Conditions: COVID-19
Keywords: Coronavirus disease 2019 (COVID-19) Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) coronavirus Non-hospitalized
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1149
Healthy volunteers: no

Brief summary:
The primary objective of the study is to assess the virologic efficacy of REGN10933+REGN10987 across different intravenous and subcutaneous doses compared to placebo.

The secondary objectives of the study are:

* To evaluate additional indicators of virologic efficacy of REGN10933+REGN10987 compared to placebo
* To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo
* To assess the concentrations of REGN10933 and REGN10987 in serum over time
* To assess the immunogenicity of REGN10933 and REGN10987

Detailed description:

Arms:
arm 1: Combination therapy intravenous (IV) single dose arm 2: Combination therapy IV single dose arm 3: Combination therapy IV single dose arm 4: Combination therapy IV single dose arm 5: Matching placebo IV single dose arm 6: Combination therapy subcutaneous (SC) single dose arm 7: Combination therapy SC single dose arm 8: Matching placebo SC single dose

Interventions: intervention 1: REGN10933+REGN10987 combination therapy intervention 2: Placebo
Intervention descriptions: intervention 1: Administered IV or SC single dose intervention 2: Administered IV or SC single dose to match

Protocol document:
Prot_000.pdf: 
aIND: 148069 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 2 STUDY TO ASSESS THE VIROLOGIC EFFICACY OF 
REGN10933+REGN10987 ACROSS DIFFERENT DOSE REGIMENS IN 
OUTPATIENTS WITH SARS-CoV-2 INFECTION 
Compound: 
REGN10933+REGN10987  
(Casirivimab + Imdevimab) 
Clinical Phase: 
2 
Protocol Number: 
R10933-10987-COV-20145 
Protocol Version: 
Amendment 2  
Amendment 2 Date of Issue: 
See appended electronic signature page 
Amendment 1 Date of Issue: 
23 December 2020 
Original Date of Issue: 
23 November 2020 
Medical /Study Director: 
 
, Clinical Sciences 
 
, Early Clinical 
Development and Experimental Sciences 
 
, Early Clinical Development 
and Experimental Sciences 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
 
 
 
 
VV-RIM-00145951-1.0 Approved - 02 Mar 2021 GMT-5:00
NCT04666441


Clinical Study Protocol 
 
R10933-10987-COV-20145 Amendment 2 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 2 
The primary purpose of this amendment is to pre-specify a first-step analysis and make 
adjustments to the planned statistical methodology.  
Description of Change 
 
Brief Rationale   
Section(s) 
Study enrollment has been closed. 
Based on assessment 
that the study is 
adequately powered 
with current enrollment  
Section 6.1 Study Description and 
Duration 
A primary efficacy analysis will be conducted as a 
first-step analysis using the first 816 patients 
enrolled in the study. This analysis represents the 
final analysis of the primary endpoint and is not 
considered an interim analysis. 
To pre-specify the first-
step analysis and other 
planned statistical 
analyses of the study 
Section 6.3 Planned Interim 
Analysis 
Section 8.7 Blinding 
Section 11 Statistical Plan 
Section 11.2 Justification of 
Sample Size 
Section 11.4.9 Timing of Statistical 
Analyses [new] 
Section 11.5 Interim Analysis 
 
The following additional changes have been made 
with respect to the statistical design of the study: 
• Virologic endpoints assessing changes in cycle 
threshold (Ct) are now exploratory; these were 
previously planned as secondary analyses 
• Exploratory endpoints have been added to assess 
the proportion of patients with ≥1 COVID-19-
related hospitalization/all-cause death or ≥1 
COVID-19-related hospitalization/emergency 
room visit/all-cause death 
• Exploratory endpoints assessing the cumulative 
incidence of various COVID-19-related 
medically-attended visits have been removed; 
corresponding proportion-based endpoints have 
been retained 
• Associated details (eg, study variables, primary 
and secondary efficacy analyses) have been 
updated to the reflect the planned statistical 
analysis 
To clarify the planned 
study analyses 
Section 4.2 Secondary Endpoints 
Section 4.3 Exploratory Endpoints 
Section 5.1 Demographic and 
Baseline Characteristics 
Figure 1 Study Flow Diagram 
Section 11.3.1 Efficacy Analysis 
Sets  
Section 11.3.1.1 The Seronegative 
Modified Full Analysis Set [new] 
Section 11.3.1.2 Per Protocol Set 
[new] 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Section 11.4.4 Control of 
Multiplicity 
Section 11.4.5.1 Adverse Events 
Clarified in the schedule of events that study visits 
are not required solely to collect continuously-
monitored assessments, if no other assessments are 
planned on that day. 
To ensure operational 
clarity and avoid 
unnecessary study visits 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #6 
Clarified that for patients with symptoms of 
COVID-19 at screening, the severity of symptoms 
will be recorded and graded in the eCRF using the 
current version of the NCI-CTCAE v5.0. 
To capture additional 
clinically-relevant 
information regarding 
COVID-19 illness 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #12 
Section 9.2.1.4 Medical History 
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Description of Change 
 
Brief Rationale   
Section(s) 
Clarified that during each indicated collection visit 
(as provided in the schedule of events), all 
previously unrecorded COVID-19-related 
medically-attended visits and details will be 
recorded, beginning from the day of dosing up to 
and including the day of collection. 
To ensure appropriate 
capturing of clinically-
relevant information 
Section 9.2.10.3 COVID-19-
Related Medically-Attended Visit 
Details 
The risk-benefit section has been updated to reflect 
the current Investigator’s Brochure (edition 5). This 
update includes the addition of hypersensitivity 
reactions (including infusion-related reactions and 
injection site reactions) as an important identified 
risk. 
To provide current 
information regarding 
the potential risks and 
benefits of 
REGN10933 + 
REGN10987 
Section 3.3 Risk-Benefit 
Provided updated CDC guidance regarding 
COVID-19 vaccination. 
To ensure accurate and 
current medical 
information 
Section 7.2.1 Inclusion Criteria, #7 
Section 8.10.1 Prohibited and 
Permitted Medications 
In light of the increasing number of therapeutic and 
preventative COVID-19 agents approved or 
conditionally authorized, reference to individual 
agents has been removed. References to FDA and 
EMA have been provided as a general resource for 
currently-available agents. 
To ensure current, 
accurate, and consistent 
information 
Section 1.6 A Randomized, 
Placebo-Controlled Study of Anti-
SARS-CoV-2 
S Protein Monoclonal Antibodies 
in Outpatients with SARS-CoV-2 
Infection 
Minor administrative changes, updates to 
background information, and other minor 
typographical corrections were made. 
To ensure current, 
accurate, and consistent 
information 
Throughout the document 
 
 
 
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Clinical Study Protocol 
 
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CONFIDENTIAL 
Amendment 1 
The primary purpose of this amendment is to modify the study design per health authority request. 
Description of Change 
 
Brief Rationale   
Section(s) 
In addition to current safety information collection, 
the following additional information will be 
collected: 
• All treatment-emergent adverse events (TEAEs) 
through day 29 
• TEAEs that led to a hospitalization or emergency 
room visit, regardless of relatedness to COVID-
19, through day 169 
• Grade ≥3 TEAEs through day 169 
• All serious adverse events (SAEs) through day 
169 
• Any clinically-significant laboratory findings  
 
Exploratory endpoints have been added and/or 
modified to accommodate the additional collection 
of safety information.  
Per health authority 
request, for more 
comprehensive analysis 
of safety profile and to 
further assess patient 
safety by extending the 
follow-up period to 
cover approximately 5 
half-lives of 
REGN10933 + 
REGN10987 
Section 2.3 Exploratory 
Objectives 
Section 3.2.1 Rationale for Study 
Design 
Section 4.3 Exploratory 
Endpoints 
Section 5.3 Safety Variables 
Section 6.1 Study Description and 
Duration 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #5, 8 
Section 9.2.4.2 Adverse Event 
Monitoring 
Section 9.2.5 Post-Day 22 
Follow-up by Phone 
Section 9.2.7 Laboratory Testing 
Section 10.1.1 General Guidelines 
Section 10.1.3 Events that 
Require Expedited Reporting to 
Sponsor 
Section 11.4.5.1 Adverse Events 
Details of COVID-19-related medically-attended 
visits will be collected through day 169. Collection 
previously ended at day 29. 
For more comprehensive 
exploratory assessment 
of clinical outcomes 
Table 1 Schedule of Events 
 
Blood samples for drug concentration and 
immunogenicity assessments will be collected on 
day 120. 
 
Anti-drug antibody (ADA) and neutralizing 
antibody (NAb)-related objectives, endpoints, and 
analyses have been added accordingly.  
For comprehensive 
analysis of drug 
concentrations and 
immunogenicity of 
REGN10933 and 
REGN10987 over time, 
at different dose levels 
and routes of 
administration 
Section 2.2 Secondary Objectives 
Section 3.3 Risk-Benefit 
Section 4.2 Secondary Endpoints 
Section 5.5 Immunogenicity 
Variables [new] 
Section 6.1 Study Description and 
Duration 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #10 
Section 11.3.4 Immunogenicity 
Analysis Set [new] 
Section 9.2.8 Drug Concentration 
Measurements and Samples 
Section 9.2.9 Immunogenicity 
Measurements and Samples [new] 
Section 11.4.8 Analysis of 
Immunogenicity Data [new] 
Section 11.4.8.1 Analysis of 
Neutralizing Antibody Data [new] 
The following study visit modifications have been 
made: 
• Phone visits were added at day 90 and day 169  
• An in-person visit was added at day 120 
To accommodate the 
additional safety, drug 
concentration, and 
immunogenicity 
assessments 
Section 3.3 Risk-Benefit 
Section 6.1 Study Description and 
Duration 
Figure 1 Study Flow Diagram 
Table 1 Schedule of Events 
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Description of Change 
 
Brief Rationale   
Section(s) 
• The study duration has been extended from 
61days to 170 days 
  
Section 9.1.2 Early Termination 
from the Study 
Grade ≥3 injection-site reactions (ISRs) will be 
reported as AESIs. Grade 2 ISRs will no longer be 
considered AESIs. 
To collect the most 
medically-relevant 
AESIs 
Section 8.5.2 Injection Reactions 
Table 1 Schedule of Events 
Section 10.1.1 General Guidelines 
Section 10.1.3 Events that 
Require Expedited Reporting to 
Sponsor 
The followings changes and clarifications were 
made with respect to assessment of women of 
childbearing potential (WOCBP) and women who 
are pregnant: 
•  In addition to the standard collection of 
pregnancy outcome information, for newborn 
infants of patients who were treated in the study 
and were pregnant at randomization or became 
pregnant at any time while in the study, the 
incidence and outcome of any SARS-CoV-2 
infection [in the newborn] will be collected on 
day 120 and day 169  
• Pregnancy testing at screening must be performed 
in all WOCBP, regardless of pregnancy status 
• Pregnancy or breastfeeding status at screening 
must be collected as medical history, if applicable 
• A paper pregnancy report form must be 
completed for each patient who becomes 
pregnant or is pregnant at the signing of consent. 
To ensure accurate 
information is collected 
regarding pregnancy; per 
health authority request, 
to assess any treatment 
effects on vertical 
transmission of SARS-
CoV-2 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #7 
Section 9.2.1.4 Medical History 
Section 9.2.5 Post-Day 22 
Follow-up by Phone 
Section 10.1.3 Events that 
Require Expedited Reporting to 
Sponsor 
Section 9.2.6 Pregnancy Test for 
Women of Childbearing Potential 
 
The following modifications have been made, and 
information provided, with respect to SARS-CoV-2 
vaccination: 
• Patients will be excluded based on prior use, 
current use, or planned use (within time period 
given per CDC guidance but no sooner than 22 
days after study drug administration) of any 
authorized or approved vaccine for SARS-CoV-2. 
• Patients will be excluded if they have any prior 
participation, current participation, or any future 
plans to participate in a clinical research study 
evaluating any authorized, approved, or 
investigational vaccine for SARS-CoV-2  
• SARS-CoV-2 vaccines will be captured as 
targeted concomitant medication.  
 
In addition, current CDC guidance related to 
vaccination has been provided for reference. This 
guidance recommends deferral of SARS-CoV-2 
vaccination for at least 90 days after administration 
of passive antibody treatment (eg, 
REGN10933+REGN10987) (CDC, 2020) 
Per current CDC 
recommendations on 
SARS-CoV-2 
vaccination 
 
Section 7.2.2 Exclusion Criteria, 
#7, #11 [new] 
Section 8.10.1 Prohibited and 
Permitted Medications 
9.2.4.3 Record Targeted 
Concomitant Medications 
Clarified that viral variants suspected to confer 
decreased susceptibility to REGN10933 and/or 
Per health authority 
request 
Section 9.2.10.1 Virology 
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Description of Change 
 
Brief Rationale   
Section(s) 
REGN10987 will be evaluated in nonclinical work 
separate from this protocol. 
Clarified that for the screening SARS-CoV-2 
diagnostic test, the sample must be collected ≤72 
hours of randomization. Samples are not valid for 
screening if collected >72 hours from 
randomization, even if the test is performed, or 
results reported, within the 72-hour window.  
To ensure appropriate 
screening for SARS-
CoV-2 infection 
Section 7.2.1 Inclusion Criteria, 
#2 
Removed language stating that if diagnostic SARS-
CoV-2 testing was performed outside of the 
allowed window, a new test is required for study 
inclusion. Language had previously been retained in 
error. Per study exclusion criteria, patients will be 
excluded if they have a positive SARS-CoV-2 
antigen or molecular diagnostic test from a sample 
collected >72 hours prior to randomization 
To ensure accurate 
information 
Section 9.2.1.2 Diagnostic Test 
for SARS-CoV-2 
Members of the clinical site study team and/or their 
immediate family will be now considered a study 
exclusion criterion. 
 
