Efficacy and Safety of Octagam 10% Therapy in COVID-19 Patients With Severe Disease Progression
Phase: PHASE3
Conditions: Covid-19
Sponsor: Octapharma

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This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
090-CSP-GAM10-10_01 /DOC ID 3228
CLINICAL STUDY PROTOCOL 
GAM10-10 
EFFICACY AND SAFETY OF OCTAGAM 10% THERAPY
IN COVID-19 PATIENTS WITH SEVERE DISEASE
PROGRESSION
Investigational Product: 
Octagam 10% - Intravenously 
Administered Immunoglobulin
Indication: 
Immunomodulation in patients with 
severe Coronavirus disease to prevent 
deterioration of clinical status
Study Design: 
Randomized, double-blind, placebo 
controlled
Sponsor: 
Octapharma USA
117 West Century Blvd
Paramus, NJ 07652
Study Number: 
GAM10-10
EudraCT and/or IND Number:
IND Number 022051 
Development Phase:
Phase 3 
Planned Core Clinical Start:
2nd Quarter 2020 
Planned Core Clinical End:
4th Quarter 2020 
Planned Follow-up Registry
Start:
3rd Quarter 2020 
Planned Follow-up Registry End: 4th Quarter 2021 
Date of Protocol: 
27-January-2021
Version: 
08 
Coordinating Investigator: 
This document contains confidential and proprietary information of Octapharma. 
Copying or distribution of this document is only permitted with the written permission of Octapharma. 
Any commercial use of the information is subject to the permission of Octapharma and a license fee. 

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Study Protocol No. GAM10-10, Version 08 CONFIDENTIAL 
27-January-2021 
 
 
Page 2 of 81 
STUDY OUTLINE 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
Octagam® 10% 
Protocol Identification Code: 
GAM10-10 
Name of Active Ingredient: 
Intravenously Administered Immunoglobulin 
Date of Final Protocol: 
27-January-2021 
 
Title of Study: 
Efficacy and safety of Octagam 10% therapy in COVID-19 patients with severe 
disease progression 
Indication: 
Immunomodulation in patients with severe Coronavirus disease to prevent 
deterioration of clinical status. 
Number of Study Center(s): 
Approximately 20 sites in the USA, Russia, and Ukraine. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 To determine if high-dose Octagam 
10% therapy will stabilize or improve 
clinical status in subjects with severe 
COVID-19 during the first seven 
days following treatment 
commencement. 
 Proportion of subjects with 
stabilized or improved clinical status 
at Day 7 of at least one category of 
the following 6-point clinical status 
scale: 
1. Hospital discharge or meet 
discharge criteria, defined as 
clinical recovery, ie, no fever, 
respiratory rate, oxygen 
saturation return to normal, and 
cough relief 
2. Hospitalization, not requiring 
supplemental oxygen 
3. Hospitalization, requiring 
supplemental oxygen (but not 
non-invasive mechanical 
ventilation [NIV]/high-flow nasal 
cannula [HFNC]), as defined by 
A-a Gradient <150 mmHg 

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Study Protocol No. GAM10-10, Version 08 CONFIDENTIAL 
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Page 3 of 81 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
Octagam® 10% 
Protocol Identification Code: 
GAM10-10 
Name of Active Ingredient: 
Intravenously Administered Immunoglobulin 
Date of Final Protocol: 
27-January-2021 
 
4. Intensive care unit 
(ICU)/hospitalization, requiring 
NIV/HFNC therapy, as defined 
by A-a Gradient ≥ 150 mmHg 
5. ICU, requiring Extracorporeal 
Membrane Oxygenation (ECMO) 
and/or Invasive Mechanical 
Ventilation (IMV) 
6. Death 
Key Secondary Efficacy 
 To compare the length of hospital stay 
in subjects treated with Octagam 10% 
compared to those that received 
placebo through Day 33.  
 Length of hospital stay (time to 
discharge) from randomization through 
Day 33. 
 To determine if high-dose Octagam 
10% therapy will stabilize or improve 
clinical status in subjects with severe 
COVID-19 during the 14 days 
following treatment commencement. 
 Proportion of subjects with stabilized or 
improved clinical status of at least one 
category on the 6-point clinical status 
scale on Day 14. 
 To compare the cumulative duration 
of IMV in subjects treated with 
Octagam 10% compared to those that 
received placebo through Day 33. 
 Cumulative duration of IMV from 
randomization through Day 33. 
 To compare the cumulative incidence 
of severe progression in subjects 
treated with Octagam 10% compared 
to those that received placebo at 
Day 33. 
 Proportion of subjects with severe 
progression defined as requiring 
ECMO, IMV and/or have died through 
Day 33. 
 To compare the length of time in ICU 
for subjects treated with Octagam 
10% compared to those that received 
placebo through Day 33. 
 Length of time in ICU from 
randomization through Day 33. 

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27-January-2021 
 
 
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 To compare cumulative mortality in 
subjects treated with Octagam 10% 
compared to those that received 
placebo at Day 33. 
 Mortality rate through Day 33. 
Other Secondary Efficacy 
 To determine if high-dose Octagam 
10% affects severe acute respiratory 
syndrome from Coronavirus 2 (SARS-
CoV-2) infection status at Day 7. 
 Results of reverse transcription 
polymerase chain reaction (RT-PCR) 
for SARS-CoV-2 from nares/throat 
swab and/or sputum and/or lower 
respiratory tract sample on Day 7. 
 To compare the cumulative incidence 
of new ICU admittance in subjects 
treated with Octagam 10% compared 
to those that received placebo at Day 
33. 
 Proportion of subjects admitted to the 
ICU from randomization through Day 
33 
 To determine if high-dose Octagam 
10% therapy will improve clinical 
status in subjects with severe COVID-
19 during the 14 days following 
treatment commencement. 
 Proportion of subjects with 
improvement on Days 7, 14, 21, and 
33. 
 To compare the cumulative incidence 
of IMV in subjects treated with 
Octagam 10% compared to those that 
received placebo through Day 33. 
 Proportion of subjects requiring IMV by 
Day 33. 
 To compare the time to recovery in 
subjects treated with Octagam 10% 
compared to those that received 
placebo through Day 33. 
 Time to recovery through Day 33 
where recovery is defined as a clinical 
status of 1 or 2. 
 To compare the time to first 
improvement in clinical status in 
subjects treated with Octagam 10% 
compared to those that received 
placebo through Day 33. 
 Time to first improvement in clinical 
status through Day 33. 
Secondary Safety 
 To describe the safety of Octagam 
10% compared to placebo when 
administered to subjects with severe 
COVID-19. 
 Incidence of all adverse events (AEs) 
 Incidence of AEs considered related to 
the Investigational Medicinal Product 
(IMP) 
 Incidence of serious adverse events 
(SAEs) 

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Page 5 of 81 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
Octagam® 10% 
Protocol Identification Code: 
GAM10-10 
Name of Active Ingredient: 
Intravenously Administered Immunoglobulin 
Date of Final Protocol: 
27-January-2021 
 
 Clinical laboratory parameters 
 Vital sign parameters 
 Radiological findings (chest 
computerized tomography [CT]/chest 
X-ray) 
Exploratory 
 To compare changes in SpO2 on 
room air from Baseline (Day 1) to all 
available on-study time points up to 
Day 33 in subjects treated with 
Octagam 10% compared to those that 
received placebo. 
 Improvement of SpO2 on room air from 
Baseline (Day 1) to Day 33 using trend 
from all available observed data. 
 To compare changes in the Modified 
Borg Dyspnea Scale from Baseline 
(Day 1) to Days 7, 14, 21, and 33 in 
subjects treated with Octagam 10% 
compared to those that received 
placebo. 
 Modified Borg Dyspnea Scale score at 
Baseline (Day 1) and on Days 7, 14, 
21, and 33. 
 To compare changes in Quality of Life 
(McGill Quality of Life Single-Item 
Scale, MQoL-SIS) score from 
Baseline (Day 1) to Days 7, 14, 21 
and 33 in subjects treated with 
Octagam 10% compared to those that 
received placebo. 
 MQoL-SIS score at Baseline (Day 1) 
and on Days 7, 14, 21 and 33. 
Study Design: 
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to 
evaluate if high-dose Octagam 10% therapy can stabilize or improve clinical status in 
subjects with severe Coronavirus disease. 

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Page 6 of 81 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
Octagam® 10% 
Protocol Identification Code: 
GAM10-10 
Name of Active Ingredient: 
Intravenously Administered Immunoglobulin 
Date of Final Protocol: 
27-January-2021 
 
Number of Subjects: 
Maximum 208 subjects will be recruited to achieve a study sample of 104 subjects 
each in the treatment and placebo groups (1:1 randomization in both arms), allowing 
for a 15% drop-out rate.  
Subject Selection Criteria: 
Inclusion Criteria: 
1. Adult aged ≥ 18 years old 
2. Provide voluntary, fully informed written and signed consent before any study-
related procedures are conducted 
3. Able to understand and comply with the relevant aspects of the study protocol 
4. Laboratory (RT-PCR) confirmed COVID-19 infection on nares/throat swab 
and/or sputum and/or lower respiratory tract samples at Screening or within 
7 days prior to Screening 
5. Hospitalized, requiring supplemental oxygen with a resting room-air SpO2 of 
≤93% or arterial oxygen partial pressure (PaO2)/fractional inspired oxygen 
(FiO2) ratio < 300 mmHg. Measurement can be taken from documented 
source records within the 24 hours prior to Screening 
6. Chest imaging confirming lung involvement 
Exclusion Criteria: 
1. Existence of other evidence that can explain pneumonia including but not 
limited to: Influenza A virus, influenza B virus, bacterial pneumonia (as 
suggested by the combined clinical picture, radiological findings and known 
laboratory results [eg, elevated procalcitonin >0.5ng/mL and concomitant 
neutrophilia]), known fungal pneumonia, suspected fungal pneumonia based 
on compromised immune system with a history of past fungal infections, 
noninfectious causes, etc. 
2. Known history of serious allergic reactions, including anaphylaxis to 
intravenous immunoglobulin (IVIG) or its preparation components 
3. Subjects with a history of thromboembolic event (TEE) within the last 
12 months, such as deep vein thrombosis, pulmonary embolism, myocardial 
infarction, ischemic stroke, transient ischemic attack, peripheral artery disease 
(Fontaine IV) 
4. Subjects with an underlying medical condition that can lead to hypercoagulable 
states and hyperviscosity such as antithrombin III deficiency, Factor V Leiden, 
Protein C deficiency, antiphospholipid syndrome, and malignancy 

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Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
Octagam® 10% 
Protocol Identification Code: 
GAM10-10 
Name of Active Ingredient: 
Intravenously Administered Immunoglobulin 
Date of Final Protocol: 
27-January-2021 
 
5. Known history of selective IgA deficiency with antibodies against IgA 
6. Subjects with conditions such as human immunodeficiency virus (HIV) 
infection, known acute or chronic hepatitis B or C (HBsAg positive or HCV 
ribonucleic acid (RNA) PCR positive or currently treated with antivirals), 
pulmonary fibrosis, elevated procalcitonin (> 0.5) with concomitant neutrophilia 
(elevated polys), heparin induced thrombocytopenia (HIT), and moderate to 
severe renal dysfunction (per investigator discretion based on estimated 
glomerular filtration rate [eGFR] <59 mL/min/1.73 m2, as defined by KDIGO 
Clinical Practice Guideline): 
 
Moderately reduced GFR (G3a): GFR = 45 to 59 ml/min/1.73 m2 
 
Moderately reduced GFR (G3b): GFR = 30 to 44 ml/min/1.73 m2 
 
Severely reduced GFR (G4): GFR = 15 to 29 ml/min/1.73 m2 
 
Kidney failure (G5): GFR <15 ml/min/1.73 m2 
7. Currently requiring IMV or having received IMV during the last 30 days 
8. Known clinically significant preexisting lung, heart, or neuromuscular disease 
that, in the investigator’s opinion, would impact subject’s ability to complete 
study or may confound the study results 
9. Body weight >125 kg 
10. Women who are pregnant or breast-feeding 
11. Subjects who received COVID-19 convalescent plasma, IVIG products, anti-
interleukin agents (eg, Tocilizumab), or interferons for their COVID-19 disease 
before enrollment or plan to receive this treatment during the course of the 
study 
12. Enrolled in other experimental interventional studies or taking experimental 
medications (ie, convalescent plasma). Diagnostic studies can be allowed if 
the anticipated total blood volume to be drawn across both studies and for 
therapeutic purposes does not exceed 450 mL over any 8-week period.  
Test Product, Dose, and Mode of Administration: 
Octagam 10%, 2 g/kg divided by 4 days (0.5 g/kg/day), administered by intravenous 
infusion over approximately 2 hours per day over 4 consecutive days. 
Duration of Treatment: 
The duration of treatment is 4 days. The duration of the entire study for each subject 
will be approximately 33 days: 
 Screening period: 1 day  
 Treatment period: 4 days 

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Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
Octagam® 10% 
Protocol Identification Code: 
GAM10-10 
Name of Active Ingredient: 
Intravenously Administered Immunoglobulin 
Date of Final Protocol: 
27-January-2021 
 
 Follow-up period: 29 days  
Reference Therapy, Dose, Mode of Administration: 
Placebo (saline), equivalent volume as test product, administered by intravenous 
infusion over approximately 2 hours per day over 4 consecutive days.  
Efficacy Parameters: 
Efficacy assessments include clinical status, oxygenation and ventilator status, 
SARS-CoV-2 RT-PCR results, oxygen saturation, modified Borg Dyspnea Scale and 
MQoL-SIS. 
Safety Parameters: 
Safety assessments include AEs and SAEs, vital signs including SpO2, clinical 
laboratory evaluations and chest CT/chest X-ray findings. 
Study Procedures: 
Investigators will enroll subjects into the study only after written informed consent has 
been obtained from subject or legally authorized representative (LAR). The Flow 
Chart of Assessments includes full details of all the procedures that will be performed 
at each study visit. Below is a brief summary of the procedures that will be performed 
during the study.  
Screening Visit: 
After written informed consent has been obtained from subject or LAR, subjects will 
be evaluated for study eligibility according to the inclusion/exclusion criteria. These 
evaluations will include confirmation of a COVID-19 diagnosis (including RT-PCR for 
SARS-CoV-2 if not available from the 7 day period prior to Screening), demographics, 
medical history, physical examinations, body weight, current medication use, vital 
signs including SpO2 saturation, clinical status and oxygenation/ ventilator status, 
blood sample collection (for evaluation of clinical safety parameters and serum 
pregnancy test, if appropriate), urine sample for legionella and pneumococcal 
antigens, chest CT/chest X-ray and completing the MQoL-SIS. 
Infusion Visits (Days 1 to 4): 
Following the completion of all Screening procedures including confirmation of 
eligibility criteria and medical history, the subject will be randomized to receive either 
Octagam 10% or placebo. The subject will receive either Octagam 10% medication 
in the dose of 2 g/kg administered over 4 days (0.5 g/kg/day), or an equivalent volume 

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Study Protocol No. GAM10-10, Version 08 CONFIDENTIAL 
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Page 9 of 81 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
Octagam® 10% 
Protocol Identification Code: 
GAM10-10 
Name of Active Ingredient: 
Intravenously Administered Immunoglobulin 
Date of Final Protocol: 
27-January-2021 
 
of placebo (saline), infused slowly over approximately 2 hours per day over 
4 consecutive 
days. 
Other 
evaluations 
will 
include 
clinical 
status 
and 
oxygenation/ventilator status, vital signs including SpO2 saturation and A-a Gradient 
(A-a Gradient collected on Day 1 only), completion of the MQoL-SIS, and the modified 
Borg Dyspnea scale, physical examinations, blood sample collection, AE monitoring, 
and concomitant medication use. 
Primary Endpoint Visit (Day 7) 
On Day 7, the following evaluations will be performed, including the primary endpoint 
evaluation: clinical status (confirmed by A-a gradient if clinical status of 3 or 4) and 
oxygenation/ventilator status; and secondary endpoint evaluations: vital signs 
including SpO2 saturation, swab for RT-PCR detection of SARS-CoV-2 infection 
status, completion of the MQoL-SIS and the modified Borg Dyspnea scale, blood 
sample collection, chest CT/chest X-ray, AE monitoring, and concomitant medication 
use. 
Follow-up Visits (Days 14 and 21) 
The subject will have 2 safety follow-up visits at which the following procedures will 
be performed: clinical status and oxygenation/ventilator status, vital signs including 
SpO2 saturation, completion of the MQoL-SIS and the modified Borg Dyspnea scale, 
AE monitoring, and concomitant medication use. 
End of Study Visit (Day 33) 
At Day 33, the following End of Study evaluations will be performed: clinical status 
and oxygenation/ventilator status, vital signs including SpO2 saturation, completion 
of the MQoL-SIS and the modified Borg Dyspnea scale, physical examination, blood 
sample collection, AE monitoring, and concomitant medication use. After Day 33, the 
core clinical study is considered completed for the subject. No further study-related 
assessments will be performed, unless safety concerns (eg, ongoing AEs) require 
follow-up. 
Telephone Visits: 
If a subject is discharged from the hospital at any time during the course of their 
participation in the study, a pulse oximeter will be provided to them to monitor their 
oxygen saturation at home. The Research Coordinator or other qualified research 
team member will contact the subject at Day 14 and Day 21 to collect data points. 
Data collection will also include the Modified Borg Dyspnea Scale, MQoL-SIS, AE 
recording, and concomitant medication review. 

