Clinical trial NCT04847141
Conditions: COVID-19 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
Keywords: Coronavirus disease Severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 COVID-19 Asymptomatic
Sponsor: Grifols Therapeutics LLC
Start date: 2021-04-28; Completion date: 2021-12-27
Enrollment: 465 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to compare the efficacy of anti-COVID-19 immune globulin (human) 20% (C19-IG 20%) (2 doses) versus placebo with regard to the percentage of asymptomatic participants who remain asymptomatic, i.e., who do not develop symptomatic coronavirus disease 2019 (COVID-19) through Day 14 as per the protocol defined criteria.

Detailed description:

Arms: arm 1: Participants will receive 1 gram (g) of C19-IG 20% subcutaneous (SC) infusion containing one syringe of 5 milliliters (mL) C19-IG 20% plus one syringe of 5 mL sterile 0.9% sodium chloride (NaCl) on Day 1. arm 2: Participants will receive 2 g of C19-IG 20% SC infusion containing two syringes 5 mL each of C19-IG 20% on Day 1. arm 3: Participants will receive C19-IG 20% matching placebo as SC infusion containing two syringes of 5 mL each sterile 0.9% NaCl injection on Day 1.
Interventions: intervention 1: C19-IG 20% intervention 2: 0.9% Sodium chloride
Intervention descriptions: intervention 1: Anti-COVID-19 Immune Globulin (Human) 20% intervention 2: C19-IG 20% matching placebo

Protocol documents:
Prot_000.pdf: 





















































































































































































































SAP_001.pdf: 
  Official Title: 
A Multicenter, Randomized, Double-blind, Parallel Group Study to 
Evaluate the Safety and Efficacy of Anti-COVID-19 Immune Globulin 
(Human) 20% (C19-IG 20%) versus Placebo in Asymptomatic Ambulatory 
Outpatients with Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) Infection 
NCT Number: 
NCT04847141 
Document Date(s): 
Statistical Analysis Plan, Version 2.0: 06 December 2021 


Grifols GC2010 Statistical Analysis Plan v2.0 
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A Multicenter, Randomized, Double-blind, Parallel Group Study to Evaluate the Safety and 
Efficacy of Anti-COVID-19 Immune Globulin (Human) 20% (C19-IG 20%) versus Placebo in 
Asymptomatic Ambulatory Outpatients with Severe Acute Respiratory Syndrome Coronavirus 2 
(SARS-CoV-2) Infection 
 
Protocol Number: GC2010 
Protocol Version: 5.0 
Protocol Date: 13 October 2021 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Version 2.0 
 
The effective date of the document is the last date of approval of the document 




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Table of Contents 
SAP REVISIONS ........................................................................................................................................ 5 
LIST OF ABBREVIATIONS ..................................................................................................................... 7 
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 .............................................................................................. 10 
2.1.4 Safety Objective ....................................................................................................................... 10 
2.2 
ENDPOINTS .................................................................................................................................. 10 
2.2.1 Primary Efficacy Endpoint ...................................................................................................... 10 
2.2.2 Secondary Efficacy Endpoints ................................................................................................. 10 
2.2.3 Exploratory Efficacy Endpoints ............................................................................................... 12 
2.2.4 Safety Endpoints ...................................................................................................................... 12 
3. 
INVESTIGATIONAL PLAN ............................................................................................................ 13 
3.1 
STUDY DESIGN ............................................................................................................................ 13 
3.2 
TREATMENT ................................................................................................................................. 14 
3.2.1 Randomization Scheme and Treatment Arm Assignment ......................................................... 14 
3.2.2 Blinding ................................................................................................................................... 14 
3.2.3 Dosing Schedule ...................................................................................................................... 15 
3.2.4 Treatment Compliance ............................................................................................................ 15 
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ......................................................... 15 
4.1 
ANALYSIS QUALITY CONTROL PROCEDURES .............................................................................. 16 
4.2 
ANALYSIS POPULATIONS ............................................................................................................. 16 
4.3 
ASSESSMENT WINDOWS .............................................................................................................. 16 
4.4 
HANDLING OF DROPOUTS OR MISSING DATA.............................................................................. 16 
4.5 
MULTIPLE COMPARISONS ............................................................................................................. 17 
4.6 
DATA DERIVATIONS AND TRANSFORMATIONS ............................................................................ 17 
5. 
STUDY SUBJECTS ........................................................................................................................... 18 
5.1 
DISPOSITION OF SUBJECTS ........................................................................................................... 18 
5.2 
PROTOCOL DEVIATIONS .............................................................................................................. 18 
5.3 
DEMOGRAPHIC CHARACTERISTICS .............................................................................................. 18 
5.4 
BASELINE CHARACTERISTICS ...................................................................................................... 18 
5.5 
MEDICAL HISTORY ...................................................................................................................... 18 
5.6 
CONCOMITANT MEDICATIONS ..................................................................................................... 19 
6. 
EFFICACY ANALYSES .................................................................................................................. 19 
6.1 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS .......................................................................... 19 
6.2 
SECONDARY EFFICACY ENDPOINTS AND ANALYSES................................................................... 20 


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Change in SARS-CoV-2 viral load ...................................................................................................... 20 
Proportion of subjects remain in an outpatient setting and maintain SpO2 ≥94% ............................. 21 
Proportion of subjects negative for SARS-CoV-2 by PCR through Day 14 and Day 29 ..................... 21 
Time to negative SARS-CoV-2 PCR from Baseline through Day 29 ................................................... 21 
Proportion of subjects requiring O2 supplementation on or before Day 29 ....................................... 21 
Duration of any oxygen use through Day 29 ....................................................................................... 22 
Ordinal scales ..................................................................................................................................... 22 
Assessment of clinical severity ............................................................................................................ 23 
Proportion of subjects requiring at least one COVID-19 related medically attended visit through 
Day 29 ................................................................................................................................................. 23 
Proportion of subjects requiring hospital admission through Day 29 ................................................ 24 
Duration of Hospitalization through Day 29 ....................................................................................... 24 
Proportion of subjects requiring ICU admission through Day 29 ...................................................... 24 
Duration of ICU stay through Day 29 ................................................................................................. 24 
Proportion of subjects requiring invasive mechanical ventilation through Day 29 ............................ 25 
Duration of invasive mechanical ventilation through Day 29 ............................................................. 25 
Mortality rate through Day 29 ............................................................................................................ 26 
Proportion of subjects with critical COVID-19 illness through Day 29 ............................................. 26 
Time to clinical progression (critical COVID-19 illness) through Day 29 ......................................... 26 
Time to COVID-19 symptoms through Day 14.................................................................................... 26 
6.3 
EXPLORATORY EFFICACY ENDPOINTS AND ANALYSES .............................................................. 27 
7. 
SAFETY ANALYSIS ........................................................................................................................ 27 
7.1 
EXTENT OF EXPOSURE AND COMPLIANCE ................................................................................... 27 
7.2 
ADVERSE EVENTS........................................................................................................................ 27 
7.2.1 Treatment-emergent Adverse Events ....................................................................................... 27 
7.2.2 Adverse Event Severity ............................................................................................................ 28 
7.2.3 Adverse Event Relationship to IP ............................................................................................ 28 
7.2.4 Serious Adverse Events ........................................................................................................... 28 
7.2.5 Adverse Event Summaries ....................................................................................................... 28 
7.3 
CLINICAL LABORATORY ASSESSMENTS ...................................................................................... 29 
7.4 
VITAL SIGNS ................................................................................................................................ 30 
8. 
DSMB ANALYSIS ............................................................................................................................ 30 
9. 
INTERIM FUTILITY ANALYSIS .................................................................................................. 30 
10. 
SAMPLE SIZE AND POWER CALCULATIONS .................................................................... 32 
11. 
REFERENCES .............................................................................................................................. 33 
12. 
APPENDIX .................................................................................................................................... 34 
12.1 
APPENDIX A: SCHEDULE OF EVENTS ........................................................................................... 34 


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SAP REVISIONS 
Version 1.0 of the SAP was finalized based on Protocol version 4.0 (28 June 2021). The following 
table details subsequent changes made to the SAP to match protocol amendment. 
 