To avoid the appearance 
of conflict of interest or 
coercion, and to ensure 
integrity of study data 
Section 7.2.2 Exclusion Criteria, 
#12 [new] 
The schedule of events was corrected to reflect 
treatment-emergent grade ≥2 hypersensitivity 
reactions will be assessed through day 29. Previous 
schedule incorrectly stated that assessment would 
occur through day 22. 
To ensure accurate 
information 
Table 1 Schedule of Events 
Updates to background information and other minor 
updates were made. 
To ensure current, 
accurate, and consistent 
information 
Throughout the document 
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Clinical Study Protocol 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAS 
Anti-drug antibody analysis set 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
Ct 
Cycle Threshold 
CTCAE 
Common Terminology Criteria for Adverse Events 
EDC 
Electronic data capture 
EOS 
End of study 
ET 
Early termination  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IV 
Intravenous 
MAV 
Medically-attended visit 
mFAS 
Modified full analysis set 
NAb 
Neutralizing antibody 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
PK 
Pharmacokinetic 
PPE 
Personal protective equipment 
RBQM 
Risk-Based Quality Monitoring 
RT-qPCR 
Quantitative reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TWA 
Time weighted average 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
Amendment 2 ...................................................................................................................................2 
Amendment 1 ...................................................................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................14 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Emergence of SARS-CoV-2 and COVID-19 .............................................................18 
1.2. 
Clinical Outcomes in Hospitalized Patients with COVID-19 ....................................18 
1.3. 
Outpatient Care as a Potential COVID-19 Treatment Setting ....................................18 
1.4. 
The Role of Spike (S) Protein in SARS-CoV-2 Pathogenesis ...................................19 
1.5. 
REGN10933+REGN10987: Human Monoclonal Antibodies that Target 
SARS-CoV-2 S Protein ..............................................................................................19 
1.6. 
A Randomized, Placebo-Controlled Study of Anti-SARS-CoV-2 S Protein 
Monoclonal Antibodies in Outpatients with SARS-CoV-2 Infection ........................19 
2. 
STUDY OBJECTIVES ..............................................................................................21 
2.1. 
Primary Objective .......................................................................................................21 
2.2. 
Secondary Objectives .................................................................................................21 
2.3. 
Exploratory Objectives ...............................................................................................21 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................22 
3.1. 
Hypotheses ..................................................................................................................22 
3.2. 
Rationale .....................................................................................................................22 
3.2.1. 
Rationale for Study Design .........................................................................................22 
3.2.2. 
Rationale for Dose Selection ......................................................................................23 
3.3. 
Risk-Benefit ................................................................................................................24 
4. 
ENDPOINTS ..............................................................................................................26 
4.1. 
Primary Endpoint ........................................................................................................26 
4.2. 
Secondary Endpoints ..................................................................................................26 
4.3. 
Exploratory Endpoints ................................................................................................26 
5. 
STUDY VARIABLES................................................................................................27 
5.1. 
Demographic and Baseline Characteristics ................................................................27 
5.2. 
Efficacy Variables ......................................................................................................27 
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5.3. 
Safety Variables ..........................................................................................................28 
5.4. 
Pharmacokinetic Variables .........................................................................................28 
5.5. 
Immunogenicity Variables ..........................................................................................28 
6. 
STUDY DESIGN .......................................................................................................28 
6.1. 
Study Description and Duration .................................................................................28 
6.2. 
End of Study Definition ..............................................................................................29 
6.3. 
Planned Interim Analysis ............................................................................................29 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............30 
7.1. 
Number of Patients Planned .......................................................................................30 
7.2. 
Study Population .........................................................................................................30 
7.2.1. 
Inclusion Criteria ........................................................................................................30 
7.2.2. 
Exclusion Criteria .......................................................................................................31 
7.3. 
Premature Withdrawal from the Study .......................................................................31 
7.4. 
Replacement of Patients .............................................................................................32 
8. 
STUDY TREATMENTS............................................................................................32 
8.1. 
Investigational and Reference Treatments ..................................................................32 
8.2. 
Background Treatment(s) ...........................................................................................32 
8.3. 
Rescue Treatment(s) ...................................................................................................32 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................32 
8.4.1. 
Dose Modification ......................................................................................................32 
8.4.2. 
Study Drug Discontinuation .......................................................................................33 
8.5. 
Management of Acute Reactions ................................................................................33 
8.5.1. 
Infusion-Related Reactions and Hypersensitivity Reactions ......................................33 
8.5.1.1. 
Interruption of the Intravenous Infusion .....................................................................33 
8.5.1.2. 
Termination of the Intravenous Infusion ....................................................................33 
8.5.2. 
Injection Reactions .....................................................................................................34 
8.6. 
Method of Treatment Assignment ..............................................................................34 
8.7. 
Blinding ......................................................................................................................35 
8.8. 
Emergency Unblinding ...............................................................................................35 
8.9. 
Treatment Logistics and Accountability .....................................................................36 
8.9.1. 
Packaging, Labeling, and Storage ..............................................................................36 
8.9.2. 
Supply and Disposition of Treatments .......................................................................36 
8.9.3. 
Treatment Accountability ...........................................................................................36 
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8.9.4. 
Treatment Compliance ................................................................................................36 
8.10. 
Concomitant Medications ...........................................................................................36 
8.10.1. 
Prohibited and Permitted Medications ........................................................................37 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................37 
9.1. 
Schedule of Events .....................................................................................................37 
9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................39 
9.1.2. 
Early Termination from the Study ..............................................................................40 
9.1.3. 
Unscheduled Visits .....................................................................................................40 
9.2. 
Study Procedures ........................................................................................................40 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................40 
9.2.1.1. 
Informed Consent .......................................................................................................40 
9.2.1.2. 
Diagnostic Test for SARS-CoV-2 ..............................................................................40 
9.2.1.3. 
Demographics .............................................................................................................41 
9.2.1.4. 
Medical History ..........................................................................................................41 
9.2.1.5. 
Weight and Height ......................................................................................................41 
9.2.2. 
Treatment ....................................................................................................................41 
9.2.3. 
Efficacy Procedures ....................................................................................................41 
9.2.3.1. 
Nasopharyngeal Swab Collection ...............................................................................41 
9.2.4. 
Safety Procedures .......................................................................................................41 
9.2.4.1. 
Vital Signs ..................................................................................................................41 
9.2.4.2. 
Adverse Event Monitoring .........................................................................................42 
9.2.4.3. 
Record Targeted Concomitant Medications ...............................................................42 
9.2.5. 
Post-Day 22 Follow-up by Phone ...............................................................................42 
9.2.6. 
Pregnancy Test for Women of Childbearing Potential ...............................................43 
9.2.7. 
Laboratory Testing ......................................................................................................43 
9.2.8. 
Drug Concentration Measurements and Samples .......................................................44 
9.2.9. 
Immunogenicity Measurements and Samples ............................................................44 
9.2.10. 
Exploratory Pharmacodynamic/Biomarker Analyses .................................................44 
9.2.10.1. 
Virology ......................................................................................................................44 
9.2.10.2. 
Serological Immunoassays for Anti-SARS-CoV-2 Antibodies .................................45 
9.2.10.3. 
COVID-19-Related Medically-Attended Visit Details ..............................................45 
10. 
SAFETY EVALUATION AND REPORTING .........................................................46 
10.1. 
Recording and Reporting Adverse Events ..................................................................46 
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10.1.1. 
General Guidelines .....................................................................................................46 
10.1.2. 
Reporting Procedure ...................................................................................................47 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................47 
10.2. 
Definitions ..................................................................................................................48 
10.2.1. 
Adverse Event .............................................................................................................48 
10.2.2. 
Serious Adverse Event ................................................................................................48 
10.2.3. 
Adverse Events of Special Interest .............................................................................49 
10.2.4. 
Infusion-Related Reactions, Injection-Site Reactions, and Hypersensitivity 
Reactions .....................................................................................................................49 
10.2.5. 
Severity .......................................................................................................................49 
10.2.6. 
Causality .....................................................................................................................51 
10.3. 
Safety Monitoring .......................................................................................................52 
10.4. 
Notifying Health Authorities, Institutional Review Board and Investigators ............52 
11. 
STATISTICAL PLAN................................................................................................53 
11.1. 
Statistical Hypothesis ..................................................................................................53 
11.2. 
Justification of Sample Size........................................................................................53 
11.3. 
Analysis Sets ...............................................................................................................53 
11.3.1. 
Efficacy Analysis Sets ................................................................................................53 
11.3.1.1. 
The Seronegative Modified Full Analysis Set ............................................................53 
11.3.1.2. 
Per Protocol Set ..........................................................................................................54 
11.3.2. 
Safety Analysis Set .....................................................................................................54 
11.3.3. 
Pharmacokinetic Analysis Set ....................................................................................54 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................54 
11.4. 
Statistical Methods ......................................................................................................55 
11.4.1. 
Patient Disposition ......................................................................................................55 
11.4.2. 
Demography and Baseline Characteristics .................................................................55 
11.4.3. 
Efficacy Analyses .......................................................................................................55 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................55 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................56 
11.4.4. 
Control of Multiplicity ................................................................................................56 
11.4.5. 
Safety Analysis ...........................................................................................................57 
11.4.5.1. 
Adverse Events ...........................................................................................................57 
11.4.5.2. 
Other Safety ................................................................................................................58 
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11.4.5.3. 
Treatment Exposure ....................................................................................................58 
11.4.5.4. 
Treatment Compliance ................................................................................................58 
11.4.6. 
Pharmacokinetics ........................................................................................................59 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................59 
11.4.7. 
Pharmacokinetics and Pharmacokinetics/Pharmacodynamics Analyses ....................59 
11.4.8. 
Analysis of Immunogenicity Data ..............................................................................59 
11.4.8.1. 
Analysis of Neutralizing Antibody Data ....................................................................60 
11.4.9. 
Timing of Statistical Analyses ....................................................................................60 
11.5. 
Interim Analysis ..........................................................................................................60 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........60 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................61 
12.1. 
Data Management and Electronic Systems ................................................................61 
12.1.1. 
Data Management .......................................................................................................61 
12.1.2. 
Electronic Systems ......................................................................................................61 
12.2. 
Study Monitoring ........................................................................................................61 
12.2.1. 
Monitoring of Study Sites ...........................................................................................61 
12.2.2. 
Source Document Requirements ................................................................................62 
12.2.3. 
Case Report Form Requirements ................................................................................62 
12.3. 
Audits and Inspections ................................................................................................62 
12.4. 
Study Documentation .................................................................................................63 
12.4.1. 
Certification of Accuracy of Data ...............................................................................63 
12.4.2. 
Retention of Records ..................................................................................................63 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................63 
13.1. 
Good Clinical Practice Statement ...............................................................................63 
13.2. 
Informed Consent .......................................................................................................63 
13.3. 
Patient Confidentiality and Data Protection ...............................................................64 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................64 
13.5. 
Clinical Study Data Transparency ..............................................................................65 
14. 
PROTOCOL AMENDMENTS ..................................................................................65 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................65 
15.1. 
Premature Termination of the Study ...........................................................................65 
15.2. 
Closeout of a Site ........................................................................................................65 
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16. 
CONFIDENTIALITY ................................................................................................66 
17. 
FINANCING AND INSURANCE .............................................................................66 
18. 
PUBLICATION POLICY ..........................................................................................66 
19. 
REFERENCES ...........................................................................................................67 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................70 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................71 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................38 
Table 2: 
NCI-CTCAE (v5.0) Severity Grading System for Adverse Events: General 
Guideline .....................................................................................................................49 
Table 3: 
NCI-CTCAE (v5.0) Severity Grading System for Anaphylaxis, Allergic 
Reaction, Infusion-Related Reaction, and Injection-Site Reaction ............................50 
Table 4: 
Statistical Testing Hierarchy .......................................................................................57 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................29 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2 Study to Assess the Virologic Efficacy of REGN10933+REGN10987 Across 
Different Dose Regimens in Outpatients with SARS-CoV-2 Infection 
Site Locations The study will be conducted in approximately 80 sites in the United States. 
Principal 
Investigator 
To be determined 
Objectives 
 
Primary 
 
• To assess the virologic efficacy of REGN10933+REGN10987 across different intravenous 
and subcutaneous doses compared to placebo 
Secondary 
 
• To evaluate additional indicators of virologic efficacy of REGN10933+REGN10987 
compared to placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo 
• To assess the concentrations of REGN10933 and REGN10987 in serum over time 
• To assess the immunogenicity of REGN10933 and REGN10987 
Study Design Note: as of protocol amendment 2, study enrollment is closed. 
This is a randomized, double-blind, placebo-controlled, parallel group study to assess the dose 
response profile of single intravenous (IV) or single subcutaneous (SC) doses of 
REGN10933+REGN10987 in outpatients with SARS-CoV-2 infection.  
Eligible patients will be randomized to receive a single dose of REGN10933+REGN10987 or 
placebo by IV or SC route. On the day of dosing, patients will have NP swabs taken for SARS-
CoV-2 RT-qPCR testing and blood drawn for safety, drug concentration, immunogenicity, and 
serologic analyses. After study drug administration, patients will have a post-dose blood 
collection (either at the end of intravenous infusion or at least 1 hour after subcutaneous 
administration). Patients will be monitored for at least 1 hour after study drug administration 
and then released from the study site, if medically appropriate.  
Information related to safety and COVID-19-related medically-attended visits will be recorded 
during planned study visits. Patients will also be asked to notify study personnel as soon as 
possible about any medically-attended visits. Note that the TEAEs that will be collected during 
the study will differ according to different periods of the study schedule. Refer to the safety 
reporting section in the protocol for more information on reporting of TEAEs and treatment-
emergent laboratory abnormalities. 
Patients will have NP swabs and blood samples collected every other day for the first week of 
the study. Additional NP swab samples will be collected once-weekly for 2 more weeks to 
assess potential persistence of viral load. A phone visit will occur during the fourth week for 
collection of safety information.  
After the first month, patients will have visits approximately once-monthly for 4 additional 
months. The penultimate visit will be in-person to collect blood samples for drug concentration 
and immunogenicity. The final visit (EOS) will be a phone call.  
Study 
Duration 
The duration of the study is 170 days for each patient. 
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 
 
Sample Size 
Up to approximately 1400 patients will be enrolled.  
Target  
Population 
This study will enroll adult, non-hospitalized patients who have a positive diagnostic test for 
SARS-CoV-2.  
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Inclusion criteria: A patient must meet the following criteria to be eligible for inclusion in 
the study. Other inclusion criteria also apply and are described in the main text. 
• Is male or female ≥18 years of age (or country’s legal age of adulthood) at randomization 
Note: upper age limit may apply; refer to other inclusion criteria. 
• Has SARS-CoV-2-positive diagnostic test from a sample collected ≤72 hours prior to 
randomization, using a validated SARS-CoV-2 antigen, RT-PCR, or other molecular 
diagnostic assay and an appropriate sample such as nasopharyngeal (NP), nasal, 
oropharyngeal (OP), or saliva 
Note: Historical record of positive result is acceptable, as long as the sample was collected 
≤72 hours prior to randomization. 
• Low-risk symptomatic patient: Has symptoms consistent with COVID-19 (as determined 
by the investigator) with onset ≤7 days before randomization, and meets all of the following 
8 criteria: 
• Age ≤50 
• No obesity, with obesity defined as BMI ≥30 kg/m2 
• Does not have cardiovascular disease or hypertension 
• Does not have chronic lung disease or asthma 
• Does not have type 1 or type 2 diabetes mellitus 
• Does not have chronic kidney disease, with or without dialysis 
• Does not have chronic liver disease 
• Is not pregnant 
or 
Asymptomatic patient: Has had no symptoms consistent with COVID-19 (as determined by 
the investigator) occurring at any time <2 months prior to randomization 
 
Exclusion criteria: A patient who meets any of the following criteria will be excluded from 
the study. Other exclusion criteria also apply and are described in the main text. 
• Was admitted to a hospital for COVID-19 prior to randomization, or is hospitalized 
(inpatient) for any reason at randomization 
• Has a known positive SARS-CoV-2 serologic test  
• Has a positive SARS-CoV-2 antigen or molecular diagnostic test from a sample collected 
>72 hours prior to randomization  
• Is immunosuppressed, based on investigator’s assessment  
Note: examples include cancer treatment, bone marrow or organ transplantation, immune 
deficiencies, HIV (if poorly controlled or evidence of AIDS), sickle cell anemia, 
thalassemia, and prolonged use of immune-weakening medications. 
• Has participated, or is participating, in a clinical research study evaluating COVID-19 
convalescent plasma, mAbs against SARS-CoV-2, or intravenous immunoglobulin (IVIG) 
within 3 months or within 5 half-lives of the investigational product (whichever is longer) 
prior to the screening visit 
• Prior, current, or planned future use of any of the following treatments: COVID-19 
convalescent plasma, mAbs against SARS-CoV-2 (eg, bamlanivimab), IVIG (any 
indication), systemic corticosteroids (any indication), or COVID-19 treatments (authorized, 
approved, or investigational) 
Note: prior use is defined as the past 30 days or within than 5 half-lives of the 
investigational product (whichever is longer) from screening. 
• Prior use (prior to randomization), current use (at randomization), or planned use (within 
time period given per CDC guidance but no sooner than 22 days of study drug 
administration) of any authorized or approved vaccine for COVID-19  
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Note: As of 02 March 2021, CDC guidance recommends deferral of SARS-CoV-2 
vaccination for at least 90 days after administration of passive antibody therapy. Additional 
information can be found in the main text. 
• Has participated, is participating, or plans to participate in a clinical research study 
evaluating any authorized, approved, or investigational vaccine for SARS-CoV-2 
Treatments 
 
IV Single 
Dose  
Co-administered REGN10933+REGN10987 combination therapy intravenous (IV) single 
dose: 
• 2400 mg (1200 mg per monoclonal antibody [mAb])  
• 1200 mg (600 mg per mAb)  
• 600 mg (300 mg per mAb) 
• 300 mg (150 mg per mAb) 
• Placebo IV single dose 
SC Single 
Dose  
Co-administered REGN10933+REGN10987 combination therapy subcutaneous (SC) single 
dose 
• 1200 mg (600 mg per mAb)  
• 600 mg (300 mg per mAb) 
• Placebo SC single dose 
Endpoints 
 
Primary 
Time-weighted average daily change from baseline in viral load (log10 copies/mL) from day 1 
to day 7, as measured by RT-qPCR in NP swab samples, in patients who have a central-lab 
determined RT-qPCR positive test and are seronegative at baseline 
Secondary 
• Time-weighted average daily change from baseline in viral load (log10 copies/mL) from day 
1 to day 5  
• Time-weighted average daily change from baseline in viral load (log10 copies/mL) in 
patients with high viral load at baseline (>104 copies/mL, >105 copies/mL, >106 copies/mL, 
>107 copies/mL) from day 1 to day 7 
• Time-weighted average daily change from baseline in viral load (log10 copies/mL) in 
patients with high viral load at baseline (>104 copies/mL, >105 copies/mL, >106 copies/mL, 
>107 copies/mL) from day 1 to day 5 
• Proportion of patients with high viral load (>104 copies/mL, >105 copies/mL, 
>106 copies/mL, >107 copies/mL) at each visit 
• Proportion of patients with viral loads below the limit of detection at each visit 
• Proportion of patients with viral loads below the lower limit of quantification at each visit 
• Change from baseline in viral load (log10 copies/mL) at each visit, as measured by RT-qPCR 
in NP samples 
• Proportion of patients with treatment-emergent SAEs through day 29 
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4 
• Proportion of patients with injection-site reactions (grade ≥3) through day 4 
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29 
• Concentrations of REGN10933 and REGN10987 in serum over time 
• Immunogenicity as measured by anti-drug antibodies (ADAs) and neutralizing antibodies 
(NAb) to REGN10933 and REGN10987  
Procedures 
and 
Assessments 
Procedures and assessments will include:  
• NP swabs for SARS-CoV-2 RT-qPCR 
• COVID-19-related medically-attended visits 
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• TEAEs, treatment-emergent SAEs, and treatment-emergent AESIs (grade ≥2 infusion-
related reactions, grade ≥3 injection-site reactions, grade ≥2 hypersensitivity reactions, and 
any TEAE that led to a hospitalization or emergency room visit, regardless of whether the 
visit is related to COVID-19) 
• Targeted concomitant medications, safety labs, vital signs, and pregnancy status 
Statistical 
Plan 
 
Statistical 
Hypothesis 
 
• H0: There is no difference between patients treated with one or more dose regimens of 
REGN10933+REGN10987 and patients treated with placebo in time weighted average 
daily change from baseline in viral load from day 1 to day 7 
• H1: REGN10933+REGN10987 reduces time weighted average daily change from baseline 
in viral load (log10 copies/mL) from day 1 to day 7, relative to placebo 
Justification 
of Sample 
Size 
 
The sample size is based on the primary virologic endpoint of the time-weighted average 
(TWA) daily change from baseline in viral load (log10 copies/mL) from day 1 to day 7, in 
patients who are seronegative and who have a positive RT-qPCR value at baseline. In the Phase 
2 portion of Study COV-2067, the mean (SD) was -0.73 (0.948) log10 copies/mL. For the 
primary hypothesis comparing each dose to placebo, approximately 57 patients per treatment 
group. With this sample size, the study has ~98% power to detect a difference of -0.73 log10 
copies/mL between any active treatment group and placebo. In order to enroll 400 seronegative 
patients, the study will randomize approximately 800 patients, assuming that 50% are 
seronegative.  
For comparisons between doses and regimens, the study plans to enroll 700 seronegative 
patients in order to have 100 patients per group. For between-group comparisons, the 95% CI 
half-width between any two treatment groups with this sample size would be 0.27 log10 
copies/mL. In order to enroll 700 seronegative patients, approximately 1400 patients will be 
randomized.  
Placebo IV and placebo SC arms will be pooled in the efficacy analyses of the viral load 
endpoints as the route of administration does not alter the pharmacodynamic response of 
patients receiving placebo. 
Primary 
Efficacy 
Analysis 
 