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Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
Octagam® 10% 
Protocol Identification Code: 
GAM10-10 
Name of Active Ingredient: 
Intravenously Administered Immunoglobulin 
Date of Final Protocol: 
27-January-2021 
 
One Year Registry Follow-up: 
After completion of the core 33-day trial, all subjects will be followed for a one-year 
follow-up registry. Subjects will be contacted by telephone or electronically by the 
Principal Investigator or the Sponsor (or its designee) every three months (±14 days) 
for one year to obtain data on health status and any residual health effects from 
COVID-19 or the study treatment. There will not be any additional in-person site visits 
required. The responsibility for the oversight of this registry follow-up period will be 
managed by a central Coordinating Principal Investigator (not the enrolling 
Investigator responsible for the 33-day core trial), unless the local Investigator elects 
to continue to oversee their subjects directly during this one-year follow-up period. 
The data recorded during this registry follow-up period will be submitted as a 
supplement to the core study data once all subjects have completed the year of 
follow-up. 
Statistical Analysis Plan: 
Assuming that the proportions of subjects who successfully achieve the primary 
endpoint are 0.6 for placebo arm and 0.8 for IVIG arm, with additional assumptions 
of normality approximation of difference of two proportions, the maximum sample size 
needed is 208 to provide at least 80% power assuming a drop-out rate of 15%. That 
is, 176 subjects will provide at least 80% of statistical power with overall type I error 
of 0.05. 
Final Analysis 
For this study, the primary population for analysis is defined as: 
 Enrolled Population (EP) 
All subjects who are enrolled in the study will be included in the enrolled population 
(EP).  
 Intent-To-Treat Analysis Population (ITT) 
All subjects who are randomized will be included in the intent-to-treat (ITT) analysis 
population and analysis will be conducted according to the study arm in which 
subjects are randomized, regardless of randomization errors or protocol violations. 
 Safety Analysis Population (SAF) 
All subjects who are randomized and received any amount of IVIG or placebo will be 
included in the modified safety analysis set (SAF) and analysis will be conducted 
according to the treatment which subjects actually received. 

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Page 11 of 81 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
Octagam® 10% 
Protocol Identification Code: 
GAM10-10 
Name of Active Ingredient: 
Intravenously Administered Immunoglobulin 
Date of Final Protocol: 
27-January-2021 
 
 Per-Protocol Analysis Population (PP) 
Per protocol (PP) analysis set includes subjects who receive at least 80% of planned 
dose (IVIG or placebo) without major protocol deviations. 
Efficacy Analysis Plan 
Descriptive statistics, including mean, standard deviation, median, maximum, and 
minimum will be provided for baseline age, weight, vital signs, physical exam, 
laboratory results, oxygen saturation. Gender, race and ethnicity, and other 
demographic information will be tabulated. Medical history will be classified using the 
Medical Dictionary for Regulatory Activities (MedDRA) classification system version 
23.0 and tabulated with start date, ongoing status, and end date, if applicable. 
The ITT set will be used for primary analysis set to analyze the primary endpoint. The 
handling of missing data is described in the body of the protocol. A subject is 
randomized to either IVIG group or placebo group. A subject is determined to be a 
success (ie, reached the primary endpoint) if the clinical status category on Day 7 is 
not worse than the clinical status category at Baseline (Day 1 prior to IMP infusion). 
Null hypothesis of no difference in proportion of subjects who reach success in two 
treatment groups will be tested versus the alternative hypothesis that there is a 
difference between proportions of subjects who reach success in two groups. 
Hypothesis testing will be performed using Cochran-Mantel-Haenszel (CMH) 
stratified by age category (≤65 versus >65) at a two-sided 0.05 significance level. The 
difference in proportion of subjects between both groups with standard deviation, and 
95% confidence interval will also be provided. 
Subgroup analysis of the primary endpoint will include sex (male/female), age (>65, 
≤65), race, ethnicity, and disease severity (according to the definitions of the 
electronic Case Report Form [eCRF]). 
Sensitivity analysis using different alternative analysis population and additional 
analysis methods will also be performed. More details will be provided in the 
Statistical Analysis Plan (SAP). 
The analysis for key secondary endpoints will be based on the ITT population. The 
hypothesis testing with p-value assessments for key secondary efficacy endpoints at 
designated timepoints will be implemented for confirmatory purpose after statistical 
significance is claimed from the primary endpoint. The following secondary endpoints 
will be analyzed by hierarchical procedure in the order specified below with overall 
two-sided type I error of 0.05:  

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Page 12 of 81 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
Octagam® 10% 
Protocol Identification Code: 
GAM10-10 
Name of Active Ingredient: 
Intravenously Administered Immunoglobulin 
Date of Final Protocol: 
27-January-2021 
 
1. Length of hospital stay (time to discharge) through Day 33 
2. Proportion of subjects with stabilized or improved clinical status of at least one 
category on the 6-point clinical status scale on Day 14. 
3. Cumulative duration of IMV through Day 33 
4. Proportion of subjects with severe progression defined as requiring ECMO, 
IMV and/or have died through Day 33 
5. Length of time in ICU from randomization through Day 33 
6. Mortality rate through Day 33 
Hypothesis testing for proportions will be conducted as described for the primary 
endpoint. Stratified log-rank tests will be performed to compare treatment effects 
between arms for time to event data using age category as a stratification variable. 
Kaplan-Meier plots will also be provided. ANOVA or Van Elteren tests will be 
performed for continuous endpoints. 
Secondary endpoints which demonstrate statistical significance will be analyzed by 
subgroups including sex (male/female), race, ethnicity, and disease severity 
(according to the definitions in the eCRF). 
A detailed SAP describing missing data handling and further details with respect to 
testing for each endpoint will be compiled as a separate document. 
Safety Analysis Plan 
Safety data analysis will be based on the SAF. Descriptive statistics will be provided 
for imaging assessments, clinical laboratory parameters, AEs, SAEs, and vital signs, 
including physical examination, concomitant medicines, concomitant procedures, 
and safety laboratory test results. 
AEs observed will be classified using the MedDRA classification system version 23.0. 
AEs will be summarized by MedDRA system organ class and preferred terms. 
Separate tabulations will also be produced for related AEs, SAEs, discontinuations 
due to AEs, and AEs of at least Grade 3 severity. A summary of the number and 
severity of treatment-emergent AEs and study drug related AEs will also be 
produced. 
Laboratory results will be graded according to the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 whenever 

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Page 13 of 81 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
Octagam® 10% 
Protocol Identification Code: 
GAM10-10 
Name of Active Ingredient: 
Intravenously Administered Immunoglobulin 
Date of Final Protocol: 
27-January-2021 
 
possible. Laboratory parameters will be summarized for changes across study using 
descriptive statistics including shifts relative to NCI-CTCAE criteria for laboratory 
abnormalities. Laboratory measures will also be compared with their corresponding 
normal ranges, and the incidence of abnormally high and abnormally low laboratory 
values will be summarized. 
 

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Page 14 of 81 
FLOW CHART OF ASSESSMENTS 
Table 1: 
Flow Chart of Assessments Performed Throughout the Study 
ASSESSMENTS 
Screening 
Visit 
(Day 0) 
Baseline/Infusion  
Visit 1  
(Day 1) 1 
 
Infusion 
Visits 2-4 
(Days 2-4) 
Primary 
Endpoint 
Visit 5  
(Day 7 or at 
discharge if 
prior to Day 
6) 2 
Safety 
Follow-up 
Visits 6 & 7  
(Days 14 & 
21) 3 
End of Study 
Visit 
(Day 33) 3 
Registry 
follow-up: 
every three 
months for 
one year 4 
Informed consent 
x 
 
 
 
 
 
 
Eligibility criteria 5 
x 
x 
 
 
 
 
 
Demographics/Baseline Characteristics 
x 
 
 
 
 
 
 
Medical history (including COVID-19 
diagnosis date) 
x 
x 
 
 
 
 
 
Diagnosis confirmation 5 
x 
 
 
x 
 
 
 
Clinical Status and Oxygenation/Ventilator 
Status Evaluation 6 
x 
x 
x 
x 
x 
x 
 
Body weight 
x 
x (if not performed 
at Screening) 
 
 
 
 
 
Vital Signs 7 
Collected throughout the study 
 
SpO2 and A-a Gradient 7 
Collected throughout the study 
 
McGill Quality of Life Single Item Scale 
x 
x 
x 
x 
x 
x 
 
Modified Borg Dyspnea Scale 
 
x 
x 
x 
x 
x 
 
Physical examination8 
x 
x (if not performed 
at Screening or 
available in 
hospital admission 
notes) 
 
 
 
x (performed 
at Day of 
Discharge) 
 
Chest CT/Chest X-ray 9 
x 
x (if not available 
at Screening) 
 
x 
 
 
 
Laboratory Sample Collection 10 
x 
x 
x 
x 
x 11 
 
 
Urine sample for legionella, pneumococcal 
antigens 
x 
 
 
 
 
 
 

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Page 15 of 81 
ASSESSMENTS 
Screening 
Visit 
(Day 0) 
Baseline/Infusion  
Visit 1  
(Day 1) 1 
 
Infusion 
Visits 2-4 
(Days 2-4) 
Primary 
Endpoint 
Visit 5  
(Day 7 or at 
discharge if 
prior to Day 
6) 2 
Safety 
Follow-up 
Visits 6 & 7  
(Days 14 & 
21) 3 
End of Study 
Visit 
(Day 33) 3 
Registry 
follow-up: 
every three 
months for 
one year 4 
Serum Pregnancy Test, if applicable 
x 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
Administration/Infusion of IMP 
 
x 
x 
 
 
 
 
Post-infusion site assessment 
 
x 
x 
 
 
 
 
AE monitoring 
 
Collected from first administration of IMP until End of Study (Day 33) 
 
Prior/Concomitant medication3 
Collected throughout the study 
Health Status12 
 
 
 
 
 
 
x 
1. 
First day of Baseline/Infusion, labeled as Visit 1/Day 1, must fall within 24 hours of Screening Visit. 
2. 
Assessments done on day of discharge if prior to Day 6 will not be repeated if already performed as part of the assessments for that day. 
3. 
Can be done via telehealth/telephone call. 
4. 
Health status questions will record COVID-19 status including, relapse or new COVID-19 infection, hospitalization(s) and cause(s) of hospitalization, and death. 
5. 
See Section 7.1.4 and 7.2.3. 
6. 
See Sections 7.2.1 and 7.2.2. 
7. 
See Section 7.3.5 for details. Vital signs will not be collected if the visit is conducted by telephone or telehealth. 
8. 
Physical Exam is only done at Baseline if not done at Screening. Screening physical exam can be assessed from hospital chart notes. 
9. 
Chest computerized tomography/Chest X-ray from within +/-1 day will be accepted for Screening and Day 7. 
10. See Section 7.3.4 for a list of safety laboratory evaluations. All laboratory samples should be drawn prior to IMP infusions at Visits 1 through 4. If the Day 1 infusion commences within 8 
hours of the blood collection for the Screening laboratory parameters, only those parameters not assessed at Screening need to be performed prior to the Day 1 infusion. 
11. Final blood sample will be drawn on day of discharge (if after Day 7) or Day 33, whichever is sooner. 
12. Can be delegated to the Sponsor / contract research organization. 

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Page 17 of 81 
TABLE OF CONTENTS 
STUDY OUTLINE .................................................................................................................... 2 
FLOW CHART OF ASSESSMENTS .................................................................................... 14 
PROTOCOL SIGNATURES .................................................................................................. 16 
TABLE OF CONTENTS ........................................................................................................ 17 
IN-TEXT TABLES ................................................................................................................. 19 
LIST OF ABBREVIATIONS .................................................................................................. 20
1 
INTRODUCTION ........................................................................................................... 22
1.1 
RATIONALE FOR CONDUCTING THE STUDY............................................................. 23
1.2 
BENEFIT-RISK STATEMENT.................................................................................... 25
2 
STUDY OBJECTIVES................................................................................................... 27
2.1 
PRIMARY OBJECTIVE............................................................................................. 27
2.2 
SECONDARY OBJECTIVES...................................................................................... 27
2.3 
EXPLORATORY OBJECTIVES .................................................................................. 28
3 
INVESTIGATIONAL PLAN ........................................................................................... 29
3.1 
PRIMARY AND SECONDARY ENDPOINTS ................................................................. 29
3.1.1 Primary Endpoint ..................................................................................... 29
3.1.2 Secondary Endpoints .............................................................................. 29
3.1.3 Exploratory Endpoints ............................................................................. 30
3.1.4 Overall Study Design and Plan................................................................ 30
3.2
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S).................... 31
3.2.1 Study Design ........................................................................................... 31
3.2.2 Control Group(s)...................................................................................... 31
3.2.3 Study Parameters.................................................................................... 31
4 
STUDY POPULATION .................................................................................................. 32
4.1
POPULATION BASE................................................................................................ 32
4.1.1
Inclusion Criteria ...................................................................................... 32 
4.1.2
Exclusion Criteria ..................................................................................... 32 
4.2
PRIOR AND CONCOMITANT THERAPY ..................................................................... 33
4.3 
WITHDRAWAL AND REPLACEMENT OF SUBJECTS .................................................... 34 
4.3.1 Premature Subject Withdrawal ................................................................ 34 
4.3.2 Treatment Failures .................................................................................. 35 
4.3.3 Subject Replacement Policy .................................................................... 35 
4.4 
ASSIGNMENT OF SUBJECTS TO TREATMENT GROUPS ............................................. 35 
4.5 
RELEVANT PROTOCOL DEVIATIONS ....................................................................... 36 
4.6 
SUBSEQUENT THERAPY ........................................................................................ 36 
5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................... 37 
5.1 
CHARACTERIZATION OF INVESTIGATIONAL PRODUCT(S) ......................................... 37 
5.2 
PACKAGING AND LABELLING .................................................................................. 37 
5.2.1 For the US sites ....................................................................................... 37 
5.2.2 For the Russia and Ukraine Sites ............................................................ 39 
5.3 
CONDITIONS FOR STORAGE AND USE .................................................................... 41 

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5.4 
DOSE AND DOSING SCHEDULE .............................................................................. 41 
5.5 
PREPARATION AND METHOD OF ADMINISTRATION .................................................. 43 
5.6 
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND ................. 43 
5.7 
TREATMENT COMPLIANCE ..................................................................................... 44 
5.7.1 Drug Dispensing and Accountability ........................................................ 44 
5.7.2 Assessment of Treatment Compliance .................................................... 44 
6 
STUDY CONDUCT ........................................................................................................ 45 
6.1 
OBSERVATIONS BY VISIT ....................................................................................... 45 
6.1.1 Screening Visit ......................................................................................... 45 
6.1.2 Baseline/Infusion, Visits 1 to 4 (Day 1 to Day 4) ..................................... 46 
6.1.3 Endpoint Visit 5 (Day 7) ........................................................................... 47 
6.1.4 Follow-up Visits 6 and 7 (Day 14 and Day 21) ........................................ 48 
6.1.5 End of Study (Final Examination) Visit (Day 33)...................................... 48 
6.1.6 Telephone Visits ...................................................................................... 49 
6.1.7 Subject Early Discontinuation .................................................................. 49 
6.1.8 Time Windows Used in this Study, Including Tolerances ........................ 50 
6.2 
DURATION OF STUDY ............................................................................................ 50 
6.2.1 Planned Duration for an Individual Subject ............................................. 50 
6.2.2 Planned Duration for the Study as a Whole ............................................ 50 
6.2.3 Premature Termination of the Study ........................................................ 50 
7 
ASSESSMENTS AND METHODS ................................................................................ 52 
7.1 
DEMOGRAPHIC AND BASELINE INFORMATION ......................................................... 52 
7.1.1 Demographic and Baseline Characteristics ............................................. 52 
7.1.2 Medical History ........................................................................................ 52 
7.1.3 Prior and Concomitant Medication Use ................................................... 52 
7.1.4 Diagnosis Confirmation ........................................................................... 52 
7.2 
EFFICACY ASSESSMENTS ...................................................................................... 52 
7.2.1 Clinical Status .......................................................................................... 52 
7.2.2 Oxygenation/Ventilator Status ................................................................. 53 
7.2.3 Viral Clearance ........................................................................................ 53 
7.2.4 SpO2 Saturation and A-a Gradient .......................................................... 53 
7.2.5 Modified Borg Dyspnea Scale ................................................................. 54 
7.2.6 McGill Quality of Life ................................................................................ 54 
7.3 
SAFETY ASSESSMENTS ......................................................................................... 55 
7.3.1 Assessments for Safety Endpoints .......................................................... 55 
7.3.2 Adverse Events (AEs) ............................................................................. 55 
7.3.3 Serious Adverse Events (SAEs) .............................................................. 58 
7.3.4 Laboratory Safety Evaluations ................................................................. 60 
7.3.5 Vital Signs and Physical Examination ..................................................... 62 
7.3.6 Chest CT/Chest X-ray ............................................................................. 62 
7.3.7 Other Relevant Safety Information .......................................................... 62 
7.4 
APPROPRIATENESS OF MEASUREMENTS ................................................................ 63 
8 
DATA HANDLING AND RECORD KEEPING .............................................................. 65 
8.1 
DOCUMENTATION OF DATA .................................................................................... 65 
8.1.1 Source Data and Records ....................................................................... 65 
8.1.2 Electronic Case Report Forms ................................................................ 65 
8.1.3 Changes to Electronic Case Report Form Data ...................................... 66 

