Clinical trial NCT04426695
Conditions: COVID-19
Keywords: Coronavirus disease 2019 (COVID-19) Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) coronavirus acute respiratory distress syndrome
Sponsor: Regeneron Pharmaceuticals
Start date: 2020-06-10; Completion date: 2021-10-22
Enrollment: 2252 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives are:

Pooled Phase 3 (Cohort 1) and Phase 2 (Cohort 1A)

* To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo in reducing viral load of SARS-CoV-2
* To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, as measured by death or mechanical ventilation

Phase 1/2 (Cohort 1)

* To exclude futility of REGN10933+REGN10987 compared to placebo, as measured by death or mechanical ventilation
* To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo

Detailed description:

Arms: arm 1: Cohort 1 (C1): O2 saturation \>93% on low-flow oxygen via nasal cannula, simple face mask, or other similar device arm 2: Cohort 1A (C1A): With COVID-19 symptoms but not requiring supplemental oxygen arm 3: Cohort 2 (C2): On high-intensity oxygen (O2) therapy but not on mechanical ventilation arm 4: Cohort 3 (C3): On mechanical ventilation
Interventions: intervention 1: REGN10933+REGN10987 combination therapy intervention 2: Placebo
Intervention descriptions: intervention 1: Administered intravenously (IV) single dose intervention 2: Placebo IV Single Dose

Protocol documents:
SAP_002.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 66 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
FINAL ANALYSIS OF PHASES 1, 2 AND 3  
OF THE STUDY COV-2066 FOR ALL COHORTS 
VERSION: FINAL 1.0 
A MASTER PROTOCOL ASSESSSING THE SAFETY, TOLERABILITY,  
AND EFFICACY OF ANTI-SPIKE (S) SARS-COV-2 MONOCLONAL ANTIBODIES 
FOR THE TREATMENT OF HOSPITALIZED PATIENTS WITH COVID-19 
Compound: 
REGN10933+REGN10987 (REGEN-COV; REGN-COV2) 
Protocol Number: 
R10933-10987-COV-2066 
Clinical Phase: 
Phases 1/2/3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatisticians: 
Clinical Trial Manager: 
Study Medical Directors: 
Version/Date: 
Original (Version 1.0) / 07 JULY 2021 
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NCT04426695


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 2 of 66 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
Study Biostatisticians  
 
 
 
See appended electronic signature page 
Project Biostatisticians  
 
 
 
See appended electronic signature page 
Study Medical Directors 
 
 
 
See appended electronic signature page 
Study Clinical Pharmacologist 
 
 
 
See appended electronic signature page 
Study Bioanalytical Scientist 
 
 
 
See appended electronic signature page 
Head of Biostatistics and Data Management 
 
 
 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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TABLE OF CONTENTS 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ..................................................................................................9 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objectives .....................................................................................................11 
1.2.2. 
Secondary Objectives .................................................................................................12 
1.2.3. 
Exploratory Objectives ...............................................................................................13 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................14 
1.2.5. 
Revision History for SAP Amendments .....................................................................14 
2. 
INVESTIGATION PLAN ..........................................................................................15 
2.1. 
Study Design and Randomization ..............................................................................15 
2.2. 
Statistical Hypothesis ..................................................................................................16 
2.3. 
Sample Size and Power Considerations .....................................................................17 
2.4. 
Study Plan ...................................................................................................................19 
2.4.1. 
Definition of Study Completion .................................................................................20 
3. 
ANALYSIS POPULATIONS ....................................................................................21 
3.1. 
Efficacy Analysis Sets ................................................................................................21 
3.2. 
Safety Analysis Set (SAF) ..........................................................................................21 
3.3. 
Pharmacokinetics Analysis Set ...................................................................................21 
3.4. 
Immunogenicity Analysis Set .....................................................................................22 
4. 
ANALYSIS VARIABLES .........................................................................................23 
4.1. 
Demographics and Baseline Characteristics ...............................................................23 
4.2. 
Medical History ..........................................................................................................25 
4.3. 
Prior / Concomitant Medications or Procedures .........................................................25 
4.4. 
Rescue Medication/or Prohibited Medication During Study ......................................26 
4.5. 
Efficacy Endpoints ......................................................................................................27 
4.5.1. 
Primary Endpoints ......................................................................................................27 
4.5.1.1. 
Primary Virologic Efficacy Endpoint .........................................................................27 
4.5.1.2. 
Primary Clinical Efficacy Endpoint ............................................................................28 
4.5.2. 
Secondary Endpoints ..................................................................................................30 
4.5.2.1. 
Secondary Virologic Efficacy Endpoints ...................................................................30 
4.5.2.2. 
Secondary Clinical Efficacy Endpoint ........................................................................31 
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Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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4.5.2.3. 
Clinical Endpoints based on Proportions ....................................................................31 
4.5.2.4. 
Clinical Endpoints based on Time and Events ...........................................................32 
4.5.3. 
Exploratory Endpoints ................................................................................................33 
4.6. 
Safety Variables ..........................................................................................................33 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................33 
4.6.2. 
Adverse Events of Special Interest .............................................................................34 
4.6.3. 
Laboratory Safety Variables .......................................................................................34 
4.6.4. 
Vital Signs ..................................................................................................................35 
4.7. 
Pharmacokinetic Variables .........................................................................................35 
4.8. 
Immunogenicity Variables ..........................................................................................36 
5. 
STATISTICAL METHODS .......................................................................................37 
5.1. 
Demographics and Baseline Characteristics ...............................................................37 
5.2. 
Medical History ..........................................................................................................37 
5.3. 
Prior / Concomitant Medications or Procedures .........................................................37 
5.4. 
Subject Disposition .....................................................................................................37 
5.5. 
Extent of Study Treatment Exposure ..........................................................................38 
5.5.1. 
Exposure to Investigational Product ...........................................................................38 
5.6. 
Analyses of Efficacy Endpoints..................................................................................38 
5.6.1. 
Analysis of Primary Efficacy Endpoints ....................................................................38 
5.6.1.1. 
Analysis of Primary Virologic Efficacy Endpoint ......................................................38 
5.6.1.2. 
Analysis of Primary Clinical Efficacy Endpoints .......................................................39 
5.6.2. 
Descriptive Analysis of Secondary Efficacy Endpoints .............................................39 
5.6.2.1. 
Descriptive Analysis of Secondary Virologic Efficacy Endpoints .............................39 
5.6.2.2. 
Descriptive Analysis of Secondary Clinical Efficacy Endpoints ...............................40 
5.6.3. 
Adjustment for Multiple Comparisons .......................................................................41 
5.6.4. 
Analysis of Exploratory Endpoints .............................................................................42 
5.7. 
Analysis of Safety Data ..............................................................................................42 
5.7.1. 
Adverse Events ...........................................................................................................42 
5.7.2. 
Clinical Laboratory Measurements.............................................................................43 
5.7.3. 
Analysis of Vital Signs ...............................................................................................43 
5.8. 
Analysis of Pharmacokinetics, Pharmacodynamics and Biomarker Data ..................44 
5.8.1. 
Analysis of Drug Concentration Data .........................................................................44 
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Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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5.8.2. 
Analysis of  Pharmacokinetics and Pharmacokinetics/Pharmacodynamics ...............44 
5.9. 
Analysis of Immunogenicity Data ..............................................................................44 
5.9.1. 
Analysis of ADA Data ................................................................................................44 
5.9.2. 
Analysis of NAb Data .................................................................................................46 
5.10. 
Association of Immunogenicity with Exposure, Safety, and Efficacy .......................46 
5.10.1. 
Immunogenicity and Exposure ...................................................................................46 
5.10.2. 
Immunogenicity and Safety and Efficacy ...................................................................46 
6. 
DATA CONVENTIONS ............................................................................................47 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................47 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................47 
6.3. 
Data Handling Convention for Missing Data .............................................................47 
6.4. 
Visit Windows ............................................................................................................48 
6.5. 
Pooling of Centers for Statistical Analyses ................................................................48 
7. 
INTERIM ANALYSIS ...............................................................................................49 
8. 
SOFTWARE ...............................................................................................................49 
9. 
REFERENCES ...........................................................................................................50 
10. 
APPENDIX.................................................................................................................51 
10.1. 
Schedule of Events for Phase 1 (Cohort 1) .................................................................51 
10.1.1. 
Footnotes for Schedule of Events (Phase 1) ...............................................................53 
10.2. 
Schedule of Events for Phase 2/3 (Cohort 1A, Cohort 1, Cohort 2, Cohort 3) ..........55 
10.2.1. 
Footnotes for Schedule of Events (Phase 2) ...............................................................57 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................59 
 
LIST OF TABLES 
Table 1: 
Cohorts of Hospitalized Patients in Study R10933-10987-COV-2066 ......................15 
Table 2:  
Statistical hypotheses ..................................................................................................16 
Table 3: 
Primary Clinical Efficacy Endpoints and Populations ...............................................29 
Table 4: 
Secondary Virologic Efficacy Endpoints and Populations .........................................30 
Table 5: 
Secondary Clinical Efficacy Endpoints and Populations ...........................................31 
Table 6: 
Secondary Clinical Endpoints based on Proportions of Patients with 
Outcome ......................................................................................................................31 
Table 7: 
Cumulative Incidence of Event Endpoints - Definitions of Events and 
Censoring Rules ..........................................................................................................32 
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Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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Table 8: 
NCI-CTCAE Severity Grading System for Adverse Events ......................................34 
Table 9: 
Hierarchical testing order ...........................................................................................41 
Table 10: Time Window for Summary of Swab Samples for SARS-CoV-RT-qPCR ...............48 
Table 11: Time Window for Summary of Laboratory Variables and Biomarkers .....................48 
 
LIST OF FIGURES 
Figure 1: 
Phase 1 – Study Flow Diagram ..................................................................................19 
Figure 2: 
Phase 2 – Study Flow Diagram ..................................................................................20 
 
 
 
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Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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List of Abbreviations and Definition of Terms  
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
aPTT 
Activated partial thromboplastin time  
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRP 
C-reactive protein 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
EUA 
Emergency Use Authorization 
FAS 
Full Analysis Set 
FDA 
United States Food and Drug Administration 
FiO2 
Fraction inspired oxygen 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
IWRS 
Interactive Web Response System 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
mFAS 
Modified Full Analysis Set 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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Abbreviation 
Definition 
NCA 
Non-compartmental analyses of Pharmacokinetic parameters 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NLR 
Neutrophil-lymphocyte ratio 
NP 
Nasopharyngeal 
PCSV 
Potentially Clinically Significant Value 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
RBC 
Red Blood Cell 
RNA 
Ribonucleic Acid 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
REGN-COV2 
(R10933+R10987) 
Co-administered REGN10933 and REGN10987 combination therapy 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SOC 
System organ class 
SpO2 
Peripheral capillary oxygen saturation 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper Limit Normal 
US 
United States (of America) 
WBC 
White blood cell 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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1. 
OVERVIEW 
1.1. 
Background/Rationale 
R10933-10987-COV-2066 (referred to as study “COV-2066” hereafter) is an adaptive phase 1/2/3, 
randomized, double-blinded, placebo-controlled master protocol to evaluate the efficacy and 
safety 
of 
co-administered 
REGN10933+REGN10987 
combination 
therapy 
(“REGN10933+REGN10987”) in hospitalized adult patients with COVID-19.  
The purpose of this statistical analysis plan (SAP) is to ensure the integrity of the study results by 
pre-specifying the statistical approaches for the analysis of study data prior to the final database 
lock. This final version of the SAP is intended to be a comprehensive and detailed description of 
the strategy and statistical methods to be used in the analysis of final data from all phases (phase 
1, phase 2, and phase 3) and all cohorts (cohort 1A, cohort 1, cohort 2, and cohort 3), based on 
Protocol Amendment 7 (dated 07 July 2021).   
Summary of Study Conduct and Patient Enrollment 
In this study, patients were enrolled in one of the following 4 cohorts based on disease severity at 
randomization: 
• Cohort 1A (Room Air): Patients with COVID-19 symptoms but not requiring 
supplemental oxygen 
• Cohort 1 (Low Flow Oxygen): Patients with O2 saturation >93% on low-flow oxygen 
via nasal cannula, simple face mask, or other similar device 
• Cohort 2 (High-Intensity Oxygen): Patients on high-intensity oxygen therapy* but 
not on mechanical ventilation 
*High-intensity oxygen therapy is defined as the use of non-rebreather mask with an oxygen flow rate 
of at least 10 L/min; use of a high flow device with at least 50% FiO2, or use of non-invasive ventilation 
to treat hypoxemia 
• Cohort 3 (Mechanical Ventilation): Patients on mechanical ventilation 
In the first-in-human (FIH) phase 1 portion of the study, patients were enrolled into cohort 1 only. 
Subsequently, in phase 2, patients were enrolled into all 4 cohorts.  
On 30 October 2020, an Independent Data Monitoring Committee (IDMC) recommended pausing 
enrollment into cohort 2 and cohort 3 based on a potential safety imbalance, while proceeding with 
enrollment in cohort 1A and cohort 1. All cohort 2 and 3 patients enrolled at the time of the 
recommendation continued in the study and were followed up through the end of study visit as per 
the protocol. This IDMC recommendation on enrollment was maintained for the duration of the 
study.  
An unblinded phase 1/2 analysis was performed on the patients who were randomized through 
01 December 2020 in phase 1 (cohort 1 only) and phase 2 (cohorts 1, 2, and 3) using a data cutoff 
date of 09 December 2020, based on a database lock on 22 December 2020 (refer to the phase 1/2 
SAP dated 21 December 2020 for details). Phase 2 cohort 1A was not included in the analysis. All 
patients enrolled into cohort 1 after 01 December 2020 were considered to be part of phase 3.  
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Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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On 09 April 2021, the Sponsor made a business decision to terminate patient enrollment in this 
study due to extremely low recruitment over several months. This decision was not based on any 
safety concerns. Accordingly, phase 3 cohort 1 and phase 2 cohort 1A enrollment was prematurely 
terminated. Until this time, only cohort 1 patients were enrolled into the phase 3 portion of the 
study. All ongoing subjects were followed up through their end of study visit as per the protocol. 
Cohort 1 reached its phase 2 enrollment goal first, and phase 3 cohort 1 started enrollment after 
01 December 2020. As cohort 1A never reached its predetermined phase 2 enrollment goal of 1000 
patients, phase 2 cohort 1A and cohort 1 enrolled concurrently. Phase 2 cohort 1A data were 
handled and overseen similar to phase 3 cohort 1 data. 
Given much smaller sample size than anticipated as a result of early termination of enrollment, the 
Sponsor has elected to pool phase 2 cohort 1A and phase 3 cohort 1 and combine the 
REGN10933+REGN10987 2.4g and 8.0g dose groups for the primary analyses. 
Overall, approximately 2252 subjects were randomized in study COV-2066:  
Phase 1 
• Cohort 1: 60 patients 
Phase 2 
• Cohort 1A: 609 patients  
• Cohort 1: 629 patients  
• Cohort 2: 164 patients  
• Cohort 3: 35 patients  
Prematurely Terminated phase 3  
• Cohort 1 (ie, subjects randomized after 01 Decemeber 2020 in cohort 1): 755 patients 
This final SAP outlines the strategy and statistical methods to be used in the final analysis of data 
from all phases and all cohorts in the prematurely terminated study COV-2066, as below: 
Efficacy Analysis 
The efficacy analysis will be performed for the modified full analysis set (mFAS, defined in 
Section 3.1) of the following pooled cohort of patients and individual subsidiary cohorts, 
representing the totality of patients in this prematurely terminated study who were not unblinded 
in the database lock on 22 December 2020. In this document, the prematurely terminated phase 3 
cohort 1 is referred as phase 3 cohort 1 and prematurely terminated phase 2 cohort 1A as phase 2 
cohort 1A. 
• Pooled phase 3 cohort 1 and phase 2 cohort 1A 
• Phase 3 cohort 1  
• Phase 2 cohort 1A 
In each of these data sets (ie, the 2 terminated cohorts and the pooled cohort), the analyses will 
be conducted in the mFAS for the following patient populations. The mFAS is defined as 
patients that have a positive central-lab confirmed SARS-CoV-2 RT-qPCR result from an NP 
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Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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swab sample and the efficacy analysis was conducted in the mFAS to ensure detectable virus 
was present at baseline. 
• Seronegative mFAS 
• High Viral Load mFAS, where high viral load is defined as >106 copies/mL at 
baseline 
• Overall mFAS 
The primary virologic endpoint is time-weighted average change from baseline viral load in 
nasopharyngeal (NP) samples through Day 7. The primary analysis will be performed in the 
Seronegative mFAS population that is combined across the 2.4 g and 8g doses and pooled across 
phase 3 cohort 1 and phase 2 cohort 1A. 
The primary clinical endpoint is death or mechanical ventilation. It will be estimated based on 
the proportion of patients who died or went on mechanical ventilation from Day 6 through Day 
29, where events occurring during the first 5 days will excluded because of the notion that 
clinical impact would occur only after achieving several days of viral suppression.  This 
observation was noted in the analysis of data from phase 1/2 portion of this study. In addition, 
the endpoint of death or mechanical ventilation from Day 1 through Day 29 will also be 
evaluated. The primary analysis will be performed for the High Viral Load mFAS, Seronegative 
mFAS, and the Overall mFAS in the pooled phase 3 cohort 1 and phase 2 cohort 1A and 
combined across the 2.4 g and 8 g doses of REGN10933+REGN10987. To control alpha at a 
strict 0.05 level, the two primary endpoints will be tested hierarchically, with the virologic 
endpoint tested first.  
Safety Analysis 
The safety analysis will be performed for the following cohorts, separately. Patients in phase 1/2 
cohort 1, phase 2 cohort 2 and cohort 3 are included into the analysis because more safety data 
were collected for the patients after the database lock on 22 December 2020. 
• Phase 2 cohort 1A 
• Phase 2 cohort 2 
• Phase 2 cohort 3 
• Phase 1/2/3 cohort 1 combined  
Pharmacokinetics (PK) and  Immunogenicity Analysis 
The PK and ADA analysis will be performed for phase 1/2/3 cohort 1 combined, phase 2 cohort 
1A, phase 2 cohort 2, and phase 2 cohort 3, separately. The NAb analysis will be performed for 
phase 2/3 patients. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
Pooled Phase 3 Cohort 1 and Phase 2 Cohort 1A 
The primary objectives include:  
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Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo 
in reducing viral load of SARS-CoV-2  
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, 
as measured by death or mechanical ventilation 
Phase 2 (Cohort 1A) 
There is no primary objective for phase 2 cohort 1A as enrollment was prematurely terminated.  
Phase 2 (Cohort 2 and Cohort 3) 
There is no primary objective for cohort 2 and cohort 3 in phase 2 as enrollment was put on hold. 
All safety and efficacy analyses are exploratory. 
Phase 3 (Cohort 1).  
There is no primary objective for phase 3 cohort 1 as enrollment was prematurely terminated. 
1.2.2. 
Secondary Objectives 
Pooled Phase 3 Cohort 1 and Phase 2 Cohort 1A 
The secondary objectives are:  
• To evaluate additional indicators of clinical efficacy of REGN10933+REGN10987 
compared to placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
Phase 2 (Cohort 1A)  
The secondary objectives are: 
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo 
in reducing viral load of SARS-CoV-2  
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, 
as measured by death or mechanical ventilation 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over 
time 
• To assess the immunogenicity of REGN10933 and REGN10987 
Phase 2 (Cohort 2 and Cohort 3) 
The secondary objectives are: 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over 
time 
• To assess the immunogenicity of REGN10933 and REGN10987 
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Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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Phase 3 (Cohort 1) 
The secondary objectives are:   
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo 
in reducing viral load of SARS-CoV-2  
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, 
as measured by death or mechanical ventilation 
• To evaluate additional indicators of clinical efficacy of REGN10933+REGN10987 
compared to placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
Phase 1/2/3 (Cohort 1)  
The secondary objectives are: 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over 
time 
• To assess the immunogenicity of REGN10933 and REGN10987 
1.2.3. 
Exploratory Objectives 
The exploratory objectives in all phases of the study are: 
• To assess viral genetic variation in patients with a positive SARS-CoV-2 RT-qPCR 
• To explore the potential association of baseline humoral immune response to 
SARS-CoV-2 on response to REGN10933+REGN10987 
• To evaluate the effects of REGN10933+REGN10987 compared to placebo on 
generation of a humoral immune response to SARS-CoV-2 (as measured by anti-
SARS-CoV-2 N protein) 
• To explore the effects of REGN10933+REGN10987 on measures of SARS-CoV-2 
infectivity as assessed in experimental laboratory assays 
• To explore biomarkers predictive of REGN10933+REGN10987 safety, efficacy, 
and/or disease progression and COVID-19 clinical outcomes 
• To 
understand 
the 
underlying 
mechanisms 
of 
action 
and 
biology 
of 
REGN10933+REGN10987, SARS-CoV-2, and COVID-19 
• To explore relationships between REGN10933+REGN10987 exposure and selected 
efficacy endpoints, safety endpoints, and/or biomarkers 
For phase 2 (cohort 2 and cohort 3), the exploratory objectives include: 
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Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
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• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, 
as measured by death or mechanical ventilation (as applicable based on the cohort) 
• To evaluate additional indicators of clinical efficacy of REGN10933+REGN10987 
compared to placebo 
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo 
in reducing viral load of SARS-CoV-2  
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
There is no modification from the statistical section in protocol amendment 7. 
1.2.5. 
Revision History for SAP Amendments 
Analyses described in this SAP supersede analyses described in any prior SAPs for this study. 
Analyses of phase 1 and phase 2 data not specified in this phase 1/2/3 SAP were based on phase 1 
SAP version 1.0 approved on 23 Jun 2020 and phase 1/ 2 SAP version 1.0 approved on 
21 Dec 2020.  
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
COV-2066 study followed an adaptive, phase 1/2/3, randomized, double-blinded, placebo-
controlled master protocol design to evaluate the efficacy, safety, and tolerability of 
REGN10933+REGN10987 in hospitalized adult patients with COVID-19. 
There is some evidence that suggests baseline clinical disease severity influences progression and 
outcomes of COVID-19. In order to evaluate potential differential treatment effects across the 
spectrum of hospitalized COVID-19 patients, eligible patients who have been hospitalized for 
≤72 hours at screening were enrolled in one of the 4 cohorts of patients with COVID-19 based on 
disease severity at randomization (see Table 1). 
Table 1: 
Cohorts of Hospitalized Patients in Study R10933-10987-COV-2066  
Study 
Cohort  
Phase 
Brief Name 
Cohort Description 
Cohort 1A  Phase 2 (Prematurely 
Terminated) 
Room Air 
Patients with COVID-19 symptoms 
but not requiring supplemental oxygen 
Cohort 1  
Phase 1 (Completed) 
Phase 2 (Completed) 
Phase 3 (Prematurely 
Terminated) 
Low Flow Oxygen 
Patients with O2 saturation >93% on 
low-flow oxygen via nasal cannula, 
simple face mask, or other similar 
device 
Cohort 2  
Phase 2 (Prematurely 
Terminated) 
High-Intensity Oxygen 
Patients on high-intensity oxygen 
therapy* but not on mechanical 
ventilation 
Cohort 3  
Phase 2 (Prematurely 
Terminated) 
Mechanical Ventilation 
Patients on mechanical ventilation 
* High-intensity oxygen therapy is defined as the use of non-rebreather mask with an oxygen flow rate of at least 
10 L/min; use of a high flow device with at least 50% FiO2, or use of non-invasive ventilation to treat 
hypoxemia. 
Patients were randomized in a stratified manner according to a central randomization scheme using 
an interactive web response system (IWRS). 
Phase 1 
In phase 1, 60 patients from Cohort 1 were randomized in a 1:1:1 allocation ratio to one of the 
following treatment groups: 
• Co-administered REGN10933+REGN10987 combination therapy, 2.4 g (1.2 g each of 
REGN10933 and REGN10987) IV single dose 
• Co-administered REGN10933+REGN10987 combination therapy, 8.0 g (4.0 g each of 
REGN10933 and REGN10987) IV single dose 
• Placebo IV single dose 
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Randomization in phase 1 were stratified by type of background standard-of-care being 
administered for COVID-19 at randomization as follows: 
• Antiviral therapies (remdesivir or other) 
• Other therapies (immune-based therapies, both antiviral and immune-based therapies, 
or no COVID-19-specific treatment) 
Phase 2/3 
In phase 2/3, patients were randomized in a 1:1:1 allocation ratio to one of the following treatment 
groups: 
• Co-administered REGN10933+REGN10987 combination therapy 2.4 g (1.2 g of 
REGN10933 plus 1.2 g of REGN10987) IV single dose 
• Co-administered REGN10933+REGN10987 combination therapy 8.0 g (4.0 g of 
REGN10933 plus 4.0 g of REGN10987) IV single dose 
• Placebo IV single dose 
Randomization in phase 2/3 was stratified by country and type of background standard-of-care 
being administered for COVID-19 at randomization as follows:  
• Antiviral therapies (remdesivir or other)  
• Non-antiviral therapies (immune-based therapies, both antiviral and immune-based 
therapies, or no COVID-19-specific treatment) 
The enrollment into Cohorts 2 and 3 were paused based on a recommendation from the IDMC 
(initial IDMC recommendation on 30 October 2020). 
Most of the patients in the study were enrolled in the United States. Other countries where patients 
were enrolled in the study include Romania, Brazil, Chile, Mexico, and Moldova. 
2.2. 
Statistical Hypothesis 
The statistical hypotheses tested in terms of the primary virologic and clinical efficacy endpoints 
are listed in Table 2. Multiplicity will be controlled using a hierarchical testing strategy as 
represented in Section 5.6.3. The mFAS, Seronegative mFAS, and High Viral Load mFAS are 
defined in Section 3.1. 
Table 2:  
Statistical hypotheses 
 
Type 
Null Hypothesis 
Primary virologic 
endpoint 
There is no difference in the time weighted average change from baseline viral load 
in NP sample through day 7 between the REGN10933+REGN10987 2.4g and 8.0g 
combined dose group and placebo in the Seronegative mFAS population in the 
pooled phase 3 cohort 1 and phase 2 cohort 1A  
Primary clinical 
endpoint 
There is no risk reduction in the  REGN10933+REGN10987 2.4g and 8.0g 
combined dose groups versus placebo in terms of cumulative incidence of death or 
mechanical ventilation from day 6 to day 29 in the High Viral Load mFAS 
population in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
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Type 
Null Hypothesis 
There is no risk reduction in the  REGN10933+REGN10987 2.4g and 8.0g 
combined dose groups versus placebo in terms of cumulative incidence of death or 
mechanical ventilation from day 6 to day 29 in the Seronegative mFAS 
population in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
There is no risk reduction in the  REGN10933+REGN10987 2.4g and 8.0g 
combined dose groups versus placebo in terms of cumulative incidence of death or 
mechanical ventilation from day 6 to day 29 in the overall mFAS population in 
the pooled phase 3 cohort 1 and phase 2 cohort 1A 
There is no risk reduction in the  REGN10933+REGN10987 2.4g and 8.0g 
combined dose groups versus placebo in terms of cumulative incidence of death or 
mechanical ventilation from day 1 to day 29 in the High Viral Load mFAS 
population in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
There is no risk reduction in the  REGN10933+REGN10987 2.4g and 8.0g 
combined dose groups versus placebo in terms of cumulative incidence of death or 
mechanical ventilation from day 1 to day 29 in the Seronegative mFAS 
population in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
There is no risk reduction in the REGN10933+REGN10987 2.4g and 8.0g combined 
dose groups versus placebo in terms of cumulative incidence of death or mechanical 
ventilation from day 1 to day 29 in the overall mFAS population in the pooled 
phase 3 cohort 1 and phase 2 cohort 1A 
2.3. 
Sample Size and Power Considerations 
The initial sample size for this adaptive study, COV-2066, was estimated separately for phase 1 
and phase 2 and was based on the original primary virologic endpoint of time-weighted average 
change from baseline to day 7 in viral load.   
In phase 1, a sample size of a total of 60 patients in Cohort 1 as the sentinel safety group was 
planned per discussions with regulatory authorities, i.e., 20 patients per arm in each of the 3 
treatment arms.  Since the goal was to assess safety and tolerability of REGN10933+REGN10987, 
this sample size would allow preliminary estimation of the incidences of SAEs and AESIs. 
Cohorts 1A, 2 and 3 were to be enrolled after phase 1, beginning with the phase 2 portion of the 
study. 
For phase 2 portion of the study, an initial sample size of 390 patients per cohort (i.e., 130 patients 
per arm) in each of cohorts 1A, 1, 2, and 3, for a total of 1560 patients was planned.  This sample 
size was based on 80% power to detect a treatment difference of 0.84 log10 copies/mL for the 
primary virologic endpoint assuming a standard deviation of 2.1 log10 copies/mL and 23% 
dropout rate.   
Per Protocol Amendment 6, an interim database lock for analysis of phase 1/2 combined data was 
planned and accordingly phase 2 sample size for Cohort 1 (low flow oxygen) was adapted to reflect 
the planned futility analysis using the primary clinical endpoint of death or mechanical ventilation.  
A total of 43 events of death or mechanical ventilation in seronegative modified Full Analysis Set 
(seronegative mFAS) patients  in Cohort 1 was estimated to achieve 80% power to detect a risk 
reduction of 50% (HR=0.5) between any REGN10933+REGN10987 dose groups (2.4g IV or 8.0g 
IV) versus placebo at α=0.1 (one-sided) level of significance.  This translated to a total sample size 
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of 250 randomized and treated patients across 3 arms, assuming patients would be followed 
through day 29, accrual takes 90 days, and 30% of FAS (randomized and treated) patients are in 
the seronegative mFAS. 
The sample size of phase 2 cohort 1A was adjusted to approximate 1000 patients based on clinical 
judgement without statistical justification. However, this target was not reached because the 
enrollment was prematurely terminated. 
 Per IDMC recommendation received on 30 October, 18 November, 10 December 2020, patient 
enrollment in cohort 2 and cohort 3 has been placed on hold based on a potential safety signal. 
Phase 3 Sample Size 
Details for sample size calculations are provided in the protocol. 
Finalization of the sample size and patient population for phase 3 was planned to be subject to 
change and would be determined after review of phase 2 data. However, enrollment of patients 
into the study was terminated prematurely by the Sponsor on 09APR2021 because of extremely 
slow enrollment in the months preceding the decision. The sample size of phase 3 was not re-
estimated.  
Approximately 2252 patients were randomized in the study, which includes 60 patients in phase 1 
Cohort 1, 629 in phase 2 Cohort 1, 755 in planned phase 3 Cohort 1, 609 in phase 2 Cohort 1A, 
164 in phase 2 Cohort 2 and 35 in phase 2 Cohort 3.  
Assuming the proportion of patients who died or went on machenical ventilation from day 1 to 
day 29 in placebo group is 13.1% which is same as the blinded proportion in the Seronegative 
mFAS patients of the pooled phase 3 cohort 1 and phase 2 cohort 1A and alpha is 0.05 2-sided, 
the 
minimal 
significant 
difference 
in 
relative 
risk 
reduction 
between 
the 
the 
REGN10933+REGN10987 2.4g and 8.0g combined dose group and placebo group is 29.0%, 
41.2%, and 36.6% for overall mFAS, Seronegative mFAS, and High Viral Load mFAS patients, 
respectively.  
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2.4. 
Study Plan 
The Study event table of phase 1 is presented in Section 10.1. The Study event table of phase 2 is 
presented in Section 10.2. 
Study flow diagrams for phase 1 and phase 2 are showin in Figure 1 and Figure 2, respectively. 
Figure 1: 
Phase 1 – Study Flow Diagram 
 
At the time of the finalization of this SAP version, REGN10989 was not studied in the clinical 
trials. 
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Figure 2: 
Phase 2 – Study Flow Diagram 
 
Phase 3  
In phase 3, patients will be assessed daily up to day 29 for clinical improvement. After day 29, 
patients will be followed-up via intermittent phone calls until EOS on day 57. 
2.4.1. 
Definition of Study Completion 
For individual patients, study completion is defined as collection of vital status information on 
their projected EOS date. All measures will be taken to obtain vital status information on the 
projected EOS date, and all patients with recorded vital status information at projected EOS date 
will be considered study completers. The end of study is considered day 169 (for phase 1) or day 
57 (for phase 2 and phase 3) (refer to Section 10 Schedule of Events). 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Council for Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following analysis sets will be used for 
all statistical analyses in the  study. 
3.1. 
Efficacy Analysis Sets 
Full Analysis Set (FAS): The full analysis set (FAS) includes all randomized patients who 
received at least one dose (full or partial) of the study drug. Analysis of the FAS population will 
be done according to the treatment allocated (as randomized). 
Modified Full Analysis Set (mFAS): The modified full analysis set (mFAS) includes all FAS 
patients with a positive SARS-CoV-2 RT-qPCR conducted in the central laboratory in NP swab 
samples at randomization and analysis is based on the treatment allocated (as randomized).  
Seronegative mFAS: The seronegative mFAS is defined as all patients in mFAS with documented 
seronegative status at the baseline.  
High Viral Load mFAS: The High Viral Load mFAS is defined as all patients in mFAS with 
baseline viral load >106  copies/mL. 
Both FAS and mFAS will be used for the summaries of demographic and baseline characteristics 
and analysis of clinical/biomarker endpoints. The mFAS will be used for the analysis of all efficacy 
endpoints, based on the principle that an anti-viral agent would only be anticipated to provide 
efficacy in patients with measurable virus at baseline. The seronegative mFAS as well as the high 
viral load mFAS will be used for the  primary analysis and descriptive analysis of certain virologic 
endpoints and clinical endpoints. Additional analyses will be performed in the seropositive mFAS, 
as needed. 
3.2. 
Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who received a dose (full or partial) 
of the study drug. Analysis of the SAF will be done according to the treatment received (as treated).  
Determination of “as treated” will be based on the actual study drug received on day 1. Since the 
treatment of “as treated” is same as “as randomized” in this study, the FAS is equivalent to the 
SAF. Therefore, the treatment administration and all clinical safety variables will be analyzed 
using the FAS. 
3.3. 
Pharmacokinetics Analysis Set 
The pharmacokinetics (PK) analysis population includes all patients who received any study drug 
of REGN10933 and REGN10987 and who had at least 1 non-missing drug concentration 
measurement following the first dose of study drug as indicated in the Schedule of Events table 
(please refer to  Section 10.2). Patients will be analyzed based on actual treatment received. 
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3.4. 
Immunogenicity Analysis Set 
The anti-drug antibody (ADA) analysis set (AAS) includes all subjects who received any study 
drug (active or placebo) and at least one non-missing ADA result from the ADA assay after a first 
dose of the study drug or placebo. 
The NAb analysis set (NAS) includes all treated subjects who received any study drug (active or 
placebo), have at least one non-missing anti-drug antibody result following the first dose of study 
drug (active or placebo), and either tested negative at all ADA sampling times or tested positive 
for ADA with at least one non-missing NAb result after first dose of the study drug (active or 
placebo). Subjects who are ADA negative are set to negative in the NAb analysis set. 
Subjects will be analyzed according to the treatment actually received. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristic variables include the following for each Cohort (1A, 
1, 2 and 3): 
• Age at screening (years) 
• Age group  (18-<40, 40-<65, >=65, >=75, >=85 years) 
• Sex (Male, Female) 
• Race (White, Black/African American, American Indian or Alaska Native, Native 
Hawaiian/Other Pacific Islander, Not Reported, Other) 
• Ethnicity (Hispanic or Latino, Not-Hispanic or Latino, Not Reported, Unknown) 
• Baseline Weight (kg) 
• Baseline Height (cm) 
• Baseline Body mass index (BMI) (kg/m2) calculated from weight and height 
• Obesity (BMI < 30 kg/m2, ≥30 kg/m2, Missing) 
• Woman of child bearing potential (WOCB) (Yes; No) 
− If “No”, then Post-menopausal, Surgically Sterile, Other 
• Baseline SARS-CoV-2 Viral Load from central lab in Nasopharyngeal Swab 
(excluding assessments at screening visit if any) (log10 copies/mL) 
• Baseline SARS-CoV-2 Viral Load based on RT-qPCR result in Nasopharyngeal Swab 
(copies/mL) 
• Baseline SARS-CoV-2 Viral Load categories (≤104 vs >104, ≤ 105 vs >105, ≤ 106 vs 
>106, ≤ 107 vs >107 copies/mL) 
• Baseline SARS-CoV-2 Qualitative PCR results (central lab result; positive, negative, 
Other [not done, borderline]) 
[Positive result is ≥ lower limit of detection (LOD) and negative is <LOD] 
• Baseline SARS-CoV-2 Serology status (negative, positive, other [i.e., borderline, not 
determined]) 
A patient’s serostatus is considered to be positive if any anti-SARS-CoV-2 antibody test (eg, 
anti-SARS-CoV-2 IgA or IgG) is positive, negative if all available tests are negative, and other if 
serostatus is not positive or negative (eg, borderline result) or is unknown. 
• Presence of neutralizing antibodies at baseline for seropositive subjects (Yes; No; 
Borderline; Unknown/Missing/indeterminate)   
• Baseline C-Reactive Protein (mg/L) 
• Baseline Neutrophils-Lymphocyte Ratio (NLR) 
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• Immunocompromised (Yes; No)  
Immunocompromised patients include those with immunological diseases, are 
immunosuppressed or have immunodeficiencies. Examples of medical history for this 
category include rheumatoid arthritis and cancer. 
• Background Standard of Care (per IRT) (Antiviral therapies; Non-antiviral therapies) 
Other baseline disease characteristic variables for this study population are as follows. 
Vital Signs at baseline – (selected from Vital Signs – At Baseline CRF) 
• Oxygen source (Supplemental Oxygen; Room Air) 
• Temperature degrees in centigrade (C) 
• Location for Temperature (oral cavity, axillary, rectal, ear, temple) 
• Respiratory Rate (breaths/min) 
• Oxygen Saturation, SpO2 % (range is 0% to 100%) 
• Oxygen Flow rate (L/min), (if not mechanically ventilated) 
• FiO2 (fraction of inspired oxygen) (range is 0.0 to 1.0), (if mechanically ventilated) 
COVID-19 Pneumonia status at baseline – (selected from Pneumonia Status at Baseline CRF, 
unless specified otherwise) 
• Duration of pneumonia (including any COVID-19 symptoms) prior to baseline 
(calculated as onset date for symptoms of pneumonia to first dose date. If date of onset 
of symptoms of pneumonia is missing, then date is not imputed.) 
• Duration of COVID-19  illness (symptoms) prior to baseline (based on Medical History 
CRF) 
• Patients using long-term oxygen therapy prior to admission for COVID-19 (e.g., use of 
Oxygen at home for COPD) (Yes/No) 
• Usual Oxygen flow rate for patients using long-term oxygen therapy prior to admission 
for COVID-19 (L/min) 
• Oxygen flow frequency for patients using long-term oxygen therapy prior to admission 
for COVID-19 
• Oxygen flow route for patients using long-term oxygen therapy prior to admission for 
COVID-19 
Clinical and Oxygen Status at randomization and pre-dose  – (selected from Clinical and 
Oyxgen Status – At Randomization as well as Pre-dose CRFs) 
• Use of supplemental oxygen (Yes; No; Missing) 
• If no, subject requiring ongoing medical care (COVID-19 related or otherwise)? (Yes; 
No; Missing) 
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• If yes, Type of Oxygen delivery device/ventilation used  
− Supplemental oxygen (not requiring high flow oxygen devices) 
− Non-invasive ventilation or high-flow oxygen devices 
− Invasive mechanical ventilation 
− Extracorporeal Membrane Oxygen ventilation (ECMO) 
• Clinical Status using Ordinal Scale 
− 1 = Death 
− 2 = Hospitalized, requiring invasive mechanical ventilation or ECMO 
− 3 = Hospitalized, requiring non-invasive ventilation or high flow oxygen devices 
− 4 = Hospitalized, requiring supplemental oxygen 
− 5 = Hospitalized, not requiring supplemental oxygen – requiring ongoing medical 
care (COVID-19 related or otherwise) 
− 6 = Hospitalized, nor requiring supplemental oxygen – no longer requires ongoing 
medical care 
− 7 = Not hospitalized 
Hospital or ICU stay – (selected from Hospital – ICU Admission and Discharge CRF) 
• Length of hospital stay including ICU prior to the first dose date (days) 
• Admitted into ICU during hospital stay prior to the first dose date (yes/no) 
• Length of ICU stay prior to the first dose date (days) 
4.2. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®). 
Medical history will include the following: 
• Prior and current symptoms related to COVID-19 
• Child-bearing potential/Menopausal history in women 
4.3. 
Prior / Concomitant Medications or Procedures 
Medications/Procedures will be recorded from the day of informed consent until the final study 
visit. Medications will be coded using the WHO Drug Dictionary (WHODD). Patients will be 
counted once in all ATC categories linked to the medication. 
Prior medications/procedures are: medications taken or procedures performed prior to 
administration of the study drug. 
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Concomitant medications/procedures are: medications taken or procedures performed 
following the first dose of study drug through the final study visit. This includes medications that 
were started before the study and are ongoing during the study 
A targeted list of following medications are expected to be recorded by the sites in the CRFs.  
• Putative COVID-19 treatments (e.g., remdesivir, convalescent serum, IVIG, IL-6 
receptor inhibitors [e.g., sarilumab, tocilizumab], JAK inhibitors [e.g., baricitinib], 
ivermectin) 
• Antipyretics (e.g., aspirin, acetaminophen, ibuprofen) 
• Anticoagulants (e.g., enoxaparin, warfarin, rivaroxaban) 
• Immunosuppressants (e.g., cyclosporine A, steroids) 
• Interferon beta 
• Theophylline 
• Antiepileptics (e.g., carbamazepine, divalproex, phenytoin) 
• Antiarrhythmics (e.g, digoxin, disopyramide, procainamide) 
• Antivirals, antibacterial, and antifungals 
• Antiparasitics (chloroquine or hydroxychloroquine) 
• Angiotensin receptor blockers (e.g., losartan, valsartan) 
• Angiotensin converting enzyme inhibitors (e.g., benazepril, lisinopril) 
Prior/Concomitant medications of interest for COVID-19: medications will be adjudicated in 
blinded manner by medical directors before database lock. 
4.4. 
Rescue Medication/or Prohibited Medication During Study 
Patients may receive rescue therapy for the treatment of COVID-19 per local standard-of-care. 
Rescue treatment(s) will not be provided as part of the study.   
Patients are not permitted to receive any medication specified in the exclusion criteria for study 
enrollment. Patients may otherwise continue their normal regimen of medications and procedures. 
SARS-CoV-2 Vaccination. Current CDC guidance recommends deferral of SARS-CoV-2 
vaccination for at least 90 days after administration of passive antibody treatment (eg, 
REGN10933+REGN10987) (CDC, 2020): 
Based on the estimated half-life of such therapies as well as evidence suggesting that reinfection 
is uncommon in the 90 days after initial infection, vaccination should be deferred for at least 
90 days, as a precautionary measure until additional information becomes available, to avoid 
interference of the antibody treatment with vaccine-induced immune responses. 
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4.5. 
Efficacy Endpoints 
4.5.1. 
Primary Endpoints 
4.5.1.1. 
Primary Virologic Efficacy Endpoint 
The primary virologic endpoint is time-weighted average change from baseline viral load in NP 
sample through day 7, as measured by quantitative reverse transcription polymerase chain 
reaction (RT-qPCR) in nasopharyngeal (NP) swab sample. The primary analysis will be 
performed for the Seronegative mFAS. 
Time-weighted average of change from baseline in viral load in the NP swab samples will be 
calculated for each patient using the trapezoidal rule as the area under the curve for change from 
baseline at each time point divided by the time interval for the observation period (e.g., time 
interval will be 6 days for the observation period day 1 through day 7, or 10 days for observation 
period day 1 through day 11, etc.).  This endpoint represents the reduction in average (mean) daily 
viral load from baseline. 
For example, the time-weighted average (TWA) change from baseline in viral load in the NP swab 
samples till the last observation day tk will be calculated using the formula 
𝑇𝑊𝐴[0−𝑘] = [∑(𝑡𝑖−𝑡𝑖−1)
𝑘
𝑖=1
∗(𝐷𝑖+ 𝐷𝑖−1)/2] (𝑡𝑘−𝑡0)
⁄
 