The primary virologic efficacy variable is the time-weighted average change from baseline in 
viral load from day 1 to day 7, as measured by RT-qPCR in NP swab samples. The primary 
analysis will be conducted in the Seronegative mFAS population.  
The analyses will be based on the observed data with no imputation for missing data. Viral 
load values less than the lower limit of quantification of the PCR assay but with positive 
qualitative results will be set to half of lower limit of quantification of the PCR assay; values 
with nondetectable RNA will be set to 0 log10 copies/mL if the reason for the negative value 
is not a failed test. Viral load values above the upper limit of quantification will be re-tested 
using the reflex test.  
The primary efficacy variable will be calculated using the linear trapezoidal rule, ie, area under 
the curve for change from baseline at each time point from day 1 to last observation divided 
by the number of days from day 1 to day of last observation. The TWA estimates the average 
over the time range of interest, adjusting for any irregular spacing of the timing when samples 
are taken (eg, if samples are missing).  
An Analysis of Covariance (ANCOVA) model with treatment group as a fixed effect and 
baseline viral load and treatment by baseline interaction as covariates will be fit to the data as 
the primary analysis. 
Timing of 
Statistical 
Analyses 
The primary efficacy analysis will be conducted as a first-step analysis using the first 816 
patients enrolled in the study up to day 7, in order to evaluate approximately 400 patients who 
are seronegative at baseline. This analysis represents the final analysis of the primary endpoint 
and is not considered an interim analysis.  
An analysis may also occur after all enrolled patients have reached at least day 7, and a 
subsequent analysis will occur once the last patient enrolled in the study completes their last 
study visit. A SAP will be issued prior to the first database lock. 
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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, two 
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 symptoms to respiratory failure and death (Wu, 2020). Among hospitalized 
patients, intensive care and/or supplemental oxygen intervention (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, and >50% lung involvement on imaging; 5% with respiratory failure, 
shock, or multiorgan failure) (Wu, 2020). 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 (Guan, 2020). 
Other reports have found that approximately 20% to 30% of hospitalized patients with COVID-19 
and pneumonia require intensive care for respiratory support (Richardson, 2020). 
1.3. 
Outpatient Care as a Potential COVID-19 Treatment Setting 
Although severe COVID-19 can occur across all age groups, accumulating data have identified 
several factors that can place patients at risk of more serious illness and potentially lead to 
hospitalization, emergency room visits, or other medically-attended visits (MAVs). These include 
age, pregnancy, as well as variety of comorbidities such as obesity and cardiovascular disease 
(Chen, 2020). An anti-viral therapeutic that could be administered to outpatients has the potential 
to significantly reduce COVID-19-related medically-attended visits, particularly among those with 
1 or more baseline risk factors Currently, there is a great need for therapies capable of reducing 
viral load and slowing or preventing COVID-19 disease progression. 
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1.4. 
The Role of Spike (S) Protein in SARS-CoV-2 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 (Huang, 2020). The 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 (Hoffmann, 2020) (Ou, 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 (Datta, 
2020), a number of efforts are underway to develop antibodies and vaccines that target the 
S protein of this novel coronavirus.  
1.5. 
REGN10933+REGN10987: Human Monoclonal Antibodies that 
Target SARS-CoV-2 S Protein 
Regeneron Pharmaceuticals, Inc (Regeneron) is currently developing human, neutralizing 
monoclonal antibodies (mAb)s directed against the S protein of SARS-CoV-2, for the treatment 
and prevention of SARS-CoV-2 infection. REGN10933 and REGN10987 are human, IgG1 mAbs 
that bind the receptor binding domain (RBD) of the SARS-CoV-2 S protein and block interaction 
with ACE2. REGN10933 and REGN10987 exhibit potent neutralization and can bind 
simultaneously to the S protein RBD. When co-administered as combination therapy, 
REGN10933+REGN10987 treatment is anticipated to neutralize SARS-CoV-2 with a reduced 
likelihood of viral escape due to genetic mutations. Importantly, these mAbs retain neutralization 
potency against multiple SARS-CoV-2 variants identified through clinical isolates, including 
recently-emerging variants such as the D614G variant, B.1.1.7 variant (first identified in the UK), 
and B.1.351 variant (first identified in South Africa) (Baum, 2020) (Korber, 2020) (Wang, 2021). 
REGN10933+REGN10987 combination therapy (also referred to as casirivimab+imdevimab) thus 
represents a promising therapeutic strategy to reduce SARS-CoV-2 viral load and COVID-19 
disease progression. 
1.6. 
A Randomized, Placebo-Controlled Study of Anti-SARS-CoV-2 
S Protein Monoclonal Antibodies in Outpatients with SARS-CoV-2 
Infection 
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 (EMA, 2021) (FDA, 2021) there remains a significant unmet medical need for 
COVID-19 treatments. Multiple COVID-19 therapies will be required, both to address the medical 
requirements of distinct patient populations and to bolster treatment supplies as caseloads continue 
to rise. The availability of multiple treatment options, and the continued collection of data on 
conditionally authorized treatments, are critically important in the setting of a global pandemic.  
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Studies are currently ongoing to assess the efficacy and safety of co-administered 
REGN10933+REGN10987 combination therapy (“REGN10933+REGN10987”) in the treatment 
and 
prevention 
of 
COVID-19. 
Available 
data 
in 
outpatients 
have 
shown 
that 
REGN10933+REGN10987 provides similar virologic and clinical efficacy when given as 2400 
mg or 8000 mg intravenous (IV) single dose (Section 3.2), with an acceptable safety profile in this 
patient population. In this phase 2 study, additional IV dose regimens, as well as subcutaneous 
(SC) dose regimens, will be evaluated in outpatients with SARS-CoV-2 infection to provide 
additional assessment of virologic efficacy and safety at lower doses. 
For more information regarding the rationale for the study design and dose selection, refer to 
Section 3.2. Additional background information on the study drug and the overall development 
program can be found in the Investigator’s Brochure. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to assess the virologic efficacy of REGN10933+REGN10987 
across different intravenous and subcutaneous doses compared to placebo.  
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate additional indicators of virologic efficacy of REGN10933+REGN10987 
compared to placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To assess 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 the study are: 
• To explore the occurrence of COVID-19-related hospitalizations, emergency room 
visits, and other medically-attended visits (MAVs) in patients treated with 
REGN10933+REGN10987 compared to those treated with placebo 
Note: The definition of a COVID-19-related MAV is provided in Section 9.2.10.3. 
• To assess viral genetic variation in patients with a positive SARS-CoV-2 quantitative 
reverse transcription polymerase chain reaction (RT-qPCR) 
• To explore relationships between REGN10933+REGN10987 exposure and selected 
efficacy endpoints, safety endpoints, and/or biomarkers 
• To explore the occurrence of all-cause hospitalizations, emergency room (ER) visits, 
or deaths in patients treated with REGN10933+REGN10987 compared to those treated 
with placebo 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
Treatment with REGN10933+REGN10987 is well tolerated and reduces SARS-CoV-2 viral load 
across multiple dose regimens compared to placebo. 
Information concerning statistical hypotheses can be found in Section 11.1. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
In an ongoing study in outpatients with COVID-19 (R10933-10987-COV-2067; hereafter COV-
2067), interim phase 1/2 and primary phase 2 analyses found that patients treated with 2400 mg or 
8000 mg of REGN10933+REGN10987 IV single dose had a greater reduction in viral load 
compared with those who received placebo. These virologic effects translated into clinical benefit, 
significantly reducing COVID-19-related MAVs in these patients (with MAV defined in the study 
as hospitalization, emergency room visit, urgent care visit, physician’s office visit, or telemedicine 
visit, with the primary reason for the visit being COVID-19). Notably, virologic and clinical 
efficacy were similar among those treated with either 2400 mg or 8000 mg, suggesting that 
maximal benefit may have already been reached at the 2400 mg dose (refer to the Investigator’s 
Brochure for more information on these analyses). 
This randomized, double-blinded, placebo-controlled, parallel group study (R10933-10987-COV-
20145) will assess the virologic efficacy, as well as safety and tolerability, of 
REGN10933+REGN10987 at different single dose regimens in outpatients with SARS-CoV-2 
infection. The purpose of this study is to identify a lower dose regimen capable of demonstrating 
the same (or similar) virologic efficacy seen at the 2400 mg IV single dose level in outpatients 
with COVID-19. These data, taken together with data on the safety profile of 
REGN10933+REGN10987 and any correlation between virologic and clinical efficacy at 1200 
mg, 2400 mg, and 8000 mg IV doses observed in Study COV-2067, will aid in identifying a dose 
regimen with the optimal risk-benefit profile in this patient population. Moreover, identifying 
lower doses that are capable of reducing viral load will bolster the ability to provide therapeutic 
doses of REGN10933+REGN10987 in the setting of a global pandemic, where supplies of 
therapeutic agents are increasingly limited as caseloads rise. 
An additional aim of this study is to assess to virologic efficacy, as well as safety and tolerability, 
of REGN10933+REGN10987 given subcutaneously in outpatients with SARS-CoV-2. Currently, 
SC administration is being explored only in the prophylaxis setting (R10933-10987-COV-2069). 
Availability of subcutaneously-administered single-dose REGN10933+REGN10987 in the 
treatment setting could potentially improve access for patients who are unable to access facilities 
capable of administering intravenous infusions.  
Since the primary endpoint of this study is virologic, the study will enroll patients with SARS-
CoV-2 infection regardless of whether they have symptoms of COVID-19. This will allow for a 
broader assessment of the potential impact of REGN10933+REGN10987 on SARS-CoV-2 viral 
burden. Study COV-2067 is currently assessing a more targeted population of symptomatic 
patients who have one or more risk factors for developing severe COVID-19. 
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As of protocol amendment 1, patients will be followed for safety monitoring for approximately 6 
months after study drug administration. This extended study duration will include approximately 
5 half-lives of REGN10933+REGN10987 (with a half-life of approximately 30 days) and allow 
an assessment of safety during the drug elimination period.  
3.2.2. 
Rationale for Dose Selection  
Initial phase 1 and phase 2 studies in outpatients with SARS-CoV-2 infection (Study COV-2067) 
assessed single IV dose administration of REGN10933+REGN10987 at 2400 mg (1200 mg per 
mAb) and 8000 mg (4000 mg per mAb). The original strategy in selecting these doses was to 
identify a target concentration in lung epithelial fluid (ELF) that approximates the effective 
concentration required for 99% viral neutralization (EC99)* of SARS-CoV-2 in vitro, and then 
identify doses anticipated to meet or exceed this concentration in lung ELF. Using observed EC99 
estimates of 0.14 µg/mL (REGN10933) and 0.78 µg/mL (REGN10987), assuming drug 
concentration in lung ELF to be 0.15x that of serum (Magyarics, 2019), and accounting for 
uncertainties related to drug PK and mAb penetration into lung ELF, 20 µg/mL (per mAb) was 
selected as the initial target concentration in serum, and a 2400 mg dose was chosen with the 
assumption that ≥95% of patients would exceed the target concentration in serum for at least 28 
days. An 8000 mg dose also was evaluated, in the event that a higher dose was required for 
efficacy. 
Data from the phase 1 and phase 2 studies confirmed that ≥95% of patients exceeded 20 µg/mL 
per mAb in serum for 28 days at the 2400 mg dose, and dose-proportional increases in exposure 
were observed at 8000 mg. Moreover, treatment with either 2400 mg or 8000 mg 
REGN10933+REGN10987 reduced viral load and led to positive trends in clinical outcomes, as 
demonstrated by similar and significant reductions in COVID-19-related MAVs at both dose levels 
(Weinreich, 2020)(for more information, refer to the Investigator’s Brochure). Based on the flat 
dose response observed for the 2400 mg and 8000 mg doses, as well as a linear PK relationship 
between the doses, the 2400 mg IV dose was chosen as the highest dose to be investigated in phase 
3 of Study COV-2067. A 1200 mg IV dose is also being investigated in that study and is expected 
to achieve approximately 50% of the concentrations observed for 2400 mg, assuming that the 
linear PK relationship between 2400 mg and 8000 mg is also observed at this lower dose. 
The purpose of the current study is to characterize the dose response relationship for 
REGN10933+REGN10987, as measured by changes in time-weighted viral load up to study day 
7. The mean total concentrations for the selected doses are anticipated to meet or exceed the target 
concentration in serum during this time period. Based on currently-available concentration data 
and assuming linear PK, the expected mean total drug concentrations in serum (sum of 
REGN10933 and REGN10987) on study day 7 for the selected IV doses of 300, 600, 1200, and 
2400 mg are 30.7, 61.3, 123, and 245 μg/mL, respectively. Assuming a lung ELF-to-serum ratio 
of 0.15x, the mean total concentration of antibody is expected to exceed either EC99 in the ELF for 
at least 6 days for all IV doses selected. On Day 15, the expected mean concentrations are 21.3, 
42.6, 85.2, and 170 μg/mL, respectively.  
In addition to intravenously administered REGN10933+REGN10987, SC doses of 600 mg and 
1200 mg will also be evaluated. From study day 2 to study day 8, the expected mean total 
concentration in serum (sum of REGN10933 and REGN10987) is expected to range between 25.8 
to 52.6 μg/mL for the 600 mg SC dose and between 51.6 and 105 μg/mL for the 1200mg SC dose. 
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On study day 15, the expected mean concentration is 41 μg/mL for the 600 mg SC dose and 81 
μg/mL for the 1200 mg SC dose. 
*Note: the EC99 values discussed here are identical to the inhibitory concentration (IC99) values discussed in the 
Investigator's Brochure. 
3.3. 
Risk-Benefit 
In Study COV-2067, virologic and clinical efficacy was observed for REGN10933+REGN10987 
in the overall population of patients that were SARS-CoV-2 RT-qPCR-positive at baseline, 
although it was more striking in individuals who had at least 1 pre-existing risk factor for severe 
COVID-19, were seronegative at baseline, or in those whose immune response was not sufficiently 
strong to reduce viral load as evidenced by high baseline viral loads. Treatment with 
REGN10933+REGN10987 was able to compensate for the absent or insufficient immune response 
and was able to reduce the mean viral load and decrease the number of MAVs. Overall, these data 
provide promising evidence for the use of REGN10933+REGN10987 in outpatients with SARS-
CoV-2 infection. 
These positive efficacy results are balanced by an acceptable safety profile. Nonclinical toxicology 
studies in nonhuman primates showed that REGN10933+REGN10987 was well-tolerated without 
adverse findings. Important identified risks, important potential risks, and other theoretical 
considerations are described below.  
Important Identified Risks. As with other protein therapeutics, hypersensitivity reactions, 
including acute infusion-related reactions (IV intravenous [IV] administration) or injection site 
reactions (SC subcutaneous [SC] administration), may develop immediately or within a few hours 
to days after study drug administration. Hypersensitivity reactions, including infusion-related 
reactions or injection site reactions, have been observed in patients who received 
REGN10988+REGN10933 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 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 
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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.  
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 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 up to day 169 (end of study; EOS). In addition, any SAEs reported 
after EOS will be recorded. 
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 clinical development of the product and the initiation and conduct of clinical trials. 
For additional information, refer to the Investigator’s Brochure. 
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4. 
ENDPOINTS 
4.1. 
Primary Endpoint 
The primary endpoint is time-weighted average daily change from baseline in viral load (log10 
copies/mL) from day 1 to day 7, as measured by RT-qPCR in nasopharyngeal (NP) swab samples, 
in patients who have a central-lab determined RT-qPCR positive test and are seronegative at 
baseline. 
4.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Time-weighted average daily change from baseline in viral load (log10 copies/mL) from 
day 1 to day 5  
• Time-weighted average daily change from baseline in viral load (log10 copies/mL) in 
patients with high viral load at baseline (>104 copies/mL, >105 copies/mL, >106 
copies/mL, >107 copies/mL) from day 1 to day 7 
• Time-weighted average daily change from baseline in viral load (log10 copies/mL) in 
patients with high viral load at baseline (>104 copies/mL, >105 copies/mL, >106 
copies/mL, >107 copies/mL) from day 1 to day 5 
• Proportion of patients with high viral load (>104 copies/mL, >105 copies/mL, 
>106 copies/mL, >107 copies/mL) at each visit 
• Proportion of patients with viral loads below the limit of detection at each visit 
• Proportion of patients with viral loads below the lower limit of quantification at each 
visit 
• Change from baseline in viral load (log10 copies/mL) at each visit, as measured by RT-
qPCR in NP samples 
• Proportion of patients with treatment-emergent SAEs through day 29 
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4 
• Proportion of patients with injection-site reactions (grade ≥3) through day 4 
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29 
• Concentrations of REGN10933 and REGN10987 in serum over time 
• Immunogenicity as measured by ADAs and NAb to REGN10933 and REGN10987  
4.3. 
Exploratory Endpoints 
Note: The definition of a COVID-19-related medically-attended visit is provided in 
Section 9.2.10.3. 
The exploratory endpoints are: 
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• Time-weighted average daily change from baseline in cycle threshold (Ct) from day 1 
to day 7, as measured by RT-qPCR in NP samples  
• Time-weighted average daily change from baseline in Ct from day 1 to day 5, as 
measured by RT-qPCR in NP samples 
• Change from baseline in Ct at each visit, as measured by RT-qPCR in NP samples 
• Proportion of patients (through day 29 and day 169) with ≥1 COVID-19-related 
hospitalization or all-cause mortality 
• Proportion of patients (through day 29 and day 169) with ≥1 COVID-19-related 
hospitalization, emergency room (ER) visit, or all-cause mortality 
• Proportion of patients (through day 29 and day 169) with ≥1 COVID-19-related 
medically-attended visit or all-cause mortality 
• Proportion of patients (through day 29 and day 169) with ≥1 COVID-19-related 
medically-attended visit by type of visit (hospitalization, emergency room visit, urgent 
care, physician’s office visit, and/or telemedicine visit)  
• Proportion of patients (through day 29 and day 169) with ≥2 COVID-19-related 
medically-attended visits or all-cause mortality  
• Days of hospitalization due to COVID-19 
• Proportion of patients (by day 29 and day 169) admitted to an intensive care unit (ICU) 
due to COVID-19 
• Proportion of patients (by day 29 and day 169) requiring supplemental oxygen due to 
COVID-19  
• Proportion of patients (by day 29 and day 169) requiring mechanical ventilation due to 
COVID-19  
• Total number of COVID-19-related MAVs through day 29 and 169 
• All-cause mortality by day 29 and day 169 
• Proportion of patients with treatment-emergent SAEs through day 169 
5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height), disease 
characteristics (eg, baseline viral load [log10 copies/mL, viral load threshold, and Ct], 
presence/absence of COVID-19-related symptoms, days since symptom onset), serology 
(negative, positive, or other), medical history, and medication history for each patient.  
5.2. 
Efficacy Variables 
Efficacy variables include viral load (log10 copies/mL and Ct). 
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5.3. 
Safety Variables 
Safety variables include incidence of TEAEs, incidence of treatment-emergent SAEs, and 
incidence of treatment-emergent AESIs as described in Section 10.1.1. 
5.4. 
Pharmacokinetic Variables 
The variables are the concentration of REGN10933 and REGN10987 in serum and time. Samples 
will be collected at the visits specified in Table 1. 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, as well as NAb status, and time point/visit. 
Samples will be collected at the visits specified in Table 1. 
6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
Note: as of protocol amendment 2, study enrollment is closed. 
This is a randomized, double-blind, placebo-controlled, parallel group study to assess the dose 
response profile of single IV or single SC doses of REGN10933+REGN10987 in outpatients with 
SARS-CoV-2 infection. The schedule of events is provided in Table 1, and the study design is 
provided in Figure 1. 
Eligible patients will be randomized to receive a single dose of REGN10933+REGN10987 or 
placebo by IV or SC route (refer to Section 8.6 for more information on treatment allocation). On 
the day of dosing, patients will have NP swabs taken for SARS-CoV-2 RT-qPCR testing and blood 
drawn for safety, drug concentration, immunogenicity, and serologic analyses. After study drug 
administration, patients will have a post-dose blood collection (either at the end of intravenous 
infusion or at least 1 hour after subcutaneous administration). Patients will be monitored for at 
least 1 hour after study drug administration and then released from the study site, if medically 
appropriate.  
Subsequent assessments and sample collections may potentially occur through a variety of in-
person and remote methods. This may include (but is not limited to) visits at the study site or place 
of infusion, home-based visits (defined as visits by home health staff, at mobile units, and/or testing 
centers), or by phone/telemedicine. Throughout the study, biological samples will be obtained by 
study personnel only at study locations where appropriate personal protective equipment (PPE) 
can be used. 
Information related to safety and COVID-19-related medically-attended visits will be recorded 
during planned study visits. Patients will also be asked to notify study personnel as soon as possible 
about any medically-attended visits. Note that the TEAEs (as defined in Section 10.1.1) that will 
be collected during the study will differ according to different periods of the study schedule 
(Table 1). Refer to Section 10.1.1 for more information on reporting of TEAEs and treatment-
emergent laboratory abnormalities. 
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Patients will have NP swabs and blood samples collected every other day for the first week of the 
study. Additional NP swab samples will be collected once-weekly for 2 more weeks to assess 
potential persistence of viral load. A phone visit will occur during the fourth week for collection 
of safety information.  
After the first month, patients will have visits approximately once-monthly for 4 additional 
months. The penultimate visit will be in-person to collect blood samples for drug concentration 
and immunogenicity. The final visit (EOS) will be a phone call. 
 
