Clinical trial NCT04480424
Conditions: COVID-19
Keywords: Coronavirus Disease Severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 Coronavirus Infections Coronaviridae Infections Virus Diseases Immunoglobulins Antibodies Gamma-globulins Immunoglobulins, Intravenous Immunologic Factors Physiological Effects of Drugs
Sponsor: Grifols Therapeutics LLC
Start date: 2020-09-17; Completion date: 2021-10-25
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to determine if a high dose of Intravenous Immune Globulin (IVIG) plus Standard Medical Treatment (SMT) can reduce all-cause mortality versus SMT alone in hospitalized participants with COVID-19 requiring admission to the ICU through Day 29.

Detailed description:

Arms: arm 1: Participants received 2 grams per kilogram (g/kg) of GAMUNEX-C, which was capped to a maximum of 160 g infusion intravenously (IV) for participants weighing more than 80 kg on Day 1. The 2 g/kg net total dose was divided either into infusions of 500 mg/kg body weight over 4 days or 400 mg/kg body weight over 5 days as per investigator's decision. Participants received standard of care interventions as per Principal Investigator's discretion from Day 1 up to Day 29. arm 2: Participants received all standard of care interventions required as per Principal Investigator's discretion throughout the participant's hospitalization, from Day 1 to Day 29.
Interventions: intervention 1: GAMUNEX-C intervention 2: Standard Medical Treatment
Intervention descriptions: intervention 1: Intravenous Immune Globulin (Human), 10% Caprylate/Chromatography Purified. intervention 2: SMT per local policies or guidelines.

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Multicenter, Randomized, Open-label  Parallel Group  Pilot Study to 
Evaluate Safety and Efficacy of High Dose Intravenous Immune Globulin (IVIG)
Plus Standard Medical Treatment  (SMT) Versus SMT Alone in Subjects With  
COVID-19 Requiring Admission to the Intensive Care Unit
NCT Number: 
NCT04480424
Document Date: 
Protocol Version 4.0: 19 July 2021























































































































































































SAP_001.pdf: 
Official Title: 
A Multicenter, Randomized, Open-label Parallel Group Pilot Study to 
Evaluate Safety and Efficacy of High Dose Intravenous Immune Globulin (IVIG)
Plus Standard Medical Treatment  (SMT) Versus SMT Alone in Subjects With  
COVID-19 Requiring Admission to the Intensive Care Unit
NCT Number: 
NCT04480424
Document Date: 
SAP Version 2.0: 15 March 2021








 
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Table of Contents 
LIST OF ABBREVIATIONS .................................................................................................................... 6 
SAP REVISIONS ........................................................................................................................................ 8 
1. 
INTRODUCTION ............................................................................................................................... 9 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................................... 9 
2.1 
OBJECTIVES ................................................................................................................................... 9 
2.1.1 Primary Efficacy Objective ....................................................................................................... 9 
2.1.2 Secondary Efficacy Objectives .................................................................................................. 9 
2.1.3 Exploratory Efficacy Objectives ............................................................................................... 9 
2.1.4 Safety Objective......................................................................................................................... 9 
2.2 
ENDPOINTS .................................................................................................................................. 10 
2.2.1 Primary Efficacy Endpoint ...................................................................................................... 10 
2.2.2 Secondary Efficacy Endpoints ................................................................................................ 10 
2.2.3 Exploratory Efficacy Endpoints .............................................................................................. 11 
2.2.4 Safety Endpoints ...................................................................................................................... 11 
3. 
INVESTIGATIONAL PLAN ........................................................................................................... 12 
3.1 
STUDY DESIGN ............................................................................................................................ 12 
3.2 
TREATMENT ................................................................................................................................ 13 
3.2.1 Randomization Scheme and Treatment Arm Assignment ........................................................ 13 
3.2.2 Blinding ................................................................................................................................... 13 
3.2.3 Dosing Schedule ...................................................................................................................... 13 
3.2.4 Treatment Compliance ............................................................................................................ 13 
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ......................................................... 13 
4.1 
DATA QUALITY ASSURANCE ...................................................................................................... 14 
4.2 
ANALYSIS POPULATIONS ............................................................................................................ 14 
4.3 
ASSESSMENT WINDOWS ............................................................................................................. 14 
4.4 
HANDLING OF DROPOUTS OR MISSING DATA ............................................................................. 14 
4.5 
MULTIPLE COMPARISONS ........................................................................................................... 15 
4.6 
DATA DERIVATIONS AND TRANSFORMATIONS ........................................................................... 15 
5. 
STUDY SUBJECTS .......................................................................................................................... 16 
5.1 
DISPOSITION OF SUBJECTS .......................................................................................................... 16 
5.2 
PROTOCOL DEVIATIONS .............................................................................................................. 16 
5.3 
DEMOGRAPHIC CHARACTERISTICS ............................................................................................. 16 
5.4 
BASELINE CHARACTERISTICS ..................................................................................................... 16 
5.5 
MEDICAL HISTORY...................................................................................................................... 16 
5.6 
CONCOMITANT MEDICATIONS .................................................................................................... 17 
6. 
EFFICACY ANALYSES .................................................................................................................. 17 
6.1 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS ......................................................................... 17 
6.2 
SECONDARY EFFICACY ENDPOINTS AND ANALYSES.................................................................. 18 


 
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Time to ICU discharge (Actual and Medical Equivalence) ................................................................ 18 
Duration of ICU stay (Actual and Medical Equivalence) ................................................................... 19 
Duration of mechanical ventilation .................................................................................................... 19 
Time to hospital discharge (Actual and Medical Equivalence) .......................................................... 19 
Duration of Hospitalization (Actual and Medical Equivalence) ........................................................ 20 
Duration of any oxygen use ................................................................................................................ 20 
Ordinal scales ..................................................................................................................................... 20 
Number of subjects developed ARDS .................................................................................................. 21 
Assessment of SOFA score .................................................................................................................. 21 
Assessment of clinical severity ............................................................................................................ 22 
Time to clinical response .................................................................................................................... 22 
6.3 
EXPLORATORY EFFICACY ENDPOINTS AND ANALYSES ............................................................. 22 
7. 
SAFETY ANALYSIS ........................................................................................................................ 23 
7.1 
EXTENT OF EXPOSURE AND COMPLIANCE .................................................................................. 23 
7.2 
ADVERSE EVENTS ....................................................................................................................... 23 
7.2.1 Treatment-emergent Adverse Events....................................................................................... 23 
7.2.2 Adverse Event Severity ............................................................................................................ 24 
7.2.3 Adverse Event Relationship to IP ............................................................................................ 24 
7.2.4 Serious Adverse Events ........................................................................................................... 24 
7.2.5 Adverse Event Summaries ....................................................................................................... 24 
7.3 
CLINICAL LABORATORY ASSESSMENTS ..................................................................................... 25 
7.4 
VITAL SIGNS................................................................................................................................ 26 
7.5 
OTHER SAFETY MEASURES ......................................................................................................... 26 
8. 
INTERIM ANALYSES .................................................................................................................... 26 
9. 
SAMPLE SIZE AND POWER CALCULATIONS ....................................................................... 26 
10. 
REFERENCES .............................................................................................................................. 27 
11. 
APPENDIX .................................................................................................................................... 28 
11.1 
APPENDIX A: SCHEDULE OF EVENTS .......................................................................................... 28 


