinued 
until the eGFR is ≥ 60. Should study drug administration be interrupted due to a change 
in renal function, the total length of treatment is determined by the day of enrollment. The 
primary treatment period is still up to 28 days from enrollment and is not extended for 
days of interrupted therapy. Subjects with interrupted or discontinued treatment due to 
renal function, will be assessed for efficacy endpoints in the same manner as all other 
subjects. 
7.1.9 Post-study Reporting Requirements 
SAEs, including deaths, regardless of cause or relationship, must be reported to Sponsor 
at the time that such events become known to the Investigator. 
Investigators are not obligated to actively seek AEs or SAEs beyond the follow up period 
for participants. However, if the Investigator learns of an SAE that occurs within 30 days 
from completion or termination visit, the Investigator should promptly document and report 
the event to the study team and medical monitor. 
7.2 
Methods and Timing for Collection and Recording of Safety Data 
Participants will be queried daily as to adverse events that have occurred since the 
previous day and the current status of any AE that was reported at a prior visit that has 
not yet resolved. Additionally, labs and ECGs will be reviewed for safety.   

 
 
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All AEs, regardless of severity, seriousness, or presumed relationship to study treatment, 
must be recorded using medical terminology in source documents and on the eCRF. 
Whenever possible, a diagnosis will be documented, in lieu of symptoms. The source 
document and the eCRF must contain the Investigator’s opinion concerning the 
relationship of the AE to study treatment. 
AEs should be described with the following attributes: 
• 
Duration (start and end dates) 
• 
Seriousness 
• 
Severity 
• 
Causality 
• 
Action(s) taken 
• 
Outcome 
7.3 
Safety and Toxicity Management 
The Medical Monitor will be responsible for the overall safety monitoring of the study. The 
site Investigator will be responsible locally for safety.  
Safety assessments include the following: 
• 
Incidence of all adverse events classified by system organ class, preferred term, 
severity, and relationship to study treatment 
• 
Changes in safety laboratory parameters  
• 
Changes in ECGs 
• 
Other clinically significant changes in safety evaluations 
7.3.1 Events Requiring Expedited Reporting 
Events requiring expedited reporting (ERER) are defined as Adverse Events including: 
 Suspected or confirmed anaphylaxis or drug-related allergic reaction 
Sites will inform the Sponsor of any ERER within 24 hours to discuss whether dosing to 
the participant should continue. 
7.3.2 Reasons to Discontinue Treatment 
Discontinuation or interruption of study drug 
Study drug will be discontinued with any of the following:  
1. Diagnosis of pregnancy.  
2. Anaphylaxis or allergic reaction possibly related to study drug 
Study drug will be temporarily halted with any of the following:  
3. If the eGFR falls below 60 mL/min/1.73 m2 
4. If the patient is intubated and/or ECMO is initiated 
5. If oral administration is not possible 
6. For those with baseline serum bilirubin in the normal range: a serum bilirubin ≥ 5 times 
the upper limit of normal (ULN)  
7. For those with baseline serum bilirubin above the normal range: a serum bilirubin ≥ 10 
times the ULN 

 
 
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8. Transaminase (ALT or AST) elevation of ≥ 20 times the ULN 
9. An absolute neutrophil count of < 1000 (Grade 4) 
10. Electrocardiographic findings of any of the following: Torsades de Pointes, polymorphic 
ventricular tachycardia 
11. Malignant hypertension characterized by a systolic BP of ≥ 220 mm Hg or a diastolic BP 
≥ 110 mm Hg with concomitant neurologic deficit or need for urgent medical intervention 
12. Headache with neurologic deficit in a patient without history of migraine or similar 
syndrome or condition 
13. Gastric hemorrhage requiring transfusion or other emergent intervention 
14. Uncontrolled emesis for greater than 24 hours, or incident emesis considered to be 
definitely or probably caused by study drug 
15. Occurrence of any opportunistic infection 
Study drug should be reinstituted when the event that resulted in temporary interruption 
of study drug administration has resolved or has improved to a Grade 2 event or lower. 
In the case that the subject has been intubated or started on ECMO, study drug should 
be restarted once extubated and/or ECMO discontinued and oral administration of 
medications is possible. Exceptions are any diagnosis of pregnancy or an opportunistic 
infection. If a second episode of the same adverse event occurs, study drug will be 
stopped and not restarted.  
If two or more episodes of anaphylaxis possibly related to study drug occur, then the 
unblinded clinical research coordinator will request that pharmacy provide a report 
regarding study drug assignments of these participants to the DSMB to determine 
potential causality. The DSMB will review and determine appropriateness of study 
continuation.   
All episodes of study drug interruption or stoppage should be reported to the Medical 
Monitor.  
Any permanent stoppage of study drug in response to meeting any of the individual 
stopping rules will be considered as meeting study endpoint for failure except for a 
diagnosis of pregnancy, or stoppage related to decreased renal function.  
Pause in Treatment or Termination of clinical trial 
The Medical Monitor or DSMB may recommend global pause of study drug administration 
to all enrolled subjects if a safety signal is encountered that requires investigation and in 
the opinion of either the Medical Monitor or DSMB that continuation during the 
investigation period would present a safety risk to enrolled subjects. The decision to 
reinstitute study medication may be made at the conclusion of the investigation. The IRB 
will be informed of all such treatment interruptions and will be provided a report of the 
investigation.  
Except for detection of a safety signal, the study will continue to the target enrollment 
unless enrollment has been increased to gain additional statistical power for assessing 
dose dependent response.    