Revision History 
SAP 
Version # 
SAP 
Section 
Modification 
Description and Rationale 
2.0 
1 
1) Changed protocol version from 
4.0 to 5.0, and protocol date from 
28 June 2021 to 13 October 2021. 
2) Added “interim futility”. 
1) and 2) Updated to match the 
protocol amendment. 
2.0 
2.2.2 
1) Added “Time to COVID-19 
symptoms specifically defined as 
the time to fulfillment of the case 
definition used for the primary 
efficacy variable through Day 14”. 
2) Moved “[*Note: ICU level care 
is defined as the medical need for 
intensive or invasive monitoring; 
immediate or impending need for 
the support of the airway, 
breathing, or circulation; and/or 
stabilization of acute severe or life- 
threatening complications of 
COVID-19]” to the end of the 
section. 
1) The new secondary efficacy 
endpoint was added to Protocol 
version 5.0. 
2) Updated to match the protocol 
amendment. 
2.0 
4.1 
Added “and interim futility”. 
Updated to match the protocol 
amendment. 
2.0 
4.4 
Added right censoring rule for time 
to COVID-19 symptoms through 
Day 14. 
Added to reflect the planned 
analysis for the new secondary 
efficacy endpoint. 
2.0 
4.6 
Added start date and event date 
derivation for time to COVID-19 
symptoms through Day 14. 
Added to reflect the planned 
analysis for the new secondary 
efficacy endpoint. 
2.0 
6 
For all efficacy analyses sections, 
changed Fisher’s exact method to 
Chi-square statistic. 
Changed to reflect the planned 
analysis. 
2.0 
6.1 
For CMH test, changed odds ratio 
to common risk difference 
Changed to reflect the planned 
analysis. 
2.0 
6.2 
Added analysis for time to COVID- 
Added to reflect the planned 
analysis for the new secondary 


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19 symptoms through Day 14. 
efficacy endpoint. 
2.0 
8 
Changed section title from 
“INTERIM ANALYSE” to 
“DSMB ANALYSIS”. 
Clarify the section is about 
DSMB analysis. 
2.0 
9 
Added the section for interim 
futility analysis 
Interim futility analysis was 
added to the protocol amendment, 
updated to match the protocol 
v5.0 and to provide the details of 
conditional power calculation. 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical, Therapeutic, and Chemical 
BMI 
Body mass index 
C19-IG 20% 
anti-COVID-19 Immune Globulin (Human) 20% 
CDF 
Cumulative distribution function 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus disease 2019 
CP 
Conditional power 
CRP 
C-reactive protein 
CTCAE 
Common terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
EUA 
Emergency Use Authorization 
ICU 
Intensive care unit 
IG 
Immune globulin 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL 
Interleukin 
IP 
Investigational product 
ITT 
Intention-to-treat 
KM 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
LS 
Least-Squares 


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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intention-to-treat 
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 
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 
SC 
Subcutaneous 
SOC 
System organ class 
SpO2 
Oxygen Saturation by pulse oximetry 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 


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1. INTRODUCTION 
 
This statistical analysis plan (SAP) is based on the Protocol # GC2010 Version 5.0, dated 13 
October, 2021, and titled “A Multicenter, Randomized, Double-blind, Parallel Group Study to 
Evaluate the Safety and Efficacy of Anti-COVID-19 Immune Globulin (Human) 20% (C19-IG 
20%) versus Placebo in Asymptomatic Ambulatory Outpatients with Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2) Infection.” See the study protocol for full details. 
This document details the statistical methods planned to perform the Data Safety Monitoring Board 
(DSMB), interim futility and final analyses of the study. 
 
2. OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 
Primary Efficacy Objective 
To compare C19-IG 20% (2 doses) versus Placebo with regard to proportion of asymptomatic 
subjects who remain asymptomatic, i.e., who do not develop symptomatic coronavirus disease 
2019 (COVID-19) through Day 14 defined as any of the following: 
Experiencing at least TWO of the following systemic symptoms: (a) Fever (≥ 38ºC), (b) 
chills, (c) myalgia, (d) headache, (e) sore throat, (f) cough, (g) fatigue that interferes with 
activities of daily living, (h) new olfactory and taste disorder(s), (i) vomiting/diarrhea (note 
that [h] new olfactory/taste disorder(s) & [i] vomiting/diarrhea Each Only count as ONE 
item of definition) 
OR 
Experiencing at least ONE of the following respiratory signs/symptoms: new or worsening 
shortness of breath or difficulty breathing, 
OR 
Experiencing peripheral oxygen saturation by pulse oximetry (SpO2) < 94% on room air 
OR 
Radiographical evidence of pneumonia (radiographic infiltrates by imaging [chest X-Ray, 
CT scan, etc.]). Note radiographical studies are to be done for suspicion of pneumonia per 
standard of care 
 
2.1.2 
Secondary Efficacy Objectives 
• To compare C19-IG 20% (2 doses) versus Placebo with regard to change in SARS-CoV-2 
viral load (log10 copies/mL) from Baseline (Day 1) to Day 7 and to Day 14. 
• To compare C19-IG 20% (2 doses) versus Placebo with regard to proportion of subjects 
who remain in an outpatient setting and maintain SpO2 ≥94% on room air on Day 3, Day 
7, and Day 14. 
• To compare C19-IG 20% (2 doses) versus Placebo with regard to proportion of subjects 
negative and time to negative SARS-Cov-2 by polymerase chain reaction (PCR) from 


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Baseline through Day 14 and through Day 29. 
• To compare C19-IG 20% (2 doses) versus Placebo with regard to clinical efficacy in 
asymptomatic ambulatory outpatients as assessed by clinical evolution to overt COVID- 
19, new dependency on oxygen and if needed duration of oxygen supplementation, clinical 
response criteria including National Early Warning Score (NEWS) [1] and ordinal clinical 
status scale [2] through Day 29. 
• To compare C19-IG 20% (2 doses) versus Placebo with regard to frequency of requirement 
for hospital-level medical care (i.e., hospitalization admission defined by need for medical 
intervention[s], not for quarantine purposes) and duration of hospitalization (if required) 
through Day 29. 
• To compare C19-IG 20% (2 doses) versus Placebo with regard to proportion of 
asymptomatic subjects with COVID-19 who require at least one COVID-19 related 
medically attended visit for management/treatment of COVID-19 (apart from routinely 
scheduled study-directed visits) which may occur in any setting through Day 29 (e.g., 
Emergency department, urgent care, outpatient clinic or professional setting wherein direct 
in-person/telemedicine medical assessment and escalation of care for COVID-19 is 
provided by licensed healthcare personnel). 
 
