Clinical trial NCT04358406
Conditions: Sars-CoV2
Keywords: COVID-19 Pneumonia Severe Cytokine storm
Sponsor: BioAegis Therapeutics Inc.
Start date: 2020-07-30; Completion date: 2022-01-28
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Study Objectives:

Primary

* To assess the efficacy (survival without organ failure on Day 14) of three doses of rhu-pGSN administered intravenously (IV) plus standard of care (SOC) to hospitalized subjects with a primary diagnosis of COVID-19 pneumonia and a severity score of 4, 5 or 6 on the World Health Organization (WHO) 9-point severity scale
* To evaluate the safety and tolerability of three IV doses of rhu-pGSN administered to hospitalized subjects with a primary diagnosis of COVID-19 pneumonia and a severity score of 4, 5, or 6 on the WHO 9-point severity scale

Secondary

* To further assess the efficacy of IV administered rhu-pGSN
* To assess changes in WHO 9-point severity score for SOC with or without rhu-pGSN
* To evaluate the effect of administered rhu-pGSN on survival rates
* To assess the relationship of pGSN levels (and other biomarkers) at baseline with clinical outcomes
* \[OPTIONAL\] To follow the pharmacokinetics (PK) of administered rhu-pGSN

Immunogenicity

• To investigate the development of antibodies against rhu-pGSN post-treatment

Detailed description:
Efficacy and safety of IV rhu-pGSN on top of SOC will be evaluated initially in 60 participants representative of the drug target population: high-risk subjects with acute severe pneumonia due to COVID-19. The rhu-pGSN dose will be based on actual body weight given at 12 mg/kg. Three doses will be given at 0, 12 and 24 hours intervals promptly after enrollment by IV infusion through a 0.2 µm filter. Participants will be randomized 1:1 rhu-pGSN or placebo. Interim safety analyses will be conducted after enrollment of 12, 24, 36, and 48 patients.

The primary efficacy outcome will be the proportion of patients surviving on Day 14 without mechanical ventilation, vasopressors or dialysis. Secondary efficacy outcomes will include: daily change in 9-point WHO severity score through at least Day 14; all-cause mortality at Days 28 and 90; time to death (Kaplan-Meier survival analysis); proportion of subjects alive on Days 7, 28, 60, and 90 without: ongoing use of vasopressors, ongoing intubation/mechanical ventilation, ongoing residence in an intensive care unit (ICU), new ongoing need for dialysis/renal replacement therapy; proportion of subjects discharged to home or immediate prior residence by Day 28; days on the ventilator; length of stay in hospital and in ICU and re-admission to an acute-care hospital up to Day 90. Safety of administration of rhu-pGSN at the indicated dosage will also be evaluated.

Baseline and sequential levels of pGSN and inflammatory biomarkers will be measured. On days 1, 28, and 90, immunogenicity due to the formation of anti-pGSN antibodies will be assessed.

Arms: arm 1: Normal saline in matched volume to treatment arm. Undistinguishable in syringe. arm 2: Recombinant human plasma gelsolin reconstituted for slow bolus injection.
Interventions: intervention 1: Recombinant human plasma gelsolin (Rhu-pGSN) intervention 2: Placebo
Intervention descriptions: intervention 1: Intravenous administration of rhu-pGSN at 12 mg/kg, 3 doses intervention 2: Normal saline in matched volume to treatment arm. Undistinguishable in syringe.

Protocol documents:
Prot_000.pdf: 
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Title page 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PROOF-OF-
CONCEPT STUDY TO EVALUATE THE EFFICACY AND SAFETY OF RECOMBINANT
HUMAN PLASMA GELSOLIN (RHU-PGSN) ADDED TO STANDARD OF CARE FOR
TREATMENT OF SUBJECTS WITH SEVERE COVID-19 PNEUMONIA 
Protocol Number: 
BTI-202 
Investigational Product: 
rhu-pGSN 
IND Number: 
N/A 
EUDRA CT Number 
2020-002460-31 
Development Phase: 
Phase 2 
Indication Studied: 
Severe pneumonia due to COVID-19 
Sponsor Name and Address: 
BioAegis Therapeutics, Inc. (BTI) 
Responsible Medical Officer: 
Mark J. DiNubile, MD FIDSA 
Coordinating Investigators 
Sandra Parra, MD and Antoni Castro, MD 
Compliance Statement: 
This study will be conducted in accordance with the 
ethical principles that have their origin in the 
Declaration of Helsinki, clinical research guidelines 
established by the Code of Federal Regulations (Title 
21, CFR Parts 50, 56, and 312), and ICH GCP 
Guidelines. Essential study documents will be archived 
in accordance with applicable regulations. 
Protocol Date: 
09 June 2021 
Version: 
4.0 
Confidentiality Statement 
This is a BioAegis Therapeutics document that contains confidential information. It is intended 
solely for the recipient clinical investigator(s) and must not be disclosed to any other party. 
Acceptance of this document constitutes the agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval of BioAegis 
Therapeutics except that this document may be disclosed to appropriate Ethics Committees 
provided that they agree to keep it confidential. This material may be used only for evaluating 
or conducting clinical trials; any other proposed use requires prior written consent from 
BioAegis Therapeutics. 
NCT04358406


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PROTOCOL APPROVAL SIGNATURE PAGE 
 
 
Protocol: 
BTI-202 
 
Title: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Proof-of-
Concept study to evaluate the Efficacy and Safety of Recombinant Human 
Plasma Gelsolin (rhu-pGSN) Added to Standard of Care for Treatment of 
Subjects with Severe COVID-19 Pneumonia 
 
Date: 
09 June 2021  
 
Version: 
 
4.0 
 
 
 
 
Reviewed and Approved by: 
 
 
 
 
  
 
09 June 2021 
Mark J. DiNubile, MD  
Chief Medical Officer 
BioAegis Therapeutics, Inc. 
 Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL ACCEPTANCE FORM 
 
Protocol: 
BTI-202 
 
Title: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Proof-of-
Concept study to evaluate the Efficacy and Safety of Recombinant Human 
Plasma Gelsolin (rhu-pGSN) Added to Standard of Care for Treatment of 
Subjects with Severe COVID-19 Pneumonia 
 
Date: 
 
09 June 2021 
 
Version: 
 
4.0 
 
 
I have carefully read the BTI-202 protocol and agree that it contains all of the necessary 
information required to conduct this study. I agree to conduct this study as described and 
according to the Declaration of Helsinki, ICH Guidelines for GCP, and all applicable regulatory 
requirements. 
 
 
 
  
Investigator’s Signature 
 Date 
 
 
 
  
Name (printed) 
  
 


BioAegis Therapeutics, Inc. 
 
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1. 
SYNOPSIS  
Name of Sponsor/Company: 
BioAegis Therapeutics Inc. 
Name of Investigational Product: 
Recombinant Human Plasma Gelsolin (rhu-pGSN) 
Name of Active Ingredient: 
rhu-pGSN 
Title of Study:  
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial to Evaluate the 
Efficacy and Safety of Recombinant Human Plasma Gelsolin (rhu-pGSN) Added to Standard of Care for 
Treatment of Subjects with Severe COVID-19 Pneumonia 
Study center(s): 1-5 sites 
Studied period (years):  
Estimated date first subject enrolled: 01 June 2020 
Estimated date last subject completed: 21 October 2021 
Phase of development:  
2 (Proof-of-Concept) 
Objectives:  
 
Primary 
• 
To assess the efficacy (survival without organ failure on Day 14) of intravenous (IV) rhu-pGSN 
plus standard of care (SOC) vs placebo plus SOC (hereafter referred to as rhu-pGSN vs placebo) 
administered to hospitalized subjects with a primary diagnosis of coronavirus 2019 (COVID-19) 
pneumonia and in Part 1, a severity score of 4, 5, or 6, or for Part 2, intubated without 
extracorporeal membrane oxygenation (ECMO) with a severity score of 6 or 7 on the World 
Health Organization (WHO) 9-point severity scale 
• 
To evaluate the safety (incidence of serious adverse events [SAEs]) of IV rhu-pGSN administered 
to hospitalized subjects with a primary diagnosis of COVID-19 pneumonia and in Part 1, a 
severity score of 4, 5, or 6, or for Part 2, intubated without ECMO with a severity score of 6 or 7 
on the WHO 9-point severity scale 
 
Secondary 
• 
To further assess the efficacy of IV administered rhu-pGSN  
• 
To measure changes in the WHO 9-point severity scale for SOC ± rhu-pGSN 
• 
To evaluate the effect of administered rhu-pGSN on survival rates  
• 
To assess the relationship of pGSN levels (and other biomarkers) at baseline with clinical 
outcomes 
• 
To follow the pharmacokinetics (PK) of administered rhu-pGSN  
 
Immunogenicity 
• To investigate the development of antibodies against pGSN post-treatment in rhu-pGSN vs 
placebo recipients compared to baseline 


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Methodology: 
This is a 2-part, randomized, double-blind, placebo-controlled, multicenter Phase 2 study to evaluate the 
efficacy and safety of rhu-pGSN plus SOC in subjects with severe COVID-19 pneumonia. Potential 
subjects hospitalized with pneumonia and laboratory-confirmed (reverse transcription polymerase chain 
reaction [RT-PCR+]) or highly suspected (compatible with at least bilobar lung involvement without any 
other plausible diagnosis) COVID-19 etiology will be screened for Part 1 within 24 hours of reaching a 
WHO severity score of 4 to 6, whether the severity score is attained on admission or during 
hospitalization, or for Part 2, within 24 hours of intubation without ECMO with a WHO severity score of 6 
or 7.  
The 9-point WHO classification scheme for severe COVID-19 pneumonia will be applied to grade the 
severity of illness as follows:  
8 
Death 
7 
Mechanical ventilation or ECMO with either vasopressor support or dialysis/renal replacement 
therapy (RRT) 
6 
Intubation with mechanical ventilation, a mask with a reservoir or oxygen with high-flow nasal 
goggles but without vasopressor support or dialysis/RRT 
5 
Noninvasive ventilation (continuous positive airway pressure [CPAP] or bilevel positive airway 
pressure [BiPAP]) or high-flow oxygen 
4 
Oxygen by mask or nasal  
3 
Hospitalized with no oxygen therapy 
2 
Limitation of activity 
1 
Infected without limitations 
0 
No clinical or virologic evidence of COVID-19 infection  
 
Once informed consent is obtained, the following assessments/procedures will be performed:  
1. Record medical history, including concomitant medications and current clinical status 
2. Perform pregnancy test (urine or blood) for women of childbearing potential 
3. Collect pretreatment blood samples for measurement of baseline pGSN level and for analysis of 
antibodies against pGSN 
4. Calculate the CURB-65 score (Confusion, Urea >7 mmol/L, Respiratory rate e30/min, Blood 
pressure systolic <90 or diastolic d60, and age e65 years) at presentation 
5. A RT-PCR test to confirm the diagnosis of COVID-19 should be documented during the current 
illness leading to the present hospitalization; if RT-PCR test is not done prior to screening, the 
test is to be performed during screening before randomization (result might not be available at 
randomization or start of study treatment). Perform physical examination (PE) and document 
radiographic evidence of pneumonia (chest x-ray [CXR] or computed tomography ([CT] scan if 
CXR is inadequate) if not already completed within the previous 48 hours per SOC 
6. Obtain blood and sputum cultures and electrocardiogram (EKG) per SOC (if not already 
performed). The microbiology lab is encouraged to perform sputum (bacterial, viral, and 
mycobacterial, as indicated) and blood cultures, sputum Gram-stains, antigen detection on 
respiratory and urine specimens, and RT-PCR diagnostic tests as possible. 
7. Measure routine lab tests and biomarkers, including ferritin, D-dimer, C-reactive protein (CRP) 
and procalcitonin level at local laboratory; collect aliquots of blood for subsequent biomarker 
assays (likely to include, but not limited to interleukin [IL]1² , IL6, IL10, tumor necrosis factor 
[TNF], etc.) for analysis at the central laboratory (see Table 5 Schedule of Assessments and 


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footnote ‘l’ for details). 
8. If eligibility criteria are satisfied, subject to be randomized (1:1 to treatment arms rhu-
pGSN:placebo) within 12 hours of informed consent (Part 1) or within 24 hours of intubation 
(Part 2). 
Randomized subjects will receive the assigned dose of rhu-pGSN or an equal volume of sterile saline 
placebo as soon as possible (ASAP), but beginning no later than 12 hours of randomization. The rhu-
pGSN dose will be based on actual body weight given at 12 mg/kg. After reconstitution, rhu-pGSN 
should not be kept at room temperature for >2 hours prior to beginning the infusion. The initial dose of 
study drug (Dose #1) will be followed by dosing at 12 (Dose #2) and 36 hours (Dose #3) after the initial 
administration. Study drug is administered as a slow IV bolus at a rate of 5-20 mL/min through a 0.2 µm 
filter. The syringe, in-line filter, and extension tubing for injection of study drug should be connected 
after disconnecting the IV as close to the subject as possible.  
The primary efficacy endpoint will be assessed on Day 14, with secondary endpoints assessed on Days 7, 
28, 60 (optional), and 90. Discharged subjects will return for follow-up evaluation on Days 14, 28, 60, 
and 90. 
Screening laboratory and other tests can serve as baseline values for participants, they do not need to be 
repeated if performed within the prior 48 hours of randomization unless otherwise dictated by SOC; 
however, the blood sample for analysis of pGSN level must be repeated if not collected within 15 minutes 
of initiating the first dose of study drug. The day of first study drug administration will be used as 
baseline (Day 1) for analysis purposes. 
Repeat CXRs, or CT scans if CXR is inadequate, and labs/cultures, etc. will be obtained during the 
hospitalization if/when indicated by SOC. 
On Days 1 (predose), 28, and 90, blood samples for analysis of antibodies against pGSN will be 
collected.  
If the patient expires, autopsy is encouraged. 
Number of subjects (enrolled):  
Part 1: A total of 60 evaluable participants randomized 1:1 to rhu-pGSN:placebo (30:30 subjects).  
Part 2: A total of 20 evaluable participants randomized 1:1 to rhu-pGSN:placebo (10:10 subjects). 
Although data will be examined both in total as well as grouped by baseline WHO score, subjects will not 
be formally stratified by severity group. 
All reported deaths and treatment-emergent SAEs will be evaluated by the Data and Safety Monitoring 
Board (DSMB) within 4 working days of notification of the Contract Research Organization 
(CRO)/Sponsor.  
In Part 1, periodic safety reviews will be conducted after 12, 24, 36, and 48 subjects have been fully 
dosed and completed assessment at Day 14. Only DSMB members will be provided with partially 
unblinded results separated into 2 groups by treatment without identifying the actual treatment. If all 
participants have completed study therapy before the last DSMB meeting involving review of 48 subjects 
after their Day 14 visit can be held, this meeting can be cancelled at the discretion of the DSMB chair. 
Data will be further unblinded and/or the study paused at the discretion of the DSMB chair; enrollment 
will continue during the safety analyses unless otherwise mandated by the DSMB chair. 
Major inclusion criteria:  
 Hospitalized with laboratory-confirmed (RT-PCR+) or highly suspected (compatible with at 
least bilobar lung involvement without another plausible diagnosis) COVID-19  
 Age e18 years 
 Part 1 only: Weight d100 kg 


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 Part 1 only: Within 24 hours of reaching a WHO severity score of 4-6 either:  
o At admission 
o While already hospitalized. 
 Part 2 only: Within 24 hours of intubation without ECMO with a WHO severity score of 6 
or 7)  
 Informed consent obtained from subject/next of kin/legal proxy 
 Primary admitting diagnosis of pneumonia supported by a compatible clinical 
presentation with a documented infiltrate consistent with pneumonia on CXR or CT, as 
assessed by the admitting emergency department (ED), clinic, or ward physician or 
equivalent caregiver  
 Recommended (not mandatory) guidance/discretionary criteria defining patients with 
pneumonia satisfying all 4 categories below: 
o At least 2 symptoms: difficulty breathing, cough, production of purulent 
sputum, or chest pain 
o At least 2 vital sign abnormalities: fever, tachycardia, or tachypnea (thresholds -
- fever: body temperature >100.4°F [38°C]; heart rate >100 beats/min; 
respiratory rate >24/min) 
o At least one finding of other clinical signs and laboratory abnormalities: 
hypoxemia (O2 saturation <90%), clinical evidence of pulmonary consolidation, 
or leukocytosis e1.5x104 or leukopenia <4x103 
o Chest imaging, or CT chest showing at least bilobar pulmonary infiltrates  
 
Principal Investigator (PI) to note radiologic findings in the electronic 
case report form (eCRF) 
 
Radiology report and conclusion should be summarized in the eCRF 
 
A copy of the radiograph attached to be saved for review, if possible 
 A hyperinflammatory status (defined by increased ferritin e500 µg/L, D-dimer 
e1000 ng/mL, or CRP e75 mg/L) 
 During the course of the study starting at screening and for at least 6 months after their 
final study treatment: 
o Female subjects of childbearing potential must agree to use 2 medically accepted 
birth control methods 
o Male subjects with a partner who might become pregnant must agree to use 
reliable forms of contraception (i.e., vasectomy, abstinence), or an acceptable 
method of birth control must be used by the partner 
o All subjects must agree not to donate sperm or eggs (ovocytes) 
Major exclusion criteria: 
 A negative RT-PCR test for COVID-19 in the absence of a positive test during the evaluation 
of the present illness (in the presence of a positive test during the current illness, preceding or 
subsequent negative tests do not disqualify the subject) 
 Extracorporeal membrane oxygenation (ECMO) 
 Pregnant or lactating women 
 Active underlying cancer treated with systemic chemotherapy or radiation therapy during 
the last 30 days 
 Transplantation of hematopoietic or solid organs 
 Chronic mechanical ventilation or dialysis 
 Otherwise unsuitable for study participation because of chronic, severe, end-stage, and life-


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limiting underlying disease unrelated to COVID-19 likely to interfere with management and 
assessment of acute pneumonia, only comfort or limited (non-aggressive) care is to be 
given, or life expectancy <6 months unrelated to acute COVID infection in the opinion of 
the Investigator  
 
Notes: 
 PK sampling is strongly encouraged. However, participants refusing some or all PK 
blood sampling can remain in the trial 
 Participants with superinfection in addition to COVID-19 are eligible 
 Caregivers can decide whether any other medications (investigational or otherwise) 
should be administered. 
Investigational product, dosage and mode of administration:  
10-mL vials containing 200 mg of lyophilized rhu-pGSN will be reconstituted to a volume of 5 mL with 
4.56 mL of sterile water and drawn up into suitably sized syringes as dictated by the dose. 
• 
After reconstitution, rhu-pGSN can be refrigerated for up to 4 hours but should not be kept at 
room temperature for more than 2 hours.   
• 
Each subject will receive 3 doses of rhu-pGSN or placebo of equal volume, with the first 
dose administered ASAP but no later than 12 hours after randomization. Doses will be given 
within 4 total hours of reconstitution. 
• 
The drug will be administered by IV bolus at a rate between 5 and 20 mL/min through a 
standard 0.2-micron filter at 12 mg/kg (based on actual body weight) at 0, 12, and 36 hours 
(± 60 minutes). 
Duration of treatment:  
3 total doses starting with Dose #1 within 12 hours of randomization, Dose #2 12 hours later, and then 
Dose #3 after another 24 hours (36 hours after the initial dose [Dose #1]). Since pGSN is consumed more 
rapidly in patients with severe illness, the second dose is being given 12 hours (not 24 hours) after the 
first dose. 
Duration of subject participation:  
Day 14 post-first dose for the primary endpoint with daily assessments (including WHO severity score) 
from Day 1 until discharge and follow-up outpatient visits at Days 14, 28, 60 (if possible), and 90 days 
and as needed. 
Reference therapy, dosage and mode of administration:  
Placebo (dosed at a volume of 0.30 mL/kg of 0.9% saline solution via IV push [matching the volume of 
rhu-pGSN for a patient of that size] injected at 5-20 mL/min though a standard 0.2-micron filter)  
Concomitant medications: 
Subjects are treated according to the current SOC in the local facility. Subjects may continue their present 
medications as directed by their caregivers. Subjects may receive concomitant medications to treat 
symptoms, AEs, and inter-current illnesses that are medically necessary as standard care. All prior and 
concomitant medications, including generic name (if possible), and start date (if known) should be 
documented in the subject's file and in the eCRF. 


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Endpoints/Outcomes: 
Primary 
• 
Safety and tolerability 
o Incidence of SAEs in rhu-pGSN vs placebo groups  
• 
Efficacy 
o Proportion of subjects alive not on vasopressors, mechanical ventilator, and dialysis on 
Day 14 
Secondary 
• 
Safety and tolerability 
o Incidence, causality, and severity of adverse events (AEs) (graded according to the 
National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events 
[CTCAE] version 5.0) in rhu-pGSN vs placebo groups  
o Frequencies of new or worsening clinically significant laboratory abnormalities in rhu-
pGSN vs placebo groups 
o Mortality rate irrespective of cause at Days 28 and 90 
• 
Efficacy 
o Daily change in 9-point WHO severity score through at least Day 14 (including after 
discharge, where feasible) 
o All-cause mortality at Days 28 and 90; time to death (Kaplan-Meier survival analysis) 
o Proportion of subjects alive on Days 7, 14, 28, 60, and 90 without: 
 
Ongoing use of vasopressors  
 
Ongoing intubation/mechanical ventilation 
 
Ongoing residence in an intensive care unit (ICU) 
 
New ongoing need for dialysis/RRT 
o Proportion of subjects discharged to home or immediate prior residence by Day 28  
o Days on the ventilator 
o Length of stay (LOS) in hospital and in ICU (days) 
o Re-admission to an acute-care hospital up to Day 90  
• 
PK  
o PK for rhu-pGSN including maximum concentration (Cmax), time to maximum 
concentration (Tmax), terminal half-life (T1/2), area under the curve from time zero to 
8 hours (AUC0-8), area under the curve from time 0 to infinity (AUCinf) for Dose #1 
within 15 minutes predose, and at 1 (±15 min), 2 (±15 min), 6 (±30 min), and 
12 (±30 min) hours after end of administration (but prior to Dose #2); for Dose #3 within 
15 minutes predose, and at 1 (±15 min), 2 (±15 min), 6 (±30 min), 12 (±30 min) and 24 
(±30 min) hours after the end of administration (participants refusing these blood 
samplings can enter and remain in the trial). 
• 
Immunogenicity 
o Presence of anti-pGSN antibodies on Days 1 (predose), 28, and 90 
Exploratory 
• 
Biomarkers 
o Changes in biomarkers and radiologic imaging over time with treatment 


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o Relationship of baseline biomarkers to clinical outcomes 
 
Note: All deaths on-study must include cause of death as per investigator assessment and relationship to 
study drug and/or COVID-19. 
Data and Safety Monitoring Board 
See charter.  
Statistical Methods and Sample Size Rationale for Power Calculations: 
All subjects given e1 dose of study drug will be included in the Full Analysis Set (FAS) according to 
actual drug received; non-completers will be counted as failures in the primary efficacy analysis. Subjects 
receiving all 3 doses and evaluable for the primary Day 14 endpoint will constitute the per-protocol 
population for efficacy assessment. WHO severity score will be recorded daily while the subject is 
hospitalized, after discharge through Day 14, where feasible, and at each follow-up visit.  
AE data will be summarized for the FAS by actual drug received using counts and proportions of subjects 
having an AE, each AE type, and an AE of each System Organ Class. SAEs and reasons for any early 
discontinuation will be summarized similarly. All deaths will be categorized by cause of death as per 
investigator assessment and relationship to study drug and/or COVID-19. 
Immunogenicity will be assessed on Days 1 (predose), 28, and 90 days in all participants. Antibodies 
against pGSN will be assayed from frozen specimens to determine whether the investigational product 
induces an antibody response in recipients. 
For Part 1, binary efficacy endpoints will be compared between treatments via stratified Cochran-Mantel-
Haenszel (CMH) test and, to accommodate continuous covariates, via logistic regression. Continuous 
efficacy and biochemical endpoints will be compared between treatments via mixed model repeated 
measures analysis or analysis of covariance, depending on whether repeated measures are available or 
not. Time-to-event analysis via stratified log rank test and Cox proportional hazards model may also be 
carried out as supplemental analyses. 
For Part 1, exploratory analyses to compare the efficacy endpoint data from the rhu-pGSN group from 
this study to that of external control data may be carried out if appropriate. Sample size may be increased 
to improve the precision of the estimates of between-treatment comparisons if appropriate and if drug 
supplies are available. 
The primary endpoint is difference between treatments in the proportion of surviving subjects off 
vasopressors, the ventilator, and dialysis on Day 14. For Part 1, the power for the study is computed for 
the expected increase in proportion of surviving subjects without these supports at Day 14 after start of 
study treatment. A total sample size of N=54 has ~80% power to yield a statistically significant 
(alpha=0.2 1-sided) difference if the TRUE underlying proportions are 20% and 5% for placebo plus 
SOC and rhu-pGSN plus SOC, respectively. The minimum OBSERVED difference from placebo plus 
SOC proportion 20% that yields statistical significance is 8.4% (20% vs 11.6%). As this is a pilot Phase 2 
proof-of-concept (POC) trial in an infection with no approved therapy and false negative error (100% 
minus power) is equally as important as false positive error, the one-sided type 1 error is set at 0.2. Thus, 
the trial is adequately powered for its primary POC objective. 
For Part 2, only descriptive statistics will be provided for exploratory analyses. Binary efficacy endpoints 
will be summarized by counts, percentages, and 95% confidence intervals (CIs) for each treatment group. 
Differences in percentages between treatment groups will be summarized by 95% CIs. Continuous 
efficacy and biochemical endpoints will be summarized by counts, means, standard deviations, median, 
minimum, maximum by treatment group. Differences in means between treatment groups will be 
summarized by 95% CIs. Natural log transformation may be necessary to better approximate a bell-
shaped distribution for the continuous endpoints. Time-to-event endpoints will be summarized by 


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Kaplan-Meier plots, medians, quartiles, minimum, and maximum by treatment group. Bayesian posterior 
probabilities that differences from zero toward beneficial treatment effect for these summary statistics 
may be computed. 
 


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2. 
TABLE OF CONTENTS AND LIST OF TABLES  
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM ........................................................................................ 3 
1. 
SYNOPSIS ............................................................................................................................ 4 
2. 
TABLE OF CONTENTS AND LIST OF TABLES ....................................................... 12 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................ 16 
4. 
INTRODUCTION ............................................................................................................. 19 
4.1. Coronavirus 2019 (COVID-19) Pneumonia ................................................................... 19 
4.2. Current Treatment of COVID-19 Pneumonia ................................................................ 19 
4.3. Plasma Gelsolin .............................................................................................................. 20 
4.4. Preclinical and Clinical Experience ................................................................................ 21 
4.4.1. Preclinical Experience ........................................................................................ 21 
4.4.2. Clinical Experience ............................................................................................. 22 
4.5. Rationale for Study ......................................................................................................... 25 
4.6. Rationale for Starting Dose ............................................................................................. 25 
4.7. Risk/Benefit Assessment ................................................................................................ 25 
4.7.1. Known Potential Risks ........................................................................................ 25 
4.7.2. Known Potential Benefits ................................................................................... 26 
4.7.3. Assessment of Potential Risks and Benefits ....................................................... 26 
5. 
TRIAL OBJECTIVES AND ENDPOINTS .................................................................... 27 
5.1. Objectives ....................................................................................................................... 27 
5.1.1. Primary Objective ............................................................................................... 27 
5.1.2. Secondary Objectives ......................................................................................... 27 
5.1.3. Immunogenicity Objective ................................................................................. 27 
5.2. Endpoints ........................................................................................................................ 27 
5.2.1. Primary Endpoint ................................................................................................ 27 
5.2.2. Secondary Endpoints .......................................................................................... 28 
5.2.3. Exploratory Endpoints ........................................................................................ 29 
6. 
INVESTIGATIONAL PLAN ........................................................................................... 30 
6.1. Overall Study Design ...................................................................................................... 30 
6.2. Data and Safety Monitoring Board ................................................................................. 32 
6.3. Dose Discontinuation Criteria ........................................................................................ 32 
6.4. Management of rhu-pGSN Injection-Related Reactions ................................................ 32 
6.5. Study Duration ................................................................................................................ 34 
6.6. Total Duration of Subject Participation .......................................................................... 35 
6.7. End of Study Definition .................................................................................................. 35 
6.8. Criteria for Treatment Discontinuation ........................................................................... 35 
6.9. Subject Replacement ....................................................................................................... 36 
6.10. Criteria for Study Termination ................................................................................... 36 


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7. 
STUDY POPULATION .................................................................................................... 37 
7.1. Number of Subjects ........................................................................................................ 37 
7.2. Subject Inclusion Criteria ............................................................................................... 37 
7.3. Subject Exclusion Criteria .............................................................................................. 38 
7.4. Subjects or Partners of Subjects of Reproductive Potential ........................................... 38 
7.5. Waivers of Inclusion/Exclusion Criteria ......................................................................... 39 
8. 
DESCRIPTION OF STUDY TREATMENT .................................................................. 40 
8.1. Description of Study Drug .............................................................................................. 40 
8.2. Description of Placebo .................................................................................................... 40 
8.3. Preparation of Study Drug for Administration ............................................................... 41 
8.4. Subject Monitoring During rhu-pGSN Administration .................................................. 41 
8.5. Study Drug Administration ............................................................................................. 41 
8.6. Shipment of Study Drug ................................................................................................. 41 
8.7. Receipt and Storage of Study Drug ................................................................................ 42 
8.8. Accountability, Handling, and Disposal of Study Drug ................................................. 42 
8.9. Concomitant Medications ............................................................................................... 42 
8.10. Method of Assigning Subjects to Treatment Groups ................................................. 42 
8.11. Treatment Compliance ............................................................................................... 43 
8.12. Randomization and Blinding ..................................................................................... 43 
8.12.1. Unblinding .......................................................................................................... 43 
9. 
STUDY ASSESSMENTS .................................................................................................. 44 
9.1. Screening Assessments ................................................................................................. 49 
9.1.1. WHO Severity Score .......................................................................................... 49 
9.1.2. HIV Testing ....................................................................................................... 49 
9.1.3. Confirmation of COVID-19 Pneumonia ....................................................... 49 
9.1.4. Pregnancy Test .................................................................................................. 49 
9.2. Safety Assessments ....................................................................................................... 49 
9.2.1. Demographic/Medical History ........................................................................ 49 
9.2.2. Vital Signs .......................................................................................................... 50 
9.2.3. Physical Examination ....................................................................................... 50 
9.2.4. Outcome Prediction Models ............................................................................. 50 
9.2.5. Electrocardiogram ............................................................................................ 50 
9.2.6. Laboratory Assessments .................................................................................. 51 
9.3. Pharmacokinetic Assessments ..................................................................................... 51 
9.4. Pharmacodynamic Assessments .................................................................................. 52 
9.5. Other Assessments ........................................................................................................ 52 
10. 
ADVERSE EVENT MANAGEMENT ............................................................................ 53 
10.1. Definition of Adverse Events ..................................................................................... 53 
10.1.1. Adverse Event (AE) ............................................................................................ 53 
10.1.2. Serious Adverse Event (SAE) ............................................................................. 53 
10.2. Clarifications to Serious Adverse Event Reporting ................................................... 53 
10.3. Assessment of Causality ............................................................................................ 54 
10.4. Assessment of Severity .............................................................................................. 54 