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8.2 
INFORMATION TO INVESTIGATORS .......................................................................... 66 
8.3 
RESPONSIBILITIES ................................................................................................. 66 
8.4 
INVESTIGATOR’S SITE FILE .................................................................................... 67 
8.5 
PROVISION OF ADDITIONAL INFORMATION .............................................................. 67 
8.6 
INDEPENDENT DATA MONITORING COMMITTEE ...................................................... 67 
9 
STATISTICAL METHODS AND SAMPLE SIZE ........................................................... 68 
9.1 
DETERMINATION OF SAMPLE SIZE.......................................................................... 68 
9.2 
STATISTICAL ANALYSIS.......................................................................................... 68 
9.2.1 Timing of Analyses .................................................................................. 68 
9.2.2 Analysis Populations ............................................................................... 69 
9.2.3 Efficacy Analysis Plan ............................................................................. 69 
9.2.4 Safety Analysis Plan ................................................................................ 72 
9.2.5 Handling of Missing Data ......................................................................... 72 
9.3 
RANDOMIZATION, STRATIFICATION, AND CODE RELEASE ........................................ 73 
10 
ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ..................... 74 
10.1 ETHICAL/REGULATORY FRAMEWORK ..................................................................... 74 
10.2 APPROVAL OF STUDY DOCUMENTS ........................................................................ 74 
10.3 SUBJECT INFORMATION AND INFORMED CONSENT ................................................. 74 
10.4 PROTOCOL AMENDMENTS ..................................................................................... 75 
10.5 CONFIDENTIALITY OF SUBJECT DATA ..................................................................... 75 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................... 76 
11.1 PERIODIC MONITORING ......................................................................................... 76 
11.2 AUDIT AND INSPECTION ......................................................................................... 76 
12 
REPORTING AND PUBLICATION ............................................................................... 77 
12.1 CLINICAL STUDY REPORT ...................................................................................... 77 
12.2 PUBLICATION POLICY ............................................................................................ 77 
13 
LIABILITIES AND INSURANCE ................................................................................... 78 
14 
REFERENCES .............................................................................................................. 79 
 
 
In-Text Tables 
Table 1: 
Flow Chart of Assessments Performed Throughout the Study ........................... 14 
Table 2: 
Time Windows Used in this Study ....................................................................... 50 
Table 3: 
Modified Borg Dyspnea Scale ............................................................................. 54 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation Description 
ABG 
Arterial blood gas 
aCL 
Anticardiolipin Antibody 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
ANOVA 
Analysis of Variance 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIDP 
Chronic inflammatory demyelinating polyneuropathy 
CMH 
Cochran-Mantel-Haenszel 
CMP 
Comprehensive Metabolic Panel 
CoV 
Coronaviruses 
COVID-19 
Coronavirus disease-2019 
CRO 
Contract Research Organisation 
CRP 
C‐reactive protein 
CT 
Computerized Tomography 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
EP 
Enrolled Population 
ESR 
Erythrocyte Sedimentation Rate 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
Database 
FDA 
Food and Drug Administration 
FiO2 
Fractional Inspired Oxygen 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HFNC 
High-Flow Nasal Cannula 
HIT 
Heparin Induced Thrombocytopenia 
HIV 
Human Immunodeficiency Virus 
hsCRP 
high‐sensitivity C‐reactive protein 
IB 
Investigators’ Brochure 
ICH 
International Council for Harmonisation 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobin 
IL 
Interleukin 

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IMP 
Investigational Medicinal Product 
IMV 
Invasive Mechanical Ventilation 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITP 
Immune Thrombocytopenia 
ITT 
Intent-To-Treat 
IV 
Intravenous 
IVIG 
Intravenous Immunoglobulin 
KDIGO 
Kidney Disease Improving Global Outcomes 
LAR 
Legally Authorized Representative 
LDH 
Lactic acid dehydrogenase 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East Respiratory Syndrome 
MIS 
Multisystem Inflammatory Syndrome 
MMN 
Multifocal Motor Neuropathy 
MQoL-SIS 
McGill Quality of Life Single-Item Scale 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NIH 
National Institutes of Health 
NIV 
Non-Invasive Mechanical Ventilation 
PaO2 
Arterial Oxygen Partial Pressure 
PP 
Per Protocol 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
RNA 
Ribonucleic acid 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
Coronavirus 2 
SDV 
Source Data Verification 
SID 
Secondary immune deficiency 
SmPC 
Summary of Product Characteristics 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure 
TACO 
Transfusion-associated circulatory overload 
TEE 
Thromboembolic Event 
TRALI 
Transfusion-related acute lung injury 
 

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Page 22 of 81 
1 
INTRODUCTION 
Coronaviruses (CoV) are enveloped ribonucleic acid (RNA) viruses capable of causing 
acute respiratory distress in humans (1). Previous outbreaks have caused Middle East 
Respiratory Syndrome (MERS/MERS-CoV) and Severe Acute Respiratory Syndrome 
(SARS/CoV). In December of 2019, a highly infectious coronavirus designated 
2019-nCoV causing the severe acute respiratory syndrome from Coronavirus 2 (SARS-
CoV-2) was found to be present in a cluster of patients linked via a seafood and wet 
animal wholesale market in Wuhan, China (2). 
Following the initial outbreak in Wuhan, the spread of Coronavirus disease-2019 
(COVID-19) via human to human transmission forced the World Health Organization 
to declare a global pandemic on March 11, 2020 (3). 
In an early description of 41 patients admitted to a hospital in Wuhan and found to be 
COVID-19 positive, the clinical manifestations showed men were affected three times 
as often as women. Furthermore, diabetes (20%), hypertension (15%) and other 
cardiovascular disease (15%) were found to be the most commonly associated 
diseases (4). Common initial symptoms were fever (98%), dry cough (76%), shortness 
of breath (55%), and myalgia or fatigue (44%) (4). Median time from symptom onset to 
dyspnea is 8 days. All patients had lymphopenia and abnormal chest computerized 
tomography (CT) findings. Adult Respiratory Distress Syndrome occurred in 29%; 
15% of all patients died (4). 
Risk of death is highest in patients with advanced age, with approximately 80% of 
deaths occurring among adults older than 60 years of age (5). The main cause of death 
is massive alveolar damage and progressive 
respiratory failure caused by 
inflammatory infiltration of the pulmonary interstitials resulting in pulmonary fibrosis (6). 
The proximate cause of death implicates an abnormal pulmonary immune response 
associated with multiple respiratory viral infections in which there is an elevation of 
cytokine and chemokine production often associated with poor clinical outcomes, 
referred to as a “cytokine storm” (7, 8). In patients with severe COVID-19, there is 
increased interleukin (IL-2, IL-7), granulocyte colony stimulating factor, interferon 
gamma, inducible protein 10, monocytes chemoattractant protein 1, macrophage 
inflammatory protein 1-alpha, and tumor necrosis factor-alpha. Elevated IL-6, C-reactive 
protein (CRP) and myoglobin are significantly associated with patients who 
die 
compared to those who are ultimately discharged (7). 
There is no known effective treatment for patients infected with COVID-19. Many 
therapies 
have 
been 
proposed 
based 
on 
anecdotal 
reports 
including 
hydroxychloroquine and azithromycin (9), corticosteroids (10), broad spectrum antiviral 
agents (11), convalescent plasma (12), and intravenous immunoglobulin (IVIG) (6). 
IVIG, which consists of pooled IgG preparations from thousands of donors and has 

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Study Protocol No. GAM10-10, Version 08 CONFIDENTIAL 
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Page 23 of 81 
been used to treat patients with immune mediated diseases for almost 40 years (13), 
is an attractive possible treatment. The adverse effect profile is well understood, as is 
its most efficacious dose (2 g/kg over 4-5 days) and expected time efficacy (2 to 10 
days; personal communication; after 2-3 doses) (14). The mechanism by which IVIG 
modulates the immune system is uncertain, but among possibilities includes blocking 
and modulation of Fc expression and signaling, increased autoantibody clearance by 
FcRn saturation, suppression of immunoglobulin production, modulation of antigen 
presenting cell activation, blockade of complement proteins, induction of regulatory 
T cells, and inhibition of differentiation and maturation of dendritic cells (14). Recent 
studies in patients with idiopathic thrombocytopenia purpura and Guillain-Barre 
syndrome show that IVIG significantly modulates inflammatory cytokines (15, 16). 
Side effects of IVIG include increased blood viscosity, thromboembolic phenomena, 
acute renal failure, increased blood pressure, and anaphylaxis (14, 17, 18). 
The published cases of IVIG showing an effect in patients with COVID-19 infection 
showed an almost immediate impact on disease progression after receiving a standard 
loading dose of IVIG (2 g/kg over 5 days), enabling discharge within 10 days of IVIG 
initiation (6). None were intubated, but all were treated while being observed to have 
increasing dyspnea and decreasing oxygen saturation levels. All had markedly 
elevated high sensitivity CRP (hsCRP) and abnormal CT scan (6). 
1.1 Rationale for Conducting the Study 
In early 2020, several case studies were published which showed the successful use 
of IVIG in treating COVID-19 patients (6, 19, 20, 21, 22). A retrospective, multicenter 
cohort study that included 325 adult critical patients from 8 centers, demonstrated that 
early high-dose IVIG administration (<7 days following admission) improves the 
prognosis of critical COVID-19 patients (19). In addition, a retrospective chart review 
of 58 patients with severe COVID-19 pneumonia compared outcomes in those 
receiving high-dose IVIG treatment ≤48 hours versus >48 hours after admission to the 
intensive care unit (ICU). Results demonstrated that high-dose IVIG received 
≤48 hours after admission to the ICU resulted in reductions in the use of mechanical 
ventilation, hospital/ICU stay, and 28-day mortality in patients with severe COVID-19 
pneumonia (20). An observational study was conducted in 10 COVID-19 patients, and 
results demonstrated that short-term moderate-dose corticosteroid combined with 
high-dose IVIG effectively reversed severe, deteriorating COVID-19 patients who failed 
initial low-dose therapy (21). It’s notable that researchers were motivated to employ 
this therapeutic regimen as it was preliminarily shown to reduce the risk of death in 
12 patients with SARS. The authors postulate that corticosteroid use at an early 
deterioration stage has a timely effect on the suppression of the inflammatory 
response. More importantly, the combination use of IVIG is believed to strengthen 

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Page 24 of 81 
immune function to prevent a potential delay in viral clearance caused by the 
corticosteroid.  
Another study conducted in three deteriorating patients with severe COVID-19 who 
received high-dose IVIG (0.3 to 0.5 g/kg/day for 5 days) demonstrated that all 
experienced a successful recovery with significant improvement in symptoms within 
24 to 48 hours. They also observed that “the first few days of deterioration may present 
a critical point when potent suppression of the inflammatory cascade could save 
patients from fatal immune-mediated injuries.” (6). 
More recently, Sakoulas et al. have performed a prospective randomized controlled 
pilot study in 34 COVID-19 patients (22). Sixteen patients received IVIG (0.5 g/kg/day 
for 4 days) plus standard of care (SOC) versus 17 patients SOC alone. Among subjects 
with A-a gradient of >200 mm Hg at enrollment, the IVIG group showed i) a lower rate 
of progression to requiring mechanical ventilation (2/14 vs 7/12, p=0.038 Fisher exact 
test), ii) shorter median hospital length of stay (11 vs 19 days, p=0.01 Mann Whitney 
U), iii) shorter median ICU stay (2.5 vs 12.5 days, p=0.006 Mann Whitey U), and 
iv) greater improvement in PaO2/FiO2 at 7 days (median [range] change from time of 
enrollment +131 [+35 to +330] vs +44·5 [-115 to +157], p=0.01, Mann Whitney-U) than 
SOC. No safety signals including thrombo-embolic events were detected. 
The benefits of IVIG in COVID-19 was further demonstrated in pediatric patients who 
developed Kawasaki-like disease, also called MIS (Multisystem Inflammatory 
Syndrome) (23, 24, 25, 26) In Feldstein et al., which documents the largest cohort of 
patient, 186 patients with MIS were treated in 26 states in the United States and 77% 
were treated successfully with IVIG (23). 
There are documented case studies of IVIG being used in patient care for various viral 
infections affecting the upper respiratory system (27). In both the United States and 
Saudi Arabia, varying levels of IVIG were used in the treatment of patients who had 
been diagnosed with MERS (28). Additionally, various forms of IVIG have been related 
to symptom improvement in patients diagnosed with SARS (29). Namely, delayed 
administration of 
pentaglobin, an IgM-enriched IVIG serum, led to improved 
radiological appearance and overall improved symptoms in 12 severe SARS patients 
(30). 
Furthermore, IVIG has been seen to have therapeutic effects in a variety of patients 
with influenza. A 2016 study carried out on immunocompromised children diagnosed 
with 2009 Influenza (H1N1) concluded that high-dose IVIG could be useful as an 
ancillary therapy for the influenza virus (31). Likewise, IVIG given at 0.4g/kg over a 
period of 4 hours, was shown to contribute to decreasing viral loads in adult patients 
diagnosed with the H1N1 virus (32). In non-human populations, a 2017 study carried 
out in ferrets demonstrated that IVIG administered at exposure to the influenza virus 

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Page 25 of 81 
(H1N1/H5N1) led to a significant reduction in lung viral load. The study went on to 
conclude that IVIG administered before the onset of a pandemic had the potential to 
modulate serious influenza infection-associated mortality and morbidity, and that it 
could be used as a prophylactic to protect vulnerable populations in the event of a 
pandemic (33). 
IVIG was first introduced in the US for the treatment of primary immune deficiency in 
the early eighties, it has increasingly been recognized not only for its ability to fight 
infections but also for its anti-inflammatory and immunomodulatory effects. Other US 
Food and Drug Administration (FDA) approved indications for IVIG include SID 
(secondary immune deficiency) CIDP (Chronic inflammatory demyelinating 
polyneuropathy), MMN (Multifocal Motor Neuropathy), Kawasaki disease and ITP 
(Immune Thrombocytopenia). IVIG has been studied for decades in numerous 
different diseases and has a good safety profile. 
The mechanism of action of IVIG is not completely understood, but it may modulate 
the immune response via multiple mechanisms, including blocking a wide array of 
proinflammatory cytokines that potentially lead to severe inflammatory responses, 
including cytokine storm, as well as Fc-gamma receptor binding of activated 
macrophages and other antigen presenting cells. 
Recently convalescent plasma was approved for Emergency Use Authorization in 
COVID-19 patients, although the National Institutes of Health (NIH) has stated that 
convalescent plasma should not be considered as SOC. There are no randomized 
prospective trials for convalescent plasma available and no control group was 
included in these studies. There are potential safety issues of convalescent plasma 
such as transmission of viruses, TACO and TRALI unlike IVIG which has been 
pathogen inactivated. One other difference between IVIG and convalescent plasma is 
the much higher Ig levels in IVIG as compared to convalescent plasma (~40 fold 
higher) which could result in greater benefits. In conclusion, the preliminary positive 
IVIG data warrants a larger prospective double-blind, placebo controlled to show 
efficacy and safety of Octagam 10% therapy in COVID-19 patients with severe 
disease progression. 
The study will be conducted in compliance with the protocol, International Conference 
on Harmonisation-Good Clinical Practice (ICH-GCP), US FDA Code of Federal 
Regulations (CFR), and other local regulatory requirements. 
1.2 Benefit-Risk Statement 
The risks of IVIG administration are well documented. In general, the incidence of 
adverse events (AEs) associated with IVIG tends to increase with the rate of infusion, 
and thus the recommended dosage, infusion rates, and monitoring procedures should 

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Page 26 of 81 
be adhered to. Patients that are naïve to IVIG are more at risk than those that are well-
maintained and on regular therapy. 
Patients with pre-existing risk factors for thrombotic events (such as advanced age, 
obesity, hypertension, diabetes mellitus and a history of vascular disease or thrombotic 
episodes, patients with acquired or inherited thrombophilic disorders, patients with 
prolonged periods of immobilization, severely hypovolemic patients, and patients with 
diseases which increase blood viscosity) may be at increased risk of developing 
thromboembolic events (TEEs) (34). Overdose is possible in overweight and elderly 
patients and in those who have impaired renal function. In patients with signs of 
cerebral or cardiac ischemia, the increase in viscosity caused by an immunoglobulin 
infusion may be a risk (34).  
The safety profile of Octagam 10% based on clinical studies and long-term post-
marketing experience is well-documented and detailed in the European Summary of 
Product Characteristics (SmPC) (35). Adverse drug reactions (ADRs) such as chills, 
headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood 
pressure, and moderate low back pain occur occasionally. These adverse effects are 
mostly transient and mild. However, some very rare adverse effects, including renal 
impairment, thrombosis, arrhythmia, aseptic meningitis, hemolytic anemia, and 
transfusion-related acute lung injury, are serious (36). AEs are rarely disabling or fatal, 
treatment involves supportive measures, and the majority of affected patients have a 
good prognosis. Reactions to IVIGs tend to be related to the dose and the rate of 
infusion. Rarely, human normal immunoglobulins may cause a sudden fall in blood 
pressure and, in isolated cases, anaphylactic shock, even when the patient has shown 
no hypersensitivity to previous administration. Cases of reversible aseptic meningitis 
and rare cases of transient cutaneous reactions have been observed with human 
normal immunoglobulin. Reversible hemolytic reactions have been observed in 
patients, especially those with blood groups A, B, and AB. 
For Octagam 10%, the same type of adverse reactions has been seen as for other 
IVIG products. No new or unknown safety problems are expected to emerge which are 
not already described in the SmPC. In the very limited number of COVID-19 cases 
treated with IVIG, no new or unknown safety concerns were reported (6). 
Based on the severe conditions of COVID-19 patients, we postulate that Octagam 10% 
treatment in COVID-19 patients outweighs potential disadvantages of IVIG. 
This trial will be conducted in accordance with local and national COVID-19 safety 
guidelines. This trial was designed with flexibility for remote telemedicine visits where 
possible to minimize the risk of exposure of patients and healthcare professionals to 
COVID-19. 