 
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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ANOVA/ANCOVA Analysis of variance/covariance 
ARDS 
Acute respiratory disease syndrome 
ATC 
Anatomical, Therapeutic, and Chemical 
BMI 
Body mass index 
CI 
Confidence interval 
CIF 
Cumulative Incidence Function 
COVID-19 
Coronavirus disease 2019 
eCRF 
Electronic Case Report Form 
CRP 
C-reactive protein 
ECMO 
Extracorporeal Membrane Oxygenation 
FEU 
Fibrinogen Equivalent Units 
ICU 
Intensive care unit 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL 
interleukin 
IP 
Investigational product 
ITT 
Intention to treat 
IV 
Intravenous 
KM 
Kaplan-Meier 
LS 
Least-Squares 
IVIG 
Intravenous immune globulin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects model for repeated measures 
NAT 
Nucleic acid amplification technology 
NCI 
National Cancer Institute 
NEWS 
National Early Warning Score 
NIH 
National Institutes of Health 


 
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Abbreviation 
Definition 
PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
PP 
Per Protocol 
PT 
Preferred term 
RT-PCR 
Reverse transcriptase PCR 
SAE 
Serious adverse event 
SAF 
Safety 
SaO2 
Arterial oxygen saturation 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SISRC 
Study-Independent Safety Review Committee 
SMT 
Standard medical treatment 
SOC 
System organ class 
SOFA 
Sequential Organ Failure Assessment 
SpO2 
Oxygen Saturation by pulse oximetry 
TEAE 
Treatment-emergent adverse event 
TNF-α 
tumor necrosis factor-α 
WHO 
World Health Organization 
 
 
 


 
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SAP REVISIONS 
Version 1.0 of the SAP was finalized based on Protocol version 3.0 (30 October 2020). The 
following table details subsequent changes made to the SAP. 
Revision History 
SAP 
Version # 
SAP 
Section 
Modification 
Description and Rationale 
2.0 
5.6 
Added “or Preferred” 
The COVID-19 specific, 
potentially disease modifying 
medications may be identified by 
Preferred term. 
2.0 
6.2 
Added "Duration of ICU stay 
(Actual and Medical Equivalence)" 
analysis section 
 
Added "Duration of Hospitalization 
(Actual and Medical Equivalence)" 
analysis section 
 
Added age and gender as covariates 
to the MMRM model 
Added to reflect the planned 
analysis. 
 
Added to reflect the planned 
analysis. 
 
Added to reflect the planned 
analysis. 
 
 


 
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1. INTRODUCTION 
This statistical analysis plan (SAP) is based on the Protocol # GC2007 Version 3.0, dated 30 
October, 2020, and titled “A Multicenter, Randomized, Open-label Parallel Group Pilot Study to 
Evaluate Safety and Efficacy of High Dose Intravenous Immune Globulin (IVIG) plus Standard 
Medical Treatment (SMT) versus SMT alone in Subjects with COVID-19 Requiring Admission 
to the Intensive Care Unit.”  See the study protocol for full details.  
This document details the statistical methods planned to perform the interim and final analyses of 
the study. 
2. OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Efficacy Objective 
To determine if high dose IVIG plus SMT can reduce all-cause mortality versus SMT alone in 
hospitalized subjects with COVID-19 requiring admission to the intensive care unit (ICU) through 
Day 29. 
2.1.2 
Secondary Efficacy Objectives 
To compare high dose IVIG plus SMT versus SMT alone with regard to clinical efficacy as 
assessed by clinical severity, duration of hospital and ICU stay, dependency on oxygen and 
ventilatory support, and clinical response criteria including National Early Warning Score 
(NEWS)[1], clinical status scale[2], and Sequential Organ Failure Assessment Score (SOFA)  
through Day 29 in hospitalized subjects ill with COVID-19 requiring admission to the ICU. 
2.1.3 
Exploratory Efficacy Objectives 
The exploratory objectives of the study are: 
• To evaluate the effect of high dose IVIG plus SMT versus SMT alone with regard to 
quantitative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and 
anti-SARS-CoV-2 antibodies in hospitalized subjects with COVID-19. 
• To evaluate whether high dose IVIG plus SMT versus SMT alone reduces the frequency 
of hyperinflammation based on a pre-specified biochemical definition through Day 29. 
• To evaluate cytokine profile changes from baseline for high dose IVIG plus SMT versus 
SMT alone through Day 29. 
2.1.4 
Safety Objective 
To determine the safety and tolerability profile through Day 29 of high dose IVIG plus SMT versus 
SMT alone in hospitalized subjects with COVID-19. 


 
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2.2 
Endpoints 
2.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is all-cause mortality rate through Day 29. 
2.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include the following: 
• Time to actual ICU discharge: defined as duration of ICU stay from Day 1 through Day 29 
o Additionally, time to a medical equivalence of ICU discharge will be recorded and 
analyzed (defined as the time point when the patient no longer requires ICU level 
care, ie, not requiring invasive mechanical ventilation, or intensive monitoring such 
as arterial line or central line placement, administration of IV vasopressors to 
support blood pressure, or O2 supplementation greater than that delivered by nasal 
cannula) 
• Duration of mechanical ventilation from Day 1 through Day 29 
• Time to actual hospital discharge: defined as duration of hospitalization from Day 1 
through Day 29 
o Additionally, time to a medical equivalence of hospital discharge will be recorded 
and analyzed (defined as the time point when the patient no longer requires 
supplemental oxygen and no longer requires ongoing medical care [yet may not be 
discharged from hospital for social or quarantine reasons]) 
• Duration of any oxygen use Day 1 through Day 29 
• Absolute value and mean change from baseline in the Ordinal scale Day 1 through Day 29  
The Ordinal scale is as follows: 
1) Death; 
2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane       
    oxygenation (ECMO); 
3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
4) Hospitalized, requiring supplemental oxygen; 
5) Hospitalized, not requiring supplemental oxygen; 
6) Not hospitalized, limitation on activities; 
7) Not hospitalized, no limitations on activities. 
• Proportion (percentage) of subjects in each severity category of the 7-point Ordinal scale 
at Day 15 and Day 29 
• Number of subjects who develop Acute Respiratory Distress Syndrome (ARDS) overall 
and distribution by severity through Day 29  
• Change from baseline in SOFA score at Day 5, Day 15, and Day 29 