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10.5. Pregnancy or Drug Exposure during Pregnancy ........................................................ 55 
10.6. Laboratory Abnormalities .......................................................................................... 55 
10.7. Reporting Adverse Events ......................................................................................... 55 
11. 
STATISTICS ...................................................................................................................... 57 
11.1. General Overview ...................................................................................................... 57 
11.2. Sample Size and Power Calculations ......................................................................... 58 
11.3. Analysis Populations .................................................................................................. 58 
11.4. Criteria for Evaluation and Statistical Methods ......................................................... 58 
11.4.1. Safety .................................................................................................................. 58 
11.4.2. Baseline Characteristics ...................................................................................... 58 
11.4.3. Pharmacokinetics and Immunogenicity .............................................................. 58 
11.4.4. Pharmacodynamics ............................................................................................. 59 
12. 
DATA RECORDING, RETENTION AND MONITORING ........................................ 60 
12.1. Case Report Forms ..................................................................................................... 60 
12.2. Records Retention ...................................................................................................... 60 
12.3. Data Monitoring ......................................................................................................... 60 
12.4. Quality Control and Quality Assurance ..................................................................... 61 
13. 
REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS ..................................... 62 
13.1. Good Clinical Practice ............................................................................................... 62 
13.2. Independent Ethics Committee Approval .................................................................. 62 
13.3. Regulatory Authority Approval ................................................................................. 62 
13.4. Other Required Approvals ......................................................................................... 62 
13.5. Informed Consent ....................................................................................................... 62 
13.6. Subject Confidentiality .............................................................................................. 63 
13.7. Disclosure of Information .......................................................................................... 63 
14. 
PUBLICATION POLICY ................................................................................................ 64 
15. 
LIST OF REFERENCES .................................................................................................. 65 
16. 
APPENDICES .................................................................................................................... 67 
 
 


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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms .......................................................................... 16 
Table 2: 
Summary of Deaths .................................................................................................... 23 
Table 3: 
Definition of Injection-Related Reactions ................................................................. 33 
Table 4: 
Investigational Product .............................................................................................. 40 
Table 5: 
Schedule of Assessments ........................................................................................... 45 
 
 
 
 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term Explanation 
ACE-2 
angiotensin-converting enzyme 2 
AE 
adverse event 
ALT 
alanine aminotransferase 
ASAP 
as soon as possible 
AST 
aspartate aminotransferase 
AUC0-8 
area under the curve from time zero to 8 hours 
AUCinf 
area under the curve from time zero to infinity 
BioAegis 
BioAegis Therapeutics, Inc. or Sponsor 
BiPAP 
bilevel positive airway pressure 
BUN 
blood urea nitrogen 
CAP 
community-acquired pneumonia 
CBC 
complete blood count 
CI 
confidence interval 
Cmax 
maximum concentration 
CMH 
Cochran-Mantel-Haenszel 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus 2019 
CPAP 
continuous positive airway pressure 
CPK 
creatine phosphokinase 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CURB-65 
Confusion, Urea >7 mmol/L, Respiratory rate 
e30/min, Blood pressure systolic <90 or diastolic 
d60, and age e65 years 
CXR 
chest x-ray 
CYP450 
cytochrome P450 
DSMB 
Data and Safety Monitoring Board 


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Abbreviation or Specialist Term Explanation 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic case report form 
ED 
emergency department 
EDC 
electronic data capture 
EKG 
electrocardiogram 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
f-actin 
filamentous actin 
FAS 
Full Analysis Set 
g-actin 
globular actin 
GCP 
Good Clinical Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of 
Technical Requirements for Pharmaceuticals for 
Human Use 
ICU 
intensive care unit 
IEC 
Independent Ethics Committee 
IL 
interleukin 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
injection-related reaction 
IUD 
intrauterine device 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LOS 
length of stay 
MV 
mechanical ventilation 
NCI 
National Cancer Institute 
NSAIDS 
non-steroidal anti-inflammatory drugs 
PDF 
portable document format 
PE 
physical examination 
PEEP 
positive end-expiratory pressure 


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Abbreviation or Specialist Term Explanation 
pGSN 
plasma gelsolin 
PI 
Principal Investigator 
The Investigator who leads the study conduct at an 
individual study site. Every study site has a Principal 
Investigator. 
PK 
pharmacokinetics 
POC 
proof of concept 
rhu-pGSN 
recombinant human plasma gelsolin 
RRT 
renal replacement therapy 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SDV 
source data verification 
SOC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
TNF 
tumor necrosis factor 
US 
United States 
VP 
vasopressor 
WHO 
World Health Organization 
 


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4. 
INTRODUCTION 
4.1. 
Coronavirus 2019 (COVID-19) Pneumonia 
Pneumonia is an inflammatory condition of the lung primarily affecting the alveoli. It is usually 
caused by infection with viruses or bacteria and less commonly other microorganisms. Certain 
drugs and other conditions such as autoimmune diseases may cause a similar clinical picture. 
Typical symptoms include a cough, chest pain, fever, and difficulty breathing. Diagnostic tools 
include chest x-rays (CXRs), serology, microscopy of a sputum smear and culture of the sputum. 
Treatment depends on the underlying cause. Pneumonia documented or presumed to be viral, 
bacterial, or fungal is treated with appropriate agents when available. If the pneumonia is severe, 
the affected person is admitted to hospital. 
Pneumonia is classified according to the etiologic organism and where the infection was 
acquired (community or hospital facility). 
Community-acquired pneumonia (CAP) is the most common type of pneumonia, and may be 
caused by pyogenic bacteria, atypical bacteria, viruses or fungi which often cannot be identified 
in real time. CAP may also have non-infectious etiologies, including allergic, immune-mediated, 
toxins, or drugs. CAP occurs throughout the world and is a leading cause of illness and death. 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-
converting enzyme 2 (ACE-2) receptors located to certain epithelial and endothelial cell 
surfaces. Lung tissue is the major, but not sole target of this novel coronavirus. The agent can 
cause fatal infections by eliciting an over-exuberant immune response leading to injurious lung 
inflammation +/- a cytokine storm. Patients may die from acute lung injury/acute respiratory 
distress syndrome or survive with debilitating pulmonary fibrosis. Interventions have been 
proposed as treatment modalities to decrease the viral load and/or to modulate the intense host 
reaction. Blunting of an overzealous inflammatory response can potentially improve respiratory 
outcomes independent of any direct antiviral effect. A coagulopathy that may result in large part 
from endothelial cell disruption can contribute to the pathogenesis by predisposing to 
disseminated microthrombi and large vessel thromboemboli. Older, hypertensive, and diabetic 
patients are at highest risk for complications and serious outcomes.  
Plasma gelsolin (pGSN), an abundant, naturally occurring, circulating protein depleted in severe 
inflammatory conditions, offers similar promise in aborting lung injury, and offers a possible 
novel therapeutic agent in this time of crisis. Since recombinant human pGSN (rhu-pGSN) is a 
pathogen-indifferent treatment acting primarily on host inflammatory responses, the microbial 
etiology of life-threatening pneumonia is not particularly relevant.  
4.2. 
Current Treatment of COVID-19 Pneumonia 
Possible treatments for COVID-19 pneumonia include corticosteroids; lopinavir/ritonavir; 
chloroquine or hydroxychloroquine +/- azithromycin; remdesivir; ACE-2 blockers; interleukin 
(IL)-1 and IL-6 inhibitors; kinase inhibitors; interferons; and passive antibody either 
convalescent plasma-derived or monoclonal; granulocyte-macrophage colony-stimulating factor 
(GM-CSF); anti-coagulants; among others. With the possible exceptions of remdesivir and 


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corticosteroids, the evidence that specific therapies favorably impact the course of the disease 
has not been persuasively demonstrated. Some interventions seem to be helpful early but not 
later in the course of illness, such as monoclonal antibodies directed against COVID-19 surface 
proteins. Antiviral agents may also be more effective before disease becomes too advanced. 
Proof-of-concept (POC) for rhu-pGSN therapy in human conditions has not yet been established 
but there are abundant animal data demonstrating survival benefits with tissue protection in 
diverse infectious and non-infectious inflammatory conditions. The recombinant human 
formulation (rhu-pGSN) developed by BioAegis Therapeutics, Inc. (BioAegis or Sponsor) has 
already been administered to patients with mild community-acquired pneumonia (CAP) in a 
small dose-ranging trial supporting safety and tolerability 
(https://clinicaltrials.gov/ct2/show/NCT03466073). 
4.3. 
Plasma Gelsolin  
Plasma gelsolin (pGSN) is a human protein produced and secreted by virtually every cell type, 
and it circulates at high levels in the blood of healthy individuals. At normal levels of 
200-300 mg/L, it is the fourth most abundant protein in the circulation. 
The therapeutic protein developed by BioAegis is rhu-pGSN and was formerly referred to as 
BG9385. It is identical to the complete natural protein and is comprised of 755 amino acids. The 
protein, like the natural protein, is non-glycosylated. The protein consists of six repeated 
domains, which make up three distinct actin binding sites, two that bind globular actin (G-actin) 
and one that binds filamentous actin (F-actin). Domain 1 plus the first 10 amino acids of 
domain 2 of gelsolin is the minimal fragment size required for its actin severing activity. Rhu-
pGSN contains multiple calcium binding sites that regulate its activity. It is a highly conserved 
protein, as far back as drosophila. 
Plasma gelsolin modulates inflammation while at the same time, boosting the body’s ability to 
clear pathogens. It functions through mechanisms quite distinct from anti-inflammatory agents, 
which are antagonists of specific mediators or inhibitors of specific enzymes. Plasma gelsolin 
functions through a pleiotropic mechanism of action, scavenging toxic actin, binding 
inflammatory mediators and enhancing pathogen clearance. pGSN levels decrease markedly in a 
variety of clinical conditions such as acute respiratory distress syndrome, sepsis, major trauma, 
prolonged hyperoxia, malaria, and liver injury. The strength of the correlation between 
magnitude of decline in pGSN and likelihood of mortality is especially striking (Lee et al, 2006; 
2008; 2009; Osborn et al, 2008). Specifically, a study of adult patients hospitalized with CAP 
showed that lower pGSN concentrations were significantly associated with more severe clinical 
outcomes (Self et al, 2018). Repletion of depressed plasma gelsolin levels with rhu-pGSN is 
expected to benefit patients through four distinct mechanisms that have been described in the 
literature: 
1.  Sequestration of released actin from sites of damage. This sequestration causes local 
depletion of pGSN while leaving large stores of pGSN continuing to circulate in healthy 
individuals. Modest reduction of systemic pGSN levels is then restored after healing is 
complete (Haddad et al, 1990; Lee et al, 1992). 


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2.  Prevention of the escape of mediators of inflammation from the local site. Local depletion 
allows appropriate inflammation/healing to proceed while high circulating levels keep the 
mediators local (Bucki et al, 2005, 2008, and 2010; Piktel et al, 2020). pGSN binds and 
dampens pro- inflammatory mediators such as platelet-activating factor, lysophosphatidic 
acid, and bacterial products (Goetzel et al, 2000; Vasconcellos and Lind, 1993; Bucki et al, 
2005; Bucki et al, 2008; Bucki et al, 2010; Osborn et al, 2007). pGSN can also bind 
fibronectin (Lind et al, 1984) and fibrin (and possibly pro-inflammatory fibrinopeptides) 
(Smith et al, 1987), and may ‘escort’ or delay binding of lysophosphatidic acid and other 
mediators to their receptors (Goetzel et al, 2000; Bucki et al, 2010). 
3.  Enhanced uptake of gram + and gram – bacteria by tissue macrophages. It has been 
shown that actin inhibits bacterial uptake and that pGSN reverses that inhibition. Excess 
actin in seriously ill individuals may account for immune suppression seen in these patients. 
4.  Improved killing of gram + and gram – bacteria by tissue macrophages. This function is 
distinct from the function that enhances bacterial uptake. It has been shown to be mediated 
by induction of NOS3 and is absent in NOS3 knock-out mice (Yang et al, 2015). 
The development of rhu-pGSN was initiated in the 1990s and included development of the 
original E. coli cell bank and conduct of non-clinical and first clinical studies with the protein 
produced from culture of aliquots of this cell bank. BioAegis took over the development of 
rhu-pGSN, established a new E. coli cell line for the production of rhu-pGSN, and implemented 
improvements in the manufacturing process of the therapeutic protein. 
4.4. 
Preclinical and Clinical Experience 
4.4.1. 
Preclinical Experience 
The preclinical studies of pGSN have revealed no safety concerns related to its mechanism of 
action or formulation. No functional effects on the respiratory system and no systemic toxicity 
attributed to rhu-pGSN or the formulation excipient, 0.1% polysorbate 80 (Tween-80), were 
observed in these studies at the highest achievable doses. No clinically relevant pathological 
effects were evident in rats or monkeys following administration of pGSN or 0.1% polysorbate 
80 vehicle for up to 28 days by inhalation or for 14 days by intravenous (IV) injection. 
Exposures to the lower respiratory tract of rats and monkeys in the repeat-inhalation dose 
toxicity studies were up to approximately 75 and 250 times, respectively, the estimated level at 
the proposed starting dose to be administered to patients with CAP. Based upon the lack of test 
article-related effects, safety margins are estimated to be in excess of 4.5 and 30 times (for rat 
and monkey, respectively) the highest planned clinical dose. 
The pharmacokinetic (PK) profile of rhu-pGSN following inhalation, intratracheal, IV, or oral 
administration is consistent with that of a relatively stable, high molecular weight protein. 
Detectable systemic absorption of rhu-pGSN following inhalation exposure is not extensive. No 
changes in endogenous plasma gelsolin levels were detected using an enzyme-linked 
immunosorbent assay (ELISA) following aerosol administration of pGSN to monkeys at 
presented dose levels up to 9,550 mg/kg. The half-life of rhu-pGSN-related radioactivity in the 
lung was approximately 10 to 16 hours in normal rats and monkeys, respectively, following 
pulmonary exposure. 


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Test article-related effects observed following repeat aerosol administration of pGSN under 
conditions of continuous pulmonary exposure was limited to minimal microscopic changes in 
the lungs of monkeys. The microscopic change is attributed to an immunogenic response as 
evidenced by the detection of antibodies to rhu-pGSN. The antibodies appeared to be directed 
against the human-specific epitopes of intact rhu-pGSN and caused no clinical or pathological 
signs of serum sickness. Thus, the immunogenic reaction to rhu-pGSN in monkeys appears to be 
a species-specific response and, therefore, is not considered to be clinically relevant. 
No cardiovascular effects were noted in monkeys receiving pGSN by either inhalation or IV 
administration. 
No eye or skin irritation was noted in rabbits after acute exposure to the product. 
In a murine model of influenza A/PR/8/34, male CD1 mice were treated with subcutaneous 
rhu-pGSN ranging in dose from 0.5 to 5 mg where treatment was initiated 3 or 6 days after 
intranasal viral challenge (Yang et al, 2020). Overall, when combining all doses regardless of the 
day treatment was initiated, mice treated with rhu-pGSN had a significantly higher survival rate 
(p=0.000001) on day 12 than those treated with vehicle. Improved survival was observed 
regardless of the day treatment was initiated.  
In a murine model of pneumococcal pneumonia, male CD1 mice were treated with 
intraperitoneal rhu-pGSN ranging in dose from 5 to 10 mg (Yang et al, 2019). Treatment was 
initiated either 2 or 3 days after intranasal challenge with Streptococcus pneumoniae type 3 or 
24 hours after infection with an antibiotic-resistant pneumonia strain, type 14, and treated for 
9 days. In both models, treatment with rhu-pGSN increased survival and reduced morbidity and 
weight loss. 
Lastly, another murine model of multidrug-resistant Pseudomonas aeruginosa pneumonia was 
used to evaluate the effect of rhu-pGSN on survival and lung injury (DiNubile et al, submitted 
for publication in 2020). Neutropenic BALB/c mice were treated subcutaneously with different 
meropenem doses ± 12 mg/day of intraperitoneal rhu-pGSN commencing 1 day before 
intratracheal challenge with multidrug-resistant P. aeruginosa. Mice were treated for 5 days and 
assessed on day 7. Overall survival was 35/64 (55%) and 46/64 (72%) in mice given meropenem 
without or with rhu-pGSN, respectively [”  (95% confidence interval) = 17% (1, 34)]. In control 
mice receiving meropenem 1250 mg/kg/day where the majority died, addition of rhu-pGSN 
increased survival from 5/16 (31%) to 12/16 (75%) [”  = 44%]. Survival with minor lung injury 
was found in 26/64 (41%) mice receiving only meropenem versus 38/64 (59%) in mice given 
meropenem plus rhu-pGSN [”  (95% confidence interval) = 19% (2, 36)]. Overall, both mortality 
and lung injury were reduced by the addition of rhu-pGSN to meropenem against carbapenem-
resistant P. aeruginosa, most prominently in situations where meropenem alone was highly 
inefficacious. 
In summary, the preclinical profile of pGSN supports continued evaluation of rhu-pGSN in 
humans and suggests that the drug is well tolerated with a low risk of respiratory or systemic 
toxicity. 
4.4.2. 
Clinical Experience 
Rhu-pGSN has been previously evaluated in 4 clinical studies. 


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Study 96-900 was a Phase 1, double-blind, randomized, controlled, within-subject, dose- 
escalation study in 24 healthy volunteers conducted in the United Kingdom. Patients were dosed 
via nebulization up to a maximum dose of 32 mg given twice per day. Adverse events (AEs) 
were minor and none were consistently attributed to treatment. No formation of antibodies to 
rhu-pGSN was observed. 
Study C96-901 was a randomized, double-blind, placebo-controlled, dose-escalating, tolerability 
study of inhaled rhu-pGSN in 21 patients with cystic fibrosis conducted at one clinical site in 
Canada. Rhu-pGSN or placebo was administered via nebulization at 3.0 mg/day (Day 1 and 2), 
10 mg/day (Day 3 and 4) and 25 mg/day (Day 5 to 9). Sixteen patients were randomized to 
rhu-pGSN and 5 patients to placebo (randomization ratio 3:1). Rhu-pGSN was well tolerated 
with no safety concerns. No patients withdrew from the study. There was no negative effect on 
pulmonary function. There were no serious adverse events (SAEs) and no AEs were considered 
likely or definitely related to treatment. 
Study CBC-101 was a randomized, double-blind, placebo-controlled, ascending dose, infusion 
trial of the PK of rhu-pGSN in patients with decreased natural gelsolin levels. This Phase 1b/2a 
study was conducted in Hong Kong and enrolled patients admitted to the ICU. Twenty-eight 
patients were enrolled; 21 patients received rhu-pGSN and 7 received placebo. The 4 cohorts 
were treated with ascending doses of rhu-pGSN via IV infusion according to the following 
scheme: 
Cohort 1: Single infusion of 3 mg/kg rhu-pGSN (10 patients) or placebo (3 patients)  
Cohort 2: Single infusion of 6 mg/kg rhu-pGSN (3 patients) or placebo (2 patients) 
Cohort 3: Daily infusion of 6 mg/kg rhu-pGSN for 3 days (6 patients) or placebo (2 patients) 
Cohort 4: Daily infusion of 6 mg/kg rhu-pGSN for 3 days (2 patients with severe multiple organ 
failure) 
The dose escalation over the successive cohorts was supervised by an independent Data and 
Safety Monitoring Board (DSMB). The DSMB had to document the safety profile of the drug 
before allowing the study to proceed to a higher dose and/or exposure. No safety concerns 
associated with rhu-pGSN were raised by the DSMB. Seven patients died during the 3-month 
observation period (Table 2); none of the deaths were assessed as related to study treatment. No 
patient who received placebo died. The incidence of death in the rhu-pGSN-treated patients 
(7/21; 33%) is within the limits of expectation for patients admitted in intensive care unit (ICU) 
with similar diagnoses. However, the incidence of death was lower than expected in the placebo 
group, most probably due to imbalances in multiple baseline clinical prognostic factors in favor 
of the placebo group when compared to the rhu-pGSN group. 
Table 2: 
Summary of Deaths 
Subject 
Cohort 
Age 
pGSN 
mU/mL 
Admission diagnosis1 VP MV 
Day of 
admission 
relative to 
infusion2 
Day of 
death3 


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G004 
1 
84 
921 
Fecal peritonitis, 
emergency 
rectosigmoidectomy, 
renal insufficiency 
Yes Yes 
-10 
5 
G006 
1 
69 
1892 
Pneumonia with 
hepatitis 
No Yes 
-10 
3 
G012 
1 
79 
524 
Sigmoid perforation, 
emergency 
rectosigmoidectomy 
No 
No 
-6 
26 
G015 
2 
79 
1161 
Pneumonia, COPD 
Yes Yes 
-15 
21 
G017 
2 
78 
963 
Peritonitis with 
terminal 
cholangiocarcinoma 
No 
No 
-10 
16 
G018 
2 
85 
1128 
Pneumonia with renal 
insufficiency 
Yes Yes 
-10 
66 
G401 
4 
83 
780 
Pneumonia with renal 
insufficiency 
Yes Yes 
-4 
7 
1 Diagnosis established at ICU admission 
2 Represents the day of hospitalization (irrespective of ICU or not) relative to day of infusion 
3 Day of death relative to first infusion 
COPD = chronic obstructive pulmonary disease; ICU = intensive care unit; MV = mechanical 
ventilation; pGSN = plasma gelsolin; VP = vasopressor. 
 
Study BTI-201 was a Phase 1b/2a, double-blind, placebo-controlled, single- and multiple-
ascending dose escalation study to evaluate the safety, PK, and pharmacodynamics of rhu-pGSN 
added to standard of care (SOC) in non-ICU patients hospitalized for mild CAP. Eligible 
subjects were randomized 3:1 to receive adjunctive IV rhu-pGSN or placebo. Thirty-three 
subjects were treated: 8 received a single dose of rhu-pGSN 6 mg/kg, and 25 received a daily 
rhu-pGSN dose of 6, 12, or 24 mg/kg over 3 consecutive days. 
Overall, AEs were mild in both treatment groups irrespective of dose. AEs were reported more 
frequently in the lowest rhu-pGSN dose cohorts and the less frequently in the highest rhu-pGSN 
dose cohorts. Treatment-emergent adverse events (TEAEs) that were reported in more than 
1 subject in the rhu-pGSN groups were: nausea (11.1% rhu-pGSN; 0% placebo) and blood 
pressure increased (11.1% rhu-pGSN; 0% placebo). No injection-related reactions were reported. 
Of the subjects treated with rhu-pGSN, no subject experienced a TEAE assessed as drug-related 
and no subject discontinued due to a TEAE. 


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Two subjects experienced SAEs: 1 SAE was reported in 1 subject who received a single dose of 
rhu-pGSN and 2 SAEs were reported in 1 subject who received placebo in the multiple-
ascending dose phase. One subject who received a single dose of rhu-pGSN had an SAE of 
pneumonia (Grade 5, not related) after being withdrawn from the study; and 1 subject who 
received placebo had SAEs of pneumonia (Grade 4, not related) and pulmonary embolism 
(Grade 5, not related).  
Pharmacokinetic analyses showed that the median rhu-pGSN half-life exceeded 17 hours with 
all dosing regimens. Overall, rhu-pGSN was well tolerated in patients admitted to non-ICU beds 
with CAP. 
4.5. 
Rationale for Study 
The damage inflicted by COVID-19 is primarily mediated through an overly exuberant host 
response to the virus, not directly by the virus itself. This overblown reaction consists of 
excessive and prolonged inflammation culminating in a cytokine storm and disseminated 
coagulopathy injuring the lungs and blood vessels. Interrupting or tempering this maladaptive 
process lessens further organ injury, restoring immune equilibrium and allowing tissue repair.  
Plasma gelsolin plays a central regulatory role (“master switch”) in diverse inflammatory 
pathways. A dual-pronged attack on COVID-19 concurrently reducing the inciting virus (with 
remdesivir or other antiviral agents) and quelling the inflammatory tsunami (with a non-toxic but 
powerful anti-inflammatory drug) could theoretically synergize in shutting down the COVID-19 
attack better than either modality alone. The action of pGSN on multiple pathways effectively 
blocks unbridled immune activation without inducing undesired side-effects or dangerous 
immunosuppression. 
The study protocol was amended to include Part 2 to evaluate rhu-pGSN in 10 subjects 
(compared to 10 placebo subjects) who are intubated without extracorporeal membrane 
oxygenation (ECMO) and therefore score as level 6 or 7 on the WHO scale. Recent data in the 
“steroid era” have suggested that immunomodulators may exert their most beneficial effects in 
critically ill patients which were not captured in the original recruitment for this study. 
Compassionate use in a single patient who scored as level 7 on the WHO scale in April 2021 
resulted in quick and dramatic improvement temporally related to rhu-pGSN administration. 
Accordingly, intubated patients may be an appropriate target population for rhu-pGSN. 
4.6. 
Rationale for Starting Dose 
The dosage for this trial was extrapolated from efficacious doses in animal studies of severe 
pneumonia. A Phase 1b/2a dose escalation study showed no drug-related or SAEs in patients 
with CAP administered 3 daily doses of rhu-pGSN at 6, 12, and 24 mg/kg of actual body weight. 
4.7. 
Risk/Benefit Assessment 
4.7.1. 
Known Potential Risks 
The safety database is limited to a total of 24 rhu-pGSN recipients. Some of these subjects 
developed apparent anti-drug antibodies, although no untoward effects were recognized. 


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4.7.2. 
Known Potential Benefits 
Rhu-pGSN may temper excessive tissue inflammation and thereby limit organ damage. 
4.7.3. 
Assessment of Potential Risks and Benefits 
Because rhu-pGSN is a naturally occurring blood protein, there is little a priori concern about 
intrinsic toxicity. Furthermore, experimental data support benefit in uncontrolled inflammatory 
states. Overall, the drug is expected to have a favorable risk:benefit ratio. 


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5. 
TRIAL OBJECTIVES AND ENDPOINTS 
5.1. 
Objectives 
5.1.1. 
Primary Objective 
• To assess the efficacy (survival without organ failure on Day 14) of IV rhu-pGSN plus 
SOC vs placebo plus SOC (hereafter referred to as rhu-pGSN vs placebo) administered to 
hospitalized subjects with a primary diagnosis of COVID-19 pneumonia and in Part 1, a 
severity score of 4, 5, or 6, or for Part 2, intubated without ECMO with a severity score 
of 6 or 7 on the World Health Organization (WHO) 9-point severity scale 
• To evaluate the safety (incidence of SAEs) of IV rhu-pGSN administered to hospitalized 
subjects with a primary diagnosis of COVID-19 pneumonia and in Part 1, a severity 
score of 4, 5, or 6, or for Part 2, intubated without ECMO with a severity score of 6 or 7 
on the WHO 9-point severity scale 
5.1.2. 
Secondary Objectives 
• To further assess the efficacy of IV administered rhu-pGSN  
• To measure changes in the WHO 9-point severity scale for SOC ± rhu-pGSN 
• To evaluate the effect of administered rhu-pGSN on survival rates 
• To assess the relationship of pGSN levels (and other biomarkers) at baseline with clinical 
outcomes 
• 
 To follow the PK of administered rhu-pGSN  
5.1.3. 
Immunogenicity Objective 
• To investigate the development of antibodies against pGSN post-treatment in rhu-pGSN 
vs placebo recipients compared to baseline 
5.2. 
Endpoints 
5.2.1. 
Primary Endpoint 
• Safety and tolerability 
o Incidence of SAEs in rhu-pGSN vs placebo groups 
• Efficacy 
o Proportion of subjects alive not on vasopressors, mechanical ventilator, and 
dialysis on Day 14 


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5.2.2. 
Secondary Endpoints 
• Safety and tolerability 
o Incidence, causality, and severity of AEs (graded according to the National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events 
[CTCAE] version 5.0) in rhu-pGSN vs placebo groups  
o Frequencies of new or worsening clinically significant laboratory abnormalities in 
rhu-pGSN vs placebo groups 
o Mortality rate irrespective of cause at Days 28 and 90 
• Efficacy 
o Daily change in 9-point WHO severity score through at least Day 14 (including 
after discharge, where feasible) 
o All-cause mortality at Days 28 and 90; time to death (Kaplan-Meier survival 
analysis) 
o Proportion of subjects alive on Days 7, 14, 28, 60, and 90 without: 
 Ongoing use of vasopressors  
 Ongoing intubation/mechanical ventilation 
 Ongoing residence in an ICU 
 New ongoing need for dialysis/renal replacement therapy (RRT) 
o Proportion of subjects discharged to home or immediate prior residence by 
Day 28  
o Days on the ventilator 
o Length of stay (LOS) in hospital and in ICU (days) 
o Re-admission to an acute-care hospital up to Day 90 
• 
PK  
o PK for rhu-pGSN including maximum concentration (Cmax), time to maximum 
concentration (Tmax), terminal half-life (T1/2), area under the curve from time zero 
to 8 hours (AUC0-8), area under the curve from time 0 to infinity (AUCinf) for 
Dose #1 within 15 minutes predose, and at 1 (±15 min), 2 (±15 min), 6 (±30 min), 
and 12 (±30 min) hours after end of administration (but prior to Dose #2); for 
Dose #3 within 15 minutes predose, and at 1 (±15 min), 2 (±15 min), 6 (±30 min), 
12 (±30 min) and 24 (±30 min) hours after the end of administration (participants 
refusing these blood samplings can enter and remain in the trial). 
• Immunogenicity 
o Presence of anti-pGSN antibodies on Days 1 (predose), 28, and 90 


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5.2.3. 
Exploratory Endpoints 
• Biomarkers 
o Changes in biomarkers and radiologic imaging over time with treatment 
o Relationship of baseline biomarkers to clinical outcomes 
Note: All deaths on-study must include cause of death as per investigator assessment and 
relationship to study drug and/or COVID-19. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a 2-part, randomized, double-blind, placebo-controlled, multicenter Phase 2 study to 
evaluate the efficacy and safety of rhu-pGSN plus SOC in subjects with severe COVID-19 
pneumonia. Potential subjects hospitalized with pneumonia and laboratory-confirmed (reverse 
transcription polymerase chain reaction [RT-PCR+]) or highly suspected (compatible with at 
least bilobar lung involvement without any other plausible diagnosis) COVID-19 etiology will 
be screened for Part 1 within 24 hours of reaching a WHO severity score of 4 to 6, whether the 
severity score is attained on admission or during hospitalization, or for Part 2, within 24 hours of 
intubation without ECMO with a WHO severity score of 6 or 7.  
The 9-point WHO classification scheme for severe COVID-19 pneumonia will be applied to 
grade the severity of illness as follows:  
8 Death 
7 Mechanical ventilation or ECMO with either vasopressor support or dialysis/RRT 
6 Intubation with mechanical ventilation, a mask with a reservoir or oxygen with high-flow 
nasal goggles but without vasopressor support or dialysis/RRT 
5 Noninvasive ventilation (continuous positive airway pressure [CPAP] or bilevel positive 
airway pressure [BiPAP]) or high-flow oxygen 
4 Oxygen by mask or nasal  
3 Hospitalized with no oxygen therapy 
2 Limitation of activity 
1 Infected without limitations 
0 No clinical or virologic evidence of COVID-19 infection  
 
Once informed consent is obtained, the following assessments/procedures will be performed:  
1. Record medical history, including concomitant medications and current clinical status 
2. Perform pregnancy test (urine or blood) for women of childbearing potential 
3. Collect pretreatment blood samples for measurement of baseline pGSN and for analysis 
of antibodies against pGSN 
4. Calculate the CURB-65 score (Confusion, Urea >7 mmol/L, Respiratory rate e30/min, 
Blood pressure systolic <90 or diastolic d60, and age e65 years) at presentation 
(Appendix A) 
5. A RT-PCR test to confirm the diagnosis of COVID-19 should be documented during the 
current illness leading to the present hospitalization; if RT-PCR test is not done prior to 
screening, the test is to be performed during screening before randomization (result might 


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not be available at randomization or start of study treatment). Perform physical 
examination (PE) and document radiographic evidence of pneumonia (CXR or computed 
tomography ([CT] scan if CXR is inadequate) if not already completed within the 
previous 48 hours per SOC 
6. Obtain blood and sputum cultures and electrocardiogram (EKG) per SOC (if not already 
performed). The microbiology lab is encouraged to perform sputum (bacterial, viral, and 
mycobacterial, as indicated) and blood cultures, sputum Gram-stains, antigen detection 
on respiratory and urine specimens, and RT-PCR diagnostic tests as possible. 
7. Measure routine lab tests and biomarkers, including ferritin, D-dimer, C-reactive protein 
(CRP) and procalcitonin level at local laboratory; collect aliquots of blood for subsequent 
biomarker assays (likely to include, but not limited to IL1² , IL6, IL10, tumor necrosis 
factor [TNF], etc.) for analysis at the central laboratory (see Table 5 Schedule of 
Assessment and footnote ‘l’ for details). 
8. If eligibility criteria are satisfied, subject to be randomized (1:1 to treatment arms rhu-
pGSN:placebo) within 12 hours of informed consent (Part 1) or within 24 hours of 
intubation (Part 2). 
Randomized subjects will receive the assigned dose of rhu-pGSN or an equal volume of sterile 
saline placebo as soon as possible (ASAP), but beginning no later than 12 hours of 
randomization. The rhu-pGSN dose will be based on actual body weight given at 12 mg/kg. 
After reconstitution, rhu-pGSN should not be kept at room temperature for >2 hours prior to 
beginning the infusion. The initial dose of study drug (Dose #1) will be followed by dosing at 12 
(Dose #2) and 36 hours (Dose #3) after the initial administration. Study drug is administered as a 
slow IV bolus at a rate of 20 mL/min through a 0.2 µm filter. The syringe, filter, and extension 
tubing for injection of study drug should be connected after disconnecting the IV as close to the 
subject as possible.  
The primary efficacy endpoint will be assessed on Day 14, with secondary endpoints assessed on 
Days 7, 28, 60, and 90. Discharged subjects will undergo follow-up evaluation on Days 14, 28, 
60, and 90. 
Screening laboratory and other tests can serve as baseline values for participants, they do not 
need to be repeated if performed within the prior 24 hours of randomization unless otherwise 
dictated by SOC; however, the blood sample for analysis of pGSN levels must be repeated if not 
collected within 15 minutes of initiating the first dose of study drug. The day of first study drug 
administration will be used as baseline (Day 1) for analysis purposes. Screening should be done 
on Day -1 up to the time of randomization. 
Repeat CXRs, or CT scans if CXR is inadequate, and labs/cultures, etc. will be obtained during 
the hospitalization if/when indicated by SOC. 
On Days 1 (predose), 28, and 90, blood samples for analysis of antibodies against pGSN will be 
collected.  
If the patient expires, autopsy is encouraged. 