Where  
• k refers to the number of post-baseline assessments (e.g., k=3 for 3 post-baseline 
assessments through day 7, i.e., day 3, day 5, and day 7) 
• Di is the change from baseline in viral load value (log10 copies/mL) obtained at time ti, 
D0 =0 
• ti is the time(day) for which Di is measured, such as t0 =  1 (day) for baseline; and {ti }= 
3, 5, 7, for i = 1 to 3 where the postbaseline assessment is taken 
• If the Di is missing due to failed test or other reasons, only the time points with non-
missing values will be included in the calculation. For example, we will calculate the 
TWA till day 7. Suppose the scheduled assessment result is missing at day 5 due to a 
failed test but non-missing at day 3 and day 7, then 
𝑇𝑊𝐴[0−3] = [(𝑡1 −𝑡0) ∗(𝐷1 + 𝐷0)/2 + (𝑡3 −𝑡1) ∗(𝐷3 + 𝐷1)/2]/(𝑡3 −𝑡0) 
Time-weighted average (TWA) change from baseline in viral load in any sample (nasopharyngeal, 
nasal or saliva) from day 1 through post-baseline day X is as described above.  It represents the 
reduction in average (mean) daily viral load for the observation period of day 1 through day X. 
Baseline is defined as the last non-missing viral load value (copies/mL) prior to the study drug 
infusion, unless specified otherwise. Patients with a missing baseline value will be excluded from 
the analysis. 
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Since viral load values (copies/mL) are expected to be highly skewed, these raw values will be 
transformed on log10 scale to achieve symmetric distribution that can be approximated with normal 
distribution. 
Viral load below the lower limit of detection (LLOD) of the assay (i.e., 299 copies/mL) will be 
imputed with 1 copy/mL, i.e., 0 log10 copies/mL.  Viral load values below the lower limit of 
quantification (LLOQ) of the assay (i.e., 714 copies/mL) but have positive results on the qualitative 
assay will be imputed as LLOQ/2 = 357 copies/mL.  The upper limit of quantification of assay 
(ULOQ) is 71 million copies/mL (i.e., ~7.85 log10 copies/mL). Original assay test results above 
the upper limit of quantification (>ULOQ) of the assay will be replaced by results based on the 
diluted and reflexed testing results, when available. Otherwise, the ULOQ will be used in the 
analysis. 
Change from baseline at day X in viral load in any sample is the post-baseline viral load at day 
X minus viral load at day 1.  Change from baseline and TWA change from baseline will be derived 
based on log10 copies/mL.   
Percent change from baseline is the change from baseline divided by day 1 viral load. Percent 
change from baseline will be derived based on raw copies/mL. 
4.5.1.2. 
Primary Clinical Efficacy Endpoint 
The primary clinical endpoint is death or mechanical ventilation. It will be estimated by the 
proportion of patients who died or went on mechanical ventilation from day 6 through day 29 
and from day 1 through day 29.  The endpoint and populations are listed in Table 3. 
The proportion from day 6 to day X = (Total number of patients who died between day 6 to day 
X [days inclusive], or ever had ordinal scale = 2 (mechanical ventilation/ECMO) at any 
timepoint on or after day 6 through day X)/(Total number in the treatment group), where the 
following patients will be excluded from both numerator and denominator. 
• Patients who died before day 6 or 
• Patients who went on mechanical ventilation before day 6 or 
• Patients who dropped out from study before day 6 
The proportion from day 1 to day X = (Total number of patients who died on or before day X, or 
ever had ordinal scale = 2 (mechanical ventilation/ECMO) at any timepoint through day 
X)/(Total number in the treatment group)  
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Table 3: 
Primary Clinical Efficacy Endpoints and Populations  
Endpoint 
Timepoint 
Population 
Proportion of patients who died or 
went on mechanical ventilation 
(for cohort 1 and cohort 1A) 
day 6 to day 
29 
1. High Viral Load mFAS 
 2. Seronegative mFAS,  
 3. mFAS 
day 1 to day 
29 
1. High Viral Load mFAS 
 2. Seronegative mFAS,  
 3. mFAS 
Definitions of death or mechanical ventilation: 
Death or mechanical ventilation is derived based on the patient vital status and the mechanical 
ventilation use recorded on Clinical status using an Ordinal Scale eCRF which is described in the 
following paragraphs. The patients who went on mechanical ventilation are those whose ordinal 
scale was 2.  
Clinical status using Ordinal Scale: The ordinal scale provides an assessment of the clinical 
status of a patient (Peterson, 2017 [1]). The 7-point ordinal scale is as follows:  
1 = Death 
2 = Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO) 
3 = Hospitalized, requiring non-invasive ventilation or high flow oxygen devices 
4 = Hospitalized, requiring supplemental oxygen 
5 = Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care 
(COVID-19-related or otherwise) 
6 = Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical 
care 
7 = Not hospitalized 
Clinical and oxygen status, vital status and hospitalization status will be collected and recorded on 
the CRFs as follows.   
• Clinical and Oxygen Status – At Randomization CRF; Clinical and Oxygen Status – 
Pre-dose CRF; and Clincal and Oxygen Status – Post-dose visits CRF: 
− Use of supplemental oxygen:  Yes/No 
− Type of Oxygen delivery device/ventilation, if using supplemental oxygen: 
Supplemental 
oxygen 
(not 
requiring 
high 
flow 
oxygen 
devices),  
Non-invasive 
ventilation 
or 
high 
flow 
oxygen 
devices,  
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Invasive 
mechanical 
ventilation,  
Extracorporeal membrane oxygenation (ECMO) 
− Vital status: Record vital status (dead or alive) of the day 
− Hospitalization Status: Starting on day 2, record daily whether patient is 
hospitalized without requiring medical care or discharged.  
• Hospital – ICU Admission and Discharge CRF:  Record hospital discharge (if 
applicable) on the day of discharge 
• Death Details CRF: Record any death (if applicable) on the day of death. 
An ordinal scale score will be generated in the electronic database based on the records on clinical 
and oxygen status. 
4.5.2. 
Secondary Endpoints 
4.5.2.1. 
Secondary Virologic Efficacy Endpoints 
The virologic efficacy endpoints are listed in Table 4.  Definitions of the endpoints are described 
in subsections below. 
Table 4: 
Secondary Virologic Efficacy Endpoints and Populations  
Endpoint 
Timepoint 
Population 
Time-weighted average change from 
baseline viral load in NP sample 
Through day 7 
mFAS 
Time-weighted average change from 
baseline viral load in NP sample 
Through day 7 
Baseline Viral load categories 
( >105, >106 copies/mL) 
mFAS 
Time-weighted average change from 
baseline viral load in NP sample  
Through day 11 
Seronegative mFAS 
Time-weighted average change from 
baseline viral load in NP sample 
Through day 11 
mFAS 
Time-weighted average change from 
baseline viral load in NP sample 
Through day 11 
Baseline Viral load categories 
(>105, >106 copies/mL) mFAS 
Time-weighted average change from 
baseline, change from baseline, and 
percent change from baseline in viral 
load in NP sample 
Through each post-
baseline timepoint until 
day 29 
1. Seronegative mFAS,  
2. Baseline Viral load 
categories ( >105, 
>106copies/mL) mFAS,  
3. mFAS 
The time-weighted average change from baseline, change from baseline, and percent change 
from baseline in viral load in NP sample are defined in Section 4.5.1.1. 
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4.5.2.2. 
Secondary Clinical Efficacy Endpoint 
The secondary clinical efficacy endpoints and populations are defined in Table 5. All clinical 
outcomes derived from the ordinal scale (Section 4.5.1.2) will be based on data until day 29.   
Definition of readmission 
Readmission  to hospital will also be based on what investigators report on Hospital – ICU 
Admission and Discharge CRF. 
Table 5: 
Secondary Clinical Efficacy Endpoints and Populations  
Endpoint 
Timepoint 
Population 
Proportion of patients who went on mechanical 
ventilation (for cohort 1 and cohort 1A) 
By day 29 
1.High viral load 
mFAS, 
2.Seronegative 
mFAS,  
3. mFAS; 
 
 
 
 
 
 
 
Proportion of patients who died 
• 
day 6 to day 29 
• 
day 1 to day 29 
Proportion of patients who were discharged 
By day 29 
Proportion of patients who died or were 
readmitted 
All available follow-up 
data 
Cumulative incidence of Death 
(i.e. Overall Survival) 
All available follow-up 
data 
Cumulative incidence of Mechanical 
Ventilation (for cohort 1 and cohort 1A) 
All available follow-up 
data up to day 29 
Cumulative incidence of Death or Mechanical 
Ventilation (for cohort 1 and cohort 1A) 
All available follow-up 
data up to day 29 
Time to Discharge 
All available follow-up 
data 
4.5.2.3. 
Clinical Endpoints based on Proportions 
Clinical endpoints based on proportions will be computed as numerator over denominator as 
given in Table 6. 
Table 6: 
Secondary Clinical Endpoints based on Proportions of Patients with 
Outcome  
Number 
Endpoint 
Timepoint 
Numerator 
Denominator 
1. 
Died 
day 6 to day X 
Total number of patients who died 
after day 5 and on or before day X  
(death data will captured from any 
CRF in the study) 
Number of patients in 
the treatment group 
excluding patients who 
died or dropped out 
before day 6 
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day 1 to day X 
Total number of patients who died 
on or before day X 
(death data will captured from any 
CRF in the study) 
Number of patients in 
the treatment group 
2. 
Went on 
Mechanical 
Ventilation 
Through day X 
Number of patients who ever went 
on mechanical ventilation or 
ECMO (ordinal scale =2) through 
day X 
Number of patients in 
the treatment group 
3. 
Discharge 
Through day X 
Number of patients who 
discharged through day X 
Number of patients in 
the treatment group 
4 
Death or 
readmission 
Through end of 
study 
Number of patients who died or 
readmitted into hospital during the 
study 
Number of patients in 
the treatment group 
4.5.2.4. 
Clinical Endpoints based on Time and Events 
Definitions of cumulative incidence of event efficacy endpoints and censoring rules are given in 
Table 7. 
Table 7: 
Cumulative Incidence of Event Endpoints - Definitions of Events and 
Censoring Rules 
Endpoint 
Event and Time 
Censor and Time 
Observation Period 
Cumulative 
Incidence of  
Death 
Event = patient died 
Time is days since first dose date, 
i.e., 
(Date of death – Date of first 
dose) 
Censor = patient is alive 
Time is days alive =  
(last follow-up date – 
Date of first dose) 
day 1 through day 169 (Phase 1 
patients only) 
day 1 through day 57 (Phase 2/3 
patients) 
Cumulative 
Incidence of  
Mechanical 
Ventilation 
Event = patient ever went on 
mechanical ventilation 
Time is days since first dose date 
until first event of ventilation, i.e., 
(Date of first mechanical 
ventilation – Date of first dose) 
Censor otherwise (even if 
never ventilated and died) 
Time is days since first 
dose until last follow-up 
= (last follow-up date – 
Date of first dose) 
day 1 through day 29 
Cumulative 
Incidence of 
Death or 
Mechanical 
Ventilation 
Event = patient died or patient 
ever went on mechanical 
ventilation 
Time is days since first dose date 
until the death date or the earliest 
date of the ordinal scale reaching 
2, whichever is earlier, i.e. (min 
(Death Date, Date of first 
mechanical ventilation) – Date of 
first dose)) 
Censor otherwise  
The censor date is the last 
follow-up date.  
Time is days since first 
dose until last follow-up  
= (last follow-up date – 
Date of first dose) 
day 1 through day 29 
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Endpoint 
Event and Time 
Censor and Time 
Observation Period 
Time to  
Discharge 
Event = First discharge and alive 
Time is days since first dose date 
until first discharge, i.e., (Date of 
first discharge – Date of first 
dose) 
Censor otherwise 
If alive, then Time = 
(End of study date – Date 
of first dose) 
If died, then Time =  168 
days for Phase 1 patients 
or 56 days for Phase 2/3 
patients 
day 1 through day 169 (Phase 1 
patients) 
day 1 through day 57 (Phase 2/3 
patients) 
4.5.3. 
Exploratory Endpoints 
The exploratory endpoints include:  
• Proportion of patients with treatment failure having mutations in the gene encoding the 
SARS-CoV-2 S protein through day 29 
• Change and percentage change in neutrophil-lymphocyte ratio (NLR) at each visit 
through day 29 
• Change and percentage change in D-dimer at each visit through day 29 
• Change and percentage change in ferritin at each visit through day 29 
• Change and percentage change in C-reactive protein (CRP) at each visit through day 29 
• Change and percentage change in lactate dehydrogenase (LDH) at each visit through 
day 29  
4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
Treatment-emergent adverse events (AEs) (grade 3 or 4; for phase 1 only), treatment-emergent 
serious adverse events (SAEs) and treatment-emergent adverse events of special interest (AESIs) 
will be collected according to the Schedule of Events (Appendix 10.1 and Appendix 10.2).  All 
adverse events are to be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition. 
Infusion-related reactions are defined as any relevant adverse event that occurs during the infusion 
or up to day 4.  
Hypersensitivity reactions are defined as any relevant adverse event that occurs during the infusion 
or up to study day 29. 
The severity of adverse events (including test findings classified as adverse events) will be graded 
using the current version of the NCI-CTCAE v5.0 (Division of Cancer Treatment and Diagnosis 
[DCTD], 2020). 
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Treatment-emergent AEs, treatment-emergent SAEs, or treatment-emergent AESIs not listed in 
the NCI-CTCAE will be graded according to the scale in Table 8. 
Table 8: 
NCI-CTCAE Severity Grading System for Adverse Events 
Grade 
Severity 
Description 
1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
2  
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL)* 
3  
Severe 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL† 
4  
Life-threatening 
Life threatening consequences; urgent intervention indicated 
5  
Death 
Death related to adverse events 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
† Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and 
not bedridden.  
4.6.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) of scientific and 
medical interest specific to this drug program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor will be done.  
In this study, the AESIs are listed below: 
• Grade ≥2 infusion related reactions 
− selected from Adverse Events CRF 
• Grade ≥2 hypersensitivity reactions 
− selected from Adverse Events CRF 
4.6.3. 
Laboratory Safety Variables 
Blood Chemistry  
Samples for laboratory testing will be collected at visits according to the schedule of events in 
Section 10.2.  
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Tests will include: 
Sodium 
Blood urea nitrogen (BUN) 
Alkaline phosphatase  
Potassium 
Aspartate aminotransferase (AST) 
Creatinine 
Chloride 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK) 
Carbon dioxide 
Total bilirubin 
Lactate dehydrogenase (LDH) 
Glucose 
Albumin  
C-reactive protein (CRP) 
Ferritin 
 
 
Hematology 
Hematology, urinalysis, and pregnancy testing samples will be analyzed by the local laboratory. 
Tests will include: 
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Platelet count 
 
Basophils 
 
 
Eosinophils 
Other Laboratory Tests 
Coagulation tests: D-dimer, prothrombin time (PT/INR), activated partial thromboplastin time 
(aPTT). 
Laboratory results, vital signs, and other diagnostic results or findings that are appraised by the 
investigator and determined by investigator to fulfil the criteria of TEAEs (grade 3 or 4), treatment-
emergent SAEs, or treatment-emergent AESIs will be reported. 
4.6.4. 
Vital Signs 
Vital signs, including temperature, blood pressure, pulse, pulse oximetry and respiratory rate are 
recorded according to Schedule of Events table (See Section 10.2).   
Body weight and height are recorded according to Schedule of Events table (See Section 10.2). 
Supplemental oxygen/FiO2 use will be measured at baseline to monitor the patient’s status 
regarding gas exchange. As applicable, the following will be recorded: 
• Oxygen flow rate in L/min (if not mechanically ventilated)  
• FiO2 (if mechanically ventilated) 
• Resting SpO2 (in %)  
4.7. 
Pharmacokinetic Variables 
The PK variable is the concentration of REGN10933 and REGN10987 antibodies in serum and 
sampling time  that a sample was collected as specified in the Schedule of Events table (See 
Section 10.2). 
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4.8. 
Immunogenicity Variables 
The immunogenicity variables are ADA and (in phase 2 and phase 3 only) NAb status, titer, and 
time-point/visit. Serum samples for ADA will be collected at the visits as specified in Section 10.2. 
Samples positive in the ADA assay will be further characterized for ADA titers and for the 
presence of NAb. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, Q1, median, Q3, standard deviation (sd), minimum, and 
maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics variables given in Section 4.1 will be summarized by 
treatment group, and all groups combined.  These will be analyzed for FAS and mFAS populations. 
Similar analysis will be performed by baseline serostatus and baseline viral load categories (≤ 106 
copies/mL and >106 copies/mL) for mFAS population. 
5.2. 
Medical History 
Medical history will be summarized by SOC (system organ class) and PT (preferred term) and by 
treatment group and all groups combined in the mFAS and FAS population. 
5.3. 
Prior / Concomitant Medications or Procedures 
Prior or concomitant medications/procedures will be summarized by treatment groups. Summaries 
will present patient counts (and percentages) for all medications, dictionary coded by 
WHODRUG, by decreasing frequency of the overall group incidence (or high dose group 
incidence in tables where the overall is not presented) of ATC followed by ATC level 2, ATC 
level 4 and preferred term.  Focus of the results will be on the list of targeted medications 
(Section 4.3) in the FAS and mFAS populations.   
Number and proportion of patients undergoing a prior/concomitant procedure(s) will be 
summarized, sorted by decreasing frequency of SOC and PT based on the incidence in the overall 
group incidence (or high dose group incidence in tables where the overall is not presented). Patients 
will be counted only once for each SOC and PT linked to the procedure. 
Prior or concomitant medications/procedures of interest for COVID-19 will be summarized 
similarly. 
5.4. 
Subject Disposition 
The following summaries will be provided for both mFAS and FAS populations. 
• The total number of randomized patients: received a randomization number 
• The total number of randomized patients who were not treated by study drug 
• The total number of randomized patients who discontinued the study, and the reasons 
for discontinuation 
• A summary of analysis sets including FAS, mFAS, SAF, PK, immunogenicity (ADA), 
and NAb analysis set (NAS)  (Section 3). 
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5.5. 
Extent of Study Treatment Exposure  
5.5.1. 
Exposure to Investigational Product 
Exposure to study drug will be examined for each patient as recorded on the Study Drug 
Administration-IV CRF. The following variables will be analyzed by treatment group: 
• Duration of intravenous infusion 
• Total volume of drug administered (units: mL) 
• Number of patients with total planned dose administered (yes/no) 
− If no, reason for not administration of total planned dose (equipment failure, 
adverse event, other) 
• Number of patients with infusion interruptions (ie, patients completed the full dose but 
had infusion interruptions) 
• Number of patients with infusion discontinuation (ie, patients didn’t completed the full 
dose infusion) 
The number and percentage of patients randomized and exposed to double-blind study drug will 
be presented for each treatment group. 
5.6. 
Analyses of Efficacy Endpoints 
The efficacy analyses will be performed for the following subjects on all efficacy endpoints, 
separately. The comparisons in all efficacy endpoints will be performed between the the 
REGN10933+REGN10987 2.4g and 8.0g combined dose group and placebo group as well as 
between each treatment group and placebo group.   
• Pooled phase 3 Cohort 1 and phase 2 cohort 1A subjects 
• Phase 3 Cohort 1 subjects (ie, subjects randomized after 01DEC2020 in Cohort 1) 
• Phase 2 cohort 1A subjects 
5.6.1. 
Analysis of Primary Efficacy Endpoints 
5.6.1.1. 
Analysis of Primary Virologic Efficacy Endpoint 
The primary analysis on the comparison between the the REGN10933+REGN10987 2.4g and 8.0g 
combined dose group and placebo with respect to the virologic endpoint of time-weighted average 
daily change from baseline in viral load (log10 copies/mL) from day 1 to day 7 and other post-
baseline visit timepoint will be performed in the Seronegative mFAS in the pooled phase 3 cohort 
1 and phase 2 cohort 1A patients. The estimand for the analysis is the difference in means between 
the the REGN10933+REGN10987 2.4g and 8.0g combined dose group and placebo in the pooled 
phase 3 cohort 1 and phase 2 cohort 1A patients. Data collected after use of convalescent plasma 
therapy or other antispike monoclonals will be excluded from efficacy analysis. All other available 
data will be used in the analysis regardless of intercurrent events such as rescue medication or 
discontinuation, i.e., treatment policy approach.  
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The analysis will be based on the observed data with no imputation for missing data except as 
defined in Section 4.5.1.1 for viral load values that are below lower limit of detection (<LLOD), 
below lower limit of quantification (<LLOQ) or above upper limit of quantification (>ULOQ) of 
the assay.   
The variable will be analyzed using the Analysis of Covariance (ANCOVA) model with treatment 
group and the type of background standard-of-care as fixed effects, and baseline viral load and 
treatment by baseline interaction as covariates.  
The least squares means estimates for time-weighted average daily change from baseline in viral 
load for each treatment group, as well as the difference between the REGN10933+REGN10987 
2.4g and 8.0g combined doses and placebo as well as between each individual dose treatment 
group and placebo, will be provided along with the corresponding two-sided p-value, standard 
error, and associated 95% confidence interval.   
5.6.1.2. 
Analysis of Primary Clinical Efficacy Endpoints 
The primary efficacy analysis will be the comparison between the the REGN10933+REGN10987 
2.4g and 8.0g combined dose group and placebo in the pooled phase 3 cohort 1 and phase 2 cohort 
1A patients.  The primary clinical endpoint defined in Section 4.5.1.2 will be analyzed using the 
landmark analysis approach for day 6 through day 29, as well as analyzed for day 1 through day 
29 in the order specified in Section 5.6.3.  
The proportion of patients who died or went on mechanical ventilation will be analyzed using 
either the exact method for binomial distribution or asymptotic normal approximation method.  If 
the number of events is small (e.g., np ≤ 5 or n(1-p) ≤ 5 in any treatment group, where n is the 
number of patients in the treatment group and p is the proportion of events), then the Fisher’s exact 
test will be applied. Otherwise, stratified Cochran-Mantel Haenszel (CMH) test, stratified by the 
type of background standard-of-care (antiviral therapies and non-antiviral therapies), will be 
applied.  Relative risk and relative risk reduction and corresponding 95% confidence intervals 
compared to placebo group will be estimated by Farrington-Manning method.  Missing data will 
be considered as non-events. 
The analysis will be performed for the High Viral Load mFAS, the Seronegative mFAS, and the 
overall mFAS.  
5.6.2. 
Descriptive Analysis of Secondary Efficacy Endpoints 
All analyses for the secondary efficacy endpoints are descriptive and all p-values are nominal. 
5.6.2.1. 
Descriptive Analysis of Secondary Virologic Efficacy Endpoints 
The time-weighted average daily change from baseline in viral load (log10 copies/mL) from day 1 
to all post-baseline visit timepoints will be descriptively analyzed similar to primary virologic 
analysis for patients by serostatus in mFAS, by baseline viral load (≤105 vs >105 copies/mL and  
≤106 vs >106 copies/mL) (with serostatus added to the ANCOVA model as a factor) in the mFAS,  
and overall mFAS (with serostatus added to the ANCOVA model as a factor). 
To assess the time course of treatment effect in viral load, the change from baseline in viral load 
(log10 copies/mL) at each visit for seronegative mFAS and overall mFAS will be analyzed using 
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a mixed-effect model for repeated measures (MMRM) with terms for baseline viral load, type of 
background standard-of-care, treatment, visit, treatment by baseline interaction, baseline by visit 
interaction, and treatment-by-visit interaction. Within-patient errors will be modeled with an 
unstructured covariance matrix. The least squares means estimates for the mean at each visit and 
mean change from baseline to each visit as well as the difference of these estimates between each 
anti-S mAb treatment arm and placebo will be provided along with the corresponding standard 
error, p-value, and associated 95% confidence interval. The percentage change from baseline in 
viral load in raw scale at each visit will be back-transformed from the log10-transformed viral 
load and presented along with the change from baseline in viral load (log10 copies/mL).  The 
analysis will be performed for patients by serostatus in the mFAS, by baseline viral load (≤105 vs 
>105 copies/mL and  ≤106 vs >106 copies/mL) (with serostatus added to the MMRM model as a 
factor) in the mFAS, and in overall mFAS (with serostatus added to the MMRM model as a 
factor). 
5.6.2.2. 
Descriptive Analysis of Secondary Clinical Efficacy Endpoints 
All clinical endpoints based on proportions (defined in Section 4.5.2.3) will be analyzed using 
similar methods as for the primary clinical efficacy endpoint described in Section 5.6.1.2. The 
analysis will be performed for patients by baseline viral load (≤106 vs >106 copies/mL) in the 
mFAS, by serostatus in the mFAS, and in overall mFAS.  
All clinical endpoints based on time-to-event (defined in Section 4.5.2.4) will be estimated using 
the Kaplan-Meier method and comparisons between treatment groups will be made using the 
stratified log-rank test with the type of background standard-of-care as stratification factor.  P-
values will be compared with 0.05 (two-sided). 
The log-rank “observed minus expected” statistic (and its variance) will be used to calculate the 
one-step estimate of the event rate ratio and confidence interval for each pairwise comparison 
versus placebo group (Peto 1977) [2].  
As sensitivity analysis, the hazard ratio and its 95% CI will be estimated by the Cox proportional-
hazards regression model with terms for treatment group,  and type of background standard-of-
care. P values from the stratified log-rank test will be reported. Hazard ratio (HR) < 1 will imply 
reduction of hazard of REGN10933+REGN10987 versus placebo. Estimates of median times 
along with 25th and 75th percentiles (if median and quartiles are reached) and associated two-sided 
95% CI will be reported using the Kaplan-Meier method.  
Landmark analysis starting from day 6 will be performed using similar Cox proportional-hazard 
model on the cumulative incidence of death or mechanical ventilation and cumulative incidence 
of death. The patients with corresponding events occurring before day 6 and patients who drop out 
early from study before day 6 will be excluded from the analysis (Dafni, U.  2011) [3].The analysis 
will be performed for patients by baseline viral load (≤106 vs >106 copies/mL) in mFAS (with 
baseline serostatus added to the stratified log-rank test and the Cox model as a factor), by serostatus 
in mFAS, and overall mFAS (with baseline serostatus added to the stratified log-rank test and the 
Cox model as a factor). 
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5.6.3. 
Adjustment for Multiple Comparisons 
Multiplicity Considerations 
The following multiplicity adjustment approach, a hierarchical procedure, will be used to control 
the overall Type-1 error rate at 0.05 for the primary virologic and clinical outcome endpoints in 
comparison between the combined doses of REGN10933+REGN10987 treatment group and 
placebo group in the pooled phase 3 cohort 1 and phase 2 cohort 1A patients. Each hypothesis will 
be formally tested only if the preceding one is significant at the 2-sided 0.05 significance level. 
The hierarchical testing order is shown in Table 9.  
Table 9: 
Hierarchical testing order 
Type 
Description 
Testing 
Order 
Primary virologic outcome 
Time-weighted average change from baseline viral load 
in NP sample through day 7 in seronegative mFAS  for 
comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
1 
Primary clinical outcome 
Proportion of patients who died or went on machenical 
ventilation from day 6 to day 29 in High Viral Load 
mFAS for comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
2 
Proportion of patients who died or went on machenical 
ventilation from day 6 to day 29 in Seronegative 
mFAS for comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
3 
Proportion of patients who died or went on machenical 
ventilation from day 6 to day 29 in overall mFAS for 
comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
4 
Proportion of patients who died or went on machenical 
ventilation from day 1 to day 29 in High Viral Load 
mFAS for comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
5 
Proportion of patients who died or went on machenical 
ventilation from day 1 to day 29 in Seronegative 
mFAS for comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
6 
Proportion of patients who died or went on machenical 
ventilation from day 1 to day 29 in overall mFAS for 
comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
7 
All other analyses for virologic and clincal endpoints will be reported descriptively for each 
individual cohort and for pairwise comparison of each REGN10933+REGN10987 dose group (2.4 
g IV or 8.0 g IV) versus placebo. 
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5.6.4. 
Analysis of Exploratory Endpoints 
The change and percentage change in NLR, D-dimer, ferritin, CRP, and LDH will be summarized 
at each visit through day 29 using descriptive statistics for mFAS and FAS. 
The proportion of  patients with treatment failure having mutations in the gene encoding the SARS-
CoV-2 S protein through day 29 will be analyzed in separate report. 
5.7. 
Analysis of Safety Data 
The analysis of safety data will be performed for cohort 1 in combined phases 1, 2 and 3, phase 2 
cohorts 1A,  2 and 3, separately in the FAS population. 
In this study, only targeted treatment-emergent adverse events will be recorded: 
• All phases:  Treatment-emergent adverse events of special interest (AESIs) 
− Grade ≥2 hypersensitivity 
− Grade ≥2 infusion-related reactions 
• All phases:  Treatment-emergent serious adverse events (SAEs) 
• All phases:  TEAEs (Grade 3 or Grade 4 only) 
The safety analysis will be based on the reported SAEs and AESIs and other safety information 
(clinical laboratory evaluations and vital signs).  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables and vital 
signs are defined in Section 10.3. 
The summary of safety results will be presented for each treatment group. 
5.7.1. 
Adverse Events 
Summaries that include frequencies and proportions of patients reporting AEs will include the PTs 
and the SOCs.  
An overview of adverse events will be provided by treatment group and for combined dose groups 
of R10933+R10987, including:  
• Total number of TEAEs, SAEs, Total number of AESIs, Serious AESIs, Grade 3 or 4 
TEAEs, as well as  
• The number and percentage of patients with  
− any TEAE, any SAE, any AESI, any serious AESI, any grade 3 or grade 4 TEAE, 
any fatal TEAEs, any TEAEs leading to withdrawal from the study, any TEAEs 
leading to study infusion discontinuation, and any TEAEs leading to study 
infusion interruption. 
Summaries of SAEs and AESIs by treatment group and for combined R10933+R10987 doses 
will include number (n) and percentage (%) of patients with at least : 
• Treatment-emergent AE by SOC and PT 
• Treatment-emergent AE by SOC and PT and CTCAE grade 
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• Treatment-emergent AE related to study treatment  by SOC and PT 
• Treatment-emergent SAE by SOC and PT 
• Treatment-emergent AESIs presented by SOC and PT 
• Treatment-emergent grade 3 or 4 AEs presented by SOC and PT 
Counts will be provided according to treatment group for each PT within each SOC. Percentages 
will be calculated using the number of patients from the FAS in each treatment group. 
Primary SOCs will be sorted according to decreasing order of frequency in combined treatment 
group. Within each primary SOC, PTs will be sorted by decreasing frequency in combined 
treatment group. 
5.7.2. 
Clinical Laboratory Measurements  
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
A treatment-emergent Potential Clinically Significant abnormal value (PCSV) is a laboratory value 
that was normal at Screening and Baseline but abnormal after treatment with study drug.  See 
Appendix 10.3 for the criteria of PCSV values.   
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test for all patients 
and separately for patients in whom the PCSV criterion was normal or missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
5.7.3. 
Analysis of Vital Signs 
Vital signs (temperature, pulse, blood pressure, SpO2, FiO2, and respiration rate) will be 
summarized using descriptive statistics. Number and percentage of patients with a potentially 
clinically significant value (PCSV) at any post-randomization time point will be summarized.  
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5.8. 
Analysis of Pharmacokinetics, Pharmacodynamics and Biomarker 
Data  
5.8.1. 
Analysis of Drug Concentration Data 
Concentrations of  REGN10933 and REGN10987 over time will be summarized by descriptive 
statistics for each treatment group. No formal statistical hypothesis testing will be performed. 
Phase 1 (Dense Sampling) 
The PK parameters to be determined after the first dose for REGN10933 and REGN10987 may 
include, but are not limited to: 
• Cmax 
• Cmax/Dose 
• tmax 
• AUClast 
• AUCinf 
• AUCinf/Dose 
• t1/2 
• CL  
• VSS  
• MRT 
Selected PK parameters will be summarized by descriptive statistics by treatment group. All 
parameters will be summarized (mean, SD, %CV, range, median, and number of samples). 
5.8.2. 
Analysis of  Pharmacokinetics and Pharmacokinetics/Pharmacodynamics  
At a minimum the viral-exposure response analysis will be performed.  
5.9. 
Analysis of Immunogenicity Data 
5.9.1. 
 Analysis of ADA Data 
Immunogenicity variables will be summarized using descriptive statistics. 
Immunogenicity will be characterized by the ADA responses and titers observed in subjects in the 
ADA analysis set. ADA response categories and titer categories are defined as follows: 
ADA response categories: 
• ADA Negative, defined as ADA negative response in the ADA assay at all time points, 
regardless of any missing samples. 
• Pre-existing immunoreactivity, defined as either an ADA positive response in the ADA 
assay at baseline with all post first dose ADA results negative, OR a positive response 
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at baseline with all post first dose ADA responses less than 9-fold over baseline titer 
levels. 
• Treatment-emergent response, defined as an ADA positive response in the ADA assay 
post first dose when baseline results are negative or missing. The treatment-emergent 
responses will be further characterized as Persistent, Indeterminate or Transient.   
− Persistent Response (only applicable to phase 1)  – Treatment-emergent ADA 
positive response with two or more consecutive ADA positive sampling time 
points, separated by at least 16-week period (based on nominal sampling time), with 
no ADA negative samples in between, regardless of any missing samples. 
− Indeterminate Response –Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay, regardless of any missing 
samples. 
− Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
• Treatment-boosted response, defined as a positive response in the ADA assay post first 
dose that is greater than or equal to 9-fold over baseline titer levels, when baseline 
results are positive. 
Titer categories (Maximum titer values) 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
The following analysis will be provided: 
• Number (n) and percent (%) of ADA-negative subjects (pre-existing immunoreactivity 
or negative in the ADA assays at all time points) by treatment arms  
• Number (n) and percent (%) of treatment-emergent ADA positive subjects by treatment 
arms and ADA titer categories 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
subjects 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
subjects 
− Number (n) and percent (%) of transient treatment-emergent ADA positive subjects 
Number (n) and percent (%) of treatment-boosted ADA positive subjects by treatment groups 
and ADA titer categories  
• Number (n) and percent (%) of treatment-boosted ADA positive subjects by treatment 
arms and ADA titer categories  
Listing of all ADA titer levels will be provided for subjects with pre-existing, treatment-emergent 
and treatment-boosted ADA response.  
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5.9.2. 
Analysis of NAb Data 
The absolute occurrence (n) and percent of subjects (%) with NAb status in the NAb analysis set 
will be provided by treatment groups. 
5.10. 
Association of Immunogenicity with Exposure, Safety, and Efficacy 
5.10.1. 
Immunogenicity and Exposure 
Potential association between immunogenicity variables and systemic exposure to REGN10933  
and REGN10987 will be explored by treatment groups. Plots of drug concentration time profiles 
may be provided to examine the potential impact of ADA response status, and titer on these 
profiles.  
5.10.2. 
Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• Infusion reactions  
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Potential association between immunogenicity variables and efficacy endpoints may be explored 
(e.g. scatter plot or spaghetti plot).  
The safety and efficacy analyses mentioned above will be conducted using the following 
categories: 
• ADA positive subjects: Subjects with treatment-emergent or treatment-boosted 
response.  
• Maximum post-baseline titer. 
• NAb positive 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Definitions of baseline for efficacy variables are defined in Section 4.5.1.1. Baseline viral load 
value will be the latest available valid measurement before the administration of study drug or the 
measurement taken within 2 hours after the administration of study drug if the pre-treatment 
measurement is missing. 
For safety variables, baseline will be the latest available valid measurement taken prior to the 
administration of study drug.  
6.2. 
Data Handling Convention for Efficacy Variables  
The virologic endpoint analysis will be based on the observed data with no imputation for missing 
data except as defined in Section 4.5.1.1 for viral load values that are below lower limit of detection 
(<LLOD), below lower limit of quantification (<LLOQ) or above upper limit of quantification 
(>ULOQ) of the assay. 
In the analysis for the clinical endpoints based on proportions of patients with the event, the 
missing data will be considered as non-events. 
6.3. 
Data Handling Convention for Missing Data 
For categorical variables, patients with missing data will be included in calculation of percentages.  
Number of patients with missing data will be presented 
Handling of Medications with Missing/Partial Dates 
To determine whether a medication is prior or concomitant medication, the missing medication 
start date is estimated as early as possible up to first dose date, and the missing medication end 
date is estimated as late as possible up to day 29. If the medication start date is missing, the onset 
day will not be imputed in medication listings. 
Handling of AE Missing and Partial Start Dates 
Every effort will be made to collect the start dates of all AEs. However, in the case the start date 
of an AE is incomplete or missing, it will be assumed to have occurred on or after the first dose 
of study medication, except if an incomplete date (e.g., month and year) clearly indicates that the 
event started prior to treatment. If the partial date indicates the same month or year of the first 
dose of study medication date, then the start date of the first dose will be imputed, otherwise, the 
missing day or month by the first day or the first month will be imputed. 
Handling of Adverse events Severity and Relatedness 
If the intensity of an SAE or AESI is missing, it will be classified as “Grade 3” in the frequency 
tables by CTC grade of SAE or AESIs. If the assessment of relationship of the investigational 
product is missing, it will be classified as related to the investigational product. 
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Date of infusion 
Date of infusion is the non-missing administration date filled in the Drug Administration–Infusion 
CRF. If the first dose of study drug administration date is missing (even after site is queried), then 
the dosing date is will be imputed with the randomization date.  If any subsequent study drug 
administration date is missing, the date of dispensation of study drug from IRT will be used. 
6.4. 
Visit Windows 
Data analyzed by-visit-analysis will be summarized by the study scheduled visits described in the 
“Schedule of Events” Appendices 10.1 and 10.2. The analysis visit windows will be exhaustive so 
that all available values obtained from unscheduled visits, early termination visit (ETV) and end 
of treatment (EOT)/end of study (EOS) have the potential to be summarized. No analysis visit 
windows will be applied for the study scheduled visits and discharge visit.  
The following analysis visit windows will be used to map the unscheduled visits, ETV and EOT 
visits for Nasopharyngeal swab, saliva and nasal samples for SARS-CoV-2 RT-qPCR, based on 
the study day during the study: 
Table 10: 
Time Window for Summary of Swab Samples for SARS-CoV-RT-qPCR 
Visit Label 
Targeted Study Day 
Analysis Window in Study Day 
Baseline 
1 
≤ 1 
Day 3 
3 
[2, 3] 
Day 5 
5 
[4, 5] 
Day 7 
7 
[6, 7] 
Day 9 
9 
[8, 9] 
Day 11 
11 
[10, 11] 
Day 13 
13 
[12, 13] 
Day 15 
15 
[14, 18] 
Day 22 
22 
[19, 25] 
Day 29 
29 
[26, 32] 
The following analysis visit windows will be used to map the unscheduled visits for laboratory 
variables, based on the study day during the double blind period: 
Table 11: 
Time Window for Summary of Laboratory Variables and Biomarkers 
Visit Label 
Targeted Study Day 
Analysis Window in Study Day 
Baseline 
1 
≤ 1 
Day 7 
7 
For phase 1 [2, 18] 
For phase 2/3 [2, 11] 
Day 15  
15 
For phase 2/3 only [12, 22] 
Day 29 
29 
For phase 1 [19, 32] 
For phase 2/3 [23, 32] 
Day 57  
57 
For phase 1 only [33,71] 
6.5. 
Pooling of Centers for Statistical Analyses 
Data from countries (US and non-US) will be pooled in the phase 1/2/3 analysis. 
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7. 
INTERIM ANALYSIS 
This SAP is for the final analysis of the study. No interim analyses were planned or conducted for 
Phase 3 portion of the study. 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above. 
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9. 
REFERENCES 
1. Peterson RL, Vock DM, Powers JH, Emery S, Cruz EF, Hunsberger S, et al. Analysis of 
an ordinal endpoint for use in evaluating treatments for severe influenza requiring 
hospitalization. Clin Trials 2017; 14(3):264-76  
2. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson 
K, Peto J and Smith PG.  Design and analysis of randomized clinical trials requiring 
prolonged observation of each patient - II Analysis and Examples.  British Journal of 
Cancer 1977; 35, 1. 
3. Dafni, U. (2011). Landmark analysis at the 25-year landmark point. Circulation: 
Cardiovascular Quality and Outcomes, 4(3), 363-371.
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10. 
APPENDIX 
10.1. 
Schedule of Events for Phase 1 (Cohort 1)   
Day 
Screening/Baseline1 
Hospitalization/Post-Discharge Period2  
EOS 
-1 to 1 
Discharge 
Before 
Day 29 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 
16, 17, 
18, 19, 
20, 21 
22 
23, 24, 
25, 26, 
27, 28 
29 57 85 113 141 169 
Screen 
Pre- 
Dose Dose Post-
Dose 
Week Number 
1 
 
1 1 1 1 1 1 2 2 2 2 2 2 2 3 
3 
4 
4 
5 
9 13 17 21 25 
Visit Number 
1 
 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16-21 22 23-28 29 30 31 32 33 34 
Window (Days) 
 
 
 
 
±1 
 
 
 
 
 
 
 ±1  ±1  ±1  ±1 
 
±3 
 
±3 ±7 ±7 ±7 ±7 ±7 
 
Screening/Baseline Only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic 
test for SARS-CoV-2 (local)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Vital signs6 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 
infusion-related reactions7,8 
 
 
← Continuous monitoring → 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 
hypersensitivity reactions7,8 
 
 
← Continuous monitoring → 
 
 
 
 
 
Treatment-emergent SAEs7,8 
 
 
← Continuous monitoring → 
Grade 3 or 4 TEAEs7,8 
 
 
← Continuous monitoring → 
Targeted concomitant 
medications8,9 
X 
X 
← Continuous monitoring → 
Post-discharge phone follow-up8 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
X 
 
X 
 
X 
X X X X 
X 
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Day 
Screening/Baseline1 
Hospitalization/Post-Discharge Period2  
EOS 
-1 to 1 
Discharge 
Before 
Day 29 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 
16, 17, 
18, 19, 
20, 21 
22 
23, 24, 
25, 26, 
27, 28 
29 57 85 113 141 169 
Screen 
Pre- 
Dose Dose Post-
Dose 
Week Number 
1 
 
1 1 1 1 1 1 2 2 2 2 2 2 2 3 
3 
4 
4 
5 
9 13 17 21 25 
Visit Number 
1 
 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16-21 22 23-28 29 30 31 32 33 34 
Window (Days) 
 
 
 
 
±1 
 
 
 
 
 
 
 ±1  ±1  ±1  ±1 
 
±3 
 
±3 ±7 ±7 ±7 ±7 ±7 
 
Pregnancy test (WOCBP)10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Laboratory Testing 
Hematology  
(including differential)11 
X 
 
 
X 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Blood chemistry (including AST, 
ALT, CRP, ferritin, LDH)11 
X 
 
 
X 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Coagulation tests  
(D-dimer, PT/INR, aPTT)11 
X 
 
 
X 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Efficacy Assessments (Virologic)  
Saliva for SARS-CoV-2 RT-qPCR 
 
X 
 
 
X 
 X  X  X  X  X  X  
X 
 
X 
 
X 
 
 
 
 
 
Nasal swab for SARS-CoV-2 RT-
qPCR 
 
X 
 
 
X 
 X  X  X  X  X  X  
X 
 
X 
 
X 
 
 
 
 
 
NP swab for SARS-CoV-2 RT-
qPCR 
 
X 
 
 
X 
 X  X  X  X  X  X  
X 
 
X 
 
X 
 
 
 
 
 