 
 
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7.3.3 Unblinding 
This is a double-blind study. Treatment assignments should be maintained as blinded 
unless such unblinding is considered as critical to the care and well-being of the subject. 
Unblinding should occur following discussion with the Sponsor Medical Monitor, however, 
emergency unblinding can occur if the Investigator deems that such a delay would unduly 
harm the subject and knowledge of the treatment assignment is a critical factor in medical 
decision making versus a discontinuation of study drug until discussion with the Medical 
Monitor. In the case of unblinding, the Investigator must record the date, time and reason 
for unblinding, however, the Investigator is not required to inform the Sponsor of treatment 
assignment. Unblinded treatment assignment will only be accessible to those who require 
such information as part of medical decision making and for those involved in Safety 
reporting to Health Authorities and/or the relevant IRB. 
 
The Investigational Pharmacy will maintain a listing of subject treatment assignments 
and will provide a mechanism for unblinding in emergency situations. 
 
 
8. 
STATISTICAL METHODS and CONSIDERATIONS 
Prior to unblinding and analysis of the final study data, a detailed Statistical Analysis Plan 
(SAP) will be written describing all analyses that will be performed for reporting of results 
from this clinical trial.  
8.1 
Data Sets to be Analyzed 
 The intention to treat population (ITT) includes all participants who are randomized to 
a treatment allocation. The ITT population will be used for the summary of all 
demographic and baseline characteristics and for analysis of the primary outcome of 
treatment failure. Subjects will be grouped in analyses and summaries based on their 
randomization allocation.  
 The modified intention to treatment (mITT) population includes all participants who are 
randomized to a treatment allocation, and who have received at least one dose of 
study drug. The mITT population will be used for the summary and analysis of the 
primary outcome of treatment failure. Participants will be grouped based on the 
treatment allocation.  
 The safety analysis set includes all mITT participants. Participants will be grouped 
based on the treatment actually received.  
 
Per-protocol (PP) analysis set includes all Safety subjects who complete the trial by 
meeting the endpoint or being discharged within 28-days without meeting the endpoint. 
Participants in this set will be grouped to treatment arms they actually received. This 
set will be used as a sensitivity analysis to summarize the primary endpoint and for 
summary of all other efficacy outcomes. 
8.2 
Sample Size  
Based on the initial data obtained to date and data in the literature [1], it is anticipated that 
approximately 50% of subjects hospitalized with PCR-positive SARS-CoV-2 infections 

 
 
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(WHO COVID-19 Classification level 3 or 4) will progress to WHO COVID-19 
classification level of 6 or greater as defined by one or more of the following: the need for 
intubation or mechanical ventilation (level 6), the need for ECMO (level 7), or any cause 
death (level 8). The sample size estimate for this proof of concept is based on Fisher’s 
Exact two-sided test for 2 proportions using NQuery 8 (www.statsols.com). Estimates of 
admitted patients requiring salvage therapy is unknown, however, the clinical data set 
who require intubation is a likely subset of those whose condition worsens but do not 
progress to respiratory compromise.  
 