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6.2. 
Data and Safety Monitoring Board 
An independent DSMB will be established to closely monitor the safety of subjects. The primary 
mission of the DSMB is to ensure that decisions are made that serve the best interests of patients 
volunteering for the study. 
The independent DSMB will be comprised of 4 voting members: 3 academicians/clinicians with 
expertise in pulmonary care, critical care, and/or infectious diseases as related to COVID-19 
pneumonia, and a statistician. Representatives from the Contract Research Organization (CRO) 
and Sponsor’s Chief Medical Officer will be able to attend the open meetings to provide 
information and administrative support to the DSMB. However, they will not have any voting 
rights and will not attend the closed meeting where unblinded data may be discussed.   
No SAEs have been associated with the investigational medicinal product. Thus, all SAEs will 
be considered as unexpected for reporting purposes. All reported deaths and treatment-emergent 
SAEs will be sent by EastHORN Safety to the DSMB within 2 working days of notification of 
the CRO/Sponsor by the sites. The events will be evaluated by the DSMB and comments 
returned to EastHORN Safety within 2 working days of notification of the DSMB. A DSMB 
meeting does not necessarily need to be convened. Ad hoc meetings will be convened whenever 
felt appropriate by a DSMB member.  
In Part 1, periodic safety reviews will be conducted after 12, 24, 36, and 48 subjects have been 
fully dosed and completed assessment at Day 14. Only DSMB members will be provided with 
partially unblinded results separated into 2 groups by treatment without identifying the actual 
treatment. If all participants have completed study therapy before the last DSMB meeting 
involving review of 48 subjects after their Day 14 visit can be held, this meeting can be 
cancelled at the discretion of the DSMB chair. 
Data may be further unblinded and/or the study paused at the discretion of the DSMB chair; 
otherwise, enrollment will continue during the safety review. 
Please refer to the DSMB Charter for further details.  
6.3. 
Dose Discontinuation Criteria 
Dosing of rhu-pGSN may be stopped during the study at the discretion of the DSMB. In general, 
doses should not be interrupted for Grade 1 AEs, but treatment to control symptoms should be 
provided, if applicable. 
6.4. 
Management of rhu-pGSN Injection-Related Reactions 
Injection-related reactions (IRRs) (Table 3) will be defined according to the NCI CTCAE, 
version 5.0 or higher. 


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Table 3: 
Definition of Injection-Related Reactions 
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
IRR 
Mild transient 
reaction; 
injection 
interruption not 
indicated; 
intervention not 
indicated 
Therapy or injection 
interruption indicated 
but responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, narcotics, 
IV fluids); 
prophylactic 
medications indicated 
for d24 hours 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication, brief 
interruption of injection, or 
both); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for clinical sequelae 
Life- 
threatening 
consequences; 
urgent 
intervention 
indicated 
Abbreviations: IRR=injection-related reaction; IV=intravenous; NSAIDs=non-steroidal anti-
inflammatory drugs. 
 
Management of Grade 1 IRRs 
If a subject presents with a Grade 1 IRR: 
• The injection may be continued; however, the rate may be reduced to 50% at the 
discretion of the Investigator. 
• If the symptoms resolve, the injection can be increased, as tolerated, to the baseline rate. 
• The subject may receive appropriate further treatment for IRRs if clinically indicated per 
the site’s standard practice for management of IRRs. 
Management of Grade 2 IRRs 
If a subject presents with a Grade 2 IRR: 
• The injection should be stopped immediately. 
• The subject should receive appropriate further treatment with an antihistamine and/or 
acetaminophen (paracetamol) if clinically indicated per the site’s standard practice for 
management of IRRs. Further medications can be administered if necessary. 
• Once the symptoms have been resolved or reduced to Grade 1, the injection can be 
continued at an injection rate of 50%. 
• If a subject who developed a Grade 2 IRR receives further injections, then premedication 
following the site’s standard practice for premedication for IRR should be given before 
all subsequent injections of rhu-pGSN given at a rate of 50% of the original rate. 


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Management of Grade 3 IRRs 
If a subject presents with a Grade 3 IRR: 
• The injection should be stopped immediately. 
• The subject must receive appropriate treatment with an antihistamine and/or 
acetaminophen (paracetamol) and/or methylprednisolone (or equivalent) and, if 
necessary, further medications (i.e., epinephrine, bronchodilator). 
• Only after the complete resolution to dGrade 1, and after having received appropriate 
prophylactic medication(s) as described above, the injection may be resumed at an 
injection rate of 25%. If, after 20 minutes, the subject’s symptoms do not return and vital 
signs are stable, the injection rate may be increased to a maximum of 50%. 
• If, after the resumption of injection, symptoms return (irrespective of grade), the injection 
must be stopped immediately, and the injection tubing should be disconnected from the 
subject. 
• Subjects experiencing a Grade 3 IRR may only receive further injections of study drug, 
provided clinically appropriate precautions are undertaken and agreed upon by 
Investigator and Medical Monitor. 
Management of Grade 4 IRRs 
If a subject presents with a Grade 4 IRR: 
• The injection should be stopped immediately, and the injection tubing should be 
disconnected from the subject. 
• The subject should receive appropriate treatment with an antihistamine and/or 
acetaminophen (paracetamol) and/or methylprednisolone (or equivalent) and, if 
necessary, further medications (i.e., epinephrine, bronchodilator). 
• The subject must not receive further injections of rhu-pGSN if rhu-pGSN is judged by 
the Investigator to be the cause of the IRR. 
6.5. 
Study Duration  
Subjects will be treated with 3 doses over 36 hours: after the initial dose is administered 
(Dose #1), then next dose (Dose #2) is administered 12 hours later, and the last dose is 
administered 24 hours later (Dose #3 administered 36 hours after Dose #1).  
Subject screening will occur for Part 1 within 24 hours of determination of WHO severity score 
of 4 to 6, whether the severity score is attained on admission or during current ongoing 
hospitalization, or for Part 2, within 24 hours of intubation without ECMO with a WHO severity 
score of 6 or 7. Eligible subjects will be randomized within 12 hours of informed consent 
(Part 1) or 24 hours of intubation (Part 2), and dosed within 12 hours of randomization (both 
parts). 
Subjects are followed for safety and efficacy through Day 90.  


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6.6. 
Total Duration of Subject Participation 
Subjects will be observed for the primary efficacy endpoint with daily assessments (including 
WHO severity score) from Day 1 through Day 14. If a subject is discharged prior to Day 14, 
he/she will be assessed, if feasible, by phone daily through Day 14, and then at follow-up visits, 
on Days 28, 60, and 90, and as needed. 
6.7. 
End of Study Definition 
End of study (EOS) will be defined as the date the last subject completes the EOS Visit 
(Day 90). The Sponsor will notify all applicable regulatory agencies in accordance with local 
requirements when the study has ended. 
6.8. 
Criteria for Treatment Discontinuation 
Subjects are free to discontinue their participation in the study at any time and without prejudice 
to further treatment. The Investigator must withdraw any subject from the study if that subject 
requests to be withdrawn, or if it is determined that continuing in the study would result in a 
significant safety risk to the subject. 
The subject's participation in this study may be discontinued for the following reasons: 
• Subject withdrew consent 
• Unacceptable AE 
• Subject is unwilling or unable to continue the study or is lost to follow up 
• Subject is non-compliant with study procedures/study protocol 
• Investigator decides that withdrawal from the study is in the best interest of the subject 
• Any clinically significant change in subject’s medical condition (at the discretion of the 
Investigator) 
• Sponsor decision to end the study 
If a subject withdraws from the study prematurely, assessments scheduled for the EOS Visit 
should be performed ASAP. If a subject refuses further assessment, the subject should be 
contacted for safety evaluations (AE/concomitant medications/potential pregnancy) 
approximately 28 and 90 days after study withdrawal. 
If such withdrawal occurs, or if the subject refuses to participate in the EOS Visit, the 
Investigator must determine the primary reason for a subject’s withdrawal from the study and 
record the information on the electronic case report form (eCRF). If the reason for withdrawal is 
an AE, monitoring should continue until the outcome is evident. The specific event or test 
result(s) must be recorded in the eCRF. At the discretion of the Sponsor, subjects may also be 
removed from the study. 
It should be clearly documented in the source data whether a subject withdrew his/her consent 
and will not enter the follow-up phase, or if a subject withdrew his/her consent for study drug 
treatment but will continue further participation in the study. 


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6.9. 
Subject Replacement 
Only subjects missing doses or discontinuing at random (non-informative) before the primary 
visit on Day 14 will be replaced as originally randomized to receive rhu-pGSN or placebo. 
Safety data from all subjects treated with e1 dose will be collected. Subjects discontinuing the 
study after the Day 14 visit will not be replaced. 
6.10. 
Criteria for Study Termination 
The Sponsor reserves the right to discontinue the study at any time for any reason. Such reasons 
may be any of, but not limited to, the following: 
• Occurrence of AEs unknown to date in respect to their nature, severity, and duration, or 
the unexpected incidence of known AEs 
• Medical or ethical reasons affecting the continued performance of the study 
If the study is prematurely terminated, the Investigator is to promptly inform the study subjects 
and Independent Ethics Committee (IEC) and should ensure appropriate follow up for the 
subjects. All procedures and requirements pertaining to the archiving of study documents should 
be followed. All other study materials (e.g., study drug, etc.) must be destroyed or returned to the 
Sponsor. 


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7. 
STUDY POPULATION 
7.1. 
Number of Subjects 
Part 1: A total of 60 evaluable participants randomized 1:1 to rhu-pGSN:placebo (30:30 
subjects). 
Part 2: A total of 20 evaluable participants randomized 1:1 to rhu-pGSN:placebo (10:10 
subjects). 
7.2. 
Subject Inclusion Criteria 
To be considered eligible to participate in this study, a subject must meet all the inclusion criteria 
listed below: 
1. Hospitalized with laboratory-confirmed (RT-PCR+) or highly suspected (compatible with 
at least bilobar lung involvement without another plausible diagnosis) COVID-19  
2. Age e18 years 
3. Part 1 only: Weight d100 kg 
4. Part 1 only: Within 24 hours of reaching a WHO severity score of 4-6 either:  
a) At admission 
b) While already hospitalized. 
5. Part 2 only: Within 24 hours of intubation without ECMO with a WHO severity score of 
6 or 7)  
6. Informed consent obtained from subject/next of kin/legal proxy 
7. Primary admitting diagnosis of pneumonia supported by a compatible clinical 
presentation with a documented infiltrate consistent with pneumonia on CXR or CT, 
as assessed by the admitting emergency department (ED), clinic, or ward physician 
or equivalent caregiver  
 Recommended (not mandatory) guidance/discretionary criteria defining patients 
with pneumonia satisfying all 4 categories below: 
o At least 2 symptoms: difficulty breathing, cough, production of purulent 
sputum, or chest pain 
o At least 2 vital sign abnormalities: fever, tachycardia, or tachypnea 
(thresholds -- fever: body temperature >100.4°F [38°C]; heart rate >100 
beats/min; respiratory rate >24/min) 
o At least one finding of other clinical signs and laboratory abnormalities: 
hypoxemia (O2 saturation <90%), clinical evidence of pulmonary 
consolidation, or leukocytosis e1.5x104 or leukopenia <4x103 
o Chest imaging or CT chest showing at least bilobar pulmonary infiltrates  
 Principal Investigator (PI) to note radiologic findings in the eCRF 
 Radiology report and conclusion should be summarized in the 
eCRF 


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 A copy of the radiograph attached to be saved for review, if 
possible 
8. A hyperinflammatory status (defined by increased ferritin e500 µg/L, D-dimer 
e1000 ng/mL, or CRP e75 mg/L) 
9. During the course of the study starting at screening and for at least 6 months after 
their final study treatment: 
a) Female subjects of childbearing potential must agree to use 2 medically 
accepted birth control methods 
b) Male subjects with a partner who might become pregnant must agree to use 
reliable forms of contraception (i.e., vasectomy, abstinence), or an acceptable 
method of birth control must be used by the partner 
c) All subjects must agree not to donate sperm or eggs (ovocytes) 
7.3. 
Subject Exclusion Criteria 
To be eligible for entry into the study, the subject must not meet any of the exclusion criteria 
listed below: 
1. A negative RT-PCR test for COVID-19 in the absence of a positive test during the 
evaluation of the present illness (in the presence of a positive test during the current 
illness, preceding or subsequent negative tests do not disqualify the subject) 
2. Extracorporeal membrane oxygenation (ECMO) 
3. Pregnant or lactating women 
4. Active underlying cancer treated with systemic chemotherapy or radiation therapy 
during the last 30 days 
5. Transplantation of hematopoietic or solid organs 
6. Chronic mechanical ventilation or dialysis 
7. Otherwise unsuitable for study participation because of chronic, severe, end-stage, and 
life-limiting underlying disease unrelated to COVID-19 likely to interfere with 
management and assessment of acute pneumonia, only comfort or limited (non-
aggressive) care is to be given, or life expectancy <6 months unrelated to acute COVID 
infection in the opinion of the Investigator  
Notes: 
• PK sampling is strongly encouraged. However, participants refusing some or all PK 
blood sampling can remain in the trial. 
• Participants with superinfection in addition to COVID-19 are eligible. 
• Caregivers can decide whether any other medications (investigational or otherwise) 
should be administered. 
7.4. 
Subjects or Partners of Subjects of Reproductive Potential 
Pregnancy is an exclusion criterion. Women of childbearing potential (<60 years of age and/or 
not post-hysterectomy) must avoid getting pregnant during the study. Female subjects of 
childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior 
to start of study drug. A serum or urine pregnancy test will be performed at the EOS Visit. 


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Women of childbearing potential should not become pregnant while on this study, or for 
6 months after receiving the last dose of study treatment. Females that can become pregnant 
must agree to use two medically accepted birth control methods during the study starting at 
screening and for at least 6 months after their final study treatment. Medically accepted forms of 
birth control include condoms, diaphragm, cervical cap, the placement of an intrauterine device 
(IUD), birth control pills, hormone implants or injections, or partners who have undergone a 
vasectomy (surgical sterility). Unless sterilized, one of these methods must be a barrier method 
such as a condom or diaphragm. Abstinence at certain times of a menstrual cycle and partner 
withdrawal are not acceptable methods of birth control. The subject should consult with her 
study doctor about the contraceptive methods that are available, and which might be the best for 
her. 
Male subjects with a partner who might become pregnant must use reliable forms of 
contraception (i.e., vasectomy, abstinence) during the study starting at screening and for at least 
6 months after their final study treatment, or an acceptable method of birth control must be used 
by the partner (i.e., oral contraceptive, IUD, hormonal implants, contraceptive injection, or a 
double- barrier method). 
Subjects will be instructed to notify the Investigator if pregnancy is discovered either during or 
within 6 months of the last dose of study drug. 
Subjects must agree not to donate sperm or eggs (ovocytes) during the study starting at screening 
and for at least 6 months after their final study treatment. 
7.5. 
Waivers of Inclusion/Exclusion Criteria 
No waivers of these inclusion or exclusion criteria (Section 7.2 and Section 7.3) will be granted 
by the Investigator and/or the Sponsor or its designee for any subject enrolling into the study. 


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8. 
DESCRIPTION OF STUDY TREATMENT 
8.1. 
Description of Study Drug 
Study drug is a recombinant human plasma gelsolin (rhu-pGSN) powder for solution (Table 4). 
Study drug will be administered to subjects randomized to rhu-pGSN as an IV bolus at a rate 
between 5 and 20 mL/min through a standard 0.2-micron filter at 12 mg/kg (based on actual 
body weight) at 0, 12, and 36 hours (± 60 minutes).  
rhu-pGSN drug product is provided as lyophilized powder containing 200 mg rhu-pGSN plus 
excipients. It is provided in 10-mL glass vials to be reconstituted to a volume of 5 mL with 
4.56 mL of sterile water yielding a final concentration of 40 mg/mL of rhu-pGSN, 2% glycine, 
4% trehalose, 0.5% arginine, and 0.1% poloxamer 188 in a 10-mM phosphate buffer, pH 7. 
Table 4: 
Investigational Product 
 
Investigational Product 
Product Name: 
rhu-pGSN 
Dosage Form: 
Powder for solution filled as a 5 mL fill in 10-mL glass vials 
Unit Dose 
rhu-pGSN reconstituted to a volume of 5 mL with 4.56 mL of 
sterile water 
Route of Administration 
Intravenous 
Physical Description 
Lyophilized powder 
Storage Conditions 
2 to 8 °C 
Manufacturer 
Drug Product: Integrity Bio, Inc., Camarillo, CA USA 
 
Vials containing rhu-pGSN study drug will be labeled according to national regulations for 
investigational products. 
8.2. 
Description of Placebo 
Placebo will be normal saline solution and will be dosed at a volume of 0.30 mL/kg of 0.9% 
saline solution via IV push [matching the volume of rhu-pGSN for a subject of that size] injected 
at 5 to 20 mL/min though a standard 0.2-micron filter at 0, 12, and 36 hours (± 60 minutes). The 
placebo requires no special manipulation. 


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8.3. 
Preparation of Study Drug for Administration 
The Investigator or designee will be responsible for administering the appropriate dose of IV 
rhu-pGSN to subjects. rhu-pGSN must be stored refrigerated at 2 to 8 °C in its original package 
in an appropriate storage facility accessible only to the pharmacist(s), the Investigator, or a duly 
designated person. 
This person will determine the dose (mg) of rhu-pGSN, calculate the volume of rhu-pGSN 
solution needed, and reconstitute each vial of study drug to a volume of 5 mL with 4.56 mL of 
sterile water. 
The individual rhu-pGSN IV push will be prepared under aseptic conditions and administered at 
the study site according to the directions of the Sponsor, which will be provided in a Pharmacy 
Manual. Any powder remaining in the vial must be discarded. After dilution, administration of 
rhu-pGSN should be initiated ASAP (within 4 hours, including no more than 2 hours at room 
temperature). Maximum allowed storage times and conditions will be detailed in the Pharmacy 
Manual. 
8.4. 
Subject Monitoring During rhu-pGSN Administration 
Vital signs should be measured as outlined in Section 9.2.2. All supportive measures consistent 
with optimal patient care will be provided throughout the study according to institution 
standards. 
Precautions for anaphylaxis should be observed during rhu-pGSN administration. Emergency 
resuscitation equipment and medications should be readily available. Additional supportive 
measures should also be available and may include, but are not limited to, epinephrine, 
antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, 
diphenhydramine, and acetaminophen (paracetamol). 
8.5. 
Study Drug Administration 
The subject will receive an IV bolus at the time points specified in Table 5 at a rate between 5 to 
20 mL/min. The syringe, filter, and extension tubing should be connected after disconnecting the 
IV as close to the subject as possible. 
Subjects are to be monitored for administration site reactions during study drug administration 
and for 1 hour after its completion. Injection-site reactions will be recorded as AEs using the 
appropriate coding terms on the eCRF. 
8.6. 
Shipment of Study Drug 
Prior to study treatment, study medications will be supplied to the clinical trial site's pharmacy or 
equivalent by the Sponsor or its designee. 
Shipment of study drug supplies for the study will be accompanied by a shipment form 
describing the contents of the shipment, drug information, and other appropriate documentation. 
The shipment form will assist in maintaining current and accurate inventory records. 


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8.7. 
Receipt and Storage of Study Drug 
All study supplies should arrive at the pharmacy or equivalent in sufficient quantity and in time 
to enable dosing as scheduled. The pharmacist or designee must ensure the acknowledgement of 
receipt of the clinical trial material (i.e., study drug) at the site, including that the material was 
received in good condition. 
The Sponsor or its designee must notify the pharmacist or designee prior to dispatch of drug 
supplies, with the anticipated date of their arrival, addressed to the site’s pharmacy. 
The investigational drug will be stored in the pharmacy or equivalent, refrigerated at 2 to 8 ºC. 
The Sponsor should be notified for any deviation from the storage conditions. 
8.8. 
Accountability, Handling, and Disposal of Study Drug 
The study site must maintain accurate records documenting dates and amount of study drug 
received. The trial site's pharmacy or equivalent will be responsible for ensuring the supervision 
of the storage and allocation of these supplies. When a shipment is received, the pharmacist or 
designee verifies the quantities received and the accompanying documentation and provides 
acknowledgement of receipt. 
Accountability logs will be provided to assist the pharmacist or designee in maintaining current 
and accurate inventory records covering receipt, dispensing, and disposition of the study drug. 
An unblinded study monitor will examine inventory during the study. Accountability records 
must be readily available and may be subject to inspection by regulatory authorities or 
independent auditors at any time. 
Drug administration will be recorded in source documents and in the eCRFs. 
At the end of the study, delivery records of study drug will be reconciled with used / unused 
supplies. A disposition form will be completed as per local regulation, since used/partially used 
vials might be required to be destroyed after use. Unused vials should be returned to the 
Sponsor. One copy of all accountability records and the disposition form will be retained by the 
Investigator for the study files. 
8.9. 
Concomitant Medications 
To date, there are no known drug interactions with rhu-pGSN. Because rhu-pGSN has no effect 
on the cytochrome p450 (CYP450) system, subjects may continue their present medications as 
directed by their caregivers. Subjects may receive concomitant medications to treat symptoms, 
AEs, and inter-current illnesses that are medically necessary as standard care. 
Medications administered within 1 month prior to screening and concomitant medications, 
including generic name (if possible), and start date if known should be documented in the 
subject's file and in the eCRF. 
8.10. 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized in a 1:1 ratio to receive SOC plus IV rhu-pGSN or placebo during 
the treatment period. See Section 8.12 for details regarding randomization. 


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8.11. 
Treatment Compliance 
The study drug will be administered by personnel at the study site to ensure compliance. 
8.12. 
Randomization and Blinding 
Following screening, subjects qualified for study entry will be randomized to receive rhu-pGSN 
or placebo during the treatment period. Randomization will be done centrally using manual 
methods. All eligible subjects will be assigned a randomization number. 
The investigational site team and the subject will be kept blinded to the treatment allocation of 
each participant. Only the designated pharmacist(s) or designee(s) will be unblinded to the 
treatment allocation. A manual system to randomly assign a treatment allocation. The treatment 
allocation will be available to the unblinded pharmacist(s). 
8.12.1. 
Unblinding 
The unblinded pharmacist(s) or designees will prepare sterile syringes with filters consisting of 
12 mg/kg rhu-pGSN or normal saline (Section 8.3) according to the treatment allocation for each 
subject. 
There is no antidote for rhu-pGSN. Unblinding should only be performed if knowledge of the 
treatment assignment will change the planned management of a medical condition. If possible, 
prior to unblinding, the need to unblind should be discussed with the Medical Monitor or 
Sponsor’s Chief Medical Officer; however, this should not delay unblinding if the Investigator 
believes it is necessary. Each case of unblinding will be documented and documentation will be 
stored separately by the unblinded pharmacist or designee. 
Subjects that are unblinded may be withdrawn from the study. The decision to withdraw a 
subject from the study because of unblinding should be discussed with the Sponsor. If the 
subject is withdrawn, the Investigator or designee must record the date and reason for 
withdrawal on the appropriate eCRF for that subject. 
 


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9. 
STUDY ASSESSMENTS  
The procedures and assessments that will be conducted during this study are described in this 
section and summarized in the Schedule of Assessments (Table 5). Detailed instructions 
regarding all laboratory procedures, including collection and handling of samples, will be 
included in the study Laboratory Manual provided by the Sponsor or its designee. 
Informed consent must be granted by each subject/next of kin/legal proxy according to hospital 
procedures and local regulations prior to the initiation of any study procedure or assessment 
(other than those considered SOC). 


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Table 5: 
Schedule of Assessments 
Visit 
Screening 
Baseline/ 
Treatment 
Continued 
Treatment 
Follow-up Visits 
Early Term/ End of Study 
Visit 
Day 
-1a 
1a 
2 
3 
7 ± 1 
14 ±2 
28 ±2 
60 ±2 
90 ± 4 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
X 
 
 
 
 
 
 
 
Randomization if 
appropriate 
 
X 
 
 
 
 
 
 
 
Medical history/signs 
and symptoms 
X 
Xb 
 
 
 
 
 
 
 
WHO Severity Scorec 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sputum cultured, e 
X 
 
 
 
 
 
 
 
 
Blood or urine 
pregnancy 
X 
(for women of 
childbearing 
potential only) 
 
 
 
 
 
X 
 
X 
(for women of childbearing 
potential only) 
HIV 
Not required 
(can be done at 
the discretion 
of caregivers) 
 
 
 
 
 
 
 
 
Confirm COVID-19 
pneumonia (CXR or 
CT, RT-PCR for 
COVID-19)e, f 
X 
 
 
 
 
X 
X 
 
 
CURB-65 score 
X 
 
 
X 
X 
X 
X 
X 
 
Physical examg 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
Abbreviated Mental 
Test Score 
X 
 
 
X 
X 
X 
X 
X 
 


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Visit 
Screening 
Baseline/ 
Treatment 
Continued 
Treatment 
Follow-up Visits 
Early Term/ End of Study 
Visit 
Day 
-1a 
1a 
2 
3 
7 ± 1 
14 ±2 
28 ±2 
60 ±2 
90 ± 4 
Vital signs, including 
pulse oximetryh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG e, i 
X 
X 
X 
X 
 
 
 
 
X 
Sampling for pGSN 
levels (including PK)j  
 
X 
X 
Xk 
X 
X 
X 
X 
X 
CBC with differential 
and reticulocyte count; 
PT (INR)/aPTT e 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
metabolic profile 
(including amylase or 
lipase) e 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
Biomarker samplingl 
 
X 
 
X 
X 
X 
X 
X 
 
Anti-rhu-pGSN 
antibody sampling 
(immunogenicity)m 
 
X 
 
 
 
 
X 
 
X 
Study drug 
administrationn 
 
Xo 
Xp 
 
 
 
 
 
 
AEs/SAEsq  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AEs=adverse events; CBC=complete blood count; Con meds=concomitant medications; CRP=C-reactive protein; CT=computed 
tomography; CURB-65=Confusion, Urea >7 mmol/L, Respiratory rate e30/min, Blood pressure systolic <90 or diastolic d60, and age e65 years 
(score); CXR=chest x-ray; EKG=electrocardiogram; HIV=human immunodeficiency virus; IL=interleukin; INR=international normalized ratio; 
PEEP=positive end-expiratory pressure; PK=pharmacokinetic; PT=prothrombin time; aPTT=activated partial thromboplastin time; RT-
PCR=reverse transcription polymerase chain reaction; SOC=standard of care; Term=termination; TNF=tumor necrosis factor; WHO=World 
Health Organization. 


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a Day 1 is the first day of study treatment. Baseline tests (including blood draws) should be performed prior to administration of the 
first dose. Screening tests may also be performed on Day 1 prior to study treatment if necessary, as long as these tests cannot affect 
eligibility. If Dose 1 is administered in the evening of Day 1, Dose 2 would be given on the second calendar day and Dose 3 would 
be given on the third calendar day, 
b Test/assessment does not have to be repeated if performed within the prior 24 hours unless dictated by SOC. 
c Assess daily from screening through Day 14 during hospitalization and after discharge, where feasible, and then at Days 28, 60, 
and 90. 
d Collect sputum sample as soon as possible if not collected at the time of hospital admission. The microbiology lab is encouraged to 
also perform sputum Gram-stains, antigen detection, immunoassay, and RT-PCR diagnostic tests when available. If fevers or chills 
are present, 2 sets of blood cultures are recommended at the discretion of the caregivers. 
e To be performed if/when indicated by SOC. 
f At screening, document radiographic evidence (CXR, or CT scan if CXR is inadequate) of COVID-19 pneumonia if not already 
completed in the previous 48 hours per SOC. On Days 14 and 28, repeat RT-PCR for COVID-19 and repeat CXR, or CT scan if 
CXR is inadequate, are encouraged but not mandatory. 
g Height and weight only to be measured at screening or baseline and as per SOC thereafter. In Part 2, height is not required at 
screening and weight may be obtained via bed scale, if possible, or estimated. 
h Record blood pressure, body temperature, respiration rate, and heart rate, as well as pulse oximetry. In Part 2, while the subject is 
intubated, the respiratory rate and the ventilator settings (i.e., tidal volume, inspired oxygen, inspiratory pressure, and PEEP) should 
be documented. To be measured during study drug administration at the following time points: predose, at the end of administration, 
and 30 minutes after the end of administration. 
i When EKGs are to be collected at the same time point as a blood collection, EKGs should be collected first. At screening, 3 serial, 
resting, supine 12-lead EKGs are to be conducted within 10 minutes total time. All other ECGs are single recordings. 
j Blood for PK will be drawn for Dose #1 within 15 minutes predose, and at 1 (±15 min), 2 (±15 min), 6 (±30 min), and 12 (±30 min) 
hours after the end of administration (but prior to Dose #2); and for Dose #3 within 15 minutes predose, and at 1 (±15 min), 
2 (±15 min), 6 (±30 min), 12 (±30 min), and 24 (±30 min) hours after the end of administration. Samples should be spun and plasma 
frozen and sent to a central lab for analysis. 
k Blood for PK will be collected 24 hours after the end of study drug administration given on Day 2 so the last sample will be 
obtained Day 3. 