Efficacy Assessments (Clinical/Oxygen Status) 
Oxygen delivery device status12 
 
X12 X12 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
 
Vital status12 
 
X12 X12 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
 
Hospitalization status12 
 
X12 X12 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
 
Pharmacokinetics/Immunogenicity 
Serum for PK13 
 
X14 
 
X14 
X 
 X  X  X  
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Serum for ADA15 
 
X15 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
X 
Pharmacodynamic/Biomarkers 
Serum for serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Pharmacogenomics Sub-Study (Optional) 
Blood for RNA3 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for DNA3 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.1.1. 
Footnotes for Schedule of Events (Phase 1) 
1. Every effort should be made to perform all screening and baseline activities on the same day. Randomization within the 
Interactive Response Technology (IRT) system and administration of study drug should occur on the same day (day 1). All 
samples will be collected before study drug administration at the baseline visit except post-infusion PK samples. 
2. For a given day, the visit may occur in clinic, as a home-based visit (defined as visits by home health care staff, at mobile units, 
and/or testing centers), or by phone. All samples will be collected as indicated whether the patient is hospitalized or has been 
discharged. 
3. Patients must provide separate consent to collect blood samples as part of the optional pharmacogenomics (PGx) sub-study. 
Blood sample for RNA must be collected pre-dose on day 1. Blood sample for DNA should be collected at the screening/baseline 
visit but may be collected at any visit.  
4. Refer to protocol Section 9.2.1.2 for diagnostic test requirements during screening. 
5. Medical history should include collecting onset of pneumonia symptoms.  
6. Vital signs (including respiratory rate, temperature, blood pressure, heart rate, and SpO2) will be taken as described in protocol 
Section 9.2.3.1.  
For patients in the phase 1 sentinel safety group only (protocol Section 3.1.1.1), vital signs will be taken once before the 
infusion, every 15 minutes during the infusion, every 30 minutes for the first 2 hours after the infusion is completed, and then 
once per hour for the following 4 hours. For all other patients, vital signs will be taken once before the infusion and once after 
the infusion is completed. 
7. Only TEAEs (grade 3 or 4), treatment-emergent SAEs, and treatment-emergent AESIs will be recorded in the eCRF.  
8. Patients discharged from the hospital may receive phone follow-up for TEAEs (grade 3 or 4), treatment-emergent SAEs, 
treatment-emergent AESIs, and/or targeted concomitant medications as indicated in the protocol table 1 (post-discharge phone 
follow-up). These visits may occur in addition to any in-person visit listed for the given day. Phone visits will have a window of 
±1 day.  
9. Medications will be reviewed and recorded. Only the targeted medications listed in protocol Section 9.2.3.3 will be recorded in 
the eCRF. 
10. Pregnancy testing will be performed locally in women of childbearing potential (WOCBP) only. Negative pregnancy test must 
be confirmed prior to study drug administration. Serum or urine pregnancy test are both acceptable. Refer to protocol Section 
9.2.3.4 for more information on pregnancy testing and contraceptive measures. 
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11. Hematology, blood chemistry, and coagulation tests will be collected at the visits indicated and results will be entered in the 
eCRF. Hematology, blood chemistry, and coagulation tests must be collected prior to randomization. Testing will be performed 
locally, and standard-of-care labs are acceptable. 
12. Clinical and oxygen status will be collected 3 times during the screening/baseline visit period: prior to randomization, just prior 
to dosing, and post-dose. Clinical and oxygen status will be collected and recorded in the eCRF as described in protocol Section 
9.2.5.2. 
13. Actual dosing time and PK sample collection times will be recorded. 
14. At the baseline visit, blood samples for PK assessment will be taken predose and within 60 minutes after the end of infusion 
(EOI). The EOI sample should be collected from the arm contralateral to that used for IV infusion. If not medically feasible, the 
EOI sample can be drawn from the same arm, but not from the infusion catheter.  
15. The window for predose ADA sample collection is as close to administration of study drug as is reasonable. Actual dosing times 
and ADA sample collection times will be recorded. 
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10.2. 
Schedule of Events for Phase 2/3 (Cohort 1A, Cohort 1, Cohort 2, Cohort 3)   
Day 
Screening/Baseline1 
Hospitalization/Post-Discharge Period2 
Follow-up 
Period 
EOS 
-1 to 1 
Discharge 
Before 
Day 29 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 
16, 17, 
18, 19, 
20, 21 
22 
23, 24, 
25, 26, 
27, 28 
29 36 43 50 57 
Screen Pre- 
Dose Dose Post-
Dose 
Week Number 
1 
 
1 1 1 1 1 1 2 2 2 2 2 2 2 3 
3 
4 
4 
5 
6 
7 
8 
9 
Visit Number 
1 
 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16-21 22 23-28 29 30 31 32 33 
Window (Days) 
 
 
 
 
±1 
 
 
 
 
 
 
 ±1  ±1  ±1  ±1 
 
±3 
 
±3 ±3 ±3 ±3 ±3 
 
Screening/Baseline Only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test 
for SARS-CoV-2 (local)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP)5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments (Virologic)  
NP swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
X 
 X  X  
X 
 X  X  X  X 
 
X 
 
X 
 
 
 
 
Efficacy Assessments (Clinical/Oxygen Status) 
Oxygen delivery device status7 
 
X7 X7 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
Vital status7 
 
X7 X7 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
Hospitalization status7 
 
X7 X7 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
Safety Assessments 
Vital signs8 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 
infusion-related reactions9,10 
 
 
← Continuous monitoring → 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 
hypersensitivity reactions9,10 
 
 
← Continuous monitoring → 
 
 
 
 
Treatment-emergent SAEs9,10 
 
 
← Continuous monitoring → 
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 56 of 66 
Day 
Screening/Baseline1 
Hospitalization/Post-Discharge Period2 
Follow-up 
Period 
EOS 
-1 to 1 
Discharge 
Before 
Day 29 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 
16, 17, 
18, 19, 
20, 21 
22 
23, 24, 
25, 26, 
27, 28 
29 36 43 50 57 
Screen Pre- 
Dose Dose Post-
Dose 
Week Number 
1 
 
1 1 1 1 1 1 2 2 2 2 2 2 2 3 
3 
4 
4 
5 
6 
7 
8 
9 
Visit Number 
1 
 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16-21 22 23-28 29 30 31 32 33 
Window (Days) 
 
 
 
 
±1 
 
 
 
 
 
 
 ±1  ±1  ±1  ±1 
 
±3 
 
±3 ±3 ±3 ±3 ±3 
 
Targeted concomitant medications10,11 
X 
X 
← Continuous monitoring → 
Post-discharge phone follow-up10 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 X 
 
X 
 
X X X X 
X 
Pregnancy follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Laboratory Testing 
Hematology (including differential)12 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Blood chemistry (including AST, 
ALT, CRP, ferritin, LDH)12 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Coagulation tests  
(D-dimer, PT/INR, aPTT)12 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Pharmacokinetics/Immunogenicity  
Serum for PK13 
 
X14 
 
X14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Serum for ADA15 
 
X15 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pharmacodynamic/Biomarkers 
Serum for serology 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum for cytokines and CK-MB 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Serum for research and cardiac 
biomarkers 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Plasma for research and cardiac 
biomarkers 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Plasma for hsTroponin-T 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Pharmacogenomics Sub-Study (Optional) 
Blood for RNA3 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for DNA3 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 57 of 66 
10.2.1. 
Footnotes for Schedule of Events (Phase 2) 
1. Every effort should be made to perform all screening and baseline activities on the same 
day. Randomization within the IRT system and administration of study drug should occur 
on the same day (day 1). All samples will be collected before study drug administration at 
baseline visit except post-infusion PK samples. 
2. For a given day, the visit may occur in clinic, as a home-based visit (defined as visits by 
home health care staff, at mobile units, and/or testing centers), or by phone. All samples 
will be collected as indicated whether the patient is hospitalized or has been discharged. 
3. Patients must provide separate consent to collect blood samples as part of the optional PGx 
sub-study. Blood sample for RNA must be collected pre-dose on day 1. Blood sample for 
DNA should be collected at the screening/baseline visit but may be collected at any visit.  
4. Refer to protocol Section 9.2.1.2 for diagnostic test requirements during screening. 
5. Pregnancy testing will be performed locally in women of childbearing potential (WOCBP) 
only. Negative pregnancy test must be confirmed prior to study drug administration. Serum 
or urine pregnancy test are both acceptable. Refer to protocol Section 9.2.3.4 for more 
information on pregnancy testing and contraceptive measures. 
6. Medical history should include collecting onset of pneumonia symptoms.  
7. Clinical and oxygen status will be collected 3 times during the screening/baseline visit 
period: prior to randomization, just prior to dosing, and post-dose. Clinical and oxygen 
status will be collected and recorded in the eCRF as described in protocol Section 9.2.5.2. 
8. Vital signs (including temperature, blood pressure, heart rate, and SpO2) will be collected 
pre-dose and post-dose, as described in protocol Section 9.2.3.1. 
9. Only treatment-emergent SAEs and AESIs will be recorded in the eCRF.  
10. Patients discharged from the hospital may receive phone follow-up for treatment-emergent 
SAEs, treatment-emergent AESIs, and/or targeted concomitant medications as indicated in 
protocol Table 2 (post-discharge phone follow-up). These visits may occur in addition to 
any in-person visit listed for the given day. Phone visits will have a window of ±1 day. 
11. Medications will be reviewed and recorded. Only the targeted medications listed in 
protocol Section 9.2.3.3 will be recorded in the eCRF. 
12. Hematology, blood chemistry, and coagulation tests will be collected at the visits indicated 
and results will be entered in the eCRF. Hematology, blood chemistry, and coagulation 
tests must be collected prior to dosing. Testing will be performed locally, and standard-of-
care labs are acceptable. 
13. Actual dosing time and PK sample collection times will be recorded.  
14. At the baseline visit, blood samples for PK assessment will be taken predose and within 60 
minutes after the end of infusion (EOI). The EOI sample should be collected from the arm 
contralateral to that used for IV infusion. If not medically feasible, the EOI sample can be 
drawn from the same arm, but not from the infusion catheter.  
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan  
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 58 of 66 
15. The window for predose ADA sample collection is as close to administration of study drug 
as is reasonable. Actual dosing times and ADA sample collection times will be recorded. 
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan 
 
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 59 of 66 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV 
Comments 
Clinical Chemistry 
ALT* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required; multiple levels are 
optional for phase 2/3 studies. If it is desirable to get the 
distribution across the different  PCSV levels, additional 
shift table on ≤3, >3 to ≤5,  > 5 to  ≤10, >10 to ≤20, and 
> 20 category for baseline vs. post baseline may be 
provided  
AST* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required, multiple levels are 
optional for phase 2/3 studies. If it is desirable to get the 
distribution across the different  PCSV levels, additional 
shift table on ≤3, >3 to ≤5,  > 5 to ≤10, >10 to ≤20, and > 
20 category for baseline vs. post baseline may be 
provided 
Alkaline Phosphatase >1.5 ULN and baseline ≤ 1.5 ULN 
Enzyme activity must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan 
 
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 60 of 66 
Parameter 
PCSV 
Comments 
Total Bilirubin* 
>1.5 and ≤ 2 ULN and baseline ≤ 1.5 ULN* 
>2 ULN and baseline ≤ 2.0 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
* At least one level is required, multiple levels are 
optional for phase 2/3 studies. If it is desirable to get the 
distribution of  significant level, additional shift table on  
≤1.5, >1.5 to ≤2.0 and > 2.0 category for baseline vs. 
post baseline may be provided 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN, and baseline Total 
Bilirubin ≤ 35% or TBILI ≤1.5 ULN 
Conjugated bilirubin determined on a case-by-case basis. 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN, and baseline ALT ≤ 3 ULN 
or TBILI ≤ 2ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required, multiple levels are 
optional for phase 2/3 studies. If it is desirable to get the 
distribution of  significant level, additional shift table on 
≤3, >3 to ≤10, and > 10 category for baseline vs. post 
baseline may be provided 
Creatinine 
≥150 μmol/L (Adults) or ≥ULN (if ULN≥150 μmol/L)  and 
baseline < 150 μmol/L or <ULN (if ULN≥150 μmol/L)   
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
3 independent criteria  
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan 
 
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 61 of 66 
Parameter 
PCSV 
Comments 
Creatinine Clearance 
(Cockcroft's formula) 
<15 ml/min and baseline ≥15 ml/min (end stage renal 
impairment) 
≥15 -<30 ml/min and baseline ≥30 ml/min  (severe renal 
impairment) 
≥30 - < 60 ml/min and baseline  ≥60 ml/min  (moderate renal 
impairment) 
≥60 - < 90 ml/min and baseline  ≥90 ml/min  (mild renal 
impairment) 
Use is optional. 
FDA draft guidance 2010 
Four independent criteria, will provide additional shift 
table if needed 
 
Uric Acid 
Hyperuricemia: 
 
Hypouricemia: 
 
>408 μmol/L or >ULN (if ULN≥408 μmol/L)  and baseline 
≤408 μmol/L or ≤ULN (if ULN≥408 μmol/L)   
<120 μmol/L or <LLN (if LLN≤120 μmol/L)  and baseline ≥ 
120 μmol/L or ≥LLN (if LLN≤120 μmol/L)   
Harrison- Principles of Internal Medicine 17th Ed., 2008. 
Two independent criteria 
Blood Urea Nitrogen 
≥17 mmol/L or ≥ULN (if ULN≥17 mmol/L)  and baseline <17 
mmol/L  or <ULN (if ULN≥17 mmol/L)   
Two independent criteria 
Chloride 
                
Hypochloremia: 
 
               
Hyperchloremia: 
 
<80 mmol/L or <LLN (if LLN≤80 mmol/L) and baseline 
≥ 80 mmol/L or ≥LLN (if LLN≤80 mmol/L) 
>115 mmol/L or >ULN (if ULN≥115 mmol/L) and baseline 
≤ 115 mmol/L  or ≤ULN (if ULN≥115 mmol/L) 
Two independent criteria  
Sodium 
                  
Hyponatremia: 
 
                 
Hypernatremia: 
 
≤129 mmol/L  or ≤LLN (if LLN≤129 mmol/L) and baseline 
> 129 mmol/L  or >LLN (if LLN≤129 mmol/L) 
≥160 mmol/L  or ≥ULN (if ULN≥160 mmol/L) and baseline 
<160 mmol/L  or <ULN (if ULN≥160 mmol/L) 
Two independent criteria 
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan 
 
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 62 of 66 
Parameter 
PCSV 
Comments 
Potassium 
                  
Hypokalemia 
 
                  
Hyperkalemia 
 
<3 mmol/L or  <LLN (if LLN≤3 mmol/L)  and baseline ≥ 3 
mmol/L or  ≥LLN (if LLN≤3 mmol/L)   
≥5.5 mmol/L or ≥ULN (if ULN≥5.5 mmol/L)  and baseline 
<5.5 mmol/L or <ULN (if ULN≥5.5 mmol/L) 
FDA Feb 2005. 
Two independent criteria 
Total Cholesterol 
≥7.74 mmol/L or ≥ULN (if ULN≥7.74 mmol/L)  and baseline  
< 7.74 mmol/L or <ULN (if ULN≥7.74 mmol/L) 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L or ≥ULN (if ULN≥4.6 mmol/L)  and baseline < 
4.6 mmol/L or <ULN (if ULN≥4.6 mmol/L) 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN  and baseline < 3 ULN  
 
Amylasemia 
≥3 ULN and baseline < 3 ULN  
 
Glucose 
                
Hypoglycaemia 
 
               
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN and baseline >3.9 mmol/L or ≥ LLN  
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) and baseline < 
11.1 mmol/L (unfasted); <7 mmol/L (fasted)  
 
ADA Jan 2008. 
HbA1c 
>8%  and baseline  ≤ 8%  
 
Albumin 
≤25 g/L or ≤LLN (if LLN≤25 g/L) and baseline >25 g/L or 
>LLN (if LLN≤25 g/L)   
 
CRP  
>2 ULN or >10 mg/L (if ULN not provided) and 
baseline  ≤2 ULN or ≤10 mg/L (if ULN not provided)  
 FDA Sept 2005. 
Hematology 
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan 
 
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 63 of 66 
Parameter 
PCSV 
Comments 
WBC 
<3.0 Giga/L or <LLN (if LLN≤3.0 Giga/L)  and baseline  ≥3.0 
Giga/L or ≥LLN (if LLN≤3.0 Giga/L) (Non-Black);  
<2.0 Giga/L or <LLN (if LLN≤2.0 Giga/L)  and baseline ≥2.0 
Giga/L or ≥LLN (if LLN≤2.0 Giga/L) (Black)* 
 
≥16.0 Giga/L or ≥ULN (if ULN≥16.0 Giga/L)  and baseline  < 
16 Giga/L or <ULN (if ULN≥16.0 Giga/L) 
Increase in WBC: not relevant. 
*The default criteria. Summary by race (black and Non-
black) are optional. 
 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L or >ULN (if ULN≥4.0 Giga/L)  and baseline ≤ 4.0 
Giga/L or ≤ULN (if ULN≥4.0 Giga/L) 
 
Neutrophils 
<1.5 Giga/L or <LLN (if LLN≤1.5 Giga/L)  for Non-Black or 
<1.0 Giga/L  or <LLN (if LLN≤1.0 Giga/L)  for Black and 
baseline  ≥1.5 Giga/L  or ≥LLN (if LLN≤1.5 Giga/L) for Non-
Black or ≥1.0 Giga/L or ≥LLN (if LLN≤1.0 Giga/L)  for Black* 
 
<1.5 Giga/L or <LLN (if LLN≤1.5 Giga/L)  and baseline ≥1.5 
Giga/L  or ≥LLN (if LLN≤1.5 Giga/L) (Non-Black);  
<1.0 Giga/L or <LLN (if LLN≤1.0 Giga/L)  and baseline ≥1.0 
Giga/L or ≥LLN (if LLN≤1.0 Giga/L)  (Black) 
 
<0.5 Giga/L regardless of baseline value or racce 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
*The default criteria. By race (black and Non-black) are 
optional. 
Monocytes 
>0.7 Giga/L or >ULN (if ULN≥0.7 Giga/L)  and baseline ≤ 0.7 
Giga/L or ≤ULN (if ULN≥0.7 Giga/L)   
 
Basophils 
>0.1 Giga/L or >ULN (if ULN≥0.1 Giga/L)  and baseline ≤ 0.1 
Giga/L or ≤ULN (if ULN≥0.1 Giga/L)   
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) and  baseline ≤0.5 
Giga/L or ≤ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of Internal Medicine 17th Ed., 2008. 
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan 
 
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 64 of 66 
Parameter 
PCSV 
Comments 
Hemoglobin 
≤115 g/L or ≤LLN (if LLN≤115 g/L) for male or ≤95 g/L or 
≤LLN (if LLN≤95 g/L)  for female and baseline  > 115 g/L  or 
>LLN (if LLN≤115 g/L)  for male or > 95 g/L or >LLN (if 
LLN≤95 g/L)  for Female* 
 
≤115 g/L or ≤LLN (if LLN≤115 g/L) and baseline > 115 g/L or 
>LLN (if LLN≤115 g/L)  for male; 
 ≤95 g/L or ≤LLN (if LLN≤95 g/L) and baseline > 95 g/L or 
>LLN (if LLN≤95 g/L)  for Female. 
 
≥185 g/L or ≥ULN (if ULN≥185 g/L)  for male or ≥165 g/L or 
≥ULN (if ULN≥165 g/L) for female and baseline  <185 g/L  or 
<ULN (if ULN≥185 g/L) for male or  <165 g/L or <ULN (if 
ULN≥165 g/L)  for Female* 
 
≥185 g/L or ≥ULN (if ULN≥185 g/L)  and baseline <185 g/L  
or <ULN (if ULN≥185 g/L)  for Male; 
≥165 g/L or ≥ULN (if ULN≥165 g/L)  and baseline < 165 g/L  
or <ULN (if ULN≥165 g/L) for Female 
 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
*The default criteria. By gender (male and female) are 
optional. 
 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other categories 
for decrease from baseline can be used (≥30 g/L, 
≥40 g/L, ≥50 g/L). 
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan 
 
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 65 of 66 
Parameter 
PCSV 
Comments 
Hematocrit 
≤0.37 v/v or ≤LLN (if LLN≤0.37 v/v)  for Male or ≤0.32 v/v or 
≤LLN (if LLN≤0.32 v/v)  for Female and baseline > 0.37 v/v or 
>LLN (if LLN≤0.37 v/v)  for Male or > 0.32 v/v or >LLN (if 
LLN≤0.32 v/v)  for Female* 
 
≤0.37 v/v or ≤LLN (if LLN≤0.37 v/v)  and baseline > 0.37 v/v 
or >LLN (if LLN≤0.37 v/v)  for Male ; ≤0.32 v/v or ≤LLN (if 
LLN≤0.32 v/v)  and baseline > 0.32 v/v  r >LLN (if 
LLN≤0.32v/v)  for Female 
 
≥0.55 v/v or ≥ULN (if ULN≥0.55 v/v)  for Male or ≥0.5 v/v or 
≥ULN (if ULN≥0.5 v/v)  for Female and baseline < 0.55 v/v or 
<ULN (if ULN≥0.55 v/v)  for Male < 0.5 v/v  or <ULN (if 
ULN≥0.5 v/v)  for Female* 
 
≥0.55 v/v or ≥ULN (if ULN≥0.55 v/v)  and baseline < 0.55 v/v  
or <ULN (if ULN≥0.55 v/v)  for Male ; ≥0.5 v/v or ≥ULN (if 
ULN≥0.5 v/v)  and baseline < 0.5 v/v  or <ULN (if ULN≥0.5 
v/v)  for Female 
Two Criteria are independent 
 
*The default criteria. By gender (male and female) are 
optional. 
RBC 
≥6 Tera/L or ≥ULN (if ULN≥6 Tera/L)  and baseline < 6 
Tera/L or <ULN (if ULN≥6 Tera/L) 
Unless specifically required for particular drug 
development, the analysis is redundant with that of Hb. 
Platelets 
<100 Giga/L or <LLN (if LLN≤100 Giga/L)  and baseline ≥100 
Giga/L or ≥LLN (if LLN≤100 Giga/L) 
≥700 Giga/L or ≥ULN (if ULN≥700 Giga/L)  and baseline < 
700 Giga/L  or <ULN (if ULN≥700 Giga/L)   
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
Two independent criteria 
Coagulation Parameters 
INR 
>2.5 
 
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2066 
Statistical Analysis Plan 
 
Date: 07 JULY 2021 
 
CONFIDENTIAL 
Page 66 of 66 
Parameter 
PCSV 
Comments 
PT 
>2.5 x ULN 
 
aPTT 
>2.5 x ULN 
 
Vital signs 
HR 
<45 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions except STANDING 
 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions except STANDING 
 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions except STANDING 
 
                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00


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                                        VV-RIM-00160102-1.0 Approved - 07 Jul 2021 GMT-5:00

Prot_000.pdf: 
EudraCT: 2020-002537-15 
IND: 148069 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A MASTER PROTOCOL ASSESSING THE SAFETY, TOLERABILITY, 
AND EFFICACY OF ANTI-SPIKE (S) SARS-COV-2 MONOCLONAL 
ANTIBODIES FOR THE TREATMENT OF HOSPITALIZED PATIENTS 
WITH COVID-19 
Compound: 
REGN10933+REGN10987 
Clinical Phase: 
1/2/3 
Protocol Number: 
R10933-10987-COV-2066 
Protocol Version: 
Amendment 9 US  
Amendment 9 US Date of Issue: 
See appended electronic signature page 
Amendment 8 US Date of Issue: 
09 Jul 2021 
Amendment 7 Date of Issue:  
07 Jul 2021 
Amendment 6 Date of Issue:  
21 Dec 2020 
Amendment 5 EU Date of Issue: 
23 Nov 2020 
Amendment 5 Date of Issue:  
07 Aug 2020 
Amendment 4 Date of Issue:  
11 Jul 2020 
Amendment 3 Date of Issue:  
04 Jul 2020  
Amendment 2 Date of Issue: 
19 June 2020 
Amendment 1 Date of Issue: 
03 June 2020 
Original Date of Issue:  
29 May 2020 
Medical/Study Director: 
 
 
 
 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
VV-RIM-00163777-1.0 Approved - 27 Aug 2021 GMT-5:00
NCT04426695


Clinical Study Protocol 
 R10933-10987-COV-2066 Amendment 9 US 
Regeneron Pharmaceuticals, Inc. 
Page 2 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00163777-1.0 Approved - 27 Aug 2021 GMT-5:00


Clinical Study Protocol 
 R10933-10987-COV-2066 Amendment 9 US 
Regeneron Pharmaceuticals, Inc. 
Page 3 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 9 US 
The primary purpose of this US-specific amendment is to amend the long COVID sub-study to 
allow the collection of additional diagnostic information to contextualize any symptoms or 
diagnoses that may confound or be associated with long COVID. 
Description of Change 
 
Brief Rationale   
Section(s) 
For patients in the long COVID sub-study, 
any new medical condition(s) diagnosed after 
randomization will be captured as an adverse 
event of special interest (AESI), but will not 
require expedited reporting to the Sponsor. 
 
Patients who previously consented to the 
long COVID sub-study but have already 
completed their end of study visit may be 
reconsented for retrospective collection of 
this information. 
To contextualize any 
symptoms or diagnoses that 
may confound or be 
associated with long COVID 
Table 3 Schedule of Events for the 
Long COVID Sub-Study at 
Participating Sites  
Section 9.1.2.1 Footnotes for Table 
2 and Table 3 Schedule of Events 
(Phase 2 and Phase 3), #19 [new] 
Section 9.2.9.4 Recording New 
Medical Diagnoses or Conditions 
[new] 
Section 10.1.1 General Guidelines 
Section 10.1.4 Other Adverse Events 
of Special Interest that do not 
Require Expedited Reporting to 
Sponsor [new] 
In the long COVID sub-study, any positive 
SARS-CoV-2 local test results obtained 
outside of the study (starting from the day at 
which they consent to protocol amendment 9 
US) will no longer require expedited 
reporting to the Sponsor. 
To provide operational 
flexibility 
Section 4.3 Exploratory Endpoints 
Section 9.2.9.3 Monitoring for 
SARS-CoV-2 Reinfection 
Section 10.1.3 Events that Require 
Expedited Reporting to Sponsor  
Section 10.1.4 Other Adverse Events 
of Special Interest that do not 
Require Expedited Reporting to 
Sponsor [new] 
Risk-benefit information was updated with 
topline phase 3 data showing clinical benefit 
of REGN10933+REGN10987. 
To provide current study drug 
information 
Section 3.3 Risk-Benefit 
Section 3.3.1 Summary of Efficacy 
and Safety Profile in Clinical Trials 
Section 3.3.2 Summary of Risks 
It was clarified that coagulation tests will not 
be collected as part of the long COVID sub-
study. 
To provide clarity for sample 
collection 
Section 9.1.2.1 Footnotes for Table 
2 and Table 3 Schedule of Events 
(Phase 2 and Phase 3), #12 
Minor updates (typographical, editorial, 
administrative) were made. 
To ensure clarity, accuracy, 
and consistency 
Throughout the document 
 
Amendment 8 US 
The primary purpose of this US-specific amendment is to implement a sub-study to obtain a better 
understanding of long COVID and the potential impact of treatment during acute infection on the 
longer-term phase of COVID-19. 
Description of Change 
 
Brief Rationale   
Section(s) 
Evaluation of Long COVID 
A long COVID sub-study will be conducted 
at select sites through day 180 in phase 2 
(cohort 1A) and phase 3 (cohort 1). The sub-
To better understand the 
patient experience of long 
COVID, and to evaluate 
Clinical Protocol Synopsis: Study 
Design 
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Description of Change 
 
Brief Rationale   
Section(s) 
study will evaluate patient-reported 
symptoms and related outcomes. In addition, 
blood samples will be collected for biomarker 
analysis and immunoprofiling, to gain a 
better understanding of the underlying 
biology of long COVID and the impact of 
prior treatment in the acute stage of disease. 
Nasopharyngeal (NP) swab samples will also 
be collected to assess for the presence of 
SARS-CoV-2 during this later stage of 
analysis. 
whether treatment of initial 
SARS-CoV-2 infection with 
study drug may provide 
subsequent clinical benefit in 
the prevention of long 
COVID 
Section 1.3 Long-Term Outcomes in 
Patients with COVID-19 
Section 2.3 Exploratory Objectives 
Section 3.2.1.7 Long COVID Sub-
Study  
Section 4.3 Exploratory Endpoints 
Section 5.6 Pharmacodynamic and 
Other Biomarker Variables 
Section 6.1.2 Study Duration 
Figure 3 Study Flow Diagram, Phase 
2 and Phase 3 
Section 7.2.1 Inclusion Criteria, #6 
Section 9.1.2 Phase 2 (Cohort 1A, 
Cohort 1, Cohort 2*, and Cohort 3*) 
and Phase 3 (Cohort 1) 
Table 3 Schedule of Events for the 
Long COVID Sub-Study at 
Participating Sites [new] 
Section 9.1.2.1 Footnotes for Table 
2 Schedule of Events (Phase 2 and 
Phase 3), #3; #16, 17 [new] 
Section 9.2.9 Long COVID Sub-
Study (at Participating Sites) 
Table 4 Symptoms Evaluated in the 
Symptom Evolution of Long 
COVID-19 (SE-LC19) Instrument 
Section 11.4.8 Exploratory Analysis 
[new] 
For patients in the long COVID sub-study 
any positive SARS-CoV-2 local test result, 
obtained from the day of consent to the long 
COVID sub-study until day 180, will be 
recorded and reported as an AESI 
To provide additional 
contextual information 
regarding SARS-CoV-2 
infection to inform long 
COVID analyses 
Section 9.1.2.1 Footnotes for Table 
2 Schedule of Events (Phase 2 and 
Phase 3), #18 [new] 
Section 9.2.9.3 Monitoring for 
SARS-CoV-2 Reinfection 
Section 10.1.1 General Guidelines 
Section 10.1.3 Events that Require 
Expedited Reporting to Sponsor 
Clarified that, for the optional 
pharmacogenomics sub-study, patients who 
consent to this sub-study will only have a 
blood sample collected for DNA. Patients 
who already consented to the sub-study will 
not be consented a second time, and patients 
who have already provided a sample for the 
PGx sub-study should not have a second 
sample collected. 
To ensure appropriate 
collection of sub-study 
samples. 
Section 9.1.2.1 Footnotes for Table 
2 Schedule of Events (Phase 2 and 
Phase 3), #3 
Section 9.2.9.4 Pharmacogenomic 
Analysis (Optional) 
Clarified that although patient-reported 
outcome (PRO) data (eg, patient-reported 
questionnaires, surveys, and instruments) are 
generally not reportable as individual AEs, if 
the investigator is made aware of any AE that 
(in his or her judgement) is related to study 
drug, the AE will follow standard AE 
reporting and recording. 
To ensure appropriate 
collection of safety-related 
data. 
Section 9.2.9 Long COVID Sub-
Study (at Participating Sites) 
Section 10.1.1 General Guidelines 
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Description of Change 
 
Brief Rationale   
Section(s) 
Updates to background information, minor 
clarifications for consistency, administrative 
changes, and other minor updates 
(typographical, editorial, formatting) were 
made. 
To ensure clarity, accuracy, 
and consistency. 
Throughout the document 
 
Amendment 7 
The primary purpose of this amendment is to update the planned statistical analysis for the final 
analysis, including changes to the objectives and endpoints, following early termination of the 
study on 09 April 2021 based on a Sponsor business decision. 
The following table outlines all changes made to the protocol and the affected sections. 
Description of Change 
Brief Rationale 
Section(s) 
Key modifications to the planned final 
statistical analysis include the following. 
Efficacy analysis 
The primary virological and clinical analyses 
will involve pooling of cohort 1 (hospitalized 
on low-flow oxygen) and cohort 1A 
(hospitalized but not requiring supplemental 
oxygen) and doses. Assessment of each 
cohort and dose alone will now be secondary.  
The primary virologic endpoint is time-
weighted average change from baseline viral 
load in nasopharyngeal (NP) sample through 
day 7 in the Seronegative mFAS in the pooled 
phase 3 cohort 1 and phase 2 cohort 1A, and 
combined across the 2.4 g and 8.0 g doses of 
REGN10933+REGN10987. 
The primary clinical endpoint is the 
proportion of patients who died or went on 
mechanical ventilation from day 6 through 
day 29 and from day 1 through day 29. The 
primary analysis will be performed for the 
High Viral Load mFAS, Seronegative mFAS, 
and Overall mFAS in the pooled phase 3 
(cohort 1) and phase 2 (cohort 1A).  
To control alpha at a strict 0.05 level, the two 
primary endpoints will be tested 
hierarchically, with the virologic endpoint 
tested first. All hierarchical testing will be 
done using the combined dose group. 
There are no primary objectives for phase 2 
cohort 1A, as enrollment was prematurely 
terminated. The clinical efficacy endpoints for 
phase 3 (cohort 1) and phase 2 (cohort 1A), 
separately, will be assessed as secondary.  
For efficacy analysis 
As a result of the study 
ending early and the 
resultant constrained 
sample size, cohorts and 
doses will be pooled in the 
primary virological and 
clinical analyses to 
enhance the ability to 
detect clinically 
meaningful treatment 
effects.  
To assess the potential 
efficacy of REGN10933+ 
REGN10987 using 
relevant measures in a 
patient population most 
likely to receive benefit 
from the therapy, based on 
preliminary data from 
clinical studies of 
REGN10933+REGN10987 
in hospitalized patients 
(Regeneron, 2020) (Horby, 
2021). The clinical 
efficacy of phase 3 (cohort 
1) and phase 2 (cohort 1A), 
separately, will be assessed 
as secondary due to 
constrained sample size 
following early study 
termination. 
 
 
 
 
Section 2.1 Primary Objectives 
Section 2.2 Secondary Objectives 
Section 4.1 Primary Endpoints 
Section 4.2 Secondary Endpoints 
Section 6.3 Planned Interim Analysis 
Section 7.1 Number of Patients 
Enrolled 
Section 11 Statistical Plan (and 
sections therein) 
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Description of Change 
Brief Rationale 
Section(s) 
Safety analysis 
The safety analysis will be performed for the 
following cohorts, separately. Patients in 
phase 1/2 (cohort 1) and phase 2 (cohort 2 and 
cohort 3) are included in these analyses since 
more safety data were collected for the 
patients after the previous database lock on 22 
December 2020: 
• Phase 2 (cohort 1A) 
• Phase 2 (cohort 2) 
• Phase 2 (cohort 3) 
• Phase 1/2/3 (cohort 1) combined 
Pharmacokinetics (PK) and 
immunogenicity analysis 
The PK and anti-drug antibody (ADA) 
analysis will be performed for phase 1/2/3 
(cohort 1) combined, phase 2 (cohort 1A), 
phase 2 (cohort 2), and phase 2 (cohort 3), 
separately. The neutralizing antibody (NAb) 
analysis will only be performed for phase 2 
and phase 3 patients. 
For safety and PK 
analysis 
To specify the safety and 
PK analysis populations 
based on patient 
enrollment  
It was noted that the Sponsor made a business 
decision to terminate patient enrollment in this 
study on 09 April 2021, and this decision was 
not based on any safety concerns. 
Patients who have been enrolled will be 
continued to be followed up according to the 
Schedule of Events. In addition, enrolled 
patients at select sites may be reconsented and 
followed for an extended period for the long 
COVID sub-study. 
Study terminated due to 
extremely low recruitment 
rates over several months 
Section 1.6 A Randomized, Placebo-
Controlled Study of Anti-SARS-
CoV-2 S Protein Monoclonal 
Antibodies in Hospitalized Patients 
with COVID-19 
Section 6.1 Study Description and 
Duration 
Section 7.1 Number of Patients 
Enrolled 
 
Minor clarifications and edits were made, 
including: 
• Treatments related to reported adverse 
events (AEs), such as supplemental oxygen 
and packed red blood cells, were added to 
the list of targeted concomitant medications 
and procedures 
• Collection details for oxygen delivery device 
status were updated to clarify timing 
• For individual patients, study completion is 
defined as the completion of the Schedule-
of-Events-defined end of study visit, 
including vital status information collection. 
• Clarified that post-discharge study visits 
may occur by phone or in person 
• In addition to anti-drug antibodies (ADA), 
neutralizing antibodies (NAb) against 
REGN10933+REGN10987 will be assessed 
in phase 2 and phase 3. 
To provide clarity 
Section 3.2.1.4 Patient Population 
and Study Cohorts 
Section 3.3 Risk-Benefit 
Section 5.5 Immunogenicity 
Variables  
Section 6.1.6 Definition of Study 
Completion 
Section 9.1.2.1 Footnotes for Table 2 
Schedule of Events (Phase 2 and 
Phase 3), footnotes #10 
Section 9.2.3.3 Targeted Medication 
and Procedure Review 
Section 9.2.5.2 Clinical and Oxygen 
Status 
Section 10.1.2 Reporting Procedure 
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Description of Change 
Brief Rationale 
Section(s) 
• The risk-benefit section and background 
information were updated. 
Risk-benefit information was updated to 
reflect the current Investigator’s Brochure. 
To provide current safety 
information 
Section 3.3 Risk-Benefit 
Updated reiteration of IDMC recommendation 
for an enrollment hold of cohort 2 and cohort 
3 as of 19 February 2021. 
To ensure current 
information 
Throughout the document 
Minor editorial changes have been made to 
accurately reflect the current statistical 
analysis and cohort designations.  
To ensure accuracy and 
readability 
Throughout the document 
Updates to background information, minor 
clarifications for consistency, and other minor 
updates (typographical, editorial, formatting) 
were made. 
To ensure clarity, 
accuracy, and consistency. 
Throughout the document 
Amendment 6 
The primary purpose of this amendment is to update the planned statistical analysis for the phase 
1/2 portion of the study prior to unblinding. The primary analysis of phase 1/2 (cohort 1) will 
exclude futility of REGN10933+REGN10987 compared with placebo, as measured by death or 
mechanical ventilation. If the study as designed is determined not to be futile, the clinical efficacy 
of REGN10933+10987 in reducing death or mechanical ventilation will be evaluated as a key 
secondary endpoint. 
Other updates include incorporating the current IDMC recommendation to hold cohort 2/3 
enrollment, pending further review of data. 
Description of Change 
Brief Rationale 
Section(s) 
Key modifications to the planned statistical 
analysis include the following: 
• The primary objective of phase 1/2 cohort 1 
will be to exclude futility of 
REGN10933+REGN10987 compared to 
placebo, as measured by death or 
mechanical ventilation. If futility is 
declared, the phase 1/2 data will be 
analyzed descriptively 
• If the study as designed is determined not 
to be futile, the clinical efficacy of 
REGN10933+10987 in reducing death or 
mechanical ventilation will be evaluated as 
a key secondary endpoint in cohort 1. This 
endpoint will be tested using a statistical 
hierarchy 
• The statistical hierarchy of key secondary 
endpoints will focus on assessments in: 1) 
patients who are seronegative at baseline 
and do not have a negative baseline RT-
qPCR; 2) patients who do not have a 
negative baseline RT-qPCR and have high 
viral load  
To determine future 
direction of program 
and assess the potential 
efficacy of REGN10933 
+ REGN10987 using 
clinically-relevant 
measures in a patient 
population most likely 
to receive benefit from 
an anti-viral therapy 
Clinical Study Protocol Synopsis: 
Objectives, Study Design, Endpoints, 
Statistical Plan 
Section 2.1 Primary Objectives 
Section 2.2 Secondary Objectives 
Section 3.1 Hypotheses 
Section 3.2.1.5 Rationale for Primary 
Objectives 
Section 4.1 Primary Endpoints 
Section 4.2 Secondary Endpoints 
Section 4.2.1 Key Secondary Endpoint 
[new] 
Section 4.2.2 Other Secondary 
Endpoints [new] 
Section 6.1 Study Description and 
Duration 
Section 6.3 Planned Interim Analysis 
Section 11 Statistical Plan 
Section 11.1.1 Statistical Hypotheses 
Section 11.2 Justification of Sample Size 
Section 11.3.1 Efficacy Analysis Sets 
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Description of Change 
Brief Rationale 
Section(s) 
• Virologic efficacy will be analyzed 
descriptively as secondary endpoints for all 
cohorts 
• Additional relevant changes have been 
made as needed to the statistical analysis 
section, including power calculations and 
methods of analyses (eg, Kaplan-Meier and 
hazard ratio) 
Additional details are provided in the phase 
1/2 Statistical Analysis Plan (SAP). 
Section 11.4.3.1 Primary Futility and 
Key Secondary Efficacy Analysis 
Section 11.4.3.2 Other Secondary 
Efficacy Analysis 
Section 11.4.4 Control of Multiplicity 
Section 11.4.5.1 Adverse Events 
Section 11.5 Interim Analysis 
Per IDMC recommendation initially received 
on 30 October and reiterated on 18 November 
and 10 December 2020, patient enrollment in 
cohort 2 and cohort 3 has been placed on hold 
pending IDMC review of further data.  
Patient enrollment in cohort 1A and cohort 1 
will continue. All currently enrolled patients 
will continue to follow the protocol schedule 
to which they were last consented. 
Per IDMC 
recommendation based 
on a potential safety 
signal and an 
unfavorable risk-benefit 
profile in cohorts 2 and 
3 at this time 
Clinical Study Protocol Synopsis: 
Population 
Section 3.2.1.4 Patient Population and 
Study Cohorts  
Section 6.1 Study Description and 
Duration 
Section 6.1.1 Study Design 
Section 6.1.2 Study Duration 
Figure 3 Study Flow Diagram, Phase 2 
Section 6.1.3 Description of Study 
Cohorts 
Section 7.1 Number of Patients Planned 
Section 7.2.1 Inclusion Criteria, #5 
Section 8.6 Method of Treatment 
Assignment 
Section 9.1.2 Phase 2 (Cohort 1A, 
Cohort 1, Cohort 2*, and Cohort 3*) 
Section 11.2.2 Phase 2 (Cohort 1A, 
Cohort 1, Cohort 2*, and Cohort 3*) 
Section 11.4.3.2 Other Secondary 
Efficacy Analysis 
Any cohort 1 patient enrolled after the first 
691 cohort 1 patients (including the 60 
patients from phase 1) will be considered part 
of phase 3. These patients will follow the 
phase 2 Schedule of Events.  
The number of enrolled and planned patient 
was also updated. 
To ensure accurate 
description of study 
phase enrollment 
Clinical Study Protocol Synopsis: 
Population 
Section 6.1.1 Study Design Section 9.1.2 
Phase 2 (Cohort 1A, Cohort 1, Cohort 
2*, and Cohort 3*) 
The number of patients enrolled to date and 
planned to be enrolled was updated 
To ensure accurate 
description of study 
phase enrollment 
Section 7.1 Number of Patients Planned 
Patients who have received anti-SARS-CoV-2 
mAbs (eg, bamlanivimab) within 5 months 
prior to randomization will be excluded. 
To avoid potential 
confounding factors for 
clinical efficacy and 
safety assessments  
Section 7.2.2 Exclusion Criteria, #7 
Added current CDC guidance related to 
vaccination, which recommends deferral of 
SARS-CoV-2 vaccination for at least 90 days 
after administration of passive antibody 
treatment (eg, REGN10933+REGN10987) 
(CDC, 2020).  
To provide current 
guidance regarding 
SARS-CoV-2 
vaccination  
Section 8.10.1 Prohibited and Permitted 
Medications 
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Description of Change 
Brief Rationale 
Section(s) 
SARS-CoV-2 vaccinations will be recorded as 
a targeted concomitant medication. 
To ensure collection of 
clinically relevant 
medical information 
Section 9.2.3.3 Targeted Medication 
Review 
Procedural details for virologic assessments 
were updated:  
• NP samples with an original result above 
the Upper Limit of Quantification (ULOQ) 
will be diluted for additional quantification 
testing. 
• Clarified that viral variants suspected to 
confer decreased susceptibility to 
REGN10933 and/or REGN10987 will be 
evaluated in nonclinical work separate from 
this protocol. 
To provide 
quantification of viral 
load at higher levels, 
and to ensure current, 
accurate, and consistent 
information related to 
planned analyses 
Section 9.2.5.1 Sample Collection for 
RT-qPCR Analysis 
Section 9.2.8.1 Virology 
Patients hospitalized for ≤72 hours (for 
reasons other than COVID-19 illness but with 
current COVID-19 symptoms) will be eligible 
to participate in the study, if they also meet 
other eligibility criteria.  
To assess the study drug 
in a broader patient 
population that may 
receive clinical benefit 
Section 7.2.1 Inclusion Criteria, #3 
The Schedule of Events footnotes were 
updated as follows: 
• Patients in cohort 1 enrolled after 691 
patients in the cohort (including phase 1 
patients) will follow the phase 2 schedule 
but will be considered enrolled in phase 3 
• Pregnancy testing will be performed locally 
• Day 1 hematology, blood chemistry, and 
coagulation test samples will be collected 
prior to dosing (rather than randomization) 
To provide operational 
clarity 
Section 9.1.1.1 Footnotes for Table 1 
Schedule of Events (Phase 1), #10 
Section 9.1.2 Phase 2 (Cohort 1A, 
Cohort 1, Cohort 2*, and Cohort 3*) 
Section 9.1.2.1 Footnotes for Table 2 
Schedule of Events (Phase 2), #5, 12 
REGN10989 monotherapy will no longer be 
considered as part of this adaptive master 
protocol. References to REGN10989 have 
correspondingly been removed from the 
statistical analysis and related areas of the 
protocol. 
Based on preclinical 
viral resistance data 
showing viral escape 
following monotherapy 
with anti-SARS-CoV-2 
monoclonal antibodies, 
this study to assess 
combination therapies 
and will no longer 
include monotherapy 
arms. 
Throughout the document 
Emergency unblinding procedures were 
clarified, including manual unblinding in case 
of IWRS unavailability. 
Per health authority 
request 
Section 8.8 Emergency Unblinding 
Updates to background information were 
made, including current authorizations and 
approvals for COVID-19 treatments and 
SARS-CoV-2 vaccines. 
To ensure current, 
accurate, and consistent 
information 
Section 1.5 A Randomized, Placebo-
Controlled Study of Anti-SARS-CoV-2 
S Protein Monoclonal Antibodies in 
Hospitalized Patients with COVID-19 
Section 3.2.1.3 Standard of Care 
Background Treatments 
Other minor typographical corrections and 
updates were made. 
To ensure document 
accuracy 
Throughout the document 
 