Although the interim analysis will utilize masked treatment assignments, the O’Brien 
Fleming group sequential sample size estimation confirms that a single interim look would 
retain a cumulative exit probability of 70% with a cumulative alpha =0.05 after the final 
analysis using the target enrollment of 132 (44 per group) to detect a reduction of those 
reaching the endpoint of treatment failure, which includes advancing to WHO COVID-19 
Classification level ≥6 from 50% (SOC treated) to 25% in either treatment group of SOC 
plus GLS-1027. Other conditions also qualify a subject as treatment failure include: need 
for salvage therapy with IL-6 monoclonal antibody; or institution of salvage therapy with 
dexamethasone (≥ 6 mg/day), withdrawing consent from the study, becoming lost to 
follow-up, or discontinuation of treatment for any reason other than renal function or 
pregnancy.  This study is not powered to assess statistically significant differences 
between GLS-1027 doses.  
8.3 
Randomization 
Randomization to treatments will occurred using a centralized randomization system.  
Randomization will be stratified by site to ensure equal distribution of treatments within each site. 
Subjects within each site will be randomly assigned in a 1:1:1 ratio to receive placebo, 120 mg 
GLS1027 or 360 mg GLS1027 daily for their duration of hospitalization or until intubation or 
mechanical ventilation constrains oral medication. 
8.4 
Demographic and Other Baseline Characteristics 
Demographic and baseline data, vital signs, medical history, concomitant illnesses, and 
current medications/treatments will be summarized by means of descriptive statistics: 
continuous variables as mean, median, standard deviation, minimum and maximum 
values and categorical variables as frequencies and percentages, grouped by treatment 
arm based on the ITT population and overall. 
8.5 
Safety Analysis 
All safety and tolerability summaries will be performed on the safety analysis population. 
8.5.1 Adverse events 
Treatment emergent AEs will be summarized by frequencies and will be presented by 
system organ class and preferred term with the number and percentage of participants 
affected. Frequencies will be presented with respect to maximum severity. Multiple 
occurrences of the same AE will be counted only once following a worst-case approach 
with respect to severity and relationship to Study Treatment.  
8.5.2 Laboratory Data 
Continuous response variables per time point will be summarized with mean, median, 
minimum, and maximum values. Categorical response variables will be summarized per 

 
 
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time point with percentages. In addition, each laboratory parameter will be summarized 
as a shift from baseline based to the last lab assessments prior to meeting the primary 
endpoint or 28 days, whichever comes last. 
8.6 
Efficacy Analysis 
The primary endpoint is treatment failure which is defined as any subject who achieved 
WHO level ≥ 6 (intubation and mechanical ventilation, requirement for ECMO, or death) 
within 28 days of initiating treatment or who meet the following reasons for treatment 
failure: 
 Receiving salvage therapy with either an IL-6 monoclonal antibody or for those 
who are prescribed daily dexamethasone starting 72 hours or later after the 1st 
dose of study drug within the 28-day primary treatment period.  
 Lost to follow-up through hospital transfer, within the 28-day primary treatment 
period.  
 Discontinuation of  study drug for any cause prior to discharge will be considered 
as a treatment failure, except for those for whom study drug was suspended due 
to a decrease in renal function (creatinine clearance of < 60 mL/min), and those 
become pregnant during treatment. These subjects will be followed for the primary 
endpoint for up to 28 days post enrollment, and for up to 56 days for safety. 
 
Subjects who complete 28 days of treatment  but remain hospitalized without increase in 
WHO COVID-19 Classification level to ≥6, will not considered be as treatment failures 
with respect to the primary endpoint. 
 
The proportion of subjects in each treatment group who reach the study endpoint of 
treatment failure by 28 days will be compared to placebo using Fisher’s Exact 2-sided 
test of proportions. Additionally, the frequency for each outcome (intubation, ECMO, 
death) will be determined within each group. The ITT, mITT and PP analysis populations 
will be used to analyze the primary endpoint.  
8.7 
Other Analysis 
Exploratory endpoints include the following which will be summarized using the PP 
populations by treatment group received: 
 Assess the number of days requiring ICU care relative to treatment group. If a 
subject does not require ICU care, the number of days will be set to zero for the 
group summary.  The number of ICU days will be summarized for all subjects in 
each group and for the proportion of those who are actually in ICU. 
 Assess the number of days of mechanical ventilation relative to treatment group. 
If a subject does not require mechanical ventilation, the number of days will be 
set to zero for the group summary.  The number of mechanical ventilation days 
will be summarized for all subjects in each group and for the proportion of those 
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 Assess incidence of WHO COVID-19 Classification levels relative to baseline 
serum IL-6 level 
 Assess incidence of WHO COVID-19 Classification levels relative to baseline 
serum ferritin level 
 Assess incidence of WHO COVID-19 Classification levels relative to baseline 
CRP  
 Assess trough level of GLS-1027 relative to serum creatinine 
 Assess the maximal level of Positive End-Expiratory Pressure (PEEP) for 
subjects who are intubated relative to treatment group.  
 Assess the number of days of PEEP > 5 cm H2O for subjects who are intubated 
relative to treatment group 
 Incidence of progression to  WHO COVID-19 Classification level 6, or 7, or 8 
(individually) 
 