2.1.3 
Exploratory Efficacy Objectives 
The exploratory objectives of the study are: 
• To evaluate the effect of C19-IG 20% (2 doses) versus Placebo with regard to change from 
baseline in inflammatory biomarkers specifically: interleukin 6 (IL-6); D-dimer; ferritin; 
C-reactive protein (CRP), and interferon γ through Day 14. 
• To evaluate the effect of C19-IG 20% (2 doses) versus Placebo with regard to quantitative 
anti-SARS-CoV-2 antibodies through Day 14. 
• Overall assessment of COVID-19 symptoms severity on Day 7 and Day 29. 
2.1.4 
Safety Objective 
• To determine the safety and tolerability profile of C19-IG 20% (2 doses) versus Placebo 
through Day 29. 
• To evaluate change from baseline in key biochemical parameters of organ 
function/dysfunction: alanine aminotransferase (ALT); lactate dehydrogenase (LDH); 
absolute lymphocyte count; creatinine through Day 14. 
 
2.2 
Endpoints 
 
2.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of asymptomatic subjects who remain 
asymptomatic. See details above in Section 2.1.1. 
 
2.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include the following: 


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• Change in SARS-CoV-2 viral load (log10 copies/mL) from Baseline (Day 1) to Day 7 and 
to Day 14. 
• Proportion of subjects who remain in an outpatient setting and maintain SpO2 ≥94% on 
room air on Day 3, Day 7, and Day 14. 
• Proportion of subjects negative for SARS-CoV-2 by PCR at multiple time points through 
Day 14 and through Day 29. 
• Time to negative SARS-CoV-2 PCR from Baseline through Day 29. 
• Proportion of subjects who require O2 supplementation on or before Day 29. 
• If requiring supplemental oxygen post randomization: Duration of any oxygen through Day 
29. 
• Absolute value and mean change from baseline in the 7-point Ordinal scale Day 1, Day 7, 
Day 14, and Day 29: 
The 7-point 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 1, Day 7, Day 14, and Day 29. 
• Assessment of Clinical Severity: Change in NEWS from baseline (at Day 7, Day 14, and 
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]). 
• Proportion of subjects who require at least one COVID-19 related medically attended visit 
for management/treatment of COVID-19 (apart from routinely scheduled study-directed 
visits) which may occur in any setting through Day 29 (e.g., Emergency department, urgent 
care, outpatient clinic or professional setting wherein direct in-person/telemedicine medical 
assessment and escalation of care for COVID-19 is provided by licensed healthcare 
personnel). 
• Proportion of subjects who require hospital admission for medical care (non-quarantine 
purpose) through Day 29. 


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• If admitted to hospital post randomization: Duration of hospital stay through Day 29. 
• Proportion of subjects who require ICU admission or initiation of ICU-level care* through 
Day 29. 
• If admitted to ICU post randomization: Duration of ICU stay through Day 29. 
• Proportion of subjects requiring invasive mechanical ventilation through Day 29. 
• If requiring invasive mechanical ventilation post randomization: Duration of invasive 
mechanical ventilation through Day 29 
• All-cause mortality through Day 29. 
• Incidence of critical COVID-19 illness, defined as any one of the following: (a) requiring 
ICU admission or ICU level of care*, (b) invasive mechanical ventilation, or (c) resulting 
in death by Day 29. 
 
• Length of time to clinical progression to critical COVID-19 illness through Day 29 (defined 
as the time to death, invasive mechanical ventilation, or ICU admission/requiring ICU level 
of care). 
• Time to COVID-19 symptoms specifically defined as the time to fulfillment of the case 
definition used for the primary efficacy variable through Day 14. 
[*Note: ICU level care is defined as the medical need for intensive or invasive monitoring; 
immediate or impending need for the support of the airway, breathing, or circulation; and/or 
stabilization of acute severe or life-threatening complications of COVID-19] 
 
2.2.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints include: 
• Change from baseline in inflammatory biomarkers specifically: IL-6; D-dimer; ferritin; 
CRP; interferon γ through Day 14. 
• Change from baseline in quantitative anti-SARS-CoV-2 IgM and IgG antibodies through 
Day 14. 
• Overall assessment of COVID-19 symptoms severity (No symptoms; Mild; Moderate; 
Severe; Potentially Life-threatening) on Day 7 and Day 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 60 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) through Day 29. 


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• Cumulative incidence of all TEAEs and potentially related TEAEs through Day 29. 
• Change from baseline in key biochemical parameters of organ function/dysfunction: ALT; 
LDH; absolute lymphocyte count; creatinine through Day 14. 
 
3. INVESTIGATIONAL PLAN 
 
3.1 
Study Design 
This is a prospective, multi-center, randomized (1:1:1), double-blind study of C19-IG 20% at 1 of 
2 dose levels versus Placebo in asymptomatic, ambulatory outpatients aged ≥18 years who are 
SARS-CoV-2 positive. Participants will be stratified by age <65 years vs ≥65 years of age. The 
study will enroll asymptomatic subjects with laboratory-confirmed novel coronavirus (SARS- 
CoV-2) infection as determined by qualitative PCR (reverse transcriptase [RT]-PCR), or other 
commercial or public health assay approved by regulatory authorities as a diagnostic for COVID- 
19 (inclusive of SARS-CoV-2 antigen testing or other approved rapid testing platforms) in any 
specimen obtained ≤ 5 days prior to randomized treatment (≤ 5 days is the post-sampling timeframe 
from date specimen obtained to administration of blinded study drug). Every effort should be made 
to reduce this time interval to the minimum as nearly immediate treatment is key for successful 
intervention. 
Approximately 801 subjects (267 per arm) will be randomized (1:1:1). Subjects randomized to 
C19-IG 20% will receive a blinded subcutaneous (SC) infusion on Day 1 at a dose of either 1 gram 
or 2 grams, according to the randomized dose assigned. Subjects randomized to Placebo will 
receive a SC infusion of sterile 0.9% sodium chloride injection, United States Pharmacopeia (0.9% 
NaCl, USP) or equivalent. Blinded study drug will be prepared and administered by an unblinded 
study nurse who is entirely independent of the evaluating study team with SC infusions using 2 
separate syringes as follows: 
• Placebo (two syringes each containing 5 mL 0.9% NaCl); 
• 1 gram C19-IG 20% (one syringe containing 5 mL C19-IG 20% Plus one syringe 
containing 5 mL 0.9% NaCl) 
• 2 grams C19-IG 20% (two syringes each containing 5 mL C19-IG 20%). 
An independent DSMB will review interim safety data when approximately 399 patients have been 
randomized and treated with follow-up through Day 29 (approximately 133 patients per 
randomized group). 
Subjects will receive one C19-IG 20%/Placebo dose via SC route on Day 1; for all subjects 
monitoring and surveillance will be continued throughout the subject’s participation in the study. 
The total estimated maximum duration of a subject’s participation in terms of actual Healthcare 
Provider Visits will be up to 30 days. Additionally, a Phone Check will occur at Day 60 for 
complete follow-up. Thus, subject participation (from Screening Visit to the Final Phone Check) 
will be approximately 60 days. 
At the Healthcare Provider visit on Day 1, all subjects will receive a pulse oximeter for home use 
and daily recording of SpO2 in order to monitor for development of hypoxia (SpO2 < 94% on 
room air). All subjects will also be instructed to measure, monitor, and record body temperature 
daily. Subjects will be evaluated at Healthcare Provider Visits on Day 3, Day 7, Day 14, and Day 