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Amendment 5 EU 
Description of Change 
Brief Rationale 
Section(s) 
Per IDMC recommendation received on 30 
October and 18 November 2020, patient 
enrollment in cohort 2 and cohort 3 has 
been placed on hold (pending IDMC review 
of further data on patients who are currently 
enrolled in these cohorts). Patient 
enrollment in cohort 1A and cohort 1 will 
continue.  
All currently enrolled patients will continue 
to follow the protocol schedule to which 
they were last consented.  
Per IDMC recommendation based 
on a potential safety signal and an 
unfavorable risk-benefit profile in 
cohorts 2 and 3 at this time 
Section 3.2.1.4 Patient 
Population and Study Cohorts  
Section 6.1 Study Description 
and Duration 
Section 6.1.1 Study Design 
Figure 3 Study Flow Diagram, 
Phase 2 
Section 6.1.2 Study Duration 
Section 6.1.3 Description of 
Study Cohorts 
Section 6.3 Planned Interim 
Analysis 
Section 7.1 Number of Patients 
Planned 
Section 7.2.1 Inclusion Criteria 
Section 8.6 Method of Treatment 
Assignment 
Section 9.1.2 Phase 2 (Cohort 
1A, Cohort 1, Cohort 2*, and 
Cohort 3*) 
Section 11.1.2 Phase 2 (Cohort 
1A, Cohort 1, Cohort 2*, and 
Cohort 3*) 
Section 11.2.2 Phase 2 (Cohort 
1A, Cohort 1, Cohort 2*, and 
Cohort 3*) 
Section 11.4.3.1.2 Phase 2 
(Cohort 1A, Cohort 1, Cohort 
2*, and Cohort 3*) 
Section 11.4.3.2.2 Phase 2 
(Cohort 1A, Cohort 1, Cohort 
2*, and Cohort 3*) 
Section 11.4.9 Control of 
Multiplicity 
Section 11.5 Interim Analysis 
Risk-benefit language was updated. 
To provide updated risk-benefit 
information for the program and 
considerations for a broader 
patient population 
Section 3.3 Risk-Benefit 
Study monitoring plan was updated to allow 
off-site/remote monitoring of study sites. 
Per health authority request; to 
provide flexibility for site 
monitoring due to COVID-19 
Section 12.2.1 Monitoring of 
Study Sites 
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Amendment 5 
Description of Change 
Brief Rationale 
Section(s) 
Study inclusion criteria was updated to 
extend COVID-19 symptom onset 
window from ≤7 days to ≤10 days prior 
to randomization. 
To broaden patient eligibility 
and better align with the 
evolving epidemiology of 
when patients present to the 
hospital relative to COVID-
19 symptom onset 
Section 7.2.1 Inclusion Criteria, #4 
Phase 2 target population was revised 
to include patients who have COVID-
19 symptoms but are not requiring 
supplemental oxygen. Approximately 
390 additional patients on room air will 
be enrolled in cohort 1A.  
To enroll patients at earlier 
stages of the disease and 
enable broader assessment of 
treatment impact on viral 
burden and other measures 
Section 3.2.1.4 Patient Population and 
Study Cohorts 
Section 3.2.1.5 Rationale for Primary 
Objectives 
Section 4.1 Primary Endpoints 
Section 4.2 Secondary Endpoints 
Section 6.1 Study Description and 
Duration 
Section 6.1.1 Study Design 
Study Duration 
Figure 3 Study Flow Diagram, Phase 2 
Section 6.1.3 Description of Study Cohorts 
Section 7.1 Number of Patients Planned 
Section 7.2 Study Population 
Section 7.2.1 Inclusion Criteria, #5 
Section 7.2.2 Exclusion Criteria, #1 
Table 2 Schedule of Events for Phase 2 
Section 11.2.2 Phase 2 (Cohort 1A, Cohort 
1, Cohort 2, Cohort 3) 
Section 11.4.3 Efficacy Analysis 
Section 11.4.4 Control of Multiplicity 
In phase 2, day 7 and day 15 blood 
samples for hematology, blood 
chemistry, and coagulation tests were 
added for all patients. Additional blood 
samples for biomarker assessments will 
be collected at baseline (post-dose) and 
on days 7, 15, and 29. 
To allow more 
comprehensive analysis of 
safety and efficacy, by 
including additional 
biomarkers associated with 
COVID-19, inflammation, 
and cardiac and/or other 
organ injury 
Section 5.6 Pharmacodynamic and Other 
Biomarker Variables 
Table 2 Schedule of Events for Phase 2 
Section 9.1.2.1 Footnotes for Table 2 
Schedule of Events (Phase 2), footnotes 
#2, #12  
Section 9.2.8.8 Serum and Plasma for 
Cardiac Biomarkers (section added) 
Section19 References 
At screening, diagnostic testing for 
SARS-CoV-2 infection will allow 
antigen tests in addition to molecular 
tests. 
To provide operational 
flexibility 
Section 7.2.1 Inclusion Criteria, #3 
Table 1 Schedule of Events for Phase 1 
(Part A and Part B) 
Table 2 Schedule of Events for Phase 2 
Section 9.2.1.2 Diagnostic Test for 
SARS-CoV-2 
Phase 2 interim analysis plans were 
updated. Sample size re-estimation 
language was removed.  
To allow flexibility of 
interim analyses  
Section 6.3 Planned Interim Analysis 
Section 11.5 Interim Analysis 
In phase 1, patients who have missing 
or negative baseline virologic sample(s) 
or are missing ≥1 follow-up virologic 
samples(s) will no longer be replaced. 
No longer necessary to 
replace patients in phase 1, 
since phase 2 now includes 
extensive analyses of 
virologic efficacy  
Section 7.4 Replacement of Patients 
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Description of Change 
Brief Rationale 
Section(s) 
Information regarding appropriate high-
altitude equivalents for sea-level 
oxygenation measurements was added. 
To provide eligibility 
guidance to study sites in 
high-altitude areas 
Section 7.2.1 Inclusion Criteria, #5 
Section 7.2.2 Exclusion Criteria, #1 
Appendix A Oxygenation Equivalence for 
Eligibility (appendix added) 
Information regarding review of 
sentinel safety group (part A) was 
added. 
To update safety information 
for the program 
Section 3.2.1.1 Phase 1 Sentinel Safety 
Group 
EudraCT number for the study was 
added; other minor editorial and 
administrative updates were made. 
To ensure accuracy and 
consistency 
Title page 
Section 1.1 Emergence of SARS CoV 2 
and COVID 19 
Section 3.2.1.1 Phase 1 Sentinel Safety 
Group 
Section 3.2.1.5 Rationale for Primary 
Objectives 
Section 4.1 Primary Endpoints 
Section 4.2 Secondary Endpoints 
Section 8.1 Investigational and Reference 
Treatments 
Section 9.1.3 Early Termination  
Section 9.2.8.4 Serological Immunoassays 
for Anti-SARS CoV 2 Antibodies 
Section 9.2.8.5 Serum and Plasma for 
Research 
Section 9.2.8.7 Cytokines 
References 
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Amendment 4 
Description of Change 
 
Brief Rationale   
Section(s) 
In phase 2, nasal swabs and saliva 
samples will no longer be collected. 
Only nasopharyngeal (NP) swabs will 
be collected in phase 2.  
To allow adequate 
assessment of virologic 
efficacy, as NP swab is the 
current gold standard to 
detect SARS-CoV-2 
Section 2.2 Secondary Objectives  
Section 4.2 Secondary Endpoints  
Figure 3 Study Flow Diagram, Phase 2 
Table 2 Schedule of Events for Phase 2 
Section 9.1.2.1 Footnotes for Table 2 
Schedule of Events (Phase 2), #7 (deleted) 
Section 9.2.5.1 Nasopharyngeal Swab, 
Nasal Swab, and Saliva Sample Collection 
Section 11.4.3.2.2 Phase 2 (Cohort 1, 
Cohort 2, Cohort 3) 
Phase 2 sample size has been 
increased to enable additional 
enrollment. 
To allow adequate 
assessment of virologic 
efficacy 
Section 6.1.1 Study Design 
Section 7.1 Number of Patients Planned 
Section 11.2.2 Phase 2 (Cohort 1, Cohort 2, 
and Cohort 3) 
An additional secondary virologic 
efficacy endpoint has been added. 
To allow adequate 
assessment of virologic 
efficacy 
Section 4.2 Secondary Endpoints 
Interim analysis plan has been updated 
to allow more flexible timing and for 
consistency throughout the protocol. 
To allow flexibility of 
interim analyses  
Section 6.3 Planned Interim Analysis 
Section 11.5 Interim Analysis 
A modified full analysis set (mFAS) 
was added and includes all 
randomized patients with a positive 
RT-qPCR for SARS-CoV-2 in NP 
swab at randomization.  
To allow adequate 
assessment of virologic 
efficacy 
Section 9.2.5.1 Nasopharyngeal Swab, 
Nasal Swab, and Saliva Sample Collection 
Section 11.3.1 Efficacy Analysis Sets 
Section 11.4.1 Patient Disposition 
Section 11.4.3.1 Primary Efficacy Analysis 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
In phase 2, hematology and 
coagulation tests will be performed at 
day 7 in patients who are hospitalized. 
To allow assessment of 
relevant biomarkers 
Table 2 Schedule of Events for Phase 2 
Section 9.1.2.1 Footnotes for Table 2 
Schedule of Events (Phase 2), #2, #12 
The following clarifications have been 
made to the Schedule of Events: 
• Clarified that at concomitant 
medications are continuously 
monitored in phase 1 and phase 2. 
• Removed incorrect vital sign 
assessments marked in dosing 
column in phase 2. 
To improve clarity of study 
schedule 
Table 1 Schedule of Events for Phase 1 
(Part A and Part B) 
Table 2 Schedule of Events for Phase 2 
 
Amendment 3 
Description of Change 
 
Brief Rationale   
Section(s) 
In phase 2, blood chemistry will be 
assessed at day 7 in patients who are 
hospitalized. 
Per health authority request 
Table 2 Schedule of Events for Phase 2  
Section 9.1.2.1 Footnotes for Table 2, 
footnote #13 
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Description of Change 
 
Brief Rationale   
Section(s) 
Primary virologic efficacy in phase 2 
will be assessed using nasopharyngeal 
(NP) swab samples. NP swab sample 
collection has been correspondingly 
added. 
To allow adequate 
assessment of virologic 
efficacy 
Section 2.2 Secondary Objectives  
Section 4.1 Primary Endpoints 
Section 4.2 Secondary Endpoints  
Table 2 Schedule of Events for Phase 2 
Section 9.2.5.1 Saliva Sample, Nasal Swab, 
and Nasopharyngeal Swab Collection 
Section 11.4.3.1 Primary Efficacy Analysis 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Additional patients may be enrolled in 
phase 1 to replace patients who have 
missing or negative baseline virologic 
sample(s) or are missing ≥1 follow-up 
virologic sample(s). 
To allow adequate 
assessment of virologic 
efficacy 
Section 7.1 Number of Patients Planned 
Section 7.4 Replacement of Patients  
 
Amendment 2 
Description of Change 
 
Brief Rationale   
Section(s) 
Grade 3 or 4 treatment-emergent AEs 
will be collected (phase 1 only) 
Per health authority request 
Section 3.2.1.5 Rationale for Primary 
Objectives 
Section 5.3 Safety Variables 
Section 6.1 Study Description and Duration 
Table 1 Schedule of Events for Phase 1 
(Part A and B) 
Section 9.1.1.1 Footnotes for Table 1 
Schedule of Events (Phase 1), #7 
Section 9.1.4 Unscheduled Visits 
Section 10 Safety Evaluation and Reporting 
(and sub-sections therein) 
Added day 57 collection of blood 
samples for safety laboratory testing 
(phase 1 only) 
Per health authority request 
Table 1 Schedule of Events for Phase 1 
(Part A and B) 
Clarified objective, endpoint, and 
procedure for assessing viral 
resistance 
Per health authority request 
Section 2.1 Exploratory Objectives 
Section 4.1 Exploratory Endpoints 
Section 9.2.8.1 Virology 
Clarified EC and IC terminology 
related to dose rationale 
To clarify in vitro data 
descriptions 
Section 3.2.2 Rationale for Dose Selection 
Added details to address controlling 
for type I error 
Per health authority request 
Section 11.4.4 Control of Multiplicity 
Added ICU-associated secondary 
endpoints; other clarifications made to 
primary and secondary efficacy 
analysis and multiplicity control 
To ensure consistency with 
planned statistical analysis 
Section 4.2 Secondary Endpoints 
Included secondary objective and 
endpoint to assess correlations in viral 
shedding across sample types 
To understand differences in 
assessing virologic efficacy 
using distinct sampling 
sources 
Section 2.2 Secondary Objectives 
Section 4.2 Secondary Endpoints 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
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Description of Change 
 
Brief Rationale   
Section(s) 
Added nasopharyngeal (NP) sampling 
to days 11 and 15 (phase 1 only) 
To provide matching sample 
types across time points 
Table 1 Schedule of Events for Phase 1 
(Part A and B) 
Study will be conducted in the US and 
other countries 
To broaden the reach of 
study 
Section 6.1 Study Description and Duration 
Added country as a stratification 
factor for randomization in phase 2 
To ensure balance in study 
populations  
Section 8.6 Method of Treatment 
Assignment 
Section 11.2 Justification of Sample Size 
Section 11.4.3.1 Primary Efficacy Analysis 
Screening for SARS-CoV-2 infection 
can be performed by any validated 
molecular diagnostic assay; historical 
record ≤72 hours of randomization is 
acceptable 
To clarify acceptable 
screening criteria 
Section 7.2.1 Inclusion Criteria, #3 
Table 1 Schedule of Events for Phase 1 
(Part A and B) 
Section 9.1.1.1 Footnotes for Table 1 
Schedule of Events (Phase 1), #4 
Table 2 Schedule of Events for Phase 2 
Section 9.1.2.1 Footnotes for Table 2 
Schedule of Events (Phase 2), #4 
Section 9.2.1.2 Molecular Diagnostic Test 
for SARS-CoV-2 
For assessment of COVID-19 
symptom onset during screening, 
symptoms are defined per investigator 
discretion 
To clarify inclusion criterion Section 7.2.1 Inclusion Criteria, #4 
Updated study stopping criteria 
To provide additional details 
for study stopping and/or 
adaptations  
Section 6.1.4.2 Study Stopping Criteria 
The Independent Data Monitoring 
Committee (IDMC) will review both 
safety and efficacy data during the 
study 
To clarify the planned 
IDMC review process 
Section 6.2.1 Independent Data Monitoring 
Committee 
Any unused or leftover biological 
samples collected during the study 
may be used for exploratory research; 
maximum time period of allowable 
storage (for both exploratory research 
samples and pharmacogenomic 
samples) may be shorter per regional 
laws and regulations 
To clarify the intended use 
and storage of samples 
Section 9.2.6 Drug Concentration 
Measurements and Samples  
Section 9.2.7 Immunogenicity 
Measurements and Samples 
Section 9.2.8 Exploratory 
Pharmacodynamic/Biomarker Analyses 
Section 9.2.9 Pharmacogenomic Analysis 
(Optional) 
The following operational changes 
have been made: 
• Phone visits have a window of ±1 
day 
• Clarified that home-based visits 
may be done by home health staff 
To provide additional 
flexibility for sample 
collection and assessments 
Section 6.1 Study Description and Duration 
Table 1 Schedule of Events for Phase 1 
(Part A and B) 
Section 9.1.1.1 Footnotes for Table 1 
Schedule of Events (Phase 1), #2, #8 
Table 2 Schedule of Events for Phase 2 
Section 9.1.2.1 Footnotes for Table 2 
Schedule of Events (Phase 2), #2, #11 
Specified parameters of early 
termination visit  
To clarify early termination 
requirement for sample 
collection and assessments 
Section 9.1.3 Early Termination from the 
Study 
Added unscheduled visit 
To provide a description of 
early termination visits 
Section 9.1.4 Unscheduled Visits 
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Description of Change 
 
Brief Rationale   
Section(s) 
Updated the list of targeted 
concomitant medications to be 
recorded 
To ensure consistency with 
the eCRF 
Section 9.2.3.3 Targeted Medication 
Review 
Temperature will not be measured 
rectally  
To clarify required 
assessments 
Section 9.2.3.1.2 Body Temperature 
Clarified a Statistical Plan in the 
Synopsis 
To align to the main text  
Synopsis: Statistical Plan 
Simplified the Schedule of Events, 
and removed visit locations; visits 
may occur at any in-person location 
except where additional phone visits 
are indicated  
To ensure clarity of study 
schedule and design  
Section 6.1.2 Study Duration 
Table 1 Schedule of Events for Phase 1 
(Part A and B) 
Section 9.1.1.1 Footnotes for Table 1 
Schedule of Events (Phase 1) 
Table 2 Schedule of Events for Phase 2 
Section 9.1.2.1 Footnotes for Table 2 
Schedule of Events (Phase 2) 
Typographical, grammatical, editorial, 
and formatting updates 
Implemented for clarity, 
accuracy, and consistency 
Throughout the document 
 
Amendment 1 
Description of Change  
Brief Rationale  
 
Section(s) 
Day 1 vital sign requirements 
(including pulse oximetry) added for 
patients in the phase 1 sentinel safety 
group 
Per health authority request 
Table 1 Schedule of Events for Phase 1 
(Part A and Part B) 
Section 9.1.1.1 Footnotes for Table 1, 
footnote #7 
Table 2 Schedule of Events for Phase 2 
Section 9.1.2.1 Footnotes for Table 2, 
footnote #9 
Independent Data Monitoring 
Committee (IDMC) description 
updated 
Operational details to be 
provided in the IDMC 
charter 
Section 6.2.1 Independent Data Monitoring 
Committee 
Clarifications of study procedures 
To improve clarity of 
procedures and planned 
analyses 
Section 9.2 Study Procedures (and sub-
sections therein) 
Editorial updates implemented 
To ensure clarity, accuracy, 
and consistency 
Section 8.7 Blinding 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACE2 
Angiotensin-converting enzyme 2 
ADA 
Anti-drug antibody 
ADE 
Antibody-dependent enhancement 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
CK-MB 
Creatine kinase-MB 
Cmax 
Maximum concentration 
COVID-19 
Coronavirus disease 2019 
CPAP 
Continuous positive airway pressure 
CRP 
C-reactive protein 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
EC50 
In vitro neutralization potency 
EC99 
Effective concentration of 99% viral neutralization 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELF 
Epithelial lining fluid 
EMA 
European Medicines Agency 
EOS 
End of study 
EUA 
Emergency Use Authorization 
FAS 
Full analysis set 
FDA 
United States Food and Drug Administration 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
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IDMC 
Independent data monitoring committee 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin  
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal antibody 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
mFAS 
Modified full analysis set 
NAb 
Neutralizing antibody 
NCI 
National Cancer Institute 
NLR 
Neutrophil-lymphocyte ratio 
NP 
Nasopharyngeal 
NT-proBNP 
N-terminal pro B-type natriuretic peptide 
OP 
Oropharyngeal  
PFU 
Plaque forming unit 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetic 
PT 
Preferred term 
PT/INR 
Prothrombin time 
RBD 
Receptor binding domain 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
REGN10933+REGN10987 Co-administered REGN10933+REGN10987 combination 
therapy 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV 
Severe acute respiratory syndrome coronavirus 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
Systems organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULOQ 
Upper limit of quantification 
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WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
 
 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................17 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................28 
1. 
INTRODUCTION ......................................................................................................35 
1.1. 
Emergence of SARS-CoV-2 and COVID-19 .............................................................35 
1.2. 
Clinical Outcomes in Hospitalized Patients with COVID-19 ....................................35 
1.3. 
Long-Term Outcomes in Patients with COVID-19 ....................................................35 
1.4. 
The Role of Spike (S) Protein in SARS-CoV-2 Viral Pathogenesis ..........................36 
1.5. 
REGN10933+REGN10987: Human Monoclonal Antibodies Against 
SARS-CoV-2 S Protein ..............................................................................................36 
1.6. 
A Randomized, Placebo-Controlled Study of Anti-SARS-CoV-2 S Protein 
Monoclonal Antibodies in Hospitalized Patients with COVID-19 ............................36 
2. 
STUDY OBJECTIVES ..............................................................................................37 
2.1. 
Primary Objectives .....................................................................................................37 
2.2. 
Secondary Objectives .................................................................................................37 
2.3. 
Exploratory Objectives ...............................................................................................39 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................40 
3.1. 
Hypotheses ..................................................................................................................40 
3.2. 
Rationale .....................................................................................................................40 
3.2.1. 
Rationale for Study Design .........................................................................................40 
3.2.1.1. 
Phase 1 Sentinel Safety Group ...................................................................................40 
3.2.1.2. 
Adaptive Master Protocol Design ...............................................................................41 
3.2.1.3. 
Standard-of-Care Background Treatments .................................................................42 
3.2.1.4. 
Patient Population and Study Cohorts ........................................................................42 
3.2.1.5. 
Rationale for Primary Objectives ...............................................................................42 
3.2.1.6. 
Rationale for Final Analysis of the Study...................................................................44 
3.2.1.7. 
Long COVID Sub-Study ............................................................................................45 
3.2.2. 
Rationale for Dose Selection ......................................................................................46 
3.3. 
Risk-Benefit ................................................................................................................47 
3.3.1. 
Summary of Efficacy and Safety Profile in Clinical Trials ........................................47 
3.3.2. 
Summary of Risks.......................................................................................................48 
4. 
ENDPOINTS ..............................................................................................................49 
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4.1. 
Primary Endpoints ......................................................................................................49 
4.2. 
Secondary Endpoints ..................................................................................................50 
4.3. 
Exploratory Endpoints ................................................................................................53 
5. 
STUDY VARIABLES................................................................................................54 
5.1. 
Demographic and Baseline Characteristics ................................................................54 
5.2. 
Efficacy Variables ......................................................................................................54 
5.3. 
Safety Variables ..........................................................................................................54 
5.4. 
Pharmacokinetic Variables .........................................................................................54 
5.5. 
Immunogenicity Variables ..........................................................................................54 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................54 
6. 
STUDY DESIGN .......................................................................................................54 
6.1. 
Study Description and Duration .................................................................................54 
6.1.1. 
Study Design ...............................................................................................................55 
6.1.2. 
Study Duration ............................................................................................................56 
6.1.3. 
Description of Study Cohorts .....................................................................................58 
6.1.4. 
Study Stopping Rules .................................................................................................58 
6.1.4.1. 
Individual Patient Stopping Rules ..............................................................................58 
6.1.4.2. 
Study Stopping Criteria ..............................................................................................58 
6.1.5. 
End of Study Definition ..............................................................................................59 
6.1.6. 
Definition of Study Completion .................................................................................59 
6.2. 
Study Committees .......................................................................................................59 
6.2.1. 
Independent Data Monitoring Committee ..................................................................59 
6.2.2. 
Sponsor Review Committee .......................................................................................59 
6.3. 
Planned Interim Analysis ............................................................................................59 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............60 
7.1. 
Number of Patients Enrolled ......................................................................................60 
7.2. 
Study Population .........................................................................................................60 
7.2.1. 
Inclusion Criteria ........................................................................................................60 
7.2.2. 
Exclusion Criteria .......................................................................................................61 
7.3. 
Premature Withdrawal from the Study .......................................................................63 
7.4. 
Replacement of Patients .............................................................................................63 
8. 
STUDY TREATMENTS............................................................................................63 
8.1. 
Investigational and Reference Treatments ..................................................................63 
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8.2. 
Background Treatments ..............................................................................................64 
8.3. 
Rescue Treatment(s) ...................................................................................................64 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................64 
8.5. 
Management of Acute Reactions ................................................................................64 
8.5.1. 
Infusion-Related Reactions and Hypersensitivity Reactions ......................................64 
8.5.1.1. 
Interruption of the Intravenous Infusion .....................................................................64 
8.5.1.2. 
Termination of the Intravenous Infusion ....................................................................65 
8.6. 
Method of Treatment Assignment ..............................................................................65 
8.7. 
Blinding ......................................................................................................................66 
8.8. 
Emergency Unblinding ...............................................................................................67 
8.9. 
Treatment Logistics and Accountability .....................................................................68 
8.9.1. 
Packaging, Labeling, and Storage ..............................................................................68 
8.9.2. 
Supply and Disposition of Treatments .......................................................................68 
8.9.3. 
Treatment Accountability ...........................................................................................68 
8.9.4. 
Treatment Compliance ................................................................................................68 
8.10. 
Concomitant Medications ...........................................................................................68 
8.10.1. 
Prohibited and Permitted Medications ........................................................................69 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................69 
9.1. 
Schedule of Events .....................................................................................................69 
9.1.1. 
Phase 1 (Cohort 1 only) ..............................................................................................70 
9.1.1.1. 
Footnotes for Table 1 Schedule of Events (Phase 1) ..................................................72 
9.1.2. 
Phase 2 (Cohort 1A, Cohort 1, Cohort 2*, and Cohort 3*) and Phase 3 
(Cohort 1) ....................................................................................................................74 
9.1.2.1. 
Footnotes for Table 2 and Table 3 Schedule of Events (Phase 2 and Phase 3) ..........78 
9.1.3. 
Early Termination from the Study ..............................................................................79 
9.1.4. 
Unscheduled Visits .....................................................................................................80 
9.2. 
Study Procedures ........................................................................................................80 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................80 
9.2.1.1. 
Informed Consent .......................................................................................................80 
9.2.1.2. 
Diagnostic Test for SARS-CoV-2 ..............................................................................80 
9.2.1.3. 
Demographics .............................................................................................................80 
9.2.1.4. 
Medical History ..........................................................................................................80 
9.2.1.5. 
Weight and Height ......................................................................................................80 
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9.2.2. 
Treatment ....................................................................................................................80 
9.2.3. 
Safety Procedures .......................................................................................................81 
9.2.3.1. 
Vital Signs ..................................................................................................................81 
9.2.3.2. 
Adverse Event Monitoring .........................................................................................81 
9.2.3.3. 
Targeted Medication and Procedures Review ............................................................82 
9.2.3.4. 
Pregnancy Test and Reporting for Women of Childbearing Potential .......................82 
9.2.4. 
Laboratory Testing ......................................................................................................83 
9.2.5. 
Efficacy Procedures ....................................................................................................84 
9.2.5.1. 
Sample Collection for RT-qPCR Analysis .................................................................84 
9.2.5.2. 
Clinical and Oxygen Status ........................................................................................84 
9.2.6. 
Drug Concentration and Measurements .....................................................................85 
9.2.7. 
Immunogenicity Measurements and Samples ............................................................85 
9.2.8. 
Exploratory Pharmacodynamic/Biomarker Procedures .............................................85 
9.2.8.1. 
Virology ......................................................................................................................85 
9.2.8.2. 
Hematology for Complete Blood Count and Differential ..........................................86 
9.2.8.3. 
Serum and Plasma for Disease Biomarkers ................................................................86 
9.2.8.4. 
Serological Immunoassays for Anti-SARS-CoV-2 Antibodies .................................86 
9.2.8.5. 
Serum and Plasma for Research .................................................................................87 
9.2.8.6. 
Complement ................................................................................................................87 
9.2.8.7. 
Cytokines ....................................................................................................................87 
9.2.8.8. 
Serum and Plasma for Cardiac Biomarkers ................................................................87 
9.2.9. 
Long COVID Sub-Study (at Participating Sites) ........................................................87 
9.2.9.1. 
Patient-Reported Evaluation of Long COVID ...........................................................88 
9.2.9.2. 
Nasopharyngeal Swab Sample and Blood Sample Collections (Long COVID 
Assessment) ................................................................................................................90 
9.2.9.3. 
Monitoring for SARS-CoV-2 Reinfection ..................................................................91 
9.2.9.4. 
Recording New Medical Diagnoses or Conditions ....................................................91 
9.2.10. 
Pharmacogenomic Analysis (Optional) ......................................................................91 
10. 
SAFETY EVALUATION AND REPORTING .........................................................92 
10.1. 
Recording and Reporting Adverse Events ..................................................................92 
10.1.1. 
General Guidelines .....................................................................................................92 
10.1.2. 
Reporting Procedure ...................................................................................................93 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................94 
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10.1.4. 
Other Adverse Events of Special Interest That Do Not Require Expedited 
Reporting to Sponsor ..................................................................................................94 
10.2. 
Definitions ..................................................................................................................94 
10.2.1. 
Adverse Event .............................................................................................................94 
10.2.2. 
Serious Adverse Event ................................................................................................94 
10.2.3. 
Adverse Events of Special Interest .............................................................................95 
10.2.3.1. 
Infusion-Related Reactions and Hypersensitivity ......................................................95 
10.2.4. 
Severity .......................................................................................................................95 
10.2.5. 
Causality .....................................................................................................................96 
10.3. 
Safety Monitoring .......................................................................................................97 
10.4. 
Notifying Health Authorities, Institutional Review Board, Ethics Committee, 
and Investigators .........................................................................................................97 
11. 
STATISTICAL PLAN................................................................................................98 
11.1. 
Statistical Hypotheses .................................................................................................99 
11.1.1. 
Pooled Phase 3 (Cohort 1) and Phase 2 (Cohort 1A) .................................................99 
11.2. 
Justification of Sample Size......................................................................................100 
11.2.1. 
Phase 1 (Sentinel Safety Group; Cohort 1 only) ......................................................100 
11.2.2. 
Phase 2 (Cohort 1A, Cohort 1, Cohort 2*, and Cohort 3*) ......................................101 
11.2.3. 
Phase 3 (Cohort 1) ....................................................................................................102 
11.3. 
Analysis Sets .............................................................................................................103 
11.3.1. 
Efficacy Analysis Sets ..............................................................................................103 
11.3.2. 
Safety Analysis Set ...................................................................................................103 
11.3.3. 
Pharmacokinetics Analysis Sets ...............................................................................103 
11.3.4. 
Immunogenicity Analysis Sets .................................................................................104 
11.4. 
Statistical Methods ....................................................................................................104 
11.4.1. 
Demography and Baseline Characteristics ...............................................................104 
11.4.2. 
Medical History ........................................................................................................104 
11.4.3. 
Prior / Concomitant Medications or Procedures .......................................................104 
11.4.4. 
Patient Disposition ....................................................................................................105 
11.4.5. 
Extent of Study Treatment Exposure ........................................................................105 
11.4.6. 
Efficacy Analyses .....................................................................................................105 
11.4.6.1. 
Primary Efficacy Analyses .......................................................................................106 
11.4.6.2. 
Analysis of Primary Virologic Efficacy Endpoint ....................................................106 
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11.4.6.3. 
Analysis of Primary Clinical Efficacy Endpoints .....................................................106 
11.4.7. 
Descriptive Analysis of Secondary Efficacy Endpoints ...........................................107 
11.4.8. 
Exploratory Analysis ................................................................................................107 
11.4.9. 
Control of Multiplicity ..............................................................................................107 
11.4.10. 
Safety Analysis .........................................................................................................108 
11.4.10.1. Adverse Events .........................................................................................................108 
11.4.10.2. Other Safety ..............................................................................................................109 
11.4.10.3. Treatment Exposure ..................................................................................................109 
11.4.10.4. Treatment Compliance ..............................................................................................109 
11.4.11. 
Pharmacokinetics ......................................................................................................109 
11.4.11.1. Analysis of Drug Concentration Data .......................................................................109 
11.4.11.2. Pharmacokinetics and Pharmacokinetics/Pharmacodynamics Analyses ..................110 
11.4.12. 
Analysis of Immunogenicity Data ............................................................................110 
11.4.12.1. Analysis of Neutralizing Antibody Data ..................................................................111 
11.4.13. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ............................111 
11.5. 
Interim Analysis ........................................................................................................111 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .......111 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................111 
12.1. 
Data Management and Electronic Systems ..............................................................112 
12.1.1. 
Data Management .....................................................................................................112 
12.1.2. 
Electronic Systems ....................................................................................................112 
12.2. 
Study Monitoring ......................................................................................................112 
12.2.1. 
Monitoring of Study Sites .........................................................................................112 
12.2.2. 
Source Document Requirements ..............................................................................112 
12.2.3. 
Case Report Form Requirements ..............................................................................113 
12.3. 
Audits and Inspections ..............................................................................................113 
12.4. 
Study Documentation ...............................................................................................114 
12.4.1. 
Certification of Accuracy of Data .............................................................................114 
12.4.2. 
Retention of Records ................................................................................................114 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................114 
13.1. 
Good Clinical Practice Statement .............................................................................114 
13.2. 
Informed Consent .....................................................................................................114 
13.3. 
Patients Confidentiality and Data Protection ............................................................115 
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13.4. 
Institutional Review Board/Ethics Committee .........................................................115 
13.5. 
Clinical Study Data Transparency ............................................................................116 
14. 
PROTOCOL AMENDMENTS ................................................................................116 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................116 
15.1. 
Premature Termination of the Study .........................................................................116 
15.2. 
Closeout of a Site ......................................................................................................116 
16. 
CONFIDENTIALITY ..............................................................................................117 
17. 
FINANCING AND INSURANCE ...........................................................................117 
18. 
PUBLICATION POLICY ........................................................................................117 
19. 
REFERENCES .........................................................................................................118 
20. 
INVESTIGATOR’S AGREEMENT ........................................................................124 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................125 
 
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LIST OF TABLES 
Table 1: 
Schedule of Events for Phase 1 ..................................................................................70 
Table 2: 
Schedule of Events for Phase 2 and Phase 3 ..............................................................75 
Table 3: 
Schedule of Events for the Long COVID Sub-Study at Participating Sites ...............77 
Table 4: 
Symptoms Evaluated in the Symptom Evolution of Long COVID-19 (SE-
LC19) Instrument ........................................................................................................89 
Table 5: 
NCI-CTCAE Severity Grading System for Adverse Events (v5.0) ...........................96 
Table 6: 
Phase 3 Statistical Hypotheses....................................................................................99 
Table 7: 
Statistical Power for Death or Mechanical Ventilation Endpoint: Phase 1/2 
Cohort 1 ....................................................................................................................102 
Table 8: 
Hierarchical Testing Order .......................................................................................107 
Table 9: 
High Altitude Equivalents for Sea-Level Oxygenation Measurements ...................126 
 
LIST OF FIGURES 
Figure 1: 
Phase 1 Sentinel Safety Group ...................................................................................40 
Figure 2: 
Study Flow Diagram, Phase 1 ....................................................................................56 
Figure 3: 
Study Flow Diagram, Phase 2 and Phase 3 ................................................................57 
LIST OF APPENDICES 
Appendix A. Oxygenation Equivalence for Eligibility .............................................................126 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Master Protocol Assessing the Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 
Monoclonal Antibodies for the Treatment of Hospitalized Patients with COVID-19 
Site 
Locations 
The study will be conducted in approximately 100 sites in the United States (US) and other countries. 
The long COVID sub-study will be conducted in approximately 5 sites in the US. 
Principal 
Investigator Eleftherios Mylonakis, MD, PhD 
Objectives 
 
Primary 
Pooled Phase 3 (Cohort 1) and Phase 2 (Cohort 1A) 
The primary objectives are:  
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo in 
reducing viral load of SARS-CoV-2  
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, as 
measured by death or mechanical ventilation 
Phase 1/2 (Cohort 1)  
The primary objective is to exclude futility of REGN10933+REGN10987 compared to placebo, as 
measured by death or mechanical ventilation 
The safety and tolerability of REGN10933+REGN10987 compared to placebo will also be evaluated. 
Phase 2 (Cohort 1A) 
There is no primary objective for phase 2 cohort 1A as enrollment was prematurely terminated. 
Phase 2 (Cohort 2 and Cohort 3) 
There is no primary objective for cohort 2 and cohort 3 in phase 2 as enrollment was put on hold. All 
safety and efficacy analyses are exploratory. 
Phase 3 (Cohort 1) 
There is no primary objective for phase 3 cohort 1 as enrollment was prematurely terminated. 
Secondary Pooled Phase 3 (Cohort 1) and Phase 2 (Cohort 1A) 
The secondary objectives are: 
• To evaluate additional indicators of clinical efficacy of REGN10933+REGN10987 compared to 
placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo 
Phase 1/2 (Cohort 1)  
The key secondary objective is to evaluate the clinical efficacy of REGN10933+REGN10987 
compared to placebo, as measured by death or mechanical ventilation  
The other secondary objectives are: 
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo in 
reducing viral load of SARS-CoV-2  
• To evaluate (descriptively) additional indicators of clinical efficacy of 
REGN10933+REGN10987 compared to placebo 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over time 
• To assess the immunogenicity of REGN10933 and REGN10987 
 
 
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Phase 2 (Cohort 1A)  
The secondary objectives are: 
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo in 
reducing viral load of SARS-CoV-2  
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, as 
measured by death or mechanical ventilation 
• To evaluate additional indicators of clinical efficacy of REGN10933+REGN10987 compared to 
placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over time 
• To assess the immunogenicity of REGN10933 and REGN10987 
Phase 2 (Cohort 2 and Cohort 3) 
The secondary objectives are: 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over time 
• To assess the immunogenicity of REGN10933 and REGN10987 
Phase 3 (Cohort 1) 
The secondary objectives are:  
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo in 
reducing viral load of SARS-CoV-2  
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, as 
measured by death or mechanical ventilation 
• To evaluate additional indicators of clinical efficacy of REGN10933+REGN10987 compared to 
placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo 
Phase 1/2/3 (Cohort 1)  
The secondary objectives are: 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over time 
• To assess the immunogenicity of REGN10933 and REGN10987 
Study 
Design 
This study is an adaptive, phase 1/2/3, randomized, double-blinded, placebo-controlled master 
protocol to evaluate the futility or efficacy, safety, and tolerability of REGN10933+REGN10987 in 
hospitalized adult patients with COVID-19.  
Study 
Duration 
The phase 1 portion of the study will last up to 170 days. 
The phase 2 portion of the study will last up to 58 days. 
The phase 3 portion of the study will last up to 58 days.  
For patients who join the long COVID sub-study, the study will last up to 181 days. 
End of 
Study 
Definition 
The end of study is defined as the date when the last living patient completes the last study visit, 
withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be contacted by 
the investigator).  
Population 
 
Target 
Population 
The study population will consist of hospitalized adult patients with COVID-19, enrolled in 1 of 4 
cohorts* based on disease severity at randomization: 
• Cohort 1A: With COVID-19 symptoms but not requiring supplemental oxygen  
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• Cohort 1: O2 saturation >93% on low-flow oxygen via nasal cannula, simple face mask, or other 
similar device 
• Cohort 2*: On high-intensity oxygen therapy† but not on mechanical ventilation 
†High-intensity oxygen therapy is defined as the use of non-rebreather mask with an oxygen flow 
rate of at least 10 L/min; use of a high flow device with at least 50% FiO2, or use of non-invasive 
ventilation to treat hypoxemia. 
• Cohort 3*: On mechanical ventilation 
* Per IDMC recommendation first received on 30 October 2020, and reiterated through 19 February 
2021, patient enrollment in cohort 2 and cohort 3 has been placed on hold. 
Sample 
Size 
Overall, approximately 2252 patients were randomized in this study:  
Phase 1 
• Cohort 1: 60 patients 
Phase 2  
• Cohort 1A: 609 patients 
• Cohort 1: 629 patients 
• Cohort 2: 164 patients 
• Cohort 3: 35 patients 
Prematurely terminated phase 3  
• Cohort 1 (ie, patients randomized after 01 December 2020): 755 patients 
Treatments Phase 1, Phase 2, and Phase 3 
• Co-administered REGN10933+REGN10987 combination therapy 2.4 g (1.2 g of REGN10933 
plus 1.2 g of REGN10987) intravenously (IV) single dose 
• Co-administered REGN10933+REGN10987 combination therapy 8.0 g (4.0 g of REGN10933 
plus 4.0 g of REGN10987) IV single dose 
• Placebo IV single dose 
Endpoints 
 