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l Collect blood for measurement of ferritin, D-dimer, CRP, and procalcitonin for evaluation at local laboratory; save an approximate 
10 mL aliquot of blood plasma or serum to be frozen at -20°C for subsequent biomarker assays (likely to include, but not limited to 
IL1² , IL6, IL10, TNF, etc.) for analysis at the central laboratory. 
m Sample to be sent to a central lab for analysis. 
n Study drug to be administered at 0, 12, and 36 hours (± 60 minutes). Subjects are to be monitored for administration site reactions 
during study drug administration and for 1 hour after its completion. 
o Initial dose must be administered no later than 12 hours after randomization. A second dose on Day 1 is to be administered 12 hours 
after the initial dose.  
p Day 2 dose to be administered 24 hours after last dose administration on Day 1 (36 hours after Dose #1). 
q From informed consent to first administration of study drug, AEs related to study procedures and all SAEs will be recorded. During 
and after first administration of study drug, all AEs and SAEs will be recorded through Day 14. After Day 14, only SAEs will be 
recorded through study completion. 
 


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9.1. 
Screening Assessments 
Potential subjects hospitalized with COVID-19 pneumonia will be screened for Part 1 within 
24 hours of reaching a WHO severity score of 4 to 6, whether the severity score is attained on 
admission or during hospitalization, or for Part 2, within 24 hours of intubation without ECMO 
with a WHO severity score of 6 or 7. 
Prior to screening, all subjects/next of kin/legal proxy must provide informed consent for study 
participation, per Section 13.5. The following assessments will be performed according to the 
time points in the Schedule of Assessments (Table 5).  
9.1.1. 
WHO Severity Score 
During screening and at the time points presented in the Schedule of Assessments (Table 5), each 
subject’s WHO severity score according to the 9-point scale (Section 6.1) will be recorded on the 
appropriate eCRF. WHO severity scores should be documented daily through Day 14 (during 
hospitalization and after discharge, where feasible). 
9.1.2. 
HIV Testing 
Subjects are not required to have a negative serology test for HIV to participate in the study. 
Testing is not required but could be done as part of SOC at the discretion of caregivers. 
9.1.3. 
Confirmation of COVID-19 Pneumonia 
Subjects are required to have pneumonia (confirmed clinically and documented on CXR or CT), 
with RT-PCR+ confirmed or highly suspected COVID-19 etiology at screening. If 
documentation is not available, the subject must undergo CXR, or a CT scan if CXR is 
inadequate, to confirm COVID-19 pneumonia. At screening, radiographic evidence (CXR, or 
CT scan) of COVID-19 pneumonia may have been completed in the previous 48 hours per 
SOC. If not already obtained and documented during the current illness leading to the present 
hospitalization, a RT-PCR test is to be performed during screening before randomization (result 
might not be available at randomization or start of study treatment). 
On Days 14 and 28, repeat RT-PCR for COVID-19 and repeat CXR, or CT scan if CXR is 
inadequate, are encouraged but not mandatory. 
9.1.4. 
Pregnancy Test 
All females of childbearing potential are required to have a negative serum or urine pregnancy 
test at screening to participate in the study. 
9.2. 
Safety Assessments 
The following assessments will be performed according to the time points in the Schedule of 
Assessments (Table 5). 
9.2.1. 
Demographic/Medical History 
A review of demographic parameters, including age, gender, race, and ethnicity will be 
performed at screening. 


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Relevant past and present medical history will be recorded. Any ongoing condition or signs and 
symptoms observed prior to the initiation of study treatment should be recorded as medical 
history. 
9.2.2. 
Vital Signs 
Vital signs will include blood pressure, body temperature, respiration rate, and heart rate, as 
well as pulse oximetry. In Part 2, while the subject is intubated, the respiratory rate and the 
ventilator settings (i.e., tidal volume, inspired oxygen, inspiratory pressure, and PEEP) should be 
documented. Vitals signs will be measured during study drug administration at the following 
time points: predose, at the end of administration, and 30 minutes after the end of 
administration. Significant findings noticed after the start of study drug that meet the definition 
of an AE must be recorded in the eCRF. 
9.2.3. 
Physical Examination 
All PEs, including measurement of body weight, will be performed by a study physician or 
designee. In Part 1, height and weight need only be measured at screening or baseline. In 
Part 2, height is not required at screening and weight may be obtained via bed scale, if possible, 
or estimated. The initial body weight measured at enrollment will be used to calculate rhu-
pGSN dosing for all doses (so that an individual subject will always receive the same dose). 
Body weight can be repeated per SOC thereafter where possible. The physical examination 
includes skin, head, ears, eyes, nose, throat, heart, lungs, abdomen, and neurologic system, 
where possible. Additional examination may be performed as found relevant by the Investigator. 
9.2.4. 
Outcome Prediction Models 
The CURB-65 (Appendix A) test will be utilized at screening. The cognitive status of the 
subject will be assessed for incorporation in the CURB-65 score by using the abbreviated 
mental test score; Appendix B.  
9.2.5. 
Electrocardiogram 
All EKGs will be conducted and read locally. When EKGs are to be collected at the same time 
point as a blood collection, EKGs should be collected first. At screening, 3 serial, resting, 
supine, 12-lead EKGs will be conducted within 10 minutes total time. The mean of the triplicate 
EKG measurements performed at screening will serve as the subject’s baseline corrected QT 
(QTc) value for all post-dose comparisons. All other ECGs will be collected as a single 
recording. 
EKG parameters to be evaluated include heart rate, the time from the onset of the P wave to the 
start of the QRS complex (PR), the duration of the entire cardiac cycle, measured in seconds 
(RR), the combination of three of the graphical deflections (QRS complex), the measure of the 
time between the start of the Q wave and the end of the T wave (QT) intervals, and the QT 
interval corrected for heart rate using Fridericia’s formula (QTcF). 


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9.2.6. 
Laboratory Assessments 
All routine clinical laboratory assessments will be performed by the hospital laboratory or 
equivalent  per SOC. Where indicated, handling and shipping clinical laboratory samples to a 
central laboratory will be outlined in the Laboratory Manual. 
Screening laboratory and other tests can serve as baseline values for participants, they do not need 
to be repeated if performed within the prior 24 hours of randomization unless otherwise dictated 
by SOC; however, the blood sample for analysis of pGSN antibodies must be repeated if not 
collected within 30 minutes of initiating the first dose of study drug. 
The laboratory evaluations will include: 
1.   Hematology: complete blood count with differential white count and reticulocyte count, 
and platelet count; PT (INR)/aPTT 
2.   Comprehensive metabolic profile including chemistries/electrolytes, total 
protein/albumin, blood urea nitrogen (BUN)/creatinine, CRP, lactate dehydrogenase (LDH), 
creatine phosphokinase (CPK), alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), total bilirubin, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-
density lipoprotein (HDL) cholesterol, alkaline phosphatase, and amylase or lipase 
3.   Respiratory function (oxygen saturation by pulse oximetry; arterial blood gas tests only 
at the caregiver’s discretion) 
Abnormal laboratory test results considered clinically significant by the Investigator or that 
require treatment should be reported as AEs in the eCRF according to the AE reporting 
instructions in Section 10.6. 
9.3. 
Pharmacokinetic Assessments 
Blood for PK will be drawn at the following time points:  
• For Dose #1: within 15 minutes predose, and at 1 (±15 min), 2 (±15 min), 6 (±30 min), 
and 12 (±30 min) hours after the end of dose administration (but prior to Dose #2) 
• For Dose #3: within 15 minutes predose, and at 1 (±15 min), 2 (±15 min), 6 (±30 min), 
12 (±30 min) and 24 (±30 min) hours after the end of dose administration 
Samples should be spun and plasma frozen and sent to a central lab for analysis. Plasma samples 
will be analyzed for maximum concentration (Cmax), time to maximum concentration (Tmax), 
terminal half-life (T1/2), area under the curve from time zero to 8 hours (AUC0-8), area under the 
curve from time 0 to infinity (AUCinf).  
Participants who refuse some or all PK blood samplings can remain in the trial. However, PK 
sampling is to be highly encouraged. 
For Dose #3, the last PK sample will occur on Day 3 (i.e., 24 hours after the end of third study 
drug administration which was initiated 36 hours after the first dose).  


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9.4. 
Pharmacodynamic Assessments 
On the study days indicated in Table 5, blood will be collected for measurement of ferritin, 
D-dimer, CRP, and procalcitonin level at local laboratory. Save aliquots of blood for subsequent 
analysis. Analyses are likely to include, but are not limited to, the following: 
• Biomarkers including, but not limited to, IL1² , IL6, IL10, TNF, etc. (see Table 5 
Schedule of Assessments and footnote ‘l’ for details). 
Blood samples may be stored for analysis for up to 5 years in the event that new biomarkers are 
discovered. 
9.5. 
Other Assessments 
Other analyses to be performed include: 
• Blood, sputum, and other cultures as clinically indicated per SOC (note that a sputum 
culture is mandatory if a sputum specimen can be obtained and blood cultures are 
strongly encouraged at entry into the study) 
 


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10. 
ADVERSE EVENT MANAGEMENT 
10.1. 
Definition of Adverse Events 
10.1.1. 
Adverse Event (AE) 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether or 
not considered casually related to the product.   
All AEs that occur during or after a subject has been administered study drug, or within 14 days 
following the last study drug administration, whether or not they are related to the study, must be 
recorded on forms provided by the Sponsor.  
10.1.2. 
Serious Adverse Event (SAE) 
An SAE is an AE occurring during any study phase (i.e., baseline, treatment, or follow up), and 
at any dose of the investigational product, comparator or placebo, that fulfils one or more of the 
following: 
• Results in death 
• It is immediately life-threatening 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
All SAEs that occur after the subject/next of kin/legal proxy has given informed consent and has 
been randomized, including before or during treatment and within 90 days following the last 
dose of study drug, whether or not judged to be related to the study, must be recorded on forms 
provided by the Sponsor. 
10.2. 
Clarifications to Serious Adverse Event Reporting 
Death is an outcome of an SAE and not an SAE in itself. When death is an outcome, report the 
event(s) resulting in death as the SAE term (e.g., “pulmonary embolism”). If the cause of death is 
unknown, report “Death, unknown cause” as the SAE term. 


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10.3. 
Assessment of Causality 
The relationship of each AE to the study drug administration will be assessed by the Investigator 
after careful consideration of all relevant factors such as (but not limited to) the underlying study 
indication, coexisting disease, concomitant medication, relevant history, pattern of the AE, 
temporal relationship to receipt of the study medication and de-challenge or re-challenge 
according to the following guidelines: 
YES (possible, probably or definitely related): there is a reasonable possibility that the study 
drug caused the event; one or more of the following criteria apply: 
• The event follows a reasonable temporal sequence from administration of study drug. 
• The event could not be reasonably attributed to the known characteristics of the subject’s 
clinical state, environment or toxic factors or other modes of therapy administered to the 
subject. 
• The event follows a known pattern of response to study drug. 
• The event disappears or decreases on cessation or reduction in dose of the study drug. In 
some situations, an AE will not disappear or decrease in intensity upon discontinuation of 
the study drug despite other clear indications of relatedness. 
NO (probably not related or definitely not related): There is no reasonable possibility that the 
study drug caused the event and none of the criteria from the previous section apply; one or more 
of the following criteria apply: 
• The event does not follow a reasonable temporal sequence from administration of study 
drug. 
• The event could be reasonably attributed to the known characteristics of the subject’s 
clinical state, concurrent illness, environment or toxic factor or other modes of therapy 
administered to the subject. 
• The event does not follow a known pattern of response to study drug. 
• The event does not disappear or decrease on cessation or reduction in dose of the study 
drug, and it does not reappear or worsen when the study drug is re-administered. 
10.4. 
Assessment of Severity 
The severity rating of an AE refers to its intensity. The severity of each AE will be categorized 
using the NCI CTCAE, version 5.0. For any term that is not specifically listed in the CTCAE 
scale, intensity should be assigned a grade of 1 through 5 using the following CTCAE 
guidelines: 
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting age- 
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Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living 
Grade 4:  Life-threatening consequences; urgent intervention indicated 
Grade 5:  Death related to AE 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 10.1.2. An AE of severe intensity 
may not be considered serious. 
10.5. 
Pregnancy or Drug Exposure during Pregnancy 
If a subject becomes pregnant during the study, administration of study drug is to be 
discontinued immediately. 
Pregnancies must be reported within 24 hours of the Investigator’s knowledge using the 
Sponsor’s pregnancy form. 
Pregnancy in itself is not regarded as an AE or SAE unless there is a suspicion that an 
investigational product may have interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
10.6. 
Laboratory Abnormalities 
To the extent possible, all laboratory abnormalities observed during the course of the study will 
be included under a reported AE term describing a clinical syndrome (e.g., elevated BUN and 
creatinine in the setting of an AE of “renal failure”). In these cases (e.g., an AE of renal failure), 
the laboratory abnormality itself (e.g., elevated creatinine) does not need to be recorded as an 
AE. 
If a laboratory abnormality cannot be reported as a clinical syndrome, AND if the laboratory 
abnormality results in a therapeutic intervention (i.e., concomitant medication or therapy), is a 
dose-limiting toxicity, or is judged by the Investigator to be of other clinical relevance, then the 
laboratory abnormality should be reported as an AE. 
Subjects experiencing AEs or clinically significant laboratory abnormalities will be assessed and 
appropriate evaluations performed until all parameters have returned to baseline levels or are 
consistent with the subject’s then-current physical condition. 
10.7. 
Reporting Adverse Events 
All AEs, serious and nonserious, will be fully documented on the appropriate eCRF. For each 
AE, the Investigator must provide its duration (start and end dates or ongoing), intensity, 
assessment of causality and whether specific action or therapy was required. 


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All AEs that occur from informed consent until the first dose of study drug should be recorded 
on the AE eCRF page only if the event was related to a study procedure. All other AEs/findings 
prior to first dose of study drug should be recorded as medical history on the applicable eCRF 
page. AEs occurring from the first dose of study drug until 14 days after the last dose of study 
drug must be recorded on the AE eCRF. An ongoing AE identified prior to 14 days after the last 
study drug administration will be followed if possible until resolution. 
All SAEs occurring any time (baseline, treatment, or follow up) during the study (related or 
unrelated) must be reported to EastHORN Safety within 24 hours of the Investigator’s 
knowledge. This should be done in accordance with the instructions on SAE Report Form 
completion and reporting 
Investigators must follow subjects with AEs/SAEs until the event has resolved, the condition has 
stabilized, withdrawal of consent, the subject is lost to follow up or death OR until the EOS 
Visit, whichever occurs first. An ongoing SAE identified by EOS will be followed if possible 
until resolution. If the subject dies, this should be captured as the outcome of the AE unless no 
link between the AE and the subject death can be established, in which case the AE will be 
marked as ongoing and the death will be reported as a separate event. 
If a subject is lost to follow up, this should be captured accordingly within the AE eCRF and on 
the follow up SAE report. 
The Sponsor or designee is responsible for notifying the relevant regulatory authorities of 
applicable suspected unexpected serious adverse reactions (SUSARs) as individual notifications 
or through periodic line listings. It is the PI’s responsibility to notify the Institutional Review 
Board (IRB) or IEC of all SAEs that occur at his or her site according to the local regulations. 
Investigators will also be notified of all unexpected, serious, drug-related events (7/15 Day 
Safety Reports) that occur during the clinical trial.  


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11. 
STATISTICS 
11.1. 
General Overview 
All subjects given e1 dose of study drug will be included in the Full Analysis Set (FAS) 
according to actual drug received; non-completers will be counted as failures in the primary 
efficacy analysis. Subjects receiving all 3 doses and evaluable for the primary Day 14 endpoint 
will constitute the per-protocol population for efficacy assessment. WHO severity score will be 
recorded daily while the subject is hospitalized, after discharge through Day 14, where feasible, 
and at each follow-up visit. 
AE data will be summarized for the FAS by actual drug received using counts and proportions of 
subjects having an AE, each AE type, and an AE of each System Organ Class. SAEs and reasons 
for any early discontinuation will be summarized similarly. All deaths will be categorized by 
cause of death as per investigator assessment and relationship to study drug and/or COVID-19 
Immunogenicity will be assessed on Days 1(predose), 28, and 90 days in all participants. 
Antibodies against pGSN will be assayed from frozen specimens to determine whether the 
investigational product induces an antibody response in recipients. 
For Part 1, binary efficacy endpoints will be compared between treatments via stratified 
Cochran-Mantel-Haenszel (CMH) test and, to accommodate continuous covariates, via logistic 
regression. Continuous efficacy and biochemical endpoints will be compared between treatments 
via mixed model repeated measures analysis or analysis of covariance, depending on whether 
repeated measures are available or not. Time-to-event analysis via stratified log rank test and 
Cox proportional hazards model may also be carried out as supplemental analyses. 
For Part 1, exploratory analyses looking at biomarkers and outcomes in each treatment arm will 
be conducted. Other exploratory analysis to compare the efficacy endpoint data from the rhu-
pGSN group from this study to that of external control data may be carried out if appropriate. 
Sample size may be increased to improve the precision of the estimates of between-treatment 
comparisons if appropriate and if drug supplies are available. 
For Part 2, only descriptive statistics will be provided for exploratory analyses. Binary efficacy 
endpoints will be summarized by counts, percentages, and 95% confidence intervals (CIs) for 
each treatment group. Differences in percentages between treatment groups will be summarized 
by 95% CIs. Continuous efficacy and biochemical endpoints will be summarized by counts, 
means, standard deviations, median, minimum, maximum by treatment group. Differences in 
means between treatment groups will be summarized by 95% CIs. Natural log transformation 
may be necessary to better approximate a bell-shaped distribution for the continuous endpoints. 
Time-to-event endpoints will be summarized by Kaplan-Meier plots, medians, quartiles, 
minimum, and maximum by treatment group. Bayesian posterior probabilities that differences 
from zero toward beneficial treatment effect for these summary statistics may be computed. 
Data from Part 1 and Part 2 of the study will be analyzed separately. 


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11.2. 
Sample Size and Power Calculations 
The primary endpoint is difference between treatments in the proportion of surviving subjects off 
vasopressors, the ventilator, and dialysis on Day 14. For Part 1, the power for the study is 
computed for the expected increase in proportion of surviving subjects without these supports at 
Day 14 after start of study treatment. A total sample size of N=54 has ~80% power to yield a 
statistically significant (alpha=0.2 1-sided) difference if the TRUE underlying proportions are 
20% and 5% for placebo plus SOC and rhu-pGSN plus SOC, respectively. The minimum 
OBSERVED difference from placebo plus SOC proportion 20% that yields statistical 
significance is 8.4% (20% vs 11.6%). As this is a pilot Phase 2 POC trial in an infection with no 
approved therapy and false negative error (100% minus power) is equally as important as false 
positive error, the one-sided type 1 error is set at 0.2. Thus, the trial is adequately powered for its 
primary POC objective. 
For Part 2, a sample size of 20 subjects was chosen to generate an estimate of any clinically 
relevant treatment effect. 
11.3. 
Analysis Populations 
The Full Analysis Set (FAS) will include subjects given e1 dose of study drug according to 
actual drug received. 
11.4. 
Criteria for Evaluation and Statistical Methods 
11.4.1. 
Safety 
AE data will be summarized by counts and proportions of subjects having an AE, each AE type, 
and an AE of each System Organ Class. These summaries will be provided for the rhu-pGSN 
and placebo groups separately. SAEs will be summarized similarly. Reasons for any early 
discontinuations will be summarized similarly. 
Laboratory data in relation to normal range values will be summarized via counts and 
percentages of subjects below, within, and above the respective normal range, and by summary 
statistics (N, mean, median, standard deviation, minimum, maximum, 90% confidence intervals, 
etc.) for baseline, each observed time point, and change from baseline at each observed time 
point for continuous lab endpoints. 
11.4.2. 
Baseline Characteristics 
Demographics and disease-related characteristics will be summarized via counts and percentages 
of subjects for categorical variables, and by N, mean, median, standard deviation, minimum, 
maximum for continuous variables. Summaries will be performed for the rhu-pGSN and placebo 
groups separately, and for all subjects combined. 
11.4.3. 
Pharmacokinetics and Immunogenicity 
To complete the PK analyses, plasma specimens will be periodically sampled relative to study 
drug administration and stored frozen for pGSN measurements. See Table 5 and Section 9.3 for 
collection time points. Plasma samples will be analyzed for Cmax, Tmax, T1/2, AUC0-8, AUCinf. 


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Immunogenicity will be assessed on Day 1(predose), 28, and 90. Antibodies against rhu-pGSN 
will be assayed from frozen specimens to determine whether the investigational product induces 
an antibody response in recipients. 
11.4.4. 
Pharmacodynamics 
Biomarker and clinical outcomes will be summarized via counts and percentages of subjects for 
categorical variables, and by summary statistics (N, mean, median, standard deviation, 
minimum, maximum, 90% confidence intervals, etc.) for baseline, each observed time point, and 
change from baseline at each observed time point for continuous variables. Data will be assessed 
via graphical and Shapiro-Wilk statistic for closeness to normal distribution and if substantial 
departure is observed, transformation (e.g., natural log, reciprocal, square root, ranks) may be 
employed to derive the summary statistics. 


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12. 
DATA RECORDING, RETENTION AND MONITORING 
12.1. 
Case Report Forms 
Data will be collected using an electronic data capture (EDC) system at the clinical site. The 
Investigator or designee will record data specified in the protocol using eCRFs. Changes or 
corrections to eCRFs will be made by the Investigator or an authorized member of the study 
staff according to the policies and procedures at the site and the eCRF completion guidelines. 
It is the responsibility of the Investigator to ensure eCRFs are complete and accurate. Following 
review and approval, the Investigator or designee will electronically sign and date the pages. 
This signature certifies that the Investigator has thoroughly reviewed and confirmed all data on 
the eCRF. Regardless of whether this responsibility has been delegated, the Investigator is 
personally responsible for the accuracy and completeness of all data included in the eCRF. 
The Sponsor or designee will provide a portable document format (PDF) file of the eCRFs to 
the site for archiving after all data have been monitored and reconciled. 
12.2. 
Records Retention 
Per Good Clinical Practice (GCP) guidelines regarding records retention, study documents are 
to be retained at the site until at least 2 years after the last approval of a marketing application 
in an International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) region or at least 2 years have elapsed since the formal discontinuation 
of clinical development of study drug. The Sponsor will notify the site of the date when study 
documentation may be destroyed. 
12.3. 
Data Monitoring 
This study will be closely monitored by representatives of the Sponsor throughout its duration. 
Monitoring will include personal visits with the Investigator and study staff, remote monitoring 
visits including Remote Source Data Verification (remote SDV) only in case onsite visits are not 
allowed in the BTI-202 study during the public health crisis due to COVID-19 as well as 
appropriate communications by telephone, fax, mail, email or use of the EDC system, if 
applicable. It is the responsibility of the monitor to inspect eCRFs at regular intervals 
throughout the study to verify the completeness, accuracy and consistency of the data and to 
confirm adherence to the study protocol and to GCP guidelines. The Investigator agrees to 
cooperate with the monitor to ensure that any problems detected during the course of this study 
are resolved promptly. The Investigator and site will permit study-related monitoring, audits, 
IEC review and regulatory inspection, including direct access to source documents. 
It is understood that study monitors and any other personnel authorized by the Sponsor and/or 
Sponsor representatives may contact and visit the Investigator and will be permitted to inspect 
all study records (including eCRFs and other pertinent data) on request, provided that subject 
confidentiality is maintained and that the inspection is conducted in accordance with local 
regulations. 


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Every effort will be made to maintain the anonymity and confidentiality of subjects during this 
study. However, because of the experimental nature of this treatment, the Investigator agrees to 
allow representatives of the Sponsor as well as authorized representatives of regulatory 
authorities to inspect the facilities used in the conduct of this study and to inspect, for purposes 
of verification, the hospital or clinic records of all subjects enrolled in the study. 
Remote monitoring is an alternative mechanism of the Sponsor oversight activities that allows 
remote evaluation of accumulating data, performed with the same frequency as onsite monitoring 
visits. 
In this study, remote SDV of data is a part of this remote monitoring visit and will be considered 
only when onsite visits will not be allowed during COVID-19 pandemic. 
It will focus on the quality control of critical data such as primary efficacy data and important 
safety data. Only the data that are necessary for this purpose will be accessed. 
Remote SDV may include a combination of the following: 
1. Sharing pseudonymized copies of trial related source documents with the monitor; this 
may be done electronically where manageable by the site staff; 
2. Direct, suitably controlled remote access to trial participants’ electronic medical records; 
The provision for source data verification to take place remotely; 
3. Video review of medical records with clinical site team support, without sending any 
copy to the monitor and without the monitor recording images during the review. 
It will be confirmed with the Principal Investigator (PI) / designee at each site to establish 
whether remote SDV would be allowed, feasible and manageable for this site and what the 
practicalities could be.  
It will be discussed with the PI and site Data Privacy Officer and decision should be taken which 
option of remote SDV, that is in line with national law, will be possible for particular site. 
Every effort will be made to maintain the anonymity, confidentiality, and protection of study 
participants rights during remote SDV. 
12.4. 
Quality Control and Quality Assurance 
The study site may be audited by a quality assurance representative of the Sponsor or its 
designee for the purpose of monitoring any aspect of the study. The Investigator agrees to 
allow the monitor and/or auditor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, and other records relative to 
study conduct. 
The Investigator should contact the Sponsor or designee immediately if contacted by a 
regulatory agency about an inspection. 


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13. 
REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS 
13.1. 
Good Clinical Practice 
The study will be performed in accordance with the protocol, guidelines for GCP established by 
the ICH, and applicable local regulatory requirements and laws. 
13.2. 
Independent Ethics Committee Approval 
The Investigator must inform and obtain approval from the IEC for the conduct of the study at 
named sites, the protocol, informed consent documents and any other written information that 
will be provided to the subjects and any advertisements that will be used. Written approval must 
be obtained prior to recruitment of subjects into the study and shipment of study drug. 
The Investigator is responsible for informing the IEC of any amendment to the protocol in 
accordance with local requirements. Amendments may be implemented only after a copy of the 
approval letter from the IEC has been transmitted to the Sponsor. Amendments that are intended 
to eliminate an apparent immediate hazard to subjects may be implemented prior to receiving 
Sponsor or IEC approval. However, in this case, approval must be obtained ASAP after 
implementation. 
Per GCP guidelines, the Investigator will be responsible for ensuring that an annual update is 
provided to the IEC to facilitate continuing review of the study and that the IEC is informed 
about the end of the study. Copies of the update, subsequent approvals and final letter must be 
sent to the Sponsor. 
13.3. 
Regulatory Authority Approval 
The study will be performed in accordance with regional regulatory requirements and will also 
meet all of the requirements of ICH GCP guidance. Amendments to the protocol will be 
submitted to the appropriate regulatory agency/agencies prior to implementation in accordance 
with applicable regulations. 
13.4. 
Other Required Approvals 
In addition to IEC and regulatory authority approval, all other required approvals (e.g. approval 
from the local research and development board or scientific committee) will be obtained prior to 
recruitment of subjects into the study and shipment of study drug. 
13.5. 
Informed Consent 
It is the responsibility of the Investigator (or designee) to obtain written informed consent from 
each subject/next of kin/legal proxy after adequate explanation of the aims, methods, and 
potential hazards of the study and before any study procedures are initiated. If written consent 
cannot be obtained prior to enrollment due to clinical circumstances, oral consent will be 
documented and written consent will be obtained later, when possible. The subject/next of 
kin/legal proxy should be given the opportunity to ask questions and allowed time to consider the 
information provided. Each subject/next of kin/legal proxy should be given a copy of the 


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informed consent document and associated materials. Documentation of informed consent must 
be retained at the site and is subject to inspection by representatives of the Sponsor or regulatory 
authorities. 
Substantial changes to the study protocol may necessitate modifications to the ICF. If an 
amended informed consent document is issued during a subject’s participation in the study, the 
subject/next of kin/legal proxy is required to provide informed consent using the updated consent 
form prior to continuing with study-related activities. 
A subject/next of kin/legal proxy unable or unwilling to provide informed consent will not be 
enrolled in the study. 
13.6. 
Subject Confidentiality 
The Investigator must ensure that subjects’ privacy is maintained. On the eCRF or other 
documents submitted to the Sponsor, subjects will be identified by a subject number or a subject 
number and initials only. Documents that are not submitted to the Sponsor (e.g., signed informed 
consent documents) should be kept in a strictly confidential file by the PI. 
The Investigator shall permit authorized representatives of the Sponsor, regulatory authorities 
and IECs to review the portion of the subject’s medical record that is directly related to the study. 
As part of the required content of informed consent documents, the subject must be informed that 
his/her records will be reviewed in this manner. 
13.7. 
Disclosure of Information 
Information concerning the study, patent applications, processes, scientific data or other pertinent 
information is confidential and remains the property of the Sponsor. The PI may use this 
information for the purposes of the study only. 
It is understood by the PI that the Sponsor will use information obtained in this clinical study in 
connection with the clinical development program, and therefore may disclose it as required to 
other clinical Investigators and to regulatory authorities. In order to allow the use of the 
information derived from this clinical study, the PI understands that he/she has an obligation to 
provide complete test results and all data obtained during this study to the Sponsor. 
Verbal or written discussion of results prior to study completion and full reporting should only 
be undertaken with written consent from the Sponsor. 


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14. 
PUBLICATION POLICY 
The results of this study will be posted on ClinicalTrials.gov and submitted for peer reviewed 
publication within one year after the end of study. 