Figure 1: 
Study Flow Diagram  
 
6.2. 
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).  
6.3. 
Planned Interim Analysis 
No formal interim analysis will be conducted. Refer to Section 11.4.9 for information on the timing 
of planned analyses for this study.  
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Up to approximately 1400 patients will be enrolled. Refer to Section 11.2 for more information. 
7.2. 
Study Population 
This study will enroll adult, non-hospitalized patients who have a positive diagnostic test for 
SARS-CoV-2. 
7.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Is male or female ≥18 years of age (or country’s legal age of adulthood) at randomization 
Note: upper age limit may apply; refer to other inclusion criteria. 
2. Has SARS-CoV-2-positive diagnostic test from a sample collected ≤72 hours prior to 
randomization, using a validated SARS-CoV-2 antigen, RT-PCR, or other molecular 
diagnostic assay and an appropriate sample such as nasopharyngeal (NP), nasal, 
oropharyngeal (OP), or saliva 
Note: Historical record of positive result is acceptable, as long as the sample was 
collected ≤72 hours prior to randomization. 
3. Low-risk symptomatic patient: Has symptoms consistent with COVID-19 (as determined 
by the investigator) with onset ≤7 days before randomization, and meets all of the 
following 8 criteria: 
a. Age ≤50 
b. No obesity, with obesity defined as BMI ≥30 kg/m2 
c. Does not have cardiovascular disease or hypertension 
d. Does not have chronic lung disease or asthma 
e. Does not have type 1 or type 2 diabetes mellitus 
f. Does not have chronic kidney disease, with or without dialysis 
g. Does not have chronic liver disease 
h. Is not pregnant 
or 
Asymptomatic patient: Has had no symptoms consistent with COVID-19 (as determined 
by the investigator) occurring at any time <2 months prior to randomization 
4. Maintains O2 saturation ≥93% on room air 
5. Is willing and able to provide informed consent signed by study patient or legally 
acceptable representative 
6. Is willing and able to comply with study procedures, including providing samples for viral 
shedding testing  
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7.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria will be excluded from the study: 
1. Was admitted to a hospital for COVID-19 prior to randomization, or is hospitalized 
(inpatient) for any reason at randomization 
2. Has a known positive SARS-CoV-2 serologic test  
3. Has a positive SARS-CoV-2 antigen or molecular diagnostic test from a sample collected 
>72 hours prior to randomization  
4. Is immunosuppressed, based on investigator’s assessment  
Note: examples include cancer treatment, bone marrow or organ transplantation, immune 
deficiencies, HIV (if poorly controlled or evidence of AIDS), sickle cell anemia, 
thalassemia, and prolonged use of immune-weakening medications. 
5. Has participated, or is participating, in a clinical research study evaluating COVID-19 
convalescent plasma, mAbs against SARS-CoV-2, or intravenous immunoglobulin (IVIG) 
within 3 months or within 5 half-lives of the investigational product (whichever is longer) 
prior to the screening visit 
6. Prior, current, or planned future use of any of the following treatments: COVID-19 
convalescent plasma, mAbs against SARS-CoV-2 (eg, bamlanivimab), IVIG (any 
indication), systemic corticosteroids (any indication), or COVID-19 treatments 
(authorized, approved, or investigational) 
Note: prior use is defined as the past 30 days or within than 5 half-lives of the 
investigational product (whichever is longer) from screening. 
7. Prior use (prior to randomization), current use (at randomization), or planned use (within 
time period given per CDC guidance but no sooner than 22 days of study drug 
administration) of any authorized or approved vaccine for COVID-19  
Note: As of 02 March 2021, CDC guidance recommends deferral of SARS-CoV-2 
vaccination for at least 90 days after administration of passive antibody therapy. Refer to 
Section 8.10.1 for more information. 
8. Has known active infection with influenza or other non-SARS-CoV-2 respiratory 
pathogen, confirmed by a diagnostic test 
9. Has known allergy or hypersensitivity to components of study drug 
10. Has been discharged, or is planned to be discharged, to a quarantine center 
11. Has participated, is participating, or plans to participate in a clinical research study 
evaluating any authorized, approved, or investigational vaccine for COVID-19 
12. Is a member of the clinical site study team or is an immediate family member of the site 
study team 
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. 
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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 follow up contact, as described in Section 9.1.2. 
7.4. 
Replacement of Patients 
Patient prematurely discontinued from the 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 dose 
levels and method of treatment allocation.  
• Co-administered REGN10933+REGN10987 combination therapy 
• Placebo 
In this study, both intravenous infusion and subcutaneous administration will be used. All patients 
allocated to a subcutaneous regimen will receive 4 injections of study drug on day 1, each 
containing 2.5 mL of active study drug or placebo.  
It is recommended that subcutaneous injection sites should be chosen among the different 
quadrants of the abdomen (avoiding navel and waist areas) and upper thighs. During the dose 
administration, each injection must be given in a different anatomical location (1 injection 
administered in the right lower quadrant of the abdomen, another in the left lower quadrant of the 
abdomen, etc).  
8.2. 
Background Treatment(s) 
No background treatment will be allowed. Patients may self-administer non-prescribed 
medications (eg, antipyretics). 
8.3. 
Rescue Treatment(s) 
Patients can receive rescue therapy for 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 
8.4.1. 
Dose Modification 
This is a single dose study; dose modification is not allowed. 
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8.4.2. 
Study Drug Discontinuation 
This is a single dose study; study drug discontinuation is not applicable. 
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 must be reported as AESIs (see Section 10.2.3). Refer to CTCAE 
severity scale in Section 10.2.5. 
8.5.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs 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. 
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 AEs occur: 
• Anaphylaxis* 
• Laryngeal/pharyngeal edema 
• Severe bronchospasm 
• Chest pain 
• Seizure 
• Severe hypotension 
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• 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 one 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) 
8.5.2. 
Injection Reactions 
Emergency equipment and medication for the treatment of systemic injection reactions (ie, 
hypersensitivity) must be available for immediate use.  
All grade ≥3 injection reactions (local or systemic) must be reported as AESIs. Refer to CTCAE 
severity scale in Section 10.2.5. 
8.6. 
Method of Treatment Assignment  
Patients will be randomized to one of the treatment arms listed below, according to a central 
randomization scheme using an interactive web response system (IWRS):  
Dose of Co-administered REGN10933+REGN10987 
Combination Therapy 
Route of 
Administration 
Randomization 
Ratio 
2400 mg (1200 mg each of REGN10933 and REGN10987) 
IV 
2 
1200 mg (600 mg each of REGN10933 and REGN10987) 
IV 
2 
600 mg (300 mg each of REGN10933 and REGN10987) 
IV 
2 
300 mg (150 mg each of REGN10933 and REGN10987) 
IV 
2 
Placebo 
IV 
1 
1200 mg (600 mg each of REGN10933 and REGN10987) 
SC 
2 
600 mg (300 mg each of REGN10933 and REGN10987)  
SC 
2 
Placebo 
SC 
1 
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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 administration. The drug solution must be provided in identical 
form for active and placebo treatments, so that they remain indistinguishable to both study 
personnel and patients.  
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 data as needed for safety review or other data review. Any team performing 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.  
Drug concentration, virology, and other 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 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 
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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. 
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. 
For more information on recording of concomitant medications, refer to Section 9.2.4.3. 
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8.10.1. 
Prohibited and Permitted Medications 
Patients are not permitted to receive any medication specified in the exclusion criteria for study 
enrollment unless medically indicated (Section 7.2.2).  
Based on CDC guidance and investigator discretion, deferring the use of any authorized or 
approved COVID-19 vaccine for at least 90 days after dosing may be considered to reduce 
potential interference of the study drug with vaccine-induced immune responses. For more 
information, refer to the current CDC guidance (CDC, 2020). Refer to Section 7.2.2 for more 
information on exclusion criteria related to COVID-19 vaccination. 
Patients may otherwise continue their normal regimen of medications and procedures. 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
Study assessments and procedures are presented by visit in Table 1. 
 
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Table 1: 
Schedule of Events 
Day 
Screening/Baseline1 
 Follow Up2 
EOS 
-1 to 1 
3 
4 
5 
7 
15 22 292 602 902 120 1692 
Screen Pre-Dose Dose Post-Dose 
Window (Days) 
 
 
 
 
 
 
 
 
±1 ±1 ±3 ±3 ±3 ±28 ±28 
 
 
 
 
Screening/Baseline Only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test for SARS-CoV-23 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 symptoms, if applicable )12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment  
Study drug administration 
 
 
X 
 
 
 
  
 
 
 
 
 
 
 
Efficacy  
Nasopharyngeal (NP) swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Safety  
Vital signs 
 
X4 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 IRRs5,6 
 
 
← cont. monitoring → 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥3 ISRs5,6 
 
 
← cont. monitoring → 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 hypersensitivity5reactions5,6 
 
 
← continuous monitoring → 
 
 
 
 
Treatment-emergent AEs5,6 
 
 
← continuous monitoring → 
 
 
 
 
Treatment-emergent grade 3 or 4 AEs5 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Treatment-emergent SAEs5,6 
 
 
← continuous monitoring → 
TEAEs that led to any hospitalization or emergency room visit5,6 
 
 
← continuous monitoring → 
Targeted concomitant medications5,6 
X 
 
← continuous monitoring → 
Pregnancy test (WOCBP)7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital status 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Pregnancy status7 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Safety information (newborns of study participants)7 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Central Laboratory Safety Testing and Serologic Testing 
Hematology (including differential)8 
X8 
 
 
 
 
 
X 
  
 
  
 
 
 
 
Blood chemistry8  
X8 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum for serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Concentration and Immunogenicity Testing 
Serum for drug concentration (PK)9 
X9 
 
X9 
X 
 
X 
X 
 
 
 
 
 
X 
 
Serum for immunogenicity (ADA)10 
X10 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Exploratory Patient Outcome Assessment 
COVID-19-related MAV details11 
 
 
← continuous monitoring → 
ADA, anti-drug antibodies; AE, adverse event; cont, continuous; EOS, end of study; IRR, infusion-related reaction; ISR, injection-site reaction; MAV, medically-attended visit; PK, pharmacokinetics; 
SAE, serious adverse event; RT-qPCR, quantitative reverse transcription polymerase chain reaction; WOCBP, women of childbearing potential. 
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9.1.1. 
Footnotes for the Schedule of Events Table 
1. Screening visit may occur on the same day as the baseline visit (day 1), or the day prior to 
the baseline visit (day -1). 
2. On visit days when sample collection is not required, the information indicated in the 
schedule may be collected by phone without an in-person visit.  
3. Refer to Section 9.2.1.2 for diagnostic test requirements during screening. 
4. Vital signs, including temperature, blood pressure, heart rate, and SpO2, will be collected 
as described in Section 9.2.4.1. Vital signs will be taken once before study drug 
administration and once after study drug administration is completed. After infusion or 
injection of study drug, patients will be observed for at least 1 hour.  
5. From day 1 to day 29, the following will be recorded: all TEAEs, treatment-emergent 
SAEs, and treatment-emergent AESIs (grade ≥2 IRRs, grade ≥3 ISRs, grade ≥2 
hypersensitivity reactions, and any treatment-emergent adverse event that led to a 
hospitalization or emergency room visit, regardless of whether the visit is related to 
COVID-19). 
From day 30 to day 169, the following will be recorded: treatment-emergent grade 3 or 4 
AEs, treatment-emergent SAEs, and treatment-emergent AESIs (any treatment-emergent 
adverse event that led to a hospitalization or emergency room visit, regardless of whether 
the visit is related to COVID-19). Refer to Section 10.1 for more information on AE 
reporting and recording requirements. 
Medications will be also be reviewed and recorded. Only the targeted medications listed in 
Section 9.2.4.3 will be recorded in the eCRF. 
6. Study visits are not required solely to collect continuously-monitored assessments, if no 
other assessments are planned on that day. 
7. Pregnancy testing will be performed in women of childbearing potential (WOCBP) only. 
For WOCBP who have symptoms of COVID-19 at screening (see Section 7.2.1), negative 
pregnancy test must be confirmed prior to study drug administration. WOCBP who are 
asymptomatic at screening may receive study drug regardless of pregnancy status. Serum 
or urine pregnancy test are both acceptable. Refer to Section 9.2.6 for more information, 
including definition of WOCBP. Note that a paper pregnancy report form must be 
completed for each patient who becomes pregnant or is pregnant at the signing of consent. 
Safety information in newborns of study participants will be collected as described in 
Section 9.2.5.  
8. The indicated blood samples may be collected at either day -1 or day 1 (screening or pre-
dose), but must be collected prior to randomization. Refer to Section 9.2.7 for more 
information on abnormal laboratory findings.  
9. Actual dosing time and drug concentration sample collection times will be recorded. 
For patients receiving IV infusion: at the screening/baseline visit, blood for assessment 
of drug concentration in serum will be taken prior to dosing (either at day -1 or day 1) and 
within 60 minutes after the end of infusion (EOI). The EOI sample should be collected 
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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.  
For patients receiving SC injection: at the screening/baseline visit, blood for assessment 
of drug concentration in serum will be taken prior to dosing (either at day -1 or day 1). The 
post-dose blood collection should occur at least 1 hour after study drug administration.  
10. The window for predose ADA sample collection should be as close to administration of 
study drug as is reasonable. Actual dosing time and ADA sample collection times, as 
applicable, will be recorded.  
11. Details of COVID-19-related MAVs will be collected as described in Section 9.2.10.3. 
12. When applicable, COVID-19 symptoms will be recorded and graded in eCRF. Symptom 
severity will also be recorded, using the current version of the NCI-CTCAE v5.0 (refer to 
Section 10.2.5). 
9.1.2. 
Early Termination from the Study 
Patients who withdraw prior to day 7 will be asked to allow an early termination (ET) visit 
consisting of day 7 assessments and sample collections. Patients who withdraw after day 7 but 
prior to day 22 will be asked to allow an ET visit consisting of day 22 assessments and sample 
collections.  
Patients who withdraw consent for the study prior to day 29 will be contacted by phone on day 29 
to obtain vital status. Patients withdrawn from the study after day 29 will be asked to complete an 
ET visit consisting of day 169 (EOS) assessments and sample collections. 
9.1.3. 
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, and treatment-emergent AESIs, 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 (Table 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.  
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 
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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.  
9.2.1.3. 
Demographics 
Refer to Section 5.1.  
9.2.1.4. 
Medical History 
Medical history will include, but is not limited to, the following:  
• COVID-19 with start date as the date of onset of first symptoms related to COVID-19, 
as well as associated symptoms and their severity graded per NCI-CTCAE v5.0 (refer 
to Section 10.2.5) 
• Whether the patient is receiving oxygen at home by nasal cannula  
• Menopausal history 
• Pregnancy or breastfeeding status, if applicable  
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. 
9.2.3. 
Efficacy Procedures  
9.2.3.1. 
Nasopharyngeal Swab Collection 
Virologic samples will be collected from patients to determine presence or absence of SARS-CoV-
2 virus, including at baseline, and to measure viral load. Samples will be used for RT-qPCR 
analysis. Samples may additionally be used for exploratory viral RNA sequencing plaque forming 
unit assays (PFU) assays and/or viral culture. Additional details regarding sample collection and 
analysis can be found in Section 9.2.10.1 and the laboratory manual. 
9.2.4. 
Safety Procedures  
9.2.4.1. 
Vital Signs 
Vital signs will include temperature, blood pressure, heart rate (per minute), SpO2.  
Temperature may be measured using the following methods: axilla, oral, tympanic, or temporal. 
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). 
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. 
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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. 
9.2.4.2. 
Adverse Event Monitoring 
The TEAEs listed in Section 10.1.1 will be recorded.  
9.2.4.3. 
Record Targeted Concomitant Medications 
A targeted list of the following concomitant medications will be recorded in the eCRF: 
• Putative COVID-19 treatments (eg, remdesivir, bamlanivimab, convalescent serum, 
IVIG, IL-6 receptor inhibitors [eg, sarilumab, tocilizumab], JAK inhibitors [eg, 
baricitinib], ivermectin)  
• SARS-CoV-2 vaccines 
• 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).  
• Influenza vaccinations 
For more information on concomitant medications, refer to Section 8.10. 
9.2.5. 
Post-Day 22 Follow-up by Phone 
Patients will be contacted by phone for post-day 22 safety assessments at the time points listed in 
Table 1. These assessments will include vital status, pregnancy status, and targeted safety 
information.  
Vital Status. Record vital status (whether the patient is dead or alive) and record the date of death, 
when applicable. 
Pregnancy Status. Record pregnancy status and date of pregnancy, when applicable. Refer to 
Section 10.1.3 for reporting requirements. 
Targeted Safety Information. Refer to Section 10.1 for more information on reporting and 
recording requirements. 
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Safety Information in Newborns of Study Participants. The incidence and outcome of any 
SARS-CoV-2 infection will be collected for newborn infants of patients who were treated in the 
study and were pregnant at randomization or became pregnant at any time in the study. Note that 
this information is in addition to outcome reporting of all pregnancies (Section 10.1.3). 
9.2.6. 
Pregnancy Test 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 and should be completed regardless of pregnancy status. 
Pregnancy test will be performed at the local laboratory. 
For WOCBP who have symptoms of COVID-19 at screening (see Section 7.2.1), negative 
pregnancy test must be confirmed prior to study drug administration. WOCBP who are 
asymptomatic at screening may receive study drug regardless of pregnancy status. 
WOCBP are defined as females 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 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 is not required for women with documented hysterectomy or 
tubal ligation. 
Information about pregnancy will be recorded as described in Section 10.1.3. 
9.2.7. 
Laboratory Testing 
Hematology and blood chemistry will be analyzed by a central laboratory. Detailed instructions 
are provided in the laboratory manual.  
Blood Chemistry 
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  
 
Hematology 
Tests will include: 
Hemoglobin 
Differential: 
Neutrophils 
Hematocrit 
 
Lymphocytes 
Red blood cells (RBCs) 
 
Monocytes 
White blood cells (WBCs) 
 
Basophils 
Platelet count 
 
Eosinophils 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
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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 are provided in Section 10.1.1. 
9.2.8. 
Drug Concentration Measurements and Samples 
Samples for assessment of drug concentration will be collected at the time points indicated in the 
schedule of events. For information concerning unused samples and exploratory research, refer to 
Section 9.2.9. 
9.2.9. 
Immunogenicity Measurements and Samples 
Samples for immunogenicity assessment will be collected at the time points listed in the schedule 
of events. 
9.2.10. 
Exploratory Pharmacodynamic/Biomarker Analyses 
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 used for assessment of 
immunogenicity if necessary. 
 