Primary 
Pooled Phase 3 (Cohort 1) and Phase 2 (Cohort 1A) 
Virologic 
The primary virologic endpoint is time-weighted average change from baseline viral load in NP sample 
through day 7, as measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) 
in nasopharyngeal (NP) swab samples.  
Note: Time-weighted average of change from baseline in viral load from day 1 to day 7 will be 
calculated for each patient using the trapezoidal rule as the area under the curve for change from 
baseline at each time point divided by the time interval for the observation period.  
Clinical 
The primary clinical endpoint is the proportion of patients who died or went on mechanical ventilation 
from day 6 through day 29 and from day 1 through day 29. 
Phase 1/2 (Cohort 1) 
Futility 
The primary endpoint is death or mechanical ventilation. 
Safety and Tolerability 
Safety and tolerability endpoints are as follows: 
• Proportion of patients with treatment-emergent SAEs through end of study  
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4  
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• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29  
Phase 2 (Cohort 2 and Cohort 3) 
There are no primary endpoints for cohort 2 and cohort 3 in phase 2.  
Secondary Phase 1/2 (Cohort 1)  
Clinical Efficacy 
The key secondary endpoint is death or mechanical ventilation.  
Other secondary endpoints include: 
Virologic Efficacy 
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 1 to day 7, 
as measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in 
nasopharyngeal (NP) swab samples  
Note: Time-weighted average of change from baseline in viral load from day 1 to day 7 will be 
calculated for each patient using the trapezoidal rule as the area under the curve for change 
from baseline at each time point divided by the time interval for the observation period.  
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 1 to day 
11, as measured by RT-qPCR in NP swab samples 
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 1 to each 
post-baseline timepoint until day 29, as measured by RT-qPCR in NP swab samples  
• Change from baseline in viral load at each post-baseline timepoint through day 29, as measured 
by RT-qPCR in NP swab samples 
• Time to sustained negative RT-qPCR (negative RT-qPCR with no subsequent positive)  
Clinical Efficacy 
• All-cause death 
• Mechanical ventilation  
• Proportion of patients who died or went on mechanical ventilation by day 29 
• Proportion of patients who died by day 29 
• Proportion of patients who went on mechanical ventilation by day 29 
• Time to discharge 
PK/ADA 
• Concentrations of REGN10987 and REGN10933 in serum and corresponding PK parameters 
• Immunogenicity, as measured by ADA and (in phase 2 and phase 3 only) NAb to REGN10933 
and REGN10987 
Phase 3 (Cohort 1) and Phase 2 (Cohort 1A), Separately 
The secondary endpoints include: 
Virologic Efficacy 
Endpoint 
Timepoint 
Population 
Time-weighted average change from baseline 
viral load in NP sample 
Through day 7 
mFAS 
Time-weighted average change from baseline 
viral load in NP sample 
Through day 7 
Baseline Viral load categories ( 
>105, >106 copies/mL) mFAS 
Time-weighted average change from baseline 
viral load in NP sample  
Through day 11 
Seronegative mFAS 
Time-weighted average change from baseline 
viral load in NP sample 
Through day 11 
mFAS 
Time-weighted average change from baseline 
viral load in NP sample 
Through day 11 
Baseline Viral load categories 
(>105, >106 copies/mL) mFAS 
Time-weighted average change from 
baseline, change from baseline, and percent 
change from baseline in viral load in NP 
sample 
Through each post-baseline 
timepoint until day 29 
1. Seronegative mFAS,  
2. Baseline Viral load categories ( 
>105, >106 copies/mL) mFAS,  
3. mFAS 
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Clinical Efficacy 
• Proportion of patients who went on mechanical ventilation by day 29 (as applicable) 
• Proportion of patients who died from day 6 to day 29 and from day 1 to day 29 
• Proportion of patients who were discharged by day 29 
• Proportion of patients who died or were readmitted to hospital over time 
• Note: Readmission to hospital will be based on investigator report. 
• Cumulative incidence of death over time (ie, overall survival) 
• Cumulative incidence of mechanical ventilation over time (as applicable) 
• Cumulative incidence of death or mechanical ventilation over time (as applicable) 
• Time to discharge 
Safety and Tolerability 
• Proportion of patients with treatment-emergent SAEs through end of study  
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4  
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29  
PK/ADA 
• Concentrations of REGN10987 and REGN10933 in serum and corresponding PK parameters 
• Immunogenicity, as measured by ADAs and NAbs to REGN10933 and REGN10987 
Phase 2 (Cohort 2 and Cohort 3) 
PK/ADA 
• Concentrations of REGN10987 and REGN10933 in serum and corresponding PK parameters 
• Immunogenicity, as measured by ADAs and NAbs to REGN10933 and REGN10987 
Procedures 
and 
Assessments 
Procedures and assessments will include the following: 
Efficacy 
• NP swabs for SARS-CoV-2 RT-qPCR 
• Clinical and oxygen status 
Safety and Tolerability 
• Record treatment-emergent SAEs, treatment-emergent AESIs 
• Blood collection for clinical laboratory evaluations 
• Vital signs 
• Procedure-related AEs (long COVID sub-study only) 
Evaluation of Long COVID (Long COVID Sub-Study Only) 
• Questionnaires to be administered by interviewers 
Statistical 
Plan 
 
Justification 
of Sample 
Size 
Phase 3: Initial Estimation 
The sample size for phase 3 was initially estimated to be 1350 patients (150 patients per arm across 3 
treatment arms in 3 cohorts). Based on the new endpoint of death or mechanical ventilation, the sample 
size for phase 3 has been re-estimated to be 2505 patients in each of cohort 1 and cohort 1A.  
The study was planned to continue enrolling additional patients seamlessly into the phase 3 portion of 
the study, until an adaptation decision on the dose(s), primary endpoint and final sample size for phase 
3 is made based on the phase 2 data analysis. A total sample size of approximately 5010 patients was 
estimated for the phase 3 portion of the study (2505 per cohort, 835 per arm across 3 treatment arms 
in 2 cohorts). For cohort 1, a total of 241 events (estimated sample size of 2505 patients [835 patients 
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per arm]) would have been needed to provide 90% power at α=0.05 (2-sided) using a log-rank test to 
detect a risk reduction of 35.8% (ie, HR=0.642) in the cumulative incidence of patients who died or 
went on mechanical ventilation, assuming a 12.5% cumulative incidence rate in the placebo group by 
day 29.  
Phase 3: Final Sample Size 
Finalization of the sample size and patient population for phase 3 was planned to be subject to change 
and would be determined after review of phase 2 data. However, enrollment of patients into the study 
was terminated prematurely by the Sponsor on 09 April 2021 because of extremely slow enrollment in 
the months preceding the decision. The sample size of phase 3 was not re-estimated.  
Approximately 2252 patients were randomized in the study, which includes 60 patients in phase 1 
cohort 1, 629 in phase 2 cohort 1, 755 in planned phase 3 cohort 1, 609 in phase 2 cohort 1A, 164 in 
phase 2 cohort 2 and 35 in phase 2 cohort 3.  
Assuming the proportion of patients who died or went on mechanical ventilation from day 1 to day 29 
in placebo group is 13.1% which is same as the blinded proportion in the Seronegative mFAS patients 
of the pooled phase 3 cohort 1 and phase 2 cohort 1A and alpha is 0.05 2-sided, the minimal significant 
difference in relative risk reduction between the REGN10933+REGN10987 2.4g and 8.0g combined 
dose group and placebo group is 29.0%, 41.2%, and 36.6% for overall mFAS, Seronegative mFAS, 
and High Viral Load mFAS patients, respectively.  
Primary 
Efficacy 
Analysis 
The efficacy analyses will be performed for the following patients on all efficacy endpoints, separately. 
The comparisons in all efficacy endpoints will be performed between the REGN10933+REGN10987 
2.4g and 8.0g combined dose group and placebo group as well as between each treatment group and 
placebo group.  
• Pooled phase 3 cohort 1 and phase 2 cohort 1A patients 
• Phase 3 cohort 1 patients (ie, patients randomized after 01 December 2020 in cohort 1) 
• Phase 2 cohort 1A patients 
Analysis of Primary Virologic Efficacy Endpoint 
The primary analysis on the comparison between the REGN10933+REGN10987 2.4g and 8.0g 
combined dose group and placebo with respect to the virologic endpoint of time-weighted average 
daily change from baseline in viral load (log10 copies/mL) from day 1 to day 7 and other post-baseline 
visit timepoint will be performed in the Seronegative mFAS in the pooled phase 3 cohort 1 and phase 
2 cohort 1A patients. The estimand for the analysis is the difference in means between the 
REGN10933+REGN10987 2.4g and 8.0g combined dose group and placebo in the pooled phase 3 
cohort 1 and phase 2 cohort 1A patients. Data collected after use of convalescent plasma therapy or 
other anti-spike monoclonals will be excluded from efficacy analysis. All other available data will be 
used in the analysis regardless of intercurrent events such as rescue medication or discontinuation, ie, 
treatment policy approach.  
The analysis will be based on the observed data with no imputation for missing data except as defined 
in the SAP for viral load values that are below lower limit of detection (<LLOD), below lower limit of 
quantification (<LLOQ) or above upper limit of quantification (>ULOQ) of the assay.  
The variable will be analyzed using the Analysis of Covariance (ANCOVA) model with treatment 
group and the type of background standard-of-care as fixed effects, and baseline viral load and 
treatment by baseline interaction as covariates.  
The least squares means estimates for time-weighted average daily change from baseline in viral load 
for each treatment group, as well as the difference between the REGN10933+REGN10987 2.4g and 
8.0g combined doses and placebo as well as between each individual dose treatment group and placebo, 
will be provided along with the corresponding two-sided p-value, standard error, and associated 95% 
confidence interval.  
Analysis of Primary Clinical Efficacy Endpoints 
The primary efficacy analysis will be the comparison between the REGN10933+REGN10987 2.4g 
and 8.0g combined dose group and placebo in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
patients. The primary clinical endpoint will be analyzed using the landmark analysis approach for day 
6 through day 29, as well as analyzed for day 1 through day 29 in the order specified in the statistical 
hierarchy.  
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The proportion of patients who died or went on mechanical ventilation will be analyzed using either 
the exact method for binomial distribution or asymptotic normal approximation method. If the number 
of events is small (eg, np ≤ 5 or n(1-p) ≤ 5 in any treatment group, where n is the number of patients 
in the treatment group and p is the proportion of events), then the Fisher’s exact test will be applied. 
Otherwise, stratified Cochran-Mantel Haenszel (CMH) test, stratified by the type of background 
standard-of-care (antiviral therapies and non-antiviral therapies), will be applied. Relative risk and 
relative risk reduction and corresponding 95% confidence intervals compared to placebo group will be 
estimated by Farrington-Manning method. Missing data will be considered as non-events. 
The analysis will be performed for the High Viral Load mFAS, the Seronegative mFAS, and the overall 
mFAS. 
Exploratory 
Long 
COVID 
Analysis 
Exploratory analyses related to long COVID will be summarized descriptively for all patients 
enrolled in the sub-study and may be reported separately from the CSR. Additional details will be 
provided in a separate long COVID statistical analysis plan (SAP) from the study SAP. 
Safety 
Analysis 
The analysis of safety data will be performed for cohort 1 in combined phases 1, 2 and 3, and phase 2 
cohorts 1A, 2 and 3, separately in the FAS population. 
In this study, only targeted treatment-emergent adverse events will be recorded: 
• 
All phases: Treatment-emergent AESIs (grade ≥2 hypersensitivity and grade ≥2 IRRs) 
• 
All phases, including long COVID sub-study: Treatment-emergent SAEs 
• 
Phase 1 only: TEAEs (grade 3 or grade 4 only) 
• 
Long COVID sub-study only: positive SARS-CoV-2 local test result, from the day of 
consent to sub-study until day 180 
The safety analysis will be based on the reported SAEs and AESIs and other safety information 
(clinical laboratory evaluations and vital signs).  
The summary of safety results will be presented for each treatment group. 
Subgroup analyses will be performed on efficacy endpoints and safety endpoints, as needed. 
 
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1. 
INTRODUCTION 
1.1. 
Emergence of SARS-CoV-2 and COVID-19 
Coronaviruses are a family of enveloped, single-stranded RNA viruses. In recent decades, 2 highly 
pathogenic strains of coronavirus were identified in humans: severe acute respiratory syndrome 
coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). 
These viruses were found to cause severe, and sometimes fatal, respiratory illness (Cui, 2019) 
(Fehr, 2015). 
In December 2019, pneumonia of unknown cause was identified in clusters of patients in Wuhan 
City, China. A novel enveloped RNA betacoronavirus – severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) – was identified in these patients, and the disease caused by 
SARS-CoV-2 infection was later designated coronavirus disease 2019 (COVID-19) by the World 
Health Organization (WHO, 2020) (Zhu, 2020). Millions of SARS-CoV-2 infections have been 
confirmed worldwide, and the rapidly-spreading, worldwide outbreak has prompted the WHO to 
declare COVID-19 a pandemic and public health emergency of international concern. 
1.2. 
Clinical Outcomes in Hospitalized Patients with COVID-19 
Patients with COVID-19 are at risk for developing a variety of respiratory conditions, ranging 
from relatively mild respiratory symptoms to severe respiratory failure and death (Wu, 2020b). 
Among hospitalized patients, intensive care and/or oxygen supplementation (eg, mechanical 
ventilation) is often required, and reported fatality rates are high. In a report from the Chinese 
Center for Disease Control and Prevention that included 44,500 confirmed infections, nearly 20% 
of patients presented with advanced respiratory symptoms (14% with dyspnea, hypoxia, or >50% 
lung involvement on imaging; 5% with respiratory failure, shock, or multiorgan failure) (Wu, 
2020b). Another analysis of patients with COVID-19 in China found that, among 1,099 
hospitalized patients, 5% had been admitted to an intensive care unit (ICU), 2.3% required invasive 
mechanical ventilation, and 1.4% died. Among patients with advanced disease on admission 
(defined as pneumonia, hypoxemia, and tachypnea), these negative outcomes rose to 19%, 14.5%, 
and 8.1%, respectively (Guan, 2020). A report of 2634 hospitalized patients with COVID-19 in 
the United States identified similar clinical outcomes: 14.2% were admitted to an ICU, 12.2% 
required invasive mechanical ventilation, and 21% died (Richardson, 2020). Other reports have 
found that approximately 20% to 30% of hospitalized patients with COVID-19 and pneumonia 
require intensive care for respiratory support (Chen, 2020) (Huang, 2020).  
1.3. 
Long-Term Outcomes in Patients with COVID-19  
Although much has been learned about acute SARS-CoV-2 infection and the resulting COVID-19 
disease course, the long-term sequelae of SARS-CoV-2 infection and COVID-19 remain poorly 
understood. Long COVID is characterized by persistent symptoms, occurring beyond 4 weeks 
from the initial SARS-CoV-2 infection, that are not explained by an alternative diagnosis 
(Nalbandian, 2021) (CDC, 2021) (NICE, 2021). Initial assessments of long COVID indicate that 
approximately 10% to 35% of patients who recover from acute SARS-CoV-2 infection may 
experience persistent symptoms suggestive of long COVID (Tenforde, 2020) (Greenhalgh, 2020). 
To date, it is unclear whether and how the treatment of acute SARS-CoV-2 infection may impact 
the subsequent development of long COVID symptomatology. 
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1.4. 
The Role of Spike (S) Protein in SARS-CoV-2 Viral Pathogenesis 
Coronaviruses consist of an RNA genome packaged in nucleocapsid (N) protein surrounded by an 
outer envelope. The envelope is comprised of membrane (M) protein and envelope (E) protein, 
which are involved in virus assembly, and spike (S) protein, which mediates entry into host cells. 
S proteins form large trimeric projections, providing the hallmark crown-like appearance of 
coronaviruses. S protein trimers bind to a host receptor and, after priming by cellular proteases, 
mediate host–virus membrane fusion (Li, 2016). S protein appears to be central to viral infectivity 
by SARS-CoV-2. SARS-CoV-2 S protein binds the host receptor angiotensin-converting enzyme 
2 (ACE2) with high affinity, and in cell assays and animal models can utilize ACE2 as a functional 
receptor for host cell entry (Ou, 2020) (Hoffmann, 2020) (Walls, 2020). 
Blockade of host cell entry through the use of neutralizing antibodies against S protein is a viable 
mechanistic strategy shown to reduce viral infectivity of SARS-CoV and MERS-CoV (Jiang, 
2020). In light of the likely pivotal role of S protein in the pathogenesis of SARS-CoV-2, a number 
of efforts are underway to develop antibodies and vaccines that target this protein.  
1.5. 
REGN10933+REGN10987: Human Monoclonal Antibodies Against 
SARS-CoV-2 S Protein 
Regeneron Pharmaceuticals, Inc. (Regeneron) has developed monoclonal antibodies (mAbs) 
directed against the RBD of the SARS-CoV-2 S protein. Casirivimab (REGN10933) and 
imdevimab (REGN10987) are human, IgG1 mAbs that bind simultaneously to the RBD and block 
interaction with ACE2. As co-administered combination therapy, casirivimab and imdevimab, also 
referred to by the proprietary name conditionally accepted by the FDA (REGEN-COV™) and by 
the EMA (RONPAPREVE®), is being evaluated for the treatment and prevention of SARS-CoV-
2 infection and retains neutralization potency against circulating SARS-CoV-2 variants of concern 
(UK B.1.1.7 [alpha], South Africa B.1.351 [beta], California B.1.429 [epsilon], India B.1.617.2 
[delta], and Brazil P.1 [gamma]) and protects against the selection of resistant variants in vitro 
(Copin, 2021) (REGEN-COV™ (casirivimab with imdevimab) [HCP Fact Sheet], 2021). 
In phase 3 clinical trials, the combination of casirivimab and imdevimab was shown to be effective 
and well-tolerated in the treatment of outpatient and hospitalized adults with COVID-19, and in 
the prevention of SARS-CoV-2 infection in adults and adolescents (Horby, 2021) (O’Brien, 
2021a) (O’Brien, 2021b) (Weinreich, 2021b).  
1.6. 
A Randomized, Placebo-Controlled Study of Anti-SARS-CoV-2 S Protein 
Monoclonal Antibodies in Hospitalized Patients with COVID-19 
Several therapeutic and preventative agents are under investigation for the treatment or prevention 
of COVID-19. While a number of these agents have received approvals or conditional 
authorizations (FDA, 2021) (EMA, 2021), there remains a significant unmet medical need for 
COVID-19 treatments in the hospitalized setting. This study is an adaptive phase 1/2/3, 
randomized, double-blinded, placebo-controlled master protocol to evaluate the futility or efficacy 
and 
safety 
of 
co-administered 
REGN10933+REGN10987 
combination 
therapy 
(“REGN10933+REGN10987”) in hospitalized adult patients with COVID-19.  
Note: On 09 April 2021, the Sponsor made a business decision to terminate patient enrollment in 
this study due to low recruitment rates. Patients who had been enrolled will continue to be followed 
up according to the Schedule of Events (Section 9.1). In addition, enrolled patients at select sites 
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may be reconsented to protocol amendment 8 US and followed in an exploratory sub-study for an 
extended period to monitor for symptoms of long COVID. 
For more information regarding the rationale for the study design, see Section 3.2.1. Additional 
background information on the study drugs and the overall development program can be found in 
the Investigator’s Brochure(s). 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
Pooled Phase 3 (Cohort 1) and Phase 2 (Cohort 1A) 
The primary objectives are:  
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo 
in reducing viral load of SARS-CoV-2  
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, 
as measured by death or mechanical ventilation 
Phase 1/2 (Cohort 1)  
The primary objective is to exclude futility of REGN10933+REGN10987 compared to placebo, 
as measured by death or mechanical ventilation 
The safety and tolerability of REGN10933+REGN10987 compared to placebo will also be 
evaluated. 
Phase 2 (Cohort 1A) 
There is no primary objective for phase 2 cohort 1A as enrollment was prematurely terminated. 
Phase 2 (Cohort 2 and Cohort 3) 
There is no primary objective for cohort 2 and cohort 3 in phase 2 as enrollment was put on hold. 
All safety and efficacy analyses are exploratory. 
Phase 3 (Cohort 1) 
There is no primary objective for phase 3 cohort 1 as enrollment was prematurely terminated. 
2.2. 
Secondary Objectives 
Pooled Phase 3 (Cohort 1) and Phase 2 (Cohort 1A) 
The secondary objectives are: 
• To evaluate additional indicators of clinical efficacy of REGN10933+REGN10987 
compared to placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
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Phase 1/2 (Cohort 1)  
The key secondary objective is to evaluate the clinical efficacy of REGN10933+REGN10987 
compared to placebo, as measured by death or mechanical ventilation  
The other secondary objectives are: 
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo 
in reducing viral load of SARS-CoV-2  
• To 
evaluate 
(descriptively) 
additional 
indicators 
of 
clinical 
efficacy 
of 
REGN10933+REGN10987 compared to placebo 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over 
time 
• To assess the immunogenicity of REGN10933 and REGN10987 
Phase 2 (Cohort 1A)  
The secondary objectives are: 
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo 
in reducing viral load of SARS-CoV-2  
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, 
as measured by death or mechanical ventilation 
• To evaluate additional indicators of clinical efficacy of REGN10933+REGN10987 
compared to placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over 
time 
• To assess the immunogenicity of REGN10933 and REGN10987 
Phase 2 (Cohort 2 and Cohort 3) 
The secondary objectives are: 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over 
time 
• To assess the immunogenicity of REGN10933 and REGN10987 
Phase 3 (Cohort 1) 
The secondary objectives are:  
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo 
in reducing viral load of SARS-CoV-2  
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, 
as measured by death or mechanical ventilation 
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• To evaluate additional indicators of clinical efficacy of REGN10933+REGN10987 
compared to placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
Phase 1/2/3 (Cohort 1)  
The secondary objectives are: 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over 
time 
• To assess the immunogenicity of REGN10933 and REGN10987 
2.3. 
Exploratory Objectives 
The exploratory objectives of all phases of the study are: 
• To assess viral genetic variation in patients with a positive SARS-CoV-2 RT-qPCR 
• To explore the potential association of baseline humoral immune response to 
SARS-CoV-2 on response to REGN10933+REGN10987  
• To evaluate the effects of REGN10933+REGN10987 compared to placebo on 
generation of a humoral immune response to SARS-CoV-2 (as measured by anti-
SARS-CoV-2 N protein) 
• To explore the effects of REGN10933+REGN10987 on measures of SARS-CoV-2 
infectivity as assessed in experimental laboratory assays 
• To explore biomarkers predictive of REGN10933+REGN10987 and safety, efficacy, 
and/or disease progression and COVID-19 clinical outcomes 
• To 
understand 
the 
underlying 
mechanisms 
of 
action 
and 
biology 
of 
REGN10933+REGN10987, SARS-CoV-2, and COVID-19 
• To explore relationships between REGN10933+REGN10987 exposure and selected 
efficacy endpoints, safety endpoints, and/or biomarkers 
For phase 2 (cohort 2 and cohort 3), the exploratory objectives include: 
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo, 
as measured by death or mechanical ventilation (as applicable based on the cohort) 
• To evaluate additional indicators of clinical efficacy of REGN10933+REGN10987 
compared to placebo 
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo 
in reducing viral load of SARS-CoV-2  
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
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For phase 2 cohort 1a and phase 3 cohort 1, an additional exploratory objective is to evaluate the 
impact of REGN10933+REGN10987 treatment, given during acute SARS-CoV-2 infection, on 
long COVID symptoms (long COVID sub-study) 
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
Treatment of hospitalized patients with COVID-19 with REGN10933+REGN10987 will improve 
clinical outcomes, be tolerated, and reduce viral load. 
Information concerning statistical hypotheses can be found in Section 11.1. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This randomized, double-blinded, placebo-controlled, adaptive phase 1/2/3 master protocol will 
assess the safety, tolerability, and efficacy of REGN10933+REGN10987 in hospitalized patients 
with COVID-19. The multicenter conduct of this study will enable generalizable evidence of the 
safety, tolerability, and efficacy of these investigational mAbs for COVID-19.  
3.2.1.1. 
Phase 1 Sentinel Safety Group  
This master protocol will include a first-in-human (FIH) phase 1 study to evaluate safety and 
tolerability. Driven by the medical urgency of the COVID-19 pandemic, the process described 
below is designed to maximize efficient enrollment of eligible patients while optimizing safety of 
FIH exposure with limited preclinical data (see Section 3.3). 
Phase 1 will include a sentinel safety group, where the initial safety data up to day 3 will be 
reviewed by an independent data monitoring committee (IDMC).  
Figure 1: 
Phase 1 Sentinel Safety Group 
 
Patients in this sentinel safety group can be derived from either of 2 concurrent FIH studies, where 
the safety and tolerability of REGN10933+REGN10987 will be evaluated: 
• R10933-10987-COV-2066, in hospitalized adult patients with COVID-19 
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• R10933-10987-COV-2067, in adult outpatients with COVID-19  
For IDMC review, patients will be pooled together from the phase 1 portions of either of the 
2 studies. Once safety data have been collected on day 3 for approximately 30 patients (from one 
or both of the studies combined), the IDMC will review the data.  
Note that phase 1 enrollment will pause during the IDMC review.  
Initiation of phase 2 enrollment is contingent upon IDMC review of phase 1 data from the sentinel 
safety group. Study stopping criteria are outlined in Section 6.1.4.2.  
After IDMC reviews and provides a positive recommendation for the phase sentinel safety group, 
enrollment of studies assessing REGN10933+REGN10987 (including REGN10933+REGN10987 
treatment arms in phase 2 of this study and R10933-10987-COV-2067) may begin. 
Once phase 2 of this study is active, phase 1 will continue to enroll to completion. However, 
phase 2 enrollment does not require the completion of phase 1 enrollment. 
Patient Population in the Phase 1 Sentinel Safety Group 
In this study, only patients from cohort 1 will be included in the sentinel safety group. Patients 
from cohort 2 and cohort 3 will not be included. Due to the advanced nature of their illness and 
confounding adverse events related to underlying COVID-19, assessing the FIH safety of the anti-
SARS-CoV-2 S protein mAbs will be challenging in cohort 2 and cohort 3 patients.  
Review of Sentinel Safety Group, Part A (Information Added to Protocol in Amendment 5) 
A 
blinded 
Sponsor 
analysis 
of 
the 
sentinel 
safety 
group 
data 
showed 
that 
REGN10933+REGN10987 was well tolerated in hospitalized or ambulatory patients with 
COVID-19, with no hypersensitivity reactions or infusion-related reactions reported. Vital signs 
and laboratory assessments did not identify any safety signals. IDMC review recommended to 
continue enrollment in the studies after unblinded data review. For more details, refer to the 
Investigator’s Brochure. 
3.2.1.2. 
Adaptive Master Protocol Design 
The study utilizes an adaptive master protocol design. The adaptive design has been selected to 
maximize the efficiency of identifying early signs of efficacy, increase the efficiency of studying 
multiple therapeutic combinations, and avoid the use of ineffective dose levels in patients with 
COVID-19.  
Due to the novel nature of the COVID-19 pandemic, efficacy endpoints are not well established, 
and the standard-of-care is expected to evolve over time. The adaptive design of this study allows 
for the assessment of virologic and clinical efficacy endpoints in phase 2, which are then 
seamlessly confirmed in the phase 3 portion of the study, as well as evaluating the benefit risk of 
the different treatment arms.  
This master protocol will allow for treatment arm(s) to be dropped if there is a clinically 
meaningful imbalance between treatment arms in the incidence of SAEs or the incidence of AESIs, 
or if there is a meaningful imbalance between treatment arms regarding efficacy endpoints. 
The design will allow for the addition of new treatment arms with other anti-SARS-CoV-2 S 
protein mAbs as they become available for clinical testing (umbrella design), refinement of disease 
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characteristics of eligible study populations (basket design), as well as other multiple adaptations, 
including dropping of a treatment arm, determination of phase 3 primary endpoints, and phase 3 
sample size estimation.  
3.2.1.3. 
Standard-of-Care Background Treatments 
Several putative COVID-19 treatments are currently under investigation and in some cases have 
been authorized, approved or allowed for compounding for use in hospitalized patients, including 
remdesivir, convalescent plasma, and dexamethasone (refer to Section 1.6). Some of these 
products may be used as standard-of-care. Although there are some exceptions for treatments 
which may confound the effectiveness of the study drug, such as convalescent plasma (refer to 
Section 7.2.2 for exclusion criteria), the study design is generally flexible on the types of putative 
treatments used in the hospitalized setting for background standard-of-care.  
This study will compare REGN10933+REGN10987 to placebo, all given in addition to the local 
standard-of-care. Since the standard-of-care for COVID-19 is evolving and will vary across sites 
and regions, randomization will be stratified based on the type of background standard-of-care: 
antiviral therapies and non-antiviral therapies as described in Section 8.6. Including this as a 
stratification factor will ensure an appropriate balance in treatment assignment across the different 
types of standard-of-care and allow evaluation of efficacy based on background treatments given.  
3.2.1.4. 
Patient Population and Study Cohorts 
There is some evidence that suggests baseline disease severity influences progression and 
outcomes of COVID19. In order to evaluate potential differential treatment effects across the 
spectrum of hospitalized COVID-19 patients, the study will be conducted and analyzed in 
4 cohorts* of hospitalized adult patients with COVID-19 that require varying degrees of oxygen 
support at randomization:  
• Cohort 1A: With COVID-19 symptoms but not requiring supplemental oxygen  
• Cohort 1: Patients on low-flow oxygen supplementation 
• Cohort 2*: Patients requiring high-intensity oxygen therapy but not on mechanical 
ventilation 
• Cohort 3*: Patients requiring mechanical ventilation  
* Per IDMC recommendation first received on 30 October 2020, and reiterated through 
19 February 2021, patient enrollment in cohort 2 and cohort 3 has been placed on hold. 
See Section 6.1.3 for further details on the study cohort definitions. 
3.2.1.5. 
Rationale for Primary Objectives 
Safety and Tolerability 
The primary objectives of phase 1 and phase 2 include safety and tolerability, evaluated by targeted 
collection of treatment-emergent serious adverse events (SAEs) throughout the study and 
treatment-emergent adverse events of special interest (AESIs) through day 29. In addition, grade 
3 and grade 4 treatment-emergent adverse events (TEAEs) will be recorded to inform safety 
assessments in later phases of the study. 
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The study population of hospitalized adult patients with COVID-19 will have a complicated 
disease presentation at baseline that could quickly and unexpectedly deteriorate and progress. As 
such, their TEAE profile will be complex and dynamic. Mainly due to their underlying disease, 
TEAEs are expected to progress or improve in severity and seriousness multiple times throughout 
the study. Accurately collecting such a large volume of TEAEs could impose unnecessary burden 
on an already over-strained healthcare system and frequent exposure to infected patients could 
increase the risk of infection to the study staff. 
Evaluating targeted grade 3 or 4 TEAEs, treatment-emergent SAEs, and treatment-emergent 
AESIs (grade ≥2 hypersensitivity reactions and grade ≥2 infusion-related reactions) will provide 
the most relevant safety information to adequately evaluate the safety and tolerability of 
REGN10933+REGN10987. This subset of grade 3 or 4 TEAEs, treatment-emergent SAEs, and 
treatment-emergent AESIs encompasses the key safety concern that would be expected for mAbs 
against exogenous targets and help evaluate unexpected SAEs. Regeneron plans to collect data on 
non-serious TEAEs (as well as serious TEAEs) in a parallel-conducted prophylaxis study 
(R10933-10987-COV-2069) and a repeated dose study in adult volunteers (R10933-10987-HV-
2093) with REGN10933+REGN10987, where the study population will not have a complicated 
disease presentation and there is a significantly lower risk of overburdening the health care delivery 
system.  
Clinical Efficacy  
The REGN10933+REGN10987 mAb combination therapy was created as a potential anti-viral 
treatment and (and as combination to prevent viral escape mutants during treatment). The 
prospective hypothesis is that REGN10933+REGN10987 is intended to substitute for the 
endogenous immune response, that this endogenous response might be delayed or inadequate in 
some patients (eg, patients who are seronegative at baseline) and that REGN10933+REGN10987 
might be expected to have most benefit in these seronegative patients who are still positive at 
baseline for the presence of virus in NP swabs based on a quantitative PCR test. Phase 1/2 data 
from the Sponsor’s parallel study in outpatients with COVID-19 (R10933-10987-COV-2067) 
prospectively validated these concepts (for both anti-viral activity and clinical benefit). 
R10933-10987-COV-2067also showed that high viral titer at baseline in outpatients is highly 
correlated with a seronegative status at baseline. However, some patients who were seropositive 
at baseline had poor outcomes, suggesting that the serologic response in some patients may not be 
of sufficient quality to suppress viral replication. Based on these data, it is hypothesized for the 
current study that clinical benefit in hospitalized patients may be greatest in patients who are still 
positive at baseline for the presence of virus in NP swabs based on a quantitative PCR test and 
seronegative and/or in patients with high viral load regardless of serologic status. 
The clinical efficacy endpoint that will be assessed is mechanical ventilation or death. This is a 
change from the endpoint initially planned for the study: a 7-point ordinal scale (rating clinical 
status from death [1] to not hospitalized [7]) used to assess changes in clinical status (see 
Section 9.2.5.2.4). Emerging insights show that the 7-point ordinal scale can be highly variable, 
particularly with respect to oxygen requirements as it depends heavily on the clinical judgement 
of the clinician. This variability makes it far less optimal for assessment of treatment effects, 
especially in relatively small sample sizes. As such, the primary clinical efficacy assessment for 
phase 1/2 has been changed to focus on mechanical ventilation or death, objective measures that 
are clinically meaningful and representative of the most severe clinical manifestations of COVID-
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19. Preventing patients from going on mechanical ventilation or from dying is a highly relevant 
clinical outcome and one that will be simpler for patients and providers to understand compared 
to the previously proposed endpoint of change in ordinal scale.  
The phase 1/2 analysis of cohort 1 will focus first on excluding futility and then to assess clinical 
efficacy of REGN10933+REGN10987 on death or mechanical ventilation (see Section 11.4.9). 
An initial evaluation of futility will be performed to understand if there is a low probability of 
achieving statistical significance for the primary endpoint of mechanical ventilation or death. If 
the study as designed is determined not to be futile, subsequent assessments of efficacy will be 
performed hierarchically in populations mostly likely to benefit from a potent anti-viral – patients 
that have not mounted an efficient immune response, ie, those that are seronegative or with high 
viral load at baseline. Additional secondary endpoints will be assessed descriptively, including in 
other sets of patients (eg, positive at baseline for the presence of virus in NP swabs based on a 
quantitative PCR test and positive, positive at baseline for the presence of virus in NP swabs based 
on a quantitative PCR test and regardless of serologic status). If the study as designed is determined 
to be futile, all analyses of clinical endpoints will be descriptive and plans for phase 3 will be 
reconsidered. 
Demonstration of a convincing benefit in patients who are seronegative and/or have high viral 
loads at baseline, and at least a neutral effect in other subsets of patients, would support 
REGN10933+REGN10987 being used in either a targeted fashion based on point of care testing 
that is now available in many hospitals, or possibly in the overall COVID-19 population depending 
on the specific results. 
Virologic Efficacy 
The primary mechanism of action of REGN10933+REGN10987 is blockade of the S protein RBD 
interaction with ACE2, leading to decreased infection of host cells. Blocking viral entry would 
result in reductions in SARS-CoV-2 RNA replication, and corresponding viral load in affected 
tissues. In phase 1 and phase 2, the primary virologic endpoint will therefore evaluate, as proof of 
mechanism, the ability of REGN10933+REGN10987 to reduce viral load in the upper respiratory 
tract. day 22 (21 days after dosing) was initially chosen as the cutoff date for this analysis, based 
on accumulating evidence that this time period approaches the lower limit of detection in samples 
collected from the upper respiratory tract in patients spontaneously recovering from COVID-19 
(He, 2020) (Cao, 2020) (Wang, 2020b).  
Subsequently, the result of a phase 1/2 analysis in R10933-10987-COV-2067 (outpatients) showed 
that the majority of viral clearance had occurred prior to day 7 (Weinreich, 2020), suggesting that 
analysis at earlier timepoints may also be of value in assessing virologic efficacy. 
3.2.1.6. 
Rationale for Final Analysis of the Study 
On 30 October 2020, an Independent Data Monitoring Committee (IDMC) recommended pausing 
enrollment into cohort 2 and cohort 3 based on a potential safety imbalance, while proceeding with 
enrollment in cohort 1A and cohort 1. All cohort 2 and 3 patients enrolled at the time of the 
recommendation continued in the study and were followed up through the end of study visit as per 
the protocol. This IDMC recommendation on enrollment was maintained for the duration of the 
study.  
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An unblinded phase 1/2 analysis was performed on the patients who were randomized through 
01 December 2020 in phase 1 (cohort 1 only) and phase 2 (cohorts 1, 2, and 3) using a data cutoff 
date of 09 December 2020, based on a database lock on 22 December 2020 (refer to the phase 1/2 
SAP dated 21 December 2020 for details). Phase 2 cohort 1A was not included in the analysis. All 
patients enrolled into cohort 1 after 01 December 2020 were considered to be part of phase 3.  
On 09 April 2021, the Sponsor made a business decision to terminate patient enrollment in this 
study due to extremely low recruitment over several months. This decision was not based on any 
safety concerns. Accordingly, phase 3 cohort 1 and phase 2 cohort 1A enrollment was prematurely 
terminated. Until this time, only cohort 1 patients were enrolled into the phase 3 portion of the 
study. All ongoing subjects were followed up through their end of study visit as per the protocol. 
Cohort 1 reached its phase 2 enrollment goal first, and phase 3 cohort 1 started enrollment after 
01 December 2020. As cohort 1A never reached its predetermined phase 2 enrollment goal of 1000 
patients, phase 2 cohort 1A and cohort 1 enrolled concurrently (refer to Section 7.1 for the number 
of patients enrolled in each phase by cohort). Phase 2 cohort 1A data were handled and overseen 
similar to phase 3 cohort 1 data. 
Given much smaller sample size than anticipated as a result of early termination of enrollment, the 
Sponsor has elected to pool phase 2 cohort 1A and phase 3 cohort 1 and combine the 
REGN10933+REGN10987 2.4g and 8.0g dose groups for the primary analyses. Analyses of each 
cohort alone and each dose alone will be descriptive and considered secondary. 
3.2.1.7. 
Long COVID Sub-Study 
Long COVID encompasses a wide variety of heterogeneous neurological, neuropsychiatric, 
autonomic, and systemic symptoms, including fatigue, cognitive difficulties, mood dysregulation, 
dyspnea, coughing, palpitations, chest pain, fever, and joint or muscle pain) and can be debilitating 
(Alwan, 2020) (del Rio, 2020). However, the clusters of symptoms reported by patients post-
COVID-19 are not unique or specific to long COVID, and for most of the symptoms there are no 
validated biomarkers for diagnosis of long COVID, with identification of long COVID largely 
constrained in medical practice to diagnostic exclusion (Burke, 2021).  
To address knowledge gaps in the etiology and symptomatology of long COVID, additional 
assessments will be conducted as a sub-study at select sites. These assessments will evaluate 
patient-reported symptoms and related outcomes, to develop a better understanding of the nature 
of long COVID and to assess whether prior treatment with REGN10933+REGN10987 during 
acute SARS-CoV-2 infection may impact subsequent symptoms and quality-of-life outcomes. In 
addition, blood samples will be collected for biomarker analysis and immunoprofiling, to gain a 
better understanding of the underlying biology of long COVID and the impact of prior treatment 
in the acute stage of disease. Nasopharyngeal (NP) swab samples will be collected to assess for 
the presence of SARS-CoV-2 during this later stage of analysis. 
Patient-Reported Symptoms. To better understand the patient experience of long COVID, 
patients will answer questions about their symptoms and how these symptoms impact their 
functioning and quality of life (Section 9.2.9.1). The analysis will largely focus on pre-defined 
groupings of symptoms identified across guidelines from the Centers for Disease Control (CDC), 
National Health Service (NHS), and the World Health Organization (WHO) (CDC, 2021) (NHS, 
2021) (WHO, 2021). Symptoms will be analyzed according to whether they are considered 
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lingering symptoms and identified across all three guidelines (category A, identified across all 
three guidelines (category B), or identified across at least two guidelines (category C) (Section 4.3 
Table 4). In addition to these areas of focus, a variety of concepts important to patients beyond 
symptoms will be evaluated, including functioning, impact on daily lives, and overall quality of 
life, in order to generate a broad depiction of long COVID in the study population. 
Blood sample collection. While the underlying biology of long COVID is unclear, potential 
mechanisms contributing to the pathophysiology of post-acute COVID-19 disease include virus-
specific pathophysiologic changes, immunologic aberrations and inflammatory damage in 
response to acute infection, and expected sequelae of post-critical illness (Nalbandian, 2021) 
(Talla, 2021). Based on these data, as well as reports of biomarkers and signatures observed in 
patients with long COVID (Nalbandian, 2021), an agnostic multiplex proteomic and 
transcriptomic profiling focused on the disease mechanism will be performed to gather additional 
insights in the sequelae of long COVID. The specific aims of this analysis are described in 
Section 9.2.9.2.  
3.2.2. 
Rationale for Dose Selection 
This study will assess a single IV dose of REGN10933+REGN10987 as combination therapy in a 
1:1 ratio. The 1:1 ratio for REGN10933+REGN10987 is thought to be appropriate as these are 
non-competing mAbs targeting non-overlapping epitopes of the RBD of the S protein of SARS-
CoV-2, with similar in vitro binding and neutralization properties (for more information, refer to 
the 
Investigator’s 
Brochure[s]). 
The 
study 
will 
evaluate 
the 
co-administered 
REGN10933+REGN10987 as combination therapy at an initial dose level of 2.4 g (1.2 g per mAb), 
which is expected to be an efficacious dose (see below). The study will also evaluate 
REGN10933+REGN10987 at a higher dose, 8.0 g (4.0 g per mAb), in the event that a higher dose 
is required for efficacy. 
Cellular entry of coronaviruses depends on binding of the S protein to a specific cellular receptor 
and subsequent S protein priming by cellular proteases. ACE2 is the receptor for cellular entry of 
SARS-CoV-2 and its gene expression has been reported in the lungs, particularly in type-2 alveolar 
epithelial cells and bronchial airway epithelium (Wu, 2020a) (Xu, 2020) (Zhao, 2020). The 
strategy taken for dose selection in this study was to identify a target concentration in lung 
epithelial lining fluid (ELF) that approximates the effective concentration of 99% viral 
neutralization (EC99)* observed against live virus SARS-CoV-2 and to then identify a dose that 
will meet or exceed this concentration in lung ELF. The EC99 against SARS-CoV-2 is 0.14 µg/mL 
(REGN10933) and 0.78 µg/mL (REGN10987). 
An average lung ELF-to-serum mean Cmax ratio of ~0.15 has been reported for other exogenous 
IgG1 mAbs for the treatment of Staphylococcus aureus lung infections (Magyarics, 2019). It is 
assumed that the lung ELF-to-serum Cmax ratio is 0.15 for REGN10933 and REGN10987. Dividing 
the target lung ELF concentration by this ratio, the associated serum concentration for these targets 
is therefore estimated to be ~at least 5 µg/mL for the combination of REGN10987+REGN10933. 
Taking into account uncertainties regarding mAb penetration into lung ELF, prediction of human 
PK, and effects of disease on PK, 20 µg/mL was selected as a target concentration in serum for the 
initial dose of REGN10933+REGN10987 combination therapy. The goal for the initial 
REGN10933+REGN10987 combination dose is for ≥95% of patients to exceed the target serum 
concentration for 28 days after dosing, for each mAb. Based on healthy subject human PK data for 
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six Regeneron mAbs directed against an exogenous target (N=6 to 12 subjects per mAb), a single 
IV combination dose of 1.2 g per mAb is predicted to result in ≥95% of patients exceeding the 
target serum concentration for 28 days after dosing, for each mAb. 
*Please note that the EC values discussed here are identical to the inhibitory concentration (IC) values discussed in 
the Investigator’s Brochure(s). 
3.3. 
Risk-Benefit 
The anticipated risks and benefits of REGN10933+REGN10987 (casirivimab+imdevimab) are 
informed by preclinical and clinical data, including data from phase 3 trials.  
For additional information concerning clinical and preclinical data, refer to the Investigator’s 
Brochure. 
3.3.1. 
Summary of Efficacy and Safety Profile in Clinical Trials 
Clinical trial data are summarized below. Overall, REGN10933+REGN10987 have demonstrated 
efficacy as an anti-viral agent for the treatment and prevention of COVID-19, across a variety of 
populations, and is generally well-tolerated with an acceptable safety profile.  
Clinical Benefit of REGN10933+REGN10987 in Clinical Trials for the Treatment of 
COVID-19. In COV-2067, the phase 3 outpatient treatment trial, a single IV dose of 
REGN10933+REGN10987 was shown (relative to placebo) to reduce COVID-19-related 
hospitalizations or all-cause death by 71.3% (2400 mg dose) and 70.4% (1200 mg dose), reduce 
symptom duration by 4 days (2400 mg and 1200 mg), and reduce viral load over the first 7 days. 
Serious adverse events occurred more frequently in the placebo group (4.0%) than in either 
treatment group (2400 mg, 1.1%; 1200 mg, 1.3%), and grade ≥2 infusion-related reactions were 
infrequent (<0.3% in all groups) (Weinreich, 2021b). Similar virologic efficacy and a similar 
safety profile were observed in the phase 1/2 portion of this trial, which evaluated 
REGN10933+REGN10987 at 8000 mg and 2400 mg IV doses (Weinreich, 2021a). 
Clinical Benefit of REGN10933+REGN10987 in Clinical Trials for the Prevention of 
COVID-19. In COV-2069, the phase 3 prevention trial in those at high risk of infection by a 
household contact, a single subcutaneous (SC) dose of REGN10933+REGN10987 (1200 mg) 
reduced (relative to placebo) symptomatic SARS-CoV-2 infection by 81.4%, and reduced overall 
SARS-CoV-2 infection by 66.4%. Serious adverse events occurred at similar frequencies in the 
treatment group (1%) and placebo group (1%). Injection-site reactions were more common in the 
treatment group (4%) compared to the placebo group (2%), but no injection-site reactions in the 
study were grade 3 or above. The majority of injection site reactions occurred within 1 day and 
resolved within 2 days (O’Brien, 2021b).  
Among a sub-group of individuals in COV-2069 who were identified as SARS-CoV-2 positive 
but asymptomatic during screening, a single SC dose of casirivimab and imdevimab (1200 mg) 
reduced (relative to placebo) progression to symptomatic disease by 31.5%, and reduced the 
duration of symptoms in those that developed symptomatic infections. Injection-site reactions 
were more common in the treatment group (4%) compared to the placebo group (1%), but no 
injection-site reactions in the study were grade 3 or above (O’Brien, 2021a).  
In COV-2069, efficacy results were similar in adolescents (age 12 to <18) as observed in adults: 
0% of subjects in the 1200 mg SC treatment group experienced symptomatic infection, compared 
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with 9.3% of subjects in the placebo group. Safety data in adolescent subjects were also similar to 
that observed in adults. Injection site reactions were more common in the treatment group (5.9%) 
compared to the placebo group (1.6%), but none were grade 3 or above in any group.  
In COV-2093, the adult volunteer study evaluating multiple doses of SC administration of 
REGN10933+REGN10987 (monthly dosing over 6 months), exploratory efficacy results showed 
benefit with chronic treatment for preventing COVID-19. This efficacy was balanced by an 
acceptable safety profile, where injection site reactions were more common in the treatment group 
(34.6%) compared with the placebo group (15.8%), but none were grade 3 or above in any group 
and all injection site reactions were either self-limiting or manageable with over-the-counter 
medications. 
3.3.2. 
Summary of Risks 
Important Identified Risks. As with other protein therapeutics, hypersensitivity reactions, 
including acute infusion-related reactions (IV administration) or injection site reactions (SC 
administration), may develop immediately or within a few hours to days after study drug 
administration. Hypersensitivity reactions, including anaphylaxis, infusion-related reactions or 
injection site reactions, have been observed in patients who received REGN10933+REGN10987 
during ongoing clinical trials. 
Important Potential Risks. The important potential risks of REGN10933+REGN10987 are the 
clinical consequences of immunogenicity and embryo-fetal toxicity. 
Protein therapeutics carry the potential risk of an immunogenic response in the form of anti-drug 
antibody (ADA) and NAb development following administration, with possible consequences on 
safety and efficacy. Therefore, blood samples for immunogenicity assessment will be collected 
during the studies.  
Reproductive and developmental toxicology studies have not been conducted; therefore, the 
effects of REGN10933, REGN10987, and REGN10933+REGN10987 combination therapy on the 
fetus and reproductive organs in males and females are unknown. Human immunoglobulin G1 
(IgG1) antibodies are known to cross the placental barrier and are present in breast milk; therefore, 
the REGN10933+REGN10987 combination therapy have the potential to be transferred from the 
mother to the developing fetus or a breastfed child. Given the high affinity and specificity of 
REGN10933 and REGN10987, off-target pharmacological effects are not anticipated in either the 
mother or the fetus, and no off-target binding of REGN10933 or REGN10987 was observed in 
any of the human or monkey tissues evaluated ex vivo in tissue cross-reactivity studies. However, 
it is unknown whether the potential transfer of the combination of REGN10933+REGN10987 
therapy provides any treatment benefit or risk to the developing fetus or a breastfed child. 
There is currently limited clinical experience in the use of REGN10933, REGN10987, and 
REGN10933+REGN10987 combination therapy in female patients who are pregnant or 
breastfeeding. The combination of REGN10933+REGN10987 therapy should be used during 
pregnancy or breastfeeding only if the potential benefit justifies the potential risk for the mother 
and the fetus or breastfed child considering all associated health factors. If a female patient is 
pregnant or were to become pregnant while receiving REGN10933+REGN10987 combination, 
the pregnancy should be followed until outcome and any safety issue observed get reported.  
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Other 
Theoretical 
Considerations. 
Theoretical 
risks 
of 
administration 
of 
the 
REGN10933+REGN10987 combination include interference with the patient’s endogenous 
immune response to either SARS-CoV-2 infection or vaccination against COVID-19. In this study, 
risk mitigation includes exclusion criteria for certain vaccination scenarios (refer to Section 7.2.2). 
A reference to current CDC guidance is provided (Section 8.10.1) to aid investigators on 
appropriate management of COVID-19 vaccination. 
Antibody-dependent enhancement (ADE) has been observed for some therapeutics targeting 
exogenous viral proteins. For antibody therapies, ADE is thought to occur when binding of 
antibody to the target viral protein enhances Fc gamma receptor (FcγR)-mediated host cell entry 
of the virus (Iwasaki, 2020). This could potentially lead to worsening of disease and, in the case 
of SARS, acute lung injury (Liu, 2019). REGN10933 and REGN10987 retain the Fc region, as 
this may play a role in protecting against viral infection (Yasui, 2014), there is no strong evidence 
of ADE in other coronavirus models (Kam, 2007) (Liu, 2019) (Luo, 2018). To date, Fc-containing 
mAbs developed by the Sponsor for Ebola virus and MERS-CoV have demonstrated specificity to 
their exogenous targets with no significant unexpected safety findings in preclinical or clinical 
studies. All patients will have follow-up assessments by phone during the drug elimination period. 
Pediatric Population. Emerging data suggest that the pediatric population is equally vulnerable 
to SARS-COV-2 infection, and may contribute significantly to viral transmission (Wang, 2016) 
(Weingartl, 2004). Moreover, neonatal transmission of SARS CoV-2 has also been reported, 
suggesting that the youngest of the pediatric population can also be at risk of infection (Lewis, 
2020) (Szablewski, 2020). If infected, the burden of severe disease in pediatric patients that 
become symptomatic and develop COVID-19 seem to be greater in those with underlying medical 
conditions. REGN10933+REGN10987 was safe and well-tolerated in the adult population and no 
new safety signals were identified in the adolescent population (>12 years). As it is an exogenous 
target, the safety of REGN10933+REGN10987 is not anticipated to be different from that observed 
in the adult patients. Additionally, nonclinical toxicology studies have not shown any safety 
findings including no tissue cross-reactivity to human fetal tissues. These data therefore favor 
assessing the safety and efficacy of REGN10933+REGN10987 in pediatric patients (for more 
information on dose rationale for these patients, refer to Section 3.2.1.6). 
Summary. Overall, the anticipated benefit of REGN10933+REGN10987 combination therapy in 
treatment of infection with SARS-CoV-2 virus, along with the risk minimization measures in 
place, support continued clinical development of the product. 
4. 
ENDPOINTS  
Endpoints are specified for each study cohort (as defined in Section 6.1.3).  
4.1. 
Primary Endpoints 
Pooled Phase 3 (Cohort 1) and Phase 2 (Cohort 1A) 
Virologic 
The primary virologic endpoint is time-weighted average change from baseline viral load in NP 
sample through day 7, as measured by quantitative reverse transcription polymerase chain reaction 
(RT-qPCR) in nasopharyngeal (NP) swab samples.  
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Note: Time-weighted average of change from baseline in viral load from day 1 to day 7 will be 
calculated for each patient using the trapezoidal rule as the area under the curve for change from 
baseline at each time point divided by the time interval for the observation period.  
Clinical 
The primary clinical endpoint is the proportion of patients who died or went on mechanical 
ventilation from day 6 through day 29 and from day 1 through day 29. 
Phase 1/2 (Cohort 1)  
Futility 
The primary endpoint is death or mechanical ventilation. 
Safety and Tolerability 
Safety and tolerability endpoints are as follows: 
• Proportion of patients with treatment-emergent SAEs through end of study  
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4  
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29  
Phase 2 (Cohort 2 and Cohort 3) 
There are no primary endpoints for cohort 2 and cohort 3 in phase 2.  
4.2. 
Secondary Endpoints 
Pooled Phase 3 (Cohort 1) and Phase 2 (Cohort 1A) 
Clinical 
• Proportion of patients who went on mechanical ventilation by day 29 
• Proportion of patients who died from day 6 to day 29 and from day 1 to day 29 
• Proportion of patients who were discharged by day 29 
• Proportion of patients who died or were readmitted to hospital over time 
Note: Readmission to hospital will be based on investigator report. 
• Cumulative incidence of death over time (ie, overall survival) 
• Cumulative incidence of mechanical ventilation over time  
• Cumulative incidence of death or mechanical ventilation over time  
• Time to discharge 
Safety and Tolerability 
• Proportion of patients with treatment-emergent SAEs through end of study  
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4  
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29  
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Phase 1/2 (Cohort 1)  
Clinical Efficacy 
The key secondary endpoint is death or mechanical ventilation. 
Other secondary endpoints include: 
Virologic Efficacy 
• Time-weighted average change from baseline in viral load (log10 copies/mL) from 
day 1 to day 7, as measured by quantitative reverse transcription polymerase chain 
reaction (RT-qPCR) in nasopharyngeal (NP) swab samples  
Note: Time-weighted average of change from baseline in viral load from day 1 to day 7 
will be calculated for each patient using the trapezoidal rule as the area under the 
curve for change from baseline at each time point divided by the time interval for the 
observation period.  
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 
1 to day 11, as measured by RT-qPCR in NP swab samples 
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 
1 to each post-baseline timepoint until day 29, as measured by RT-qPCR in NP swab 
samples  
• Change from baseline in viral load at each post-baseline timepoint through day 29, as 
measured by RT-qPCR in NP swab samples 
• Time to sustained negative RT-qPCR (negative RT-qPCR with no subsequent) positive  
Clinical Efficacy 
• All-cause death 
• Mechanical ventilation  
• Proportion of patients who died or went on mechanical ventilation by day 29 
• Proportion of patients who died by day 29 
• Proportion of patients who went on mechanical ventilation by day 29 
• Time to discharge 
PK/ADA 
• Concentrations of REGN10987 and REGN10933 in serum and corresponding PK 
parameters 
• Immunogenicity, as measured by ADA and (in phase 2 and phase 3 only) NAb to 
REGN10933 and REGN10987 
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Phase 3 (Cohort 1) and Phase 2 (Cohort 1A), Separately 
The secondary endpoints include: 
Virologic Efficacy 
Endpoint 
Timepoint 
Population 
Time-weighted average change from 
baseline viral load in NP sample 
Through day 7 
mFAS 
Time-weighted average change from 
baseline viral load in NP sample 
Through day 7 
Baseline Viral load categories 
( >105, >106 copies/mL) 
mFAS 
Time-weighted average change from 
baseline viral load in NP sample  
Through day 11 
Seronegative mFAS 
Time-weighted average change from 
baseline viral load in NP sample 
Through day 11 
mFAS 
Time-weighted average change from 
baseline viral load in NP sample 
Through day 11 
Baseline Viral load categories 
(>105, >106 copies/mL) mFAS 
Time-weighted average change from 
baseline, change from baseline, and 
percent change from baseline in viral 
load in NP sample 
Through each post-
baseline timepoint until 
day 29 
1. Seronegative mFAS,  
2. Baseline Viral load 
categories ( >105, >106 
copies/mL) mFAS,  
3. mFAS 
Clinical Efficacy 
• Proportion of patients who went on mechanical ventilation by day 29 (as applicable) 
• Proportion of patients who died from day 6 to day 29 and from day 1 to day 29 
• Proportion of patients who were discharged by day 29 
• Proportion of patients who died or were readmitted to hospital over time 
Note: Readmission to hospital will be based on investigator report. 
• Cumulative incidence of death over time (ie, overall survival) 
• Cumulative incidence of mechanical ventilation over time (as applicable) 
• Cumulative incidence of death or mechanical ventilation over time (as applicable) 
• Time to discharge 
Safety and Tolerability 
• Proportion of patients with treatment-emergent SAEs through end of study  
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4  
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29  
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PK/ADA 
• Concentrations of REGN10987 and REGN10933 in serum and corresponding PK 
parameters 
• Immunogenicity, as measured by ADAs and NAbs to REGN10933 and REGN10987 
Phase 2 (Cohort 2 and Cohort 3) 
PK/ADA 
• Concentrations of REGN10987 and REGN10933 in serum and corresponding PK 
parameters 
• Immunogenicity, as measured by ADAs and NAbs to REGN10933 and REGN10987 
4.3. 
Exploratory Endpoints 
The exploratory endpoints include:  
• Proportion of patients with treatment failure having mutations in the gene encoding the 
SARS-CoV-2 S protein through day 29 
• Change and percentage change in neutrophil-lymphocyte ratio (NLR) at each visit 
through day 29 
• Change and percentage change in D-dimer at each visit through day 29 
• Change and percentage change in ferritin at each visit through day 29 
• Change and percentage change in C-reactive protein (CRP) at each visit through day 29 
• Change and percentage change in lactate dehydrogenase (LDH) at each visit through 
day 29  
The exploratory long COVID endpoints for the sub-study are listed below.  
• Proportion of patients with ≥1 symptom from SE-LC19 Category A by day 180 
• Proportion of patients with ≥1 symptom from SE-LC19 Category B by day 180 
• Proportion of patients with ≥1 symptom from SE-LC19 Category C by day 180 
• Proportion of patients with ≥2 symptoms from SE-LC19 Category A by day 180 
• Proportion of patients with ≥2 symptoms from SE-LC19 Category B by day 180 
• Proportion of patients with ≥ 2 symptoms from SE-LC19 Category C by day 180 
Note: SE-LC19 symptom categories are provided in Table 4. 
• Change from baseline in viral load through day 29, and at day 120 and day 169, as 
measured by RT-qPCR in nasopharyngeal swab samples 
• Proportion of patients with positive SARS-CoV-2 test results after randomization 
through day 169 
Additional analyses related to psychometric validation of the SE-LC19 as well as potential 
biomarkers predicting long COVID will be outlined in separate SAP(s). 
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5. 
STUDY VARIABLES  
This section provides variables to be measured in the study. For description corresponding study 
procedures, refer to Section 9.2.3. 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
disease characteristics, targeted medical history, and targeted medication history for each patient. 
5.2. 
Efficacy Variables 
Efficacy variables include viral load (log10 copies/mL), oxygen supplementation status, 
hospitalization and readmission status, and all-cause mortality. 
5.3. 
Safety Variables 
Safety variables include incidence of TEAEs (grade 3 or 4; for phase 1 only), treatment-emergent 
SAEs, and treatment-emergent AESIs (as defined in Section 10.1.3). 
5.4. 
Pharmacokinetic Variables 
For phase 1, the PK variables are the concentration of REGN10933, and REGN10987 in serum 
and time. For phase 2, the PK variables are the concentration of REGN10933, and REGN10987 
in serum and time. The PK sampling time points are specified in the schedule of events (Table 1 
for phase 1; Table 2 for phase 2 and phase 3). 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, time-point/visit, and in phase 2 and phase 3 
only, NAb status. Samples in this study will be collected at the clinic visits specified in the schedule 
of events (Table 1 for phase 1; Table 2 for phase 2 and phase 3). 
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Exploratory biomarker variables include, but not be limited to, parameters reported in complete 
blood counts with differential, and levels of D-dimer, ferritin, CRP, LDH, serum cytokines, 
complement, cardiac biomarkers, and parameters related to long COVID questionnaires. 
These results may be reported outside of the clinical study report (CSR).  
6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This study is an adaptive, phase 1/2/3, randomized, double-blinded, placebo-controlled master 
protocol to evaluate the futility or efficacy, safety, and tolerability of REGN10933+REGN10987 
in hospitalized adult patients with COVID-19. The study will be conducted in approximately 100 
sites, in the US and other countries. 
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Eligible patients who have been hospitalized for ≤72 hours at screening will be enrolled in 1 of 4 
cohorts* based on disease severity at randomization (as defined in Section 6.1.3). 
Phase 2 will initiate following IDMC clearance of a pooled phase 1 sentinel safety group across 
2 studies (R10933-10987-COV-2066 and R10933-10987-COV-2067), and after initiation will 
enroll concurrently with phase 1. Once phase 2 is active, phase 1 will continue to enroll to 
completion, but phase 2 enrollment does not require the completion of phase 1 enrollment (for 
complete description and rationale for this process, refer to Section 3.2.1.1). 
* Per IDMC recommendation first received on 30 October 2020, and reiterated through 
19 February 2021, patient enrollment in cohort 2 and cohort 3 has been placed on hold.  
Note: On 09 April 2021, the Sponsor made a business decision to terminate patient enrollment in 
this study due to low recruitment rates. Patients who had been enrolled will continue to be followed 
up according to the Schedule of Events (Section 9.1). In addition, enrolled patients at select sites 
may be reconsented to protocol amendment 8 US and followed in an exploratory sub-study for an 
extended period to monitor for symptoms of long COVID. 
6.1.1. 
Study Design 
Phase 1 (Cohort 1 only) 
Phase 1 will assess the safety, tolerability, and efficacy of REGN10933+REGN10987 in 
60 patients from cohort 1.  
Patients may receive background standard-of-care for COVID-19 per local guidelines, including 
direct and immune-based treatments (for exceptions, see Section 7.2.2).  
Patients will be randomized in a 1:1:1 allocation ratio to one of the following: 
• REGN10933+REGN10987 2.4 g (1.2 g of each mAb) IV single dose 
• REGN10933+REGN10987 8.0 g (4.0 g of each mAb) IV single dose 
• Placebo IV single dose 
Phase 2 (Cohort 1A, Cohort 1, Cohort 2*, and Cohort 3*) and Phase 3 (Cohort 1) 
In phase 2, the efficacy, safety, and tolerability of REGN10933+REGN10987 will be evaluated in 
patients who have been hospitalized for ≤72 hours at screening. Patients will be enrolled in cohort 
1A, cohort 1, cohort 2*, or cohort 3*.  
* Per IDMC recommendation first received on 30 October2020, and reiterated through 
19 February 2021, patient enrollment in cohort 2 and cohort 3 has been placed on hold. 
Statistical analyses will be conducted separately in each cohort.  
In addition to background standard-of-care, patients in each cohort will be randomized in a 1:1:1 
allocation ratio to one of the following: 
• REGN10933+REGN10987 2.4 g (1.2 g of each mAb) IV single dose 
• REGN10933+REGN10987 8.0 g (4.0 g of each mAb) IV single dose 
• Placebo IV single dose 
Randomization in each cohort will be stratified as described in Section 8.6. 
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Note that patients in cohort 1 enrolled after the first 691 patients (including phase 1 patients) will 
follow the phase 2 schedule of events but will be considered enrolled under phase 3. 
6.1.2. 
Study Duration 
Phase 1 (Cohort 1 only) 
The phase 1 portion of the study will last up to 170 days. See Table 1 for the schedule of events 
and sample collections: 
• Screening/Baseline: Patients will undergo a screening and baseline period for up to 
2 days (day -1 to 1).  
• Hospitalization and post-discharge period: Patients will be assessed daily up to day 
29 while hospitalized. Patients who are discharged before day 29 will be followed up 
—in person for sample collections, and may also be followed up by phone or 
telemedicine for assessments. After day 29, all patients will be followed up monthly.  
• End of study (EOS): On day 169, patients will have an in-person EOS visit for sample 
collection and assessments.  
 