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15. 
LIST OF REFERENCES 
Bucki R, Georges P, Espinassous Q, et al. Inactivation of endotoxin by human plasma gelsolin. 
Biochemistry 2005; 44:9590–7. 
Bucki R, Byfield F, Kulakowska A, et al. Extracellular Gelsolin Binds Lipoteichoic Acid and 
Modulates Cellular Response to Proinflammatory Bacterial Wall Components. J Immunol 2008; 
181:4936- 44. 
Bucki R, Kulakowska A, Byfield FJ, et al. Plasma gelsolin modulates cellular response to 
sphingosine 1-phosphate. Am J Physiol, Cell Physiol. 2010; 299:C1516–23. 
DiNubile, M., Levinson SL, Stossel TP, et al. Recombinant human plasma gelsolin (rhu-pGSN) 
improves survival and attenuates lung injury in a murine model of multi-drug resistant 
Pseudomonas aeruginosa pneumonia. Manuscript submitted for publication in 2020, in review.  
Goetzel EJ, Lee H, Azuma T, et al. Gelsolin Binding and Cellular Presentation of 
Lysophosphatidic Acid. J Biol Chem 2000; 275:14573-8. 
Haddad JG, Harper KD, Guoth M, et al. Angiopathic consequences of saturating the plasma 
scavenger system for actin. Proc Natl Acad Sci USA. 1990; 87:1381-5. 
Lee WM, Galbraith RM. The extracellular actin-scavenger system and actin toxicity. N Engl J 
Med 1992; 326:1335-41. 
Lee P, Drager L, Stossel T, et al. Relationship of plasma gelsolin levels in outcomes of critically 
ill surgical patients. Ann Surg 2006; 243:399-403. 
Lee PS, Patel S, Christiani DC, et al. Plasma gelsolin depletion and circulating actin in sepsis: a 
pilot study. PLoS ONE 2008; 3:e3712. 
Lee P, Sampath K, Karumanchi S, et al. Plasma Gelsolin and Circulating Actin Correlate with 
Hemodialysis Mortality. J Am Soc Nephrol 2009; 20:1140-8. 
Lind SE, Janmey PA. Human plasma gelsolin binds to fibronectin. J Biol Chem 1984; 
259:13262-6. 
Osborn TM, Dahlgren C, Hartwig JH, et al. Modifications of cellular responses to 
lysophosphatidic acid and platelet-activating factor by plasma gelsolin. Am J Physiol Cell 
Physiol 2007; 292:C1323-30. 
Osborn T, Verdrengh M, Stossel T, et al. Decreased levels of the gelsolin plasma isoform in 
patients with rheumatoid arthritis. Arthritis Res Ther 2008, 10:R117. 
Piktel E, Wnorowska U, Cie[luk M, et al. Recombinant human plasma gelsolin stimulates 
phagocytosis while diminishing excessive inflammatory responses in mice with Pseudomonas 
aeruginosa sepsis. Int J Mol Sci 2020; 21:pii:E2551. 
Self WH, Wunderink RG, DiNubile MJ, et al. Low admission plasma gelsolin concentrations 
identify community-acquired pneumonia patients at high risk for severe outcomes. Clin Infect 
Dis 2019; 69:1218-25. 


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Smith DB, Janmey PA, Herbert TJ, et al. Quantitative measurement of plasma gelsolin and its 
incorporation into fibrin clots. J Lab Clin Med 1987; 110:189-95. 
Vasconcellos CA and Lind SE. Coordinated inhibition of actin-induced platelet aggregation by 
plasma gelsolin and vitamin D-binding protein. Blood 1993; 82:3648-57. 
Yang Z, Chiou T, Stossel T, et al. Plasma gelsolin improves lung host defense against 
pneumonia by enhancing macrophage NOS3 function. Am J Physiol Lung Cell Mol Physiol 
2015; 309: L11–L16. 
Yang Z, Bedugnis A, Levinson S, et al. Delayed administration of recombinant plasma gelsolin 
improves survival in a murine model of severe influenza [version 2] F1000Research 2020; 
8:1860. 
Yang Z, Bedugnis A, Levinson S, et al. Delayed administration of recombinant plasma gelsolin 
improves survival in a murine model of penicillin-susceptible and penicillin-resistant 
pneumococcal pneumonia. J Infect Dis 2019; 220:1498-1502. 
 
 


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16. 
APPENDICES 
Appendix A: CURB-65 Score 
The score is an acronym for each of the risk factors measured. Each risk factor scores one point, 
for a maximum score of 5: 
• Confusion of new onset (defined by the Abbreviated Mental Test Score [see Appendix B] 
of 8 or less [2 or more incorrect answers]) 
• Blood Urea nitrogen greater than 7 mmol/l (19 mg/dL) 
• Respiratory rate of 30 breaths per minute or greater 
• Blood pressure less than 90 mmHg systolic or diastolic blood pressure 60 mmHg or less 
• Age 65 or older 


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Appendix B: Abbreviated Mental Test Score 
The following or similar questions (adapted per country) are put to the patient. Each question 
correctly answered scores one point. A score of 8 or less suggests cognitive impairment at the 
time of testing, although further and more formal tests are necessary to confirm a diagnosis of 
dementia, delirium or other causes of cognitive impairment. 
Question 
Score 
What is your age? (1 point) 
What is the time to the nearest hour? (1 point) 
Give the patient an address and ask him or her to repeat it 
at the end of the test. (1 point) 
e.g. 42 West Street 
What is the year? (1 point) 
What is the name of the office or doctor you are 
seeing today? (1 point) 
Can the patient recognize two persons (the doctor, 
nurse, home help, etc.)? (1 point) 
What is your date of birth? (day and month sufficient) 
(1 point) 
In what year was the 9-11 terrorist attack? (1 point) 
(other dates can be used, with a preference for dates 
sometime in the past) 
Name the present president of the USA. (1 point) 
Count backwards from 10 down to 1. (1 point) 


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Appendix C: Protocol Amendment Summaries of Changes  


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Appendix C1: Summary of Changes v1.0 to v2.0 
Summary of Changes to Protocol BTI-202 Ver 1.0 to 2.0 
29 June 2020 
Page # 
of 
Redline 
Version 
Section 
Old Text 
New Text 
Rationale 
Global 
 
14 May 2020 
version 1.0 
29 June 2020 
version 2.0 
Protocol amendment 
1 
Title Page 
EUDRA CT Number: N/A 
EUDRA CT Number: 2020-002460-31 
Updated to add 
EUDRA CT number. 
6, 
28/29 
Synopsis 
(Number of 
subjects) and 
Section 6.2 
p. 6, “All SAEs and deaths and 
unexpected treatment-emergent SAEs 
will be evaluated by the Data and 
Safety Monitoring Board (DSMB) 
within 96 hours of occurrence. 
Periodic safety reviews will be 
conducted after enrollment of 12, 24, 
36, and 48 patients. Data will be 
unblinded and/or the study paused at 
the discretion of the DSMB chair; 
enrollment will continue during the 
interim analyses unless otherwise 
mandated by the DSMB chair. 
p. 6, “All deaths and unexpected 
treatment-emergent SAEs will be 
evaluated by the Data and Safety 
Monitoring Board (DSMB) within 4 
working days of occurrence. Periodic 
safety reviews will be conducted after 
enrollment of 12, 24, 36, and 48 
patients. Data will be unblinded and/or 
the study paused at the discretion of the 
DSMB chair; enrollment will continue 
during the safety analyses unless 
otherwise mandated by the DSMB 
chair.” 
Clarified definition of 
SAEs to be evaluated 
by DSMB and the 
timing to be 
implemented. 
p. 28/29 “A DSMB will be 
established to monitor safety of 
subjects. The DSMB will be 
comprised of 3 members: a 
representative of the Contract 
Research Organization (CRO), a 
representative of the Sponsor, and an 
independent expert in COVID-19 
p. 28/29, “An independent DSMB will 
be established to closely monitor the 
safety of subjects. The primary mission 
of the DSMB is to ensure that decisions 
are made that serve the best interests of 
patients volunteering for the study. 
The independent DSMB will be 
comprised of  4  voting members: 3 


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pneumonia. 
All SAEs and deaths will be 
evaluated by the DSMB within 
96 hours of occurrence. Periodic 
safety reviews will be conducted after 
enrollment of 12, 24, 36, and 48 
patients. Data will be unblinded 
and/or the study paused at the 
discretion of the DSMB chair; 
enrollment will continue during the 
interim analyses unless otherwise 
mandated by the DSMB chair. 
Further details will be included in the 
DSMB charter.” 
academicians with expertise in 
pulmonary care, critical care, and/or 
infectious diseases as related to 
COVID-19 pneumonia  and a 
statistician.  Representatives from the 
CRO and Sponsor’s Chief Medical 
Officer  will be able to attend the open 
meetings to provide information and 
administrative support to the DSMB.  
However,  they will not have any 
voting rights and will not attend the 
closed meeting where unblinded data 
may be discussed.   
All deaths and unexpected treatment-
emergent SAEs will be evaluated by the 
DSMB within 4 working days of 
occurrence, but a DSMB meeting does 
not necessarily need to be convened. 
Ad hoc meetings will be convened 
whenever felt appropriate by a DSMB 
member.  Periodic safety reviews will 
be conducted after the last enrolled 
subject in each group of 12, 24, 36, and 
48 patients has reached the primary 
Day 14 timepoint. Data may be 
unblinded and/or the study paused at 
the discretion of the DSMB chair; 
otherwise, enrollment will continue 
during the safety review. 
Please refer to the DSMB Charter for 
further details.” 
39, 40 
Section 8.8 
and 8.12 
p. 39 “When a shipment is received, 
the pharmacist verifies the quantities 
p. 39 “When a shipment is received, 
the pharmacist verifies the quantities 
IWRS system is not to 
be implemented in the 


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received and the accompanying 
documentation and provides 
acknowledgement of receipt via the 
interactive web response system 
(IWRS).” 
received and the accompanying 
documentation and provides 
acknowledgement of receipt.” 
study. 
p. 40 “Randomization will be done 
centrally using the IWRS. All eligible 
subjects will be assigned a 
randomization number. 
The investigational site team and the 
subject will be kept blinded to the 
treatment allocation of each 
participant. Only the designated 
pharmacist(s) will be unblinded to 
the treatment allocation. The 
unblinded pharmacist will utilize the 
IWRS system to randomly assign a 
treatment allocation.” 
p. 40 “Randomization will be done 
centrally using manual methods. All 
eligible subjects will be assigned a 
randomization number. 
The investigational site team and the 
subject will be kept blinded to the 
treatment allocation of each participant. 
Only the designated pharmacist(s) will 
be unblinded to the treatment 
allocation. A manual system to 
randomly assign a treatment 
allocation.” 
44 
Table 5 
Schedule of 
Assessments 
Footnote ‘a’ 
Footnote ‘a’: “Day 1 is the first day 
of study treatment. Baseline tests 
(including blood draws) should be 
performed prior to administration of 
the first dose. Screening tests may 
also be performed on Day 1 prior to 
study treatment if necessary, as long 
as these tests cannot affect 
eligibility.” 
Footnote ‘a’: “Day 1 is the first day of 
study treatment. Baseline tests 
(including blood draws) should be 
performed prior to administration of 
the first dose. Screening tests may also 
be performed on Day 1 prior to study 
treatment if necessary, as long as these 
tests cannot affect eligibility. If Dose 1 
is administered in the evening of Day 
1, Dose 2 would be given on the 
second calendar day and Dose 3 would 
be given on the third calendar day,” 
Clarified timing of 
doses if given at 
specific times on Day 
1. 
  


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Appendix C2: Summary of Changes v2.0 to v3.0 
Summary of Changes to Protocol BTI-202 Ver 2.0 to 3.0 
29 January 2021 
Page # 
of 
Redline 
Version 
Section 
Old Text 
New Text 
Rationale 
Global 
 
29 June 2020 
version 2.0 
29 January 2021 
version 3.0 
Protocol amendment 
4 
Synopsis 
Estimated date last subject 
completed: 30 September 2020 
Estimated date last subject 
completed: 01 May 2021 
Enrollment not as fast as 
expected. 
4, 8, 9, 
25, 26, 
35, 48 
Synopsis 
(Objectives, 
Notes, 
Endpoints/ 
Outcomes) 
and Sections 
5.1.2, 5.2.2, 
7.3, 9.3 
p.4 & 25, “[Optional] To follow the 
pharmacokinetics (PK) of 
administered rhu-pGSN.” 
p. 4 & 25, “To follow the 
pharmacokinetics (PK) of 
administered rhu-pGSN.” 
 
Clarifies that PK 
sampling is not 
mandatory but is strongly 
encouraged. 
p.8, 35, & 48 “Participants refusing 
PK blood samplings can remain in 
the trial.” 
p. 8, 35, & 48, “PK sampling is 
strongly encouraged. However, 
participants refusing some or all PK 
blood sampling can remain in the 
trial.” 
p.9 & 26, “PK(Optional)” 
p. 9 & 26, “PK” 
5, 27 
Synopsis, 
Section 6.1 
• Mechanical ventilation or 
extracorporeal membrane 
oxygenation (ECMO), 
vasopressor support, 
dialysis/renal replacement 
therapy (RRT). 
• Intubation with mechanical 
• Mechanical ventilation or 
extracorporeal membrane 
oxygenation (ECMO) with 
either vasopressor support or 
dialysis/renal replacement 
therapy (RRT) 
• Intubation with mechanical 
Either vasopressor 
support or dialysis/renal 
replacement therapy 
(RRT) define WHO 7; 
both are excluded from 
WHO 6. 


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ventilation, a mask with a 
reservoir or oxygen with 
high-flow nasal goggles  
ventilation, a mask with a 
reservoir or oxygen with 
high-flow nasal goggles but 
without vasopressor support 
or dialysis/RRT 
5, 
27/28, 
46 
Synopsis, 
Section 6.1, 
9.1.3 
p.5 & 27/28, “Perform physical 
examination (PE) and document 
radiographic evidence of pneumonia 
(chest x-ray [CXR] or computed 
tomography ([CT] scan if CXR is 
inadequate) if not already completed 
within the previous 48 hours per 
SOC” 
p. 5 & 27/28, “A RT-PCR test to 
confirm the diagnosis of COVID-19 
should be documented during the 
current illness leading to the present 
hospitalization; if RT-PCR test is not 
done prior to screening, the test is to 
be performed during screening before 
randomization (result might not be 
available at randomization or start of 
study treatment). Perform physical 
examination (PE) and document 
radiographic evidence of pneumonia 
(chest x-ray [CXR] or computed 
tomography ([CT] scan if CXR is 
inadequate) if not already completed 
within the previous 48 hours per 
SOC.” 
Added to indicate that an 
RT-PCR test to confirm 
COVID-19 is needed 
during screening if not 
done prior to screening, 
even if the result is to be 
available only after 
screening. A CXR or CT 
chest is needed at or 
within 48 hours of entry.  
Both are necessary to 
fulfill the inclusion 
criterion of being 
“Hospitalized with 
laboratory-confirmed 
(RT-PCR+) or highly 
suspected (compatible 
with at least bilobar lung 
involvement without 
another plausible 
diagnosis) COVID-19. 
p. 46, “Subjects are required to have 
a laboratory-confirmed (RT-PCR+) 
or highly suspected COVID-19 
pneumonia at screening. If 
confirmation is not available, the 
subject must undergo CXR, or a CT 
scan if CXR is inadequate, to 
confirm COVID-19 pneumonia. At 
screening, radiographic evidence 
(CXR, or CT scan) of COVID-19 
pneumonia may have been 
p.46, “Subjects are required to have 
pneumonia (confirmed clinically and 
documented on CXR or CT), with 
RT-PCR+ confirmed or highly 
suspected COVID-19 etiology at 
screening. If documentation is not 
available, the subject must undergo 
CXR, or a CT scan if CXR is 
inadequate, to confirm COVID-19 
pneumonia. At screening, 


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completed in the previous 48 hours 
per SOC.” 
radiographic evidence (CXR, or CT 
scan) of COVID-19 pneumonia may 
have been completed in the previous 
48 hours per SOC. If not already 
obtained and documented during the 
current illness leading to the present 
hospitalization, a RT-PCR test is to 
be performed during screening 
before randomization (result might 
not be available at randomization or 
start of study treatment).” 
5/6, 28, 
49 
Synopsis, 
Section 6.1, 
9.4 
“Save an approximate 10 mL aliquot 
of blood plasma or serum to be 
frozen at -20° C for subsequent 
biomarker assays (likely to include, 
but not limited to interleukin [IL]1² , 
IL6, IL10, tumor necrosis factor 
[TNF], etc.) for analysis at the central 
laboratory.”  
“Collect aliquots of blood for 
subsequent biomarker assays (likely 
to include, but not limited to 
interleukin [IL]1² , IL6, IL10, tumor 
necrosis factor [TNF], etc.) for 
analysis at the central laboratory (see 
Table 5 Schedule of Assessments and 
footnote ‘l’ for details).” 
The detail of volume and 
storage was omitted for 
simplicity. It is 
mentioned later in the 
schedule of assessment in 
what is now footnote ‘l’. 
6, 29 
Synopsis and 
section 6.2 
p.6 & 29, “All deaths and unexpected 
treatment-emergent SAEs will be 
evaluated by the Data and Safety 
Monitoring Board (DSMB) within 4 
working days of occurrence” 
p.6, “All reported deaths and 
treatment-emergent SAEs will be 
evaluated by the Data and Safety 
Monitoring Board (DSMB) within 4 
working days of notification of the 
Contract Research Organization 
(CRO)/Sponsor.” 
 
 
p.29, “No SAEs have been associated 
with the investigational medicinal 
product. Thus, all SAEs will be 
considered as unexpected for 
reporting purposes. All reported 
Because the CRO and 
Sponsor are not always 
immediately notified 
when SAEs occur. This 
change is intended to 
allow enough time for the 
DSMB to receive 
notification of and 
evaluate the SAEs. 


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deaths and treatment-emergent SAEs 
will be sent by EastHORN Safety to 
the DSMB within 2 working days of 
notification of the CRO/Sponsor by 
the sites. The events will be 
evaluated by the DSMB and 
comments returned to EastHORN 
Safety within 2 working days of 
notification of the DSMB.” 
6, 29 
Synopsis and 
section 6.2 
p.6, “Periodic safety reviews will be 
conducted after enrollment of 12, 24, 
36, and 48 patients.  
Data will be unblinded and/or the 
study paused at the discretion of the 
DSMB chair.” 
 
  
p.29,” Periodic safety reviews will be 
conducted after the last enrolled 
subject in each group of 12, 24, 36 
and 48 patients has reached the 
primary Day 14 time point. Data may 
be unblinded and/or the study paused 
at the discretion of the DSMB chair” 
p.6 & 29, “Periodic safety reviews 
will be conducted after 12, 24, 36, 
and 48 subjects have been fully dosed 
and completed assessment at Day 14. 
Only DSMB members will be 
provided with partially unblinded 
results separated into 2 groups by 
treatment without identifying the 
actual treatment. If all participants 
have completed study therapy before 
the last DSMB meeting involving 
review of 48 subjects after their Day 
14 visit can be held, this meeting can 
be cancelled at the discretion of the 
DSMB chair. Data will be further 
unblinded and/or the study paused at 
the discretion of the DSMB chair.” 
Clarifies that periodic 
safety reviews should be 
performed after a 
specified number of 
patients in each group 
have reached assessment 
Day 14 and NOT after 
they were enrolled. 
Depending on the 
enrolment progress, the 
DSMB meeting after 48 
patients might not be 
performed if all subjects 
required for the study are 
fully dosed at the time of 
the DSMB meeting to 
review the preceding 48 
subjects. 
7, 34, 
47 
Synopsis, 
Sections 7.2, 
9.2.2 
p. 7 & 34, “oral or core temperature” 
 
p. 47, “oral temperature” 
p. 7, 34 & 47 “body temperature” 
The change is to permit 
body temperature to be 
taken as is customary at 
the site, not necessarily 
by the oral route. 


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7, 34 
Synopsis, 
Section 7.2 
“Radiology report to be placed in the 
eCRF” 
“Radiology report and conclusion 
should be summarized in the eCRF”  
Changed to reflect that a 
formal report does 
necessarily need to be 
included but at least a 
summary of the report 
and findings should be 
included in the eCRF. 
7, 35 
Synopsis, 
Section 7.3 
“A negative RT-PCR test for 
COVID-19 during the evaluation of 
the present illness.” 
“A negative RT-PCR test for 
COVID-19 in the absence of a 
positive test during the evaluation of 
the present illness (in the presence of 
a positive test during the current 
illness, preceding or subsequent 
negative tests do not disqualify the 
subject).” 
Added to indicate that a 
negative RT-PCR test is 
not an automatic 
disqualifier from the 
study provided there are 
other positive tests 
during the current illness. 
9, 10, 
26, 32, 
44, 46, 
54 
Synopsis, 
sections 5.2.2, 
6.6, 9, 9.1.1, 
11.1 
p. 9 & 26, “Daily change in 9-point 
WHO severity score through at least 
Day 14.” 
p.9 & 26, “Daily change in 9-point 
WHO severity score through at least 
Day 14 (including after discharge, 
where feasible).” 
Added to avoid missing 
data after discharge when 
possible regarding daily 
assessment of the 9-point 
WHO score, should a 
subject be discharged 
before Day 14. 
p.10 & 54, “WHO severity score will 
be recorded daily as long as the 
subject is hospitalized, and at each 
follow-up visit.”  
p.10 & 54, “WHO severity score will 
be recorded daily while the subject is 
hospitalized, after discharge through 
Day 14, where feasible, and at each 
follow-up visit.” 


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p. 32, “Subjects will be observed 
through Day 14 for the primary 
efficacy endpoint with daily 
assessments (including WHO 
severity score) from Day 1 through 
discharge, and then follow-up visits 
at Days 14, 28, 60 (if possible), and 
90, and as needed.” 
p. 32, “Subjects will be observed for 
the primary efficacy endpoint with 
daily assessments (including WHO 
severity score) from Day 1 through 
Day 14. If a subject is discharged 
prior to Day 14, he/she will be 
assessed, if feasible, by phone daily 
through Day 14, and then at follow-
up visits, on Days 28, 60, and 90, and 
as needed.” 
p. 44, Footnote “c” was added in Table 5: Schedule of Assessment: "Assess 
daily from screening through Day 14 during hospitalization and after 
discharge, where feasible, and then at Days 28, 60, and 90.” 
Corresponding superscript was added in Row 5 “Who Severity Score” of 
Table 5. 
p. 46, “During screening and at the 
time points presented in the Schedule 
of Assessments (Table 5), each 
subject’s WHO severity score 
according to the 9-point scale 
(Section 6.1) will be recorded on the 
appropriate eCRF.” 
p. 46, “During screening and at the 
time points presented in the Schedule 
of Assessments (Table 5), each 
subject’s WHO severity score 
according to the 9-point scale 
(Section 6.1) will be recorded on the 
appropriate eCRF. WHO severity 
scores should be documented daily 
through Day 14 (during 
hospitalization and after discharge, 
where feasible).” 


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39 
 
Section 8.8 
“A disposition form will be 
completed to verify that all used, 
unused or partially used supplies 
have been returned or destroyed 
following appropriate accountability 
review by the monitor.” 
“A disposition form will be 
completed as per local regulation, 
since used/partially used vials might 
be required to be destroyed after use. 
Unused vials should be returned to 
the Sponsor.” 
Provides clarity that 
disposition of 
used/partially used drug 
should be done according 
to local regulation and 
that unused drug vials 
should be returned to the 
Sponsor. 
39 
Section 8.9 
“All prior and concomitant 
medications, including generic name 
(if possible), and start date if known 
should be documented in the subject's 
file and in the eCRF.” 
“Medications administered within 
1 month prior to screening and 
concomitant medications, including 
generic name (if possible), and start 
date if known should be documented 
in the subject's file and in the eCRF.” 
Provides guidance for the 
timeline of medications 
taken before screening 
that need to be reported. 
41, 46, 
50, 52, 
58, 59 
Sections 9, 
9.1, 10.1.2, 
10.7, 13.5 
p. 41, “Written informed consent 
must be granted by each subject prior 
to the initiation of any study 
procedure or assessment (other than 
those considered SOC).” 
 
p. 41, “Written or oral informed 
consent must be granted by each 
subject/next of kin/legal proxy 
according to hospital procedures and 
local regulations prior to the 
initiation of any study procedure or 
assessment (other than those 
considered SOC).” 
Corrected to be 
consistent with inclusion 
criteria that states that the 
next of kin or legal proxy 
can provide consent and 
clarifies that informed 
consent can be either 
written or oral which was 
changed as an adaptation 
to the COVID-19 crisis 
in case informed consent 
cannot be given by 
writing. 
p.46, “Prior to screening, all subjects 
must provide informed consent” 
p.46, “Prior to screening, all 
subjects/next of kin/legal proxy must 
provide informed consent” 
p.50, “All SAEs that occur after any 
subject has signed the consent form 
and has been randomized, …” 
p.50, “All SAEs that occur after the 
subject/next of kin/legal proxy has 
given written or oral consent and has 
been randomized, ….” 


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p.52, “All AEs that occur from the 
signing of the informed consent form 
(ICF) until the first dose…” 
p.52, “All AEs that occur from 
informed consent until the first 
dose…” 
In section 13.5 in p. 58 & 59,“/next of kin/legal proxy” was added next to the 
word “Subject” when mentioned and “or oral” was added next to the word 
“written” 
42 
Section 9: 
Table 5 
Remove what is now superscript “d” (was part of “c”) from Confirm 
COVID-19 pneumonia (CXR or CT, RT-PCR for COVID-19) row 
Footnote “d” that refers 
to collecting sputum is 
not applicable for 
confirming COVID-19 
pneumonia. 
42 
Section 9: 
Table 5 
Remove superscripts of what is now footnote “f” (was “e”) from time points 
in Confirm COVID-19 pneumonia (CXR or CT, RT-PCR for COVID-19 row 
columns “Screening” and “Follow up visits 14 and 28” ) 
Removed for simplicity 
as the footnote “f” itself 
describes when the 
indicated tests should be 
done. 
42, 44 
& 47 
Section 9: 
Table 5, 
Section 9.2.3 
Add footnote “g”: “Height and weight only to be measured at screening or 
baseline and as per SOC thereafter” and corresponding superscript in the 
table, row Physical exam 
Added to emphasize that 
weight does not 
necessarily need to be 
repeated after screening 
or baseline unless 
dictated by SOC. 
p. 47, “Height need only be 
measured at the screening 
examination. The initial body weight 
measured at enrollment will be used 
to calculate rhu-pGSN dosing for all 
doses (so that an individual subject 
will always receive the same dose). 
Body weight can be repeated per 
SOC thereafter where possible.” 
p. 47, “Height and weight need only 
be measured at screening or baseline. 
The initial body weight measured at 
enrollment will be used to calculate 
rhu-pGSN dosing for all doses (so 
that an individual subject will always 
receive the same dose). Body weight 
can be repeated per SOC thereafter 
where possible.” 


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43 
Section 9: 
Table 5 
Remove footnote “b” from Biomarker sampling row 
Samples are required to 
be collected at baseline. 
43 
Section 9: 
Table 5 
Remove superscript of footnote “b” from Anti-rhu-pGSN antibody sampling 
(immunogenicity) row, column “Baseline/Treatment” 
Footnote “b” refers to 
tests done as dictated by 
SOC. Since 
immunogenicity is not 
part of SOC, “b” 
superscript was removed. 
43 
Section 9: 
Table 5 
Remove superscript “n” (was previously “l”) from Study drug administration 
row, column “Baseline/Treatment” 
Footnote “n” (previously 
“l”) is not applicable as it 
is a general description of 
study treatment at all 
days of treatment and not 
just at Day 1. 
43 & 
45 
Section 9: 
Table 5 
Row 21 “AEs (only SAEs after Day 
14)” 
Row 21: “AEs/SAEsq” 
Clarify that after Day 14, 
only SAEs will be 
recorded throughout the 
remainder of the study. 
Added footnote “q”: “From informed consent to first administration of study 
drug, related AEs and any SAEs will be recorded. During and after first 
admin of study drug, all AEs and SAEs will be recorded through Day 14. 
After Day 14, only SAEs will be recorded through study completion” 
Row 21“AEs/SAEs q”: Added “X” in “Screening” Column 
46 
Section 9.1.2 
“Testing could be done at the 
discretion of caregivers.” 
“Testing is not required but could be 
done as part of SOC at the discretion 
of caregivers.” 
Added to clarify that HIV 
testing is not required per 
protocol. 
48 
Section 9.2.6 
“Comprehensive metabolic profile 
including chemistries/electrolytes, 
total protein/albumin, blood urea 
nitrogen (BUN)/creatinine, CRP, 
“Comprehensive metabolic profile 
including chemistries/electrolytes, 
total protein/albumin, blood urea 
nitrogen (BUN)/creatinine, CRP, 
LDH indicates “lactate” 
(not “lactose”) 
dehydrogenase. Tests re: 
lipid parameters 


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lactose dehydrogenase (LDH), 
creatine phosphokinase (CPK), 
alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), 
total bilirubin, alkaline phosphatase, 
and amylase or lipase.” 
 
lactate dehydrogenase (LDH), 
creatine phosphokinase (CPK), 
alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), 
total bilirubin, total cholesterol, 
low-density lipoprotein (LDL) 
cholesterol, high-density 
lipoprotein (HDL) cholesterol, 
alkaline phosphatase, and amylase or 
lipase.” 
highlighted were added 
as requested by one of 
the investigators. 
53 
Section 10.7 
All SAEs occurring any time 
(baseline, treatment, or follow up) 
during the study (related or 
unrelated) must be reported to the 
Sponsor and the responsible person at 
the CRO within 24 hours of the 
Investigator’s knowledge. 
All SAEs occurring any time 
(baseline, treatment, or follow up) 
during the study (related or 
unrelated) must be reported to 
EastHORN Safety within 24 hours of 
the Investigator’s knowledge. 
Added to clarify to whom 
SAEs should be first 
reported. 
56, 57 
Section 12.3 
p. 56, “Monitoring will include 
personal visits with the Investigator 
and study staff, as well as 
appropriate communications …” 
p. 56, “Monitoring will include 
personal visits with the Investigator 
and study staff, remote monitoring 
visits including Remote Source Data 
Verification (remote SDV) only in 
case onsite visits are not allowed in 
the BTI-202 study during the public 
health crisis due to COVID-19 as 
well as appropriate 
communications…” 
Allows for remote data 
monitoring which was 
implemented as an 
adaptation to the 
COVID-19 pandemic. 
A paragraph was added at the end of this section in p. 57 to explain the 
specifics of remote data monitoring: “Remote monitoring is an alternative 
mechanism....and protection of study participants rights during remote 


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SDV” 
 
Other changes:  
• Few additional language corrections were included in different places in the text. 
• Some background about COVID19 was updated as shown in Section 4.2. 
• Footnote lettering of Table 5: Schedule of Assessments was updated as required by insertions and deletions. 
• Starting with Section 8.7, “or designee” was added next to “pharmacist” and “equivalent” next to “pharmacy” to accommodate 
local practices if necessary.  


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Appendix C3: Summary of Changes v3.0 to v4.0 
Summary of Changes to Protocol BTI-202 Ver 3.0 to 4.0 
09 June 2021 
Page # of 
Redline 
Version 
Section 
Old Text 
New Text 
Rationale 
Global 
Global 
29 January 2021 
version 3.0 
09 June 2021 
version 4.0 
Protocol amendment 
Global 
Global 
(see protocol) 
(see protocol) 
Updated abbreviations on 
first use and added new 
abbreviations, as needed. 
Global 
Global 
(N/A) 
Defined criteria subjects in Part 1: 
…in Part 1, a severity score of 4, 5, or 
6,… 
 
Defined criteria for subjects in Part 2: 
…or for Part 2, intubated without 
extracorporeal membrane oxygenation 
(ECMO) with a severity score of 6 or 7 
on the World Health Organization 
(WHO) 9-point severity scale 
The study was amended to 
include subjects who are 
intubated without ECMO 
with a WHO severity score 
of 6 or 7. To distinguish 
this group of subjects, the 
study was divided into 2 
parts and the differences 
between subjects in the 2 
parts is defined throughout 
the protocol. 
4 
Synopsis 
01 May 2021 
21 October 2021 
Estimated last subject 
completion date updated to 
reflect addition of new 
subjects in Part 2. 
5, 36, 
40, 55 
Synopsis, 
Section 6.1, 
Section 6.5, 
Section 9.1 
…within 24 hours of reaching a WHO 
severity score of 4 to 6, whether the 
severity score is attained on admission or 
during hospitalization. 
…for Part 1 within 24 hours of reaching 
a WHO severity score of 4 to 6, whether 
the severity score is attained on 
admission or during hospitalization, or 
for Part 2, within 24 hours of intubation 
without ECMO with a WHO severity 
Specified the time within 
which subjects in Part 2 
must be screened. 