Assess SARS-CoV-2 IgM antibody responses relative to treatment group  
No adjustments or imputations will be made for deaths or other forms of missingness 
except those already described above.  
  
8.8 
Interim Analysis 
A masked interim analysis will be performed when 22 subjects in each group have been 
assessed for the primary endpoint of treatment failure.  Unless safety is of concern, the 
study will not be stopped for futility and enrollment will continue to at least the targeted 
sample size of 132. 
8.9 
Missing Values 
Subjects may have a missing endpoint for the following reasons: 
 Lost to follow up due to transfer to another hospital 
 Remains in the hospital for >28 days without ever achieving WHO COVID-19 
Classification level ≥ 6. 
 
Withdrawal of consent prior to meeting endpoint 
If a subject is lost to follow-up due to transfer to another hospital, the subject will be 
considered a treatment failure per the ITT and mITT populations and will be excluded 
from the analysis per the PP population. Missing primary endpoint assessment because 
of continued hospitalization beyond 28 days will be counted as treatment success if the 
subject has not met the criteria for WHO COVID-19 Classification level ≥ 6 at any time up 
to 28 days.   Subject who withdraw consent without being assessed for the primary 
endpoint will be considered treatment failure. To minimize missing values, enrolled 
participants will be followed through to the end of the primary study period (through to 
hospital discharge, death, or 28 days from treatment initiation) for safety and efficacy 
assessment. Additionally, safety and clinical status will be monitored through to Day 56 
as per the schedule of events.  

 
 
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9. 
DATA COLLECTION, MONITORING, AND AE REPORTING 
9.1 
Confidentiality 
Information about study participants will be kept confidential to the best of the study site’s 
ability. 
In the event that a participant revokes authorization to collect or use personal health 
information (PHI), the sponsor retains the ability to use all information collected prior to 
the revocation of participant authorization. For participants that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission to 
collect at least vital status (i.e., that the participant is alive) at the end of their scheduled 
study period. 
9.2 
Source Documents 
Source data is all information, original records or clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source data are contained in original source documents. Examples of these original 
documents and data records include (as applicable): hospital records, clinical and office 
charts, laboratory notes, memoranda, participant’s diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, participant files, pharmacy 
records, laboratory records, medical records (including electronic records) relative to the 
clinical trial.  
9.3 
Data Collection 
Data will be collected using Electronic Data Capture (EDC). Participants will be identified 
by PID#. Initial data collection may utilize a paper form of the EDC. Any such records will 
be maintained as source data.  
9.4 
Record Retention 
It is the Investigator’s responsibility to retain study essential documents as per country 
regulations: in the US for at least 2 years after the last approval of a marketing application 
in their country and until there are no pending or contemplated marketing applications in 
their country or at least 2 years have elapsed since the formal discontinuation of clinical 
development 
of 
the 
investigational 
product. 
The 
sponsor 
will 
inform 
the 
investigator/institution as to when these documents are no longer needed to be retained. 
9.5 
Safety and Quality Monitoring and Record Availability 
Monitoring 
Monitoring of the clinical trial will be performed by experienced monitors, who will report 
to the Sponsor as outlined in the Monitoring Plan. 
Record availability and auditing 
The investigator will make study documents (e.g., ICFs, drug accountability forms) and 
pertinent hospital or clinic records readily available for inspection by the local IRB, the site 
monitors, regulatory agencies, GeneOne Life Science, Inc. or its designee for 
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Participation as an investigator in this study implies acceptance of potential inspection by 
regulatory authorities and applicable compliance and quality assurance offices. 
9.6 
Adverse event (AE) Reporting 
AEs will be recorded and forwarded to regulatory agencies as required. 
9.6.1 Study Reporting Period of Adverse Events 
All AEs will be recorded throughout the study and the 28 day follow-up period.  
9.6.2 Study Reporting Period for Serious Adverse Events  
SAE’s will be recorded throughout the study and the 28-day follow-up period. 
Expedited reporting of SAEs will be determined by GeneOne Life Science using reference 
safety information specified in the Investigator’s Brochure. An event may qualify for 
expedited reporting to regulatory authorities if it is an SAE, SUSAR in line with relevant 
regulatory requirements.  
At any time after completion of the SAE reporting period, if an Investigator becomes aware 
of an SAE that is suspected by the Investigator to be related to the study drug, the event 
will be reported to the Sponsor. 
SAE TELEPHONE AND CONTACT INFORMATION: 
SAE REPORTING 
 