Figure 2: 
Study Flow Diagram, Phase 1 
 
Phase 2 (Cohort 1A, Cohort 1, Cohort 2*, and Cohort 3*) and Phase 3 (Cohort 1) 
* Per IDMC recommendation first received on 30 October 2020, and reiterated through 19 
February 2021, patient enrollment in cohort 2 and cohort 3 has been placed on hold. 
The phase 2 and phase 3 portions of the study will last up to 58 days. See Table 2 for a schedule 
of events and sample collections. 
Patients in phase 2 (cohort 1A) and phase 3 (cohort 1) who consent to the long COVID sub-study 
at participating sites will follow the main study Schedule of Events (Table 2) until day 57, then 
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follow the long COVID sub-study Schedule of Events (Table 3) from day 58 to day 180. Patients 
who do not consent to these additional assessments will follow Table 2 until day 57. 
• Screening/Baseline: Patients will undergo a screening and baseline period for up to 
2 days (day -1 to 1).  
• Hospitalization and post-discharge period: Patients will be assessed daily up to day 
29 while hospitalized. Patients who are discharged before day 29 will be followed up 
in person for sample collections, and may also be followed up by phone or telemedicine 
for assessments. After day 29, all patients will be followed up weekly.  
• End of study (for patients not participating in the long COVID sub-study at 
participating sites): On day 57, patients will be followed up by phone or telemedicine 
for an EOS visit.  
• Long COVID sub-study follow-up (at participating sites): On day 120, patients will 
be followed up for questionnaires and sample collections. 
• Long COVID sub-study end of study (at participating sites): On day 180, patients 
will be followed up for questionnaires and sample collections.  
 
Figure 3: 
Study Flow Diagram, Phase 2 and Phase 3 
 
* Per IDMC recommendation first received on 30 October 2020, and reiterated through 19 February 2021, patient 
enrollment in cohort 2 and cohort 3 has been placed on hold. 
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Phase 3  
In phase 3, patients will be assessed daily up to day 29 for clinical improvement. After day 29, 
patients will be followed-up until EOS on day 57.  
6.1.3. 
Description of Study Cohorts 
Eligible patients who have been hospitalized for ≤72 hours at screening will be enrolled in 1 of 4 
cohorts* based on disease severity at randomization: 
• Cohort 1A: With COVID-19 symptoms but not requiring supplemental oxygen  
• Cohort 1: O2 saturation >93% on low-flow oxygen via nasal cannula, simple face 
mask, or other similar device 
• Cohort 2*: On high-intensity oxygen therapy† but not on mechanical ventilation 
†High-intensity oxygen therapy is defined as the use of non-rebreather mask with an 
oxygen flow rate of at least 10 L/min; use of a high flow device with at least 50% FiO2, 
or use of non-invasive ventilation to treat hypoxemia. 
• Cohort 3*: On mechanical ventilation 
* Per IDMC recommendation first received on 30 October 2020, and reiterated through 
19 February 2021, patient enrollment in cohort 2 and cohort 3 has been placed on hold. 
6.1.4. 
Study Stopping Rules 
6.1.4.1. 
Individual Patient Stopping Rules 
For an individual patient, the infusion rate can be slowed, interrupted, or stopped if there is a 
suspected drug-related event during the infusion suggestive of severe hypersensitivity or an 
infusion-related reaction, as per investigator discretion if it is deemed to be in the patient’s best 
interest (see Section 8.5). As this is a single dose study, there are no other study drug 
discontinuation rules.  
Patient stopping rules from the study include withdrawal of consent.  
6.1.4.2. 
Study Stopping Criteria 
The Sponsor may decide to stop or make adaptations to the study based upon the recommendations 
by an IDMC and/or review of the totality of evidence (see Section 6.2.1). 
A treatment arm may be dropped if there is a clinically meaningful imbalance between treatment 
arms in both of the following criteria:  
• Incidence of treatment-emergent SAEs evaluated as related to study treatment  
and 
• A risk-benefit imbalance based upon any key efficacy and safety endpoint of the study 
such that one dosing arm appears to be doing substantially better than another without 
requiring any specific statistical level of precision 
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6.1.5. 
End of Study Definition 
The end of study is defined as the date when the last living patient completes the last study visit, 
withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be contacted 
by the investigator).  
6.1.6. 
Definition of Study Completion 
For individual patients, study completion is defined as collection of vital status information on 
their projected EOS date. All measures will be taken to obtain vital status information on the 
projected EOS date, and all patients with recorded vital status information at projected EOS date 
will be considered study completers. The end of study is considered day 169 (for phase 1) or day 57 
(for phase 2) (Section 9.1).  
6.2. 
Study Committees  
6.2.1. 
Independent Data Monitoring Committee 
An IDMC will actively review data throughout the study to monitor patient safety and efficacy 
data. The IDMC can make recommendations about early study closure or changes to the study 
conduct. The operation of the IDMC is governed by a charter describing further details, such as 
procedures (including but not limited to periodic safety monitoring) and requirements for reporting 
its observations to the Sponsor. 
An IDMC will review pooled safety data up to day 3 in the sentinel safety group as described in 
Section 3.2.1.1. In addition, the IDMC will conduct periodic data reviews, for instance, after all 
patients are enrolled into phase 1. Additional periodic reviews will be conducted during phase 2 
and 3 of this study as detailed in the IDMC charter. These data reviews will include all available 
efficacy and safety data, including deaths, from all enrolled study participants up to the data cut-
point for the analysis. The IDMC will meet regularly throughout the course of the study to review 
safety data and make recommendations on study conduct. 
6.2.2. 
Sponsor Review Committee 
Periodic data reviews may be performed by selected unblinded senior Sponsor physicians and a 
statistician with no direct involvement in the study. Reviews will assess the totality of evidence 
and may be used to determine study adaptations (see Section 3.2.1.2). 
6.3. 
Planned Interim Analysis  
A description of the statistical methods to be employed is in Section 11.5, and blinding 
implications are discussed in Section 8.7. 
No interim analyses are planned.  
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Enrolled 
See Section 8.1 for treatment arms. 
On 30 October 2020, an IDMC recommended pausing patient enrollment into cohort 2 and 
cohort 3 based on a potential safety imbalance, while proceeding with enrollment in cohorts 1A 
and 1. This IDMC recommendation was reiterated through 19 February 2021, and study 
investigators were advised by the Sponsor to follow all ongoing patients through their end of study 
visit as per the protocol. This IDMC recommendation on enrollment was maintained for the 
duration of the study.  
Subsequently, on 09 April 2021, the Sponsor made a business decision to terminate patient 
enrollment due to low recruitment rates. This decision was not based on any safety concerns. 
Accordingly, phase 3 cohort 1 and phase 2 cohort 1A enrollment were prematurely terminated due 
to slow enrollment rate. Until this time, only cohort 1 patients were enrolled into the phase 3 
portion of the study. 
Overall, approximately 2252 patients were randomized in this study:  
Phase 1 
• Cohort 1: 60 patients 
Phase 2  
• Cohort 1A: 609 patients 
• Cohort 1: 629 patients 
• Cohort 2: 164 patients 
• Cohort 3: 35 patients 
Prematurely terminated phase 3  
• Cohort 1 (ie, patients randomized after 01 December 2020): 755 patients 
7.2. 
Study Population  
The study population will consist of hospitalized adult patients with COVID-19.  
7.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Has provided informed consent (signed by study patient or legally acceptable 
representative) 
2. Male or female adult ≥18 years of age (or country’s legal age of adulthood) at 
randomization 
3. Has SARS-CoV-2-positive antigen or molecular diagnostic test (by validated SARS-CoV-
2 antigen, RT-PCR, or other molecular diagnostic assay, using an appropriate sample such 
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as NP, nasal, oropharyngeal [OP], or saliva) ≤72 hours prior to randomization and no 
alternative explanation for current clinical condition. A historical record of positive result 
from test conducted ≤72 hours prior to randomization is acceptable. 
4. Has symptoms consistent with COVID-19, as determined by investigator, with onset ≤10 
days before randomization  
5. Hospitalized for ≤72 hours with at least 1 of the following at randomization; patients 
meeting more than one criterion will be categorized in the most severely affected category: 
a. Cohort 1A: With COVID-19 symptoms but not requiring supplemental oxygen  
b. Cohort 1: Maintains O2 saturation >93% on low-flow oxygen via nasal cannula, simple 
face mask, or other similar device  
Note: Sites located in high-altitude areas (>1500 m above sea level) should refer to 
Table 9 to get the appropriate high-altitude equivalents for sea-level oxygenation 
measurements. 
c. Cohort 2*: High-intensity oxygen therapy without mechanical ventilation, where high-
intensity is defined as receiving supplemental oxygen delivered by 1 of the following 
devices:  
− Non-rebreather mask (with an SpO2 ≤96% while receiving an oxygen flow rate of 
at least 10 L/min) 
− High-flow device (eg, AIRVO™ or Optiflow™) with at least 50% FiO2 
− Non-invasive ventilator, including continuous positive airway pressure (CPAP) to 
treat hypoxemia (excluding isolated use for sleep-disordered breathing) 
d. Cohort 3*: On mechanical ventilation 
* Per IDMC recommendation first received on 30 October 2020, and reiterated through 
19 February 2021, patient enrollment in cohort 2 and cohort 3 has been placed on hold. 
6. Long COVID sub-study: Is able to understand and complete study-related questionnaires  
7.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria will be excluded from the study: 
1. Phase 1 only: Patients maintaining O2 saturation >94% on room air 
Note: For sites in high-altitude areas, refer to Table 9. Patients on room air will not be 
excluded from phase 2.  
2. In the opinion of the investigator, unlikely to survive for >48 hours from screening 
3. Receiving extracorporeal membrane oxygenation (ECMO)  
4. Has new-onset stroke or seizure disorder during hospitalization 
5. Initiated on renal replacement therapy due to COVID-19 
6. Has circulatory shock requiring vasopressors at randomization  
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Note: Patients who require vasopressors for sedation-related hypotension or reasons other 
than circulatory shock may be eligible in this study. 
7. Patients who have received convalescent plasma, IVIG, or mAbs against SARS-CoV-2 
(eg, bamlanivimab) within 5 months prior to randomization or plan to receive during the 
study period for any indication 
8. Participation in a clinical research study, including any double-blind study, evaluating an 
investigational product within 30 days and less than 5 half-lives of the investigational 
product prior to the screening visit 
Note: The use of remdesivir, hydroxychloroquine, or other treatments (except for 
COVID-19 convalescent plasma or IVIG) being used for COVID-19 treatments in the 
context of the local standard-of-care or an open-label study or compassionate use protocol 
is permitted. 
9. Any physical examination findings, history of illness, and/or concomitant medications that, 
in the opinion of the study investigator, might confound the results of the study or pose an 
additional risk to the patient by their participation in the study. 
10. Known allergy or hypersensitivity to components of study drug  
11. Pregnant or breastfeeding women 
12. Continued sexual activity in women of childbearing potential (WOCBP)* or sexually 
active men who are unwilling to practice highly effective contraception prior to the initial 
dose/start of the first treatment, during the study, and for at least 6 months after the last 
dose.  
Highly effective contraceptive measures in women include:  
• Stable use of combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation initiated 2 or more 
menstrual cycles prior to screening 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal ligation 
• Vasectomized partner,† and/or  
• Sexual abstinence‡,§ 
Male study participants with WOCBP partners are required to use condoms unless they 
are vasectomized† or practice sexual abstinence.‡,§ 
* WOCBP are defined as women who are fertile following menarche until becoming 
postmenopausal, unless permanently sterile. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
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FSH measurement is insufficient to determine the occurrence of a postmenopausal 
state. The above definitions are according to Clinical Trial Facilitation Group (CTFG) 
guidance. Pregnancy testing and contraception are not required for women with 
documented hysterectomy or tubal ligation. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
† Vasectomized partner or vasectomized study participant must have received medical 
assessment of the surgical success. 
‡ Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drugs. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
§ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should 
not be used together. 
7.3. 
Premature Withdrawal from the Study  
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or Sponsor have the right to withdraw a patient from the study if it is no 
longer in the interest of the patient to continue in the study, or if the patient’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow 
study procedures). An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of patients should be avoided. 
Patient who are withdrawn prematurely from the study will be asked to complete an early 
termination visit and have follow-up contact as described in Section 9.1.3. 
7.4. 
Replacement of Patients  
Patients prematurely discontinued from study will not be replaced.  
8. 
STUDY TREATMENTS  
8.1. 
Investigational and Reference Treatments 
Instructions on dose preparation are provided in the pharmacy manual. See Section 8.6 for the 
method of treatment allocation. 
Phase 1, Phase 2, and Phase 3 
• Co-administered REGN10933+REGN10987 combination therapy 2.4 g (1.2 g of 
REGN10933 plus 1.2 g of REGN10987) IV single dose 
• Co-administered REGN10933+REGN10987 combination therapy 8.0 g (4.0 g of 
REGN10933 plus 4.0 g of REGN10987) IV single dose 
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• Placebo IV single dose 
8.2. 
Background Treatments 
Patients may receive the standard-of-care for the treatment of COVID-19 per local guidelines (if 
not specified in the exclusion criteria; see Section 7.2.2). Background treatments may include: 
• Antiviral therapies (remdesivir or other)  
• Immune-based therapies (tocilizumab, sarilumab, steroids, or other) 
• Antiviral and immune-based therapies 
8.3. 
Rescue Treatment(s) 
Patients may receive rescue therapy for the treatment of COVID-19 per local standard-of-care. 
Rescue treatment(s) will not be provided as part of the study. 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules 
This is a single dose study. Dose modification for an individual patient is not allowed. Study 
treatment discontinuation is not applicable to this study. 
8.5. 
Management of Acute Reactions  
8.5.1. 
Infusion-Related Reactions and Hypersensitivity Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available for 
immediate use if required for treatment. All grade ≥2 infusion-related reactions and grade ≥2 
hypersensitivity reactions (using the CTCAE severity scale specified in Section 10.2.4) must be 
reported as AESIs (see Section 10.2.3).  
8.5.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following adverse events are observed: 
• Sustained/severe cough 
• Rigors/chills 
• Rash, pruritus (itching) 
• Urticaria (hives, welts, wheals) 
• Diaphoresis (sweating) 
• Hypotension 
• Dyspnea (shortness of breath) 
• Vomiting 
• Flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate. 
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If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
8.5.1.2. 
Termination of the Intravenous Infusion 
The infusion should be terminated and not restarted if any of the following adverse events occur: 
• Anaphylaxis* 
• Laryngeal/pharyngeal edema 
• Severe bronchospasm 
• Chest pain 
• Seizure 
• Severe hypotension 
• Other neurological symptoms (confusion, loss of consciousness, paresthesia, paralysis, 
etc) 
• Any other symptom or sign that, in the opinion of the investigator, warrants termination 
of the IV infusion 
*Consider anaphylaxis if the following is observed (Sampson, 2006): acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) and at least 1 of the following:  
• Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
8.6. 
Method of Treatment Assignment  
Patients will be randomized according to a central randomization scheme using an interactive web 
response system (IWRS).  
Phase 1 
60 patients will be randomized in a 1:1:1 allocation ratio to 1 of the following:  
• Co-administered REGN10933+REGN10987 combination therapy, 2.4 g (1.2 g each of 
REGN10933 and REGN10987) IV single dose  
• Co-administered REGN10933+REGN10987 combination therapy, 8.0 g (4.0 g each of 
REGN10933 and REGN10987) IV single dose  
• Placebo IV single dose 
Randomization will be stratified by type of background standard-of-care being administered for 
COVID-19 at randomization as follows:  
• Antiviral therapies (remdesivir or other)  
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• Non-antiviral therapies (immune-based therapies, both antiviral and immune-based 
therapies, or no COVID-19-specific treatment) 
Phase 2  
Note: Per IDMC recommendation first received on 30 October 2020, and reiterated through 
19 February 2021, randomization to cohort 2 and cohort 3 has been placed on hold. 
For each of the study cohorts in phase 2, patients will be randomized in a 1:1:1 ratio to receive 1 of 
the treatments below: 
• Co-administered REGN10933+REGN10987 combination therapy 2.4 g (1.2 g of 
REGN10933 plus 1.2 g of REGN10987) IV single dose 
• Co-administered REGN10933+REGN10987 combination therapy 8.0 g (4.0 g of 
REGN10933 plus 4.0 g of REGN10987) IV single dose 
• Placebo IV single dose 
Randomization will be stratified by country and type of background standard-of-care being 
administered for COVID-19 at randomization as follows:  
• Antiviral therapies (remdesivir or other)  
• Non-antiviral therapies (immune-based therapies, both antiviral and immune-based 
therapies, or no COVID-19-specific treatment) 
Phase 3 
Patients will be randomized in a 1:1:1 ratio to receive 1 of the treatments below: 
• Co-administered REGN10933+REGN10987 combination therapy 2.4 g (1.2 g of 
REGN10933 plus 1.2 g of REGN10987) IV single dose 
• Co-administered REGN10933+REGN10987 combination therapy 8.0 g (4.0 g of 
REGN10933 plus 4.0 g of REGN10987) IV single dose 
• Placebo IV single dose 
Randomization will be stratified by country and type of background standard-of-care being 
administered for COVID-19 at randomization as follows:  
• Antiviral therapies (remdesivir or other)  
• Non-antiviral therapies (immune-based therapies, both antiviral and immune-based 
therapies, or no COVID-19-specific treatment) 
The treatment arms, patient cohorts, sample size, and treatment allocation scheme for phase 3 may 
be reconsidered after review of phase 1/2 data. 
8.7. 
Blinding  
A pharmacist or qualified personnel at the site, not otherwise associated with the conduct of the 
study, will reconstitute the drug for IV administration. The drug infusion solution must be provided 
in identical form for active and placebo treatments, so that they remain indistinguishable to both 
study personnel and patients.  
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Study patients, the principal investigators, and study site personnel (with the exception of the 
unblinded pharmacist at each site) will remain blinded to all randomization assignments 
throughout the study. The Regeneron medical/study director, study monitor, and any other 
Regeneron and contract research organization (CRO) personnel who are in regular contact with 
the study site will remain blinded to all patient randomization assignments in all phases of the 
study.  
Selected individuals from the Sponsor not involved in the conduct of the study may have access 
to unblinded phase 1 or phase 2 data as needed for safety review or other data review (see 
Section 6.2.2). The team performing the interim data reviews will be separate from the ongoing 
study team. No study personnel involved in the day-to-day conduct of the study will have access 
to any unblinded data before the database is locked for this study.  
Anti-drug antibody, drug concentration, and biomarker results will not be communicated to the 
sites, and the Sponsor’s blinded operational team will not have access to results associated with 
patient identification until after the database is locked. 
8.8. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy) and when a treatment decision is contingent 
on knowing the patient’s treatment assignment.  
If unblinding is required: 
• Only the investigator will make the decision to unblind the treatment assignment 
• Only the affected patients will be unblinded 
• Unblinding is performed using the IWRS, which will notify the Sponsor. The 
designated study pharmacist(s)/designee at the study site will provide the treatment 
assignment to the investigator. If the study pharmacist(s)/designee is not available, the 
investigator for the site will unblind the patient.  
• If the IWRS is unavailable, the investigator will ask the unblinded study 
pharmacist(s)/designee to perform manual unblinding. All manual unblinding 
procedure will be adequately documented, including the reason why the IWRS was not 
used. 
• The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency and when a treatment decision is contingent on knowing the patient’s treatment 
assignment. In the event that there is no study pharmacist, the individual at the site fulfilling that 
role will be the only unblinded member of the site personnel. 
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8.9. 
Treatment Logistics and Accountability 
8.9.1. 
Packaging, Labeling, and Storage  
A medication numbering system will be used to label unblinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
The unblinded pharmacist will prepare the unblinded investigational product and dispense it in a 
blinded manner to the blinded study staff for administration to the patient. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.9.2. 
Supply and Disposition of Treatments  
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed at the site with approval 
by the Sponsor or returned to the Sponsor or designee. 
8.9.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication 
• Dispensed to each patient 
• Returned from each patient (if applicable), and 
• Disposed of at the site or returned to the Sponsor or designee 
All accountability records must be made available for inspection by the Sponsor and regulatory 
agency inspectors; photocopies must be provided to the Sponsor at the conclusion of the study. 
8.9.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the Sponsor 
and regulatory agency inspectors. 
8.10. 
Concomitant Medications  
Any treatment administered from the first dose of study drug to the final study visit will be 
considered concomitant medication. This includes medications that were started before the study 
and are ongoing during the study. 
If the local standard-of-care per written policies or guidelines include remdesivir or other agents, 
then they are permitted during the study (if not specified in the exclusion criteria; see 
Section 7.2.2). 
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Concomitant medications in a hospitalized population change daily and are difficult to collect and 
attribute to success and failure of therapy and impact on safety. Therefore, only select concomitant 
medications (listed in Section 9.2.3.3) will be captured in this trial. The select list of medications 
will be assessed according to the schedule of events (Table 1 for phase 1; Table 2 for phase 2 and 
phase 3).  
8.10.1. 
Prohibited and Permitted Medications  
Patients are not permitted to receive any medication specified in the exclusion criteria for study 
enrollment (Section 7.2.2).  
Patients may otherwise continue their normal regimen of medications and procedures. 
SARS-CoV-2 Vaccination. Current CDC guidance recommends deferral of SARS-CoV-2 
vaccination for at least 90 days after administration of passive antibody treatment (eg, 
REGN10933+REGN10987) (CDC, 2020): 
Based on the estimated half-life of such therapies as well as evidence suggesting that reinfection 
is uncommon in the 90 days after initial infection, vaccination should be deferred for at least 
90 days, as a precautionary measure until additional information becomes available, to avoid 
interference of the antibody treatment with vaccine-induced immune responses. 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit for phase 1 (Table 1) 
and phase 2 (Table 2). 
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9.1.1. 
Phase 1 (Cohort 1 only) 
Table 1: 
Schedule of Events for Phase 1  
Day 
Screening/Baseline1 
Hospitalization/Post-Discharge Period2  
EOS 
-1 to 1 
Discharge 
Before 
Day 29 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 
16, 17, 
18, 19, 
20, 21 
22 
23, 24, 
25, 26, 
27, 28 
29 57 85 113 141 169 
Screen 
Pre- 
Dose Dose Post-
Dose 
Week Number 
1 
 
1 1 1 1 1 1 2 2 2 2 2 2 2 3 
3 
4 
4 
5 
9 13 17 21 25 
Visit Number 
1 
 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16-21 22 23-28 29 30 31 32 33 34 
Window (Days) 
 
 
 
 
±1 
 
 
 
 
 
 
 ±1  ±1  ±1  ±1 
 
±3 
 
±3 ±7 ±7 ±7 ±7 ±7 
 
Screening/Baseline Only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic 
test for SARS-CoV-2 (local)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Vital signs6 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 
infusion-related reactions7,8 
 
 
← Continuous monitoring → 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 
hypersensitivity reactions7,8 
 
 
← Continuous monitoring → 
 
 
 
 
 
Treatment-emergent SAEs7,8 
 
 
← Continuous monitoring → 
Grade 3 or 4 TEAEs7,8 
 
 
← Continuous monitoring → 
Targeted concomitant 
medications8,9 
X 
X 
← Continuous monitoring → 
Post-discharge phone follow-up8 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
X 
 
X 
 
X 
X X X X 
X 
Pregnancy test (WOCBP)10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Laboratory Testing 
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Day 
Screening/Baseline1 
Hospitalization/Post-Discharge Period2  
EOS 
-1 to 1 
Discharge 
Before 
Day 29 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 
16, 17, 
18, 19, 
20, 21 
22 
23, 24, 
25, 26, 
27, 28 
29 57 85 113 141 169 
Screen 
Pre- 
Dose Dose Post-
Dose 
Week Number 
1 
 
1 1 1 1 1 1 2 2 2 2 2 2 2 3 
3 
4 
4 
5 
9 13 17 21 25 
Visit Number 
1 
 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16-21 22 23-28 29 30 31 32 33 34 
Window (Days) 
 
 
 
 
±1 
 
 
 
 
 
 
 ±1  ±1  ±1  ±1 
 
±3 
 
±3 ±7 ±7 ±7 ±7 ±7 
 
Hematology  
(including differential)11 
X 
 
 
X 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Blood chemistry (including AST, 
ALT, CRP, ferritin, LDH)11 
X 
 
 
X 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Coagulation tests  
(D-dimer, PT/INR, aPTT)11 
X 
 
 
X 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Efficacy Assessments (Virologic)  
Saliva for SARS-CoV-2 RT-qPCR 
 
X 
 
 
X 
 X  X  X  X  X  X  
X 
 
X 
 
X 
 
 
 
 
 
Nasal swab for SARS-CoV-2 RT-
qPCR 
 
X 
 
 
X 
 X  X  X  X  X  X  
X 
 
X 
 
X 
 
 
 
 
 
NP swab for SARS-CoV-2 RT-
qPCR 
 
X 
 
 
X 
 X  X  X  X  X  X  
X 
 
X 
 
X 
 
 
 
 
 
Efficacy Assessments (Clinical/Oxygen Status) 
Oxygen delivery device status12 
 
X12 X12 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
 
Vital status12 
 
X12 X12 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
 
Hospitalization status12 
 
X12 X12 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
 
Pharmacokinetics/Immunogenicity 
Serum for PK13 
 
X14 
 
X14 
X 
 X  X  X  
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Serum for ADA15 
 
X15 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
X 
Pharmacodynamic/Biomarkers 
Serum for serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Pharmacogenomics Sub-Study (Optional) 
Blood for RNA3 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for DNA3 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.1.1.1. 
Footnotes for Table 1 Schedule of Events (Phase 1) 
1. Every effort should be made to perform all screening and baseline activities on the same 
day. Randomization within the Interactive Response Technology (IRT) system and 
administration of study drug should occur on the same day (day 1). All samples will be 
collected before study drug administration at the baseline visit except post-infusion PK 
samples. 
2. For a given day, the visit may occur in clinic, as a home-based visit (defined as visits by 
home health care staff, at mobile units, and/or testing centers), or by phone. All samples 
will be collected as indicated whether the patient is hospitalized or has been discharged. 
3. Patients must provide separate consent to collect blood samples as part of the optional 
pharmacogenomics (PGx) sub-study. Blood sample for RNA must be collected pre-dose 
on day 1. Blood sample for DNA should be collected at the screening/baseline visit but 
may be collected at any visit.  
4. Refer to Section 9.2.1.2 for diagnostic test requirements during screening. 
5. Medical history should include collecting onset of pneumonia symptoms.  
6. Vital signs (including respiratory rate, temperature, blood pressure, heart rate, and SpO2) 
will be taken as described in Section 9.2.3.1.  
For patients in the phase 1 sentinel safety group only (Section 3.2.1.1), vital signs will 
be taken once before the infusion, every 15 minutes during the infusion, every 30 minutes 
for the first 2 hours after the infusion is completed, and then once per hour for the following 
4 hours. For all other patients, vital signs will be taken once before the infusion and once 
after the infusion is completed. 
7. Only TEAEs (grade 3 or 4), treatment-emergent SAEs, and treatment-emergent AESIs will 
be recorded in the eCRF.  
8. Patients discharged from the hospital may receive phone follow-up for TEAEs (grade 3 or 
4), treatment-emergent SAEs, treatment-emergent AESIs, and/or targeted concomitant 
medications as indicated in Table 1 (post-discharge phone follow-up). These visits may 
occur in addition to any in-person visit listed for the given day. Phone visits will have a 
window of ±1 day.  
9. Medications will be reviewed and recorded. Only the targeted medications listed in 
Section 9.2.3.3 will be recorded in the eCRF. 
10. Pregnancy testing will be performed locally in women of childbearing potential (WOCBP) 
only. Negative pregnancy test must be confirmed prior to study drug administration. Serum 
or urine pregnancy test are both acceptable. Refer to Section 9.2.3.4 for more information 
on pregnancy testing and contraceptive measures. 
11. Hematology, blood chemistry, and coagulation tests will be collected at the visits indicated 
and results will be entered in the eCRF. Hematology, blood chemistry, and coagulation 
tests must be collected prior to randomization. Testing will be performed locally, and 
standard-of-care labs are acceptable. 
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12. Clinical and oxygen status will be collected 3 times during the screening/baseline visit 
period: prior to randomization, just prior to dosing, and post-dose. Clinical and oxygen 
status will be collected and recorded in the eCRF as described in Section 9.2.5.2. 
13. Actual dosing time and PK sample collection times will be recorded. 
14. At the baseline visit, blood samples for PK assessment will be taken predose and within 60 
minutes after the end of infusion (EOI). The EOI sample should be collected from the arm 
contralateral to that used for IV infusion. If not medically feasible, the EOI sample can be 
drawn from the same arm, but not from the infusion catheter.  
15. The window for predose ADA sample collection is as close to administration of study drug 
as is reasonable. Actual dosing times and ADA sample collection times will be recorded. 
 