 
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• Assessment of Clinical Severity: Change in NEWS from baseline (Day 1 through Day 29).  
The NEWS has demonstrated an ability to discriminate patients at risk of poor 
outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen 
saturation, any supplemental oxygen, temperature, systolic blood pressure, heart 
rate, level of consciousness [Alert, Voice, Pain, Unresponsive]).  
• Time to clinical response: NEWS ≤ 2 maintained for 24 hours, Day 1 through Day 29 
2.2.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include: 
• Change from baseline in quantitative SARS-CoV-2 viral load by nucleic acid amplification 
technology (NAT) or polymerase chain reaction (PCR; real-time reverse transcriptase 
[RT]-PCR) to Days 5, 15, and 29 
• Change from baseline in quantitative anti- SARS-CoV-2 immunoglobulin M (IgM) and 
IgG antibodies to Days 5, 15, and 29 
• Proportion of subjects with evidence of hyperinflammation on Day 1, Day 5, Day 15, and 
Day 29 defined as: 
a) Lymphocyte counts <1000 cells/μL, AND  
b) Two of the following 4 criteria: 
i) 
Ferritin > 500ng/mL, 
ii) 
LDH > 300 U/L, 
iii) 
D-Dimers > 1000 ng/mL (fibrinogen equivalent units [FEU]) or > 2 times upper 
normal limit, 
iv) 
C-reactive protein (CRP) > 70 mg/L 
• Change from baseline in cytokine profile (interleukin (IL)-1β, IL-10, IL-6, IL-8 IL-2, 
interferon γ, and tumor necrosis factor-α [TNF-α]) to Days 5, 15, and 29 
2.2.4 
Safety Endpoints 
The safety endpoints include: 
• Cumulative incidence of treatment-emergent serious adverse events (SAEs) and potentially 
related SAEs through Day 90 Phone Check 
• Cumulative incidence of Grade 3-5 treatment-emergent adverse events (TEAEs) and 
potentially related severe TEAEs through Day 29 as defined in the Common terminology 
Criteria for Adverse Events (CTCAE), US Department of Health and Human Services, 
National Institutes of Health (NIH), and National Cancer Institute (NCI) 
• Cumulative incidence of all TEAEs and potentially related TEAEs through Day 29 


 
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3. INVESTIGATIONAL PLAN 
3.1 
Study Design 
This is a prospective, multi-center, randomized (1:1), open-label, pilot study of high dose IVIG 
plus SMT versus SMT alone in subjects with COVID-19 who are hospitalized and require ICU 
admission. The first 6 subjects randomized will be staggered with an interval of no less than 1 
week between subjects. If there are no definitely related SAEs reported 1 week after the 
randomization of the 6th subject, competitive enrollment would ensue thereafter. If a definitely 
related SAE were to be reported among these 6 subjects, the Study-Independent Safety Review 
Committee (SISRC) would carefully review and evaluate the case and make appropriate 
recommendations with regard to study status. 
In this study, symptomatic subjects with positive PCR (RT-PCR) or other FDA-approved or 
regulatory-authority-approved diagnostic assay for SARS-CoV-2 in any specimen during the 
current hospital admission prior to randomization will receive SMT or SMT plus a net total dose 
of IVIG of 2 g/kg (body weight) administered in divided doses over 4 to 5 consecutive days at the 
Principal Investigator (PI)’s discretion. The maximum dose will be capped at 160 g (equivalent to 
body weight of 80 kg). 
Specifically, subjects randomized to combination high dose IVIG will receive the first intravenous 
(IV) infusion of IVIG on Day 1. The total net dose of 2 g/kg body (capped at a maximum of 160 
g for subjects weighing more than 80 kg) will be administered in divided doses over consecutive 
days. At the discretion of the PI, the 2 g/kg net total dose may be divided either into (a) infusions 
of 500 mg/kg body weight over 4 days OR (b) 400 mg/kg body weight over 5 days.  
Approximately 100 subjects (who meet the inclusion/exclusion criteria specified in Protocol 
Sections 5.1 & 5.2) will be randomized in a 1:1 (IVIG plus SMT : SMT alone) ratio with an interim 
analysis after 50 subjects (approximately 25 per group). There will be no interruption in study 
conduct during interim analysis as this simply represents sponsor safety due diligence. 
All subjects will be followed daily through Day 10. After Day 10, if subjects are discharged from 
the hospital, evaluations at Day 15 and 29 are required. Berlin criteria for ARDS and SOFA score 
will be assessed on Day 1, 5, 15, and 29. Subjects remaining hospitalized will be followed daily 
through Day 29. Phone Checks will occur at Day 60 and Day 90 for vital status (living or 
deceased), any hospital re-admissions or serious/non-serious AEs after the Day 29 Final Clinic 
Visit. See Appendix A for the Schedule of Events. 
Clinical trial finalization will coincide with the last study visit of the last subject enrolled in the 
clinical trial. For an individual subject, end of study for the purposes of determining disposition 
and successful study completion is the Day 29/Final Clinic Visit performed at the scheduled on-
study timeframe. 
An overview of the study design is presented below: 


 
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3.2 
Treatment 
3.2.1 
Randomization Scheme and Treatment Arm Assignment 
Subjects will be randomized 1:1 to receive either combination treatment with Gamunex-C plus 
SMT or SMT alone. A central randomization will be used for this study. A randomization list 
containing the randomization numbers and the corresponding randomized treatment assignments 
will be generated and be stored in a secured area that is only accessible to the randomization team.  
3.2.2 
Blinding 
Not applicable as this is an open-label study.     
3.2.3 
Dosing Schedule 
During this clinical trial, subjects randomized to receive combination Gamunex-C plus SMT will 
receive a total dose of 2 g/kg body weight (capped to a maximum of 160 g for subjects weighing 
more than 80 kg) in divided doses at the discretion of the PI over 4 or 5 days. The first IV infusion 
will be on Day 1. 
3.2.4 
Treatment Compliance 
Reasons for any deviation from the administration of less than 100% of the investigational product 
(IP) dose must be recorded in the subject’s medical records. 
The investigator or designee is responsible for maintaining accurate records of Gamunex-C 
administered at his/her study center. 
4. GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
Unless otherwise specified, continuous variables will be summarized using descriptive statistics 
(n, mean, standard deviation, median, minimum, and maximum).  Categorical variables will be 
summarized showing the number and percentage of subjects within each category.   
Summary results will be provided for each treatment group.  All tabulations will be based on 
pooled data across centers. 
All statistical tests will be two-sided and tested at the 5% level of significance.   