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Page 27 of 81 
2 
STUDY OBJECTIVES 
2.1 Primary Objective 
 To determine if high-dose Octagam 10% therapy will stabilize or improve clinical 
status in subjects with severe COVID-19 during the first seven days following 
treatment commencement. 
2.2 Secondary Objectives 
Key Secondary Efficacy Objectives 
 To compare the length of hospital stay in subjects treated with Octagam 10% 
compared to those that received placebo through Day 33. 
 To determine if high-dose Octagam 10% therapy will stabilize or improve clinical 
status in subjects with severe COVID-19 during the 14 days following treatment 
commencement. 
 To compare the cumulative duration of invasive mechanical ventilation (IMV) in 
subjects treated with Octagam 10% compared to those that received placebo 
through Day 33. 
 To compare the cumulative incidence of severe progression in subjects treated 
with Octagam 10% compared to those that received placebo at Day 33. 
 To compare the length of time in ICU in subjects treated with Octagam 10% 
compared to those that received placebo at Day 33. 
 To compare cumulative mortality in subjects treated with Octagam 10% compared 
to those that received placebo at Day 33. 
 
Other Secondary Efficacy Objectives 
 To determine if high-dose Octagam 10% affects severe acute respiratory 
syndrome from Coronavirus 2 (SARS-CoV-2) infection status at Day 7. 
 To compare the cumulative incidence of new ICU admittance in subjects treated 
with Octagam 10% compared to those that received placebo at Day 33. 
 To determine if high-dose Octagam 10% therapy will improve clinical status in 
subjects with severe COVID-19 during the 14 days following treatment 
commencement. 
 To compare the cumulative incidence of IMV in subjects treated with Octagam 
10% compared to those that received placebo through Day 33. 
 To compare the time to recovery in subjects treated with Octagam 10% compared 
to those that received placebo through Day 33. 

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 To compare the time to first improvement in clinical status in subjects treated with 
Octagam 10% compared to those that received placebo through Day 33. 
 
Secondary Safety Objective 
 To describe the safety of Octagam 10% compared to placebo when administered 
to subjects with severe COVID-19. 
2.3 Exploratory Objectives 
 To compare changes in SpO2 on room air from Baseline (Day 1) to all available 
on-study time points up to Day 33 in subjects treated with Octagam 10% 
compared to those that received placebo. 
 To compare changes in the Modified Borg Dyspnea Scale from Baseline (Day 1) 
to Days 7, 14, 21, and 33 in subjects treated with Octagam 10% compared to 
those that received placebo. 
 To compare changes in Quality of Life (McGill Quality of Life Single-Item Scale, 
MQoL-SIS) score from Baseline (Day 1) to Days 7, 14, 21, and 33 in subjects 
treated with Octagam 10% compared to those that received placebo. 

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3 
INVESTIGATIONAL PLAN 
This is a Phase 3 randomized, double-blind, placebo-controlled, study of 
Octagam 10% in COVID-19 subjects. 
3.1 Primary and Secondary Endpoints 
3.1.1 Primary Endpoint 
 Proportion of subjects with stabilized or improved clinical status at Day 7 of at least 
one category on a 6-point clinical status scale. 
Clinical status categories will be defined as: 
1. Hospital discharge or meet discharge criteria (discharge criteria are defined as 
clinical recovery, ie, no fever, respiratory rate, oxygen saturation return to 
normal, and cough relief). 
2. Hospitalization, not requiring supplemental oxygen. 
3. Hospitalization, requiring supplemental oxygen (but not non-invasive 
mechanical ventilation (NIV)/high-flow nasal cannula [HFNC]) as defined by 
A-a Gradient <150 mmHg. 
4. ICU/hospitalization, requiring NIV/HFNC therapy, as defined by A-a Gradient 
≥150 mmHg. 
5. ICU, requiring extracorporeal membrane oxygenation (ECMO) and/or IMV. 
6. Death. 
A subject meets the success criteria of stabilization or improvement if the clinical status 
category on Day 7 is not worse than the clinical status category at Baseline (Day 1 
prior to IMP infusion). 
3.1.2 Secondary Endpoints 
3.1.2.1 Key Secondary Efficacy Endpoints 
The following key secondary endpoints will be included in formal hypothesis testing 
procedures as described in the statistical section of this protocol. 
 Length of hospital stay (time to discharge) from randomization through Day 33 
 Proportion of subjects with stabilized or improved clinical status of at least one 
category on the 6-point clinical status scale on Day 14 

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 Cumulative duration of IMV from randomization through Day 33 
 Proportion of subjects with severe progression defined as requiring ECMO, 
IMV and/or have died through Day 33 
 Length of time in ICU from randomization through Day 33 
 Mortality rate through Day 33 
3.1.2.2 Other Secondary Efficacy Endpoints 
 Results of reverse transcription polymerase chain reaction (RT-PCR) for 
SARS-CoV-2 from nares/throat swab and/or sputum and/or lower respiratory tract 
sample on Day 7. 
 Proportion of subjects admitted to the ICU from randomization through Day 33 
 Proportion of subjects with improvement on Days 7, 14, 21, and 33 
 Proportion of subjects requiring IMV by Day 33  
 Time to recovery through Day 33 where recovery is defined as a clinical status of 
1 or 2 
 Time to first improvement in clinical status through Day 33 
3.1.2.3 Safety Endpoints 
 Incidence of all AEs 
 Incidence of AEs considered related to the investigational medicinal product (IMP) 
 Incidence of serious adverse events (SAEs) 
 Clinical laboratory parameters 
 Vital sign parameters 
 Radiological findings (chest CT/chest X-ray) 
3.1.3 Exploratory Endpoints 
 Improvement of SpO2 on room air from Baseline (Day 1) to Day 33 using trend from 
all available observed data. 
 Modified Borg Dyspnea Scale score at Baseline (Day 1) and on Days 7, 14, 21, and 
33. 
 MQoL-SIS score at Baseline (Day 1) and on Days 7, 14, 21, and 33. 
3.1.4 Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled, multicenter, two-arm adaptive 
Phase 3 study designed to evaluate if high-dose Octagam 10% therapy can stabilize 
or improve clinical status in subjects with severe COVID-19. 
Following Screening procedures, subjects that meet eligibility criteria will be 
randomized to receive either Octagam 10% in a dose of 2 g/kg over 4 days 
(0.5 g/kg/day), or an equivalent volume of placebo (saline). The infusion will be 

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administered over a period of 2 hours per day over a total of 4 consecutive days. The 
first dosing will take place within 24 hours of the Screening Visit. 
Approximately 208 male or female adult subjects will be recruited so that approximately 
104 subjects in each treatment arm will complete the study. Each subject’s 
participation will last a total of approximately 33 days, including 29 days for safety 
follow-up, followed by a one-year registry follow-up. 
This study is planned to start in Q2 2020 and to be completed by Q4 2020, resulting in 
a maximal overall duration of 7 months. The planned follow-up registry will begin in Q3 
2020 and to be completed in Q4 2021. 
3.2 Discussion of Study Design and Choice of Control Group(s) 
3.2.1 Study Design 
Given that this is an efficacy and safety study with the objective of determining if high-
dose Octagam 10% therapy will stabilize or improve clinical status in subjects with 
severe COVID-19, a randomized, double-blind, placebo-controlled, multicenter study 
design is considered standard for this type of research (ie, the evaluation of the safety 
and efficacy of active versus placebo). 
3.2.2 Control Group(s) 
A placebo control has been chosen given the objectives of the study to determine the 
effects of active treatment with Octagam 10%. Choosing placebo as a control has a 
long history of being the standard for clinical investigations of new therapies for a given 
indication. 
3.2.3 Study Parameters 
Efficacy assessments include clinical status, ventilator status/means to maintain 
oxygen status, SARS-CoV-2 RT-PCR results, oxygen saturation, modified Borg 
Dyspnea Scale and MQoL-SIS. Safety assessments include AEs and SAEs, vital signs 
including SpO2, clinical laboratory evaluations and CT/chest X-ray findings. The 
efficacy and safety assessments used in this study are consistent with those widely 
used, generally recognized as reliable, accurate, and relevant in this type of research, 
and are adequate to form the primary basis for the determination of safety and efficacy. 

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4 
STUDY POPULATION 
4.1 Population Base 
Approximately 208 male or female adult subjects with laboratory-confirmed COVID-19 
will be eligible for inclusion in this clinical study. 
4.1.1 Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for the study: 
1. Adult aged ≥ 18 years old. 
2. Provide voluntary, fully informed written and signed consent before any study-
related procedures are conducted. 
3. Able to understand and comply with the relevant aspects of the study protocol. 
4. Laboratory (RT-PCR) confirmed COVID-19 infection on nares/throat swab 
and/or sputum and/or lower respiratory tract samples at Screening or within 
7 days prior to Screening. 
5. Hospitalized requiring supplemental oxygen with a resting room-air SpO2 of 
≤ 93% or arterial oxygen partial pressure (PaO2)/fractional inspired oxygen 
(FiO2) ratio < 300 mmHg. Measurement can be taken from documented source 
records in the 24 hours prior to Screening. 
6. Chest imaging confirming lung involvement. 
4.1.2 Exclusion Criteria 
Subjects who meet any of the following criteria are not eligible for the study: 
1. Existence of other evidence that can explain pneumonia including but not limited 
to: Influenza A virus, influenza B virus, bacterial pneumonia (as suggested by 
the combined clinical picture, radiological findings and known laboratory results 
[eg, elevated procalcitonin >0.5ng/mL and concomitant neutrophilia]), known 
fungal pneumonia, suspected fungal pneumonia based on compromised 
immune system with a history of past fungal infections, noninfectious causes, 
etc. 
2. Known history of serious allergic reactions, including anaphylaxis, to IVIG or its 
preparation components. 
3. Subjects with a history of thromboembolic event (TEE) within the last 
12 months, such as deep vein thrombosis, pulmonary embolism, myocardial 
infarction, ischemic stroke, transient ischemic attack, peripheral artery disease 
(Fontaine IV). 

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4. Subjects with an underlying medical condition that can lead to hypercoagulable 
states and hyperviscosity such as antithrombin III deficiency, Factor V Leiden, 
Protein C deficiency, antiphospholipid syndrome, and malignancy. 
5. Known history of selective IgA deficiency with antibodies against IgA. 
6. Subjects with conditions such as human immunodeficiency virus (HIV) infection, 
known acute or chronic hepatitis B or C (HBsAg positive or HCV RNA PCR 
positive or currently treated with antivirals), pulmonary fibrosis, heparin induced 
thrombocytopenia (HIT), and moderate to severe renal dysfunction (per 
investigator discretion based on estimated glomerular filtration rate [eGFR] 
<59 mL/min/1.73 m2, as defined by KDIGO Clinical Practice Guideline): 
 Moderately reduced GFR (G3a): GFR = 45 to 59 ml/min/1.73 m2 
 Moderately reduced GFR (G3b): GFR = 30 to 44 ml/min/1.73 m2 
 Severely reduced GFR (G4): GFR = 15 to 29 ml/min/1.73 m2 
 Kidney failure (G5): GFR <15 ml/min/1.73 m2. 
7. Currently requiring invasive mechanical ventilation or having received invasive 
mechanical ventilation in the last 30 days. 
8. Known clinically significant preexisting lung, heart, neuromuscular or other 
disease that, in the investigator’s opinion, would impact the subject’s ability to 
complete study or may confound the study results. 
9. Body weight > 125kg. 
10. Women who are pregnant or breast-feeding. 
11. Subjects who received COVID-19 convalescent plasma, IVIG products, anti-
interleukin agents (eg, Tocilizumab), or interferons for their COVID-19 disease 
before enrolment or plan to receive this treatment during the course of the study. 
12. Enrolled in other experimental interventional studies or taking experimental 
medications (ie, convalescent plasma). Diagnostic studies can be allowed if the 
anticipated total blood volume to be drawn across both studies and for 
therapeutic purposes does not exceed 450 mL over any 8-week period. 
4.2 Prior and Concomitant Therapy 
Concomitant medication includes all pharmaceutical agents, vitamins, nutritional 
supplements, and herbal medicines used by the subject with the exception of 
Octagam 10% or placebo. Details on medications taken within 1 week prior to 
Screening and any concomitant medications taken during the study must be recorded 
in the electronic Case Report Form (eCRF). This includes off-label use of any drugs, 
devices, or interventions that have been used to manage COVID-19. Use of antivirals 

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(eg, remdesivir), corticosteroids, chloroquine or hydroxychloroquine, antibiotics, 
anticoagulants, or antiplatelet agents is allowed and must be documented in eCRF. 
The use of medications being administered as part of other experimental studies or the 
use of experimental non-IVIG products, COVID-19 convalescent plasma, or interferons 
are forbidden. Should a circumstance arise where it is considered to be in the best 
interests of a subject to administer such a product, the subject should not receive 
further study infusions (Octagam 10% or placebo) if these are still ongoing. The other 
medications administered should be documented as concomitant medications, and the 
subject should continue to be followed up per protocol. 
4.3 Withdrawal and Replacement of Subjects 
4.3.1 Premature Subject Withdrawal 
Subjects have the right to withdraw from the study at any time for any reason, without 
the need to justify their decision. The Investigator also has the right to withdraw 
subjects in case of AEs, poor compliance, or other reasons. Since an excessive rate 
of withdrawals can render the study non-interpretable, any unnecessary withdrawal of 
subjects should be avoided. 
In addition to the ongoing safety monitoring and periodic Independent Data Monitoring 
Committee (IDMC) data review, the following rule will be implemented to apply 
temporary suspension of study drug administration, pending a safety investigation, for 
an unacceptable increased venous TEE or acute renal failure risk in the Octagam 10% 
group compared to the placebo group:  
 For both venous TEEs or acute renal failures, the event risk will be calculated 
separately as (number of events reported)/(number of daily infusions) in both 
treatment groups, and the 90% confidence interval (CI) for the resulting risk ratio 
(ROctagam/RPlacebo) will be determined by means of the / relrisk option of the 
SAS procedure FREQ. In case no events are observed in the placebo group, 
1 will be added to each cell in the 2X2 table to enable this risk ratio evaluation. 
The stopping rule will be triggered if the lower confidence limit is greater than 
1.0. 
 This stopping rule will be applied whenever an unblinded evaluation is done, 
and a total of 40 daily infusions or more have been administered. 
 For the first 40 daily infusions (ie, first 10 subjects that complete infusion cycle 
per protocol) a fixed rule will be applied by the IDMC to temporarily suspend 
study drug administration in case the number of related serious TEEs or acute 
renal failures as assessed by IDMC in the Octagam 10% group is triple the 
number in the placebo group. If no TEE or acute renal failure is observed in the 

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placebo group during this initial study phase, temporary suspension of study 
drug administration and safety investigation will be initiated if three related 
serious TEEs as assessed by IDMC or acute renal failures have been reported 
in the Octagam 10% group.  
For any withdrawals after study entry, the Investigator will obtain all the required details 
and document the reason(s) for discontinuation. If the reason for withdrawal of a 
subject is an AE, the main specific event or laboratory test will be recorded, and the 
Investigator will make thorough efforts to clearly document the outcome. 
Other reasons for premature termination of subjects may be: 
 Withdrawal of subject’s consent. 
 Pregnant and lactating subjects will be immediately excluded from the study. 
 Investigator’s opinion that the subject may be severely harmed if he/she 
continues study participation, namely by the treatment and procedures 
requested by the study protocol. 
 Occurrence of a condition or disease that interferes with the study treatment or 
represents an exclusion criterion. 
 Administration of IVIG other than Octagam 10%.  
 Subjects do not comply with the study protocol. 
4.3.2 Treatment Failures 
Treatment failures will be offered SOC therapy. 
4.3.3 Subject Replacement Policy 
Subjects withdrawn from the study for any reasons will not be replaced. 
4.4 Assignment of Subjects to Treatment Groups 
The Investigator will enter a unique identifier of each subject in both the eCRF and the 
confidential subject identification list. The randomization numbers will be allocated 
sequentially in the order in which the subjects are enrolled. The Investigator will inform 
the monitor of new subjects enrolled. 
Subjects who withdraw from the study or complete the study are not permitted to 
re-enroll. 

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4.5 Relevant Protocol Deviations 
In case of any major protocol deviation, the Investigator and Octapharma will decide 
on the further participation of the subject in this study after having discussed all relevant 
aspects. 
A list of all included subjects with all deviations from the intended study procedures 
and other criteria that may affect the validity of subject data for statistical analysis will 
be prepared after the clinical phase of the study is completed. The list will be discussed 
prior to study unblinding by a panel consisting of the clinical study manager, a medical 
expert of the Sponsor, the data manager, and the study statistician. This panel will 
decide upon the inclusion of each subject in the analysis populations. 
4.6 Subsequent Therapy 
If a subject decides to withdraw from the study or is withdrawn by the Investigator, 
she/he will continue to receive SOC therapy. 