MEDICAL MONITOR: 
Catalyst Pharmacovigilance 
 
Joel Maslow, MD PhD MBA 
 
safety@catalystcr.com 
 
MAILING ADDRESS: 
PHONE: 
(484) 965-9147p; (610) 331-7844 c 
 
GeneOne Life Science, Inc. 
MEDICAL LIAISON: 
Celine Remigio, RN DPT 
 
1040 DeKalb Pike 
CELL: 
(914) 606-1199 
 
Suite 200 
EMAIL: 
cremigio@geneonels-us.com 
 
Blue Bell, PA 19422 
24 hr Answering Service 
(215) 703-5843 
 
 
GeneOne FACSIMILE: 
(484) 965-9146 
 
 
GeneOne Safety Email 
GeneOneSafety@geneonels-us.com 
 
 
 
The report should contain as much clinical safety information as possible, but at minimum, 
the initial report must include the following information: 
• 
Participant number and Study name 
• 
Date of Onset and Date of Resolution (if applicable) 
• 
Detailed description of event 
• 
Investigational product (if known) 
 
Causal relationship of event to investigational product 
• 
Reporter name and contact information 
Follow-up reports will be sent as soon as more information becomes available. Events for 
which the study participant seeks medical care, the study site will attempt to obtain 
relevant medical records to include as source documents. These include but are not 
limited to discharge summary, results of relevant laboratory tests, and reports of relevant 
radiographic studies. In the case of death, the investigator will attempt to procure relevant 
reports (such as autopsy reports, medical examiner report, discharge summary).  

 
 
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Each SAE must be followed by the investigator until resolution, stabilization, or return to 
baseline, even if this extends beyond the end of the study, with follow-up report filed to 
provide a summary of the event through resolution.  
The electronic data capture (EDC) system is integrated to the safety database (Veeva) 
vault and all SAE information will be collected electronically. A paper SAE form will be 
available as a back-up. Copies (or electronic copy) will be provided to GeneOne Life 
Science or its representative, who will be responsible for reporting to regulatory 
authorities as indicated, and copy will be forwarded to the study sites IRB/REC.  
9.6.3 Notification of Serious Adverse Events 
In accordance with local regulations, the Sponsor shall notify the appropriate regulatory 
authorities, and all participating investigators in a written safety report of any adverse 
experience associated with the use of the product that is both serious and unexpected 
(e.g., FDA Form 3500A in the US). SUSARs reports shall be made as soon as possible 
and in no event later than 15 calendar days after the Sponsor’s initial receipt of the 
information. Written notification may be submitted on the form described above or 
equivalent or in a narrative format and shall bear prominent identification of its contents. 
Each written notification to regulatory agencies shall be transmitted to the division that 
has responsibility for review. In each written safety report, the Sponsor shall identify all 
safety reports previously filed concerning a similar adverse experience, and shall analyze 
the significance of the adverse experience in light of the previous, similar reports. The 
Sponsor shall also notify the relevant regulatory authorities by telephone, facsimile, or 
email transmission of all deaths and any unexpected fatal or life-threatening experience, 
regardless of causality, as soon as possible but in no event later than 7 calendar days 
after the Sponsor’s initial receipt of the information. Each telephone call or facsimile 
transmission to regulatory agencies shall be transmitted to the division that has 
responsibility for review.  
Follow up information to a safety report shall be submitted as soon as the relevant 
information is available. If the results of a Sponsor’s event investigation show that an 
adverse drug experience not initially determined to be reportable is, in fact, reportable, 
the Sponsor shall report such experience in a written safety report as soon as possible, 
but in no event later than 15 calendar days after the determination is made. Results of 
investigations of other safety information shall be submitted, as appropriate, in an 
information amendment or annual report. In the event of death, if an autopsy is performed, 
a copy of the report, redacted for PHI but labeled with the PID#, should be sent to 
GeneOne Life Science, Inc. 
9.7 
Study Termination 
GeneOne Life Science reserves the right to terminate the study for safety or 
administrative reasons, including lack of enrollment, at any time. Investigational product 
must be returned to GeneOne, unless instructed otherwise. Document retention will follow 
local regulation.   