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29 (or if hospitalized, assessments required for Day 7, Day 14, and Day 29 will be performed in 
hospital). 
Additionally, subjects will be assessed as outpatients by Phone Check on Day 5, Day 9, and Day 
11. The Phone Checks serve as surveillance for development of symptomatic COVID-19, sentinel 
alarm symptoms or symptoms that may indicate clinical deterioration (e.g., dyspnea) and to record 
the patient’s daily entries for SpO2 and body temperature. 
Following the Day 29 assessment time point, one more final Phone Check will be performed at 
Day 60 for vital status (living or deceased), any hospital admissions, ICU admissions, requirement 
for invasive mechanical ventilation, need for oxygen supplementation, or serious/non-serious 
adverse events after the Day 29 Healthcare Provider Visit, and to confirm resolution of any 
COVID-19 sequelae. See Appendix A for the Schedule of Events. 
An overview of the study design is presented below: 
 
 
3.2 
Treatment 
 
3.2.1 
Randomization Scheme and Treatment Arm Assignment 
Eligible subjects will be randomized 1:1:1 to Placebo or to C19-IG 20% via a SC infusion on Day 
1 at a dose of either 1 gram or 2 grams, according to the randomized dose assigned. A central 
randomization stratified by age group (age <65 years versus ≥ 65 years) will be used for this study. 
Randomization will be centralized and will be performed via an Interactive Web Response System 
after subject inclusion. A randomization list containing the randomization numbers and the 
corresponding randomized treatment assignments will be generated and stored in a secured area 
that is only accessible to the randomization team. 
 
3.2.2 
Blinding 
There will be a designated unblinded study nurse for preparation and administration of study drug 
who is entirely independent of the team evaluating the patient with SC infusions using 2 separate 
syringes as described above in Section 3.1. 
The designated unblinded study nurse will be the only unblinded study person at each site. 
Preparation of study drug (Anti-COVID-19 Immune Globulin [Human] and placebo) and SC 
administration of study drug will be the responsibility of the local unblinded study nurse. 
Since this is a double-blind, placebo-controlled study, measures will be taken to assure that the 


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placebo infusion will be indistinguishable in terms of commensurate volume from Anti-COVID- 
19 Immune Globulin (Human) infusion volume to that required for the appropriate dose of Anti- 
COVID-19 Immune Globulin (Human) to maintain blinding. For all 3 arms a 10-mL volume (2 
syringes each containing 5 mL volumes of various composition) will be prepared so that there is 
no difference in infusion volume or apparent configuration. 
Furthermore, results of the central laboratory analysis of quantitative viral load and quantitative 
IgM and IgG anti-SARS-CoV-2 antibodies will not be shared with the Investigator, blinded study 
staff, clinical research organization or blinded Sponsor personnel involved in study conduct. 
 
3.2.3 
Dosing Schedule 
Subjects randomized to C19-IG 20% will receive a blinded single dose via SC infusion of C19-IG 
20%. Randomization to active treatment arms will specify either a dose of 1 gram or 2 grams C19- 
IG 20%. Subjects randomized to Placebo will receive blinded sterile 0.9% sodium chloride 
injection United States Pharmacopeia (0.9% NaCl, USP) or equivalent. Blinded study drug will be 
prepared and administered by an unblinded study nurse who is entirely independent of the 
evaluating study team with SC infusions using 2 separate syringes as described above in Section 
3.1. 
 
3.2.4 
Treatment Compliance 
Reasons for any deviation from the administration of less than 100% of the blinded investigational 
product (IP) dose must be recorded in the subject’s medical records. 
The investigator or designee is responsible for maintaining accurate records of C19-IG 
20%/Placebo 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. 
Unscheduled visits will be excluded from the summaries but will be included in the data listings. 
All p-values will be displayed to four decimal places, with p-values less than 0.0001 presented as 
'<0.0001'. Minimum and maximum values will be reported in the units of collection with 3 
decimals being maximum value; the mean will be presented with 1 decimal place more and the 
standard deviation 2 decimal places more than the units of collection. Percentages for categorical 
summaries will be represented to 1 decimal place. 
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. 


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 will perform all efficacy and safety analyses described in this SAP and Grifols will review 
them. 
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 
Analysis Quality Control Procedures 
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 the DSMB and interim futility analyses 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 four analysis populations will be defined for this study: 
The intent-to-treat (ITT) population is defined as all subjects who are randomized. 
The modified intent-to-treat (mITT) population is defined as the subset of subjects included in the 
ITT who are also dosed. The mITT population will be used for all efficacy analyses. As sensitivity 
analysis, the primary efficacy analysis will also be carried out using the ITT population if different 
from the mITT population. 
The Per-Protocol (PP) population is defined as the subset of subjects included in the mITT 
population who do not present major protocol violations which might have an impact on the 
primary efficacy endpoint(s), and complete at least 80% of the IP. The primary efficacy analyses 
will be carried out using the PP population if different from the mITT population. 
The Safety (SAF) population is defined as subjects who receive at least any amount of blinded 
C19-IG 20%/Placebo. All safety analyses will be carried out using the SAF population based on 
the treatment actually received rather than randomized treatment. 
The validity of a subject for inclusion in each of these populations (ITT, mITT, Safety, and PP) 
will be assessed before unblinding the database and documented in a blinded review report. 
 
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. 
Missing data on the time to event endpoints will have events coded as right censored per the 


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following table: 
Table 1 Missing Data Coding for Time to Event Data Analyses 
 
Endpoint 
Right Censoring 
Time to negative SARS-CoV-2 by 
PCR 
Subjects who did not have negative SARS-CoV-2 by PCR 
will be right censored as of the date of last non-missing 
assessment of SARS-CoV-2 by PCR on or prior to Day 29. 
Time to Clinical Progression (death, 
invasive mechanical ventilation, or 
ICU admission/requiring ICU level 
of care) 
Subjects who did not meet the criteria for clinical 
progression will be right censored as of the date of last 
subject contact on or prior to Day 29. 
Time to COVID-19 symptoms 
(fulfillment of the case definition 
used for the primary efficacy 
variable through Day 14) 
Subjects who did not meet the criteria will be right censored 
as of the date of last non-missing assessment of clinical 
features/symptoms on or prior to Day 14. 
 
4.5 
Multiple Comparisons 
A hierarchical ordered testing procedure will be employed for handling the multiplicity issue to 
maintain the overall family-wised alpha level at 0.05 for comparisons between each dose and 
placebo. The null hypothesis for 1g vs placebo is tested only if the superiority for the 2g dose 
compared to placebo has been shown at a two-sided significance level of 5%. The order in which 
the null hypotheses are tested for the primary endpoint is predetermined as below: 
1. H01: no difference between 2g and placebo on primary efficacy endpoint 
2. H02: no difference between 1g and placebo on primary efficacy endpoint 
The primary efficacy analysis will be carried out on the mITT population and repeated on the ITT 
and PP population (if different from the mITT population). 
There will be no adjustment for multiple comparisons on secondary and exploratory efficacy 
endpoints. 
 