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5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
5.1 Characterization of Investigational Product(s) 
Octagam is a 10% IVIG ready for intravenous administration. Octagam 10% is 
produced from a pool of at least 1000 donations of human fresh frozen plasma per 
batch. The large donor pool ensures that the product contains a broad range of 
antibodies directed against pathogens and foreign antigens, which is far more diverse 
than that of plasma from an individual donor. Donor plasma sampling, the 
manufacturing of the product and the measures to ensure the product's viral safety are 
subject to strict regulations laid down by regulatory authorities. Octapharma exclusively 
uses plasma which has been tested by nucleic acid testing techniques. 
During the manufacturing process of Octagam 10%, significant viral reduction is 
obtained via a combination of 3 validated manufacturing steps: cold-ethanol 
fractionation, solvent/detergent treatment with tri-n-butyl phosphate and Octoxynol 
(Triton X100), and pH 4 treatment. The efficacy of the virus inactivation procedures 
has been extensively validated according to relevant international guidelines. The 
composition with the most important ingredients and the biochemical characteristics 
are summarized in the Investigators’ Brochure (IB).  
For placebo, saline for intravenous infusion will be used. 
5.2 Packaging and Labelling 
5.2.1 For the US sites 
Octagam 10% delivered as ready-to-use solution in glass bottles; commercially labeled 
product will be provided to the clinical study sites. Appropriately trained study staff may 
over-label the commercial supplies with an investigational product label, provided by 
the Sponsor, that will meet all FDA requirements under 21 CFR 312.6 and shall include 
the statement: Caution: New Drug—Limited by Federal (or United States) law to 
investigational use, as permitted in accordance with local Standard Operating 
Procedures (SOPs). Investigational product labels will also be provided for placebo 
supplies that will be sourced from the site pharmacy’s commercial supplies. 
After transfer and pooling into Polyvinyl Chloride-free, Diethylhexylphthalate-free and 
latex–free, infusion bags, the medication (Octagam 10% or placebo) will be blinded 
with an over pouch and re-labeled (both the infusion bag [as permitted in accordance 
with local SOPs] and the over pouch). The over-label for the infusion bags and over 
pouches will also include the 21 CFR 312.6 required statement: Caution: New Drug—
Limited by Federal (or United States) law to investigational use. 
Instructions for over-labeling both Octagam 10% and saline with investigational 
product labels will be provided in a study-specific pharmacy manual. 

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US Master Label – Octagam 10%: 
Caution: New Drug-Limited by Federal (or United States) law to investigational use 
 
 Study: GAM10-10 
Octagam 10% 
Unit size: ______ mL 
1 mL contains: 100 mg protein of which 96% is human normal immunoglobulin. 
Infusion solution for intravenous administration. 
To be stored at +2°C (36°F) to +8°C (46°F) and protected from light. Must not be frozen. 
Must be inspected visually for particulate matter and discoloration prior to administration. 
Do not use non-homogenous solutions or those that have a deposit. 
To be warmed up to room or body temperature before use. 
Dosage: refer to Clinical Study Protocol, Section 5.4 
Patient no.: |__|__|__|__|__|  
Visit no.: |____|  
Infusion Day: |____| 
Sponsor: Octapharma USA, INC. 117 West Century Road, Paramus, NJ, 07652 
 
Batch no.: ___________________ 
Expiration date: __________________ 
 
US Master Label – Saline: 
Caution: New Drug-Limited by Federal (or United States) law to investigational use 
 
Study: GAM10-10 
Sodium Chloride 0.9% w/v solution  
Unit size: ______ mL 
Sterile solution for intravenous infusion 
1000 mL of solution contain  
 
Sodium chloride 9.00 g 
 
Electrolyte concentrations mmol per 1000 mL (approx): 
 
Sodium 
154 mmol 
 
Chloride 
154 mmol 
Do not store above +25°C (+77°F) [depending on product purchased] 
Only to be used if solution is clear and container undamaged 
Dosage: refer to Clinical Study Protocol, Section 5.4 
Sponsor: Octapharma USA, INC. 117 West Century Road, Paramus, NJ, 07652 
 
Batch no.: ______________ 
Expiration date: __________________ 
 

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US Master Label – Blinded label for infusion bags and over pouch: 
Caution: New Drug-Limited by Federal (or United States) law to investigational use 
 
 Study: GAM10-10 
Octagam 10% OR Sodium Chloride 0.9% w/v solution 
Unit size: ______ mL 
1 mL contains either 100 mg protein of which 96% is human normal immunoglobulin OR 
sodium chloride 0.9% w/v solution. 
Infusion solution for intravenous administration. 
Patient no.: |__|__|__|__|__| 
Visit no.: |____|  
Infusion Day: |____| 
Investigator: _________________________________________________ 
Date and time of preparation: _________________ 
If not infused immediately, to be stored at +2°C (36°F) to +8°C (46°F) until 
Expiration date and time: __________________ 
Must not be frozen. 
To be warmed up to room or body temperature before use. 
Sponsor: Octapharma USA, INC. 117 West Century Road, Paramus, NJ, 07652 
 
 
5.2.2 For the Russia and Ukraine Sites 
Octagam 10% will be delivered as ready-to-use solution in glass bottles; labeled and 
packed as clinical kits will be provided to the clinical study sites. 
Marketed saline solution for intravenous infusion, that can be used in the respective 
countries, will be purchased by Sponsor or designee and provided to the local 
pharmacies or sites. Saline should be stored and transported at +0°C to 30°C. 
Instructions for over-labeling both Octagam 10% and saline with investigational 
product labels will be provided in a study-specific pharmacy manual. 
After transfer and pooling into Polyvinyl Chloride-free, Diethylhexylphthalate-free and 
latex–free, infusion bags, the medication (Octagam 10% or placebo) will be blinded 
with an overpouch and blinded labels will be applied on the infusion bag and the 
overpouch. 

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EU Master Label – Octagam 10%: 
FOR CLINICAL TRIAL USE ONLY 
Study: GAM10-10 
Octagam 10% 
Unit size: ______ mL 
1 mL contains: 100 mg protein of which  95% is human normal immunoglobulin. 
Infusion solution for intravenous administration. 
To be stored at +2°C to +8°C and protected from light. Must not be frozen. 
Must be inspected visually for particulate matter and discoloration prior to administration. 
Do not use non-homogenous solutions or those that have a deposit. 
To be warmed up to room or body temperature before use. 
Dosage: refer to Clinical Study Protocol, Section 5.4 
Patient No.: __________ 
Visit Day.: ____ 
 
Investigator: _________________________________________________ 
Sponsor: Octapharma USA, INC. 117 West Century Road, Paramus, NJ, 07652 
 
Batch no.: ______________ 
Expiration date: __________________ 
 
EU Master Label – Saline: 
FOR CLINICAL TRIAL USE ONLY 
Study: GAM10-10 
Sodium Chloride 0.9% w/v solution 
Unit size: ______ mL 
Sterile solution for intravenous infusion 
1000 mL of solution contain  
 
Sodium chloride 9.00 g 
 
Electrolyte concentrations mmol per 1000 mL (approx): 
 
Sodium 
154 mmol 
 
Chloride 
154 mmol 
To store this product below 30°C. Do not freeze.  
Only to be used if solution is clear and container undamaged 
Dosage: refer to Clinical Study Protocol, Section 5.4 
Patient No.: __________ 
Visit Day.: ____ 
 
Investigator: _________________________________________________ 
Sponsor: Octapharma USA, INC. 117 West Century Road, Paramus, NJ, 07652 
 
Batch no.: ______________ 
Expiration date: __________________ 

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27-January-2021 
 
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EU Master Label – Blinded label for infusion bags and over pouch: 
FOR CLINICAL TRIAL USE ONLY 
Study: GAM10-10 
Octagam 10% OR Sodium Chloride 0.9% w/v solution  Volume:_____ mL 
1 mL contains: 100 mg protein of which  95% is human normal immunoglobulin OR 
sodium chloride 0.9% w/v solution. 
Infusion solution for intravenous administration. 
To be stored at +2°C to +25°C. Must not be frozen. 
To be warmed up to room temperature before use. 
Dosage: see study protocol Section 5.4 
Patient No: __________ Visit Day.: ____ 
 
Bag number: __ of __ 
Date and time of preparation: __________________ 
Infusion to be completed latest by (Date and time):______________ 
Investigator: ____________________________________ 
Any unused solution residues or waste material to be disposed according to local 
requirements at the study site. 
Sponsor: Octapharma USA, INC. 117 West Century Road, Paramus, NJ, 07652
 
5.3 Conditions for Storage and Use 
Octagam 10% should be stored and transported light-protected at +2°C to +8°C (36°F 
to 46°F) and must not be frozen. Octagam 10% must not be used after its expiration 
date. 
Saline should be stored and transported according to its product information. Storage 
conditions will be stated on the IMP label. 
The authorized personnel at the individual pharmacies will ensure that the IMP is 
stored in appropriate conditions with restricted access and in compliance with national 
regulations. 
5.4 Dose and Dosing Schedule 
Octagam 10% is available in glass bottles with different volumes of human 
immunoglobulin. Glass bottles of different volume should be combined in order to 
reach the required amount of IgG. 
Octagam 10% or placebo will be administered by intravenous infusions on 
4 consecutive days. The amount of Octagam 10% calculated on the dosage delivery 
schedule is 2 g/kg divided evenly over 4 days (0.5 g/kg/day). 
If a subject is randomized to receive placebo, the same volume with the same infusion 
rate as would have been applied in case the subject would have been randomized to 

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Page 42 of 81 
2.0 g/kg Octagam 10% will be used. Therefore, they will receive an equal dose of 
placebo given over 4 days. 
Body weight is to be measured at Screening or within 24 hours of first IMP 
administration and reported to the pharmacist or designee as it is needed for the 
preparation of the following study medication dosages. 
All subjects should be clinically assessed for being adequately hydrated prior to IMP 
administration. TEE prophylaxis should be considered. 
The initial infusion rate for each infusion episode will be: 
 0.01 mL/kg/min (60 mg/kg/h) for the first 30 minutes (± 5 minutes) 
 if tolerated, advanced to 0.02 mL/kg/min (120 mg/kg/h) for the next 30 minutes 
(± 5 minutes) 
 if tolerated, advanced to 0.04 mL/kg/min (240 mg/kg/h) for the remainder of the 
infusion 
The interval of 30 minutes may be prolonged as per discretion of the investigator. 
In subjects at risk for thromboembolic adverse reactions and acute renal failure (such 
as advanced age, hypertension, history of thrombotic episodes, subjects with 
prolonged periods of immobilization, concomitant nephrotoxic medication, diabetes 
mellitus, overweight, hypovolemia), Octagam 10% should be administered at the 
minimum rate of infusion practicable. 
If AEs occur during the infusion, the rate is to be reduced to half the rate at which the 
event occurred, or the infusion is to be interrupted until symptoms subside. The infusion 
may then be resumed at a rate tolerated by the subject. In case of severe 
hypersensitivity or anaphylaxis, the infusion will not be restarted and all treatment with 
the IMP will be withdrawn. The subject will continue to be followed up in accordance 
with study-specific procedures as specified in the protocol with the exception that no 
further administrations of IMP will be performed. The subject will receive ongoing 
treatment in accordance with local SOC. 
Events that will prevent the scheduled administration of study drug will include but not 
limited to:  
 Uncontrolled blood pressure elevation (ie, systolic is ≥ 160 mmHg or diastolic is 
≥ 90 mmHg) 
 Chest pain with or without electrocardiogram changes 
 Thrombotic events 
 New onset seizures 

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 Acute Kidney Injury (AKI) as defined by KDIGO Clinical Practice Guideline for 
AKI as any of the following: 
o Increase in serum creatinine by ≥ 0.3 mg/dl (≥ 26.5 µmol/l) within 48 hours 
o or Increase in serum creatinine to ≥ 1.5 times baseline, which is known or 
presumed to have occurred within the prior 7 days 
o or Urine volume < 0.5 ml/kg/h for 6 hours 
 Stroke 
 Myocardial infarction. 
5.5 Preparation and Method of Administration 
Each bottle of Octagam 10% must be examined visually by the pharmacist or designee 
for particulate matter and discoloration prior to pooling. Non-homogenous solutions or 
those that have a deposit must not be pooled. The same procedures should be 
performed also for placebo. 
The preparation of IMP should be performed under aseptic conditions preferably using 
a sterile bench, as described in the manual handed out to the hospital pharmacist or 
designee. IMP administration should be completed no later than 8 hours after 
preparation. 
The Octagam 10% must be allowed to warm to room or body temperature prior to IMP 
administration. The same holds true for placebo for subjects in the placebo arm. 
Subjects must be monitored before infusion and carefully observed for any symptoms 
at least once throughout the infusion period and at least 1 hour thereafter. 
5.6 Blinding, Emergency Envelopes, and Breaking the Study Blind 
The Investigators will be provided with an unblinding procedure to disclose the actual 
treatment of a particular subject in case of medical emergency; this can be a sealed 
envelope or its electronic equivalent. 
To maintain blinding, infusions will be administered using blinded infusion over 
pouches and sites may opt to also use opaque or covered infusion lines. The blinded 
label will be fixed onto the infusion bag as well as to the opaque over pouch by the 
unblinded hospital pharmacist or designee. An over pouch (normally used for light 
protection) will be put over the infusion bag to maintain blinding. The new labels will be 
identical for both Octagam 10% and placebo, so that the content of the bags is only 
known to the unblinded hospital pharmacist or designee. 

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The unblinded pharmacist or designee will prepare and send the blinded infusion 
bag(s) per subject (and potentially with the opaque infusion line) to infusion center for 
administration. 
To further assure the double-blind character of this study, the Investigator or designee 
who administers the medication to the subject will not be involved in any other 
evaluations other than drawing blood samples or checking for vital signs. 
Breaking the blind in individual subjects during the double-blind study is permitted only 
in case of a SAE or unexpected ADR when knowing the type of the administered IMP 
is required for therapeutic decisions regarding this event to be taken. 
A designated unblinded statistical team not otherwise involved in the study is unblinded 
to create randomization materials and provide the IDMC with unblinded study results 
as described in the IDMC charter and Statistical Analysis Plan (SAP).  
Additional information on analysis timing and unblinded analyses can be found in 
Section 9.2.1. 
5.7 Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
Any IMP provided to the site will be accounted for. This includes IMP received at the 
site and IMP dispensed to subjects. A Drug Inventory and Dispensing Log will be kept 
current by the unblinded staff, detailing the dates and quantities of IMP received and 
dispensed to each subject and the remaining quantity. 
The inventory and dispensing log will be available to the unblinded monitor to verify 
drug accountability during the study. 
Unused IMP can be destroyed at the study site or returned to the Sponsor depot for 
destruction. Destruction can be initiated only after accountability has been verified and 
fully reconciled by the unblinded monitor and after the Sponsor has granted written 
approval of destruction. IMP that was already used for preparation of the infusion can 
be destroyed after preparation. 
5.7.2 Assessment of Treatment Compliance 
All subjects will be infused at the study site under the surveillance of authorized study 
personnel. Infusion details will be documented together with the batch number(s) in 
the source data and eCRF. 

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6 
STUDY CONDUCT  
The flow chart of assessments by study visit is given in Table 1. Details regarding each 
assessment are provided in Section 7. 
6.1 Observations by Visit 
It is anticipated that all study visits will occur while subjects are hospitalized. If a subject 
is discharged from the hospital prior to the End of Study Visit (Day 33), final safety 
blood samples (see Section 7.3.4) will be taken on day of discharge, and study data 
for follow-up visits thereafter will be collected by telephone or telehealth (see 
Section 6.1.6). 
6.1.1 Screening Visit  
The following assessments will be performed during the Screening Visit, which should 
take place within 24 hours (1 day) before the first administration of IMP, unless 
otherwise indicated: 
1. Obtaining voluntarily given, written (signed and dated) informed consent prior to 
any Screening procedures being performed. Consent can be given by legally 
authorized representative (LAR) if subject is not able to give consent. 
2. Inclusion and exclusion criteria and diagnosis confirmation (including swab for 
RT-PCR confirmation of SARS-CoV-2 infection or review of results from swab 
performed during the 7 days prior to Screening) 
3. Demographic, baseline characteristics, and medical history (including COVID-
19 diagnosis date (see Section 7.1.4) and infection symptoms) 
4. Body weight 
5. Prior medication use 
6. Vital signs including SpO2 saturation (see Section 7.2.4) or arterial blood gas to 
confirm eligibility  
7. MQoL-SIS 
8. Physical examination 
Note: may be extracted from hospital admission information 
9. Clinical Status and Oxygenation/Ventilator Status Evaluation 
10. Blood sampling for clinical laboratory evaluations (specified in Section 7.3.4)  
Note: clinical laboratory samples taken within 7 days before Screening may be 
used for Screening assessments  
11. Serum pregnancy test for females of child-bearing potential 

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12. Urine sample for legionella and pneumococcal antigens 
13. Chest CT/Chest X-ray 
Note: may be performed within ± 1 day of Screening Visit 
6.1.2 Baseline/Infusion, Visits 1 to 4 (Day 1 to Day 4) 
After screening and confirmation of eligibility, subjects will be randomized to receive 
either placebo or Octagam 10% (blinded). Administration of the first infusion must be 
started within 1 day (24 hours) after the screening visit. In this acute disease setting, 
the clinical status of patients can change rapidly. If a patient’s eligibility status changes 
(eg, they require intubation and mechanical ventilation or meet other exclusion criteria) 
between initial confirmation of eligibility and randomization, they will not be randomized 
and will be considered a screening failure.  
The first infusion of IMP should be initiated as soon as possible after randomization. 
Eligibility will not be re-assessed again between randomization and dosing. All 
randomized patients will therefore be dosed irrespective of changes in their clinical 
condition between randomization and dosing unless the Investigator decides that 
administration of the IMP would place the patient at additional risk. 
The following activities/assessments will be performed before the IMP infusion on 
Day 1: 
1. Confirmation of inclusion and exclusion criteria 
2. Body weight (if not performed at Screening) 
3. Vital signs 
4. Physical Examination (if not performed at Screening or available from hospital 
admission notes, see Section 6.1.1) 
5. Confirm medical history 
6. Chest CT/Chest X-ray (at Day 1 if not available at Screening, see 
Section 7.3.6) 
7. A-a Gradient (see Section 7.2.4) 
8. Clinical Status and Oxygenation/Ventilator Status Evaluation 
9. Blood sampling for clinical laboratory evaluations (specified in Section 7.3.4) 
10. Randomization 
The following activities/assessments will be performed before the IMP infusion on 
Days 2 through 4: 
 