 
 
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10. 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be allowed. Any proposed presentation, abstract and/or 
manuscript must be made available to GeneOne at least 60 days prior to submission. GeneOne 
shall have fifteen (15) days for review. If GeneOne considers that material would reveal 
protectable intellectual property, GeneOne may request a delay in submission for a maximum of 
three (3) months from the date of receipt in order for patent application(s) to be filed with the 
United States Patent and Trademark Office and/or foreign patent office(s). 
11. 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
Alk Phos 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CI 
Confidence interval 
CMP 
Complete Metabolic Profile 
CPAP 
Continuous positive airway pressure 
CPK 
Creatinine phosphokinase 
COPD 
Chronic obstructive pulmonary disease 
CRP 
C-reactive protein 
CTCAE 
National Cancer Institute Common terminology criteria for adverse events 
CXR 
Chest X-ray (chest radiograph) 
CRS 
Cytokine release syndrome 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram (synonymous with EKG) 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate (Cockroft-Gault formula) 
ERER 
Event requiring expedited reporting 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
HMGB1 
High mobility group box protein-1  
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICU 
Intensive Care Unit 
IL 
Interleukin 

 
 
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IRB 
Investigation review board 
ITT 
Intention-to-treat 
LDH 
Lactate dehydrogenase 
LPS 
Lipopolysaccharide 
mAb 
Monoclonal antibody 
MERS-CoV Middle East respiratory syndrome coronavirus  
NS 
Not stated 
PBMC 
Peripheral blood mononuclear cell 
PEEP 
Positive end-expiratory pressure 
PHI 
Personal health information 
PID# 
Participant identification designation number 
PK 
Pharmacokinetic 
PM 
Particulate matter 
PM2.5 
Particulate matter of a size < 2.5 μm 
PP 
Per-protocol 
SARS-CoV Severe acute respiratory syndrome coronavirus 
SARS-CoV-2 Severe acute respiratory syndrome coronavirus, type 2 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SOC  
Standard of care 
SUSAR 
Suspected unexpected serious adverse reaction 
TBI 
Traumatic brain injury 
ULN 
Upper limit of normal 
 
12. 
REFERENCES 
 
1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult 
inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020 
395(10229):1054-1062. 
2. Karki R, Sharma BR, Tuladhar S, WIlliams EP, Zalduondo L, Samir P, et al. Synergism of TNF-alpha and 
IFN-gamma triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection 
and cytokine shock syndromes. Cell 2020; S0092-8674(20)31542-7. Online ahead of print. PMID: . 
3. Stojanovic I, Cuzzocrea S, Mangano K, Mazzon E, Miljkovic D, Wang M, et al. In vitro, ex vivo and in 
vivo immunopharmacological activities of the isoxazoline compound VGX-1027: modulation of 
cytokine synthesis and prevention of both organ-specific and systemic autoimmune diseases in 
murine models. Clin Immunol 2007 123(3):311-323. 

 
 