 
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Analyses will be performed using SAS for Windows statistical software, version 9.4 or higher 
(SAS, Cary, NC), except where other software may be deemed more appropriate. In the event that 
other software is used to perform some analyses, the details will be provided in the Clinical Study 
Report. 
will perform all efficacy and safety analyses described in this SAP.   
Subject data will be listed, sorted by treatment group and subject number. When applicable, listings 
will be additionally sorted by visit and assessment date/time. 
4.1 
Data Quality Assurance 
Once all the source verification is complete, all queries are resolved, and the database has been 
updated appropriately, the database will be locked and made available to 
Biostatistics for final 
analysis.  
Data may be pulled by 
 Biostatistics for interim analysis at a time when source verification 
and query resolution is ongoing. 
All SAS programs used to create analysis data sets, tables, and listings are double programmed. 
The SAS outputs will be compared and the programs will be updated until the outputs match. 
4.2 
Analysis Populations 
The following three analysis populations will be defined for this study: 
The intent-to-treat (ITT) population is defined as all subjects who are randomized. All efficacy 
analyses will be carried out using the ITT population based on the randomized treatment. 
The Per-Protocol (PP) population is defined as the subset of subjects included in the ITT 
population who do not present major protocol violations which might have an impact on the 
primary efficacy endpoint, and complete at least 80% of the IP. The primary efficacy analyses will 
be carried out using the PP population if different from the ITT population. 
The Safety (SAF) population for the combination arm is defined as the subset of subjects who 
receive at least any amount of Gamunex-C in addition to SMT. The SAF population for the SMT 
alone arm will include all subjects randomized to this arm, because by definition SMT is 
universally provided and hence all randomized subjects would have received SMT. All safety 
analyses will be carried out using the SAF population based on the treatment actually received 
rather than randomized treatment. 
4.3 
Assessment Windows 
Data will be summarized by nominal study visit recorded in the database. 
4.4 
Handling of Dropouts or Missing Data 
Missing data will be treated as missing and no method for imputation is planned for study 
population or safety analyses except for the partial end dates/times for concomitant medications 
(Section 5.6) and partial onset dates/times for AEs (Section 7.2.1). When applicable, missing data 
for binary and selected continuous efficacy endpoints will be imputed using a most 
conservative/worst case approach, and the related details are described in Section 6. 
Time to event endpoints will have events coded as right censored or competing events per the 


 
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following table: 
Table 1 Missing Data and Competing Events Coding for Time to Event Data Analyses 
Endpoint 
Right Censoring and Competing Events 
Subject Survival  
Subjects who are still alive as of the last known follow-up will 
be right censored as of the date of last subject contact when the 
subject was known to be alive. 
Time to actual ICU Discharge 
or Medical Equivalence of  
ICU Discharge (if different 
from actual ICU discharge 
date) 
Subjects who did not discharge or medical equivalence of 
discharge from the ICU at any time during follow-up will be right 
censored as of the date of last subject contact when the subject 
was known to be in the ICU. Subject death will be considered a 
competing event. Competing risk methods e.g., cumulative 
incidence function (CIF) will be used to account for competing 
events in the analysis. 
Time to actual Hospital 
Discharge or Medical 
Equivalence of Hospital 
Discharge (if different from 
actual hospital discharge date) 
Subjects who did not discharge or medical equivalence of 
discharge from the hospital at any time during follow-up will be 
right censored as of the date of last subject contact when the 
subject was known to be in the hospital. Subject death will be 
considered a competing event. Competing risk methods e.g., 
cumulative incidence function (CIF) will be used to account for 
competing events in the analysis. 
Time to Clinical Response 
Subjects who did not experience clinical response or died at any 
time during follow-up will be right censored as of the date of last 
non-missing assessment of NEWS on or prior to Day 29.  
4.5 
Multiple Comparisons 
Because of the exploratory nature of this study, there will be no adjustment for multiple 
comparisons.     
4.6 
Data Derivations and Transformations 
The following derivations will be used in this study: 
Study Day:  
• Date of assessment – date of randomization + 1 for assessments done on or after date of 
randomization 
• Date of assessment – date of randomization for assessments done before date of 
randomization 
Baseline Observation: the last non-missing value prior to randomization.  
Duration:  
• Duration in days = end date – start date + 1 
• Duration in minutes = end time in minutes – start time in minutes  


 
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Origin or Start Date for Time to Event Endpoints:  
• Time to death: date of randomization 
• Time to ICU Discharge (actual and medical equivalence, if applicable): date of 
randomization or date of ICU admission, whichever was later  
• Time to Hospital Discharge (actual and medical equivalence, if applicable): date of 
randomization 
• Time to Clinical Response: date of randomization 
Event Date for Time to Clinical Response:  
• If a subject met the criteria for clinical response at multiple assessments, the date of the 
first assessment meeting the definition of clinical response will be used as the event date 
for deriving time to clinical response. 
5. STUDY SUBJECTS 
5.1 
Disposition of Subjects 
A table of frequency counts and percentages of all subjects who are screened, randomized, and in 
each analysis population will be provided. Subject disposition including study completion status 
and reasons for early termination will be tabulated by treatment group and overall.  A by subject 
listing will be provided. 
5.2 
Protocol Deviations 
Distribution of the types of protocol deviations and the number of subjects that deviate from the 
protocol will be tabulated for the treatment groups in the ITT population. Protocol deviations will 
also be tabulated by severity (e.g., minor or major). A listing of all protocol deviations will be 
provided. 
5.3 
Demographic Characteristics 
Descriptive statistics will be used to summarize the demographic characteristics (age, gender, race, 
ethnicity, height, weight, and Body Mass Index [BMI]) for the ITT population.  A by subject listing 
will be provided. 
5.4 
Baseline Characteristics 
Baseline characteristics of ITT subjects including historical SARS-CoV-2 results and pregnancy 
test will be listed and tabulated if appropriate.   
5.5 
Medical History 
All medical conditions will be classified by system organ class (SOC) and preferred term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA). The number and percent of 
subjects with each medical condition will be presented for each SOC and PT for the ITT 
population. 


 
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5.6 
Concomitant Medications 
All concomitant medications collected will be coded using the World Health Organization (WHO) 
Drug Dictionary.  The number and percent of ITT subjects using concomitant medications will be 
tabulated by Anatomical, Therapeutic, and Chemical (ATC) level 2 and by ATC level 4.  If the 
ATC level 2 or 4 term is missing, the higher ATC level term will be used in the medication 
summary table and data listing. 
Prior medications will be summarized separately from concomitant medications, for the overall 
ITT population. 
Prior medications are defined as medications that ended prior to the date of randomization. 
Concomitant medications are defined as medications that started at any time but ended on or after 
the date of randomization, including those that are ongoing at study completion. In the case of a 
missing or partial end date/time, in order to determine whether a medication is prior or 
concomitant, the following conservative imputation rule will be used: the unknown portions of a 
medication end date/time will be imputed to the latest possible. The imputed medication end 
date/time will then be compared with the date of randomization to determine if the medication is 
prior or concomitant.  
Note the imputed end date/time will only be used to determine whether a medication is prior or 
concomitant. The actual date/time reported on the electronic case report forms (eCRFs) will be 
presented in the listings. 
All concomitant medications collected will be reviewed in a data review meeting conducted prior 
to database lock. ATC or Preferred terms for COVID-19 specific, potentially disease modifying 
medications will be identified by the study team.  Subsequently, a tabular summary by treatment 
group of these COVID-19 specific concomitant mediations based on the identified ATC terms will 
be generated. If clinically important imbalance was observed in the use of these medications 
between the 2 treatment groups, additional supplemental efficacy analyses may be performed in a 
post-hoc manner to adjust for the difference(s) in such medication use.  
In addition, the daily fluid balance (intake and output) will be recorded while subjects are in 
hospital through Day 10. A sensitivity analysis on potential effects of fluid balance will be 
performed by using descriptive statistics.  
6. EFFICACY ANALYSES 
All efficacy analyses will be carried out using the ITT population. Data on all efficacy endpoints 
will be listed and tabulated if appropriate. 
6.1 
Primary Efficacy Endpoint and Analysis 
The primary efficacy analysis will be carried out on the ITT population. If there is difference 
between the PP population and ITT population, the analysis will be repeated using the PP 
population. 
The primary efficacy variable is all-cause mortality rate through Day 29. Subject status 
(Alive/Death) will be recorded in the database. If the vital status of the subject is missing, then the 
subject will be treated as death for the primary analysis.  