Vital signs 

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 
Clinical Status and Oxygenation/Ventilator Status Evaluation 
 
Blood sampling for clinical laboratory evaluations (specified in 
Section 7.3.4) 
All blood sampling (Section7.3.4) will be done before IMP infusion on all dosing 
days. If the Day 1 infusion commences within 8 hours of the blood collection for the 
Screening laboratory parameters, only those parameters not assessed at Screening 
need to be performed prior to the Day 1 infusion. Physical examination and body 
weight will be performed at Baseline (Day 1) only if it is not performed at Screening. 
During and after IMP administration (Day 1 through Day 4): 
The subject will receive either Octagam 10% medication in the dose of 2 g/kg 
administered over 4 days (0.5 g/kg/day), or an equivalent volume of placebo (saline), 
infused slowly over approximately 2 hours per day over 4 consecutive days. Note: 
Subjects must be monitored before infusion and carefully observed for any symptoms 
at least once throughout the infusion period and at least 1 hour thereafter. 
The following activities/assessments will be performed on Day 1 through Day 4: 
1. Infusion of IMP according to randomization code: Octagam 10% or placebo 
2. Vital signs (taken once during and again after infusion) 
3. SpO2 saturation (see Section 7.2.4) 
4. Post-infusion site assessment 
5. Modified Borg Dyspnea Scale  
6. MQoL-SIS 
7. AE monitoring 
8. Concomitant medication use review and documentation 
6.1.3 Endpoint Visit 5 (Day 7) 
The following assessments will be performed 3 days after the end of daily infusions 
(Day 7 or on day of discharge if prior to Day 6 and restrictions prevent inpatient Day 7 
visit and not already performed as part of the assessments for that day): 
1. Vital signs 
2. SpO2 saturation and A-a Gradient (see Section 7.2.4) (for subjects discharged 
prior to Day 6, telephone contact will be made with the subject on Day 7 to 
ascertain SpO2) 
3. Swab for RT-PCR detection of SARS-CoV-2 to determine infection status 
4. Clinical Status and Oxygenation/Ventilator Status Evaluation 

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5. Modified Borg Dyspnea Scale 
6. MQoL-SIS 
7. Chest CT/Chest X-ray 
8. Blood sampling for clinical laboratory evaluations (specified in Section 7.3.4)  
9. AE monitoring 
10. Concomitant medication use 
6.1.4 Follow-up Visits 6 and 7 (Day 14 and Day 21) 
The following safety assessments will be performed at Day 14 and Day 21 (see 
Section 6.1.6. if subject has been discharged): 
1. Vital signs  
2. SpO2 saturation (see Section 7.2.4) 
3. Clinical Status and Oxygenation/Ventilator Status Evaluation 
4. Modified Borg Dyspnea Scale  
5. MQoL-SIS 
6. AE monitoring 
7. Concomitant medication use 
6.1.5 End of Study (Final Examination) Visit (Day 33) 
An End of Study Visit will be performed and include the following assessments (see 
Section 6.1.6 if subject has been discharged): 
1. Vital signs 
2. Physical examination 
Note: may be extracted from daily physical examinations in hospital chart 
3. SpO2 saturation (see Section 7.2.4) 
4. Clinical Status and Oxygenation/Ventilator Status Evaluation 
5. Modified Borg Dyspnea Scale 
6. MQoL-SIS 
7. Blood sampling for clinical laboratory evaluations (specified in Section 7.3.4) 
8. AE monitoring 
9. Concomitant medication use 

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After Day 33, the core clinical study is considered completed for the subject. No further 
study-related assessments will be performed, unless safety concerns (eg, ongoing 
AEs) require follow-up. After completion of the core 33-day trial, all subjects will be 
followed for a one-year follow-up registry. Subjects will be contacted by telephone or 
electronically by the Principal Investigator or the Sponsor (or its designee) every three 
months (± 14 days) for one year to obtain data on health status and any residual health 
effects from COVID-19 or the study treatment. There will not be any additional in-
person site visits required. The responsibility for the oversight of this registry follow-up 
period will be managed by a central Coordinating Principal Investigator (not the 
enrolling Investigator responsible for the 33-day core trial), unless the local Investigator 
elects to continue to oversee their subjects directly during this one-year follow-up 
period. The data recorded during this registry follow-up period will be submitted as a 
supplement to the core study data once all subjects have completed one year of 
follow-up. 
6.1.6 Telephone Visits 
If a subject is discharged from the hospital at any time during the course of their 
participation in the study, a pulse oximeter will be provided to them to monitor their 
oxygen saturation at home. The Research Coordinator or other qualified research team 
member will contact the subject on Day 7 (if discharge took place on Day 5 or earlier), 
Day 14, Day 21, and Day 33 (if discharge took place prior to Day 33) at approximately 
the same time (± 2 hours) as the pre-infusion SpO2 measurement recorded at Baseline 
(Day 1), to collect the following data points:  
1. Clinical Status  
2. SpO2 saturation taken on resting room-air 
3. AE and Concomitant medication review 
4. Modified Borg Dyspnea Scale 
5. MQoL-SIS 
6.1.7 Subject Early Discontinuation 
A study subject has a right to refuse study treatment and study visits at any time and 
for any reason. A subject can also withdraw from the study or study drug treatment for 
AEs, in which case the subject will be followed until resolution of the AE. Every effort 
will be made to assess the effect and outcome of the AE. 

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6.1.8 Time Windows Used in this Study, Including Tolerances 
In this study, the following time windows and tolerances apply: 
Table 2: 
Time Windows Used in this Study 
Time point 
Time stated 
Tolerance 
Screening Visit 
24 hours before Visit 1 
Max of 26 hours 
Visits 1 to 4 
Day 1 to 4 
None 
Visit 5 
Day 7 or discharge day 
± 1 day 
Visit 6 and 7 
Days 14 and 21 
± 2 days 
End of Study Visit 
Day 33 
± 3 days 
Q3 month post-study follow-up 
Every 3 months after completion of 
core trial or early termination 
± 14 days 
6.2 Duration of Study 
6.2.1 Planned Duration for an Individual Subject 
The duration of the core study for each subject will be approximately 33 days: 1 day 
for Screening, 4 days for the treatment, and 29 days for safety follow-up and end of 
study assessments. Subsequently, subjects will be followed remotely for an additional 
year to record any new COVID-19 safety developments. 
6.2.2 Planned Duration for the Study as a Whole 
The study will be considered completed when all subjects have completed the planned 
observation period/End of Study Visit. 
The estimated start of the study (enrollment of first subject) is Q2 2020 and the 
estimated end of the study (last visit of last subject) is Q4 2020. 
6.2.3 Premature Termination of the Study 
Both the Investigator and the Sponsor reserve the right to terminate the study at any 
time. In this event, any necessary procedures will be arranged on an individual study 
basis after review and consultation by both parties. In terminating the study, the 
Sponsor and the Investigators will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 
Regulatory authorities and Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB) should be informed in accordance with national regulations. 
Early termination of the study as a whole or by center may apply for the following 
reasons: 

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6.2.3.1 Early Termination of the Entire Clinical Study 
At any time, the study as a whole will be terminated prematurely if: 
 New toxicological or pharmacological findings or safety reports invalidate the 
earlier positive benefit-risk-assessment. 
 Any other reason rendering the continuation of the study impossible for the 
Sponsor. 
6.2.3.2 Early Termination at an Individual Study Center 
At any time, the study can be terminated at an individual center if: 
 The center cannot comply with the requirements of the protocol. 
 The center cannot comply with GCP standards. 
 The required recruitment rate is not met. 
Should the study be prematurely terminated, all study materials must be returned to 
the Sponsor. 

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7 
ASSESSMENTS AND METHODS 
7.1 Demographic and Baseline Information 
The following information will be recorded during the Screening Visit: 
7.1.1 Demographic and Baseline Characteristics 
The demographic and baseline characteristics will include sex, age, race/ethnic origin, 
and weight. 
7.1.2 Medical History 
The medical history will be obtained by interviewing the subject and/or review of 
hospital charts. Records of past diseases and treatments (eg, hospital discharge 
letters) will be obtained for the study files, if available. 
7.1.3 Prior and Concomitant Medication Use 
Prior and concomitant medication use will be obtained by interview and/or review of 
hospital charts. Prior medications are defined as any taken within 1 week of the 
Screening Visit until the start of IMP infusion. Concomitant medications are defined as 
any with a start date and time after the start of the Day 1 infusion and their use will be 
collected throughout the study. Data collected will include the dose, route, and dates 
and times of administration, the identity of the concomitant medication, the reason for 
administration, as well as any changes in therapy during the course of the study. 
7.1.4 Diagnosis Confirmation 
COVID-19 infection will be confirmed using RT-PCR evaluated on nares/throat swab 
and/or sputum and/or lower respiratory tract samples. A positive result taken in the 7 
days prior to Screening is acceptable. 
7.2 Efficacy Assessments 
7.2.1 Clinical Status 
Clinical status categories will be defined according to the following 6-category clinical 
status scale:  
1. Hospital discharge or meet discharge criteria (discharge criteria are defined as 
clinical recovery, ie, no fever, respiratory rate, oxygen saturation return to 
normal, and cough relief). 
2. Hospitalization, not requiring supplemental oxygen. 
3. Hospitalization, requiring supplemental oxygen (but not NIV/HFNC), as defined 
by A-a Gradient < 150 mmHg. 

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4. ICU/hospitalization, requiring NIV/HFNC therapy, as defined by A-a Gradient 
≥ 150 mmHg. 
5. ICU, requiring ECMO and/or IMV.  
6. Death.  
7.2.2 Oxygenation/Ventilator Status 
Oxygenation status and/or ventilation status will be recorded at each scheduled visit, 
and in between visits if there is a change in status. The following will be captured: 
Supportive measure required to maintain oxygen saturation: 
 Nasal canula ≤ 4 L/min 
 Nasal canula > 4 L/min 
 Face mask 
 Non-breather face mask 
 Non-invasive ventilation 
 Invasive mechanical ventilation. 
Data will be used to calculate the incidence of invasive mechanical ventilation, duration 
of invasive mechanical ventilation and other changes in oxygenation status as 
required. 
7.2.3 Viral Clearance 
COVID-19 infection status will be re-assessed on Day 7 using an RT-PCR assay to 
evaluate viral clearance. A nares/throat swab and/or sputum and/or lower respiratory 
tract sample will be taken for the assessment. If the initial Day 7 RT-PCR test is 
negative, a repeat test will be performed as soon as possible and no later than at the 
Day 14 visit. 
7.2.4 SpO2 Saturation and A-a Gradient 
SpO2 will be recorded throughout the study, at a similar time each day, on room-air if 
possible. Measurements on Days 1 to 4 will be taken prior to infusion. Readings on 
Days 7, 14, 21, and 33 should be taken at approximately the same time each day as 
the pre-infusion measurements (± 2 hours). The pre-infusion value on Day 1 will serve 
as the baseline value. If a subject is discharged from the hospital at any time during 
the course of their participation in the study, a pulse oximeter will be provided to them 
to monitor their oxygen saturation at home. A call will be made to the subject at 
approximately the same time as the Day 1 pre-infusion SpO2 measurement was taken 
(± 2 hours). 

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A-a Gradient will be recorded at Baseline (predose on Day 1) and Day 7 only if patient 
remains at a clinical status of 3 or 4 (see Section 7.2.1) using arterial blood gas (ABG) 
results. ABGs on Day 7 should be drawn at approximately the same time as the 
Baseline (Day 1) draw (± 2 hours). 
7.2.5 Modified Borg Dyspnea Scale 
Dyspnea will be measured by the modified Borg Dyspnea Scale which assesses 
dyspnea on a numerical scale from 0 (representing no dyspnea) to 10 (maximal 
dyspnea). 
Table 3: 
Modified Borg Dyspnea Scale 
Patient Instructions 
The Borg scale is used to help us understand the intensity or severity of your 
breathing. 
It starts at number 0 where your breathing is causing you no difficulty at all 
and progresses through to number 10 where your breathing difficulty is 
maximal. 
How much difficulty is your breathing causing you right now? 
0 
Nothing at all 
0.5 
Very, very slight (just noticeable) 
1 
Very slight 
2 
Slight 
3 
Moderate 
4 
Somewhat severe 
5 
Severe 
6 
 
7 
Very severe 
8 
 
9 
Very, very severe (almost maximal) 
10 
Maximal 
Source: https://scholarblogs.emory.edu/buddterrace/files/2016/03/Modified-Borg-Dyspnea-Scale.pdf 
7.2.6 McGill Quality of Life 
Quality of Life (QoL) will be measured by the McGill Quality of Life Single-Item Scale. 
The MQoL-SIS (see below) is a validated 1-item multidimensional tool designed to 
measure physical well-being, physical symptoms, psychological symptoms, existential 
well-being and support, as well as overall quality of life. 
Considering all parts of my life – physical, emotional, social, spiritual, and financial – 
over the past two (2) days the quality of my life has been: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Very bad  
 
 
 
 
 
 
 
 
Excellent 

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7.3 Safety Assessments 
7.3.1 Assessments for Safety Endpoints 
The following drug safety information shall be collected: 
 AEs and SAEs temporally associated with the administration of IMP or placebo 
(for definitions and reporting requirements, see Sections 7.3.2, 7.3.3, and 
7.3.3.1) 
 Vital signs including SpO2  
 Clinical laboratory evaluations 
 Radiological findings as reported on Chest CT or Chest X-ray 
 Pregnancies, drug overdose, interaction, medication error, lack of efficacy, and 
post-study SAEs (see Section7.3.7). 
7.3.2 Adverse Events (AEs) 
7.3.2.1 Definitions 
Adverse event (AE): An AE is any untoward medical occurrence in a study subject 
receiving an IMP and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use 
of an IMP, whether or not related to the IMP. 
Adverse drug reaction (ADR): An ADR is any noxious and unintended response to 
an IMP related to any dose. The phrase ‘response to an IMP’ means that a causal 
relationship between the IMP and an AE carries at least a reasonable possibility, ie, the 
relationship cannot be ruled out. 
Other significant AEs: Any marked laboratory abnormalities or any AEs that lead to 
an intervention, including withdrawal of drug treatment, dose reduction, or significant 
additional concomitant therapy. 
Withdrawal due to AE/ADR: AE/ADR leading to discontinuation of treatment with 
IMP. Any such events will be followed up by the Investigator until the event is resolved 
or until the medical condition of the subject is stable. All follow-up information collected 
will be made available to the Sponsor. 
7.3.2.2 Collection of AEs 
The condition of the subject will be monitored throughout the study. At each visit, 
whether scheduled or unscheduled, AEs will be elicited using a standard nonleading 
question such as “How have you been since the last visit/during the previous study 

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period?” In addition, the Investigator will check the subject diaries (if applicable) for any 
documented event. 
Any AE or ADR which occurs during the study will be noted in detail on the appropriate 
pages of the eCRF. If the subject reports several signs or symptoms representing a 
single syndrome or diagnosis, the diagnosis should be recorded in the eCRF. The 
Investigator will grade the severity of all AEs or ADRs (mild, moderate, or severe), the 
seriousness (non-serious or serious), and the causality as defined in Sections 7.3.2.3, 
7.3.3, and 7.3.2.4. The Sponsor is responsible for assessing the expectedness of each 
ADR (expected or unexpected) as defined in Section 7.3.2.5. 
In the event of clinically significant abnormal laboratory findings, the tests will be 
confirmed, and the subject followed up until the laboratory values have returned to 
normal and/or an adequate explanation for the abnormality has become available. 
Abnormal laboratory results will only be recorded as AEs in the following 
circumstances: 
 The abnormality requires medical intervention or concomitant therapy, and/or 
 The abnormality suggests a disease and/or organ toxicity which is assessed 
as having developed or evolved since Screening. 
In all cases, diagnoses should be documented, if possible. 
Diseases, signs and symptoms, and/or laboratory abnormalities already present before 
the first administration of IMP will not be considered AEs unless an exacerbation in 
intensity or frequency (worsening) occurs. 
The Investigator will provide detailed information about any abnormalities and about 
the nature of and reasons for any action taken as well as any other observations or 
comments that may be useful for the interpretation and understanding of an AE or 
ADR. 
7.3.2.3 Severity of AEs 
The intensity/severity of AEs will be graded as follows: 
Mild: an AE, usually transient, which causes discomfort but does not interfere with the 
subject’s routine activities 
Moderate: an AE which is sufficiently discomforting to interfere with the subject’s 
routine activities 
Severe: an AE which is incapacitating and prevents the pursuit of the subject’s routine 
activities 
The grading of an AE is up to the medical judgment of the Investigator and will be 
decided on a case-by-case basis. 