4.6 
Data Derivations and Transformations 
The following derivations will be used in this study: 
Study Day: 
• Date of assessment – date of study drug administration + 1 for assessments done on or after 
date of study drug administration 
• Date of assessment – date of study drug administration for assessments done before date 
of study drug administration 
Baseline Observation: the last non-missing value prior to study drug administration. 
Duration: 
• Duration in days = end date – start date + 1 


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• Duration in minutes = end time in minutes – start time in minutes 
Origin or Start Date for Time to Event Endpoints: 
• Time to negative SARS-CoV-2 by PCR: date of study drug administration 
• Time to Clinical Progression: date of study drug administration 
• Time to COVID-19 symptoms through Day 14: date of study drug administration 
Event Date for Time to negative SARS-CoV-2 by PCR: 
• The date of the first negative result from the SARS-CoV-2 assessment by PCR will be used 
as the event date for deriving time to negative SARS-CoV-2. 
Event Date for Time to Clinical Progression 
• The event date will be the date of death, the start date of invasive mechanical ventilation, 
or the date of ICU admission/requiring ICU level of care, whichever occurs first. 
Event Date for Time to COVID-19 symptoms through Day 14 
• The event date will be the first time point when any element of the case definition for 
primary efficacy variable is fulfilled through Day 14 
 
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 mITT 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 mITT population. A by subject 
listing will be provided. 
 
5.4 
Baseline Characteristics 
Baseline characteristics of mITT subjects including historical SARS-CoV-2 results, comorbidity, 
and pregnancy test will be listed and summarized by treatment group and overall if appropriate. 
 
5.5 
Medical History 
All medical conditions will be classified by system organ class (SOC) and preferred term (PT) 


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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 mITT 
population. 
 
5.6 
Concomitant Medications 
All concomitant medications collected will be coded using the World Health Organization (WHO) 
Drug Dictionary. The number and percent of mITT 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 
mITT population. 
Prior medications are defined as medications that ended prior to the date of study drug 
administration. Concomitant medications are defined as medications that started at any time but 
ended on or after the date of study drug administration, 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 study drug administration 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. 
 
6. EFFICACY ANALYSES 
 
All efficacy analyses will be carried out using the mITT 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 mITT population. The analysis will be 
repeated using the ITT and PP population if different from the mITT population, 
The primary efficacy variable is the proportion of asymptomatic subjects who remain 
asymptomatic through Day 14. Subject clinical features/symptoms and radiographical evidence of 
pneumonia will be recorded in the database; the oxygen saturation by pulse oximetry on room air 
will be recorded daily through Day 14 by subject at home on the “SpO2 and Temperature Log”, as 
well as on the “Patient’s Measured Oxygen Saturation” eCRF at the protocol-specified healthcare 
provider visits. In the case when multiple SpO2 values are recorded on the same day, the lower 
value will be used for the analysis. 
The null hypothesis is that the proportion of subjects who meet the primary endpoint in a given 
C19-IG 20% dose group (2 g and 1 g) will be no different than the proportion of subjects in placebo 
group; H0: πt - πc = 0. The alternative hypothesis is that the proportion of subjects who meet the 
primary endpoint at Day 14 in a given C19-IG 20% dose group will be different than the proportion 


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of subjects in placebo; H1: πt - πc ≠ 0. 
Separate comparisons will be made for each C19-IG 20% dose group. If the 2 g dose group fails 
to demonstrate superiority compared to placebo at two-sided significance level of 5%, the test for 
1 g dose group compared with placebo will be considered as exploratory rather than as 
confirmatory. 
The proportion of subjects who meet the primary endpoint within each treatment group will be 
presented along with a two-sided exact (Clopper-Pearson) 95% confidence interval (CI). 
The observed difference in the proportion of subjects who meet the primary endpoint between each 
C19-IG 20% dose group and placebo along with the exact unconditional 95% CI for risk difference 
will be calculated. The null hypothesis will be tested using Chi-square statistic and the p-value will 
be reported. 
Sensitivity analysis on primary endpoint will be performed using the Cochran-Mantel-Haenszel 
(CMH) test, stratified by randomization strata (age <65 years versus ≥ 65 years). The common risk 
difference in the proportion of subjects meeting the primary endpoint between each C19-IG 20% 
dose group and placebo, together with the associated 95% CIs and p-value will be presented. 
Subgroup analyses based on the presence of comorbidities associated with increased risk of serious 
COVID-19 will be performed on the primary endpoint using the method described above with Chi-
square test, if appropriate. If data permit, a subgroup analysis based on the number of comorbidities 
(<2 comorbidities vs. >=2 comorbidities) will also be performed. 
Subgroup analyses by perceived comorbidities will include the following conditions: Cancer; 
Chronic kidney disease; Chronic obstructive pulmonary disease (COPD); Heart conditions, such 
as heart failure, coronary artery disease, or cardiomyopathies; Immunocompromised state from 
solid organ transplant; Obesity (BMI of 30 kg/m2) or higher; Diabetes mellitus. The information 
of subject comorbidity will be recorded on the eCRF. 
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. 
Data for COVID-19 clinical features/symptoms will be listed and summarized by treatment group 
at each time point. Radiographic evidence of pneumonia data will be presented in a listing. 
6.2 
Secondary Efficacy Endpoints and Analyses 
Change in SARS-CoV-2 viral load 
Change in SARS-CoV-2 viral load (log10 copies/mL) from Baseline to Day 7 and to Day 14 will 
be compared between each C19-IG 20% dose group and placebo using the analysis of covariance 
(ANCOVA) model, including the change from baseline value as a dependent variable; treatment 
group as a fixed effect; and baseline SARS-CoV-2 viral load value, age and gender as covariates. 
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 at Day 
7 and Day 14. 
Subgroup analyses based on the presence of comorbidities associated with increased risk of serious 


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COVID-19 will be performed on change in SARS-CoV-2 viral load using the method described 
above with ANCOVA model at Day 7 and Day 14. If data permit, a subgroup analysis based on 
the number of comorbidities (<2 comorbidities vs. >=2 comorbidities) will also be performed. 
 
Proportion of subjects remain in an outpatient setting and maintain SpO2 ≥94% 
Subjects remain in an outpatient setting is defined as no hospitalization or ICU admission through 
Day 3, Day 7, and Day 14. 
In the case when multiple SpO2 values are recorded on the same day, e.g. SpO2 values from subject 
self-reported at home and from healthcare provider visit on the same day, the lower value will be 
used for the analysis. 
The proportion of subjects who remain in an outpatient setting and maintain SpO2 ≥94% on room 
air at each timepoint within each treatment group will be presented along with a two-sided exact 
(Clopper-Pearson) 95% CI. 
The observed difference in the proportion of subjects who remain in an outpatient setting and 
maintain SpO2 ≥94% on room air at any timepoint between each C19-IG 20% dose group and 
placebo along with the exact unconditional 95% CI for risk difference will be calculated. The null 
hypothesis will be tested using Chi-square statistic and the p-value will be reported. . 
 
Proportion of subjects negative for SARS-CoV-2 by PCR through Day 14 and Day 29 
The proportion of subjects with negative SARS-CoV-2 by PCR through Day 14 and Day 29 within 
each treatment group will be presented along with a two-sided exact (Clopper-Pearson) 95% CI. 
At each time point, the observed difference in the proportion of subjects with negative PCR test 
results between each C19-IG 20% dose group and placebo along with the exact unconditional 95% 
CI for risk difference will be calculated. The null hypothesis will be tested using Chi-square 
statistic and the p-value will be reported. 
 