 
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The null hypothesis is that the all-cause mortality rate through Day 29 in subjects administered 
Gamunex-C plus SMT will be no different than the rate in subjects provided SMT alone; H0: πt - 
πc = 0.  The alternative hypothesis is that the all-cause mortality rate through Day 29 in subjects 
administered Gamunex-C plus SMT will be different than the rate in subjects provided SMT alone; 
H1: πt - πc ≠ 0. 
The proportion of subjects who die within each treatment group will be presented along with a 
two-sided exact (Clopper-Pearson) 95% confidence interval (CI). 
The observed difference in the mortality rate (proportion of deceased subjects) between treatment 
groups along with the exact unconditional 95% CI for risk difference will be calculated. The null 
hypothesis will be tested using Fisher’s exact method and the p-value will be reported. 
An alternative primary analysis will be performed in which the survival rates will be estimated 
using the Kaplan-Meier (KM) method. The KM estimates along with 95% CIs and survival curves 
will be provided. Based on the KM estimates, the survival probabilities and associated 95% CIs 
on Days 15 and 29 will be reported; in addition, the 25th, 50th (median), and 75th percentiles of the 
survival time with associated 95% CIs will be provided, as data permit. The survival rates between 
treatment groups will be compared using Log-rank test and the p-value from Log-rank test will be 
presented. 
Subgroup analyses of the primary efficacy endpoint by baseline characteristics such as age group 
(with age cutoffs defined either by absolute values or by a summary metric [e.g., median] of the 
observed baseline values) and gender will be performed using the analysis method described 
above, if appropriate. 
If for one or more subjects the actual treatment received is different from the randomized treatment 
and if deemed necessary, sensitivity analysis of the primary efficacy endpoint will be performed 
by repeating the primary efficacy analysis as described above in this section, but with subjects 
grouped according to the actual treatment received instead of the randomized treatment. 
6.2 
Secondary Efficacy Endpoints and Analyses 
Time to ICU discharge (Actual and Medical Equivalence) 
Time to actual ICU discharge is defined as duration of actual ICU stay from Day 1 through Day 
29 that is recorded on the eCRF All Visits page “General Duration of Hospitalization, & Overall 
Requirement for Mechanical Ventilation, ICU Admission and/or Oxygen Supplementation”. The 
proportion of subjects who are discharged from the ICU will be estimated using the CIF. Deaths 
that occur prior to discharge from the ICU will be treated as a competing risk.  The estimated 
cumulative incidence and associated two-sided 95% CI on Days 15 and 29 will be displayed. Test 
for equality of the CIF between treatment groups will be conducted using Gray’s test[3]. 
Additionally, medical equivalence of ICU discharge date will be recorded on the eCRF if it is 
different from the actual ICU discharge date, and the time to medical equivalence of ICU discharge 
will be analyzed using the same method as described above. The proportion of subjects who are 
medical equivalence of discharge from the ICU will be estimated using the CIF. Deaths that occur 
prior to medical equivalence of ICU discharge will be treated as a competing risk.  The estimated 
cumulative incidence and associated two-sided 95% CI on Days 15 and 29 will be displayed. Test 
for equality of the CIF between treatment groups will be conducted using Gray’s test. 


 
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Duration of ICU stay (Actual and Medical Equivalence) 
The duration (number of days) of ICU stay from post-randomization through Day 29 will be 
calculated based on ICU admission and discharge (actual and medical equivalence) dates recorded 
on the eCRF.  Number of days in the ICU will be compared between treatment groups using an 
ANOVA model, including number of days in the ICU as a dependent variable and treatment group 
as a fixed effect. From this model, the LS means and 95% CIs for each treatment group, the 
treatment difference in the LS means, the 95% CI for the difference, and the associated p-value 
will be presented. If appropriate, an ANCOVA model may instead be used to additionally adjust 
for baseline characteristics such as age and gender. 
Subjects who died while in the ICU will be assigned as in the ICU for the number of days remaining 
from the day of death to Day 29 for the analysis. Subjects who were at ICU at study completion 
will be assigned an ICU end date equals to the date of completion for the purpose of deriving the  
number of ICU days. 
Duration of mechanical ventilation 
The duration (number of days) on mechanical ventilation from post randomization through Day 
29 will be calculated based on the start/stop dates of mechanical ventilation recorded on the eCRF 
All Visits page “General Duration of Hospitalization, & Overall Requirement for Mechanical 
Ventilation, ICU Admission and/or Oxygen Supplementation”.  Number of days on mechanical 
ventilation will be compared between treatment groups using an ANOVA model, including 
number of days on mechanical ventilation as a dependent variable and treatment group as a fixed 
effect. From this model, the LS means and 95% CIs for each treatment group, the treatment 
difference in the LS means, the 95% CI for the difference, and the associated p-value will be 
presented. If appropriate, an ANCOVA model may instead be used to additionally adjust for 
baseline characteristics such as age and gender. 
Subjects who died during the hospitalization without a stop date of mechanical ventilation recorded 
on the eCRF will be assigned as being on mechanical ventilation for the number of days remaining 
to Day 29 for the analysis.  Subjects who had mechanical ventilation ongoing at study completion 
will be assigned a mechanical ventilation end date equals to the date of completion for the purpose 
of deriving duration of mechanical ventilation. Subjects who are never placed on mechanical 
ventilation through Day 29 will be included in the analysis with a value of zero days on mechanical 
ventilation. 
A listing of all mechanical ventilation and oxygen administration data collected throughout the 
study will be provided. 
Time to hospital discharge (Actual and Medical Equivalence) 
Time to actual hospital discharge is defined as duration of hospitalization from Day 1 through Day 
29 that is recorded on eCRF All Visits page “General Duration of Hospitalization, & Overall 
Requirement for Mechanical Ventilation, ICU Admission and/or Oxygen Supplementation”. The 
proportion of subjects who are discharged from the hospital will be estimated using the CIF. Deaths 
that occur prior to discharge from the hospital will be treated as a competing risk.  The estimated 
cumulative incidence and associated two-sided 95% CI on Days 15 and 29 will be displayed. Test 
for equality of the CIF between treatment groups will be conducted using Gray’s test. 
Additionally, medical equivalence of hospital discharge date will be recorded on the eCRF if it is 