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4. Mangano K, Sardesai NY, Quattrocchi C, Mazzon E, Cuzzocrea S, Bendtzen K, et al. Effects of the 
immunomodulator, VGX-1027, in endotoxin-induced uveitis in Lewis rats. Br J Pharmacol 2008 
155(5):722-730. 
5. Zhang JL, Huang WM, Zeng QY. Atractylenolide I protects mice from lipopolysaccharide-induced 
acute lung injury. Eur J Pharmacol 2015 765:94-99. . 
6. Xu M, Li F, Wang M, Zhang H, Xu L, Adcock IM, et al. Protective effects of VGX-1027 in PM2.5-induced 
airway inflammation and bronchial hyperresponsiveness. Eur J Pharmacol 2019; 842:373-383. 
7. Cui Y, Zhang ZF, Froines J, Zhao J, Wang H, Yu SZ, et al. Air pollution and case fatality of SARS in the 
People's Republic of China: an ecologic study. Environ Health; 2(1):15. 
8. Lagadec P, Balaguer T, Boukhechba F, Michel G, Bouvet-Gerbettaz S, Bouler JM, et al. Calcium 
supplementation decreases BCP-induced inflammatory processes in blood cells through the NLRP3 
inflammasome down-regulation. Acta Biomaterialia 2017; 57:462-471. 
9. Laird MD, Shields JS, Sukumari-Ramesh S, Kimbler DE, Fessler RD, Shakir B, et al. High mobility group 
box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 
4. Glia 2014 62(1):26-38. 
10. Ahmad SF, Nadeem A, Ansari MA, Bakheet SA, Alasmari F, Alasmari AF, et al. The potent 
immunomodulatory compound VGX-1027 regulates inflammatory mediators in CD4+ T cells, which are 
concomitant with the prevention of neuroimmune dysregulation in BTBR T+ Itpr3tf/J mice. Life Sci 
2019 Oct 11:116930. 
11. Lee JC, Menacherry S, Diehl MC, Giffear MD, White CJ, Juba R, et al. Safety, bioavailability, and 
pharmacokinetics of VGX-1027-A novel oral anti-inflammatory drug in healthy human subjects. Clin 
Pharmacol Drug Dev 2016 5(2):91-101. 
 
 

 
 
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13. 
APPENDICES 
APPENDIX A: Exclusionary period for anti-cytokine agents 
CATEGORY 
Generic name 
Brand name 
Exclusionary 
period  
IL-1 inhibitors 
Rilonacept 
Arcalyst 
35 days 
 
Canakinumab 
Ilaris 
30 days 
 
Anakinra 
Kineret 
30 days 
IL-6 inhibitors 
Toclizumab 
Actemra 
50 days 
 
SIltuximab 
Sylvant 
100 days 
 
Sarilumab 
Kevzara 
105 days 
 
Atezolizumab 
Tencentriq 
135 days 
 
Clazakizumab 
 
120 days 
 
Olokizumab 
 
120 days 
 
Sirukumab 
 
120 days 
JAK inhibitors 
Ruxolitinib 
Jakafi 
30 days 
 
Tofacitinib 
Xeljanz 
30 days 
 
Oclacitinib 
Apoquel 
30 days 
 
Baricitinib 
Olumiant 
30 days 
 
Peficitinib 
Smyraf 
30 days 
 
Fedratinib 
Inrebic 
30 days 
 
Upadacitinib 
Rinvoq 
30 days 
 
Filgotinib 
 
30 days 
 
Cerdulatinib 
 
30 days 
 
Gandotinib 
 
30 days 
 
Lestaurtinib 
 
30 days 
 
Momelotinib 
 
30 days 
 
Pacritinib 
 
30 days 
 
Abrocitinib 
 
30 days 
TNFα inhibitors 
Infliximab 
Remicade 
50 days 
 
Etanercept 
Enbrel 
30 days 
 
Adalimumab 
Humira 
75 days 
 
Certolizumab 
Cimzia 
55 days 
 
Golimumab 
Simponi 
60 days 
 
Note 1: This appendix may be updated through the clinical trial as new agents are either 
approved or brought into clinical practice. The time prior to enrollment that each drug is 
to be excluded is listed, but may be updated if new information is published regarding 
modifications to drug half-life.  
Note 2: The decision to initiate treatment with any of the agents listed below is 
determined either according to the hospital specific SARS-CoV-2 Treatment Algorithm 
or per individual physician decision. If any agent is started post-enrollment, use should 
be documented as a concomitant medication. Other study procedures should continue 
as per the schedule of events.  
 
 

 
 
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APPENDIX B: WHO COVID-19 Classification  
PATIENT STATE 
DESCRIPTOR 
SCORE  
Uninfected 
No clinical or virologic evidence of 
infection 
0 
Ambulatory 
Infected, with no limitation of activities  
 
1 
 
Infected, with limitation of activities 
 
2 
Hospitalized 
No oxygen therapy 
 
3 
     Mild disease 
Oxygen by mask or nasal canula 
 
4 
Hospitalized 
Non-invasive ventilation or high-flow 
oxygen  
5 
     Severe disease 
Intubation with mechanical ventilation 
 
6 
 
Ventilation plus any of vasopressor Rx, 
RRT, ECMO 
7 
Death 
Death 
 
8