Time to negative SARS-CoV-2 PCR from Baseline through Day 29 
The time from baseline to the first occurrence of negative SARS-CoV-2 by PCR through Day 29 
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 
negative SARS-CoV-2 by PCR and associated 95% CIs on Days 14 and 29 will be reported; in 
addition, the 25th, 50th (median), and 75th percentiles of the time to negative SARS-CoV-2 by 
PCR with associated 95% CIs will be provided, as data permit. The survival rates between each 
C19-IG 20% dose group and placebo will be compared using Log-rank test. The p-value from Log-
rank test will be presented. 
 
Proportion of subjects requiring O2 supplementation on or before Day 29 
The proportion of subjects requiring oxygen supplementation through Day 29 within each 
treatment group will be presented along with a two-sided exact (Clopper-Pearson) 95% CI. 
The observed difference in the proportion of subjects requiring oxygen supplementation between 
each C19-IG 20% dose group and placebo along with the exact unconditional 95% CI for risk 
difference will be calculated. The null hypothesis will be tested using Chi-square statistic and the 
p-value will be reported. 


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Duration of any oxygen use through Day 29 
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 each C19-IG 20% dose group and placebo using an ANCOVA model, including number 
of days on oxygen as a dependent variable, treatment group as a fixed effect, and baseline 
characteristics such as age and gender as covariates. 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. 
In the event the data is highly skewed, e.g. very few subjects received supplemental oxygen, a 
sensitivity analysis using a non-parametric Wilcoxon Rank Sum test will be performed. The p- 
value from Wilcoxon Rank Sum test, as wells as the Hodges-Lehmann estimate of the treatment 
difference and the corresponding 95% CI will be provided. 
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 from both 
subject self-monitoring at home and health provider visits will be provided. 
 
Ordinal scales 
a) The absolute value and change from baseline in the Ordinal scale from Day 1 through Day 
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 and 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 at Days 3, 7, 14, and 29 visits 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 3, 7, 14, and 29. 
b) The proportion of subjects in each severity category of the 7-point Ordinal scale at Days 1, 
3, 7, 14, and 29 visits will be summarized by treatment group. The difference in severity 


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category distribution between each C19-IG 20% dose group and placebo at Day 3, Day 7, 
Day 14, 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 3, Day 7, Day 14, and Day 29. 
The proportional odds assumption will be tested using a score test at the two-sided alpha 
level of 0.05. If 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. The p-value from Wilcoxon Rank Sum test, 
as well as the Hodges-Lehmann estimate of the treatment difference and the corresponding 
95% CI will be provided. 
 
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 mixed-effects 
model for repeated measures (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 at Days 3, 7, 14, 
and 29 visits 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 for Day 3, Day 7, Day 14, and Day 29. 
 
Proportion of subjects requiring at least one COVID-19 related medically attended visit 
through Day 29 
The proportion of subjects requiring at least one COVID-19 related medically attended visit for 
management/treatment of COVID-19 (apart from routinely scheduled study-directed visits) within 
each treatment group will be presented along with a two-sided exact (Clopper-Pearson) 95% CI. 
The observed difference in the proportion of subjects requiring at least one COVID-19 related 
medically attended visit between each C19-IG 20% dose group and placebo along with the exact 
unconditional 95% CI for risk difference will be calculated. The null hypothesis will be tested 
using Chi-square statistic and the p-value will be reported. 


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A listing of all medically attended visit data collected through the study will be provided. 
 
Proportion of subjects requiring hospital admission through Day 29 
The proportion of subjects requiring hospital admission through Day 29 within each treatment 
group will be presented along with a two-sided exact (Clopper-Pearson) 95% CI. 
The observed difference in the proportion of subjects requiring hospital admission between each 
C19-IG 20% dose group and placebo along with the exact unconditional 95% CI for risk difference 
will be calculated. The null hypothesis will be tested using Chi-square statistic and the p-value will 
be reported. 
 
Duration of Hospitalization through Day 29 
The duration (number of days) of hospitalization from post-randomization through Day 29 will be 
calculated based on hospital admission and discharge dates recorded on the eCRF. Number of 
days in the hospital will be compared between each C19-IG 20% dose group and placebo using an 
ANCOVA model, including number of days in the hospital as a dependent variable, treatment 
group as a fixed effect, and baseline characteristics such as age and gender as covariates. 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. 
In the event the data is highly skewed, e.g. very few subjects hospitalized, a sensitivity analysis 
using a non-parametric Wilcoxon Rank Sum test will be performed. The p-value from Wilcoxon 
Rank Sum test, as wells as the Hodges-Lehmann estimate of the treatment difference and the 
corresponding 95% CI will be provided. 
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. Subjects who never been hospitalized 
through Day 29 will be included in the analysis with a value of zero days in the hospital. 
 
Proportion of subjects requiring ICU admission through Day 29 
The proportion of subjects requiring ICU admission through Day 29 within each treatment group 
will be presented along with a two-sided exact (Clopper-Pearson) 95% CI. 
The observed difference in the proportion of subjects requiring ICU admission between each C19- 
IG 20% dose group and placebo along with the exact unconditional 95% CI for risk difference will 
be calculated. The null hypothesis will be tested using Chi-square statistic and the p-value will be 
reported. 
 
Duration of ICU stay through Day 29 
The duration (number of days) of ICU stay from post-randomization through Day 29 will be 
calculated based on ICU admission and discharge dates recorded on the eCRF. Number of days 
in the ICU will be compared between each C19-IG 20% dose group and placebo using an 
ANCOVA model, including number of days in the ICU as a dependent variable, treatment group 
as a fixed effect, and baseline characteristics such as age and gender as covariates. From this model, 
the LS means and 95% CIs for each treatment group, the treatment difference in the LS 


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means, the 95% CI for the difference, and the associated p-value will be presented. 
In the event the data is highly skewed, e.g. very few subjects admitted to ICU, a sensitivity analysis 
using a non-parametric Wilcoxon Rank Sum test will be performed. The p-value from Wilcoxon 
Rank Sum test, as wells as the Hodges-Lehmann estimate of the treatment difference and the 
corresponding 95% CI will be provided. 
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. Subjects who never been in the ICU through Day 29 will be included in the 
analysis with a value of zero days in the ICU. 
 
Proportion of subjects requiring invasive mechanical ventilation through Day 29 
The proportion of subjects requiring invasive mechanical ventilation through Day 29 within each 
treatment group will be presented along with a two-sided exact (Clopper-Pearson) 95% CI. 
The observed difference in the proportion of subjects requiring invasive mechanical ventilation 
between each C19-IG 20% dose group and placebo along with the exact unconditional 95% CI for 
risk difference will be calculated. The null hypothesis will be tested using Chi-square statistic and 
the p-value will be reported. 
 
Duration of invasive mechanical ventilation through Day 29 
The duration (number of days) on invasive mechanical ventilation from post randomization 
through Day 29 will be calculated based on the start/stop dates of invasive 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 invasive mechanical ventilation will be compared between each C19-IG 20% 
dose group and placebo using an ANCOVA model, including number of days in on invasive 
mechanical ventilation as a dependent variable, treatment group as a fixed effect, and baseline 
characteristics such as age and gender as covariates. 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. 
In the event the data is highly skewed, e.g. very few subjects on invasive mechanical ventilation, 
a sensitivity analysis using a non-parametric Wilcoxon Rank Sum test will be performed. The p- 
value from Wilcoxon Rank Sum test, as wells as the Hodges-Lehmann estimate of the treatment 
difference and the corresponding 95% CI will be provided. 
Subjects who died during the hospitalization without a stop date of invasive 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 invasive 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 invasive mechanical ventilation through Day 29 will be included in the analysis with a 
value of zero days on mechanical ventilation. 
Data collected on “Respiratory Support” eCRF through Day 60/Final Phone Check visit will be 
presented in a listing. 