 
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different from the actual hospital discharge date, and the time to medical equivalence of hospital 
discharge will be analyzed using the same method as described above. The proportion of subjects 
who are medical equivalence of discharge from the hospital will be estimated using the CIF. Deaths 
that occur prior to medical equivalence of hospital discharge will be treated as a competing risk.  
The estimated cumulative incidence and associated two-sided 95% CI on Days 15 and 29 will be 
displayed. Test for equality of the CIF between treatment groups will be conducted using Gray’s 
test. 
Duration of Hospitalization (Actual and Medical Equivalence) 
The duration (number of days) of hospitalization from post-randomization through Day 29 will be 
calculated based on hospital admission and discharge (actual and medical equivalence) dates 
recorded on the eCRF.  Number of days in the hospital will be compared between treatment groups 
using an ANOVA model, including number of days in the hospital as a dependent variable and 
treatment group as a fixed effect. From this model, the LS means and 95% CIs for each treatment 
group, the treatment difference in the LS means, the 95% CI for the difference, and the associated 
p-value will be presented. If appropriate, an ANCOVA model may instead be used to additionally 
adjust for baseline characteristics such as age and gender. 
Subjects who died while in the hospital will be assigned as in the hospital for the number of days 
remaining from the day of death to Day 29 for the analysis. Subjects who were in the hospital at 
study completion will be assigned a hospitalization end date equals to the date of completion for 
the purpose of deriving the duration of hospitalization. 
Duration of any oxygen use 
The duration (number of Days) of any oxygen use from Day 1 through Day 29 will be calculated 
based on the start/stop date of using oxygen supplementation recorded on the eCRF All Visits page 
“General Duration of Hospitalization, & Overall Requirement for Mechanical Ventilation, ICU 
Admission and/or Oxygen Supplementation”. Number of days on oxygen will be compared 
between treatment groups using an analysis of variance (ANOVA) model, including number of 
days on oxygen as a dependent variable and treatment group as a fixed effect. From this model, 
the LS means and 95% CIs for each treatment group, the treatment difference in the LS means, the 
95% CI for the difference, and the associated p-value will be presented. If appropriate, an analysis 
of covariance (ANCOVA) model may instead be used to additionally adjust for baseline 
characteristics such as age and gender. 
Subjects who died during the hospitalization without a stop date of using oxygen supplementation 
recorded on the eCRF will be assigned as being on oxygen for the number of days remaining to 
Day 29 for the analysis.  Subjects who had oxygen use ongoing at study completion will be assigned 
an oxygen use end date equals to the date of completion for the purpose of deriving duration of 
oxygen use. Subjects who never received supplemental oxygen through Day 29 will be included 
in the analysis with a value of zero days of oxygen use. 
A listing of all supplemental oxygen and saturation (SpO2 and SaO2) data collected throughout the 
study will be provided. 
Ordinal scales 
a) The absolute value and change from baseline in the Ordinal scale from Day 1 through Day 


 
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29 will be summarized by treatment group and visit using descriptive statistics.   
Mean change in Ordinal scales through Day 29 will be evaluated by fitting a linear mixed-
effects model for repeated measures (MMRM).  The model will include change from 
baseline in Ordinal scale as the repeated dependent variable; treatment (as a class variable), 
visit (as a class variable), and treatment-by-visit interaction as fixed effects; baseline 
Ordinal scale, age and gender as covariates; and measures within subject at each visit as a 
repeated measure. An unstructured covariance matrix will be used to model the within-
subject error. If the fit of the unstructured covariance structure fails to converge, a 
compound symmetry covariance structure will be used. Parameters will be estimated using 
restricted maximum likelihood with the Kenward-Roger method for calculating the 
denominator degrees of freedom. Data collected starting at the Day 2 visit and up to the 
Day 29 visit will be included in this analysis. Missing data will not be imputed. From this 
model, the least-squares (LS) means and 95% CIs for each treatment group, the treatment 
difference in the LS means, the 95% CI for the difference, and the associated p-value will 
be reported on Days 15 and 29, as well as for the average across all post-baseline visits. 
b) The proportion of subjects in each severity category of the 7-point Ordinal scale at Day 15 
and Day 29 will be tabulated. The difference in severity category distribution between 
treatment groups at Day 15 and Day 29 will be examined using proportional-odds 
cumulative logit model. The cumulative logits model will compare lower ordinal scales to 
higher ones, or equivalently, less favorable outcomes to more favorable ones. The model 
may be adjusted for baseline characteristics such as age and gender, if appropriate. The 
estimated odds ratio and 95% CI will be presented. Graphical illustrations of the fitted 
model will also be presented for Day 15 and Day 29.  
The proportional odds assumption will be tested using a score test at the two-sided alpha 
level of 0.05. In the event that the proportional odds assumption is not satisfied, given the 
anti-conservative nature of the score test, the proportional odds model will still be used for 
the analysis, and the results will be presented along with the score test p-value to help put 
these results in context. If the proportion odds assumption is rejected or if the proportional 
odds model fails to converge, a sensitivity or alternative analysis using a non-parametric 
Wilcoxon Rank Sum test will be performed to estimate the median difference between the 
treatment groups. 
Number of subjects developed ARDS 
Berlin criteria for ARDS will be assessed on Days 1, 5, 15, and 29. The presence of ARDS and 
the degree of ARDS by Berlin criteria (Mild, Moderate, Severe) will be tabulated by treatment 
group at each visit. 
Assessment of SOFA score 
The SOFA score will be assessed on Days 1, 5, 15, and 29. Change from baseline in SOFA score 
to Days 5, 15, and 29 will be summarized for each treatment group by visit. 
Mean change in SOFA scores through Day 29 will be evaluated by fitting a linear mixed-effects 
model for repeated measures (MMRM).  The model will include change from baseline in SOFA 
score as the repeated dependent variable; treatment (as a class variable), visit (as a class variable 
including Days 5, 15, and 29), and treatment-by-visit interaction as fixed effects; baseline SOFA 