 
 
9.2.10.1. 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 may be performed on viral nucleic acid 
isolated from nasopharyngeal swab, 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 
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 clinical study report. 
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Viral Infectivity 
To explore the effects of REGN10933+REGN10987 on infectivity of SARS-CoV-2, we may use 
PFU, viral culture or viral subgenomic mRNA 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 may be an indicator of actively-infected cells. These 
data may be associated with RT-qPCR measuring viral load.  
The results of the viral infectivity assays may not be included in the clinical study report. 
9.2.10.2. 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 virology and other clinical outcomes.  
9.2.10.3. COVID-19-Related Medically-Attended Visit Details 
A COVID-19-related medically-attended visit will be defined as follows: hospitalization, ER visit, 
urgent care visit, physician’s office visit, or telemedicine visit, with the primary reason for the visit 
being COVID-19.  
Medically-attended visits related to COVID-19, as determined by the investigator, will be recorded 
in the eCRF. During each indicated collection visit (refer to Table 1), all previously unrecorded 
COVID-19-related medically-attended visits and details will be recorded, beginning from the day 
of dosing up to and including the day of collection. 
Details will include at minimum: 
• Type of visit (hospitalization, ER, urgent care, physician’s office visit, telemedicine) 
• Date of visit 
• If hospitalized due to COVID-19, length of visit 
• Reason (List all COVID-19-related symptom[s] or clinical manifestation[s]) that 
prompted medically-attended visit 
• If hospitalized due to COVID-19, whether ICU care was given 
• If hospitalized due to COVID-19, whether mechanical ventilation was required 
• Treatments given for COVID-19 (including, but not limited to supplemental oxygen, 
corticosteroids, COVID-19 convalescent plasma, remdesivir, bamlanivimab, 
baricitinib, etc) 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events  
10.1.1. 
General Guidelines 
In this study, the following TEAEs will be recorded: 
• Treatment-emergent AEs, up to day 29 
• Treatment-emergent AESIs (Section 10.1.3) as follows: 
− Grade ≥2 infusion-related reactions, up to day 4 
− Grade ≥3 injection-site reactions, up to day 4 
− Grade ≥2 hypersensitivity reactions, up to day 29 
− Any TEAE that led to a hospitalization or emergency room visit, regardless of 
whether the visit is related to COVID-19, up to day 169  
• Treatment-emergent AEs (grade 3 or 4 only), from day 30 to day 169 
• Treatment-emergent SAEs, up to day 169 
The investigator must promptly record the above TEAEs occurring during the observation period 
(see Section 11.4.5.1). Note that the length of this period differs in each study phase, owing to 
different final study visit days. 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 TEAEs 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 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. Isolated abnormal laboratory results, vital sign 
findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported as 
AEs if they are symptomatic, require corrective treatment, or constitute an AE in the investigator’s 
clinical judgement. For events that are serious due to hospitalization or ER visit, the reason must 
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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 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, AESIs, and pregnancies are to be reported according to the 
procedures in Section 10.1.3. 
10.1.2. 
Reporting Procedure 
The treatment-emergent AEs defined in Section 10.1.1 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, 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.  
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 AESI (serious and nonserious), defined as:  
− Grade ≥2 infusion-related reactions 
− Grade ≥3 injection-site reactions 
− Grade ≥2 hypersensitivity reactions  
− Any TEAE that led to a hospitalization or emergency room visit, regardless of 
whether the visit is related to COVID-19 
• 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 during the study or existing at the 
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time of signing the informed consent form. A paper pregnancy report form must be 
completed for each patient who becomes pregnant or is pregnant at the signing of 
consent.  
Any complication of pregnancy affecting a female 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, including testing results for SARS-
CoV-2 infection in the newborn, if performed. 
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). 
• 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 hospitalization (admission 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 (refer to Section 10.1.1 
Section 10.1.2).  
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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. 
10.2.4. 
Infusion-Related Reactions, Injection-Site Reactions, and Hypersensitivity 
Reactions 
Infusion-related reactions are defined as any relevant adverse event that occurs during intravenous 
infusion or up to day 4.  
Injection-site reactions are defined as any relevant adverse event that occurs during subcutaneous 
injection or up to day 4.  
Hypersensitivity reactions are defined as any relevant adverse event that occurs during intravenous 
infusion or subcutaneous injection or up to study day 29. 
10.2.5. 
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.  
Treatment-emergent AEs, SAEs, or AESIs not listed in the NCI-CTCAE will be graded according 
to the scale in Table 2. The grading systems for anaphylaxis, allergic reaction (hypersensitivity), 
infusion-related reaction, and injection-site reaction are provided in Table 3. 
Table 2: 
NCI-CTCAE (v5.0) Severity Grading System for Adverse Events: General 
Guideline  
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)1 
3 
Severe 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL2 
4 
Life-threatening 
Life threatening consequences; urgent intervention indicated 
5 
Death 
Death related to adverse events 
1 Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
2 Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and 
not bedridden.  
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Table 3: 
NCI-CTCAE (v5.0) Severity Grading System for Anaphylaxis, Allergic Reaction, Infusion-Related Reaction, 
and Injection-Site Reaction  
Grade 
CTCAE Term 
Anaphylaxis1 
Allergic Reaction 
(hypersensitivity)2 
Infusion-Related Reaction3 
Injection-Site Reaction4 
1 
N/A 
Systemic intervention 
not indicated 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
Tenderness with or without 
associated symptoms (eg, 
warmth, erythema, itching) 
2 
N/A 
Oral intervention 
indicated 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for ≤24 hours 
Pain; lipodystrophy; edema; 
phlebitis 
3 
Symptomatic bronchospasm, 
with or without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Bronchospasm; 
hospitalization 
indicated for clinical 
sequelae; intravenous 
intervention indicated 
Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
clinical sequelae 
Ulceration or necrosis; 
severe tissue damage; 
operative intervention 
indicated 
4 
Life-threatening 
consequences; urgent 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Life-threatening consequences; urgent 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
5 
Death 
Death 
Death 
Death 
1 Disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, 
causing a hypersensitivity immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of 
consciousness and may lead to death 
2 Disorder characterized by an adverse local or general response from exposure to an allergen. 
3 Disorder characterized by adverse reaction to the infusion of pharmacological or biological substances 
4 Disorder characterized by an intense adverse reaction (usually immunologic) developing at the site of an injection.  
 
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10.2.6. 
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 
− 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. 
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• 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 and 
Investigators 
During the study, the Sponsor and/or the CRO will inform health authorities, 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 unless delegated to the Sponsor. 
Event expectedness for study drug is assessed against the Reference Safety Information section of 
the Investigator’s Brochure 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 IRB as appropriate. 
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11. 
STATISTICAL PLAN 
This section summarizes the statistical analyses for this study and provides the basis for the 
statistical analysis plan (SAP) for the study.  
Endpoints are listed in Section 4. Analysis variables are listed in Section 5.  
11.1. 
Statistical Hypothesis 
The statistical hypothesis for the primary virologic efficacy endpoint is: 
• H0: There is no difference between patients treated with one or more dose regimens of 
REGN10933+REGN10987 and patients treated with placebo in time weighted 
average daily change from baseline in viral load from day 1 to day 7 
• H1: REGN10933+REGN10987 reduces time weighted average daily change from 
baseline in viral load (log10 copies/mL) from day 1 to day 7, relative to placebo 
11.2. 
Justification of Sample Size 
The sample size is based on the primary virologic endpoint of the time-weighted average (TWA) 
daily change from baseline in viral load (log10 copies/mL) from day 1 to day 7, in patients who are 
seronegative and who have a positive RT-qPCR value at baseline. In the Phase 2 portion of Study 
COV-2067, the mean (SD) was -0.73 (0.948) log10 copies/mL (see the Investigator's Brochure). 
For the primary hypothesis comparing each dose to placebo, approximately 57 patients per 
treatment group. With this sample size, the study has ~98% power to detect a difference of -0.73 
log10 copies/mL between any active treatment group and placebo. In order to enroll 400 
seronegative patients, the study will randomize approximately 800 patients, assuming that 50% 
are seronegative.  
For comparisons between doses and regimens, the study plans to enroll 700 seronegative patients 
in order to have 100 patients per group. For between-group comparisons, the 95% CI half-width 
between any two treatment groups with this sample size would be 0.27 log10 copies/mL. In order 
to enroll 700 seronegative patients, approximately 1400 patients will be randomized.  
Placebo IV and placebo SC arms will be pooled in the efficacy analyses of the viral load endpoints 
as the route of administration does not alter the pharmacodynamic response of patients receiving 
placebo. 
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Sets 
11.3.1.1. The Seronegative Modified Full Analysis Set  
The Overall modified Full Analysis Set (mFAS) includes all randomized patients with a positive 
central-lab determined SARS-CoV-2 RT-qPCR result from NP swab samples at randomization 
and is based on the treatment received (as treated). If a pre-treatment qualitative test is missing, 
then a qualitative test that is within post-treatment plus 2 hours may be used. 
The Seronegative mFAS is the subset of patients in the mFAS population who are seronegative 
at baseline. The Seronegative mFAS will be used for all efficacy and pharmacodynamic analyses. 
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The Seronegative mFAS is the primary analysis population; secondary analyses will be conducted 
in the Overall mFAS population.  
Note that since the primary objective of this study is to estimate the dose- and exposure-response 
of REGN10933+REGN10987 in reducing viral load, patients are included in the treatment actually 
received, not as randomized.  
In the Seronegative mFAS and mFAS populations, the placebo IV and placebo SC arms will be 
pooled for all analyses of virologic endpoints. Active dose groups will not be pooled. 
11.3.1.2. Per Protocol Set  
The Per Protocol Set (PPS) includes all randomized patients who receive treatment with positive 
central-lab determined SARS-CoV-2 RT-qPCR result from NP swab samples at randomization 
and is based on the treatment received (as treated).  
The PPS further excludes patients (1) who do not receive the full dose, (2) receive convalescent 
plasma therapy or SARS-CoV-2 antivirals, and (3) receive COVID-19 vaccination on or prior to 
the day 7 visit. Like the mFAS, the placebo IV and placebo SC arms will be pooled. Active dose 
groups will not be pooled. If all the patients in the mFAS are fully dosed and there are no 
applicable protocol deviations regarding (2) and (3), the PPS is the Overall mFAS. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated). Determination of “as treated” will be based on the 
actual study drug received on day 1. Demographic and baseline characteristics, treatment 
compliance/administration and all clinical safety variables will be analyzed using the SAF. 
In the SAF population, the placebo arms for the IV and SC routes of administration will be 
summarized separately. 
11.3.3. 
Pharmacokinetic Analysis Set 
The PK Analysis Set (PKAS) includes all randomized patients who received any study drug (SAF) 
and who have at least 1 non-missing drug concentration measurement following study drug 
administration. Patients will be analyzed according to the actual treatment received. 
11.3.4. 
Immunogenicity Analysis Sets 
The immunogenicity analysis set for a potential interim analysis is dependent on assay availability. 
The ADA Analysis Set (AAS) includes all treated patients who received any study drug and have 
at least 1 non-missing ADA result after first dose of the study drug. 
The NAb Analysis Set (NAS) includes all patients who received any study drug and who are 
negative in the ADA Assay or with at least one non-missing result in the NAb assay after first dose 
of the study drug. Patients who are ADA negative are set to negative in the NAb Analysis Set. 
Patients will be analyzed according to the actual treatment received. 
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11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum. For categorical or ordinal data, frequencies and percentages will be displayed for 
each category. 
Baseline is defined as the last assessment obtained before the first dose of study drug.  
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients: met the inclusion/exclusion criteria regarding 
the target indication and signed the ICF 
• The total number of randomized patients: received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.  
11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
The primary virologic efficacy variable is the time-weighted average change from baseline in viral 
load from day 1 to day 7, as measured by RT-qPCR in NP swab samples. The primary analysis 
will be conducted in the Seronegative mFAS population.  
The analyses will be based on the observed data with no imputation for missing data. Viral load 
values less than the lower limit of quantification of the PCR assay but with positive qualitative 
results will be set to half of lower limit of quantification of the PCR assay; values with 
nondetectable RNA will be set to 0 log10 copies/mL if the reason for the negative value is not a 
failed test. Viral load values above the upper limit of quantification will be re-tested using the 
reflex test.  
The primary efficacy variable will be calculated using the linear trapezoidal rule, ie, area under the 
curve for change from baseline at each time point from day 1 to last observation divided by the 
number of days from day 1 to day of last observation. The TWA estimates the average over the 
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time range of interest, adjusting for any irregular spacing of the timing when samples are taken 
(eg, if samples are missing).  
An Analysis of Covariance (ANCOVA) model with treatment group as a fixed effect and baseline 
viral load and treatment by baseline interaction as covariates will be fit to the data as the primary 
analysis. 
In addition, the least squares mean estimates for the TWA mean change from baseline in viral load 
will be presented for each treatment group, as well as for the difference between each 
REGN10933+REGN10987 treatment group and placebo as well as between active treatment 
groups. p-Values will be presented comparing the active arms to placebo. 95% confidence intervals 
will be reported between the active doses. Accompanying descriptive analyses will be provided at 
the individual time points used to calculate the TWA. To explore the dose response, other modeling 
approaches such as Emax will be described in the SAP.  
For efficacy analyses, the placebo IV and placebo SC arms are pooled. 
11.4.3.2. Secondary Efficacy Analysis 
A mixed effect model for repeated measures (MMRM) will assess the time course of treatment 
effect in viral load, the change from baseline in viral load (log10 copies/mL) at each visit for both 
the Seronegative mFAS and the Overall mFAS. There will be terms for baseline, treatment, visit, 
treatment-by-baseline interaction, baseline-by-visit interaction, and treatment-by visit interaction. 
Within-patient errors will be modeled with an unstructured, heterogeneous autoregressive (1), or 
compound symmetry covariance matrix in that order if a model does not converge. 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-spike mAb treatment arm and placebo 
will be provided along with the corresponding standard error, p-value, and associated 95% 
confidence interval.  
In the Seronegative mFAS, the proportion of patients who have PCR below the limit of detection 
(LOD), below the lower limit of quantification (LLOQ), or have qPCR levels >10^4, >10^5, 
>10^6, or >10^7 will be tabulated over time. The numbers of patients in each category will be 
tested using Fisher’s Exact test. Corresponding p-values and confidence intervals will be 
presented. 
Analyses of the virologic endpoints with in the Overall mFAS population will also be performed 
in subsets defined by the baseline viral load (>104 copies/mL, >105 copies/mL, >106 copies/mL, 
>107 copies/mL). The TWA, the time course of change, and other virologic endpoints will be 
summarized and/or analyzed within each of these categories.  
11.4.4. 
Control of Multiplicity 
The overall type I error rate will be controlled for the primary hypothesis at the two-sided 0.05 
level by the use of a step-down testing approach, starting at the top dose (Table 4). Each test 
compares a specific treatment group to pooled placebo. The highest dose will be tested first; if 
significant, the second highest dose will be tested; and so on. No multiplicity adjustments will be 
made for secondary endpoints, nor for comparisons between active doses.  
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Table 4: 
Statistical Testing Hierarchy 
Hierarchy Number 
Description 
1 
2400 mg IV versus pooled placebo 
2 
1200 mg IV versus pooled placebo 
3 
1200 mg SC versus pooled placebo 
4 
600 mg IV versus pooled placebo 
5 
600 mg SC versus pooled placebo 
6 
300 mg IV versus pooled placebo 
 