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7.3.2.4 Causality of AEs 
The relationship of AEs to the administered IMP will be assessed by the Investigator: 
Probable: reports including good reasons and sufficient documentation to assume a 
causal relationship, in the sense of plausible, conceivable, likely, but not necessarily 
highly probable. A reaction that follows a reasonable temporal sequence from 
administration of the IMP; or that follows a known or expected response pattern to the 
suspected medicine; or that is confirmed by stopping or reducing the dosage of the 
medicine and that could not reasonably be explained by known characteristics of the 
subject’s clinical state. 
Possible: reports containing sufficient information to accept the possibility of a causal 
relationship, in the sense of not impossible and not unlikely, although the connection 
is uncertain or doubtful, for example because of missing data or insufficient evidence. 
A reaction that follows a reasonable temporal sequence from administration of the IMP; 
that follows a known or expected response pattern to the suspected medicine; but that 
could readily have been produced by a number of other factors. 
Unlikely: reports not following a reasonable temporal sequence from IMP 
administration. An event which may have been produced by the subject’s clinical state 
or by environmental factors or other therapies administered. 
Not related (unrelated): events for which sufficient information exists to conclude that 
the etiology is unrelated to the IMP. 
Unclassified: reports which for one reason or another are not yet assessable, 
eg, because of outstanding information (can only be a temporary assessment). 
7.3.2.5 Classification of ADRs by Expectedness 
ADRs will be classified by the Sponsor as either expected or unexpected: 
Expected: an ADR that is listed in the current edition of the IB or other reference safety 
information. 
Unexpected: an ADR that is not listed in the current edition of the IB or other reference 
safety information, or that differs because of greater severity or greater specificity. 
7.3.2.6 Outcome of AEs 
The outcome of all reported AEs will be documented as follows: 
1. Recovered, resolved 
2. Recovering, resolving 
3. Not recovered, not resolved 
4. Recovered, resolved with sequelae 

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5. Fatal 
6. Unknown 
NOTE: A subject’s death per se is not an event, but an outcome. The event which 
resulted in the subject’s death must be fully documented and reported, even in case 
the death occurs within 4 weeks after IMP treatment end and regardless of whether or 
not it is considered treatment-related. 
7.3.2.7 Action(s) Taken 
AEs requiring action or therapy must be treated with recognized standards of medical 
care to protect the health and well-being of the subject. Appropriate resuscitation 
equipment and medicines must be available on site for anaphylaxis or other 
emergencies to ensure the best possible treatment. In case of anaphylaxis, the infusion 
will be stopped, and the subject will be withdrawn from the study. 
The action taken by the Investigator must be documented: 
a) General actions taken in the event of an AE 
– None 
– Medication (other than IMP) or other (eg, physical) therapy started 
– Test performed 
– Other (to be specified) 
b) IMP-related actions taken in the event of an AE 
– None 
– Product withdrawn 
– Dose reduced 
– Dose increased 
The Investigator will follow up on each AE until it has resolved or until the medical 
condition of the subject has stabilized. Any relevant follow-up information will be 
reported to the Sponsor. 
7.3.3 Serious Adverse Events (SAEs) 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
 results in death, 
 is life-threatening (see below), 
 requires hospitalization or prolongation of existing hospitalization, 

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 results in persistent or significant disability/incapacity, 
 is a congenital anomaly/birth defect, 
 is another important medical event. 
NOTE: The term ‘life-threatening’ refers to an event in which the subject was, in the 
view of the reporting Investigator, at immediate risk of death at the time of the event; it 
does not refer to an event which may hypothetically have caused death had it been 
more severe. 
In deciding whether an AE/ADR is serious, medical judgment should be exercised. 
Thus, important AEs/ADRs that are not immediately life-threatening or do not result in 
death or hospitalization, but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the definitions above, should also be 
considered serious. 
In addition, although not classified under the seriousness criteria, all suspected 
transmissions of an infectious agent should be reported as SAE. A suspected virus 
transmission means that virus antigen has been detected in the subject. A passive 
transmission of antibodies alone does not constitute a suspected virus transmission. 
7.3.3.1 SAE Reporting Timelines 
All SAEs, whether or not they are suspected to be related to study treatment, are to be 
reported immediately by telephone, fax, or email to the Clinical Project Manager or 
designee with the contact details provided to each site in the Investigator Site Binder. 
The contact details will also be communicated at the study initiation visit. 
In addition, within 24 hours after recognition of the event, an Octapharma Serious 
Adverse Event Report must be completed and submitted to: 
Octapharma’s Corporate Drug Safety Unit 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
 
 
24 hours emergency telephone numbers: 
 
 
The Investigator must update the Octapharma Serious Adverse Event Report as soon 
as any additional information becomes available. The Investigator must also report 
SAEs to the IRB/IEC as required by local and national laws. The Investigator must 
maintain documentation of all communications to and from the IRB/IEC. 

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In accordance with 21 CFR 312.32 and local authorities, the Sponsor will submit to the 
FDA unexpected adverse reactions within 15 calendar days. Unexpected fatal or life-
threatening adverse reactions will be submitted within 7 calendar days. 
7.3.3.2 Waivers from SAE Reporting Requirement 
Waivers from the SAE reporting requirement include surgeries that are elective or were 
planned before study entry or prolongations of existing hospitalizations for economic 
or social, but not medical, reasons. Such surgeries or prolongations of hospitalizations 
should not be considered SAEs. 
7.3.4 Laboratory Safety Evaluations 
The following laboratory parameters will be investigated during the study at the time 
points specified in Table 1: Flow Chart of Assessments and below. 
All laboratory assessment will be performed at the local laboratories for each study 
site. In Russia and Ukraine, a central local laboratory could be used for all or part of 
the tests depending on the site facilities. Samples will be drawn prior to IMP infusions 
on Day 1 through Day 4, if appropriate: 
Laboratory Measures at Screening: 
– Comprehensive Metabolic Panel (CMP) 
– Complete blood count (CBC) with differential 
– D-Dimer 
– Fibrinogen 
– Prothrombin time (PT), partial thromboplastin time (PTT), international 
normalized ratio (INR) 
– hsCRP 
– Erythrocyte sedimentation rate (ESR) 
– Ferritin, lactic acid dehydrogenase (LDH) 
– Cytokines (IL-1Beta, IL-6, TNF-alpha, IFN-gamma) 
– C3, C4, CH50 
– Total CK, CK-MB fraction, myoglobin 
– High sensitivity Troponin I (hs-cTnI) or cTnI-ultra 
– Serum pregnancy 
– Blood culture 
– Urine legionella, pneumococcal antigens 

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Laboratory measures for Day 1 through Day 3 (If less than 8 hours between 
Screening lab draw and Baseline Day 1, Baseline labs do not need to be redrawn): 
– BUN 
– Serum creatinine 
– Sodium 
– Potassium 
– D-Dimer 
– Arterial Blood Gases (Day 1 only) 
Laboratory measures for Day 4: 
– BUN 
– Creatinine 
– Sodium 
– Potassium 
– PT, PTT, INR 
– CBC with differential 
– D-Dimer 
Laboratory measures for Day 7: 
– CMP 
– ESR 
– Fibrinogen 
– PT, PTT, INR 
– CBC with differential 
– hsCRP 
– D-Dimer 
– Ferritin, LDH 
– Arterial Blood Gases (for patients with a clinical status of 3 or 4) 
Laboratory measures for Day of Discharge (only if discharge is after Day 7) or Day 33, 
whichever is sooner: 
– CMP 
– CBC with differential 

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– hsCRP 
– Cytokines (IL-1Beta, IL-6, TNF-alpha, IFN-gamma) 
– C3, C4, CH50 
– Total CK, CK-MB fraction, myoglobin 
– D-Dimer 
– Ferritin, LDH 
– High sensitivity Troponin I (hs-cTnI) or cTnI-ultra 
– PT, PTT, INR 
– Fibrinogen 
The methods of determination and normal ranges for each parameter will be provided 
in the clinical study report. 
7.3.5 Vital Signs and Physical Examination 
Vital signs measurements, blood pressure, pulse, respiration rate, and body 
temperature (°C) will be recorded as indicated in Table 1: Flow Chart of Assessments. 
Routine complete physical examination will be performed at the visits specified in 
Table 1: Flow Chart of Assessments. Any clinically significant worsening, as deemed 
by Principal Investigator, or new abnormality found during the exam will be 
documented as an AE. 
7.3.6 Chest CT/Chest X-ray 
A non-contrast Chest CT or Chest X-ray will be performed at Screening and Day 7 to 
assess clinically significant changes from Baseline (Day 1) as determined by the 
Investigator. 
7.3.7 Other Relevant Safety Information 
a) Post-study related safety reports 
Any SAE which occurs up to 4 weeks after the last IMP administration should be 
reported by the Investigator to the Sponsor in case the Investigator becomes aware of 
it. Proactive monitoring for post-study SAEs is not required. 
In case a post-study SAE is identified, the Investigator should complete an SAE form 
and state the relation to the clinical study in the report. 
Deaths occurring within 4 weeks after the last IMP administration should also be 
reported, regardless of whether or not they are considered treatment-related. 

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b) Pregnancies  
Every effort will be made to avoid pregnancy during the use of an IMP. Pregnancies 
occurring during the study (fetal exposure to the IMP) need to be reported. 
In case of pregnancy during the study, the Investigator should complete the Pregnancy 
Notification Form and send or fax it to the Clinical Project Manager or designee (see 
Section 7.3.3.1). 
Follow-up information on the outcome of both mother and fetus will be requested by a 
Sponsor representative. 
c) Overdose, interaction, medication error, and lack of efficacy 
The following safety relevant information should be reported as AE or, if the reaction 
fulfills one of the criteria for seriousness, as SAE. 
d) Drug overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose 
higher than specified in the protocol and higher than the known therapeutic dose that 
is of clinical relevance. The reaction must be clearly identified as an overdose. 
e) Drug interaction 
A drug interaction is a situation in which a substance or medicinal product affects the 
activity of an IMP, ie, increases or decreases its effects, or produces an effect that 
none of the products would exhibit on its own. The reaction must be clearly identified 
as a drug interaction. 
f) Medication error 
A medication error involves the inadvertent administration or unintended use of a 
medicinal product which may be caused by the naming, presentation of pharmaceutical 
form/packaging, or instructions for use/labelling. The reaction must be clearly identified 
as a medication error. 
g) Lack of efficacy 
Lack of efficacy is suspected when the therapeutic result is not as expected. 
7.4 Appropriateness of Measurements 
Efficacy evaluations, including assessing clinical status, measuring the modality 
required to maintain oxygen levels, measuring SpO2 saturation, A-a Gradient, and 
ventilator status, are standard methods to evaluate maintenance or improvement of 
clinical status and respiratory deterioration. These evaluations are widely used, 
generally recognized as reliable, accurate, and relevant in this type of research, and 
are adequate to form the primary basis for the determination of efficacy. The 6-category 

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clinical status scale has recently been used in COVID-19 Remdesivir clinical studies 
(37). 
Monitoring AEs, vital signs, laboratory safety tests, and physical examinations are 
standard procedures used to evaluate the safety of investigational products in clinical 
studies. The MQoL-SIS is a standardized, validated instrument that has been used in 
clinical studies. 

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8 
DATA HANDLING AND RECORD KEEPING 
8.1 Documentation of Data 
8.1.1 Source Data and Records 
Source data are defined as all information related to clinical findings, observations, or 
other activities in the study, written down in original records or certified copies of 
original records, allowing reconstruction and evaluation of the clinical study. 
The Investigator will maintain adequate source records (eg, case histories or subject 
files for each subject enrolled). Source records should be preserved for the maximum 
period of time required by local regulations. 
For each subject enrolled, the Investigator will indicate in the source record(s) that the 
subject participates in this study. 
Data entered in the eCRF must be supported by source data in the subject records. 
The Investigator will permit study-related monitoring, audit(s), IEC/IRB review(s), and 
regulatory inspection(s), by providing direct access to the source data/records. 
The Investigator may authorize site staff (eg, sub-investigators, nurses) or an external 
third-party to enter study data into the eCRF. The delegation of this task will be 
documented on the Delegation of Authority Log or the Central Data Entry Agreement 
if delegated to an external 3rd party. 
8.1.2 Electronic Case Report Forms 
For each subject enrolled, an eCRF will be completed within the Electronic Data 
Capture (EDC) system and approved by the Investigator or an authorized sub-
investigator.  
Study site staff (eg, research nurse) or delegated third-party personnel will be 
responsible for entering subject data into the validated EDC system. All site or 
delegated third-party personnel will be trained on the EDC system and study-specific 
eCRFs prior to receiving access to the live database for data entry. 
The site or delegated third-party personnel is also provided with the approved eCRF 
Completion Guidelines to assist in data entry and data issues/questions. The site will 
be notified once the database is active to begin data entry. Additional training may be 
provided as refreshers throughout the study, if needed. All persons allowed to enter or 
change eCRF data must be listed in the Delegation of Authority Log or delegated via 
the Central Data Entry Agreement. 

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8.1.3 Changes to Electronic Case Report Form Data 
Monitors will perform source data verification (SDV) as defined for the study. 
If any errors or discrepancies in the eCRFs are found during data entry or review, 
discrepancies will be generated programmatically within the EDC system, and ‘manual’ 
queries will be generated by either a monitor or Data Management. 
Discrepancies and queries can only be corrected by the Investigator(s) or other 
authorized site personnel or designee. An audit trail documents all changes to the data 
over the entire study period. If the reason for a change is not obvious, a comment must 
be supplied in the query’s response, stating the reason for the change, prior to closing. 
The study monitor should provide guidance to Investigator(s) and the Investigator(s)’ 
designated representatives on making such corrections. 
Once queries have been resolved by the site staff or designee, the resolutions are 
assessed by Data Management. If the query response provided confirms the data as 
correct, the discrepancy will be closed. If the response does not adequately address 
the question raised, a new query will be issued for further clarification. 
Manual checks are performed, and programs are run throughout the study, until the 
data is clean, and the database is ready for lock. All discrepancies will be resolved 
prior to database lock. There will be a final run of the programmed checks to ensure 
all discrepancies are closed out, SDV will be confirmed as complete by the monitor, 
and all eCRFs will be approved by the Investigator prior to database lock. 
8.2 Information to Investigators 
An IB will be handed out to the Investigator before the start of the study. The IB contains 
all information in the Sponsor’s possession necessary for the Investigator to be fully 
and accurately informed about the safety of the IMP under evaluation and the 
respective benefit-risk ratio. 
The IB will be updated by the Sponsor at regular intervals and whenever relevant new 
information concerning the IMP becomes available. 
The Investigator will be informed about the methods for rating relevant study outcomes 
and for completing CRFs to reduce discrepancies between participating Investigator 
and study sites. 
The Investigator will be kept informed of important data that relate to the safe use of 
the IMP as the study proceeds. 
8.3 Responsibilities 
The Investigator is accountable for the conduct of the clinical study. Responsibilities 
may be delegated to appropriately qualified persons. 

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A Delegation of Authority Log will be filled in and signed by the Investigator. In 
accordance with this authority log, study site staff (eg, sub-investigators, nurses) is 
authorized to perform tasks relating to the study. 
8.4 Investigator’s Site File 
At each study site, the Investigator is responsible for maintaining all records to enable 
the conduct of the study to be fully documented. Essential documents as required by 
GCP guidelines and regulations (eg, copies of the protocol, study approval letters, all 
original informed consent forms, site copies of all CRFs, drug dispensing and 
accountability logs, correspondence pertaining to the study, etc.) should be filed 
accurately and kept by the Investigator for the maximum period of time required by 
local regulations. 
The Investigator is responsible for maintaining a confidential subject identification code 
list, which provides the unique link between named source records and CRF data for 
the Sponsor. The Investigator must arrange for the retention of this confidential list for 
the maximum period of time required by local regulations. 
No study document should be destroyed without prior written agreement between the 
Investigator and the Sponsor. Should the Investigator elect to assign the study 
documents to another party, or move them to another location, the Sponsor must be 
notified in writing. 
8.5 Provision of Additional Information 
On request, the Investigator will supply the Sponsor with additional data relating to the 
study, or copies of relevant source records, ensuring that the subject’s confidentiality 
is maintained. This is particularly important when CRFs are illegible or when errors in 
data transcription are encountered. In case of particular issues or governmental 
queries, it is also necessary to have access to the complete study records, provided 
that the subject’s confidentiality is protected in accordance with applicable regulations. 
8.6 Independent Data Monitoring Committee 
An IDMC will be established by the Sponsor. The IDMC will be composed of 
recognized experts in the field who are not actively recruiting subjects. 
The IDMC will review relevant data periodically during the study and will give advice 
on the continuation, modification, or termination of the study. A written study-specific 
procedure will define in detail the composition, responsibilities, and procedures of the 
IDMC. 