 
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score, age and gender as covariates; and measures within subject at each visit as a repeated 
measure. An unstructured covariance matrix will be used to model the within-subject error. If the 
fit of the unstructured covariance structure fails to converge, a compound symmetry covariance 
structure will be used. Parameters will be estimated using restricted maximum likelihood with the 
Kenward-Roger method for calculating the denominator degrees of freedom. Missing data will not 
be imputed. From this model, the least-squares (LS) means and 95% CIs for each treatment group, 
the treatment difference in the LS means, the 95% CI for the difference, and the associated p-value 
will be reported on Days 5, 15 and 29, as well as for the average across all post-baseline visits. 
Assessment of clinical severity 
The NEWS will be calculated based on 7 clinical parameters and recorded on the eCRF. The 
absolute value and change from baseline in the total score from Day 1 through Day 29 will be 
summarized by treatment group and visit using descriptive statistics.   
Change in NEWS total score through Day 29 will be evaluated by fitting a linear MMRM.  The 
model will include change from baseline in NEWS total score as the repeated dependent variable; 
treatment (as a class variable), visit (as a class variable), and treatment-by-visit interaction as fixed 
effects; baseline NEWS total score, age and gender as covariates; and measures within subject at 
each visit as a repeated measure. An unstructured covariance matrix will be used to model the 
within-subject error. If the fit of the unstructured covariance structure fails to converge, a 
compound symmetry covariance structure will be used. Parameters will be estimated using 
restricted maximum likelihood with the Kenward-Roger method for calculating the denominator 
degrees of freedom. Data collected starting at the Day 2 visit and up to the Day 29 visit will be 
included in this analysis. Missing data will not be imputed. From this model, the least-squares (LS) 
means and 95% CIs for each treatment group, the treatment difference in the LS means, the 95% 
CI for the difference, and the associated p-value will be reported on Days 15 and 29, as well as for 
the average across all post-baseline visits.  
Time to clinical response 
Clinical response is defined as the NEWS score <=2 maintained for 24 hours from Day 1 through 
Day 29. The time to the first occurrence of clinical response will be estimated using the Kaplan-
Meier (KM) method.  The KM estimates along with 95% CI, and survival curves will be provided. 
Based on the KM estimates, the probabilities of achieving first clinical response and associated 
95% CIs on Days 15 and 29 will be reported; in addition, the 25th, 50th (median), and 75th 
percentiles of the time to first clinical response with associated 95% CIs will be provided, as data 
permit. The survival rates between treatment groups will be compared using Log-rank test. The p-
value from Log-rank test will be presented. 
6.3 
Exploratory Efficacy Endpoints and Analyses 
• Change from baseline in quantitative SARS-CoV-2 viral load by NAT or PCR (RT-PCR) to 
Days 5, 15, and 29 will be summarized for each treatment group by visit. 
• Change from baseline in quantitative anti- SARS-CoV-2 IgM and IgG antibodies to Days 5, 
15, and 29 will be summarized for each treatment group by visit. 
• The proportion of subjects with evidence of hyperinflammation on Days 1, 5, 15, and 29 will 
be tabulated by treatment group. For this analysis, the denominator for calculating the 


 
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proportion at each visit and within each treatment group will be the number of subjects with 
nom-missing values for Lymphocyte counts AND for at least 2 of the following 4 lab 
parameters: Ferritin, LDH, D-Dimers, and C-reactive protein (i.e., the number of subjects for 
whom evidence of hyperinflammation could be assessed). 
• Change from baseline in cytokine profile (IL-1β, IL-10, IL-6, IL-8 IL-2, interferon γ, and TNF-
α) to Days 5, 15, and 29 will be summarized for each treatment group by visit. 
7. SAFETY ANALYSIS 
Safety assessments will include assessment of AEs, chemistry, hematology (complete blood count 
and differential), COVID-19 clinical features, vital signs, and hospital interventions.  All safety 
summaries (or analyses if applicable) will be conducted using the SAF population. No formal 
hypothesis testing will be performed to compare differences between treatment groups. 
7.1 
Extent of Exposure and Compliance 
The number of doses received, duration of infusion in minutes, infusion rate, the occurrence of 
dose interruption, whether 100% of study drug infused, total volume prepared, and total volume 
infused will be summarized for the Gamunex-C plus SMT group.  In addition, treatment 
compliance will be calculated and summarized for this treatment group. The summaries will 
include descriptive statistics of the treatment compliance as well as number and percentage of 
subjects with compliance between 80% and 120%. 
Treatment compliance (%) will be calculated as follows: 
(Total volume infused over all infusions [mL] /  
Total volume prepared over all infusions [mL]) x 100. 
7.2 
Adverse Events 
All AEs and serious AEs (SAEs) occurring on Day 1 through the Day 29 (±1 day)/Final Visit must 
be fully recorded in the subject’s medical record and eCRF, and SAE form (if serious). At the time 
of the Day 60 (±2 days) and Day 90 (±2 days) Phone Checks any additional SAEs/non-serious 
AEs will also be collected and recorded. AEs will be classified by SOC and PT using the most 
recent version of MedDRA. 
7.2.1 
Treatment-emergent Adverse Events 
For summary purposes, AEs will be classified as treatment-emergent AEs (TEAEs) or non-
treatment-emergent AEs (non-TEAEs) depending on the comparison of AE onset date/time with 
the date of randomization. A TEAE will be defined as an AE which occurred on or after the date 
of randomization. For adverse events with incomplete start dates/times, the same imputation 
algorithm for missing or partial date/time information as described in Section 5.6 will be used for 
the determination of an AE being treatment emergent or not. Briefly, the unknown portions of an 
AE onset date/time will be imputed to the latest possible before being compared to the date of 
randomization. 
Non-TEAEs will be summarized separately from TEAEs by SOC and PT for each treatment group 
and overall. 


 
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7.2.2 
Adverse Event Severity 
Refer to the study protocol, Section 8.3.5. 
7.2.3 
Adverse Event Relationship to IP 
Refer to the study protocol, Section 8.3.4. 
7.2.4 
Serious Adverse Events 
Refer to the study protocol, Section 8.3.7. 
7.2.5 
Adverse Event Summaries 
All AEs (serious and non-serious) occurring after randomization and before the end of study, 
regardless of relationship to IP, will be included and classified by SOC and PT using MedDRA.        
For TEAEs, the following will be summarized and presented for the SAF population: 
i. 
An overall summary of TEAEs, which includes:   
a. the number and percentage of subjects experiencing a TEAE 
b. the number and percentage of subjects experiencing a TEAE by strongest 
relationship to IP 
c. the number and percentage of subjects experiencing a TEAE by greatest severity 
d. the number and percentage of subjects experiencing a TEAE with Grade >=3 
e. the number and percentage of subjects experiencing a treatment-emergent SAE 
f. the number and percentage of subjects experiencing a TEAE leading to death 
g. the number and percentage of subjects experiencing a TEAE leading to study 
withdrawal 
ii. 
the number and percentage of subjects experiencing a TEAE by SOC and PT. 
iii. 
the number and percentage of subjects experiencing an adverse drug reaction (ADR; i.e.,  
potentially related TEAE) by SOC and PT, where an ADR is defined as any TEAE with a 
causal relationship to IP assessed as ‘Possibly Related’ or ‘Definitely Related’. 
iv. 
the number and percentage of subjects experiencing a TEAE by SOC, PT and the strongest 
relationship to IP 
v. 
the number and percentage of subjects experiencing a TEAE by SOC, PT and the greatest 
severity 
vi. 
the number and percentage of subjects experiencing a TEAE with Grade >=3 by SOC and 
PT 
vii. 
the number and percentage of subjects experiencing an ADR with Grade >=3 by SOC and 
PT 
viii. 
the number and percentage of subjects experiencing a treatment-emergent SAE by SOC 
and PT 
ix. 
the number and percentage of subjects experiencing a potentially related treatment-