11.4.5. 
Safety Analysis 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, 3 periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before study 
drug administration 
• The 29-day observation period is defined as the time of study drug administration to 
day 29.  
• The full observation period is defined as the time of the administration of the study 
drug to the last follow-up 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 
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 preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries by treatment group will include the following: 
• The number (n) and percentage (%) of patients with at least 1 treatment-emergent AE 
through day 29 by SOC and PT 
• The number (n) and percentage (%) of patients with at least 1 treatment-emergent grade 
3 or 4 AE through day 169 by SOC and PT 
• The number (n) and percentage (%) of patients with at least 1 treatment-emergent SAE 
through day 29 by SOC and PT 
• The number (n) and percentage (%) of patients with at least 1 infusion-related reaction 
(grade ≥2), through day 4 by PT 
• The number (n) and percentage (%) of patients with at least 1 injection-site reaction 
(grade ≥3), through day 4 by PT 
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• The number (n) and percentage (%) of patients with at least 1 hypersensitivity reaction 
(grade ≥2), through day 29 by PT 
Summaries of SAEs and AESIs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 event by SOC and PT 
• SAEs and AESIs by severity (according to the grading scale outlined in Section 10.2.5), 
presented by SOC and PT 
• SAEs and AESIs by relationship to treatment (related, not related), presented by SOC 
and PT 
• Treatment-emergent SAEs and AESIs  
Deaths and other SAEs will be listed and summarized by treatment arm. 
11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
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. 
Listings will be provided with flags indicating the out of laboratory range values. 
11.4.5.3. Treatment Exposure 
The number and percentage of patients randomized and exposed to double-blind study drug, and 
duration of exposure to treatment during the study will be presented by treatment group.  
11.4.5.4. Treatment Compliance 
Treatment compliance in terms of total dose and infusion interruption will be summarized. The 
analysis methods will be detailed in the SAP. 
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11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
The concentrations of REGN10933 and REGN10987 in serum over time will be summarized 
descriptively for each of the treatment groups  
11.4.7. 
Pharmacokinetics and Pharmacokinetics/Pharmacodynamics Analyses 
Exposure-response analyses for select efficacy and safety endpoints and/or biomarkers may be 
performed, as appropriate. Details of the exposure-response analyses will be documented 
separately. 
11.4.8. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA and Nab response and titers observed in 
patients in the ADA and NAb analysis sets. ADA response categories and titer categories are 
defined as follows: 
ADA Response Categories: 
• ADA Negative, defined as ADA negative response in the ADA assays for 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. 
• 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 analyses will be provided: 
• Number (n) and percent (%) of ADA-negative patients (pre-existing immunoreactivity or 
negative in the ADA assay at all time points) by treatment groups  
• Number (n) and percent (%) of treatment-emergent ADA positive patients by treatment 
groups and ADA titer categories  
• Number (n) and percent (%) of treatment-boosted ADA positive patients by treatment 
groups and ADA titer categories  
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
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11.4.8.1. Analysis of Neutralizing Antibody Data 
The absolute occurrent (n) and percent of patients (%) with NAb status in the NAb analysis set 
will be provided by treatment groups.  
11.4.9. 
Timing of Statistical Analyses 
The primary efficacy analysis will be conducted as a first-step analysis using the first 816 patients 
enrolled in the study up to day 7, in order to evaluate approximately 400 patients who are 
seronegative at baseline (refer to Section 11.2 for more information). This analysis represents the 
final analysis of the primary endpoint and is not considered an interim analysis.  
An analysis may also occur after all enrolled patients have reached at least day 7, and a subsequent 
analysis will occur once the last patient enrolled in the study completes their last study visit. A 
SAP will be issued prior to the first database lock. 
Note: Individuals unblinded to patient-level data for the first-step analysis or subsequent analyses 
will no longer be directly involved in the day-to-day conduct of the study. Patient-level results will 
not be released to any site-facing personnel or anyone who is directly involved in the day-to-day 
conduct of the study.  
11.5. 
Interim Analysis 
No formal interim analysis will be conducted. Refer to Section 11.4.9 for information on the timing 
of planned analyses for this study.  
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. 
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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.  
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 investigator must allow study related monitoring activities to occur. 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 
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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. 
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 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. 
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In all instances, the confidentiality of the data must be respected. 
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. A copy of the IRB -approved ICF and documentation of 
approval must be provided to the Sponsor before study drug will be shipped to the study site. 
For patients at or above the legal age of adulthood, it is the responsibility of the investigator or 
authorized designee (if acceptable by local regulations) to obtain informed consent from each 
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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 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 the 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. 
Patient 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, 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 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 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 approval letter with a current list of the IRB members and their functions must 
be received by the Sponsor prior to shipment of drug supplies to the investigator. The approval 
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letter should include the study number and title, the documents reviewed, and the date of the 
review. 
Records of the IRB 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-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 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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2020. 
CDC. Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently 
Authorized in the United States.Centers for Disease Control and Prevention. 
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Published 2020. Accessed 26 Jan 2021. 
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical 
characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive 
study. Lancet 2020; 395(10223):507-513. 
Cui J, Li F,Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 2019; 
17(3):181-192. 
Datta PK, Liu F, Fischer T, Rappaport J,Qin X. SARS-CoV-2 pandemic and research gaps: 
Understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy. 
Theranostics 2020; 10(16):7448-7464. 
EMA. Treatments and Vaccines for COVID-19: Authorised Medicines. 2021. 
FDA. Coronavirus Disease 2019 (COVID-19).FDA. https://www.fda.gov/emergency-
preparedness-and-response/counterterrorism-and-emerging-threats/coronavirus-disease-2019-
covid-19. Published 2021. 
Fehr AR,Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods 
Mol Biol. 2015: 1-23. 
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus 
Disease 2019 in China. N Engl J Med 2020; 382(18):1708-1720. 
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-
2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease 
Inhibitor. Cell 2020; 181(2):271-280.e278. 
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 
2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223):497-506. 
Iwasaki A,Yang Y. The potential danger of suboptimal antibody responses in COVID-19. Nat 
Rev Immunol 2020:1-3. 
Jiang S, Hillyer C,Du L. Neutralizing Antibodies against SARS-CoV-2 and Other Human 
Coronaviruses. Trends Immunol 2020; 41(5):355-359. 
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Kam YW, Kien F, Roberts A, Cheung YC, Lamirande EW, Vogel L, et al. Antibodies against 
trimeric S glycoprotein protect hamsters against SARS-CoV challenge despite their capacity to 
mediate FcgammaRII-dependent entry into B cells in vitro. Vaccine 2007; 25(4):729-740. 
Korber B, Fischer W, Gnanakaran S, Yoon H, Theiler J, Abfalterer W, et al. Spike mutation 
pipeline reveals the emergence of a more transmissible form of SARS-CoV-2. bioRxiv 
2020:2020.2004.2029.069054. 
Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H, et al. Anti-spike IgG causes severe acute lung 
injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight 2019; 
4(4). 
Luo F, Liao FL, Wang H, Tang HB, Yang ZQ,Hou W. Evaluation of Antibody-Dependent 
Enhancement of SARS-CoV Infection in Rhesus Macaques Immunized with an Inactivated 
SARS-CoV Vaccine. Virol Sin 2018; 33(2):201-204. 
Magyarics Z, Leslie F, Bartko J, Rouha H, Luperchio S, Schorgenhofer C, et al. Randomized, 
Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study of the Penetration of a 
Monoclonal Antibody Combination (ASN100) Targeting Staphylococcus aureus Cytotoxins in 
the Lung Epithelial Lining Fluid of Healthy Volunteers. Antimicrob Agents Chemother 2019; 
63(8). 
Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al. Characterization of spike glycoprotein of SARS-
CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020; 
11(1):1620. 
Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. 
Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized 
With COVID-19 in the New York City Area. JAMA 2020; 323(20):2052-2059. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report--second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. Ann Emerg Med 2006; 47(4):373-380. 
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT,Veesler D. Structure, Function, and 
Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 2020; 181(2):281-292.e286. 
Wang P, Lihong L, Iketani S, Luo Y, Guo Y, Wang M, et al. Increased Resistance of SARS-
CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization. bioRxiv 
2021:2021.2001.2025.428137. 
Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, et al. REGN-COV2, a 
Neutralizing Antibody Cocktail, in Outpatients with Covid-19. N Engl J Med 2020. 
WHO. Novel Coronavirus (2019-nCoV) Situation Report – 22. 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/. Published 
2020. Accessed 24 Apr 2020. 
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Wu Z,McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 
2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese 
Center for Disease Control and Prevention. JAMA 2020. 
Yasui F, Kohara M, Kitabatake M, Nishiwaki T, Fujii H, Tateno C, et al. Phagocytic cells 
contribute to the antibody-mediated elimination of pulmonary-infected SARS coronavirus. 
Virology 2014; 454-455:157-168. 
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with 
Pneumonia in China, 2019. N Engl J Med 2020; 382(8):727-733. 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol, “A Phase 2 Study to Assess the Virologic Efficacy of 
REGN10933+REGN10987 Across Different Dose Regimens in Outpatients with SARS-CoV-2 
Infection”, 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. 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 Phase 2 Study to Assess the Virologic Efficacy of REGN10933+REGN10987 
Across Different Dose Regimens in Outpatients with SARS-CoV-2 Infection 
Protocol Number: 
R10933-10987-COV-20145 
Protocol Version: 
Amendment 2  
 
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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Signature Page for VV-RIM-00145951 v1.0
Signature Page for VV-RIM-00145951 v1.0 Approved
ESig Approval
ESig Approval
ESig Approval
ESig Approval
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 50 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
Clinical Study Protocol Title: A Phase 2 Study to Assess the Virologic Efficacy of 
REGN10933+REGN10987 Across Different Dose Regimens in Outpatients with SARS-CoV-2 
Infection  
Compound: 
REGN10933+REGN10987 
Protocol Number: 
R10933-10987-COV-20145 
Clinical Phase:  
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date:  
Original Statistical Analysis Plan /01MAR2021 
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Statistical Analysis Plan 
 
Date: 01MAR2021 
 
CONFIDENTIAL 
Page 2 of 50 
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 Biostatistician  
 
 
 
See appended electronic signature page 
Study Clinical Pharmacology 
 
 
 
See appended electronic signature page 
Study Bioanalytical Sciences 
 
 
 
See appended electronic signature page 
Study Medical Director 
 
 
 
See appended electronic signature page 
Project Biostatistician 
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
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Statistical Analysis Plan 
 
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Page 3 of 50 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................7 
1.1. 
Background/Rationale ..................................................................................................7 
1.2. 
Study Objectives ...........................................................................................................7 
1.2.1. 
Primary Objectives .......................................................................................................7 
1.2.2. 
Secondary Objectives ...................................................................................................7 
1.2.3. 
Exploratory Objectives .................................................................................................8 
1.2.4. 
Endpoints ......................................................................................................................8 
1.2.5. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.6. 
Revision History for SAP Amendments .....................................................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design and Randomization ..............................................................................11 
2.2. 
Power Considerations .................................................................................................12 
2.3. 
Study Plan ...................................................................................................................12 
3. 
ANALYSIS POPULATIONS ....................................................................................13 
3.1. 
The Seronegative Modified Full Analysis Set (mFAS) ..............................................13 
3.2. 
Per Protocol Set (PPS) ................................................................................................13 
3.3. 
The Safety Analysis Set (SAF) ...................................................................................13 
3.4. 
Pharmacokinetic Analysis Set ....................................................................................14 
3.5. 
The Immunogenicity Analysis Set..............................................................................14 
4. 
ANALYSIS VARIABLES .........................................................................................15 
4.1. 
Demographic and Baseline Characteristics ................................................................15 
4.2. 
Medical History ..........................................................................................................15 
4.3. 
Pre-Treatment / Concomitant Medication ..................................................................15 
4.4. 
Rescue Medication/or Prohibited Medication During Study ......................................15 
4.5. 
Efficacy Variable ........................................................................................................15 
4.5.1. 
Primary Efficacy Variable ..........................................................................................15 
4.5.2. 
Secondary Efficacy Variables .....................................................................................16 
4.5.3. 
Exploratory Efficacy Variables ..................................................................................16 
4.6. 
Safety Variables ..........................................................................................................18 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................18 
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4.6.2. 
Adverse Events of Special Interest .............................................................................18 
4.6.3. 
Laboratory Safety Variables .......................................................................................18 
4.6.4. 
Vital Signs ..................................................................................................................19 
4.7. 
Pharmacokinetic Variables and Anti-Drug Antibody (ADA) Variables ....................19 
4.8. 
Immunogenicity Variables ..........................................................................................19 
5. 
STATISTICAL METHODS .......................................................................................20 
5.1. 
Demographics and Baseline Characteristics ...............................................................20 
5.2. 
Medical History ..........................................................................................................20 
5.3. 
Prior / Concomitant Medications ................................................................................20 
5.4. 
Rescue / Prohibited Medications ................................................................................20 
5.5. 
Patient Disposition ......................................................................................................20 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................21 
5.7. 
Hypothesis Test ..........................................................................................................21 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................21 
5.7.2. 
Analysis in Patients with High Viral Loads ...............................................................22 
5.7.3. 
Subgroup Analyses .....................................................................................................23 
5.7.4. 
Dose Response Modelling ..........................................................................................23 
5.7.5. 
Analysis of Secondary Efficacy Variables .................................................................24 
5.7.6. 
Analysis of Other Secondary Efficacy .......................................................................24 
5.8. 
Analysis of Safety Data ..............................................................................................25 
5.8.1. 
Adverse Events ...........................................................................................................25 
5.8.2. 
Clinical Laboratory Measurements.............................................................................26 
5.8.3. 
Vital Signs ..................................................................................................................26 
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data ...........................................26 
5.9.1. 
Analysis of Pharmacokinetic Data ..............................................................................26 
5.9.2. 
Analysis of Pharmacokinetic/Pharmacodynamic Data ...............................................27 
5.9.3. 
Analysis of Immunogenicity Data ..............................................................................27 
5.9.3.1. 
Analysis of ADA Data ................................................................................................27 
5.9.3.2. 
Analysis of NAb Data .................................................................................................28 
6. 
ASSOCIATION OF IMMUNOGENICITY WITH EXPOSURE, SAFETY 
AND EFFICACY .......................................................................................................29 
6.1. 
Immunogenicity and Exposure ...................................................................................29 
6.2. 
Immunogenicity and Safety and Efficacy ...................................................................29 
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7. 
DATA CONVENTIONS ............................................................................................30 
7.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................30 
7.2. 
Data Handling Convention for Efficacy Variables .....................................................30 
7.3. 
Data Handling Convention for Missing Data .............................................................30 
7.4. 
Visit Windows ............................................................................................................31 
7.5. 
Unscheduled Assessments ..........................................................................................32 
7.6. 
Pooling of Centers for Statistical Analyses ................................................................32 
8. 
INTERIM ANALYSIS ...............................................................................................33 
9. 
SOFTWARE ...............................................................................................................34 
10. 
REFERENCES ...........................................................................................................35 
11. 
APPENDIX.................................................................................................................36 
11.1. 
Schedule of Events .....................................................................................................37 
11.2. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................39 
11.3. 
SAS Code for Dose Response Modelling ...................................................................46 
 
LIST OF TABLES 
Table 1: 
Treatment Arms and Randomization Ratio ................................................................11 
Table 2: 
Efficacy Variables ......................................................................................................16 
Table 3: 
Exploratory Efficacy Variables ..................................................................................17 
Table 4: 
Set of Candidate Dose Response Models ...................................................................23 
Table 5: 
Secondary Efficacy .....................................................................................................24 
Table 6: 
Analysis Windows ......................................................................................................31 
Table 7: 
Schedule of Events .....................................................................................................37 
Table 8: 
Criteria for Potentially Clinicially Significant Values (PCSV) ..................................39 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................12 
Figure 2: 
Testing Hierarchy .......................................................................................................22 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
Ct 
Cycle Threshold 
CTCAE 
Common Terminology Criteria for Adverse Events 
EDC 
Electronic data capture 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
MAV 
Medically-attended visit 
mFAS 
Modified full analysis set 
NAb 
Neutralizing Antibody 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
PK 
Pharmacokinetic 
PPE 
Personal protective equipment 
RBQM 
Risk-Based Quality Monitoring 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RT-qPCR 
Quantatitive Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TWA 
Time weighted average 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock 
and unblinding of the treatment assignments. The SAP is intended to be a comprehensive and 
detailed description of the strategy and statistical methods to be used in the analysis of data for 
R10933-10987-COV-20145 study. 
This analysis plan will be issued prior to the first database lock and unblinding of the treatment 
codes.  
1.1. 
Background/Rationale 
This is a randomized, double-blind, placebo-controlled, parallel group study to assess the dose 
response profile of single intravenous (IV) or single subcutaneous (SC) doses of 
REGN10933+REGN10987 in outpatients with SARS-CoV-2 infection. 
Studies are currently ongoing to assess the efficacy and safety of co-administered 
REGN10933+REGN10987 combination therapy (“REGN10933+REGN10987”) in the treatment 
and 
prevention 
of 
COVID-19. 
Available 
data 
in 
outpatients 
have 
shown 
that 
REGN10933+REGN10987 provides similar virologic and clinical efficacy when given as 
2400 mg or 8000 mg IV single dose with an acceptable safety profile in this patient population. In 
this phase 2 study, additional IV single dose regimens, as well as SC single dose regimens, will be 
evaluated in outpatients with SARS-CoV-2 infection to provide additional assessment of virologic 
efficacy and safety at lower doses. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective of the study is to assess the virologic efficacy of 
REGN10933+REGN10987 across different IV and SC doses compared to placebo. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate additional indicators of virologic efficacy of REGN10933+REGN10987 
compared to placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To assess the concentrations of REGN10933 and REGN10987 in serum over time 
• To assess the immunogenicity of REGN10933 and REGN10987 
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1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To explore the occurrence of COVID-19 related hospitalizations, emergency room 
visits, and other medically-attended vists (MAVs) in patients treated with 
REGN10933+REGN10987 compared to those treated with placebo 
Note: A COVID-19 related medically-attended visit will be defined as follows: 
hospitalization, ER visit, urgent care visit, physician’s office visit, or telemedicine visit, 
with the primary reason for the visit being COVID-19. 
• To assess viral genetic variation in patients with a positive SARS-CoV-2 quantitative 
reverse transcription polymerase chain reaction (RT-qPCR) 
• To explore relationships between REGN10933+REGN10987 exposure and selected 
efficacy endpoints, safety endpoints, and/or biomarkers 
• To explore the occurrence of COVID-19-related hospitalizations, COVID-19-related 
emergency room (ER) visits, or all-cause deaths in patients treated with 
REGN10933+REGN10987 compared to those treated with placebo 
1.2.4. 
Endpoints 
The efficacy analysis sets are defined in sections 5.7.1 and 5.7.3. 
Primary Endpoint 
The primary endpoint is time-weighted average daily change from baseline in viral load (log10 
copies/mL) from day 1 to day 7, as measured by RT-qPCR in nasopharyngeal (NP) swab samples, 
in patients who have a central-lab determined RT-qPCR positive test and who are seronegative at 
baseline. 
Secondary Endpoints 
• Time-weighted average daily change from baseline in viral load (log10 copies/mL) from 
day 1 to day 5  
• Time-weighted average daily change from baseline in viral load (log10 copies/mL) in 
patients with high viral load at baseline (>104 copies/mL, >105 copies/mL, >106 
copies/mL, >107 copies/mL) from day 1 to day 7 
• Time-weighted average daily change from baseline in viral load (log10 copies/mL) in 
patients with high viral load at baseline (>104 copies/mL, >105 copies/mL, >106 
copies/mL, >107 copies/mL) from day 1 to day 5 
• Proportion of patients with high viral load (>104 copies/mL, >105 copies/mL, 
>106 copies/mL, >107 copies/mL) at each visit 
• Proportion of patients with viral loads below the limit of detection at each visit 
• Proportion of patients with viral loads below the lower limit of quantification at each 
visit 
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• Change from baseline in viral load (log10 copies/mL) at each visit, as measured by RT-
qPCR in NP samples 
• Proportion of patients with treatment-emergent SAEs through day 29 
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4 
• Proportion of patients with injection-site reactions (grade ≥3) through day 4 
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29 
• Concentrations of REGN10933 and REGN10987 in serum over time 
• Immunogenicity as measured by ADAs and NAb to REGN10933 and REGN10987  
Exploratory Endpoints 
• Time-weighted average daily change from baseline in cycle threshold (Ct) from day 1 
to day 7, as measured by RT-qPCR in NP samples  
• Time-weighted average daily change from baseline in Ct from day 1 to day 5, as 
measured by RT-qPCR in NP samples 
• Change from baseline in Ct at each visit, as measured by RT-qPCR in NP samples 
• Proportion of patients (through day 29 and day 169) with ≥1 COVID-19-related 
hospitalization or all-cause mortality 
• Proportion of patients (through day 29 and day 169) with ≥1 COVID-19-related 
hospitalization, COVID-19-related emergency room (ER) visit, or all-cause mortality 
• Proportion of patients (through day 29 and day 169) with ≥1 COVID-19-related 
medically-attended visit or all-cause mortality 
• Proportion of patients (through day 29 and day 169) with ≥1 COVID-19-related 
medically-attended visit by type of visit (hospitalization, emergency room visit, urgent 
care, physician’s office visit, and/or telemedicine visit)  
• Proportion of patients (through day 29 and day 169) with ≥2 COVID-19-related 
medically-attended visits or all-cause mortality  
• Days of hospitalization due to COVID-19 
• Proportion of patients (by day 29 and day 169) admitted to an intensive care unit (ICU) 
due to COVID-19 
• Proportion of patients (by day 29 and day 169) requiring supplemental oxygen due to 
COVID-19  
• Proportion of patients (by day 29 and day 169) requiring mechanical ventilation due to 
COVID-19  
• Total number of COVID-19-related MAVs through day 29 and 169 
• All-cause mortality by day 29 and day 169 
• Proportion of patients with treatment-emergent SAEs through day 169 
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1.2.5. 
Modifications from the Statistical Section in the Final Protocol 
Not applicable. 
1.2.6. 
Revision History for SAP Amendments 
This is the first version of the SAP. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This randomized, double-blinded, placebo-controlled, parallel group study will assess the 
virologic efficacy, as well as safety and tolerability, of REGN10933+REGN10987 at different IV 
and SC single-dose regimens in outpatients with SARS-CoV-2 infection. The purpose of this study 
is to identify the lowest dose regimen capable of demonstrating the same (or similar) virologic 
efficacy seen at the 2400 mg IV dose level in outpatients with COVID-19. These data, taken 
together with data on the safety profile of REGN10933+REGN10987 and any correlation between 
virologic and clinical efficacy at 1200 mg, 2400 mg, and 8000 mg IV doses observed in study 
R10933-10987-COV-2067, will aid in identifying a dose regimen with the optimal risk-benefit 
profile in this patient population. Moreover, identifying lower doses that are capable of reducing 
viral load will bolster the ability to provide therapeutic doses of REGN10933+REGN10987 in the 
setting of a global pandemic, where supplies of therapeutic agents are increasingly limited as 
caseloads rise. 
An additional aim of this study is to assess virologic efficacy, as well as safety and tolerability, of 
REGN10933+REGN10987 given subcutaneously in outpatients with SARS-CoV-2. Currently, SC 
administration is being explored only in the household transmission setting (R10933-10987-COV-
2069). Availability of subcutaneously-administered single-dose REGN10933+REGN10987 in the 
treatment setting could potentially improve access for patients who are unable to access facilities 
capable of administering intravenous infusions. 
Up to 1400 total patients will be enrolled in up to approximately 80 sites in the United States. 
Patients will be randomized to one of the treatment arms listed below, according to a central 
randomization scheme using an interactive web response system (IWRS): 
Table 1: 
Treatment Arms and Randomization Ratio  
 