 
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9.1.2. 
Phase 2 (Cohort 1A, Cohort 1, Cohort 2*, and Cohort 3*) and Phase 3 (Cohort 
1) 
Patients in cohort 1 enrolled after 691 patients in the cohort (including phase 1 patients) will follow 
the below schedule but will be considered enrolled in phase 3. 
Patients who are not enrolled in the long COVID sub-study (at participating sites) will follow 
Table 2 through EOS on day 57. Patients who enroll in the long COVID sub-study will follow 
Table 2 from screening to day 57, and Table 3 from day 58 to EOS on day 180.  
* Per IDMC recommendation first received on 30 October 2020, and reiterated through 19 February 2021, patient 
enrollment in cohort 2 and cohort 3 has been placed on hold. All currently enrolled patients will have assessments 
and procedures performed according to the Schedule of Events in the protocol version to which they were last 
consented. 
 
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Table 2: 
Schedule of Events for Phase 2 and Phase 3 
Day 
Screening/Baseline1 
Hospitalization/Post-Discharge Period2 
Follow-
up Period EOS16 
-1 to 1 
Discharge 
Before 
Day 29 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 
16, 17, 
18, 19, 
20, 21 
22 
23, 24, 
25, 26, 
27, 28 
29 36 43 50 
57 
Screen Pre- 
Dose Dose Post-
Dose 
Week Number 
1 
 
1 1 1 1 1 1 2 2 2 2 2 2 2 3 
3 
4 
4 
5 
6 7 8 
9 
Visit Number 
1 
 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16-21 22 23-28 29 30 31 32 
33 
Window (Days) 
 
 
 
 
±1 
 
 
 
 
 
 
 ±1  ±1  ±1  ±1 
 
±3 
 
±3 ±3 ±3 ±3 
±3 
 
Screening/Baseline Only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test 
for SARS-CoV-2 (local)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP)5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments (Virologic)  
NP swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
X 
 X  X  
X 
 X  X  X  X 
 
X 
 
X 
 
 
 
 
Efficacy Assessments (Clinical/Oxygen Status) 
Oxygen delivery device status7 
 
X7 X7 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
Vital status7 
 
X7 X7 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
Hospitalization status7 
 
X7 X7 
 
X 
X 
X X X X X X X X X X X X X X 
X 
X 
X 
X 
 
 
 
 
Safety Assessments 
Vital signs8 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 
infusion-related reactions9,10 
 
 
← Continuous monitoring → 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 
hypersensitivity reactions9,10 
 
 
← Continuous monitoring → 
 
 
 
 
Treatment-emergent SAEs9,10 
 
 
← Continuous monitoring → 
Targeted concomitant medications10,11 
X 
X 
← Continuous monitoring → 
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Day 
Screening/Baseline1 
Hospitalization/Post-Discharge Period2 
Follow-
up Period EOS16 
-1 to 1 
Discharge 
Before 
Day 29 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 
16, 17, 
18, 19, 
20, 21 
22 23, 24, 
25, 26, 
27, 28 
29 36 43 50 
57 
Screen Pre- 
Dose Dose Post-
Dose 
Week Number 
1 
 
1 1 1 1 1 1 2 2 2 2 2 2 2 3 
3 
4 
4 
5 
6 7 8 
9 
Visit Number 
1 
 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16-21 22 23-28 29 30 31 32 
33 
Window (Days) 
 
 
 
 
±1 
 
 
 
 
 
 
 ±1  ±1  ±1  ±1 
 
±3 
 
±3 ±3 ±3 ±3 
±3 
 
Post-discharge phone follow-up10 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 X 
 
X 
 
X X X X 
X 
Pregnancy follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Laboratory Testing 
Hematology (including differential)12 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Blood chemistry (including AST, 
ALT, CRP, ferritin, LDH)12 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Coagulation tests  
(D-dimer, PT/INR, aPTT)12 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Pharmacokinetics/Immunogenicity  
Serum for PK13 
 
X14 
 
X14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Serum for ADA15 
 
X15 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pharmacodynamic/Biomarkers 
Serum for serology 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum for cytokines and CK-MB 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Serum for research and cardiac 
biomarkers 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Plasma for research and cardiac 
biomarkers 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Plasma for hsTroponin-T 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
 
 
Pharmacogenomics Sub-Study (Optional) 
Blood for RNA3 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for DNA3 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3: 
Schedule of Events for the Long COVID Sub-Study at Participating Sites 
Day 
Long COVID Follow Up16 
EOS16 
120 
180 
Visit Number 
34 
35 
Window (Days) 
±7 
±7 
 
Questionnaires  
 
 
SE-LC1917 
X 
X 
PGIS17 
X 
X 
Return to usual health17 
X 
X 
Return to usual activities17 
X 
X 
SF-3617 
X 
X 
WPAI+CIQ17 
X 
X 
EQ-5D-5L17 
X 
X 
Safety 
 
 
Treatment-emergent SAEs9 
← Continuous monitoring → 
Hematology (including differential)12,17 
X 
X 
Blood chemistry12,17 
X 
X 
SARS-CoV-2 vaccination status 
X 
X 
Sample Collections 
 
 
NP swab for SARS-CoV-2 RT-qPCR17 
X 
X 
Blood for PBMCs17 
X 
X 
Serum for exploratory long COVID research (SARS-CoV-
2 serology, proteomics, and other research)17 
X 
X 
Plasma for exploratory long COVID research17 
X 
X 
Additional Adverse Events of Special Interest  
Details of positive SARS-CoV-2 local test result18 
continuous monitoring → 
New medical diagnoses or conditions19 
X 
X 
Pharmacogenomics Sub-Study (Optional) 
Blood for DNA3 
X3 
 
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9.1.2.1. 
Footnotes for Table 2 and Table 3 Schedule of Events (Phase 2 and Phase 3) 
1. Every effort should be made to perform all screening and baseline activities on the same 
day. Randomization within the IRT system and administration of study drug should occur 
on the same day (day 1). All samples will be collected before study drug administration at 
baseline visit except post-infusion PK samples. 
2. For a given day, the visit may occur in clinic, as a home-based visit (defined as visits by 
home health care staff, at mobile units, and/or testing centers), or by phone. All samples 
will be collected as indicated whether the patient is hospitalized or has been discharged. 
3. Patients who consent to the optional pharmacogenomics (PGx) sub-study should have a 
blood sample for DNA collected. This may be done during any in-person study visit. 
Efforts should be made to consent patients to the PGx sub-study if they have not already 
consented. Patients who already consented to the sub-study will not be consented a second 
time, and patients who have already provided a DNA sample for the PGx sub-study should 
not have a second sample collected. Refer to Section 9.2.9.4 for more information about 
the PGx sub-study. 
4. Refer to Section 9.2.1.2 for diagnostic test requirements during screening. 
5. Pregnancy testing will be performed locally in women of childbearing potential (WOCBP) 
only. Negative pregnancy test must be confirmed prior to study drug administration. Serum 
or urine pregnancy test are both acceptable. Refer to Section 9.2.3.4 for more information 
on pregnancy testing and contraceptive measures. 
6. Medical history should include collecting onset of pneumonia symptoms.  
7. Clinical and oxygen status will be collected 3 times during the screening/baseline visit 
period: prior to randomization, just prior to dosing, and post-dose. Clinical and oxygen 
status will be collected and recorded in the eCRF as described in Section 9.2.5.2. 
8. Vital signs (including temperature, blood pressure, heart rate, and SpO2) will be collected 
pre-dose and post-dose, as described in Section 9.2.3.1. 
9. Only treatment-emergent SAEs and AESIs will be recorded in the eCRF.  
10. Patients discharged from the hospital will have weekly follow-up for treatment-emergent 
SAEs, treatment-emergent AESIs, and/or targeted concomitant medications as indicated in 
Table 2 (post-discharge phone follow-up), which may occur as a phone call or an in-person 
visit. These visits may occur in addition to any in-person visit for sample collection listed 
for the given day. Phone visits will have a window of ±1 day. 
11. Medications will be reviewed and recorded. Only the targeted medications listed in 
Section 9.2.3.3 will be recorded in the eCRF. 
12. Hematology, blood chemistry, and coagulation tests will be collected at the visits indicated 
and results will be entered in the eCRF. Note that coagulation tests will not be collected as 
part of the long COVID sub-study. Hematology, blood chemistry, and coagulation tests 
must be collected prior to dosing. Testing will be performed locally, and standard-of-care 
labs are acceptable. 
13. Actual dosing time and PK sample collection times will be recorded.  
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14. At the baseline visit, blood samples for PK assessment will be taken predose and within 60 
minutes after the end of infusion (EOI). The EOI sample should be collected from the arm 
contralateral to that used for IV infusion. If not medically feasible, the EOI sample can be 
drawn from the same arm, but not from the infusion catheter.  
15. The window for predose ADA sample collection is as close to administration of study drug 
as is reasonable. Actual dosing times and ADA sample collection times will be recorded. 
16. For patients who are not enrolled in the long COVID sub-study, day 57 will be the EOS 
per Table 2. Patients enrolled in the long COVID sub-study will follow Table 2 from 
screening to day 57, and Table 3 from day 58 to their EOS on day 180.  
For patients who consent to the long COVID sub-study after day 120, the day 120 sample 
collections may be performed outside of the specified visit window. Efforts should be made 
to collect these samples for all consenting patients. 
17. On visit days when other assessments or sample collections are required, the site will verify 
that questionnaires have been completed prior to all other assessments or collections. The 
order of questionnaire completion is as follows: SE-LC19, PGIS, return to usual health, 
return to usual activities, SF-36, WPAI+CIQ, EQ-5D-5L. 
Note that questionnaires will only be administered to sites when regionally available, and 
will only be administered to patients who are able to complete the questionnaires in the 
language available at their site. 
Refer to Section 9.2.9 for additional information regarding assessments and procedures 
related to long COVID analyses. Note that in addition to the analyses planned in this study, 
exit interviews may be conducted by a third party as part of a separate study. Refer to 
Section 9.2.10; additional information, including study visits and windows for these 
interviews, will be detailed in the separate study. 
18. Patients in the long COVID sub-study will be asked to report any positive SARS-CoV-2 
local test results obtained during the period indicated, starting from the day at which they 
consent to the sub-study. Refer to Section 9.2.9.3 for additional information regarding 
collection and reporting. 
19. For patients in the long COVID sub-study, any new medical condition(s) diagnosed after 
randomization will be recorded. Refer to Section 9.2.9.4 for additional information 
regarding collection and reporting. 
9.1.3. 
Early Termination from the Study 
Patients who are withdrawn from the study prior to day 29 will be asked to complete an early 
termination (ET) visit consisting of day 29 assessments and sample collections. In phase 1, patients 
withdrawn from the study after day 29 will be asked to complete an ET visit consisting of the EOS 
visit (day 169) assessments and sample collections. In phase 2, patients withdrawn from the study 
after day 29 will be asked to complete an ET phone visit consisting of the EOS visit (day 57) 
assessments. 
All patients who are withdrawn from the study will be contacted by phone to obtain vital status. 
For patients in phase 1, this call will occur on day 169. For patients in phase 2, this will occur on 
day 57. 
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9.1.4. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of 
treatment-emergent SAEs, AESIs, and (for phase 1) grade 3 or 4 TEAEs, or for any other reason, 
as warranted. 
9.2. 
Study Procedures  
This section describes the procedures and collections that will be performed in this study. 
Procedures and collections will occur according to the schedule of events in Section 9.1. 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population. 
9.2.1.1. 
Informed Consent 
Informed consent must be obtained according to the requirements described in Section 13.2. 
Optional informed consent may be obtained for participation in the pharmacogenomic sub-study 
described in Section 9.2.10. 
9.2.1.2. 
Diagnostic Test for SARS-CoV-2 
The investigator or sub-investigator will verify that the patient has tested positive for SARS-CoV-
2, either at screening or by historical record (refer to Section 7.2.1 for detailed screening 
requirements). For tests performed at screening, the local testing result, specimen type, assay type, 
and date of the test will be recorded in the eCRF. If testing was performed outside of the allowed 
window (Section 7.2.1), a new test is required for study inclusion. 
9.2.1.3. 
Demographics 
See Section 5.1. 
9.2.1.4. 
Medical History 
Medical history will include the following:  
• Onset of pneumonia symptoms (collected on the Pneumonia Status at Baseline eCRF) 
• Prior and current symptoms related to COVID-19 
• Menopausal history 
9.2.1.5. 
Weight and Height 
Weight and height will be recorded at the screening/baseline visit. 
9.2.2. 
Treatment 
See Section 8.1. 
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9.2.3. 
Safety Procedures  
9.2.3.1. 
Vital Signs 
Vital signs will include respiratory rate (phase 1 only), temperature, blood pressure, heart rate, and 
SpO2. Vital signs will be assessed according to the schedule of events in Section 9.1. 
9.2.3.1.1. Respiratory Rate (Phase 1 Only) 
In phase 1, respiratory rate (per minute) will be measured before and after infusion. 
9.2.3.1.2. Body Temperature 
Body temperature measurement will occur before taking antipyretics or more than 4 hours after 
last dose of antipyretics. Temperature will be measured to monitor the patient’s status regarding 
fever. Temperature may be measured using the following methods: axilla, oral, tympanic, or 
temporal according to local hospital protocols and according to the manufacturer’s instructions for 
use of the device. Body temperature should be measured using the same method each time. 
Temperature should be measured after at least 5 minutes of rest (supine or sitting).  
9.2.3.1.3. Blood Pressure 
Blood pressure should be measured after the patient has been resting quietly for at least 5 minutes 
and may be obtained from a seated or supine position. 
9.2.3.1.4. Heart Rate 
Pulse (per minute) will be measured. 
9.2.3.1.5. Oxygen Saturation Level (SpO2) and Fraction of Inspired Oxygen (FiO2) 
Supplemental oxygen/FiO2 use will be measured to monitor the patient’s status regarding gas 
exchange. As applicable, the following will be recorded: 
• Oxygen flow rate in L/min (if not mechanically ventilated)  
• FiO2 (if mechanically ventilated) 
• Resting SpO2 (in %) will be measured in all patients to assess arterial oxyhemoglobin 
saturation. SpO2 will be measured using a fingertip or similar non-invasive device 
following 5 minutes of rest (inactivity) while supine, semi-recumbent, or sitting and 
will only be measured in the presence of a good SpO2 wave form. SpO2 must be 
measured simultaneously with recorded supplemental oxygen/FiO2 data. 
9.2.3.2. 
Adverse Event Monitoring 
Treatment-emergent serious adverse events (as defined in Section 10.2.1) and treatment-emergent 
AESIs (as defined in Section 10.2.3) will be recorded. In phase 1, TEAEs (grade 3 or 4) will also 
be recorded. 
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9.2.3.3. 
Targeted Medication and Procedures Review 
A targeted list of the following concomitant medications and procedures will be recorded in the 
eCRF: 
• Putative COVID-19 treatments (eg, remdesivir, convalescent serum, IVIG, IL-6 
receptor inhibitors [eg, sarilumab, tocilizumab], JAK inhibitors [eg, baricitinib], 
ivermectin)  
• SARS-CoV-2 vaccinations 
• Antipyretics (eg, aspirin, acetaminophen, ibuprofen) 
• Anticoagulants (eg, enoxaparin, warfarin, rivaroxaban) 
• Immunosuppressants (eg, cyclosporine A, corticosteroids) 
• Interferon beta  
• Theophylline 
• Antiepileptics (eg, carbamazepine, divalproex, phenytoin) 
• Antiarrhythmics (eg, digoxin, disopyramide, procainamide) 
• Antivirals, antibacterial, and antifungals 
• Antiparasitics (chloroquine or hydroxychloroquine) 
• Angiotensin receptor blockers (eg, losartan, valsartan) 
• Angiotensin converting enzyme inhibitors (eg, benazepril, lisinopril)  
• Treatment related to reported AEs (eg, supplemental oxygen, packed red blood cells) 
9.2.3.4. 
Pregnancy Test and Reporting for Women of Childbearing Potential 
Pregnancy testing may be satisfied by either serum pregnancy test or by urine β-HCG. Pregnancy 
tests are a requirement for WOCBP only. Pregnancy test will be performed at the local laboratory. 
WOCBP and female partners of male patients will be advised to use highly-effective contraception 
for 6 months after the receiving study drug (see Section 7.2.2).  
In phase 2, WOCBP will be followed up for any pregnancy at the EOS phone visit. 
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9.2.4. 
Laboratory Testing 
Blood Chemistry  
Samples for laboratory testing will be collected at visits according to the schedule of events in 
Section 9.1.  
Tests will include: 
Sodium 
Blood urea nitrogen (BUN) 
Alkaline phosphatase  
Potassium 
Aspartate aminotransferase (AST) 
Creatinine 
Chloride 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK) 
Carbon dioxide 
Total bilirubin 
Lactate dehydrogenase (LDH) 
Glucose 
Albumin  
C-reactive protein (CRP) 
Ferritin 
 
 
Hematology 
Hematology samples will be analyzed by a local laboratory. Detailed instructions for blood sample 
collection are in the laboratory manual provided to study sites. 
The results of hematology testing that is performed as part of the patient’s standard-of-care will be 
shared with the Sponsor. When CBC is performed as part of the patient’s clinical care, the results 
will be entered in eCRF according to the schedule of events in Section 9.1.  
Tests will include: 
Hemoglobin 
Differential: 
Neutrophils 
Hematocrit 
 
Lymphocytes 
Red blood cells (RBCs) 
 
Monocytes 
White blood cells (WBCs) 
 
Basophils 
Platelet count 
 
Eosinophils 
Other Laboratory Tests 
Coagulation tests: D-dimer, prothrombin time (PT/INR), activated partial thromboplastin time 
(aPTT) 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.  
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as treatment-emergent SAEs are provided in 
Section 10.1.1. 
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9.2.5. 
Efficacy Procedures  
9.2.5.1. 
Sample Collection for RT-qPCR Analysis 
Virologic samples will be used to determine presence or absence of SARS-CoV-2 virus, including 
at baseline, and to measure viral load via RT-qPCR analysis. Samples may additionally be used 
for exploratory viral RNA sequencing (NP, nasal, saliva) and/or viral culture (NP, nasal). Only NP 
swabs will be collected for virology testing after phase 1. NP samples with an original RT-qPCR 
result above the Upper Limit of Quantification (ULOQ) will be diluted and retested by RT-qPCR. 
Additional details regarding sample collection and analysis can be found in the laboratory manual. 
Patient refusal to provide virologic samples will not be noted as a protocol deviation.  
9.2.5.2. 
Clinical and Oxygen Status  
Clinical and oxygen status will be collected and recorded in the eCRF as follows: 
• Oxygen delivery device status: day 2: record the worst status since 2 hours after EOI 
up to 00:00 on day 2; day 3 and later: record the worst status in the past 24 hours (00:00 
to 00:00) of that study day (eg, for day 3, record the worst status between 00:00 and 
23:59 on day 3). 
• Vital Status: Record vital status (dead or alive) of the day and record any death (if 
applicable) on the day of death. 
• Hospitalization Status: Starting on day 2, record daily whether patient is hospitalized 
without requiring medical care or discharged.  
These records will be used to calculate the daily ordinal scale (Section 9.2.5.2.4). 
9.2.5.2.1. Oxygen Delivery Device Status 
The type of oxygen delivery device used will be recorded (eg, nasal cannula, simple face mask, 
non-rebreather mask, non-invasive ventilation, or invasive mechanical ventilation).  
The most invasive type of oxygen devices used in the past 24 hours (00:00 to 00:00) will be 
recorded. 
9.2.5.2.2. Vital Status 
The patients’ vital status (ie, whether they are alive or not) as of the current day will be recorded. 
9.2.5.2.3. Hospitalization Status 
The patients’ hospitalization status (ie, whether the patient is hospitalized requiring medical care 
or not and if the patient was discharged) will be recorded. This will be used to calculate the daily 
ordinal score. 
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9.2.5.2.4. Clinical Status Assessment (7-Point Ordinal Scale) 
Based on the clinical and oxygen status (described in Section 9.2.5.2), an ordinal scale score will 
be generated automatically and used to assess clinical improvement. The ordinal scale score rates 
a patient’s clinical status as follows (Peterson, 2017): 
[1] Death 
[2] Hospitalized, requiring invasive mechanical ventilation or ECMO 
[3] Hospitalized, requiring non-invasive ventilation or high flow oxygen devices 
[4] Hospitalized, requiring supplemental oxygen 
[5] Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care 
(COVID-19-related or otherwise) 
[6] Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care 
[7] Not hospitalized 
9.2.6. 
Drug Concentration and Measurements 
Samples for PK assessment will be collected at the indicated timepoints in the schedule of events. 
For information concerning unused samples and exploratory research, refer to Section 9.2.8. 
9.2.7. 
Immunogenicity Measurements and Samples 
Samples for ADA and NAb assessments will be collected at the timepoints listed in the schedule 
of events. For information concerning unused samples and exploratory research, refer to 
Section 9.2.8. 
9.2.8. 
Exploratory Pharmacodynamic/Biomarker Procedures 
This section describes planned exploratory analyses, some of which may not be reported in the 
CSR. 
Note that any biological samples collected during the study which are not used for their planned 
purpose, or for which material remains after their planned analysis, may be kept for up 15 years 
after study completion (or for a shorter time period if required per regional laws and regulations) 
for use in exploratory research related to how the study drugs work and to study SARS-CoV-2. 
9.2.8.1. 
Virology 
Viral Sequencing 
In support of public health initiatives to track SARS-CoV-2 genetic variants, as well as to monitor 
for possible viral resistance, viral genome sequencing will be performed on all viral nucleic acid 
isolated from NP, nasal swab, and/or saliva samples, at baseline and in cases of a positive RT-
qPCR result. Sequencing analyses will consist of the entire viral genome, including the full gene 
sequence that encodes the SARS-CoV-2 S protein. 
Viral sequencing may be performed on post-treatment samples to assess the emergence of 
sequence variants and to understand the potential relationship between genetic mutations and mAb 
functional activity. Viral sequencing may also be done on placebo controls to determine whether 
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any genetic mutations observed in the mAb treatment group are naturally emergent genetic 
variants.  
Viral variants suspected to confer decreased susceptibility to REGN10933 and/or REGN10987 
will be evaluated in nonclinical work separate from this protocol. 
The results of the viral sequencing may not be included in the CSR. 
Viral Infectivity 
To explore the effects of REGN10933+REGN10987 on infectivity of SARS-CoV-2, we may use 
plaque forming unit (PFU), viral culture, or subgenomic mRNA viral RT-qPCR assays. In vitro 
SARS-CoV-2 infectivity of cultured cells may be explored using NP samples. Infectivity of cells 
grown in culture may be assessed by PFU assays and/or immunofluorescence assays. We may also 
use sub-genomic viral mRNA transcript assays, such as RT-qPCR or subgenomic mRNA 
sequencing, or other measures of in vivo infectivity potential. Viral sub-genomic mRNA is 
transcribed only in infected cells and is not packaged into virions, and therefore an indicator of 
actively-infected cells. These data may be associated with other RT-qPCR measuring viral load.  
9.2.8.2. 
Hematology for Complete Blood Count and Differential 
Neutrophil-lymphocyte ratio (NLR) will be assessed, as well as other hematological biomarkers. 
NLR is an inflammatory marker that may serve as an independent risk factor for in-hospital 
mortality of patients with COVID-19. Assessment of NLR trends may therefore aid in identifying 
patients with COVID-19 who are at higher risk of complications (Liu, 2020) (Qin, 2020). 
Relationships will be evaluated between NLR and clinical outcomes in treatment versus placebo 
arms. 
9.2.8.3. 
Serum and Plasma for Disease Biomarkers 
Changes in concentrations of serum/plasma biomarkers associated with inflammation and disease 
progression will be assessed, including the relationship between concentration changes and clinical 
outcomes in treatment versus placebo arms. The association between changes in disease related 
biomarkers with clinical endpoints will be evaluated.  
Biomarkers may include (but are not limited to) CRP, LDH, D-Dimer, and ferritin will be assessed 
as exploratory endpoints. CRP is a general inflammation marker that correlates with severity of 
COVID-19 including lung lesions, supplemental O2 requirements, and death (Qin, 2020) (Young, 
2020) (Wang, 2020a) (Ruan, 2020) (Luo, 2020). LDH was identified as a predictive factor for 
early recognition of lung injury and advanced COVID-19 cases (Han, 2020). Ferritin is a general 
inflammation marker associated with severity of COVID-19 (Qin, 2020). D-dimer levels >1 
μg/mL have been reported to identify patients with poor prognosis for COVID-19 (Zhou, 2020). 
9.2.8.4. 
Serological Immunoassays for Anti-SARS-CoV-2 Antibodies 
To explore the impact of baseline humoral activity against SARS-CoV-2 on the response to 
REGN10933+REGN10987, serological immunoassays will be used to detect antibodies at 
baseline against the SARS-CoV-2 S protein and/or N protein. Neutralization assays may also be 
used to evaluate the function of endogenous baseline anti--SARS-CoV-2 antibodies. Associations 
will be evaluated with clinical outcomes. Measurement of antibodies against the N protein post-
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treatment will also be used to evaluate whether or not REGN10933+REGN10987 effects the 
endogenous humoral immune response to SARS-CoV-2. 
9.2.8.5. 
Serum and Plasma for Research 
Research serum and plasma are being collected and banked for exploratory research related to 
COVID-19, SARS-CoV-2, REGN10933+REGN10987, host and viral biological pathways, and 
other mechanisms related to disease activity and clinical outcomes.  
9.2.8.6. 
Complement 
Complement activation has been hypothesized to contribute to the maladaptive inflammatory 
response seen in some patients with advanced COVID-19. Circulating complement biomarker 
concentrations may be assessed in order to understand the involvement of the classical lectin 
and/or alternative complement pathways in the pathogenesis of COVID-19 and clinical outcomes. 
9.2.8.7. 
Cytokines 
The initial inflammatory responses to an infection are rapid and non-specific, regulated by 
proinflammatory cytokines such as interleukin-6 (IL-6). As IL-6 has been implicated in the 
severity of COVID-19, IL-6 and other cytokines, including but not limited to, IL-8, IL-1ß, IFNγ, 
TNFα, IL-10 and MIP-1 may be measured. Additional cytokines may be interrogated through the 
use of cytokine panels.  
9.2.8.8. 
Serum and Plasma for Cardiac Biomarkers 
SARS-CoV-2 has been shown to infect the myocardium, and emerging evidence suggests that 
myocardial damage may be a long-term clinical consequence of COVID-19 (Lindner, 2020) 
(Puntmann, 2020). Cardiac biomarkers, including troponins, N-terminal pro B-type natriuretic 
peptide (NT-proBNP), and creatine kinase-MB (CK-MB), can be elevated in patients with 
COVID-19 and have been shown to correlate with adverse outcomes (Puntmann, 2020) (Sandoval, 
2020) (Shi, 2020). Relationships may be evaluated between these biomarkers, as well as other 
biomarkers and clinical outcomes in treatment versus placebo arms. 
If initial analyses reveal no signal of cardiac injury, subsequent analyses may be omitted. 
9.2.9. 
Long COVID Sub-Study (at Participating Sites) 
To better understand the nature of long COVID, as well as the potential relationship between prior 
treatment of SARS-CoV-2 infection with REGN10933+REGN10987 and subsequent 
development of long COVID, study participants in this sub-study will be evaluated using 
questionnaires (SE-LC19, PGIS, PGIC return to usual health, return to usual activities, SF-36, 
WPAI+CIQ, EQ-5D-5L), as well as NP swab and blood sample collections. All questionnaires 
will be administered by interviewers by phone or in person.  
Note that patient-reported outcome data are generally not reportable as individual AEs, with 
exceptions as described in Section 10.1.1. 
In addition to the procedures outlined in this study, separate exit interviews may be conducted by 
a third party as part of a separate study investigating the symptom experience and impact 
experience of COVID-19. Sites will facilitate the identification of eligible patients according to 
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the pre-specified eligibility criteria of the separate study, and will provide patient contact 
information to the third party. Patients who meet eligibility criteria for this separate study may be 
contacted by the third party to determine their interest in the study. 
9.2.9.1. 
Patient-Reported Evaluation of Long COVID 
Symptom Evolution of Long COVID-19 (SE-LC19) 
In an effort to better understand the symptomatic course of long COVID, the Sponsor developed 
the Symptom Evolution of COVID-19 (SE-LC19). The SE-LC19 expands upon the SE-C19, 
which was developed with the aim of evaluating the acute phase of the disease course.  
The SE-LC19 consists of 40 symptoms, identified based on an evaluation of the currently-available 
literature on symptoms associated with long COVID (CDC, 2021) (NHS, 2021) (WHO, 2021). 
Table 4 lists the symptoms evaluated in the SE-LC19. 
 
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Table 4: 
Symptoms Evaluated in the Symptom Evolution of Long COVID-19 (SE-
LC19) Instrument 
Symptom Evolution of Long COVID-19 (SE-LC19) 
All SE-LC19 Symptoms 
SE-LC19 Category A 
SE-LC19 Category B 
SE-LC19 Category C 
Altered or loss of smell  
Altered or loss of smell  
Altered or loss of smell  
Altered or loss of smell  
Altered or loss of taste  
Altered or loss of taste  
Altered or loss of taste  
Altered or loss of taste  
Body aches such as muscle pain 
or joint pain  
Body aches such as muscle 
pain or joint pain  
Body aches such as muscle 
pain or joint pain  
Body aches such as muscle 
pain or joint pain  
Cough  
Cough  
Cough  
Cough  
Fatigue  
Fatigue  
Fatigue  
Fatigue  
Headache  
Headache  
Headache  
Headache  
Shortness of breath or difficulty 
breathing  
Shortness of breath or 
difficulty breathing  
Shortness of breath or 
difficulty breathing  
Shortness of breath or 
difficulty breathing  
Chest pain 
 
Chest pain 
Chest pain 
Feeling depressed  
Symptoms Included: 7 
Feeling depressed  
Feeling depressed 
Rapid, strong or irregular 
heartbeat 
 
Rapid, strong or irregular 
heartbeat 
Rapid, strong or irregular 
heartbeat 
Brain fog  
 
 
Brain fog  
Diarrhea  
 
Symptoms Included: 10 
Diarrhea  
Dizziness  
 
 
Dizziness  
Feeling Anxious  
 
 
Feeling Anxious  
Fever  
 
 
Fever  
Loss of concentration  
 
 
Loss of concentration  
Memory problems  
 
 
Memory problems  
Pins and needles or numbness  
 
 
Pins and needles or numbness  
Pressure or tightness in chest  
 
 
Pressure or tightness in chest  
Rash  
 
 
Rash  
Sore throat  
 
 
Sore throat  
Stomachache  
 
 
Stomachache  
Chills 
 
 
 
Confusion 
 
 
Symptoms Included: 22 
Difficulty sleeping 
 
 
 
Earache 
 
 
 
Feeling irritable 
 
 
 
Feeling lightheaded 
 
 
 
Hair loss 
 
 
 
Hot flushes 
 
 
 
Inability to find the right words  
 
 
Loss of appetite 
 
 
 
Nausea 
 
 
 
Phlegm 
 
 
 
Red or watery eyes 
 
 
 
Ringing or buzzing in ears 
 
 
 
Runny nose  
 
 
 
Sneezing 
 
 
 
Sweats 
 
 
 
Vomiting  
 
 
 
 
 
 
 
Symptoms Included: 40 
 
 
 