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score of 6 or 7. 
5, 37, 
40 
Synopsis, 
Section 6.1, 
Section 6.5 
…subject to be randomized (1:1 to 
treatment arms rhu-pGSN:placebo) 
within 12 hours of informed consent 
…subject to be randomized (1:1 to 
treatment arms rhu-pGSN:placebo) 
within 12 hours of informed consent 
(Part 1) or within 24 hours of intubation 
(Part 2)… 
Specified the time within 
which subjects in Part 2 
must be randomized. 
6, 43 
Synopsis, 
Section 7.1 
A total of 60 evaluable participants 
randomized 1:1 to rhu-pGSN:placebo 
(30:30 subjects). 
Part 1: A total of 60 evaluable 
participants randomized 1:1 to rhu-
pGSN:placebo (30:30 subjects).  
Part 2: A total of 20 evaluable 
participants randomized 1:1 to rhu-
pGSN:placebo (10:10 subjects). 
Updated to reflect the 
addition of Part 2 and 20 
additional subjects. 
6, 38 
Synopsis, 
Section 6.2 
Periodic safety reviews will be 
conducted after 12, 24, 36, and 48 
subjects have been fully dosed and 
completed assessment at Day 14. 
In Part 1, periodic safety reviews will be 
conducted after 12, 24, 36, and 48 
subjects have been fully dosed and 
completed assessment at Day 14. 
Updated to clarify that the 
listed time points for 
periodic safety reviews 
apply to only Part 1. 
6, 43 
Synopsis, 
Section 7.2 
- Weight d100 kg 
- Within 24 hours of reaching a WHO 
severity score of 4-6 either:  
o 
At admission 
o 
While already 
hospitalized. 
- Part 1 only: Weight d100 kg 
- Part 1 only: Within 24 hours of 
reaching a WHO severity score of 4-6 
either:  
o 
At admission 
o 
While already hospitalized. 
- Part 2 only: Within 24 hours of 
intubation without ECMO with a 
WHO severity score of 6 or 7) 
Updated inclusion criteria 
to reflect that the weight 
limit only applies to 
subjects in Part 1 and to 
distinguish between the 
severity of disease required 
for subjects enrolled in 
Part 1 vs. Part 2. 
10, 63 
Synopsis, 
Section 11.1 
(Added “For Part 1” to existing text; see 
protocol) 
For Part 2, only descriptive statistics will 
be provided for exploratory analyses. 
Binary efficacy endpoints will be 
summarized by counts, percentages, and 
95% confidence intervals (CIs) for each 
treatment group. Differences in 
percentages between treatment groups 
will be summarized by 95% CIs. 
Continuous efficacy and biochemical 
Updated statistical analyses 
to reflect distinctions 
between analyses to be 
performed in Part 1 vs. 
Part 2. 


BioAegis Therapeutics, Inc. 
 
Clinical Study Protocol 
rhu-pGSN 
 
BTI-202 
Version 4.0 dated 09 June 2021 
86 
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endpoints will be summarized by counts, 
means, standard deviations, median, 
minimum, maximum by treatment 
group. Differences in means between 
treatment groups will be summarized by 
95% CIs. Natural log transformation 
may be necessary to better approximate 
a bell-shaped distribution for the 
continuous endpoints. Time-to-event 
endpoints will be summarized by 
Kaplan-Meier plots, medians, quartiles, 
minimum, and maximum by treatment 
group. Bayesian posterior probabilities 
that differences from zero toward 
beneficial treatment effect for these 
summary statistics may be computed. 
31 
Section 4.5 
(N/A) 
The study protocol was amended to 
include Part 2 to evaluate rhu-pGSN in 
10 subjects (compared to 10 placebo 
subjects) who are intubated without 
extracorporeal membrane oxygenation 
(ECMO) and therefore score as level 6 
or 7 on the WHO scale. Recent data in 
the “steroid era” have suggested that 
immunomodulators may exert their most 
beneficial effects in critically ill patients 
which were not captured in the original 
recruitment for this study. 
Compassionate use in a single patient 
who scored as level 7 on the WHO scale 
in April 2021 resulted in quick and 
dramatic improvement temporally 
related to rhu-pGSN administration. 
Accordingly, intubated patients may be 
an appropriate target population for rhu-
pGSN. 
Added the rationale for the 
addition of Part 2 to the 
study. 


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Clinical Study Protocol 
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Version 4.0 dated 09 June 2021 
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40 
Section 6.5 
Eligible subjects will be…dosed within 
12 hours of randomization. 
Eligible subjects will be…dosed within 
12 hours of randomization (both parts). 
Updated to specify that 
subjects in both parts of the 
study must be dosed within 
12 hours of randomization. 
50, 59, 
69 
Section 9, 
Section 10.1.2, 
Section 13.5 
Written or oral informed consent… 
Informed consent… 
Updated to reflect that 
subjects in Part 2 may not 
be able to provide written 
consent initially. 
53, 56 
Schedule of 
Assessments 
Table 5, 
Section 9.2.3 
Height and weight only to be measured 
at screening or baseline and as per SOC 
thereafter. 
(In Part 1, h)Height and weight only to 
be measured at screening or baseline and 
as per SOC thereafter. In Part 2, height is 
not required at screening and weight 
may be obtained via bed scale, if 
possible, or estimated. 
Added text to clarify the 
different measurement 
requirements for height and 
weight in Part 1 vs. Part 2. 
 
53, 56 
Schedule of 
Assessments 
Table 5, 
Section 9.2.2 
Record blood pressure, body 
temperature, respiration rate, and heart 
rate, as well as pulse oximetry. 
Record blood pressure, body 
temperature, respiration rate, and heart 
rate, as well as pulse oximetry. In Part 2, 
while the subject is intubated, the 
respiratory rate and the ventilator 
settings (i.e., tidal volume, inspired 
oxygen, inspiratory pressure, and PEEP) 
should be documented. 
Added text to specify which 
settings related to 
intubation should be 
documented in Part 2. 
56 
Section 9.2.3 
The physical examination includes skin, 
head, ears, eyes, nose, throat, heart, 
lungs, abdomen, and neurologic system. 
The physical examination includes skin, 
head, ears, eyes, nose, throat, heart, 
lungs, abdomen, and neurologic system, 
where possible. 
Added “where possible” to 
the body parts/systems to be 
examined to reflect that 
there may be differences in 
physical examinations for 
subjects in Part 1 vs. Part 2. 
63-64 
Section 11.2 
(Added “For Part 1” to existing text; see 
protocol) 
For Part 2, a sample size of 20 subjects 
was chosen to generate an estimate of 
any clinically relevant treatment effect. 
Clarified the rationale for 
sample size in Part 2. 
68 
Section 13.5 
It is the responsibility of the Investigator 
(or designee) to obtain written or oral 
informed consent from each subject/next 
of kin/legal proxy after adequate 
explanation of the aims, methods, and 
It is the responsibility of the Investigator 
(or designee) to obtain written informed 
consent from each subject/next of 
kin/legal proxy after adequate 
explanation of the aims, methods, and 
Updated to reflect that in 
Part 2, written consent may 
not be possible to obtain 
prior to enrollment due to 
clinical circumstances, but 


BioAegis Therapeutics, Inc. 
 
Clinical Study Protocol 
rhu-pGSN 
 
BTI-202 
Version 4.0 dated 09 June 2021 
88 
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potential hazards of the study and before 
any study procedures are initiated. 
potential hazards of the study and before 
any study procedures are initiated. If 
written consent cannot be obtained prior 
to enrollment due to clinical 
circumstances, oral consent will be 
documented and written consent will be 
obtained later, when possible. 
oral consent will be 
documented and written 
consent obtained later, 
when possible.  
 

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Statistical Analysis Plan 
 
Sponsor 
Name 
BioAegis 
Therapeutics, Inc. 
Protocol ID 
BTI-202     
NCT04358406 
Protocol Version 
2.0 (dated 29 June 
2020) 
Study 
Name 
BTI-202 
Study 
Title 
A Phase  2 Randomized, Double-Blind, Placebo-Controlled, Proof- 
of-Concept study to evaluate the Efficacy and Safety of 
Recombinant Human Plasma Gelsolin (rhu-pGSN) Added to 
Standard of Care for Treatment of Subjects with Severe COVID-19 
Pneumonia. 
CRF Version 
1.118 
Document ID 
BTI-202_Statistical Analysis 
Plan 
Document 
Version 1.00 
 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 
Author 1: 
 
Bharathy Prasath 
Study Statistician 
 
05-Aug-2021 
 
 
Author 2: 
 
Shweta Padmanaban 
Lead Statistician 
05-Aug-2021 
 
 
Reviewer / 
Approver: 
 
 
Mark DiNubile, MD 
Chief Medical Officer, BioAegis Therapeutics 
 
05-Aug-2021 


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1 Table of Contents 
1 Abbreviations and Definitions 
......................................................................................................... 7 
2 Introduction .................................................................................................................................... 9 
2.1 Background ............................................................................................................................. 9 
2.2 Rationale 
............................................................................................................................... 
10 
2.2.1 
Rationale for Study 
........................................................................................................ 
10 
2.2.2 
Rationale for Starting Dose 
............................................................................................ 
10 
3 Study Objectives 
............................................................................................................................ 
10 
3.1 Primary Objective 
.................................................................................................................. 
10 
3.2 Secondary Objectives 
............................................................................................................ 
10 
3.3 Immunogenicity Objective .................................................................................................... 
11 
4 Study Design 
.................................................................................................................................. 
11 
4.1 Overview 
............................................................................................................................... 
11 
4.2 Sample Size Justification........................................................................................................ 
11 
4.3 Randomization and Blinding.................................................................................................. 
11 
4.4 Unblinding 
............................................................................................................................. 
12 
4.5 Inclusion/Exclusion Criteria 
................................................................................................... 
12 
4.5.1 
Inclusion Criteria............................................................................................................ 
12 
4.5.2 
Exclusion Criteria 
........................................................................................................... 
13 
4.6 Treatment Allocation............................................................................................................. 
13 
5 Assessment Schedule 
.................................................................................................................... 
14 
6 Interim Analysis 
............................................................................................................................. 
15 
7 Efficacy and Safety Endpoints ....................................................................................................... 
15 
7.1 Primary Endpoints 
................................................................................................................. 
15 
7.1.1 
Safety and tolerability ................................................................................................... 
15 
7.1.2 
Efficacy 
.......................................................................................................................... 
16 
7.2 Secondary Endpoints 
............................................................................................................. 
16 
7.2.1 
Safety and tolerability ................................................................................................... 
16 
 


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7.2.2 
Efficacy 
.......................................................................................................................... 
16 
7.2.3 
PK (Optional) 
................................................................................................................. 
16 
7.2.4 
Immunogenicity............................................................................................................. 
16 
7.3 Exploratory Endpoints 
........................................................................................................... 
17 
7.3.1 
Biomarkers 
.................................................................................................................... 
17 
8 Statistical Methods 
........................................................................................................................ 
17 
8.1 General Conventions 
............................................................................................................. 
17 
8.2 Multiplicity Adjustment 
......................................................................................................... 
17 
8.3 Re-estimation of Sample Size 
.................................................................................................... 18 
9 Data handling Procedures 
............................................................................................................. 
18 
9.1 Handling Missing/Incomplete Data 
....................................................................................... 
18 
9.2 Partial dates .......................................................................................................................... 
18 
9.3 Handling Outliers 
................................................................................................................... 
19 
9.4 Blinded Review Meeting........................................................................................................ 
19 
10 Analysis Sets 
.................................................................................................................................. 
19 
10.1 Screened Analysis Set 
................................................................................................................ 19 
10.2 All-enrolled Analysis Set ............................................................................................................ 20 
10.3 Randomized Analysis Set 
....................................................................................................... 
20 
10.4 Full Analysis Set 
..................................................................................................................... 
20 
10.5 Safety Analysis Set 
................................................................................................................. 
20 
10.6 Per-Protocol Analysis Set....................................................................................................... 
21 
10.7 PK Analysis Set 
............................................................................................................................ 21 
11 Analysis Variables 
.......................................................................................................................... 
21 
11.1 Analysis Set Flags 
................................................................................................................... 
21 
11.2 Treatment groups 
.................................................................................................................. 
21 
11.3 Analysis Visits 
........................................................................................................................ 
21 
11.3.1 Timepoints 
..................................................................................................................... 
22 
11.3.2 Study Period 
.................................................................................................................. 
22 


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11.3.3 Visit Imputation 
............................................................................................................. 
22 
11.3.4 Repeat Assessments 
...................................................................................................... 
23 
11.4 Study Duration ...................................................................................................................... 
23 
11.5 Discontinued Subjects 
........................................................................................................... 
23 
11.6 Replacement Subjects 
........................................................................................................... 
23 
11.6.1 Common Derivations 
..................................................................................................... 
24 
11.7 Baseline 
................................................................................................................................. 
24 
11.7.1 Change from Baseline.................................................................................................... 
24 
11.8 Protocol Deviations 
............................................................................................................... 24 
11.9 Treatment Compliance 
.......................................................................................................... 
24 
11.10 Medical History and Concurrent Diseases 
......................................................................... 
25 
11.11 Prior and Concomitant Medications.................................................................................. 
25 
11.12 Adverse Events 
.................................................................................................................. 
25 
11.13 Laboratory Assessments 
.................................................................................................... 
25 
11.14 EKG Measurements 
........................................................................................................... 
25 
11.15 Unit Conversion 
................................................................................................................. 
26 
11.16 Efficacy Endpoints ............................................................................................................. 
26 
11.16.1 
Hospitalization due to COVID-19 
.................................................................................. 26 
11.16.2 
CURB-65 Score 
........................................................................................................... 
26 
11.16.3 
Abbreviated Mental Health Score 
............................................................................. 
26 
11.16.4 
WHO Severity Scores 
................................................................................................. 
27 
11.16.5 
Subjects Discharged .................................................................................................. 
27 
11.17 Criterion Flags 
.................................................................................................................... 
27 
11.18 Time to Death 
.................................................................................................................... 
28 
11.19 Self-Evident Corrections 
.................................................................................................... 
28 
12 Statistical Analysis 
......................................................................................................................... 
28 
12.1 Subject Disposition 
................................................................................................................ 
28 
12.2 Visit Attendance 
.................................................................................................................... 
29 


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12.3 Protocol Deviations 
............................................................................................................... 
29 
12.4 Demographic and Baseline 
Characteristics ........................................................................... 
29 
12.5 Baseline Characteristics 
......................................................................................................... 
30 
12.6 Medical/Surgical History ....................................................................................................... 
30 
12.7 Prior and Concomitant Medications ..................................................................................... 
30 
12.8 Extent of Exposure ................................................................................................................ 
31 
12.9 Efficacy Analyses ................................................................................................................... 
31 
12.9.1 Primary Efficacy analysis 
................................................................................................ 
31 
12.9.1.1 Proportion of Subjects Alive on Day 14 
................................................................. 
31 
12.9.2 Secondary Efficacy Analyses 
.......................................................................................... 
32 
12.9.2.1 Change in WHO Severity Scores 
............................................................................ 
32 
12.9.2.2 Time to Death (Days) 
............................................................................................. 
33 
12.9.2.3 Proportion of Subjects Alive on Days 7, 14, 28, 60 and 
90 
.................................... 
34 
12.9.2.4 Proportion of Subjects Discharged 
........................................................................ 
34 
12.9.2.5 Hospitalization due to COVID 19 
........................................................................... 
35 
12.9.2.6 Comparison of Days in Hospital, ICU and Ventilation............................................ 
35 
12.9.3 Other Analyses 
.............................................................................................................. 
36 
12.9.3.1 Arterial Blood Gas Test 
.......................................................................................... 
36 
12.9.3.2 Hypotension requiring treatment beyond fluids (Vasopressors) .......................... 
36 
12.9.3.3 CURB-65 Score 
....................................................................................................... 
36 
12.9.3.4 Abbreviated Mental Health Score 
......................................................................... 
37 
12.9.3.5 Sputum Microbiology, Blood cultures and Dialysis ............................................... 
37 
12.9.3.6 Confirmation of COVID-19 
pneumonia 
.................................................................. 
37 
12.9.4 Pharmacodynamic Parameters ..................................................................................... 
37 
12.9.5 Plasma Concentration 
................................................................................................... 
38 
12.9.5.1 Continuous Summary 
............................................................................................ 38 
12.9.5.2 Plasma Concentration Time Plots 
.......................................................................... 
38 
12.9.6 Pharmacokinetic Parameters ........................................................................................ 
38 
12.9.6.1 Continuous Summary 
............................................................................................ 
38 
12.9.7 Immunogenicity............................................................................................................. 
38 
12.10 Safety Analyses 
.................................................................................................................. 
39 


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12.10.1 
Adverse Events 
.......................................................................................................... 
39 
12.10.1.1 Overall Adverse Events 
.......................................................................................... 
39 
12.10.1.2 Summary of Treatment Emergent Adverse Events by SOC and PT 
........................ 40 
12.10.1.3 Summary of Adverse Events by Relationship and Intensity .................................. 
40 
12.10.2 
Summary of Death .................................................................................................... 
40 
12.10.3 
Laboratory Assessments 
............................................................................................ 
40 
12.10.3.1 Continuous Summary 
............................................................................................ 
40 
12.10.3.2 Categorical Summary ................................................................................................ 40 
12.10.3.3 Listings 
................................................................................................................... 
41 
12.10.4 
Other Safety Analyses ............................................................................................... 
41 
12.10.4.1 Vital Signs 
.............................................................................................................. 
41 
12.10.4.2 Physical Examination 
............................................................................................. 
42 
12.10.4.3 Electrocardiogram Assessments 
............................................................................ 
42 
12.10.5 
Exploratory Analyses 
................................................................................................. 
42 
13 Changes to Planned Analyses 
........................................................................................................ 
43 
14 Index of Tables, Listings and Graphs ............................................................................................. 
44 
15 References 
..................................................................................................................................... 
45 
16 Appendices 
.................................................................................................................................... 
46 
16.1 Summary of Statistical Analyses 
............................................................................................ 
46 
17 Change Log 
.................................................................................................................................... 
47 


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1 Abbreviations and Definitions 
 
Abbreviation or Specialist Term 
Explanation 
ACE-2 
angiotensin-converting enzyme 2 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC0-8 
Area under the curve from time zero to 8 
hours 
AUCinf 
Area under the curve from time zero to 
infinity 
BioAegis 
BioAegis Therapeutics, Inc. Or Sponsor 
BiPAP 
Bilevel positive airway pressure 
BUN 
Blood urea nitrogen 
CAP 
Community-acquired pneumonia 
CBC 
Complete blood count 
Cmax 
Maximum concentration 
CMH 
Cochran-mantel-Haenszel 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus 2019 
CPAP 
Continuous positive airway pressure 
CPK 
Creatine phosphokinase 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse 
Events 
CURB-65 
Confusion, Urea >7 mmol/L, Respiratory rate 
≥30/min, Blood pressure systolic <90 or 
diastolic ≤60, and age ≥65 
years 
CXR 
Chest x-ray 
CYP450 
Cytochrome P450 
DBL 
Database Lock 
DSMB 
Data and Safety Monitoring Board 
ECMO 
Extracorporeal membrane 
oxygenation 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EKG 
Electrocardiogram 
EOS 
End of study 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonization of 
Technical Requirements for Pharmaceuticals 
for Human Use 
ICU 
Intensive care unit 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
IRR 
Injection-related reaction 
IUD 
Intrauterine device 
 
 
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Analysis 
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IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower Limit of Quantification 
MV 
Mechanical ventilation 
NCI 
National cancer institute 
PE 
Physical examination 
pGSN 
Plasma gelsolin 
PK 
Pharmacokinetics 
POC 
Proof of concept 
PT 
Preferred Term 
rhu-pGSN 
Recombinant human plasma gelsolin 
RRT 
Renal replacement therapy 
RT-PCR 
Reverse transcription polymerase chain 
reaction 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome 
coronavirus 2 
SOC 
Standard of care 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse 
reaction 
T
1/2 
Terminal half-life 
TEAE 
Treatment-emergent adverse event 
T
max 
Time to maximum concentration 
VP 
Vasopressor 
WHO 
World health organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2 Introduction 
A Phase  2 Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial to Evaluate the 
Efficacy and Safety of Recombinant Human Plasma Gelsolin (rhu-pGSN) Added to Standard of Care for 
Treatment of Subjects with Severe COVID-19 Pneumonia. 
 
Potential subjects hospitalized with laboratory-confirmed (reverse transcription polymerase chain 
reaction [RT-PCR+]) or highly suspected (compatible with at least bilobar lung involvement without 
another plausible diagnosis) COVID-19 pneumonia will be screened within 24 hours of reaching a WHO 
severity score of 4 to 6, whether the severity score is attained on admission or during hospitalization. 
 
2.1 Background 
Pneumonia is an inflammatory condition of the lung primarily affecting the alveoli. It is usually caused 
by infection with viruses or 
bacteria and less commonly other microorganisms. Certain drugs and other 
conditions such as autoimmune diseases may cause a similar clinical picture. 
 
Typical symptoms include a cough, chest pain, fever, and difficulty breathing. Diagnostic tools include 
chest  x-rays (CXRs), serology, microscopy of  a sputum smear and culture of the sputum. Treatment 
depends on the underlying cause. Pneumonia documented or presumed to be viral, bacterial, or fungal 
is treated with appropriate agents when available. If the pneumonia is severe, the affected person is 
admitted to hospital. 
 
Pneumonia is classified according to the etiologic organism and where the infection was acquired 
(community or hospital facility). 
 
Community-acquired pneumonia (CAP) is the most common type of pneumonia, and may be caused 
by pyogenic bacteria, atypical bacteria, viruses or fungi which often cannot be identified in real time. 
CAP may also have non-infectious etiologies, including allergic, immune-mediated, toxins, or drugs. 
CAP occurs throughout the world and is a leading cause of illness and death. 
 
Severe acute respiratory syndrome coronavirus  2 (SARS-CoV-2) binds to the angiotensin-converting 
enzyme 2 (ACE-2) receptors located to certain epithelial and endothelial cell surfaces. Lung tissue is the 
major, but not sole target of this novel coronavirus. The agent can cause fatal infections by eliciting an 
over-exuberant immune response leading to injurious lung inflammation +/- a cytokine storm. Patients 
may die  from acute lung injury/acute respiratory distress syndrome or  survive  with  debilitating 
pulmonary fibrosis. Interventions have been proposed as treatment modalities to decrease the viral 
load and/or to modulate the intense host reaction. Blunting of an overzealous inflammatory response 
can potentially improve respiratory outcomes independent of any direct antiviral effect.  A 
coagulopathy that may result in large part from endothelial cell disruption can contribute to the 
pathogenesis by predisposing to disseminated microthrombi and large vessel thromboemboli. Older, 
hypertensive, and diabetic patients are at highest risk for complications and serious outcomes. 
 
Plasma gelsolin (pGSN), an abundant, naturally occurring, circulating protein depleted in severe 
inflammatory conditions, offers similar promise in aborting lung injury, and offers  a possible novel 
therapeutic agent in this time of crisis. Since recombinant human pGSN (rhu-pGSN) is  a pathogen- 
indifferent treatment acting primarily on host inflammatory responses, the microbial etiology of life- 
threatening pneumonia is not particularly relevant. 


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2.2 Rationale 
 
2.2.1 
Rationale for Study 
The damage inflicted by COVID-19 is primarily mediated through an overly exuberant host response to 
the virus, not directly by the virus itself. This overblown reaction consists of excessive and prolonged 
inflammation culminating in a cytokine storm and disseminated coagulopathy injuring the lungs and 
blood vessels. Interrupting or tempering this maladaptive process lessens further organ injury, 
restoring immune equilibrium and allowing tissue repair. 
 
Plasma gelsolin plays a central regulatory role (“master switch”) in diverse inflammatory pathways. A 
dual-pronged attack on COVID-19 concurrently reducing the inciting virus (with remdesivir or other 
antiviral agents) and quelling the inflammatory tsunami (with  a non-toxic but powerful anti- 
inflammatory drug) could theoretically synergize in shutting down the COVID-19 attack better than 
either modality alone. The action of pGSN on multiple pathways effectively blocks unbridled immune 
activation without inducing undesired side-effects or dangerous immunosuppression. 
 
2.2.2 
Rationale for Starting Dose 
The dosage for this trial was extrapolated from efficacious doses in animal studies of severe 
pneumonia. A Phase 1b/2a dose escalation study showed no drug-related or SAEs in patients with 
CAP administered 3 daily doses of rhu-pGSN at 6, 12, and 24 mg/kg of actual body weight. 
 
3 Study Objectives 
 
3.1 Primary 
Objective 
• To assess the efficacy (survival without organ failure on Day 14) of IV rhu-pGSN plus SOC vs 
placebo plus SOC (hereafter referred to as rhu-pGSN vs placebo) administered to hospitalized 
subjects with a primary diagnosis of COVID-19 pneumonia and a severity score of 4, 5, or 6 on 
the World Health Organization (WHO) 9-point severity scale. 
• To evaluate the safety (incidence of SAEs) of IV rhu-pGSN administered to hospitalized subjects 
with a primary diagnosis of 
COVID-19 pneumonia and a severity score of 4, 5, or 6 on the WHO 
9-point severity scale. 
 
3.2 Secondary 
Objectives 
• To further assess the efficacy of IV administered rhu-pGSN 
• To measure changes in the WHO 9-point severity scale for SOC ± rhu-pGSN 
• To evaluate the effect of administered rhu-pGSN on survival rates 
• To assess the relationship of pGSN levels (and other biomarkers) at baseline with clinical 
outcomes 
• [OPTIONAL] To follow the PK of administered rhu-pGSN 


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3.3 Immunogenicity Objective 
• To investigate the development of antibodies against pGSN post-treatment in rhu-pGSN vs 
placebo recipients compared to baseline. 
 
4 Study Design 
 
4.1 Overview 
This is  a randomized, double-blind, placebo-controlled, multicenter Phase  2 study to evaluate the 
efficacy and safety of rhu-pGSN plus SOC in subjects with severe COVID-19 pneumonia. Potential 
subjects hospitalized with laboratory-confirmed (reverse transcription polymerase chain reaction [RT- 
PCR+]) or highly suspected (compatible with at least bilobar lung involvement without another 
plausible diagnosis) COVID-19 pneumonia will be screened within 24 hours of reaching a WHO severity 
score of 4 to 6, whether the severity score is attained on admission or during hospitalization. 
 
4.2 Sample 
Size 
Justification 
The primary endpoint is difference between treatments in the proportion of  surviving subjects off 
vasopressors, the ventilator, and dialysis on Day 14. Here the power for the study is computed for the 
expected increase in proportion of surviving subjects without these supports at Day 14 after start of 
study treatment.  A total sample size of N=54 has ~80% power to yield  a statistically significant 
(alpha=0.2 1-sided) difference if the 
TRUE underlying proportions are 20% and 5% for placebo plus SOC 
and rhu-pGSN plus SOC, respectively. The minimum OBSERVED difference from placebo plus SOC 
proportion 20% that yields statistical significance is 8.4% (20% vs 11.6%). As this is a pilot Phase 2 POC 
trial in an infection with no approved therapy and false negative error (100% minus power) is equally 
as important as false positive error, the one-sided type 1 error is set at 0.2. Thus, the trial is adequately 
powered for its primary POC objective. 
 
4.3 Randomization 
and 
Blinding 
Following screening, subjects qualified for study entry will be randomized to receive rhu-pGSN or 
placebo during the treatment period. Randomization will be done centrally using manual methods. All 
eligible subjects will be assigned a randomization number. 
 
The investigational site team and the subject will be kept blinded to the treatment allocation of each 
participant. Only the designated pharmacist(s) will be unblinded to the 
treatment allocation. A manual 
system to randomly assign a treatment allocation. The treatment allocation will be available to the 
unblinded pharmacist(s). 
 
Details regarding Randomization and Blinding is maintained in the following study documents: 
 
• BTI-202_Randomization Plan, version 1.00 (dated 28-Jul-2020) 
 
• BTI-202_Unblinding Plan, version 1.00 (dated 28-Jul-2020) 


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4.4 Unblinding 
The unblinded pharmacist(s) will prepare sterile syringes with filters consisting of 12 mg/kg rhu-pGSN 
or normal saline (Section 8.3) according to the treatment allocation for each subject. 
 
There is no antidote for rhu-pGSN. Unblinding should only be performed if knowledge of the treatment 
assignment will change the planned management of  a medical condition. If possible, prior to 
unblinding, the need to unblind should be discussed with the Medical Monitor or Sponsor’s Chief 
Medical Officer; however, this should not delay unblinding if the Investigator believes it is necessary. 
Each case of unblinding will be documented and documentation will be stored separately by the 
unblinded pharmacist. 
 
Subjects that are 
unblinded 
may be withdrawn from 
the 
study. 
The decision 
to withdraw a subject from 
the study because of unblinding should be discussed with the Sponsor. If the subject is withdrawn, the 
Investigator or designee must record the date and reason for withdrawal on the appropriate eCRF for 
that subject. 
 
4.5 Inclusion/Exclusion 
Criteria 
 
4.5.1 
Inclusion Criteria 
To be 
considered 
eligible 
to 
participate in 
this 
study, a 
subject must 
meet 
all 
the 
inclusion criteria 
listed 
below: 
1) Hospitalized with laboratory-confirmed (RT-PCR+) or highly suspected (compatible with at least 
bilobar lung involvement without another plausible diagnosis) COVID-19 
2) Age ≥18 years 
3) Weight ≤100 kg 
4) Within 24 hours of reaching a WHO severity score of 4-6 either: 
a) At admission 
b) While already hospitalized. 
5) Informed consent obtained from subject/next of kin/legal proxy 
6) Primary admitting diagnosis of pneumonia supported by a compatible clinical presentation with a 
documented infiltrate consistent with pneumonia on CXR or CT, as assessed by the admitting 
emergency department (ED), clinic, or ward physician or equivalent caregiver 
a) Recommended  (not  mandatory)  guidance/discretionary  criteria  defining  patients  with 
pneumonia satisfying all 4 categories below: 
i) At least 2 symptoms: difficulty breathing, cough, production of purulent sputum, or chest 
pain 
ii) At least 2 vital sign abnormalities: fever, tachycardia, or tachypnea (thresholds -- fever: 
oral or core temperature >100.4°F [38°C]; heart rate >100 beats/min; respiratory rate 
>24/min) 
iii) At least one finding of other clinical signs and laboratory abnormalities: hypoxemia (O2 
saturation <90%), clinical evidence of pulmonary consolidation, or leukocytosis ≥1.5x104 
or leukopenia <4x103 
iv) Chest imaging or CT chest showing at least bilobar pulmonary infiltrates 


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(1) Principal Investigator (PI) to note radiologic findings in the eCRF 
(2) Radiology report to be placed in the eCRF 
(3) A copy of the radiograph attached to be saved for review 
b) A hyperinflammatory status (defined by increased ferritin ≥500 μg/L, D-dimer ≥1000 ng/mL, 
or CRP ≥75 mg/L) 
7) During 
the 
course 
of 
the 
study 
starting 
at 
screening 
and 
for 
at 
least 6 
months 
after 
their 
final 
study 
treatment: 
a) Female subjects of childbearing potential must agree to use 2 medically accepted birth control 
methods 
b) Male subjects with a partner who might become pregnant must agree to use reliable forms of 
contraception (i.e., vasectomy, abstinence), or an acceptable method of birth control must be 
used by the partner 
c) All subjects must agree not to donate sperm or eggs (ovocytes) 
 
4.5.2 
Exclusion Criteria 
To be eligible for entry into 
the study, the subject must not meet any of the exclusion criteria listed 
below: 
 
1. Only negative RT-PCR tests for COVID-19 (in the absence of a PCR positive test) during the 
evaluation of the present illness 
2. Extracorporeal membrane oxygenation (ECMO) 
3. Pregnant or lactating women 
4. Active underlying cancer treated with 
systemic chemotherapy or radiation therapy during the 
last 30 days 
5. Transplantation of hematopoietic or solid organs 
6. Chronic mechanical ventilation or dialysis 
7. Otherwise unsuitable for study participation because of chronic, severe, end-stage, and life- 
limiting underlying disease unrelated to COVID-19 likely to interfere with management and 
assessment of acute pneumonia, only comfort or limited (non-aggressive) care is to be given, or 
life expectancy <6 months unrelated to acute COVID infection in the opinion of the Investigator 
Notes: 
• Participants refusing PK blood samplings can remain in the trial. 
• Participants with 
superinfection in addition to COVID-19 are eligible. 
• Caregivers can decide whether any other medications (investigational or otherwise) should be 
administered. 
 