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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 analysis. 
The proportion of subjects who die through Day 29 within each treatment group will be presented 
along with a two-sided exact (Clopper-Pearson) 95% CI. 
The observed difference in the mortality rate (proportion of deceased subjects) between each C19- 
IG 20% dose group and placebo along with the exact unconditional 95% CI for risk difference will 
be calculated. The null hypothesis will be tested using Chi-square statistic and the p-value will be 
reported. 
Subject status after Day 29 (vital status [living or deceased], any hospital admissions, ICU 
admissions, requirement for invasive mechanical ventilation, need for oxygen supplementation) 
collected at Day 60/Final Phone Check visit will be presented in a listing. 
 
Proportion of subjects with critical COVID-19 illness through Day 29 
Critical COVID-19 illness is defined as any of the following: (a) requiring ICU admission or ICU 
level of care, (b) invasive mechanical ventilation, or (c) resulting in death by Day 29. 
The proportion of subjects with critical COVID-19 illness defined above within each treatment 
group will be presented along with a two-sided exact (Clopper-Pearson) 95% CI. 
The observed difference in the proportion of subjects with critical COVID-19 illness between each 
C19-IG 20% dose group and placebo along with the exact unconditional 95% CI for risk difference 
will be calculated. The null hypothesis will be tested using Chi-square statistic and the p-value will 
be reported. 
 
Time to clinical progression (critical COVID-19 illness) through Day 29 
Clinical progression is defined as death, start of invasive mechanical ventilation, or ICU 
admission/requiring ICU level of care through Day 29, whichever occurs first. The time to clinical 
progression will be estimated using the KM method. The KM estimates along with 95% CI, and 
survival curves will be provided. Based on the KM estimates, the probabilities of experiencing 
clinical progression and associated 95% CIs on Days 14 and 29 will be reported; in addition, the 
25%, 50% (median), and 75% percentiles of the time to clinical progression with associated 95% 
CIs will be provided, as data permit. The survival rates between each C19-IG 20% dose group and 
placebo will be compared using Log-rank test. The p-value from Log-rank test will be presented. 
 
Time to COVID-19 symptoms through Day 14 
Time to COVID-19 symptoms is defined as the time from study drug administration to the first 
time point when any element of the case definition for primary efficacy variable is fulfilled through 
Day 14. The time to COVID-19 symptoms will be estimated using the KM method. The KM 
estimates along with 95% CI, and survival curves will be provided. Based on the KM estimates, 
the probabilities of experiencing COVID-19 symptoms and associated 95% CIs at Day 14 will be 
reported; in addition, the 25%, 50% (median), and 75% percentiles of the time to COVID-19 
symptoms with associated 95% CIs will be provided, as data permit. The survival rates between 
each C19-IG 20% dose group and placebo will be compared using Log-rank test. The p-value from 
Log-rank test will be presented. 


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6.3 
Exploratory Efficacy Endpoints and Analyses 
• Change from baseline in inflammatory biomarkers specifically: IL-6; D-dimer; ferritin; CRP; 
interferon γ through Day 14 will be summarized for each treatment group by visit. 
• Change from baseline in quantitative anti-SARS-CoV-2 IgM and IgG antibodies through Day 
14 will be summarized for each treatment group by visit. 
• Overall assessment of COVID-19 symptoms severity on Day 7 and Day 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, and vital signs. 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 duration of infusion in minutes, total volume prepared, and total volume infused will be 
summarized by treatment group. For each syringe, the occurrence of dose interruption and whether 
100% of study drug infused will also be summarized by treatment group. In addition, treatment 
compliance will be calculated and summarized for each 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% in each treatment group. 
Treatment compliance (%) will be calculated as follows: 
(Total volume infused [mL] / Total volume prepared [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) Phone Check 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/time of study drug administration. A TEAE will be defined as an AE which occurred on 
or after the date/time of study drug administration. 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/time of study drug administration. 
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 8.2.5. 
 
7.2.3 
Adverse Event Relationship to IP 
Refer to the study protocol, Section 8.2.4. 
 
7.2.4 
Serious Adverse Events 
Refer to the study protocol, Section 8.2.7. 
 
7.2.5 
Adverse Event Summaries 
All AEs (serious and non-serious) occurring from Day 1 through 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: 
1. the number and percentage of subjects experiencing a TEAE 
2. the number and percentage of subjects experiencing a TEAE by strongest 
relationship to IP 
3. the number and percentage of subjects experiencing a TEAE by greatest severity 
4. the number and percentage of subjects experiencing a TEAE with Grade >=3 
5. the number and percentage of subjects experiencing a treatment-emergent SAE 
6. the number and percentage of subjects experiencing a TEAE leading to death 
7. 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 and grade (mild [Grade 1], moderate [Grade 2], severe [Grade 3], Life-threatening [Grade 
4], Fatal [Grade 5]), relationship to IP, date/time and day of onset, date/time and day of resolution, 
action taken with regard to IP, whether additional non-drug or 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 
All routine laboratory analyses including serum chemistry (creatinine, albumin, ALT, total 
bilirubin, and LDH) and hematology (hemoglobin, hematocrit, platelet count, absolute neutrophil 
& lymphocyte count, leukocyte count with differential) will be conducted by a central laboratory. 
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. 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. 
When there are repeat scheduled measurements for a given visit, only the last measurement will 
be used in the table summaries. 
Listings will include normal ranges and flags for values outside of the reference ranges, when 
available. 


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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 including clinically significant change from baseline (no/yes) will be 
summarized by presenting the number and percentage of subjects for each category at each post- 
baseline time point. 
 
8. DSMB ANALYSIS 
 
An independent DSMB will review interim safety data when approximately 399 patients have been 
randomized and treated with follow-up through Day 29 (approximately 133 patients per 
randomized group). 
The DSMB’s specific activities will be defined by a mutually agreed charter, which will define the 
DSMB’s membership, conduct and meeting schedule. 
 