 
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emergent SAE by SOC and PT 
x. 
the number and percentage of subjects experiencing a TEAE leading to death by SOC and 
PT 
xi. 
the number and percentage of subjects experiencing a TEAE leading to study withdrawal 
by SOC and PT 
In the overall summary of TEAEs table (i), besides tabulating the number and percentage of 
subjects, the total number of TEAE episodes will also be provided. If a subject has repeated 
episodes of a particular TEAE, all episodes will be counted in the summary table.   
In the remaining summary tables, the incidence of TEAEs will be calculated by dividing the 
number of subjects who have experienced the event by the total number of subjects.  Thus, the 
incidence of TEAEs is shown in terms of the total number of subjects and not in terms of the total 
number of episodes.  If a subject has repeated episodes of a particular TEAE, only the most severe 
episode, or the episode with the strongest causal relationship to IP, will be counted in the summary 
tables.  
A subject with more than one type of TEAE in a particular SOC or PT will be counted only once 
in the total of subjects experiencing TEAEs in that particular SOC or PT.  
All occurrences of all AEs and SAEs will be listed for each subject, grouped by treatment group.  
The listing will contain the following information: treatment group, verbatim term, SOC, PT, 
severity (mild, moderate, severe [Grade 3-5]), grade, relationship to IP if applicable, date/time and 
day of onset, date/time and day of resolution, action taken with regard to IP, whether additional 
non-drug treatment was given to treat the adverse event, the outcome, whether the event was an 
SAE, whether it led to study withdrawal, whether it occurred during IP infusion, and whether it is 
a TEAE. Listings will be sorted by treatment group, subject identification number, onset date, 
SOC, and PT. If the onset date is completely missing, then these events will be presented first. If 
the onset date is missing a month or a day, then these events will be presented before any complete 
dates. 
7.3 
Clinical Laboratory Assessments 
Clinical laboratory tests will be obtained at the time points presented in Appendix A.  Continuous 
clinical laboratory values will be summarized by presenting descriptive statistics of raw data and 
change from baseline values at each time point for each treatment group, if feasible. If necessary, 
quantitative lab values reported in different units for the same lab parameter will be converted to 
the same units prior to being summarized. Qualitative results at each time point measured will be 
summarized by presenting the number and percentage of subjects for each category. Shift tables, 
based on the high/low flags, will also be summarized by treatment group at each visit for all 
laboratory tests with normal ranges, when available. 
Laboratory parameter results from unscheduled visits will be excluded from table summaries but 
will be included in data listings.  When there are repeat scheduled measurements for a given visit, 
only the last measurement will be used in the table summaries.   
Listings will include flags for values outside of the reference ranges, when available, and clinical 
significance if a laboratory result is deemed abnormal when applicable. 


 
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7.4 
Vital Signs 
Descriptive summaries of the vital signs (both raw and change from baseline values) including 
systolic and diastolic blood pressure, pulse, respiratory rate, and body temperature will be prepared 
for each treatment group by visit.  
Qualitative results at each time point measured, including severe dehydration (no/yes), sternal 
capillary refill time >2 seconds (no/yes/unknown), and clinically significant (no/yes), will be 
summarized by presenting the number and percentage of subjects for each category. 
For Gamunex-C plus SMT group, vital signs will also be collected within 1 hour prior to the start 
of Gamunex-C infusion, 30 minutes after the start of infusion, and hourly through the end of 
Gamunex-C infusion. The raw data and change from baseline values, as well as whether clinically 
significant at each time point will be summarized for the Gamunex-C plus SMT group only. 
Unscheduled visits will be excluded from the summaries but will be included in the data listings.  
7.5 
Other Safety Measures 
Data for COVID-19 clinical features will be listed and tabulated by treatment group. 
Data for hospital interventions will be listed and summarized by presenting frequency counts and 
percentages for each category.  The duration (number of days) of extracorporeal support and 
inotropes/vasopressors administration will be calculated based on the start/stop dates recorded on 
the eCRF and summarized descriptively. Subjects who were never on extracorporeal support or 
inotropes/vasopressors will be included in the descriptive summary with a value of zero days of 
duration. 
Body weight assessments will be summarized by presenting descriptive statistics of raw data and 
change from baseline values at each time point by treatment group. 
8. INTERIM ANALYSES 
An interim analysis will be conducted after 50 subjects (approximately 25 per group) for safety 
variables through Day 29. Due to the exploratory nature of this phase 2 study, the multiplicity 
adjustments will not be considered. This interim evaluation simply represents Sponsor safety due 
diligence. This interim analysis will analyze safety variables including, but not limited to, the 
following: adverse events (see Section 7.2), clinical laboratory parameters (see Section 7.3), and 
vital signs (see Section 7.4). The relevant methods described in Section 7 (Safety Analysis) of this 
SAP intended for the final analysis will also be applicable to the interim analysis. 
9. SAMPLE SIZE AND POWER CALCULATIONS 
Because of the urgency and lack of previous prospective COVID-19 data, sample size estimation 
remains incompletely defined; however the size of this pilot study is commensurate with other 
Phase 2 investigations ongoing during the COVID-19 pandemic. Approximately 100 subjects are 
allowed to be randomized as part of a humanitarian effort against COVID-19.    


 
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10. REFERENCES 
1. https://www.mdcalc.com/national-early-warning-score-news 
2. https://clinicaltrials.gov/ct2/show/NCT04280705 
3. Gray, R.J. (1988). A class of K-sample tests for comparing the cumulative incidence of a 
competing risk. Ann Stat, 16(3):1141-1154.  
 


 
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11. APPENDIX 
11.1 
Appendix A: Schedule of Events 
 


 
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Schedule of Events (Continued) 
 


 
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Schedule of Events (Continued) 
  


 
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Schedule of Events (Continued) 
 


 
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Schedule of Events (Continued) 
 






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the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact 
  
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
Please send an email to
  
 
To advise 
 of your new email address  
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at 
 and in the 
body of such request you must state: your previous email address, your new email address.   
If you created a DocuSign account, you may update it with your new email address through your 
account preferences.  
 
To request paper copies from 
  
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to esign@ctifacts.com and in the body of 
such request you must state your email address, full name, mailing address, and telephone 
number.  
 
To withdraw your consent with 
  


To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 
i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to
 and in the body of such request you must state your 
email, full name, mailing address, and telephone number.  
 
Required hardware and software  
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.  
 
Acknowledging your access and consent to receive and sign documents electronically  
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
 
You can access and read this Electronic Record and Signature Disclosure; and 
 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
 
Until or unless you notify 
 as described above, 
you consent to receive exclusively through electronic means all notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided 
or made available to you by 
 during the course 
of your relationship with 
.