4.6  Treatment 
Allocation 
Subjects will be randomized in  a 1:1 ratio to receive SOC plus IV rhu-pGSN or placebo during the 
treatment period. 


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5 Assessment Schedule 
 
 
 
 


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6 Interim Analysis 
There is no formal interim analysis planned as per study protocol, however, an independent DSMB 
will be established to closely monitor the safety of subjects. The primary mission of the DSMB is to 
ensure that decisions are made that serve the best interests of patients volunteering for the study. 
Other details regarding the DSMB Meeting are mentioned in the DSMB Charter Document (version 
2.0, 07-Aug-2020). 
 
7 Efficacy and Safety 
Endpoints 
 
7.1 Primary 
Endpoints 
 
7.1.1 
Safety and tolerability 
• Incidence of SAEs in rhu-pGSN vs placebo groups 


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7.1.2 
Efficacy 
• Proportion of subjects alive not on vasopressors, mechanical ventilator, and dialysis 
on Day 14. 
 
7.2 Secondary 
Endpoints 
 
7.2.1 
Safety and tolerability 
• Incidence, causality, and severity of AEs (graded according to the National Cancer 
Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) 
in rhu-pGSN vs placebo groups 
• Frequencies of new or worsening clinically significant laboratory abnormalities in 
rhu- 
pGSN vs placebo groups 
• Mortality rate irrespective 
of cause at Days 28 and 90 
 
7.2.2 
Efficacy 
• Daily change in 9-point WHO severity score through at 
least Day 14 
• All-cause mortality at Days 28 and 90; time to death (Kaplan-Meier survival analysis) 
• Proportion of subjects alive on Days 7, 14, 28, 60, and 90 without: 
▪ Ongoing use of vasopressors 
▪ Ongoing intubation/mechanical ventilation 
▪ Ongoing residence in an ICU 
▪ New ongoing need for dialysis/renal replacement therapy (RRT) 
• Proportion of subjects discharged to home or immediate prior residence by Day 28 
• Days on the ventilator 
• Length of stay (LOS) in hospital and in ICU (days) 
• Re-admission to an acute-care hospital up to Day 90 
 
7.2.3 
PK (Optional) 
• PK for rhu-pGSN including maximum concentration (Cmax), time to maximum 
concentration (Tmax), terminal half-life (T1/2), area under the curve from time zero to 
8 hours (AUC0-8), area under the curve from time 0 to infinity (AUCinf) for Dose #1 
within 15 minutes predose, and at 1 (±15 min), 2 (±15 min), 6 (±30 min), and 12 (±30 
min) hours after end of administration (but prior to Dose #2); for Dose #3 within 15 
minutes predose, and at 1 (±15 min), 2 (±15 min), 6 (±30 min), 12 (±30 min) and 24 
(±30 min) hours after the end of administration (participants refusing these blood 
samplings can enter and remain in the trial). 
 
7.2.4 
Immunogenicity 
• Presence of anti-pGSN antibodies on Days 1 (predose), 28, and 90 


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7.3 Exploratory 
Endpoints 
 
7.3.1 
Biomarkers 
• Changes in biomarkers and radiologic imaging over time with treatment 
• Relationship of baseline biomarkers to clinical outcomes 
 
8 Statistical Methods 
 
8.1 General 
Conventions 
All analyses will be done using SAS (version 9.4, SAS Institute Inc., Cary, NC, USA). 
Efficacy and Safety endpoints will be analyzed in  a descriptive manner. Continuous data will be 
reported using the following descriptive statistics: 
1. Number of observations (n) 
2. Mean and Standard deviation (SD) 
3. Interquartile Range (IQR) 
4. Minimum (min) and Maximum (max) 
5. Median 
In addition: 
6. Geometric mean & Standard deviation 
7. Coefficient of variation (CV%) 
8. Geometric CV% 
will be reported for plasma concentration data and PK parameters. Categorical data will be presented 
using frequency (n = number of subjects; m = number of events) and percentage (%). 
Listings will be provided for 
all data recorded in eCRF to 
study subject profiles. 
All 
listings will be sorted 
by treatment, subject ID, and date (if applicable). Unscheduled visit data will only be listed and not 
included in summaries. 
 
All  p-values will be displayed to four decimal places, with  p-values less than 0.0001 presented as 
'<0.0001' and p-values greater than 0.9999 presented as ‘>0.9999’. Minimum and maximum values 
will be reported in the units of collection with 3 decimals being maximum value; the mean will be 
presented with 1 decimal place more and the standard deviation 2 decimal places 
more than the units 
of collection. Percentages for categorical summaries will be represented to 1 decimal place. 
 
8.2 Multiplicity 
Adjustment 
Since there is only one primary efficacy hypothesis defined in the study as per the protocol (difference 
between treatments in the proportion of surviving patients off vasopressors, the ventilator, and 
dialysis on Day 14), multiplicity adjustment is not required for the primary endpoint. Hypothesis tests 
for secondary endpoints will be performed, and caution must be taken when interpreting these 
results. Adjusted p-values using Bonferroni method may be reported from post-hoc tests if deemed 
necessary. 


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8.3 Re-estimation 
of 
Sample 
Size 
Exploratory analyses to compare the efficacy endpoint data from the rhu-pGSN group from this study 
to that of external control data may be carried out if appropriate. Sample size may be increased to 
improve the precision of the estimates of between-treatment comparisons if appropriate and if drug 
supplies are available. 
 
9 Data handling Procedures 
 
9.1 Handling 
Missing/Incomplete 
Data 
Plasma concentration results missing, or below lower limit of quantification (LLOQ) will be set to 0 for 
pre-dose measurements. Missing PK parameters will be imputed at the LLOQ value. Plasma 
concentration results missing or below LLOQ for post-dose measurements will not be imputed. 
 
Handling of missing data for efficacy analyses is defined in the respective sections below. 
 
9.2 Partial dates 
Partial dates are not expected for start and end dates of adverse events. Queries will be raised and 
resolved in case of partial dates in AE prior to database lock. 
 
Partial  dates  may  be  imputed  for  medications  and  diseases  to  determine  whether  they  are 
concomitant medications or concurrent diseases using the algorithm given below. 
For medical history, end dates will be imputed as follows: 
• If marked “ongoing” with no end date, then this will be considered as concurrent disease. 
• If only year is present, then impute date and month as 31-DEC. 
• If month and year are present, then impute date with last date of the month. 
• If date and year are present, then impute month as DEC. 
• If year is missing, then impute subject’s last visit date in the study. 
If the imputed end date is later than subject’s last visit date, then the subject’s last visit date will be 
imputed. In case of ambiguity, then the worst case is considered (that is, concurrent diseases) for 
safety analyses. 
Example, 
 
Partial End Date 
Imputed End Date 
--JUN2019 
30JUN2019 
-----2019 
31DEC2019 
12---2018 
12DEC2018 
14MAR---- 
Subject’s last visit date 
 
For concomitant medications, start dates will be imputed as follows: 
• If only year is present, then impute date and month as 01-JAN. 
• If month and year are present, then impute date with first date of the month. 
• If date and year are present, then impute month as month as JAN. 
• If year is missing, then impute subject’s first IMP date in the study. 


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If the imputed start date is 
earlier than subject’s first IMP date, then the subject’s first IMP date will 
be imputed. In case of ambiguity, then the worst case is considered (that is, concomitant 
medications) for safety analyses. 
 
Example, 
 
Partial Start Date Imputed Start Date 
--JUN2019 
01JUN2019 
-----2019 
01JAN2019 
12---2018 
12JAN2018 
14MAR---- 
Subject’s first IMP date 
Imputed dates will be used for analyses and collected dates will be recorded in database will be 
displayed in listings. 
 
9.3 Handling 
Outliers 
Safety 
and 
Efficacy 
endpoints 
will be cleaned 
and 
reviewed periodically during 
the 
course 
of the study. 
There are no outliers expected during database lock. In exceptional cases, the handling conditions for 
these will be discussed during the blinded review meeting prior to DBL. 
 
9.4 Blinded 
Review 
Meeting 
• Exclusion of subjects from each of the population definitions defined in Section 10 will be 
reviewed and finalized. 
• Protocol deviation classifications will be reviewed and finalized. 
• Any repeat assessments for safety and efficacy endpoints, and its inclusion in summaries will 
be finalized. 
• Conversion factors for laboratory parameters to SI units will be confirmed. 
• Any subjects who did not take treatment as planned will be reviewed. 
• Timing of replacement subjects to be reviewed after discontinuation of original subjects. 
• Any self-evident corrections in spelling of free text values will be confirmed. 
• Incorrect derivations in EDC derived values to be verified. 
• Changes from planned analyses / extent of exploratory or additional analyses will be 
finalized. 
• Any outlier values identified during pre-final data review will be closed. 
 
10 Analysis Sets 
The membership of the analysis sets will be reviewed and finalized during the blinded review of the 
data conducted prior to database lock. 
 
10.1 Screened 
Analysis 
Set 
The Screened Analysis Set includes all subjects who gave informed consent. 


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The Screened Analysis Set will be used for summary of subject disposition. There will not be any 
treatment wise analysis when using the Screened Analysis Set. 
 
10.2 All-enrolled 
Analysis 
Set 
The All-enrolled Analysis Set includes all subjects who gave informed consent and enrolled in the 
trial. The All-enrolled set will be used to list all screened subjects. 
 
The all-enrolled analysis set will be used for summary 
of subject disposition. There will not be any 
treatment wise analysis when using the all-enrolled analysis set. 
 
10.3 Randomized 
Analysis 
Set 
The 
Randomized 
Analysis 
Set 
includes 
all 
subjects 
who 
passed 
eligibility 
criteria 
and 
were 
randomized. 
 
The Randomized Analysis Set  will  be used  for  summaries of subject disposition, demographics, 
baseline characteristics and protocol deviations. Subjects will be analyzed according to the treatment 
group they were assigned at randomization. 
 
Note: If a subject is randomized but did not take the study drug, then the subject will be included 
only in the Screened, All-Enrolled and Randomized Analysis Sets. Subjects with negative COVID RT- 
PCR results post randomization will still be included. 
 
10.4 Full Analysis Set 
All subjects given ≥1 dose of study drug will be included in the Full Analysis Set (FAS) according to 
actual drug received. 
 
The FAS is the primary analysis set to analyze all efficacy endpoints. Subject disposition, demographic 
and baseline characteristics of the FAS will also be presented. Subjects will be analyzed according to 
the treatment group they actually received. Differences between planned and actual treatment, if 
any, will be discussed during the blinded review meeting. 
 
Note: if a subject had inadvertently taken the study drug without randomization and/or had negative 
COVID RT-PCR results post study drug administration, the subject would still be included in the Full 
analysis set. 
 
10.5 Safety 
Analysis 
Set 
The Safety Analysis Set includes all subjects who received at least one dose of study drug. 
 
The Safety Analysis Set will be used for the analysis of safety. Subjects will be analyzed as treated, 
regardless of the randomized treatment assigned, if this differs from that to which the subject was 
randomized. Any differences between planned and actual treatment, if any, will be discussed during 
the blinded review meeting. 
 
Note: if a subject had inadvertently taken the study drug without randomization and/or had negative 
COVID RT-PCR results post study drug administration, the subject would still be included in the Safety 
Analysis Set. 


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Note: FAS and Safety Analysis Set are the same as per definition. To be in line with study protocol, FAS 
will be used for all efficacy analysis, Safety Analysis Set will be used for all safety analysis (Adverse 
events, Lab values, Vital Signs, Physical Examination, EKG etc.). 
 
10.6 Per-Protocol 
Analysis 
Set 
The Per-Protocol Analysis Set includes all subjects who completed Day 14, took all three doses, and 
had no Important protocol deviations that may affect the primary endpoint of the study. 
 
The exclusion of subjects from the per-protocol analysis set will be discussed and finalized during the 
blinded review meeting prior to DBL. Protocol deviations that can potentially unblind treatment codes 
will be reviewed independently by authorized personnel and its impact on population flags will be 
confirmed prior to DBL. 
 
The PPAS is also used to analyze efficacy endpoints. Demographic and baseline characteristics of the 
PPAS will also be presented. Subjects will be analyzed according to the treatment group they actually 
received. 
 
10.7 PK 
Analysis Set 
The PK 
Analysis Set will include all subjects in 
the FAS 
who have sufficient 
concentration data 
to obtain 
reliable estimates of the key PK parameters and have no important protocol deviations that can 
influence the validity of the data for the PK endpoints. 
 
PK Analysis Set will be finalized after review of concentration data post DBL and unblinding. 
 
11 Analysis Variables 
 
11.1 Analysis Set Flags 
Analysis Set flags will be finalized and authorized by the Study Statistician and Sponsor during blinded 
review meeting prior to database lock as per definitions provided in Section 10. These flags will be 
included in the analysis datasets. 
 
11.2 Treatment 
groups 
All analyses will be summarized by treatment group. The following treatment groups will be defined 
in the analysis datasets. 
 
• rhu-pGSN 
 
• Placebo 
 
11.3 Analysis 
Visits 
All analysis datasets with measurements taken at more than one visit/time point will have analysis 
visit and timepoint as defined below. 
 
Visit as in CRF 
Visit Representation in summaries 
Screening 
- 
- 
Baseline 
 
 


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Visit as in CRF 
Visit Representation in summaries 
Day 1 
Day 1 
Day 2 
Day 2 
Day 3 
Day 3 
Day 7 
Day 7 
Day 14 
Day 14 
Day 28 
Day 28 
Day 60 
Day 60 
End of Study / Early Termination 
Early Termination 
End of Study / Early Termination 
End of Study 
 
The End of Study and Early Termination visits will be presented separately. Screening Visit will be 
summarized only in listings except for the demographic and baseline characteristics data. 
A subject is considered to have attended any visit only if at least one assessment has been taken at 
the visit. 
 
11.3.1 Timepoints 
Vital signs and PK Samples will be collected at various 
timepoints, these will be included for 
summaries as follows: 
 
Endpoints 
Timepoint in Analysis 
Vital Signs 
Dose X, Pre-Dose 
Dose X, End of Study Drug Administration 
Dose X, 30 Minutes Post-Dose 
Plasma concentration 
Pre-Dose 
1 Hour Post-Dose 
X Hours Post-Dose 
 
11.3.2 Study 
Period 
Study Periods will be assigned as follows: 
 
• Informed Consent Date to the day before first IMP date – ‘Screening’ 
 
• Date of first IMP to Day 14 – ‘Treatment Period’ 
 
• Day 15 to End of Study – ‘Follow-up Period’ 
 
11.3.3 Visit Imputation 
For assessments where shift summaries are required (WHO Severity Score and CURB-65 Score), 
records will be imputed for all subjects in Safety Analysis Set in all scheduled visits and marked as 
‘Missing  / Not Done’ if either the  subjects did not attend the visit or discontinued or had missing 
assessment at the respective visit. 
 
 
 
 
 


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11.3.4 Repeat Assessments 
If there are any repeat assessments, they will be logged as unscheduled visits and the reason for 
unscheduled visit will be marked as repeat assessment. In such cases, these unscheduled visits will be 
mapped to the visit for which repeat assessment was taken. In case of multiple repeat assessments 
on the same day, the latest assessment will be considered for analysis. 
For WHO Severity scores, if there are more than one repeat assessments on the same day, then 
highest non-missing score 
will be considered for analysis. 
 
11.4 Study 
Duration 
Study Duration (days) = (Date of Last Visit –First IMP Date) + 1. 
 
11.5 Discontinued 
Subjects 
Discontinued subjects will have safety assessments taken at Early Withdrawal visits. These will be 
presented separately and will not be combined with EOS if results are available. 
 
The reason for discontinuation from the study will be 
mapped in the analysis as follows: 
 
Primary reason for early discontinuation (As in 
CRF) 
Reason for early termination from the study 
Subject withdrew consent 
Subject withdrew consent 
Unacceptable AE 
Unacceptable AE 
Pregnancy 
Pregnancy 
Subject is unwilling or unable to continue the 
study or is lost to follow up 
Subject unwilling / lost to follow-up 
Subject is non-compliant with study 
procedures/study protocol 
Protocol Deviation 
Investigator decides that withdrawal from the 
study is in the best interest of the subject 
At the discretion of the Investigator 
Any clinically significant change in subject’s 
medical condition (at the discretion of the 
Investigator) 
At the discretion of the Investigator due to 
change in medical condition 
Treatment unblinded 
Treatment Unblinded 
Sponsor decision to end the study 
Sponsor decision to end the study 
Death 
Death 
Other 
Other 
 
11.6 Replacement 
Subjects 
If one of the eligible subjects is included in the study as replacement, then the subject will be flagged 
as replacement subject with  subject ID of the replaced subject. For example, if subject XXXY is 
replaced, then replacement subject XXXX will be flagged as ‘Replacement for XXXY’. These flags will be 
used only in listings, and not in any analyses. Summaries will include data for replacement subjects 
like any other subject in that treatment group. 


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11.6.1 Common Derivations 
The following variables will be derived in analyses datasets and used in summaries as per the 
formula below: 
 
• BMI (kg/m
2) = Weight in kg / (Height in cm x 0.01)2. Height from screening, and 
weight from 
respective visit will be used. 
 
• Age (years) = ((Date of Informed consent – Date of Birth) + 1)/365.25 
 
• QTcF (msec) = QT (msec) / (RR (msec)/1000)
1/3 
 
• Duration (days) = (End Date – Start Date) + 1 
 
• Start Day (days) = (Start Date – First IMP date) + 1 
 
These variables will be derived and verified against EDC calculated values, if available. In cases where 
they do not match, queries will be raised. If not reconciled until database lock, derived values will be 
considered correct and will be used for analysis. 
 
11.7 Baseline 
All analysis datasets having measurements taken at more than one visit/time point will have baseline 
flags. Baseline is defined as the latest non-missing measurement prior to IMP administration including 
repeat assessments and unscheduled visits. In case of multiple results at the same date/time, worst 
result will be considered as baseline in the following order or hierarchy: Abnormal CS, Abnormal NCS, 
Normal, Missing. 
 
11.7.1 Change from Baseline 
Change between Baseline and post-baseline result will be calculated as: 
Change from baseline = Result at Visit X – Baseline Result 
11.8 Protocol 
Deviations 
Protocol Deviations will be classified by the Sponsor as ‘Important/Major’ and ‘Not Important’. The 
deviations will be reviewed during the blinded review 
meeting and finalized prior to DBL. 
 
11.9 Treatment 
Compliance 
The following variables will be derived for treatment compliance summaries: 
 
• Cumulative IV Planned to be administered (mL) = Planned Dose for Dose 1 (mL) + Planned 
Dose for Dose 2 (mL) + Planned Dose for Dose 3 (mL) 
 
• Cumulative Actual IV administered (mL)  = Total amount infused for Dose  1 (mL)  + Total 
amount infused for Dose 2 (mL) + Total amount infused for Dose 3 (mL) 
 
• Treatment Duration (hours) = End Date and Time of Last Dose – Start Date and Time of First 
Dose 


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• Treatment 
Comp
l
iance 
(%) 
=
 
  
Cumulative 
Actual 
IV 
Administered  
Cumulative P
lanned 
IV 
to be
 Admisitered
 
x 100. 
Treatment compliance is based on volume of IV administered, and not IMP dose, hence placebo 
group will also have this calculation done. 
 
11.10 Medical 
History 
and 
Concurrent 
Diseases 
If a condition has end date 
prior to first dose of IMP or if end date is missing and the Ongoing status 
= No, then these will be flagged as Medical / Surgical History. If a condition has end date on or after 
first dose of IMP or if the Ongoing status = Yes, then these will be flagged as Concurrent Diseases. 
 
11.11 Prior 
and Concomitant 
Medications 
The following will be the definitions for classification of Prior and Concomitant 
Medications: 
 
Start Date 
End Date 
Study Period 
Prior / Concomitant 
Before IMP 
Before IMP 
N/A 
Prior Medication 
Before/After IMP and 
before Day 14 
On or Before Day 14 
Treatment Period 
Concomitant 
Medication 
Before/After IMP and 
before Day 14 
After Day 14 and On 
or Before EOS 
Treatment Period 
Concomitant 
Medication 
After Day 14 
After Day 14 
Follow-up Period 
Concomitant 
Medication 
 
Note: Worst case scenario 
of the 
medication being concomitant to the study drug administration will 
be considered. 
 
11.12 Adverse 
Events 
A Treatment-Emergent Adverse Event (TEAE) is defined as any AE that begins/ worsens after the first 
IMP administration. 
Related Adverse Events include 
Possibly, 
Probably 
and 
Definitely 
Related 
Adverse 
Events. Not 
Related 
Adverse Events include Probably and Definitely not related Adverse Events. 
 
11.13 Laboratory 
Assessments 
Laboratory results with modifiers will be analyzed with the maximum or minimum value defined 
without the modifiers. For example, a value of “<5” will be considered as “5” for summaries. 
 
11.14 EKG 
Measurements 
Average of triplicate measurements will be calculated for the following EKG parameters at 
Screening: Heart rate (bpm), RR (msec), PR (msec), QRS (msec), QT (msec), QTcF (msec). 
 
Average of triplicate measurements = (Measurement 1 + Measurement 2 + Measurement 3) / 3 
 
Note that, if any one measurement is missing, the average of the other 2 measurements will be 
taken. 


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11.15 Unit 
Conversion 
For laboratory parameters, units will be converted and summarized in SI units. Reference used for 
conversion factors will be documented in the respective footnotes. 
 
11.16 Efficacy 
Endpoints 
 
11.16.1 Hospitalization due 
to COVID-19 
 
• Days in X = (End Date of X - Start Date of X) + 1 
• Cumulative X Days = Sum of all (Days in X) 
Note: X denotes Hospitalization, Intensive Care Unit (ICU) and Intubation / Mechanical Ventilations. 
• Duration of COVID-19 illness before hospitalization (days)  = (Initial Hospitalization Date  – 
COVID-19 confirmation date) + 1 
Note: The earliest COVID-19 confirmation date will be considered irrespective of whether or not it is 
prior to informed consent date. 
If a subject has discontinued from the study and X is ongoing or the end date is missing, then X will be 
considered as ongoing at Day 14 for that subject. For cumulative X days calculation, disposition date 
will be considered as end date. If a subject had Ongoing Hospitalization at end of study, then end date 
is considered as subject’s disposition date. 
Note: X denotes Hospitalization, Intensive Care Unit (ICU) and Intubation / Mechanical Ventilations. 
 
11.16.2 URB-65 Score 
The score is an acronym for each of the risk factors measured. Each 
risk factor scores one point, for a 
maximum score of 5: 
• Confusion of new onset (defined by the Abbreviated Mental Test Score [see Appendix B] of 8 or 
less [2 or more incorrect answers]) 
• Blood Urea nitrogen greater than 7 mmol/l (19 mg/dL) 
• Respiratory rate of 30 breaths per minute or greater 
• Blood pressure less than 90 mmHg systolic or diastolic blood pressure 60 mmHg or less 
• Age 65 or older 
 
11.16.3 bbreviated 
Mental Health Score 
The questions are put to the patient. Each question correctly answered scores one point. A score 
of 8 or less suggests cognitive impairment at the time of testing, although further and more 
formal tests are necessary to confirm a diagnosis of dementia, delirium or other causes of 
cognitive impairment. 
 
• What is your age? (1 point) 
• What is the time to the nearest hour? (1 point) 
• Give the patient an address and ask him or her to repeat it at the end of the test. (1 
point) 


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• e.g. 42 West Street 
• What is the year? (1 point) 
• What is the name of the office or doctor you are seeing today? (1 point) 
• Can the patient recognize two persons (the doctor, nurse, home help, etc.)? (1 point) 
• What is your date of birth? (day and month sufficient) (1 point) 
• In what year was the 9-11 terrorist attack? (1 point) (other dates can be used, with a 
preference for dates sometime in the past) 
• Name the present president of the USA. (1 point) 
• Count backwards from 10 down to 1. (1 point) 
 
11.16.4 WHO Severity Scores 
The 9-point WHO classification scheme from 0 to 8 for COVID-19 pneumonia will be applied to grade 
the severity of illness as follows: 
• 8 - Death 
• 7 - Mechanical ventilation or extracorporeal membrane oxygenation (ECMO), vasopressor 
support, dialysis/renal replacement therapy (RRT) 
• 6 - Intubation with mechanical ventilation, a mask with a reservoir or oxygen with high-flow 
nasal goggles. 
• 5 - Noninvasive ventilation (continuous positive airway pressure [CPAP] or bilevel positive 
airway pressure [BiPAP]) or high-flow oxygen 
• 4 - Oxygen by mask or nasal 
• 3 - Hospitalized with no oxygen therapy 
• 2 - Limitation of activity 
• 1 - Infected without limitations 
• 0 - No clinical or virologic evidence of COVID-19 infection 
Higher WHO Severity Score indicates worser conditions. 
 
11.16.5 Subjects Discharged 
Subjects will be considered as discharged at all visits after the discharge date. If there is more than 
one hospitalization for a subject, then the latest hospitalization will be considered. 
 
11.17 Criterion Flags 
• Subjects who are alive at the given timepoints with the below mentioned criteria will be 
flagged as ‘Y’ in the analysis datasets. All subjects within Per-Protocol and FAS will be flagged 
irrespective of their disposition status. Any ambiguity in subject status will be considered as 
failure and flagged as ‘N’. 
 
Criterion Flag Criteria 
Other Criteria 
Flag 01 
Alive on Day 14 Without the following (end date prior to day 14): 
• Ongoing use of vasopressors 
• Ongoing intubation/mechanical ventilation 


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• New  ongoing  need  for  dialysis/renal  replacement 
therapy (RRT) 
Flag 02 
Alive on Day 7 
Without the following (end date prior to day X): 
• Ongoing use of vasopressors 
• Ongoing intubation/mechanical ventilation 
• Ongoing residence in an ICU 
• New  ongoing  need  for  dialysis/renal  replacement 
therapy (RRT) 
Flag 03 
Alive on Day 14 
Flag 04 
Alive on Day 28 
Flag 05 
Alive on Day 60 
Flag 06 
Alive on Day 90 
• Subjects who were discharged will be flagged ‘Y’ in the analysis datasets based on the 
following criteria: 
 
Criterion Flag Criteria 
Flag 07 
Discharged on Day 14 
Flag 08 
Discharged on Day 28 
Flag 09 
Discharged on Day 60 
Flag 10 
Discharged on Day 90 
If a subject does not meet the given criteria, they will be flagged as ‘N’. All subjects within Per- 
Protocol and FAS will be flagged irrespective of their disposition status. 
 
11.18 Time 
to Death 
Time to Death will be calculated as follows: 
• Time to Death = (Date of Death – Date of First IMP) + 1 
Subjects 
without death in 
the trial 
will be censored at 
either 
the date 
of 
withdrawal 
or 
the date 
of last 
visit, whichever occurs earlier. 
 
11.19 Self-Evident 
Corrections 
In some instances, spelling errors may be corrected in analysis mapping for ‘Other, Specify’ fields 
(free text). These will be reconciled and confirmed during clean file meeting. 
 
12 Statistical Analysis 
 
12.1 Subject Disposition 
Number of subjects in screened, all-enrolled and randomized Analysis Set, number and percentage for 
subjects in safety Analysis Set, FAS, per protocol Analysis Set, subjects who completed the study, study 
duration (days), number of subjects who terminated the study early along with their reasons will be 
summarized by treatment. Reason for discontinuation will be displayed in the descending order of 
“Total” column. 
 
Screened and All-enrolled Analysis Set will be presented only for Total columns. All other summaries 
will be presented by treatment groups. A CONSORT flowchart will also be presented to visualize the 
flow of disposition. 


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Note that randomized Analysis Set will be displayed by planned treatment and all 
other 
categories will 
be displayed by actual treatment. 
 
Percentages will not be displayed for screened and all-enrolled Analysis Set. The percentages by 
treatment group for randomized analysis set will be based on all-enrolled Analysis Set. All other 
percentages will be based on randomized Analysis Set. Percentages for categories of reason for 
discontinuation from the study will be based on the number of subjects who discontinued from the 
study. 
 
In DDP: Table 14.1.1.1, Figure 14.1.1.1 
 
Subject disposition information, status of inclusion exclusion criteria, randomization  details and 
subjects excluded from Analysis Set along with reasons will be listed by subject. All derived variable 
summarized in the tables will also be listed. 
 
In DDP: Listings 16.2.1.1, 16.2.1.2, 16.2.1.3 and 16.2.3.1 
 
12.2 Visit 
Attendance 
Number and percentage of subjects who attended each visit (Screening, Day 1, Day 2, Day 3, Day 7, 
Day 14, Day 28, Day 60, Early Withdrawal and End of Study) will be summarized by treatment group. 
Percentages will be based on FAS. 
 
In DDP: Table 14.1.2.1 
 
12.3 Protocol 
Deviations 
Number and percentage of subjects with any deviation and number of deviations will be summarized 
by treatment. The same will be sub-classified by grade (important/not important) and category 
(Informed consent deviation, Entry Deviation, Dosing Deviation, Withdrawal Deviation, Operational 
Deviation, Other, COVID-19 Deviation etc.). Deviation categories will be displayed in descending order 
of the “Total” column. 
 
Percentages will be based on Randomized Analysis Set. 
In DDP: Table 14.1.3.1 
Protocol deviations will be 
listed by subject. 
In DDP: Listing 16.2.2.1 
12.4 Demographic and 
Baseline 
Characteristics 
Subject demographics will be summarized by treatment. Categorical and continuous variables will be 
provided in the same table. The following variables will be presented: age (years), sex, ethnicity, race, 
height (cm), weight (kg), BMI (kg/m
2), childbearing potential and methods of birth control for the 
subject as 
well as 
the partner. Percentages will be based on the non-missing results within the Analysis 
Sets. Percentages for Childbearing potential and method of birth control will be based only on female 
population. 
Method 
of 
birth 
control 
for 
the 
subject’s partner 
will 
be 
based 
only 
on 
the 
male 
population 
reporting birth control. 