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9 
STATISTICAL METHODS AND SAMPLE SIZE 
This section provides a summary of statistical methods along with the definition of 
analysis populations. More details will be included in a SAP maintained in a separate 
document, prepared and approved by the Sponsor prior to study unblinding or before 
the project manager or study statistician can access the data, whichever happens 
earlier. 
9.1 Determination of Sample Size 
A subject is determined to reach the primary endpoint “stabilization or improvement in 
clinical status defined as maintenance or improvement by one category on a 
6-category clinical status scale on Day 7” if the clinical status category on Day 7 is not 
worse than the clinical status category at Baseline (Day 1 prior to IMP infusion). 
The study is determined to be successful if the proportion of subjects randomized to 
the IVIG group who reach the primary endpoint is significantly greater than the 
proportion of subjects randomized to the placebo group who reach the primary 
endpoint. 
High-dose IVIG is used as a therapeutic option for severe-type COVID-19 (37) and 
given the severity of the population in our study as compared to the reference study, 
we assume 80% of subjects in the IVIG group and 60% of subjects in the placebo 
group will meet the primary endpoint. 
With overall two-sided significance level of 0.05 when testing the difference in 
proportions between two treatment groups using normality approximation, 176 
subjects (n=88 for each treatment group) will provide statistical power of at least 80%. 
Assuming a drop-out rate of 15% from Baseline (Day 1) relative to the efficacy 
assessment date at Day 7 after first dose for both groups, a final sample size of 208 
(n=104 for each treatment group) is sufficient to maintain the minimum statistical power 
as 80%. 
9.2 Statistical Analysis 
9.2.1 Timing of Analyses 
The final primary analysis will take place after database lock. 
The primary analysis may also be conducted prior to database lock but after the last 
subject enrolled completes their Day 33 visit (or discontinues). If conducted, this 
analysis would be distributed to a limited unblinded team to evaluate the need to submit 
an emergency use application. Full details on this process will be provided in an 
unblinding plan and the clinical study report. 
Upon end of study follow up, an end of study analysis may be conducted. 

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9.2.2 Analysis Populations 
The analysis population is a cohort of study subjects defined for analysis for different 
scientific purposes and interpretation. For this study, the populations for analysis are 
defined as: 
I. 
Enrolled Population (EP) 
All subjects who are enrolled in the study will be included in the enrolled 
population (EP). 
II. 
Intent-To-Treat Analysis Population (ITT) 
All subjects who are randomized will be included in the intent-to-treat (ITT) 
analysis population and analysis will be conducted according to the study 
arm in which subjects are randomized, regardless of randomization errors 
or protocol violations. 
III. 
Safety Analysis Population (SAF) 
All subjects who are randomized and received any amount of IVIG or 
placebo will be included in the safety analysis set (SAF) and analysis will be 
conducted according to the treatment which subjects actually received. 
IV. 
Per-Protocol Population (PP) 
The Per-Protocol (PP) Population includes subjects who receive at least 
75% of the planned dose (3 completed infusions of IVIG or placebo) without 
major protocol deviations that would potentially interfere with the efficacy 
assessment. 
9.2.3 Efficacy Analysis Plan 
9.2.3.1 Baseline and Demographic Data 
Descriptive statistics, including mean, standard deviation, median, maximum, and 
minimum will be provided for baseline age, weight, vital signs, physical exam, 
laboratory results, and oxygen saturation. Gender, race and ethnicity, and other 
demographic information will be tabulated. Medical history will be classified using the 
Medical Dictionary for Regulatory Activities (MedDRA) classification system 
version 23.0 and tabulated with start date, ongoing status, and end date, if applicable. 
9.2.3.2 Primary and Secondary Endpoints 
The ITT set will be used as the primary analysis set to analyze the primary endpoint. 
The handling of missing data is described in later section. A subject is determined to 
be a success if the clinical status category on Day 7 is not worse than the clinical status 
category at Baseline (Day 1, prior to IMP infusion). Subjects who use prohibited 

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concomitant medication (medications being administered as part of other experimental 
studies or the use of experimental non-IVIG products, such as COVID-19 convalescent 
plasma, or interferons) prior to the Day 7 clinical status assessment will be counted as 
failure.  
A sensitivity analysis using all available data, regardless of prohibited medication 
usage, will be conducted. 
The null hypothesis of no difference in proportion of subjects who reach success 
(clinical status not worse than the clinical status category at Baseline at Day 7) in two 
treatment groups will be tested versus the alternative hypothesis that there is a 
difference between proportions of subjects who reach success in two groups. 
Hypothesis testing will be performed using Cochran-Mantel-Haenszel (CMH) stratified 
by age category (≤65 versus >65) at a two-sided 0.05 significance level. The difference 
in proportions between the two groups with standard deviation, and 95% Miettinen-
Nurminen CI will also be provided. 
The durability of the treatment effect will be reviewed based on the comparison 
between treatment arms of proportions who are stabilized or improved at Day 14, 
Day 21 and Day 33 in the final analysis. No formal hypothesis testing will be made for 
the Day 21 and Day 33 analyses and the comparison will be carried out by difference 
of proportions, standard error and 95% CI of the difference of proportions between two 
treatment groups. 
The analysis for secondary endpoints will be based on the ITT population. The 
hypothesis testing with p-value assessments for key secondary endpoints will be 
implemented for confirmatory purpose after statistical significance is claimed from the 
primary endpoint. The following key secondary endpoints will be analyzed by 
hierarchical procedure in the order specified below with overall two-sided type I error 
of 0.05:  
1. Length of hospital stay (time to discharge) through Day 33 
2. Proportion of subjects with stabilized or improved clinical status of at least one 
category on the 6-point clinical status scale on Day 14. 
3. Cumulative duration of IMV through Day 33 
4. Proportion of subjects with severe progression defined as requiring ECMO, 
IMV and/or have died through Day 33 
5. Length of time in ICU through Day 33 
6. Mortality rate through Day 33 
Length of hospitalization is defined as (date of discharge – randomization date + 1). 
Subjects who are still hospitalized as of Day 33, subjects with missing end dates due 

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to withdrawal, subjects with unusable end dates due to prohibited medication use, or 
those who died on/prior to Day 33 will be censored at Day 33. The median time to 
discharge and associated 95% CI for each treatment arm will be estimated using the 
Kaplan-Meier method. Comparisons between treatment arms will be performed using 
a log-rank test, stratified by age category. A rate ratio and associated 95% CI, 
equivalent to a hazard ratio from a Cox proportional hazard model stratified by age, 
will also be presented. 
Proportion of subjects that stabilized or improved at Day 14 is defined analogously to 
the primary endpoint and hypothesis testing for proportions will be conducted as 
described for the primary endpoint. 
Cumulative duration on IMV through Day 33 is defined as (IMV end date – IMV start 
date + 1). Subjects who do not require IMV will have a duration set to 0. Subjects who 
die on or prior to Day 33 or are still on IMV at Day 33, will have a duration set to their 
actual/projected Day 33 date for the IMV end date, so long as prohibited medication 
was not administered. If IMV end date is missing but subject is discharged from ICU or 
hospital, then IMV end date will be set to the earlier of the ICU or hospital discharge 
date. Otherwise, subjects without usable IMV end date information due to withdrawal 
or prohibited medication use will use a projected Day 33 date for the IMV end date. 
Comparisons between treatment arms will be performed using a stratified Wilcoxon-
Mann-Whitney (van Elteren) test with age category as a stratification factor. 
Proportion of subjects with severe progression will be defined as the proportion that 
require ECMO, IMV, or died prior to Day 33. For this analysis, subjects who use 
prohibited medication prior to the earliest date of progression or Day 33 will not be 
included in analyses. Hypothesis testing for this endpoint will be conducted as 
described for the primary analysis. 
Length of time in ICU includes number of days spent in the ICU from randomization 
through Day 33 and is defined as [ICU discharge date – (later of ICU admittance date, 
randomization date) + 1]. Subjects who are not admitted to the ICU will have a duration 
set to 0. Subjects who die on or prior to Day 33 or are still in the ICU at Day 33, will 
have a duration set to their actual/projected Day 33 date for the discharge date, so 
long as prohibited medication was not administered. If ICU discharge date is missing 
but subject is discharged from hospital, then ICU discharge date will be set to hospital 
discharge date. Otherwise, subjects without usable ICU end date information due to 
withdrawal or prohibited medication use will use a projected Day 33 date for the ICU 
end date. Comparisons between treatment arms will be performed using a stratified 
Wilcoxon-Mann-Whitney (van Elteren) test with age category and baseline ICU status 
(In ICU at baseline versus not in ICU at baseline) as stratification factors. 

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Mortality rate is defined as the proportion of subjects who have died on or prior to 
Day 33. For this analysis, subjects who use prohibited medication prior to the earliest 
of death or Day 33 will not be included in analyses. Hypothesis testing will be 
performed as described for the primary analysis. 
Key secondary endpoints which demonstrate statistical significance will be analyzed 
by subgroups including sex (male/female), race, ethnicity, geographic region, and 
disease severity (according to the definitions in the eCRF). All key secondary 
endpoints will be analyzed by age using testing analogous (unstratified) testing 
methodology to the specified analyses. Sensitivity analyses, using all available data, 
regardless of prohibited medication usage, will be conducted where applicable.  
Additional details for missing data handling for key secondary endpoints are described 
in Section 9.2.4. 
A detailed SAP describing additional missing data handling, additional sensitivity and 
subgroup analyses, and further details with respect to testing for each endpoint will 
be compiled as a separate document. 
9.2.4 Safety Analysis Plan 
Safety data analysis will be based on the SAF. Descriptive statistics will be provided 
for imaging assessments, clinical laboratory parameters, AEs, SAEs, and vital signs, 
including physical examination, concomitant medicines, concomitant procedures, and 
safety laboratory test results. 
AEs observed will be classified using the MedDRA classification system version 23.0. 
AEs will be summarized by MedDRA system organ plan and preferred terms. Separate 
tabulations will be produced for related AEs, SAEs, discontinuations due to AEs, and 
events of at least Grade 3 severity. A summary of the number and severity of 
treatment-emergent AEs and study drug related AEs will also be produced. 
Laboratory results will be graded according to the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 whenever possible. 
Laboratory parameters will be summarized for changes across study using descriptive 
statistics including shifts relative to NCI-CTCAE criteria for laboratory abnormalities. 
Laboratory measures will also be compared with their corresponding normal ranges, 
and the incidence of abnormally high and abnormally low laboratory values will be 
summarized. 
9.2.5 Handling of Missing Data 
In support of the primary and key secondary endpoints of stabilization or improvement 
in clinical status the following imputation methods will be used. For subjects with clinical 
status assessment at Baseline (Day 1) and at least one non-missing post-baseline 
clinical status assessment, last observation carried forward (LOCF) will be used to 

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impute the missing data at Day 7. However, if there is available data that otherwise 
indicates events such as death, ECMO or IMV, ICU admittance, occurred after the last 
non-missing clinical status assessment but on or prior to Day 7, the clinical status will 
be imputed according to the worst-case of either the LOCF or the clinical information 
available. Subjects with missing data at Baseline (Day 1) will be imputed as failure. 
Subjects with no post-baseline clinical status assessment on or prior to Day 7 will be 
imputed as failure.  
Sensitivity analyses will be implemented by assuming all failure (worst case scenario) 
if subject has missing data at Baseline (Day 1) or Day 7, and where subjects with 
missing data are excluded.  
Missing data for the outcome of clinical status at Day 14 will be imputed in the same 
fashion as in primary endpoint. 
For the key secondary endpoint involving severe progression (ECMO, IMV, death, ICU 
admittance), subjects who withdrew early from study prior to Day 33 without evidence 
of events will be treated as not having the event. Sensitivity analyses will be conducted 
(1) treating them as failures (having the event at their last study visit) and (2) excluding 
them from the analyses. An additional analysis of these endpoints will be provided, 
treating prohibited medication use prior to Day 33 as an event, as well as allowing for 
status (event or success) without regard to prohibited medication use. 
9.3 Randomization, Stratification, and Code Release 
Each eligible subject will be randomized to either the treatment (IVIG) or placebo 
groups by study site. The randomization will be conducted using permuted blocks with 
block size randomly selected in each site stratum. A randomization statistician, not 
otherwise involved in the study, will generate the randomization list using a validated 
randomization program and deliver the allocation schedule to the unblinded study 
pharmacist in a secure and confidential manner. For Russia and Ukraine, this will be 
delivered with the help of the interactive response technology system. The pharmacist 
at the dispensing site will be unblinded to treatment and is responsible for blinding the 
study drug so that the infusion nurse, subject, and other study staff remain blinded to 
treatment. Moreover, since the pharmacist is not involved in the recruitment or 
management of subject, allocation concealment will be preserved. The process of 
blinding the study drug will be described in detail in another study supporting 
document.  

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10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS 
10.1 Ethical/Regulatory Framework 
This study will be conducted in accordance with the ethical principles laid down in the 
Declaration of Helsinki. The study protocol and any subsequent amendment(s) will be 
submitted to an IEC/IRB and to the Regulatory Authority. The study will be conducted 
in compliance with the protocol, GCP guidelines, and applicable regulatory 
requirements. 
The regulatory application or submission for regulatory approval will be made by the 
Sponsor or designated third party (eg, contract research organization [CRO]) as 
required by national law. 
10.2 Approval of Study Documents 
The study protocol, a sample of the subject information and informed consent form, 
any other materials provided to the subjects, and further requested information will be 
submitted by the Sponsor or the Investigator to the appropriate IEC/IRB and the 
Regulatory Authority. The study must be approved by the IEC/IRB and the Regulatory 
Authority before any IMP may be shipped to the study sites and any subject is exposed 
to a study-related procedure. 
The Sponsor, the Investigator, and any third party (eg, CRO) involved in obtaining 
approval must inform each other in writing that all ethical and legal requirements have 
been met before the first subject is enrolled in the study. 
10.3 Subject Information and Informed Consent 
The Investigator will obtain freely given written consent from each subject after an 
appropriate explanation of the aims, methods, anticipated benefits, potential hazards, 
and any other aspect of the study which is relevant to the subject’s decision to 
participate. The informed consent form must be signed, with name and date and time 
noted by the subject, before the subject is exposed to any study-related procedure, 
including Screening tests for eligibility. 
For subjects not capable of giving legal consent, written consent must be obtained from 
the LAR. 
The Investigator will explain that the subjects are completely free to refuse to enter the 
study or to withdraw from it at any time, without any consequences for their further care 
and without the need to justify. The Investigator will complete the informed consent 
section of the CRF for each subject enrolled. 

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Each subject will be informed that his/her medical (source) records may be reviewed 
by the study monitor, a quality assurance auditor, or a health authority inspector, in 
accordance with applicable regulations, and that these persons are bound by 
confidentiality obligations. 
10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed upon between the Investigator 
(Coordinating Investigator in multi-center studies) and the Sponsor prior to its 
implementation. Any such amendments will be submitted to the competent IEC/IRB 
and/or competent authority responsible as required by applicable regulations. 
IEC/IRB approval will, at a minimum, be requested for any change to this protocol 
which could affect the safety of the subjects, the objective/design of the study, any 
increase in dosage or duration of exposure to the IMP, an increase in the number of 
subjects treated, the addition of a new test or procedure, or the dropping of a test 
intended to monitor safety. 
10.5 Confidentiality of Subject Data 
The Investigator will ensure that the subject’s confidentiality is preserved. On CRFs 
submitted to the Sponsor, the subjects will not be identified by their names, but by a 
unique subject identifier.  
Transmission of any confidential subject documents from the investigative site to the 
Sponsor’s 3rd party designee (eg, consent forms, source records, etc.) will occur via a 
secure cloud-based portal with advanced security features such as audit trails and 
two-factor authentication upon each log-in. This usage is compliant with the FDA 
Guidance on Conducting Clinical Trials during the COVID-19 Public Health Emergency 
(dated 03Jun2020). Subjects have consented to the recording and inspection of their 
personal data via the informed consent form, by the Sponsor or designee, in addition 
to ethics committees, national and international competent authorities and the FDA. 
 

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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Periodic Monitoring 
Due to the current COVID-19 pandemic travel and hospital visitation restrictions, most 
hospitals do not permit monitors to visit the sites or pharmacies to conduct in-person 
study monitoring and data review. In order for the Sponsor to maintain oversight of the 
study data investigators must make study source records available for remote review 
by the study monitor in compliance with local and federal guidelines. Data monitoring 
will be conducted on an ongoing basis.  
If in-person monitoring visits become possible, the monitor will review all study-related 
source data/records, verify the adherence to the protocol and the completeness, 
correctness, and accuracy of all CRF entries compared to source data. The 
Investigator will cooperate with the monitor to ensure that any discrepancies identified 
are resolved. 
The monitor must be given direct access to source documents (original documents, 
data, and records). Direct access includes permission to examine, analyze, verify, and 
reproduce any records and reports that are important to the evaluation of the clinical 
study. Source data will be available for all data in the CRFs, including all laboratory 
results. 
The Clinical Monitoring Plan will describe the requirements for remote and in-person 
monitoring procedures. 
11.2 Audit and Inspection 
The Investigator will make all study-related source data and records available to a 
qualified quality assurance auditor mandated by the Sponsor, or to IEC/IRB/regulatory 
inspectors, after reasonable notice. The main purposes of an audit or inspection are to 
confirm that the rights and welfare of the subjects have been adequately protected, 
and that all data relevant for the assessment of safety and efficacy of the IMP have 
been reported to the Sponsor. 

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12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and the Sponsor’s SOPs) 
will be prepared by the Sponsor after completion of the study. The Coordinating 
Investigator will approve the final study report after review. 
12.2 Publication Policy 
The results of this study may be published or presented at scientific meetings. 
If this is envisaged by an Investigator, the Investigator agrees to inform the Sponsor 
and to submit all manuscripts or abstracts to the Sponsor prior to submission to an 
editorial board or scientific review committee. This will allow the Sponsor to protect 
proprietary information and to provide comments based on information that may not 
yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will support 
publication of multi-center studies only in their entirety and not as individual center 
data. Authorship will be determined by mutual agreement. 

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Page 78 of 81 
13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a subject in association 
with the IMP or participation in the study, the Sponsor will contract insurance in 
accordance with local regulations. 
The Investigator is responsible for dispensing the IMP according to this protocol and 
for its secure storage and safe handling throughout the study. 

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9