Category A: Symptoms defined as “lingering” and identified across all three guidelines. 
Category B: identified across all three guidelines. 
Category C: identified across at least two or three guidelines. 
Guidelines: (CDC, 2021) (NHS, 2021) (WHO, 2021) 
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Global Impression Items 
The Patient Global Impression of Severity (PGIS) questionnaire will assess the overall subjective 
experience of COVID-19 symptom severity over time. The Return to Usual Health and Return to 
Usual Activities questionnaires will evaluate whether patients have returned to their usual health 
or activities prior to their COVID-19 illness. 
SF-36 
The SF-36 is a short-form, 36-question survey assessing health and quality of life. Questions are 
aggregated into eight scales, which each measure a distinct aspect of health. A score from 0 to 100 
is generated for each scale, where higher scores represent less disability on the scale. The scales 
are further aggregated into two summary scores (also ranging from 0 to 100), which measure 
overall physical health and mental health.  
WPAI+CIQ 
The Work Productivity and Activity Impairment and Classroom Impairment Questions 
(WPAI+CIQ) questionnaire measures the effect of a specific health problem (eg, infection with 
SARS-CoV-2) on work productivity and activity impairment. The specific outcomes measured by 
the questionnaire are absenteeism (work time missed), presenteeism (impairment while working), 
overall work impairment (absenteeism plus presenteeism), and activity impairment (impairment 
in regular activities). Each score is represented as a percentage, with higher scores indicating less 
productivity or greater impairment. 
EQ-5D-5L  
The EQ-5D-5L covers 5 health domains: mobility, self-care, usual activities, pain, and anxiety. 
Patients rate each domain on 5 level severity scale: having no problems, having slight problems, 
having moderate problems, having severe problems, and being unable to do/having extreme 
problems. In addition to the 5 domains, patients record their overall health on a visual analog scale, 
ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).  
9.2.9.2. 
Nasopharyngeal Swab Sample and Blood Sample Collections (Long COVID 
Assessment) 
Nasopharyngeal (NP) swab samples will be collected to assess the presence or absence of 
SARS-CoV-2 by RT-qPCR, and may be used for viral sequencing as described in Section 9.2.8.1 
Additional details regarding sample collection can be found in the laboratory manual. 
Serum, plasma, and PBMC samples will be collected and banked for subsequent analyses. Such 
analyses may include, but are not limited to, multiplex proteomic profiling, high-throughput RNA 
sequencing, flow cytometry, and serologic immunoassays to detect antibodies against 
SARS-CoV-2.  
The serum, plasma, and PBMC-based analyses will be used to address scientific questions related 
to long COVID, such as the identification of prognostic biomarkers, understanding whether long 
COVID represents a single versus multiple unique pathologies, and associating biomarker profiles 
with patient-reported outcomes data. Analyses performed from banked samples may also be 
integrated with biomarker and other data from samples that were collected during the acute phase 
of SARS-CoV-2 infection. This will enable relationships between acute and long-term phases of 
COVID-19 to be explored, including better understanding the biology of COVID-19 over time, 
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and evaluating potential biomarkers during acute infection that may be predictive of casirivimab 
and imdevimab response during the long-term phase of disease. 
Unused or residual samples may be retained as described in Section 9.2.8. 
9.2.9.3. 
Monitoring for SARS-CoV-2 Reinfection 
Patients in the long COVID sub-study will be asked to report any positive SARS-CoV-2 local test 
results obtained outside of the study, starting from the day at which they consent to the long 
COVID sub-study. Test results obtained prior to the date of consent will not be collected. Positive 
results will be reported as an AESI (Section 10.1.4). 
Details regarding the positive SARS-CoV-2 local test result (eg, date of testing, specimen type, 
assay used) will be captured in the corresponding AESI data collection page. 
9.2.9.4. 
Recording New Medical Diagnoses or Conditions 
In the long COVID sub-study, any new medical condition(s) diagnosed after randomization (eg, 
newly diagnosed diabetes mellitus) will be captured and reported as an AESI, but will not require 
expedited reporting (Section 10.1.4). 
Patients who previously consented to the sub-study but have already completed their end of study 
visit will be asked to consent to have this information collected. 
Details regarding the new diagnoses or conditions (eg, preferred term [PT] for the diagnosis, date 
of diagnosis, and any other available information) will be captured in the corresponding AESI data 
collection page. 
9.2.10. 
Pharmacogenomic Analysis (Optional) 
Eligible patients who agree to participate in the genomics sub-study will be required to consent to 
this optional sub-study before collection of samples. When enrollment was open, newly-enrolled 
patients had blood samples collected for both DNA and RNA. Patients who are currently enrolled 
and subsequently consent to the sub-study will only have a blood collection for DNA. Patients 
who have already consented to this sub-study cannot consent a second time. 
The blood sample for RNA must be collected pre-dose on day 1. Blood sample for DNA should 
be collected at the screening/baseline visit but may be collected at any visit.  
The samples will be collected for pharmacogenomics analyses to understand the genetic and/or 
transcriptional determinants of efficacy and safety associated with the treatments in this study and 
the molecular basis of COVID-19 (and long COVID, as applicable). These samples will be single-
coded as defined by the International Council for Harmonisation (ICH) guideline E15. Samples 
will be stored for up to 15 years after the final date of the database lock (or for a shorter time period 
if required per regional laws and regulations). If there are specific site or country requirements 
involving the pharmacogenomic analyses which the Sponsor is unable to comply with, samples 
will not be collected at those sites.  
The purpose of the pharmacogenomic analyses is to identify genomic and/or transcriptional 
associations with clinical or biomarker response to REGN10933+REGN10987, other COVID-19 
clinical outcome measures and possible treatment-emergent SAEs and AESIs. In addition, 
associations between genomic variants and prognosis or progression of COVID-19 (and long 
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COVID, as applicable). may also be studied. These data may be used or combined with data 
collected from other studies to identify and validate genomic and transcriptional markers related 
to the study drug, target pathway, COVID-19, or long COVID. 
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions. Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing (or other methods for quantitating RNA expression) may also be performed. The list 
of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period.  
Results from the genomic and transcriptional analyses will not be reported in the CSR. 
10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events  
10.1.1. 
General Guidelines 
In this study, only targeted treatment-emergent AEs will be recorded: 
• All phases: Treatment-emergent AESIs (grade ≥2 hypersensitivity and grade ≥2 IRRs; 
see Section 10.1.3) 
• All phases, including long COVID sub-study: Treatment-emergent SAEs 
• Phase 1 only: TEAEs (grade 3 or grade 4 only) 
• Long COVID sub-study only: positive SARS-CoV-2 local test result, from the day of 
consent to sub-study until day 180 
• Long COVID sub-study only: Any new medical condition that was diagnosed after 
randomization, until day 180 
The investigator must promptly record treatment-emergent SAEs, treatment-emergent AESIs), and 
(in phase 1 only) grade 3 or 4 TEAEs occurring during the observation period (see 
Section 11.4.10.1). Medical conditions that existed or were diagnosed prior to the signing of the 
informed consent will be recorded as part of medical history. Abnormal laboratory values and vital 
signs observed at the time of informed consent should also be recorded as medical history. Any 
subsequent worsening (ie, any clinically significant change in frequency and/or intensity) of a pre-
existing condition that is temporally associated with the use of the study drug should also be 
recorded as TEAE, provided that it fulfills the above criteria. 
Throughout the study, the investigator will determine whether any treatment-emergent SAEs, 
treatment-emergent AESIs, and (in phase 1 only) grade 3 or 4 TEAEs have occurred by evaluating 
the patient. These events may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit. Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms. The investigator must assess all TEAEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2. 
The investigator’s assessment must be clearly documented in the site’s source documentation with 
the investigator’s signature. The investigator should follow up on TEAEs (grade 3 or 4), treatment-
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emergent SAEs, and treatment-emergent AESIs until they have resolved or are considered 
clinically stable. 
Always report the diagnosis as the AE term. When a diagnosis is unavailable, report the primary 
sign or symptom as the AE term with additional details included in the narrative until the diagnosis 
becomes available. If the signs and symptoms are distinct and do not suggest a common diagnosis, 
report them as individual entries.  
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
investigator to determine their clinical significance and whether they fulfil the criteria of TEAEs 
(grade 3 or 4), treatment-emergent SAEs, or treatment-emergent AESIs and will need to be 
reported. Isolated abnormal laboratory results, vital sign findings, or other diagnostic findings (ie, 
not part of a reported diagnosis) should be reported as TEAEs if they fulfill reporting criteria for 
the study (ie, treatment-emergent SAE, treatment-emergent AESI, TEAE [grade 3 or 4]) or require 
corrective treatment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization). A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-planned (prior to 
signing the informed consent form [ICF]) procedures, treatments requiring hospitalization for pre-
existing conditions that do not worsen in severity, and admission for palliative or social care should 
not be reported as SAEs (see Section 10.2 for definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Any treatment-emergent SAE that may occur subsequent to the reporting period (end of study) 
that the investigator assesses as related to study drug should also be reported. 
All treatment-emergent SAEs, treatment-emergent AESIs, and pregnancies are to be reported 
according to the procedures in Section 10.1.3.  
Note that patient-reported outcome (PRO) data (eg, patient-reported questionnaires, surveys, and 
instruments) are generally not reportable as individual AEs. However, if the investigator is made 
aware of any AE that (in his or her judgement) is related to study drug, the AE will be reported 
and recorded as described in Section 10.1.2. 
10.1.2. 
Reporting Procedure  
All treatment-emergent SAEs, treatment-emergent AESIs, and (in phase 1 only) treatment-
emergent grade 3 or 4 AEs must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the blinded study drug. A detailed narrative summarizing 
the course of the event, including its evaluation, treatment, and outcome should be provided on the 
AE eCRF. Specific or estimated dates of event onset, treatment, and resolution should be included, 
when available. Medical history, concomitant medications, relevant concomitant procedures, and 
laboratory data that are relevant to the event should also be summarized in the narrative. For fatal 
events, the narrative should state whether an autopsy was or will be performed and include the 
results if available. Information not available at the time of the initial report must be documented 
in a follow-up report. Source documents (including hospital or medical records, diagnostic reports, 
etc) will be summarized in the narrative on the AE eCRF and retained at the study center and 
available upon request.  
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Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the Sponsor (or designee) within 24 hours of 
learning of the event: 
• Treatment-emergent SAEs 
• Treatment-emergent AESIs (serious and nonserious), defined as: 
− Grade ≥2 infusion-related reactions 
− Grade ≥2 hypersensitivity reactions  
• Pregnancy: Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the Sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female study patient or female partner of a male study 
patient for up to 6 months after the last dose of study drug. Any complication of 
pregnancy affecting a female study patient or female partner of a male study patient, 
and/or fetus and/or newborn that meets the SAE criteria must be reported as an SAE. 
Outcome for all pregnancies should be reported to the Sponsor. 
10.1.4. 
Other Adverse Events of Special Interest That Do Not Require Expedited 
Reporting to Sponsor 
The following is considered an AESI and will require additional data collection (Section 9.2.9.4). 
However, these AESIs do not require expedited reporting to the Sponsor: 
• Long COVID sub-study only: positive SARS-CoV-2 local test result 
• Long COVID sub-study only: any new medical condition that was diagnosed after 
randomization  
10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug (ICH 
E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
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• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an adverse event that had occurred 
in a more severe form, might have caused death. 
• Requires in-patient re-hospitalization (readmission after discharge) or prolongation 
of existing hospitalization. In-patient hospitalization is defined as a hospital admission 
(any duration) or an emergency room visit for longer than 24 hours. Prolongation of 
existing hospitalization is defined as a hospital stay that is longer than was originally 
anticipated for the event or is prolonged due to the development of a new adverse event 
as determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).  
• Is a congenital anomaly/birth defect 
• Is an important medical event – Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse).  
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical interest specific to the Sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the Sponsor can be appropriate. Such an event might warrant further investigation in order to 
characterize and understand it.  
Adverse events of special interest for this study are defined in Section 10.1.3.  
10.2.3.1. Infusion-Related Reactions and Hypersensitivity 
Infusion-related reactions are defined as any relevant adverse events that occurs during the infusion 
or up to day 4.  
Hypersensitivity reactions are defined as any relevant adverse event that occurs during the infusion 
or up to study day 29. 
10.2.4. 
Severity 
The severity of adverse events (including test findings classified as adverse events) will be graded 
using the current version of the NCI-CTCAE v5.0 (Division of Cancer Treatment and Diagnosis 
[DCTD], 2020). TEAEs that are evaluated as CTCAE grade 3 or 4 will be collected in addition to 
treatment-emergent SAEs and treatment-emergent AESIs as discussed above.  
Treatment-emergent AEs, treatment-emergent SAEs, or treatment-emergent AESIs not listed in 
the NCI-CTCAE will be graded according to the scale in Table 5.  
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Table 5: 
NCI-CTCAE Severity Grading System for Adverse Events (v5.0) 
Grade 
Severity 
Description 
1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
2  
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL)* 
3  
Severe 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL† 
4  
Life-threatening 
Life threatening consequences; urgent intervention indicated 
5  
Death 
Death related to adverse events 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
† Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.  
10.2.5. 
Causality 
The Investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions. The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset versus time drug was administered 
• Nature of the reactions: immediate versus long term 
• Clinical and pathological features of the events  
• Existing information about the drug & same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The adverse event follows a reasonable temporal sequence from study drug 
administration and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
or 
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− The adverse event follows a reasonable temporal sequence from study drug 
administration and is a known reaction to the drug under study or its class of drugs 
or is predicted by known pharmacology. 
• Not Related: 
− The adverse event does not follow a reasonable sequence from study drug 
administration or can be reasonably explained by the nature of the reaction, 
patient’s clinical state (eg, disease under study, concurrent diseases, and 
concomitant medications) or other external factors. 
Causality to the study conduct (protocol specified procedure): 
• Related: 
− The adverse event follows a reasonable temporal sequence from a protocol 
specified procedure and cannot be reasonably explained by the nature of the 
reaction, patient’s clinical (eg, disease under study, concurrent diseases, 
concomitant medications), or other external factors. 
• Not Related: 
− The adverse event does not follow a reasonable sequence from a protocol specified 
procedure or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications) or other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the Sponsor in a timely fashion. The Sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments 
(eg, Global Patient Safety; Biostatistics and Data Management). Safety monitoring will be 
performed on an ongoing basis (eg, individual review of SAEs) and on a periodic cumulative 
aggregate basis. 
10.4. 
Notifying Health Authorities, Institutional Review Board, Ethics 
Committee, and Investigators 
During the study, the Sponsor and/or the CRO will inform health authorities, ECs/Institutional 
Review Board (IRBs), and the participating investigators of any SUSARs (Suspected Unexpected 
Serious Adverse Reactions) occurring in other study centers or other studies of the active study 
drug, as appropriate per local reporting requirements. In addition, the Sponsor and/or CRO will 
comply with any additional local safety reporting requirements. All notifications to investigators 
will contain only blinded information.  
Upon receipt of the Sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the IRB/EC unless delegated to the Sponsor. 
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Event expectedness for study drug is assessed against the Reference Safety Information section of 
the Investigator’s Brochure(s) that is effective for expedited safety reporting.  
At the completion of the study, the Sponsor will report all safety observations made during the 
conduct of the trial in the Clinical Study Report to health authorities and ECs/IRB as appropriate. 
11. 
STATISTICAL PLAN  
This section provides the basis for the statistical analysis plans (SAPs) for the study. There will be 
separate SAPs for different portions of the study. The phase 1/2 SAP(s) specified the analysis for 
portions of phase 1 and phase 2 patients. The phase 1/2/3 SAP specifies the final efficacy and 
safety analyses for the remaining patients across all three study phases. The final SAPs will be 
issued before the first database lock in each portion of the study. 
Endpoints are listed in Section 4. Analysis variables are listed in Section 5.  
Overview of the Final Statistical Analysis Plan 
This final SAP outlines the strategy and statistical methods to be used in the final analysis of data 
from all phases and all cohorts in the prematurely terminated study COV-2066, as below: 
Efficacy Analysis 
The efficacy analysis will be performed for the modified full analysis set (mFAS, defined in 
Section 11.3) of the following pooled cohort of patients and individual subsidiary cohorts, 
representing the totality of patients in this prematurely terminated study who were not unblinded 
in the database lock on 22 December 2020. In this document, the prematurely terminated phase 3 
cohort 1 is referred as phase 3 cohort 1 and prematurely terminated phase 2 cohort 1A as phase 2 
cohort 1A. 
• Pooled phase 3 cohort 1 and phase 2 cohort 1A 
• Phase 3 cohort 1  
• Phase 2 cohort 1A 
In each of these data sets (ie, the 2 prematurely terminated cohorts and the pooled cohort), the 
analyses will be conducted in the mFAS for the following patient populations. The mFAS is 
defined as patients that have a positive central-lab confirmed SARS-CoV-2 RT-qPCR result from 
an NP swab sample and the efficacy analysis was conducted in the mFAS to ensure detectable 
virus was present at baseline. 
• Seronegative mFAS 
• High Viral Load mFAS, where high viral load is defined as >106 copies/mL at baseline 
• Overall mFAS 
The primary virologic endpoint is time-weighted average change from baseline viral load in 
nasopharyngeal (NP) samples through Day 7. The primary analysis will be performed in the 
Seronegative mFAS population that is combined across the 2.4 g and 8g doses and pooled across 
phase 3 cohort 1 and phase 2 cohort 1A. 
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The primary clinical endpoint is death or mechanical ventilation. It will be estimated based on the 
proportion of patients who died or went on mechanical ventilation from Day 6 through Day 29, 
where events occurring during the first 5 days will excluded because of the notion that clinical 
impact would occur only after achieving several days of viral suppression. This observation was 
noted in the analysis of data from phase 1/2 portion of this study. In addition, the endpoint of death 
or mechanical ventilation from Day 1 through Day 29 will also be evaluated. The primary analysis 
will be performed for the High Viral Load mFAS, Seronegative mFAS, and the Overall mFAS in 
the pooled phase 3 cohort 1 and phase 2 cohort 1A and combined across the 2.4 g and 8 g doses 
of REGN10933+REGN10987. To control alpha at a strict 0.05 level, the two primary endpoints 
will be tested hierarchically, with the virologic endpoint tested first.  
Safety Analysis 
The safety analysis will be performed for the following cohorts, separately. Patients in phase 1/2 
cohort 1, phase 2 cohort 2 and cohort 3 are included into the analysis because more safety data 
were collected for the patients after the database lock on 22 December 2020. 
• Phase 2 cohort 1A 
• Phase 2 cohort 2 
• Phase 2 cohort 3 
• Phase 1/2/3 cohort 1 combined  
Pharmacokinetics (PK) and Immunogenicity Analysis 
The PK and ADA analysis will be performed for phase 1/2/3 cohort 1 combined, phase 2 cohort 
1A, phase 2 cohort 2, and phase 2 cohort 3, separately. The NAb analysis will be performed for 
phase 2/3 patients. 
11.1. 
Statistical Hypotheses  
11.1.1. 
Pooled Phase 3 (Cohort 1) and Phase 2 (Cohort 1A) 
The statistical hypotheses are presented in Table 6. 
Table 6: 
Phase 3 Statistical Hypotheses 
Type 
Null Hypothesis 
Primary virologic 
endpoint 
There is no difference in the time weighted average change from baseline viral 
load in NP sample through day 7 between the REGN10933+REGN10987 2.4g 
and 8.0g combined dose group and placebo in the Seronegative mFAS 
population in the pooled phase 3 cohort 1 and phase 2 cohort 1A  
Primary clinical 
endpoint 
There is no risk reduction in the REGN10933+REGN10987 2.4g and 8.0g 
combined dose groups versus placebo in terms of cumulative incidence of death 
or mechanical ventilation from day 6 to day 29 in the High Viral Load mFAS 
population in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
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Type 
Null Hypothesis 
There is no risk reduction in the REGN10933+REGN10987 2.4g and 8.0g 
combined dose groups versus placebo in terms of cumulative incidence of death 
or mechanical ventilation from day 6 to day 29 in the Seronegative mFAS 
population in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
There is no risk reduction in the REGN10933+REGN10987 2.4g and 8.0g 
combined dose groups versus placebo in terms of cumulative incidence of death 
or mechanical ventilation from day 6 to day 29 in the overall mFAS 
population in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
There is no risk reduction in the REGN10933+REGN10987 2.4g and 8.0g 
combined dose groups versus placebo in terms of cumulative incidence of death 
or mechanical ventilation from day 1 to day 29 in the High Viral Load mFAS 
population in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
There is no risk reduction in the REGN10933+REGN10987 2.4g and 8.0g 
combined dose groups versus placebo in terms of cumulative incidence of death 
or mechanical ventilation from day 1 to day 29 in the Seronegative mFAS 
population in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
There is no risk reduction in the REGN10933+REGN10987 2.4g and 8.0g 
combined dose groups versus placebo in terms of cumulative incidence of death 
or mechanical ventilation from day 1 to day 29 in the overall mFAS 
population in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
11.2. 
Justification of Sample Size 
The initial sample size for this study was estimated separately for phase 1 and phase 2 (ie, prior to 
protocol amendment 6) and it was based on the original primary endpoint: virologic efficacy 
endpoint of time-weighted average change from baseline in viral load. The final estimates on 
sample size were based on assumptions related to the clinical endpoint of death or mechanical 
ventilation (see Section 11.2.3).  
11.2.1. 
Phase 1 (Sentinel Safety Group; Cohort 1 only) 
The sample size for phase 1 is a total of 60 patients randomized in a 1:1:1 allocation ratio to 
REGN10933+REGN10987 combination therapy 2.4 g IV, REGN10933+REGN10987 
combination therapy 8.0 g IV, or placebo, ie, approximately 20 patients per arm across 3 treatment 
arms, stratified by the background standard-of-care. The sentinel safety group consists of the first 
30 patients randomized in the combined phase 1 portions of R10933-10987-COV-2066 and 
R10933-10987-COV-2067. 
Since one of the objectives of phase 1 is to assess safety and tolerability, the sample size will allow 
preliminary estimation of the incidences of SAE and AESIs in these investigational treatment arms 
relative to placebo.  
The primary efficacy endpoint in phase 1 is the virologic endpoint of time-weighted average 
change from baseline in viral load (log10 copies/mL) in NP swab samples from day 1 to day 22. 
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Due to lack of data from the literature on the variation of time-weighted average change from 
baseline in viral load in COVID-19, the standard deviation of actual viral load values at a timepoint 
from the literature was used for the following calculation. Assuming standard deviation of 2.1 log10 
copies/mL (Cao, 2020), a sample size of 20 patients per arm in phase 1 will have at least 80% 
power to detect a difference of 1.91 log10 copies/mL between the treatment arm and placebo group, 
using a two-sample t-test at a 2-sided significance of α=0.05. The smallest treatment difference is 
approximately 1.34 log10 copies/mL. 
11.2.2. 
Phase 2 (Cohort 1A, Cohort 1, Cohort 2*, and Cohort 3*) 
* Per IDMC recommendation first received on 30 October 2020, and reiterated through 19 
February 2021, patient enrollment in cohort 2 and cohort 3 has been placed on hold. 
The sample size of phase 2 cohort 1A was adjusted to approximate 1000 patients based on clinical 
judgement without statistical justification. However, this target was not reached because the 
enrollment was prematurely terminated due to slow enrollment rate.  
Phase 2 will evaluate the efficacy and safety of 2 doses of REGN10933+REGN10987 versus 
placebo within cohort 1A, cohort 1, cohort 2 and cohort 3, ie, phase 2 contains 3 treatment arms 
each across 4 cohorts. Randomization will be stratified according to Section 8.6. 
Initial Estimation of Phase 2 Sample Size 
The sample size for phase 2 was originally based on the primary virologic endpoint of 
time-weighted average change from baseline in viral load (log10 copies/mL) from day 1 to day 22, 
using a 2-sample t-test at a 2-sided significance of α=0.05.  
Similar to phase 1, the standard deviation of actual viral load values at a timepoint from the 
literature was used for sample size calculation due to lack of corresponding data from the literature. 
Assuming a ~23% dropout rate (including missing data at baseline) and a standard deviation of 
2.1 log10 copies/mL (Cao, 2020), a sample size of 130 patients per arm (ie, 100 patients per arm 
with available data) across 3 treatment arms within each of the 4 cohorts, ie, 390 patients per cohort 
(for a total of 1560 patients in the phase 2 portion of the study) will have 80% power to detect a 
difference of 0.84 log10 copies/mL between each treatment arm and placebo in a cohort. If a 
standard deviation of 3.8 log10 copies/mL is assumed (Wang, 2020b), the detectable difference at 
80% power would be 1.51 log10 copies/mL. 
Phase 1/2 Estimation of Sample Size 
Per protocol amendment 6, statistical power calculations are provided for the cumulative incidence 
of death or mechanical ventilation for phase 1/2 cohort 1. 
For phase 1/2 analysis in cohort 1, assuming a total number of events (death or mechanical 
ventilation) will be 35, that the cumulative incidence of death or mechanical ventilation in placebo 
is 25% at day 29 (placebo rate was 12.5% in Sponsor’s Kevzara® [sarilumab] study 6R88-COV-
2040 in COVID-19 hospitalized randomized and treated patients receiving low flow oxygen 
supplementation at baseline; further assume placebo rate is twice this in seronegative mFAS), and 
using a futility threshold of α=0.3 (1-sided), the minimum hazard ratio (HR) between 
REGN10933+REGN10987 dose group versus placebo that excludes futility is 0.827 (ie, minimum 
risk reduction 17.3%). If the observed risk reduction is approximately 17% or lower, the 
assessment of efficacy in cohort 1 as currently designed will be declared futile. 
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The alpha level for futility in this study is consistent with that used in the ACTIV-3 protocol for a 
similar cohort of patients with COVID-19 (NIAID, 2020). 
For phase 1/2 key secondary analyses in cohort 1, and using assumptions about event rates as 
described above, about 43 total events in the seronegative mFAS will be needed to achieve 80% 
power to detect a risk reduction of 50% (HR=0.5) between any REGN-COV2 dose group versus 
placebo, at α=0.1 (one-sided) level of significance. Assuming patients are followed through day 
29, and accrual takes 90 days, and assuming that 30% of FAS (randomized and treated) patients 
are in the seronegative mFAS, a total of approximately 250 randomized and treated patients across 
3 arms will be needed in phase 1/2 in the three treatment groups. 
Table 7: 
Statistical Power for Death or Mechanical Ventilation Endpoint: Phase 1/2 
Cohort 1  
α 
(Overall 
Type 1 error) 
Power 
Cumulative incidence of 
death or mechanical 
ventilation in Placebo by 
Day 29 (assumption) 
Hazard 
Ratio 
# of Events 
needed in 
seronegative 
mFAS 
Total 
Sample Size 
estimated 
0.1 (one-sided) 
80% 
25% 
0.5 
43 
250 
0.1 (one-sided) 
80% 
25% 
0.6 
78 
413 
0.1 (one-sided) 
90% 
25% 
0.5 
62 
360 
0.1 (one-sided) 
90% 
25% 
0.6 
114 
604 
11.2.3. 
Phase 3 (Cohort 1)  
Initial estimation 
The sample size for phase 3 was initially estimated to be 1350 patients (150 patients per arm across 
3 treatment arms in 3 cohorts). Based on the new endpoint of death or mechanical ventilation, the 
sample size for phase 3 has been re-estimated to be 2505 patients in each of cohort 1 and cohort 
1A.  
The study was planned to continue enrolling additional patients seamlessly into the phase 3 portion 
of the study, until an adaptation decision on the dose(s), primary endpoint and final sample size 
for phase 3 is made based on the phase 2 data analysis. A total sample size of approximately 5010 
patients was estimated for the phase 3 portion of the study (2505 per cohort, 835 per arm across 3 
treatment arms in 2 cohorts). For cohort 1, a total of 241 events (estimated sample size of 2505 
patients [835 patients per arm]) would have been needed to provide 90% power at α=0.05 (2-sided) 
using a log-rank test to detect a risk reduction of 35.8% (ie, HR=0.642) in the cumulative incidence 
of patients who died or went on mechanical ventilation, assuming a 12.5% cumulative incidence 
rate in the placebo group by day 29.  
Final sample size 
Finalization of the sample size and patient population for phase 3 was planned to be subject to 
change and would be determined after review of phase 2 data. However, enrollment of patients 
into the study was terminated prematurely by the Sponsor on 09 April 2021 because of extremely 
slow enrollment in the months preceding the decision. The sample size of phase 3 was not re-
estimated.  
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Approximately 2252 patients were randomized in the study, which includes 60 patients in phase 1 
cohort 1, 629 in phase 2 cohort 1, 755 in planned phase 3 cohort 1, 609 in phase 2 cohort 1A, 164 
in phase 2 cohort 2 and 35 in phase 2 cohort 3.  
Assuming the proportion of patients who died or went on mechanical ventilation from day 1 to 
day 29 in placebo group is 13.1% which is same as the blinded proportion in the Seronegative 
mFAS patients of the pooled phase 3 cohort 1 and phase 2 cohort 1A and alpha is 0.05 2-sided, 
the 
minimal 
significant 
difference 
in 
relative 
risk 
reduction 
between 
the 
REGN10933+REGN10987 2.4g and 8.0g combined dose group and placebo group is 29.0%, 
41.2%, and 36.6% for overall mFAS, Seronegative mFAS, and High Viral Load mFAS patients, 
respectively.  
11.3. 
Analysis Sets  
11.3.1. 
Efficacy Analysis Sets 
Full Analysis Set (FAS): The full analysis set (FAS) includes all randomized patients who 
received at least one dose (full or partial) of the study drug. Analysis of the FAS population will 
be done according to the treatment allocated (as randomized). 
Modified Full Analysis Set (mFAS): The modified full analysis set (mFAS) includes all FAS 
patients with a positive SARS-CoV-2 RT-qPCR conducted in the central laboratory in NP swab 
samples at randomization and analysis is based on the treatment allocated (as randomized).  
Seronegative mFAS: The seronegative mFAS is defined as all patients in mFAS with documented 
seronegative status at the baseline.  
High Viral Load mFAS: The High Viral Load mFAS is defined as all patients in mFAS with 
baseline viral load >106 copies/mL. 
Both FAS and mFAS will be used for the summaries of demographic and baseline characteristics 
and analysis of clinical/biomarker endpoints. The mFAS will be used for the analysis of all efficacy 
endpoints, based on the principle that an anti-viral agent would only be anticipated to provide 
efficacy in patients with measurable virus at baseline. The seronegative mFAS as well as the high 
viral load mFAS will be used for the primary analysis and descriptive analysis of certain virologic 
endpoints and clinical endpoints. Additional analyses will be performed in the seropositive mFAS, 
as needed. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received a dose (full or partial) 
of the study drug. Analysis of the SAF will be done according to the treatment received (as treated). 
Determination of “as treated” will be based on the actual study drug received on day 1. Since the 
treatment of “as treated” is same as “as randomized” in this study, the FAS is equivalent to the 
SAF. Therefore, the treatment administration and all clinical safety variables will be analyzed 
using the FAS.  
11.3.3. 
Pharmacokinetics Analysis Sets 
The pharmacokinetics (PK) analysis population includes all patients who received any study drug 
of REGN10933 and REGN10987 and who had at least 1 non-missing drug concentration 
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measurement following the first dose of study drug as indicated in the Schedule of Events table. 
Patients will be analyzed based on actual treatment received. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set (AAS) includes all subjects who received any study drug (active or placebo) 
and at least one non-missing ADA result from the ADA assay after a first dose of the study drug 
or placebo. 
The NAb analysis set (NAS) includes all treated subjects who received any study drug (active or 
placebo), have at least one non-missing ADA result following the first dose of study drug (active 
or placebo), and either tested negative at all ADA sampling times or tested positive for ADA with 
at least one non-missing NAb result after first dose of the study drug (active or placebo). Subjects 
who are ADA negative are set to negative in the NAb analysis set. 
Subjects will be analyzed according to the treatment actually received. 
11.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, Q1, median, Q3, standard deviation (SD), minimum, and 
maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
11.4.1. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics variables will be summarized by treatment group, and 
all groups combined. These will be analyzed for FAS and mFAS populations. Similar analysis will 
be performed by baseline serostatus and baseline viral load categories (≤ 106 copies/mL and >106 
copies/mL) for mFAS population. 
11.4.2. 
Medical History 
Medical history will be summarized by SOC and PT and by treatment group and all groups 
combined in the mFAS and FAS population. 
11.4.3. 
Prior / Concomitant Medications or Procedures 
Prior or concomitant medications/procedures will be summarized by treatment groups. Summaries 
will present patient counts (and percentages) for all medications, dictionary coded by 
WHODRUG, by decreasing frequency of the overall group incidence (or high dose group 
incidence in tables where the overall is not presented) of ATC followed by ATC level 2, ATC 
level 4 and PT. Focus of the results will be on the list of targeted medications in the FAS and 
mFAS populations.  
Number and proportion of patients undergoing a prior/concomitant procedure(s) will be 
summarized, sorted by decreasing frequency of SOC and PT based on the incidence in the overall 
group incidence (or high dose group incidence in tables where the overall is not presented). Patients 
will be counted only once for each SOC and PT linked to the procedure. 
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Prior or concomitant medications/procedures of interest for COVID-19 will be summarized 
similarly. 
11.4.4. 
Patient Disposition 
The following summaries will be provided for both mFAS and FAS populations. 
• The total number of randomized patients: received a randomization number 
• The total number of randomized patients who were not treated by study drug 
• The total number of randomized patients who discontinued the study, and the reasons 
for discontinuation 
• A summary of analysis sets including FAS, mFAS, SAF, PK, immunogenicity (ADA), 
and NAb analysis set (NAS)  
11.4.5. 
Extent of Study Treatment Exposure 
The following variables will be analyzed by treatment group: 
• Duration of intravenous infusion 
• Total volume of drug administered (units: mL) 
• Number of patients with total planned dose administered (yes/no) 
− If no, reason for not administration of total planned dose (equipment failure, 
adverse event, other) 
• Number of patients with infusion interruptions (ie, patients completed the full dose but 
had infusion interruptions) 
• Number of patients with infusion discontinuation (ie, patients didn’t completed the full 
dose infusion) 
The number and percentage of patients randomized and exposed to double-blind study drug will 
be presented for each treatment group. 
11.4.6. 
Efficacy Analyses 
The efficacy analyses will be performed for the following patients on all efficacy endpoints, 
separately. The comparisons in all efficacy endpoints will be performed between the 
REGN10933+REGN10987 2.4g and 8.0g combined dose group and placebo group as well as 
between each treatment group and placebo group.  
• Pooled phase 3 cohort 1 and phase 2 cohort 1A patients 
• Phase 3 cohort 1 patients (ie, patients randomized after 01 December 2020 in cohort 1) 
• Phase 2 cohort 1A patients 
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11.4.6.1. Primary Efficacy Analyses 
11.4.6.2. Analysis of Primary Virologic Efficacy Endpoint 
The primary analysis on the comparison between the REGN10933+REGN10987 2.4g and 8.0g 
combined dose group and placebo with respect to the virologic endpoint of time-weighted average 
daily change from baseline in viral load (log10 copies/mL) from day 1 to day 7 and other post-
baseline visit timepoint will be performed in the Seronegative mFAS in the pooled phase 3 cohort 
1 and phase 2 cohort 1A patients. The estimand for the analysis is the difference in means between 
the REGN10933+REGN10987 2.4g and 8.0g combined dose group and placebo in the pooled 
phase 3 cohort 1 and phase 2 cohort 1A patients. Data collected after use of convalescent plasma 
therapy or other anti-spike monoclonals will be excluded from efficacy analysis. All other 
available data will be used in the analysis regardless of intercurrent events such as rescue 
medication or discontinuation, ie, treatment policy approach.  
The analysis will be based on the observed data with no imputation for missing data except as 
defined in the SAP for viral load values that are below lower limit of detection (<LLOD), below 
lower limit of quantification (<LLOQ) or above upper limit of quantification (>ULOQ) of the 
assay.  
The variable will be analyzed using the Analysis of Covariance (ANCOVA) model with treatment 
group and the type of background standard-of-care as fixed effects, and baseline viral load and 
treatment by baseline interaction as covariates.  
The least squares means estimates for time-weighted average daily change from baseline in viral 
load for each treatment group, as well as the difference between the REGN10933+REGN10987 
2.4g and 8.0g combined doses and placebo as well as between each individual dose treatment 
group and placebo, will be provided along with the corresponding two-sided p-value, standard 
error, and associated 95% confidence interval.  
11.4.6.3. Analysis of Primary Clinical Efficacy Endpoints 
The primary efficacy analysis will be the comparison between the REGN10933+REGN10987 2.4g 
and 8.0g combined dose group and placebo in the pooled phase 3 cohort 1 and phase 2 cohort 1A 
patients. The primary clinical endpoint defined in Section 4.1 will be analyzed using the landmark 
analysis approach for day 6 through day 29, as well as analyzed for day 1 through day 29 in the 
order specified in Section 11.4.9.  
The proportion of patients who died or went on mechanical ventilation will be analyzed using 
either the exact method for binomial distribution or asymptotic normal approximation method. If 
the number of events is small (eg, np ≤ 5 or n(1-p) ≤ 5 in any treatment group, where n is the 
number of patients in the treatment group and p is the proportion of events), then the Fisher’s exact 
test will be applied. Otherwise, stratified Cochran-Mantel Haenszel (CMH) test, stratified by the 
type of background standard-of-care (antiviral therapies and non-antiviral therapies), will be 
applied. Relative risk and relative risk reduction and corresponding 95% confidence intervals 
compared to placebo group will be estimated by Farrington-Manning method. Missing data will 
be considered as non-events. 
The analysis will be performed for the High Viral Load mFAS, the Seronegative mFAS, and the 
overall mFAS.  
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11.4.7. 
Descriptive Analysis of Secondary Efficacy Endpoints 
All analyses for the secondary efficacy endpoints are descriptive and all p-values are nominal. 
Details are provided in the SAP. 
11.4.8. 
Exploratory Analysis 
Exploratory analyses related to long COVID will be summarized descriptively. Additional 
details will be provided in a separate long COVID statistical analysis plan (SAP) from the study 
SAP. This SAP may also describe additional analyses of symptoms and/or biomarkers. 
11.4.9. 
Control of Multiplicity 
The following multiplicity adjustment approach, a hierarchical procedure, will be used to control 
the overall Type-1 error rate at 0.05 for the primary virologic and clinical outcome endpoints in 
comparison between the combined doses of REGN10933+REGN10987 treatment group and 
placebo group in the pooled phase 3 cohort 1 and phase 2 cohort 1A patients. Each hypothesis will 
be formally tested only if the preceding one is significant at the 2-sided 0.05 significance level. 
The hierarchy is provided in Table 8. 
Table 8: 
Hierarchical Testing Order 
Type 
Description 
Testing 
Order 
Primary 
virologic 
outcome 
Time-weighted average change from baseline viral load in NP sample through 
day 7 in seronegative mFAS for comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
1 
Primary 
clinical 
outcome 
Proportion of patients who died or went on mechanical ventilation from day 6 
to day 29 in High Viral Load mFAS for comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
2 
Proportion of patients who died or went on mechanical ventilation from day 6 
to day 29 in Seronegative mFAS for comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
3 
Proportion of patients who died or went on mechanical ventilation from day 6 
to day 29 in overall mFAS for comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
4 
Proportion of patients who died or went on mechanical ventilation from day 1 
to day 29 in High Viral Load mFAS for comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
5 
Proportion of patients who died or went on mechanical ventilation from day 1 
to day 29 in Seronegative mFAS for comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
6 
Proportion of patients who died or went on mechanical ventilation from day 1 
to day 29 in overall mFAS for comparing the combined doses of 
REGN10933+REGN10987 versus placebo 
7 
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11.4.10. 
Safety Analysis 
The analysis of safety data will be performed for cohort 1 in combined phases 1, 2 and 3, and phase 
2 cohorts 1A, 2 and 3, separately in the FAS population. 
In this study, only targeted treatment-emergent adverse events (as defined in Section 10.1.1) will 
be recorded. 
The safety analysis will be based on the reported SAEs and AESIs and other safety information 
(clinical laboratory evaluations and vital signs).  
The summary of safety results will be presented for each treatment group. 
11.4.10.1. Adverse Events 
Definitions 
For safety variables, 2 periods are defined: 
• The pre-treatment period is defined as the time from signing the ICF to before the study 
drug administration. 
• The observation period is defined as the time of study drug administration to the last 
study visit.  
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the observation period. 
Analysis 
The verbatim text, the PT, and the primary system organ class (SOC) will be listed in subject 
listings. Summaries that include frequencies and proportions of patients reporting AEs will include 
the PTs and the SOCs. 
All adverse events reported in this study will be coded using the currently available version of the 
Medical Dictionary for Regulatory Activities (MedDRA®). Coding will be to lowest level terms. 
The PT, and the primary system organ class (SOC) will be listed. 
Summaries that include frequencies and proportions of patients reporting AEs will include the PTs 
and the SOCs.  
An overview of adverse events will be provided by treatment group and for combined dose groups 
of R10933+R10987, including:  
• Total number of TEAEs, SAEs, Total number of AESIs, Serious AESIs, Grade 3 or 4 
TEAEs, as well as  
• The number and percentage of patients with any TEAE, any SAE, any AESI, any 
serious AESI, any grade 3 or grade 4 TEAE, any fatal TEAEs, any TEAEs leading to 
withdrawal from the study, any TEAEs leading to study infusion discontinuation, and 
any TEAEs leading to study infusion interruption. 
Summaries of SAEs and AESIs by treatment group and for combined R10933+R10987 doses 
will include number (n) and percentage (%) of patients with at least: 
• Treatment-emergent AE by SOC and PT 
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• Treatment-emergent AE by SOC and PT and CTCAE grade 
• Treatment-emergent AE related to study treatment by SOC and PT 
• Treatment-emergent SAE by SOC and PT 
• Treatment-emergent AESIs presented by SOC and PT 
• Treatment-emergent grade 3 or 4 AEs presented by SOC and PT 
Counts will be provided according to treatment group for each PT within each SOC. Percentages 
will be calculated using the number of patients from the FAS in each treatment group. 
Primary SOCs will be sorted according to decreasing order of frequency in combined treatment 
group. Within each primary SOC, PTs will be sorted by decreasing frequency in combined 
treatment group. 
11.4.10.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, SpO2, FiO2, and respiration rate) will be 
summarized using descriptive statistics. Number and percentage of patients with a potentially 
clinically significant value (PCSV) at any post-randomization time point will be summarized. 
Laboratory Tests 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test for all patients 
and separately for patients in whom the PCSV criterion was normal or missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
11.4.10.3. Treatment Exposure 
Exposure to study drug will be examined for each patient. The total number of doses administered 
to each patient and exposure related parameters (eg, duration of IV infusion, total volume of drug 
administered, etc) will be analyzed and summarized using descriptive statistics by treatment arm 
in the SAF. 
11.4.10.4. Treatment Compliance 
Treatment compliance in terms of total dose and infusion interruption will be summarized. The 
analysis methods will be detailed in the SAP.  
11.4.11. 
Pharmacokinetics 
11.4.11.1. Analysis of Drug Concentration Data 
Concentrations of REGN10933 and REGN10987 over time will be summarized by descriptive 
statistics for each treatment group. No formal statistical hypothesis testing will be performed. 
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11.4.11.2. Pharmacokinetics and Pharmacokinetics/Pharmacodynamics Analyses 
At a minimum the viral-exposure response analysis will be performed.  
11.4.12. 
Analysis of Immunogenicity Data 
Immunogenicity variables will be summarized using descriptive statistics. 
Immunogenicity will be characterized by the ADA responses and titers observed in subjects in the 
ADA analysis set. ADA response categories and titer categories are defined as follows: 
ADA response categories: 
• ADA Negative, defined as ADA negative response in the ADA assay at all time points, 
regardless of any missing samples. 
• Pre-existing immunoreactivity, defined as either an ADA positive response in the ADA 
assay at baseline with all post first dose ADA results negative, OR a positive response 
at baseline with all post first dose ADA responses less than 9-fold over baseline titer 
levels. 
• Treatment-emergent response, defined as an ADA positive response in the ADA assay 
post first dose when baseline results are negative or missing. The treatment-emergent 
responses will be further characterized as Persistent, Indeterminate or Transient.  
− Persistent Response (only applicable to phase 1) – Treatment-emergent ADA 
positive response with two or more consecutive ADA positive sampling time 
points, separated by at least 16-week period (based on nominal sampling time), with 
no ADA negative samples in between, regardless of any missing samples. 
− Indeterminate Response –Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay, regardless of any missing 
samples. 
− Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
• Treatment-boosted response, defined as a positive response in the ADA assay post first 
dose that is greater than or equal to 9-fold over baseline titer levels, when baseline 
results are positive. 
Titer categories (Maximum titer values) 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
The following analysis will be provided: 
• Number (n) and percent (%) of ADA-negative subjects (pre-existing immunoreactivity 
or negative in the ADA assays at all time points) by treatment arms  
• Number (n) and percent (%) of treatment-emergent ADA positive subjects by treatment 
arms and ADA titer categories 
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− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
subjects 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
subjects 
− Number (n) and percent (%) of transient treatment-emergent ADA positive subjects 
Number (n) and percent (%) of treatment-boosted ADA positive subjects by treatment groups 
and ADA titer categories  
• Number (n) and percent (%) of treatment-boosted ADA positive subjects by treatment 
arms and ADA titer categories  
Listing of all ADA titer levels will be provided for subjects with pre-existing, treatment-emergent 
and treatment-boosted ADA response.  
11.4.12.1. Analysis of Neutralizing Antibody Data 
The absolute occurrence (n) and percent of subjects (%) with NAb status in the NAb analysis set 
will be provided by treatment groups. 
11.4.13. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
The concentrations of exploratory PD/Biomarkers over time will be summarized using descriptive 
statistics and may be reported separately from the CSR. 
11.5. 
Interim Analysis  
No interim analyses are planned.  
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and Sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the Sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.  
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12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, SAEs, baseline findings, medication, medical history) will be done using 
internationally recognized and accepted dictionaries. 
The eCRF data for this study will be collected with an electronic data capture (EDC) Medidata 
Rave. 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IWRS system – randomization, study drug supply 
• EDC system – data capture – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
12.2. 
Study Monitoring 
12.2.1. 
Monitoring of Study Sites 
Regeneron uses a study-specific risk based approach to study monitoring and oversight, aligned 
with risk based quality principles, outlined in ICH E6 (R2) Guideline for Good Clinical Practice. 
Risk-Based Quality Monitoring (RBQM) methodology focuses on employing a fit-for-purpose 
monitoring strategy, supported either directly by Regeneron as sponsor, or via our CRO partners. 
RBQM strategies include reduced source data verification (SDV), targeted source data review 
(SDR), the use of off-site/remote and triggered on-site monitoring visits, and Centralized 
Monitoring to identify site level risks and study level trends.  
The study monitors will perform ongoing source data review to verify that data recorded in the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and eCRF data are timely, accurate and complete. 
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The investigator must keep all source documents on file with the eCRF. Case report forms and 
source documents must be available at all times for inspection by authorized representatives of the 
Sponsor and regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (eCRFs) within the EDC system by trained site personnel. All required eCRFs must be 
completed for each and every patient enrolled in the study. The investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the Sponsor in the eCRFs. After 
review of the clinical data for each patient, the investigator must provide an electronic signature. 
A copy of each patient eCRF casebook is to be retained by the investigator as part of the study 
record and must be available at all times for inspection by authorized representatives of the 
Sponsor and regulatory authorities. 
Corrections to the eCRF will be entered in the eCRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system. For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections 
This study may be subject to a quality assurance audit or inspection by the Sponsor regulatory 
authorities. Should this occur, the investigator is responsible for: 
• Informing the Sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the Sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the Sponsor immediately 
• Taking all appropriate measures requested by the Sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, 
eCRFs, medical records, correspondence, ICFs, IRB/EC files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities. Conditions of study material storage are also subject to inspection. 
In addition, representatives of the Sponsor may observe the conduct of any aspect of the clinical 
study or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
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12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRF that will be provided to the Sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of eCRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The investigator must obtain written approval from the Sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the Sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the Sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
An informed consent form (ICF) can be defined as either a paper consent form or an electronically-
delivered consent (eConsent). An eConsent may be provided only where allowable by local laws 
and regulations and by site policies.  
Due to disease severity, quarantine restrictions and/or other reasons related to COVID-19, it may 
be necessary to implement temporary or alternative measures to obtain informed consent per 
procedures outlined in the investigator site file.  
The ICF used by the investigator must be reviewed and approved by the Sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the Sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
informed consent from each patient prior to his/her participation in the study and after the aims, 
methods, objectives, and potential hazards of the study have been explained to the patient in 
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language that he/she can understand. The ICF should be signed and dated by the patient and by the 
investigator or authorized designee who reviewed the ICF with the patient.  
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately. All study patients must be informed of the new information and provide their written 
consent if they wish to continue in the study. The original signed revised ICF must be maintained 
in the patient’s study record and a copy must be given to the patient. 
13.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on eCRFs or other documents submitted to the Sponsor. Documents that will not be submitted to 
the Sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator's personal data, which may be included in the Sponsor database, will 
be treated in compliance with all applicable laws and regulations. The Sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the Sponsor prior to shipment of drug supplies to the investigator. The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
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Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. Treatment codes will be disseminated to each investigation site 
thereafter. 
14. 
PROTOCOL AMENDMENTS 
The Sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment. Where required per local legislation, regulatory authority approval will also 
be sought.  
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-
OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The Sponsor has the right to terminate the study prematurely. Reasons may include efficacy, 
safety, or futility, among others. Should the Sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
Closeout of a Site 
The Sponsor and the investigator have the right to close out a site prematurely. 
Investigator’s Decision 
The investigator must notify the Sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the Sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The Sponsor will notify the investigator(s) of a decision to close-out a study site in writing. 
Reasons may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
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In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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19. 
REFERENCES 
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manifesto for tackling persisting symptoms of covid-19. Bmj 2020; 370:m3565. 
 
Burke MJ,del Rio C. Long COVID has exposed medicine's blind-spot. The Lancet Infectious 
Diseases 2021. 
 
Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir-Ritonavir in Adults 
Hospitalized with Severe Covid-19. N Engl J Med 2020; 382(19):1787-1799. 
 
CDC. Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently 
Authorized 
in 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A MASTER PROTOCOL ASSESSING THE SAFETY, 
TOLERABILITY, AND EFFICACY OF ANTI-SPIKE (S) SARS-CoV-2 MONOCLONAL 
ANTIBODIES FOR THE TREATMENT OF HOSPITALIZED PATIENTS WITH COVID-19 
and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the Sponsor or a 
partnership in which the Sponsor is involved. I will immediately disclose it in writing to the 
Sponsor if any person who is involved in the study is debarred, or if any proceeding for debarment 
is pending, or, to the best of my knowledge, threatened. 
This document contains confidential information of the Sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, 
Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
 A Master Protocol Assessing the Safety, Tolerability, and Efficacy of Anti-Spike 
(S) SARS-CoV-2 Monoclonal Antibodies for the Treatment of Hospitalized Patients with 
COVID-19 
Protocol Number: 
R10933-10987-COV-2066 
Protocol Version: 
Amendment 9 US 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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APPENDIX A. Oxygenation Equivalence for Eligibility 
Sites located in high-altitude areas (>1500 m above sea level) should use Table 9 to get the 
appropriate high-altitude equivalents for sea-level oxygenation measurements.  
Table 9: 
High Altitude Equivalents for Sea-Level Oxygenation Measurements 
Eligibility 
Criterion 
Protocol-Defined Threshold (Sea-
Level Measurement) 
High-Altitude Equivalent For 
Eligibility 
Inclusion 
criterion 5b 
O2 saturation >93% 
O2 saturation >90% 
Inclusion 
criterion 5c 
SpO2 ≤96% 
SpO2 ≤93% 
Exclusion 
criterion 1 
(Phase 1 only) 
O2 saturation >94% 
O2 saturation >91% 
 
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Signature Page for VV-RIM-00163777 v1.0
Signature Page for VV-RIM-00163777 v1.0 Approved
ESig Approval
ESig Approval
ESig Approval
ESig Approval
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