Dose of Co-administered REGN10933+REGN10987 
Combination Therapy 
Route of 
Administration 
Randomization 
Ratio 
2400 mg (1200 mg each of REGN10933 and 
REGN10987) 
IV 
2 
1200 mg (600 mg each of REGN10933 and 
REGN10987) 
IV 
2 
600 mg (300 mg each of REGN10933 and REGN10987) 
IV 
2 
300 mg (150 mg each of REGN10933 and REGN10987) 
IV 
2 
Placebo 
IV 
1 
1200 mg (600 mg each of REGN10933 and 
REGN10987) 
SC 
2 
600 mg (300 mg each of REGN10933 and REGN10987) 
SC 
2 
Placebo 
SC 
1 
 
This randomization ratio means ~200 subjects in each arm receiving REGN10933+REGN10987 
and ~200 subjectes receiving placebo (i.e., 100 with IV and 100 with SC).  For the purpose of all 
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virological and efficacy analyses, the placebo arms from the two routes of administration will be 
pooled because the route of administration does not alter the pharmacodynamic response of 
patients receiving placebo. Treatment groups for active doses will not be pooled. 
2.2. 
Power Considerations 
 
The sample size is based on the primary virologic endpoint of the time-weighted average (TWA) 
daily change from baseline in viral load (log10 copies/mL) from day 1 to day 7, in patients who are 
seronegative and who have a positive RT-qPCR value at baseline.  In the Phase 2 portion of Study 
R10933-10987-COV-2067, the mean (SD) was -0.73 (0.948) log10 copies/mL (see Investigator's 
Brochure).  For the primary hypothesis comparing each dose to placebo, approximatey 57 patients 
per treatment group will provide ~98% power to detect a difference of -0.73 log10 copies/mL 
between any active treatment group and placebo. In order to enroll 400 seronegative patients, the 
study will randomize approximately 800 patients, assuming that 50% are seronegative.  
For comparisons between doses and regimens, the study plans to enroll 700 seronegative patients 
in order to have 100 patients per group. For between-group comparisons, the 95% CI half-width 
between any two treatment groups with 100 patients per group would be 0.27 log10 copies/mL.  In 
order to enroll 700 seronegative patients, approximately 1400 patients will be randomized.   
2.3. 
Study Plan 
Patients will have NP swabs and blood samples collected every other day for the first week of the 
study. Additional NP swabs will be collected once-weekly for two weeks to assess potential 
persistence of viral load. A phone visit will occur during the fourth week for collection of safety 
information. 
After the first month, patients will have visits approximately once-monthly for four additional 
months. The penultimate visit will be in-person to collect blood samples for drug concentration 
and immunogenicity. The final visit (EOS) will be a phone call. 
Figure 1: 
Study Flow Diagram 
 
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3. 
ANALYSIS POPULATIONS  
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis. 
3.1. 
The Seronegative Modified Full Analysis Set (mFAS) 
The Overall modified Full Analysis Set (Overall mFAS) includes all randomized patients who 
receive treatment with positive central-lab determined SARS-CoV-2 RT-qPCR result from NP 
swab samples at randomization and is based on the treatment received (as treated). If a pre-
treatment qualitatitive test is missing then a qualitatitive test that is within post-treatment plus 2 
hours may be used.  
The Seronegative mFAS is the subset of patients in the mFAS population who are seronegative 
at baseline. The Seronegative mFAS will be used for all efficacy and pharmacodynamic analyses. 
The Seronegative mFAS is the primary analysis population; secondary analyses will be conducted 
in the Overall mFAS population. 
Note that since the primary objective of this study is to estimate the dose- and exposure-response 
of REGN10933+REGN10987 in reducing viral load, patients are included in the treatment actually 
received, not as randomized.  
In the Seronegative mFAS and Overall mFAS populations, the placebo IVand placebo SC arms 
will be pooled for all analyses of virologic endpoints, Active dose groups will not be pooled. 
3.2. 
Per Protocol Set (PPS) 
The Per Protocol Set (PPS) includes all randomized patients who receive treatment with positive 
central-lab determined SARS-CoV-2 RT-qPCR result from NP swab samples at randomization 
and is based on the treatment received (as treated). The PPS will exclude patients (1) who do not 
receive the full dose, (2) receive convalescent plasma therapy or SARS-CoV-2 antivirals, and (3) 
receive COVID-19 vaccination on or prior to the day 7 visit. Like the mFAS, the placebo IV and 
placebo SC arms will be pooled. Active dose groups will not be pooled. If all the patients in the 
mFAS are fully dosed and there are no applicable protocol deviations regarding (2) and (3), the 
PPS will be the same as the Overall mFAS. 
3.3. 
The Safety Analysis Set (SAF) 
The Safety Analysis Set (SAF) includes all randomized patients who received any study drug; it 
is based on the treatment received (as treated). Determination of “as treated” will be based on the 
actual study drug received on day 1. Demographic and baseline characteristics, treatment 
compliance/administration and all clinical safety variables will be analyzed using the SAF. 
In the SAF population, the placebo arms for the IV and SC routes of administration will be 
summarized separately. 
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3.4. 
Pharmacokinetic Analysis Set  
The PK Analysis Set (PKAS) includes all patients who received any study drug and who have at 
least 1 non-missing drug concentration measurement following study drug administration. Patients 
will be analyzed according to the actual treatment received.  
3.5. 
The Immunogenicity Analysis Set   
The immunogenicity analysis set for a potential interim analysis is dependent on assay availability. 
The ADA Analysis Set (AAS) includes all treated patients who received any study drug and have 
at least 1 non-missing ADA result after first dose of the study drug. 
The NAb Analysis Set (NAS) includes all patients who received any study drug and who are 
negative in the ADA Assay or with at least one non-missing result in the NAb assay after first dose 
of the study drug. Patients who are ADA negative are set to negative in the NAb Analysis Set. 
Patients will be analyzed according to the actual treatment received. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (age, gender, race, and ethnicity), and 
baseline viral load measured with both log10 copies/mL and Cycle Threshold (Ct), viral load 
threshold, presence/absence of COVID-19 related symptoms, serology (i.e., negative, positive, or 
other), medical history, and medication history for each patient. 
4.2. 
Medical History 
Medical history includes (and may be include more such as risk factors) 
• COVID-19 with start date as the date of onset of first symptoms related to COVID-19, 
as well as associated symptoms and their severity graded by NCI-CTCAE v5.0 
• Whether the patient is receiving oxygen at home by nasal cannula 
• Menopausal history 
• Pregnancy or breastfeeding status, if applicable 
4.3. 
Pre-Treatment / Concomitant Medication 
Prior and comcomitant medications will be summarized separately. 
4.4. 
Rescue Medication/or Prohibited Medication During Study 
Patients can receive rescue therapy for COVID-19 per local standard-of-care. Rescue treatment(s) 
will not be provided as part of the study. Medications that are prohibited by the protocol will be 
reviewed and identified by the study clinician and reported in the protocol deviations.  
4.5. 
Efficacy Variable 
4.5.1. 
Primary Efficacy Variable 
 
The primary efficacy measurement is the  viral load of patients in the Seronegative mFAS as 
measured by central laboratory RT-qPCR (log10 copies/mL). The primary efficacy variable is the 
time-weighted average (TWA) change from baseline in viral load (log10 copies/mL) from day 1 to 
day 7 as measured by RT-qPCR in NP swabs.  The TWA is calculated using the trapezoidal rule 
as the area under the curve (AUC) divided by this observational period as follows: 
𝑇𝑊𝐴= 𝐴𝑈𝐶/(𝑡𝑘−𝑡1) = [∑(𝑡𝑖
𝑘
𝑖=2
−𝑡𝑖−1) ∗(𝑉𝑖+ 𝑉𝑖−1)/2]/(𝑡𝑘−𝑡1) 
where  𝑉𝑖 is the result of change in viral load (log10 copies/mL) at time point 𝑡𝑖 from baseline. As 
baseline is time point t1, then 𝑉1 = 0.  
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4.5.2. 
Secondary Efficacy Variables 
The table below describes the primary and secondary efficacy variables labelled ‘P’ or ‘S’, 
respectively. An ‘X’ means that variable will not be analyzed. The two columns on the far right 
describe the analysis sets for the efficacy analysis.  
Table 2: 
Efficacy Variables  
 
Efficacy Variable 
Endpoint 
Type 
Baseline Viral 
Load Subgroup 
Seronegative 
mFAS 
Overall 
mFAS 
 
Change from BL in viral load – 
TWA (days 1 to 7) 
Continuous 
All 
P 
S 
Continuous >104 copies/mL 
X 
S 
Continuous >105 copies/mL 
X 
S 
Continuous >106 copies/mL 
X 
S 
Continuous >107 copies/mL 
X 
S 
 
Change from BL in viral load – 
TWA (days 1 to 5) 
Continuous 
All 
S 
S 
Continuous >104 copies/mL 
X 
S 
Continuous >105 copies/mL 
X 
S 
Continuous >106 copies/mL 
X 
S 
Continuous >107 copies/mL 
X 
S 
Proportion of patients with viral 
load  >104 copies/mL at each visit 
Categorical 
All 
S 
S 
Proportion of patients with viral 
load  >105 copies/mL at each visit 
Categorical 
All 
S 
S 
Proportion of patients with viral 
load  >106 copies/mL at each visit 
Categorical 
All 
S 
S 
Proportion of patients with viral 
load  >107 copies/mL at each visit 
Categorical 
All 
S 
S 
Proportion of patients <LLOQ 
Categorical 
All 
S 
S 
Proportion of patients <LOD 
Categorical 
All 
S 
S 
Change from BL in viral load at 
each visit 
Continuous 
All 
S 
S 
Denote baseline as BL, Limit of Detection as LOD, and Lower Limit of Quanitification as LLOQ. 
4.5.3. 
Exploratory Efficacy Variables 
These variables will be studied using the Seronegative mFAS.  
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Table 3: 
Exploratory Efficacy Variables 
Efficacy Variable 
Category 
Time Period 
Type 
Change from BL in Ct – TWA  
All 
D7 and D5 
Continuous 
Change from BL in Ct at each visit 
All 
D22 
Continuous 
 
COVID-19 related MAVs or all-cause 
mortality 
All 
D29 and D169 Proportion with 
≥1 event 
All 
D29 and D169 Proportion with 
≥2 events 
≥1 COVID-19-related hospitalization or 
all-cause mortality 
All 
D29 and D169 Proportion 
≥1 COVID-19-related hospitalization, ER 
visit, or all-cause mortality 
All 
D29 and D169 Proportion 
 
 
 
 
 
COVID-19 related MAVs 
All 
D29 and D169 Proportion with 
≥1 event 
Hospitalization 
D29 and D169 Count  
ER Visit 
D29 and D169 Count 
Urgent Care 
D29 and D169 Count 
Physician’s office 
visit 
D29 and D169 Count 
Telemedicine 
D29 and D169 Count 
Days of COVID-19 hospitalization 
All 
Whole Study 
Count 
Patients admitted to ICU from COVID-
19 
All 
D29 and D169 Proportion 
Patients requiring supplemental oxygen 
from COVID-19 
All 
D29 and D169 Proportion 
Patients requiring mechanical ventilation 
due to COVID-19 
All 
D29 and D169 Proportion  
COVID-19-related MAVs 
All 
D29 and D169 Count 
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Denote Medically-Attended Visits as MAVs and the emergency room as ER. Count refers to the frequency of times 
event occurs per patient. 
4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
An Adverse Event (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 
be study (ICH E2A Guideline). 
A Serious Adverse Event (SAE) either results in death, is life-threatening, requires in-patient 
hospitalization or prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, congenital anomaly/birth defect, or is an important medical event. The 
protocol provides the details. 
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition during the observation period. 
4.6.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner as described in the protocol. In 
this study, AESI are listed below (as provided in the protocol), along with each AESI detailed 
definition: Treatment-emergent AESI (serious and nonserious) are flagged in the CRFs, defined 
as: 
• Grade ≥ 2 infusion-related reactions up to day 4 
• Grade ≥ 3 injection-site reactions up to day 4 
• Grade ≥ 2 hypersensivity reactions up to day 29 
• Any treatment-emergent AE (TEAE) that led to a hospitalization or emergency room 
visit, regardless of whether the visit is related to COVID-19 
4.6.3. 
Laboratory Safety Variables 
The laboratory safety variables are blood chemistry and hematology. The tests for blood chemistry 
include: Sodium, Potassium, Chloride, Carbon Dioxide, Glucose, Blood urea nitrogren (BUN), 
Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Total bilirubin, Albumin, 
Alkaline phosphatase, Creatinine, Creatine phosphokinase (CPK), and Lactate dehydrogenase 
(LDH). Hematology tests include Hemoglobin, Hematocrit, Red blood cells (RBCs), White blood 
cells (WBCs), Platelet count, Differential Neutrophils, Lymphocytes, Monocytes, Basophils, and 
Eosinophils. Clinical laboratory values will be converted to standard international (SI) units and 
grouped by function in summary tables. Clinical laboratory values will be converted and analyzed 
in both standard international (SI) units and US conventional units provided by the central 
laboratory. Both actual test values and “change from baseline” values (defined as the post-baseline 
value minus the baseline value) over time will be summarized, where the post-baseline visits will 
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be assigned to the Global Analysis Windows. Potentially clinically significant values (PCSV) 
ranges will be applied to the laboratory test values as applicable (see PCSV criteria in Appendix 
11.2). 
4.6.4. 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Potentially clinically significant values (PCSV) ranges will be applied to corresponding vital sign 
parameter values according to (see PCSV criteria in Appendix 11.2). 
4.7. 
Pharmacokinetic Variables and Anti-Drug Antibody (ADA) 
Variables  
The pharmacokinetic (PK) variables are the concentration of REGN10933 and REGN10987 in 
serum and time. Samples are collected at the timepoints outlined in the Schedule of Events 
(Appendix 11.1). 
4.8. 
Immunogenicity Variables  
The immunogenicity variables are ADA response status, titer, NAb status, and time-point/visit. 
Samples for ADA analysis are collected at the timepoints outlined in the Schedule of Events 
(Appendix 11.1). 
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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, median, standard deviation, Q1, Q3, minimum, and 
maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
Baseline is defined as the last assessment obtained before the first dose of study drug (i.e., either 
at screening or pre-dose assessment). 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group 
and overall for the study. For viral load, there will be summaries and visualizations of key disease-
related characteristics. 
5.2. 
Medical History 
Medical history will be summarized by SOC and PT and by treatment group and all groups 
combined in the SAF population. 
5.3. 
Prior / Concomitant Medications  
All prior medications, dictionary coded by WHODRUG (WHO Drug Global version 01MAR2020 
B3), will be descriptively summarized by treatment group and overall for the study, for subjects in 
SAF population. All procedures, dictionary coded by MedDRA v23.1, will be summarized in the 
same fashion as prior/concomitant medications.  
Summaries will present patient counts (and percentages) for all prior medications, by decreasing 
frequency of the overall group incidence of ATC followed by ATC level 2, ATC level 4 and 
preferred term. For prior procedure, summaries will be by SOC and PT, sorted by decreasing 
frequency of SOC and PT based on the incidence in the overall group incidence. Patients will be 
counted only once for each SOC and PT linked to the procedure. 
All concomitant medications/procedures will be descriptively summarized by treatment group, for 
subjects in SAF. 
5.4. 
Rescue / Prohibited Medications 
Patients can receive rescue therapy for COVID-19 per local standard-of-care. Rescue treatment(s) 
will not be provided as part of the study. Listing of prohibited medications will be provided for 
patients in SAF. 
5.5. 
Patient Disposition 
Using the SAF, appropriate summaries of the patient disposition will be displayed. Summaries of 
total screened patients, numbers of each analysis set by treatment and total will be available. The 
following will be provided: 
• The total number of screened patients: met the inclusion/exclusion criteria regarding 
the target indication and signed the ICF 
• The total number of randomized patients: received a randomization number 
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• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• Thte total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
Using the SAF, summaries of discontinuation and/or dropouts by reasons and treatments will be 
presented. 
5.6. 
Extent of Study Treatment Exposure and Compliance 
This is a single dose study, with the site administering the doses. A listing will be provided of 
patients who are randomized but not dosed as well as infusions or injections that were either 
interrupted or not completed. Treatment compliance in terms of total dose and infusion interruption 
will be summarized by treatment group. 
The extent of follow-up in the SAF population will be summarized. The numbers of patients 
completing 29 days and 169 days of follow-up will be tabulated.  
The number and percentage of patients randomized and exposed to double-blind study drug,and 
duration of exposure to treatment during the study will be presented by treatment group. 
5.7. 
Hypothesis Test 
The statistical hypothesis for the primary virologic efficacy endpoint is: 
𝐻0: There is no difference between patients treated with one or more dose regimens of 
REGN10933+REGN10987 and patients treated with placebo in time weighted average 
daily change from baseline in viral load from day 1 to day 7 
𝐻1: REGN10933+REGN10987 reduces time weighted average daily change from baseline 
in viral load (log10 copies/mL) from day 1 to day 7, relative to placebo 
The type I error rate is 0.05.  
5.7.1. 
Analysis of Primary Efficacy Variable 
The primary virologic efficacy variable is the time-weighted average change from baseline in viral 
load from day 1 to day 7, as measured by RT-qPCR in NP swab samples. The primary analysis 
will be conducted in the Seronegative mFAS population.  An Analysis of Covariance (ANCOVA) 
model with treatment group as a fixed effect and baseline viral load and treatment by baseline 
interaction as covariates will be fit to the data as the primary analysis. For efficacy analysis, the 
placebo IV and placebo SC arms are pooled. 
A step-down testing approach will be used for comparing active treatment groups to the pooled 
placebo to control type I error rate at 0.05. The pairwise comparisons are performed using the t-
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test. Figure 2 below illustrates this hierarchy. If a test is insignificant, then the formal testing 
procedure stops at that step.  
 