9. INTERIM FUTILITY ANALYSIS 
 
An interim analysis will be conducted in the December 2021 timeframe based on all available data 
assessable for the primary endpoint and key secondary efficacy endpoints to assess whether the 
trial will be terminated due to lack of efficacy (futility). The unblinded output will be reviewed by 
an independent unblinded team, and the study team will remain blinded. 
The decision for the interim analysis will be based on the conditional power (the power conditional 
on the observed data accumulated at the interim analysis) for the primary outcome, as well as 
assessment of the secondary efficacy outcomes. 
The futility analysis will include for the primary efficacy endpoint variable, all patients with data 
through Day 14, and for the following secondary efficacy endpoint variables, all patients with data 
through Day 14 or Day 29, as specified for each endpoint: 
• Time to COVID-19 symptoms specifically defined as the time to fulfillment of the case 
definition used for the primary efficacy variable through Day 14. 
• Proportion of subjects who remain in an outpatient setting and maintain SpO2 ≥94% on 
room air on Day 3, Day 7, and Day 14. 
• Proportion of subjects who require O2 supplementation on or before Day 29. 
• If requiring supplemental oxygen post randomization: Duration of any oxygen through Day 
29. 
• Absolute value and mean change from baseline in the 7-point Ordinal scale at Day 1, Day 
7, Day 14, and Day 29 
• Proportion (percentage) of subjects in each severity category of the 7-point Ordinal scale 
at Day 1, Day 7, Day 14, and Day 29. 
• Assessment of Clinical Severity: Change in NEWS from baseline (at Day 7, Day 14, and 


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Day 29). 
• Proportion who require at least one COVID-19 related medically attended visit for 
management/treatment of COVID-19 (apart from routinely scheduled study-directed 
visits) which may occur in any setting through Day 29 (e.g., Emergency department, urgent 
care, outpatient clinic or professional setting wherein direct in-person/telemedicine 
medical assessment and escalation of care for COVID-19 is provided by licensed 
healthcare personnel). 
• Proportion of subjects who require hospital admission for medical care (non-quarantine 
purposes) through Day 29. 
• If admitted to hospital post randomization: Duration of hospital stay through Day 29. 
• Proportion of subjects who require ICU admission or initiation of ICU-level care* through 
Day 29. 
• If admitted to ICU post randomization: Duration of ICU stay through Day 29. 
• Proportion of subjects requiring invasive mechanical ventilation through Day 29. 
• If requiring invasive mechanical ventilation post randomization: Duration of invasive 
mechanical ventilation through Day 29. 
• All-cause mortality through Day 29. 
• Incidence of critical COVID-19 illness, defined as any one of the following: (a) requiring 
ICU admission or ICU level of care*, (b) invasive mechanical ventilation, or (c) resulting 
in death by Day 29. 
• Length of time to clinical progression to critical COVID-19 illness through Day 29 (defined 
as the time to death, invasive mechanical ventilation, or ICU admission/requiring ICU level 
of care). 
After this interim analysis, the 1 gram dose arm may be terminated, the trial may be terminated (if 
the 2 gram dose is discontinued, the 1 gram dose will also be terminated), or the study will continue 
as originally planned unless discontinued for business or feasibility reasons in a setting of changing 
epidemic dynamics in the geographic catchment of the trial. 
The futility analysis will not inflate the type I error since the trial will not be stopped to claim 
efficacy. The primary and key secondary efficacy outcomes will be analyzed using the methods 
described above in Section 6.1 and 6.2. No subgroup or sensitivity analyses are planned for the 
futility analysis. 
Suppose at the time of data-cut for the futility analysis, x0 subjects meet the primary efficacy 
endpoint among m0 subjects in the placebo group, and x1 subjects have events among m1 subjects 
in the treatment group (1 gram or 2 grams C19-IG 20%). Let 𝑝𝑝𝑔𝑔 = 𝑥𝑥𝑔𝑔⁄𝑚𝑚𝑔𝑔 for group g = 0, 1; and 
𝑝𝑝𝑝 = (𝑥𝑥0 
+ 𝑥𝑥1 )⁄(𝑚𝑚0 + 𝑚𝑚1 ). 𝑍𝑍1 =  
𝑝𝑝1−𝑝𝑝0 
 
√(𝑚𝑚−1+ 𝑚𝑚−1)𝑝𝑝(1−𝑝𝑝) is the z-score corresponding to the Chi- 
0 
1 
square statistic. 
Let the final sample size be n0 and n1 in the placebo and treated (1 gram or 2 grams C19-IG 20%) 


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groups respectively. Let Z1-α/2 be the 1- α/2 = 97.5% percentile of the normal distribution, which 


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can be calculated as the PROBIT function in SAS. Let 𝑡𝑡 = (𝑛𝑛−1 + 𝑛𝑛−1)⁄(𝑚𝑚−1 + 𝑚𝑚−1). The 
0 
1 
0 
1 
conditional power (CP) for the primary efficacy endpoint (each of C19-IG 20% dose groups 
compares to placebo) will be calculated using the formula: 
 
𝑍𝑍1−𝛼𝛼/2− 𝑍𝑍1⁄√𝑡𝑡 
𝐶𝐶𝐶𝐶 = 1 − 𝛷𝛷 ( 
 
 
) 
√1−𝑡𝑡 
where Φ is the cumulative distribution function (CDF) for N (0,1). 
 
10. 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 study is commensurate with other Phase 3 
investigations ongoing during the COVID-19 pandemic. 
For overall context, one may reference the mAb data for casirivimab and imdevimab (Regeneron 
cocktail) in support of their Emergency Use Authorization (EUA) granted 20 November 2020. The 
R10933-10987-COV-2067 study on which the data analysis for the EUA was based included 799 
enrolled subjects (~266/arm). 
If it is assumed that 80% of patients in the Placebo control arm will remain asymptomatic at Day 
14 [3] (subset of ~314 patients PCR + at baseline) then the sample size projections in the table 
below emerge for various degrees of C19-IG 20% treatment effect (delta). 
Practically speaking then the sample size becomes ~240 patients/arm for a significance level alpha 
(0.025) and 80% power (Table 2). Assuming a 10% withdrawal rate, 267 patients per arm would 
be needed. Furthermore, this calculation provides a per group sample size commensurate with the 
per arm group size supporting Regeneron’s EUA for casirivimab and imdevimab. 
Table 2 Sample Size Estimation 
 
Based on the above extrapolation/estimate, and allowing for a total of 3 arms, randomized 1:1:1 to 
Placebo and 2 dose levels of C19-IG 20% approximately 801 subjects are allowed to be 
randomized as part of a humanitarian effort against COVID-19. N=267 subjects per group should 
allow differentiation in disease evolution for patients randomized to C19-IG 20% versus the 
control Placebo arm. 
Sample size estimation was also calculated with regard to consideration of the viral load first 
secondary endpoint. A sample size of ~172 patients/arm would theoretically provide the trial with 
80% power to detect a difference of 0.5 log10 in the mean reduction of SARS-CoV-2 viral load at 
a two-sided significance level of α = 0.025, assuming an expected standard deviation of 1.5 [3, 4]. 
A 0.5 log10 copies/mL difference in reduction was chosen to represent the minimal threshold for a 


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biologically relevant change for analyses based on analogy with other viruses[5]. However, it is 
unknown whether this degree of viral load reduction will be realized as a result of the planned 
dosages of C19-IG 20% within this clinical setting. The larger sample size per arm provides a 
greater level of assurance in this regard. 
 
11. REFERENCES 
 
1. https://www.mdcalc.com/national-early-warning-score-news 
2. https://clinicaltrials.gov/ct2/show/NCT04280705 
 
3. Mitjà O, Corbacho-Monné M, Ubals M, et al. BCN-PEP-CoV2 Research Group. A Cluster 
Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. N Engl Med 2020; 
DOI: 0.1056/NEJMoa2021801. 
 
4. To KK-WW, Tsang OT-YY, Leung W-SS, et al. Temporal profiles of viral load in posterior 
oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV- 
2: an observational cohort study. Lancet Infect Dis 2020; 20:565. 
5.  Mitjà O, Corbacho-Monné M, Ubals M, et al. BCN PEP-CoV-2 RESEARCH GROUP. 
Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized- 
Controlled Trial. Clin Infect Dis. 2020:ciaa1009. doi: 10.1093/cid/ciaa1009. 


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12. APPENDIX 
 
12.1 
Appendix A: Schedule of Events 
 


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