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The summaries will be repeated for all randomized, FAS, per protocol and PK Analysis Sets (as per ICH 
E3 Guidelines). Note that Safety Analysis Set and FAS are same as per definition; hence, the analysis is 
not repeated for the Safety Analysis Set. 
 
In DDP: Table 14.1.4.1, 14.1.4.2, 14.1.4.3 and 14.1.4.4 
 
Subject demographics will be listed by subject. 
In DDP: Listing 16.2.4.1 
12.5 Baseline 
Characteristics 
Descriptive statistics for the baseline diagnostic parameters will be summarized by treatment group. 
The parameters will include: Temperature  (
oC), Heart Rate (beats/min), Respiratory Rate 
(breaths/min), Oxygen Saturation (%), Ferritin, D-Dimer, CRP, and 
Procalcitonin. 
 
The summaries will be repeated for FAS and per-protocol Analysis Sets. If all the Analysis Sets are 
same, summary will be presented only for FAS. Note that Safety Analysis Set and FAS are same as 
per definition; hence, the analysis is not repeated for the safety analysis set. 
 
In DDP: Table 14.1.5.1 and Table 14.1.5.2 
 
Baseline Diagnostic Criteria will be listed by subject. 
In DDP: Listing 16.2.4.2 
12.6 Medical/Surgical 
History 
Number and percentage of subjects with any medical / surgical history and number of events will be 
summarized by treatment. 
The same will be 
classified 
by System Organ 
Class (SOC) and 
Preferred Term 
(PT). 
The SOC and PT will be displayed in the descending order of frequency in “Total”. Medical history 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 or Higher. 
 
Percentages will be based on Safety Analysis Set. 
 
The summary will be presented for medical  / surgical history and concurrent diseases separately. 
History and Concurrent Diseases will be flagged as mentioned in Section 11.10. 
 
In DDP: Tables 14.1.6.1 and 14.1.6.2 
 
Medical/Surgical History will be listed by subject and body system. 
In DDP: Listing 16.2.4.3 
12.7 Prior 
and Concomitant 
Medications 
Number and percentage of subjects who have taken any prior  / concomitant medication will be 
summarized by treatment and study period. The same will be classified by Therapeutic Main group 
(ATC Level 2) and Chemical Subgroup (ATC Level 4). If ATC level 4 is missing, ATC levels 2 or 3 will be 
used. The 
therapeutic 
main 
group 
and chemical subgroup will be 
displayed in 
the 
descending order 
of 


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frequency  in  “Total”  for  Treatment  Period.  Medications  will  be  coded  using  the  World  Health 
Organization’s Drug-Dictionary (WHODrug) version September 2020 or latest. 
Percentages will be based on Safety Analysis Set. 
The  summary  will  be  presented  for  prior  and  concomitant  medications  separately.  Prior  and 
concomitant medications will be flagged as mentioned in section 11.11. 
 
In DDP: Tables 14.1.7.1 and 14.1.7.2 
 
All 
medications 
will 
be 
listed 
by 
subject 
and 
therapeutic 
subgroup. 
Prior 
and 
concomitant 
medications 
will be flagged. Subjects will be grouped by treatment. 
 
In DDP: Listing 16.2.4.4 
 
12.8 Extent of Exposure 
Number and percentage of subjects exposed to treatment over time (1
st dose, 2
nd dose, and 3
rd dose), 
cumulative planned IV to be administered (mL), cumulative actual IV administered (mL),  % 
compliance, and number and percentage of subjects with dose interruptions for each dose (1
st dose, 
2nd dose, and  3
rd dose) along with reason for interruptions will be summarized by treatment. Both 
continuous and categorical summary will be presented in the same table. Percentages will be based 
on FAS. Percentages for reason for interruptions will be based on the number of subjects whose dose 
was interrupted in the respective dose. 
 
In DDP: Table 14.1.8.1 
 
IV administration data will be listed by subject for FAS. Subjects will be grouped by treatment. 
In DDP: Listing 16.2.5.1 
12.9 Efficacy 
Analyses 
All efficacy analyses will be based on FAS. Analyses will be repeated for Per-Protocol Analysis Set to 
check the robustness of the results (sensitivity analyses). 
 
12.9.1 Primary Efficacy analysis 
 
12.9.1.1 Proportion 
of 
Subjects Alive on Day 
14 
Number and percentage of subjects alive on Day 14 without the following will be summarized. 
Percentages will be based on the corresponding analysis set. Subjects who discontinued from the 
study early or whose survival status is inconclusive on Day 14 will be considered as failure (Not 
Alive). 
 
• Ongoing use of vasopressors 
 
• Ongoing intubation/mechanical ventilation 
 
• New ongoing need for dialysis/renal replacement therapy (RRT) 


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The proportion of subjects alive will be compared across treatment arms using a Cochran-Mantel- 
Haenszel (CMH) method. The common Risk Difference along with associated 80% CI will be reported. 
Unadjusted p-value for testing the null hypothesis that there is no strong correlation between 
treatment and subject status will also be reported. As this is a pilot Phase 2 proof-of-concept (POC) 
trial in an infection with no approved therapy and false negative error (100% minus power) is equally 
as important as false positive error, the one-sided type 1 error is set at 0.2. 
 
Reference SAS Program: 
 
proc freq data=<input> ; 
tables <status>*<treatment> / cmh riskdiff(common) alpha=0.2; 
run; 
 
The analyses will be based on FAS and repeated for Per-Protocol Analysis Set. 
In DDP: Tables 14.2.1.1 and 14.2.1.2, Listing 16.2.6.2, 16.2.6.3, and 16.2.6.4 
12.9.2 Secondary Efficacy Analyses 
 
12.9.2.1 Change 
in 
WHO Severity 
Scores 
 
12.9.2.1.1 
Shift 
Summary 
Shift in WHO severity scores from baseline (scores 4-6) to each post-baseline visit (Days 2, 3, 7, 14, 
28, 60 and 90) will be presented by treatment groups. Subjects whose values are missing or 
assessment is not done will be presented as ‘Missing / Not Done’. Percentages will be based on 
corresponding population. 
 
In DDP: Tables 14.2.2.1 and 14.2.2.2 
 
12.9.2.1.2 
Box 
Plot 
Box plot will be plotted to visualize the trend in average WHO Severity scores at baseline and post- 
baseline visits (Days 2, 3, 7, 14, 28, 60 and 90). X axis will represent visit and Y axis will represent 
WHO severity scores. Each treatment group will be plotted in a separate page. Number of subjects at 
each visit will be annotated below the X-axis. 
 
In DDP: Figures 14.2.2.3 and 14.2.2.4 
 
12.9.2.1.3 
MMRM 
WHO Severity score change from baseline to each visit will also be analyzed using a mixed model for 
repeated measures under missing at random framework using WHO scores collected at scheduled 
visits. Change from baseline to each 
visit 
will be specified as the dependent 
variable. Treatment group, 
visit, baseline WHO Score and an interaction effect between treatment-by-visit and baseline WHO 
score-by-visit will be specified as independent variables. Least square estimates of the mean change 
from baseline and confidence intervals of this estimate will be created for each treatment group by 
the model. Treatment group will be compared with the Placebo group in a pairwise fashion at each 
visit. 
 
Further, the 
difference in 
the dependent 
variable between 
the 
treatment 
groups 
will be 
estimated 
for 
each of these comparisons, as well as 95% confidence intervals for these estimates and  p-values 


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testing the null hypothesis that the difference between the treatment groups is zero. All these 
hypothesis tests will be made using the same mixed model for repeated measures. The approach 
allows for the repeated measures within subjects to be taken into account. An unstructured 
covariance will be  assumed to allow the variances and covariances to differ between visits and 
treatments. 
 
Reference SAS Program: 
 
proc mixed data = XXX; 
class trta subjectid visit; 
model chg = trta visit bsl_who trta*visit bsl_who*visit; 
repeated visit / subject=subjectid type=un; 
lsmeans trta*visit / diff cl pdiff; 
lsmeans trta / diff cl pdiff; 
run; 
 
Reference: Tables 14.2.2.5 and 14.2.2.6 
 
12.9.2.1.4 
Listing 
WHO Severity scores for all visits will be listed by subject and grouped by treatment groups. 
In DDP: Listing 16.2.6.1 
12.9.2.2 Time 
to Death 
(Days) 
 
12.9.2.2.1 
Log-Rank 
Test 
Time-to-event statistics including number of subjects with event (see section 11.18), censored, mean, 
standard error, median time along with 95% CI, 25th and 75th quartiles, minimum and maximum will 
be reported in a summary table. Log Rank test will be performed to compare the survival probability 
curves between treatment groups and corresponding unadjusted p-values will be included. 
 
Percentage of subjects alive at Day 28 and 
Day 90 will be estimated using Kaplan-Meier method. 
95% CI for the point estimate will also be presented. 
 
Reference SAS Program: 
 
proc lifetest data = <input> plots=survival; 
time <duration>*<censor>(1); 
strata <treatment>/ test=LOGRANK; 
run; 
 
 
12.9.2.2.2 
Cox 
Proportional 
Model 
Cox regression will be performed with WHO Severity score at baseline as continuous covariate in the 
model to compare hazard between treatment and placebo and to estimate hazard ratio. Hazard Ratio 
along with 95% CI will be reported in the same table mentioned in section 12.9.2.2.1. 
 
Reference SAS Program: 
 
proc phreg data=<data> ; 
class treatment; 
model time*status(01) =treatment bsl_who/rl; 


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run; 
hazardratio 'Treatment vs Placebo' treatment; 
 
In DDP: Tables 14.2.3.1 and 14.2.3.2 
 
12.9.2.2.3 
Kaplan-Meier 
Curve 
Time to death will also be analyzed using Kaplan-Meier curves. X-axis will be the time (days) and Y- 
axis will be the survival probability. Censored values will be represented with symbol ‘|’ and 
stratified by treatment groups. Number of subjects at 
risk over time will be annotated below the X- 
axis. 
 
In DDP: Figures 14.2.3.3 and  14.2.3.4 
 
12.9.2.2.4 
Listing 
Death Details will be listed by subject. 
In DDP: Listing 16.2.7.4 
12.9.2.3 Proportion 
of Subjects Alive on Days 7, 14, 
28, 
60 and 90 
Number and percentage of subjects alive on Days 7, 14, 28, 60 and 90 without the following will be 
summarized. Percentages will be based on FAS. Subjects who discontinued from the study early or 
whose survival status is inconclusive on respective day will be considered as failure (Not Alive). 
 
• Ongoing use of vasopressors 
 
• Ongoing intubation/mechanical ventilation 
 
• Ongoing residence in an ICU 
 
• New ongoing need for dialysis/renal replacement therapy (RRT) 
 
The analyses described in Section 12.9.1.1 will be repeated for each day as part of secondary 
analyses. 
 
In DDP: Tables 14.2.4.1 and 14.2.4.2, Listing
 16.2.6.2, 16.2.6.3, 16.2.6.4 
 
12.9.2.3.1 
Proportion of Subjects Alive controlling 
for stratification factor 
Additionally, the proportion of subjects alive on Days 7, 14, 28, 60 and 
90 will be 
compared across 
treatment arms controlling for stratification factor (WHO Severity score at baseline) using a Cochran- 
Mantel-Haenszel (CMH) method will be reported for each day as mentioned above. The common 
Risk Difference along with 
associated 95% CI will be reported. Unadjusted p-value for testing the null 
hypothesis that there is no strong correlation between treatment and subject status will also be 
reported. 
 
In DDP: Tables 14.2.4.3 and 14.2.4.4 
 
12.9.2.4 Proportion 
of 
Subjects 
Discharged 
Number and percentage of subjects who were discharged on or before Days 14, 
28, 60 and 90 will be 
summarized by treatment group. Proportions within each treatment group along with 95% CI will be 


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provided using Clopper-Pearson method for each visit. Risk Differences between treatment groups 
and p-value from testing the null hypothesis that there are no differences between treatment 
groups will be reported based on Fisher’s Exact test. The summary will be based on FAS and 
repeated for Per-Protocol Analysis Set. 
 
Reference SAS Program: 
 
/* 95% CI for binomial (exact Clopper-Pearson) */ 
 
proc freq Data=XXX alpha=0.05; 
by treatment; 
tables flag/binomial(level=’1’ exact); 
run; 
 
/* 95% CI for risk difference and p-value from Fisher’s test */ 
 
proc freq Data=XXX alpha=0.05; 
tables treatment*flag/riskdiff(cl=exact); 
exact riskdiff fisher; 
run; 
 
In DDP: Tables 14.2.5.1 and 14.2.5.2 and Listing 16.2.6.2 
 
12.9.2.5 Hospitalization 
due 
to 
COVID 
19 
Number and percentage of subjects re-admitted to an acute-care hospital and subjects who are 
ongoing hospitalization at Day 14 will be summarized. Descriptive summaries for Duration of COVID- 
19 illness before hospitalization and cumulative number of hospitalization days will also be 
summarized. 
 
Number and percentage of subjects who have been to the ICU and subjects who are still in ICU at 
End of Study will be summarized. Descriptive summary for cumulative number of ICU days will also 
be summarized. 
 
Number and percentage of subjects who had Intubation / Mechanical Ventilations and subjects who 
are still in Intubation / Mechanical Ventilations at End of Study will be summarized. Descriptive 
summary for cumulative number of Intubation / Mechanical Ventilations days will also be 
summarized. 
 
All summaries will be based on FAS and per-protocol analysis sets. Percentages 
will be based on the 
corresponding analysis sets. 
 
In DDP: Table 14.2.6.1 and 
Table 14.2.6.2 
 
Hospitalization, ICU and Intubation / Mechanical Ventilations will be listed by subject. 
In DDP: Listings 16.2.6.2, 16.2.6.3, and 16.2.6.4 
12.9.2.6 Comparison of Days 
in 
Hospital, 
ICU and Ventilation 
Cumulative number of days for Hospitalization, ICU and Intubation / Mechanical Ventilation will be 
compared across treatment groups using non-parametric Wilcoxon Rank Sum test. The test will be 
two-sided with level of significance of 5%. Descriptive summaries of cumulative number of days, 


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difference in treatment groups, 95% CI and unadjusted p-value will be reported. P-value will be from 
testing the null hypothesis that mean of cumulative days across treatment groups are same. 
 
Reference SAS Program: 
 
proc npar1way data=<data>; 
class <treatment>; 
var <days>; 
run; 
 
In DDP: Table 14.2.6.3 and 
Table 14.2.6.4 
 
12.9.3 Other Analyses 
 
12.9.3.1 Arterial 
Blood Gas 
Test 
Descriptive summary of absolute results and change from baseline for Arterial blood gas test 
parameters in baseline and post-baseline visits will be 
summarized by treatment groups. The 
parameters to be summarized are, pH, pCO2, pO2, %O2 and cmH
2O. The summary will be presented 
for FAS and per-protocol analysis set. 
 
In DDP: Tables 14.2.7.1 and 14.2.7.2 
 
Absolute results change from baseline, etc. for all parameters will be listed by subject and grouped 
by treatment and visit. 
 
In DDP: Listing 16.2.6.6 
 
12.9.3.2 Hypotension 
requiring 
treatment 
beyond 
fluids 
(Vasopressors) 
Number and percentage of  subjects who have taken any vasopressors will be summarized by 
treatment. The same will be classified  by Therapeutic Main group  (ATC Level 2) and  Chemical 
Subgroup (ATC Level 4). If ATC level 4 is missing, ATC levels 2 or 3 will be used. The therapeutic main 
group and chemical subgroup will be displayed in the descending order of frequency in “Total”. 
Medications will be coded using the World Health Organization’s Drug-Dictionary (WHODrug) version 
September 2020 or latest. 
 
The summary will be presented for FAS and per-protocol analysis set. Percentages will be based on 
corresponding analysis sets. 
 
In DDP: Tables 14.2.8.1 and 14.2.8.2 
 
All medications will be listed by subject and therapeutic subgroup. Subjects will be grouped by 
treatment. 
 
In DDP: Listing 16.2.6.7 
 
12.9.3.3 CURB-65 
Score 
Shift in CURB-65 scores from baseline (scores 1-5) to each post-baseline visit (Days 3, 7, 14, 28 and 
60) will be presented by treatment groups. Subjects 
whose values are missing or assessment is not 
done will be presented as ‘Missing / Not Done’. 


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The summary will be presented for FAS and per-protocol analysis set. Percentages will be based on 
corresponding analysis sets. 
 
In DDP: Tables 14.2.9.1 and 14.2.9.2 
 
CURB-65 scores will be listed by subject and grouped by treatment groups and 
visits. 
In DDP: Listing 16.2.6.8 
12.9.3.4 Abbreviated 
Mental 
Health 
Score 
Descriptive summaries for the total score and change from baseline to post-baseline visits will be 
summarized by treatment groups. The summary will be based on FAS and per-protocol analysis set. 
Percentages will be based on the corresponding analysis sets. 
 
In DDP: Tables 14.2.10.1 and 14.2.10.2 
 
Abbreviated mental health scores will be listed by subjects. 
In DDP: Listing 16.2.6.9 
12.9.3.5 Sputum 
Microbiology, 
Blood 
cultures and 
Dialysis 
Sputum microbiology, Blood cultures and Dialysis/RRT data will only be listed by subject. 
In DDP: Listing 16.2.6.11, 16.2.6.12 and 16.2.6.5 
12.9.3.6 Confirmation 
of 
COVID-19 
pneumonia 
Confirmation of COVID-19 
pneumonia by RT-PCR, CXR scan radiologic findings, and CT scan 
radiologic findings will be listed by subject. 
 
Note: Subject who have screening COVID-19 confirmation before Informed Consent Date will be 
discussed during the Blinded Review Meeting prior to DB Lock. 
 
In DDP: Listing 16.2.6.10 
 
12.9.4 Pharmacodynamic Parameters 
Descriptive summary of parameters for baseline, each post baseline visit, and change from baseline 
at each visit and time point will be presented by treatment group. The summary will be based on FAS 
analysis set. The decision on whether biomarker results will be analyzed, and list of biomarkers to be 
analyzed will be made after database lock. 
 
All PD parameters will be listed for FAS analysis set. 
In DDP: Table 14.4.1.1 And Listing 16.2.10.1 


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12.9.5 Plasma Concentration 
 
12.9.5.1 Continuous 
Summary 
Descriptive summaries including geometric mean and SD, co-efficient of variation (%), geometric co- 
efficient of variation (%) of plasma concentrations will be presented by gender, time point and 
treatment groups. The summary will be based on PK analysis set. 
 
All plasma concentration results will be listed by subject for PK analysis set. 
In DDP: Table 14.5.1.1, Listing 16.2.10.2 
12.9.5.2 Plasma 
Concentration 
Time 
Plots 
Drug concentration profiles will be generated as follows: 
 
• Mean Plasma concentration vs time will be presented for  subjects within each treatment 
group along with error bars. Each group will be differentiated by color and symbol with 
appropriate legend. Y axis will be plasma concentration in ng/mL and X axis will be timepoints 
in hours. X axis will be displayed linearly proportionate to the actual timepoints. 
 
• Log transformed plots will also be presented for the mean plots. 
In DDP: Figures 14.5.1.2 and 14.5.1.3 
12.9.6 Pharmacokinetic Parameters 
The following PK parameters will be derived from plasma concentration using Phoenix WinNonLin 
software version 8.3 or higher for each measured analyte: 
 
• Area under the plasma concentration-time curve from time of dosing (zero) to time t of the 
last measured 
concentration above the limit of quantification (AUC
0-t) 
• Area under the plasma concentration-time curve (AUC) from 0 to infinity (AUC
0-inf) 
elimination half-life (t
1/2) 
• Observed 
maximum plasma concentration (C
max) 
• Time to observed maximum plasma concentration in plasma (T
max) 
• Elimination half-life (t
1/2) 
 
12.9.6.1 Continuous 
Summary 
Descriptive summaries including geometric mean and SD, co-efficient of variation (%), geometric co- 
efficient of variation (%) of PK parameters will be presented by gender and treatment group. The 
summary will be based on PK analysis set. 
 
All PK parameters will be listed for PK analysis set. 
In DDP: Table 14.5.1.6, Listing 16.2.10.3 
12.9.7     Immunogenicity 
Number and percentage of subjects for presence of antibodies against rhu-pGSN will be summarized 
by treatment and visit. Percentages will be based on the FAS analysis set. 


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All Immunogenicity parameters will be listed for FAS analysis set. 
In DDP: Table 14.6.1.1 and 
Listing 16.2.10.4 
12.10 Safety 
Analyses 
 
12.10.1 rse Events 
All Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 23.0 or Higher. All summaries will be based on Safety analysis set. 
 
12.10.1.1 
Overall 
Adverse 
Events 
Number and percentage of subjects and number of events will be summarized by treatment for the 
following categories: 
 
1. All adverse events reported 
 
2. Treatment emergent adverse events (TEAEs) 
 
3. Serious TEAEs 
 
4. Related TEAEs 
 
5. Related Serious TEAEs 
 
6. Adverse events led to death 
 
7. Adverse events led to study discontinuation 
 
8. Grade 3 or higher TEAEs 
 
9. Grade 3 or higher related AEs 
 
10. Adverse events by severity 
 
11. Injection related Adverse Events by Severity 
 
12. Adverse events by relationship to IMP 
 
13. Adverse events by relationship to study procedure 
 
14. Adverse events by outcome 
 
15. Adverse events by action taken with treatment 
 
Severity grading is based on NCI CTCAE, version 5.0. Percentages will be based on Safety analysis set. 
If a subject has multiple occurrences with different intensity/ relationships, then all the occurrences 
will be counted. 
 
In DDP: Table 14.3.1.1 


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All adverse events will be listed by subject and system organ class. Adverse events will be grouped by 
subjects. Day the Adverse event started, and Duration of AEs will also be included in the listing. 
 
In DDP: Listing 16.2.7.1 
 
12.10.1.2 
Summary 
of 
Treatment 
Emergent Adverse Events by 
SOC and 
PT 
Number and percentage of subjects and number of adverse events will be summarized by treatment, 
system organ class and preferred terms. Percentages will be based on safety analysis set. Events will 
be displayed in the descending order of frequency in “Total”. 
 
The same will be repeated for treatment-emergent related AEs, treatment-emergent serious AEs, 
treatment-emergent related serious AEs. Serious AEs and Deaths will be listed separately for 
respective sections in CSR (as per ICH E3). 
 
In DDP: Tables 14.3.1.2 to 14.3.1.8, Tables 14.3.2.1 and 14.3.2.2 
 
12.10.1.3 
Summary 
of 
Adverse 
Events 
by 
Relationship and 
Intensity 
Number and percentage of subjects and number of events in each system organ class, preferred term 
and intensity (Grade 1-5) will be summarized by relationship for treatment-emergent adverse events 
and treatment. System organ class and preferred term will be displayed by descending order of 
frequency in “Total”. Intensity will be displayed in the alphabetical order. 
 
In DDP: Table 14.3.1.9 
 
12.10.2 Summary of Death 
Number and percentage of deaths due to any cause, AE leading to Death by preferred term, Death 
due to COVID-19 (WHO score = 8) by visit will be summarized by treatment groups. Percentages are 
based on Safety analysis set. 
 
In DDP: Table 14.3.2.3 
 
12.10.3 aboratory Assessments 
 
12.10.3.1 
Continuous 
Summary 
Descriptive summary of absolute result and change from baseline in laboratory data will be presented 
by parameter and visit for safety analysis set. Each category (Hematology, Clinical Chemistry and 
Coagulation) will be represented in separate tables. Note that Laboratory assessments will be done 
only if required by SOC. 
 
In DDP: Tables 14.3.4.1, 14.3.4.2, and 14.3.4.3 
 
12.10.3.2 
Categorical 
Summary 
Number and percentage of subjects reporting laboratory interpretations (Normal, Abnormal Not CS 
and Abnormal CS, Not Done, Not required as per SOC) will be summarized by treatment, parameter, 
and visit. Each category (hematology, clinical chemistry, and coagulation) will be represented in 
separate tables. 
Percentages will be based 
on number 
of subjects with non-missing results in each visit 
within safety analysis set. 


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In DDP: Tables 14.3.4.4, 14.3.4.5 and 14.3.4.6 
 
12.10.3.3 
Listings 
All laboratory results will be listed for all subjects by visit and parameter. Out of range results will be 
highlighted. 
 
In DDP: Listings 16.2.8.1, 16.2.8.2 and 
16.2.8.3 
 
Subjects with clinically significant laboratory results and subjects with out-of-range results will be 
separately listed by category, visit and parameter. 
 
In DDP: Listings 16.2.8.4, Table 14.3.4.7 
 
HIV and Pregnancy tests will only be listed by subject. 
In DDP: Listing 16.2.8.5 and 16.2.8.6 
Parameters  collected  in  each  laboratory  category  are  listed  below.  In  summaries  and  listings, 
parameters will be sorted in the order as below: 
 
Category 
Parameters 
Hematology 
Hemoglobin, Hematocrit, RBC, WBC, Platelet Count, 
Neutrophils, Lymphocytes, Monocytes, Eosinophils, 
Basophils, Reticulocyte Count, 
Clinical Chemistry 
Albumin, Alkaline Phosphatase, Alanine Aminotransferase 
(ALT), Aspartate Aminotransferase (AST), Bicarbonate, 
Direct Bilirubin, Total Bilirubin, Blood Urea Nitrogen, 
Lactate Dehydrogenase (LDH), Chloride, Creatine 
Phosphokinase (CPK), Creatinine, Amylase, Lipase, 
Potassium, Total Protein, Sodium, Ferritin,  D-dimer, CRP, 
Procalcitonin, Urea, Total cholesterol (TC), HDL-C, LDL-C, 
Triglycerides 
Coagulation 
PT, PTT, aPTT, International Normalized Ratio (INR) 
 
12.10.4 Other Safety Analyses 
 
12.10.4.1 
Vital 
Signs 
Descriptive summary of absolute result and change from baseline in vital signs will be presented by 
treatment, parameter and visit for Safety analysis set. Parameters to be included: Weight (kg), BMI 
(kg/m
2), Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Respiratory rate 
(breaths/min), Heart rate (beats/min) and Temperature  
(
oC). In summaries and listings, parameters 
will be sorted in the order mentioned. 
 
In DDP: Table 14.3.5.1 


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Vital signs will be listed by subjects and visit for safety analysis set. 
In DDP: Listing 16.2.9.1 
12.10.4.2 
Physical 
Examination 
Number and percentage of subjects with results (Normal, Abnormal Not CS, Abnormal CS, Not Done) 
will be summarized by treatment, body system and visit. Body systems to be summarized are: Skin, 
HEENT, Neurologic, Lungs, Abdomen, and Heart. Percentages will be based on safety analysis set. Any 
additional body systems assessments as ‘Other’ will be listed and not summarized. 
 
In DDP: Table 14.3.5.2 
 
Physical Examination will be listed by subject and visit. 
In DDP: Listing 16.2.9.2 
12.10.4.3 
Electrocardiogram 
Assessments 
Descriptive summary of absolute result and change from baseline in EKG Results will be presented by 
treatment, parameter and 
visit for Safety analysis set. 
The parameters to be presented are: Heart Rate 
(beats/min), PR (msec), RR (sec), QRS (msec), QT (msec) and QTcF (msec). Note that EKG assessment 
will be done only if required by SOC. 
 
Number and percentage of subjects with findings (Normal, Abnormal Not CS, Abnormal CS, Not Done, 
Not Required as per SOC) will be summarized by treatment, parameter, and visit. Percentages will be 
based on safety analysis set. 
 
In DDP: Table 14.3.5.3 and Table 14.3.5.4 
 
EKG Findings will be listed by subject and visit. 
In DDP: Listing 16.2.9.3 
12.10.5  Exploratory Analyses 
Exploratory analyses looking at biomarkers and outcomes in each treatment arm will be conducted. 
The decision on whether biomarker results will be analyzed, and list of biomarkers to be analyzed will 
be made after database lock. 


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13 Changes to Planned Analyses 
• One of the Secondary Efficacy Endpoints as per protocol is “Daily change in  9-point WHO 
severity score 
through at least Day 14”. Since the WHO Severity Score is 
required 
only on 
Days 
1, 2, 3, 7 and 14 (on other days, it is not mandatory), the analysis of the WHO Severity score 
will be done for “Change in 9-point WHO severity score through Day 14 on scheduled visits”. 
All WHO Severity scores will be listed. 
 
• Exploratory analysis to compare the efficacy endpoint data from the rhu-pGSN group from 
this study to that of external control data was not considered feasible at the time of database 
lock, so this analysis will not be performed. 


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14 Index of Tables, Listings and Graphs 
Refer BTI_Data Display Plan (Ver: 1.00) for the list of Tables, Listings and Graphs. 


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15 References 
Provide list of references used to create this document. 
 
• ICH. ICH Harmonized Tripartite Guideline: Statistical Principles for Clinical Trials E9. 1998. 
 
• ASA. Ethical Guidelines for Statistical Practice. Prepared by the Committee on Professional 
Ethics. 1999. 
 
• ICH. ICH Harmonized Tripartite Guideline: Structure and Content of Clinical Study Reports E3. 
1995. 
 
• BTI-201 CSR v1.0 Final 24Dec2019_signed (Phase 1 study protocol) 
 
• BTI-201-Statistical-Anal-PF-v2-Amen-1_2018-12-03 (Phase 1 study SAP) 
 
• CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group 
randomised trials 


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16 Appendices 
 
16.1 Summary 
of 
Statistical Analyses 
 
Endpoints 
Analysis Set 
Primary 
Analyses 
Supportive Analyses 
Incidence of SAEs in rhu-pGSN vs 
placebo groups 
Safety analysis 
set 
Descriptive 
Summaries 
- 
Proportion of subjects alive not on 
vasopressors, mechanical 
ventilator, and dialysis on Day 14. 
FAS (primary), 
Per-Protocol 
analysis set 
Cochran- 
Mantel- 
Haenszel 
(CMH) 
method 
- 
Adverse Events, Clinically 
Significant Laboratory Results 
Safety analysis 
set 
Descriptive 
Summaries 
- 
Change in WHO Severity Score 
FAS, Per- 
Protocol 
analysis set 
Shift 
summaries, 
Box Plots, 
MMRM 
- 
Mortality Rate and Time to Death FAS (primary), 
Per-Protocol 
analysis set 
Log Rank 
Test, Cox 
Regression 
Model, 
Kaplan- 
Meier Curve 
- 
Proportion of Subjects alive 
without support 
FAS (primary), 
Per-Protocol 
analysis set 
CMH 
- 
Days on the Ventilator 
FAS (primary), 
Per-Protocol 
analysis set 
Descriptive 
Summaries, 
Wilcoxon 
Rank Sum 
Test 
- 
Hospitalization and ICU days 
FAS (primary), 
Per-Protocol 
analysis set 
Descriptive 
Summaries 
- 
Plasma Concentration 
PK analysis set Descriptive 
Summaries 
and Plots 
 
PK Parameters 
PK analysis set Descriptive 
Summaries 
- 
Immunogenicity 
PK analysis set Descriptive 
Summaries 
- 
Biomarkers 
Safety analysis 
set 
Descriptive 
Summaries 
- 


 
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17 Change Log 
 
Version 
Authored by 
Change Date 
Change Details 
Reviewed by 
Review Date 
1.00 Bharathy Prasath 
Shweta Padmanaban 
05-Aug-2021 
First version approved 
Mark DiNubile 
05-Aug-2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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