Figure 2: 
Testing Hierarchy 
 
 
 
The least squares mean estimates and 95% confidence intervals for the TWA mean change from 
baseline in viral load will be presented for each treatment group, as well as for the difference 
between each REGN10933+REGN1097 treatment group and placebo along along with the p-
values for the comaprisons. Accompanying descriptive analyses will be provided at the individual 
timepoints used to calculate the TWA. 
No hypothesis testing is planned for the between active dose comparisons. Only estimates and 
95% confidence intervals will be reported for the between active dose comparisons.  
5.7.2. 
Analysis in Patients with High Viral Loads 
Within the Overall mFAS population, analysis of the change from baseline in viral load at each 
visit will be performed in baseline viral load categories (>104 copies/mL, >105copies/mL, >106 
copies/mL, >107copies/mL) using the same method as described above using ANCOVA. 
2400 mg IV vs  
Pooled Placebo
1200 mg IV vs 
Pooled Placebo
1200 mg SC vs 
Pooled Placebo
600 mg IV vs 
Pooled Placebo
600 mg SC vs 
Pooled Placebo
300 mg IV vs 
Pooled Placebo
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5.7.3. 
Subgroup Analyses  
Subgroup analysis by gender, symptomatic vs. asymptomatic, race (white vs. other), and baseline 
viral load (above or below median) may be performed in seronegative mFAS in order to assess the 
consistency of results. 
5.7.4. 
Dose Response Modelling  
Several dose response models will be explored for the TWA of change in baseline in viral load 
(log10 copies/mL) from day 1 to day 7, and then a single model is selected using Akaike’s 
Information Criteria (AIC). The AIC considers a trade-off between increasing the number of 
parameters in terms of goodness-of-fit by introducing a penalty for the number of parameters. The 
model with the lowest AIC value is selected. The models under consideration are linear, hyperbolic 
Emax, and sigmoidal Emax. Additional models may be considered. As the dose response testing and 
modelling is for estimation, there will be no adjustment for multiplicity. 
Table 4: 
Set of Candidate Dose Response Models  
 
Name 
Model 
Description 
Sigmoidal 
Emax 
𝑦𝑖= 𝐸0 + 𝐸𝑚𝑎𝑥
𝐷𝑖
ℎ
𝐸𝐷50
ℎ+ 𝐷𝑖
ℎ+ 𝜖𝑖 
 
i: the patient ID 
yi: the response for the ith patient  
E0: the placebo effect 
Emax: The maximum effect attributable to the 
drug 
ED50: The dose that produces one-half of 
Emax 
h: The hill parameter and determines the 
steepness of the slope 
Di: The dose-level for the ith patient 
𝜖𝑖: The error term for the ith patient where 
each error term is independent and 
identically Normally distributed with mean 0 
and standard deviation σ. 
 
Hyperbolic 
Emax 
𝑦𝑖= 𝐸0 + 𝐸𝑚𝑎𝑥
𝐷𝑖
𝐸𝐷50 + 𝐷𝑖
+ 𝜖𝑖 
 
Special case of above model where ℎ= 1 
Linear 
𝑦𝑖= 𝐸0 + 𝛽1 ∗𝐷𝑖+ 𝜖𝑖 
𝛽1: Linear effect term 
Exponential 
𝑦𝑖= 𝐸0 + 𝐸1 (exp (𝐷𝑖
𝛿) −1)
+ 𝜖𝑖 
𝐸1: Exponential term 
𝛿: Scale 
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5.7.5. 
Analysis of Secondary Efficacy Variables 
For the analysis of primary and secondary efficacy variables, the table below summarizes the 
quantities and corresponding methods for analysis. The details of methods are described the 
paragraphs that follow. 
Table 5: 
Secondary Efficacy  
Measurement 
Units 
Metric 
Method 
Viral load (D1-5) 
log10 copies/mL 
TWA 
ANCOVA 
Viral load  
log10 copies/mL 
Change from BL in viral load at each 
visit 
MMRM 
Viral load 
log10 copies/mL 
Proportions <LLOQ, <LOD, >104, 
>105, >106, or >107 
Fisher’s 
Exact 
Test/Logistic 
Regression 
Percent change in 
Viral Load  
copies/mL 
Percent change in viral load 
(copies/mL) to each time point  
MMRM 
A mixed effect model for repeated measures (MMRM) will assess the time course of treatment 
effect in viral load, the change from baseline in viral load (log10 copies/mL) at each visit for both 
the Seronegative mFAS and the Overall mFAS populations. The model will include terms for 
baseline, 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; heterogeneous autoregressive (1), or compound symmetry covariance matrix 
will be considered in that order if a model does not converge. 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-spike mAb treatment arm and placebo will be provided along 
with the corresponding standard error, p-value, and associated 95% confidence interval.  
In the Seronegative mFAS, the proportion of patients who have PCR below the limit of detection 
(LOD), below the lower limit of quantification (LLOQ), or have qPCR levels >104, >105, >106, or 
>107 will be tabulated over time. The numbers of patients in each category will be tested using 
Fisher’s Exact test. Corresponding p-values and confidence intervals will be presented. 
There may be additional analysis of the proportions of patients who have PCR below the limit of 
detection, below the lower limit of quantification, or have quantatitive PCR levels above >104, 
>105, >106, or >107 will be tabulated over time using logistic regression model with terms for 
treatment arm, baseline viral load, and the treatment-by-baseline viral load interaction. Adjusted 
odds ratios and corresponding p-values and confidence intervals may be estimated from the model. 
5.7.6. 
Analysis of Other Secondary Efficacy 
The table in subsection 4.5.2 describes the other secondary efficacy variables. All variables will 
be tabulated.  
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5.8. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed in the SAF population.   
5.8.1. 
Adverse Events  
Safety data will be summarized in three periods: 
1. The pretreatment period, i.e., from signing the ICF to before the study drug administration 
2. The 29-day observation period, i.e., from the time of the administration of the study drug 
to the last follow-up visit. 
3. The full observation period, i.e., from the time of the administration of the study drug to 
the last follow-up visit. 
For patients that are vaccinated for SARS-CoV-2, only the safety data before vaccination will be 
used in the primary safety analysis. A secondary safety analysis will use all data collected.  
Analysis 
All SAEs and AESIs 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 preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries by treatment group will include the following: 
• The number (n) and percentage (%) of patients with at least 1 treatment-emergent 
adverse events (AEs) through day 29 by system organ class and PT 
• The number (n) and percentage (%) of patients with at least 1 treatment-emergent 
serious adverse events (SAEs) through day 29 by system organ class and PT 
• The number (n) and percentage (%) of patients with at least 1 infusion-related reactions 
(grade ≥2), through day 4 by PT 
• The number (n) and percentage (%) of patients with at least 1 injection-site reaction 
grade ≥3), through day 4 by PT 
• The number (n) and percentage (%) of patients with at least 1 hypersensitivity reactions 
(grade ≥2), through day 29 by PT 
• Any TEAE that led to a hospitalization or emergency room visit, regardless of whether 
the visit is related to COVID-19, up to day 169 
• Treatment-emergent AEs (grade 3 or 4) from day 30 to day 169 
• Treatment-emergent SAEs, up to day 169 
Summaries of SAEs and AESIs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 event by SOC and PT 
• SAEs and AESIs by severity (according to the grading scale described in the protocol), 
presented by SOC and PT 
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• SAEs and AESIs by relationship to treatment (related, not related), presented by SOC 
and PT 
• Treatment-emergent SAEs and AESIs  
• The number (n) and percentage (%) of patients with Grade 3 or Grade 4 treatment-
emergent adverse events. 
Deaths and other SAEs will also be listed and summarized by treatment arm. Tables describing 
the adverse events will be made covering the two periods, except the observation period will be 
broken into two divisions: day 1 to day 29 and day 1 to day 169. 
There will also be lists of every Treatment-Emergent Adverse Event (TEAE). Then there will be 
a list of TEAEs for the proportion that occurs greater than or equal to 5% and a list of TEAEs for 
the proportion that occurs greater than or equal to 10%. 
5.8.2. 
Clinical Laboratory Measurements  
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with 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. 
5.8.3. 
Vital Signs 
Vital signs (temperature, blood pressure, heart rate (per minute), SpO2) will be summarized at 
baseline and post-dose with descriptive statistics.  Graphs of mean (+/- SE) value may be provided.   
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data  
5.9.1. 
Analysis of Pharmacokinetic Data  
Concentrations of REGN10933 and REGN10987 in serum, separately and combined, will be 
summarized at each time point by treatment group using descriptive statistics. No formal statistical 
analysis will be performed. 
Pharmacokinetic parameters will be determined for individual subjects by non-compartmental 
methods using Phoenix WinNonlin (version 8.1, Certara, L.P.), for both REGN10933 and 
REGN10987. Pharmacokinetic parameters will summarized by treatment group using descriptive 
statistics. 
The following PK parameters to be estimated include are but not limited to, and if supported by 
the data: 
IV doses: Cmax, Tmax, C7, AUC0-7 days, AUClast, AUCinf, CL, MRT, Vz, Vss, t½.   
SC doses: Cmax, Tmax, C7, AUC0-7 days, AUClast, AUCinf, CL/F, Vz/F, t½. 
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5.9.2. 
Analysis of Pharmacokinetic/Pharmacodynamic Data 
Exposure-response analyses for select efficacy and safety endpoints and/or biomarkers may be 
performed, as appropriate. Details of the exposure-response analyses will be documented 
separately. 
5.9.3. 
Analysis of Immunogenicity Data  
5.9.3.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.8 will be summarized using descriptive 
statistics.  
Immunogenicity will be characterized by ADA Responses and titers observed in patients in the 
ADA analysis set. ADA response categories and titer categories are defined as follows:  
ADA Response Categories: 
• ADA Negative, defined as an ADA negative response in the ADA assay at all time 
points collected, 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 a positive response in the ADA assay post 
first dose when baseline results are negative or missing.  
• 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 (<1,000) 
− −      Moderate (≥1,000 to ≤10,000) 
− −      High (>10,000) 
The following analysis will be provided: 
• Number (n) and percent (%) of ADA-negative patients (pre-existing 
immunoreactivity or negative in the ADA assay at all time points) by treatment 
groups  
• Number (n) and percent (%) of treatment-emergent ADA positive patients by treatment 
groups and ADA titer categories  
• Number (n) and percent (%) of treatment-boosted ADA positive patients by treatment 
groups and ADA titer categories  
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
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5.9.3.2. 
Analysis of NAb Data 
The absolute occurrence (n) and percent of patients (%) with NAb status in the NAb analysis set 
will be provided by treatment groups. 
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6. 
ASSOCIATION OF IMMUNOGENICITY WITH EXPOSURE, 
SAFETY AND EFFICACY 
6.1. 
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, titer and NAb on these 
profiles. 
6.2. 
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:  
• Injection site reaction (serious or severe and lasting 24 hours or longer) 
• 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: patients with treatment-emergent or treatment-boosted response. 
• ADA negative: patients with pre-existing immunoreactivity or negative in the ADA 
assay at all time points. 
• Patients with persistent treatment-emergent ADA response 
• NAb positive patients: ADA positive patients who were positive in the NAb assay at 
any time point analyzed.  
• Maximum post-baseline titer in treatment-emergent or treatment-boosted ADA 
positive patients:  
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000) 
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7. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
7.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product (either 
screening or pre-dose).  
For determining if a patient is positive for SARS-CoV-2, latest qualitatative PCR tests taken prior 
to the dose administration will be used. If the pre-dose qualitative PCR is not available, the tests 
up to 2 hours post-dose will be used to determine baseline PCR status.  For analyses of quantitative 
RT-qPCR levels, only values from NP swabs take before dosing will be used.   
7.2. 
Data Handling Convention for Efficacy Variables  
For efficacy variables, only observed data will be used. If the viral load is not available at the 
scheduled time point 𝑡𝑖 or missing due to failed test or other reasons, only the time points with 
non-missing values will be included for TWA calculation. The nominal visits and results from 
these visits will be used to compute the TWA (the primary endpoint). Patients without a baseline 
will be excluded from the analysis. Additionally, patients who do not have any viral measurements 
during first 7 days post baseline will be excluded. 
Viral loads less the lower limit of quantification of the PCR assay but with positive qualitative 
results will be set to half of the lower limit of quantification of the PCR assay; values with 
nondetectable RNA will be set to 0 log10 copies/mL if the reason for the negative value is a not a 
failed test. Viral load values above the upper limit of quantification will be re-tested using the 
reflex test and the corresponding quantatitive value will be used in the analysis. If two or more 
measurements correspond to the same visit, the “worst” value will be used. For viral load, the 
“worst” value is the highest. For Ct analysis, the “worst” value is the lowest value.  
7.3. 
Data Handling Convention for Missing Data 
For efficacy variables, only observed data will be used. If samples are missing, then the TWA 
estimates adjust using irregular spacing of the timing. 
Adverse Event 
If the severity of a TEAE is missing, it will be classified as “severe” or “Grade 3” in the frequency 
tables by intensity of TEAEs. If the assessment of relationship of a TEAE to the investigational 
product is missing, it will be classified as related to study drug. 
Every effort will be made to collect the start dates of all AEs and concomitant medications. If the 
end data of the AE is missing, then the data of the last follow-up date. When the partial AE 
date/time information does not indicate that the AE started prior to study treatment or after the 
TEAE period, the AE will be classified as treatment-emergent. 
Medication/Procedure 
If a medication date or time is missing or partially missing and it cannot be determined whether it 
was taken prior or concomitantly or stopped prior to the  study treatment administration, it will be 
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considered as concomitant medication/procedure by imputing the start date on the date of first 
study treatment administration. 
Potentially Clinically Significant Value (PCSV) 
If a subject has a missing baseline value, this subject will be grouped in the category 
“normal/missing at baseline.” 
For PCSVs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSV will be based 
only on the second condition. 
For a PCSV defined on a threshold and/or a normal range, this PCSV will be derived using this 
threshold if the normal range is missing; e.g., for eosinophils the PCSV is >0.5 giga/L or >ULN if 
ULN ≥0.5 giga/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSVs. 
7.4. 
Visit Windows 
Below are the definitions for the visit windows programmatically imposed on all available 
measures from unscheduled visits collected over the course of the study including early terminatin 
visit and the end of study vitsit.   No analysis visit windows will be applied for the study scheduled 
visits.  
The visit windows are constructed using ranges applied to the number of days in study (study days) 
when the measure is collected. Below are the relevant definitions for the analysis visit windows: 
1. The first study treatment occurs on study day 1.  
2. Study day is defined as the number of days since the first study treatment administration 
+1. 
3. Since the protocol specifies that measurements be collected before study treatment is 
administered on a given day, it is appropriate that baseline includes day 1. 
4. For randomized but not treated subjects, day 1 is the day of randomization. 
Table 6: 
Analysis Windows  
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   (Week 1) 
7 
[6, 10] 
Day 15 (Week 2) 
15 
[11, 18] 
Day 22 (Week 3) 
22 
[19, 25] 
Day 29 (Week 4) 
29 
[26, 45] 
Day 60 
60 
[46, 86] 
Day 90 
90 
[87, 93] 
Day 120 
120 
[94, 144] 
Day 169 
169 
>144 
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If a subject has multiple efficacy assessment visits within an analysis vsit window, the one with 
worst result will be selected (e.g. highest quantitative viral load).  Extra assessments (laboratory 
data or vital signs associated with non-protocol clinical visits or obtained in the course of 
investigating or managing adverse events) will be included in the listings, but not summaries 
except for the endpoint determination. If more than one laboratory value is available for a given 
visit, the “worst” will be used in summaries and all observations will be presented in listings. 
7.5. 
Unscheduled Assessments 
For efficacy, safety laboratory data, and vital signs, unscheduled visit measurements may be used 
to provide a measurement for a time point, including baseline, if appropriate according to their 
definitions. The measurements may also be used to determine abnormal values, AESIs, and 
PCSVs. 
7.6. 
Pooling of Centers for Statistical Analyses 
Not applicable. 
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8. 
INTERIM ANALYSIS 
There is no formal interim analysis planned for this study.  
When approximately 800 patients complete the day 7 visit, a first-step analysis will be performed. 
Since this is the final analysis of the primary endpoint, it is not considered an interim analysis. 
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9. 
SOFTWARE 
All analyses will be done using SAS EG version 9.4 and R Version 3.5.1 or higher.  
Non compartmental analysis of PK data will be performed using Phoenix WinNonlin (version 8.1, 
Certara, L.P.). 
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10. 
REFERENCES 
1. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and  content of 
clinical study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
2. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
3. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
4. Menon, S. M. and Zink, R. C. Ed. Modern Approaches to Clinical Trials Using SAS®: 
Classical, Adaptive, and Bayesian Methods. SAS Institute Inc., Cary, NC, USA. 2015. 
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11. 
APPENDIX 
 
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11.1. 
Schedule of Events 
Table 7: 
Schedule of Events  
Day 
Screening/Baseline1 
 Follow Up2 
EOS 
-1 to 1 
3 
4 
5 
7 
15 22 292 602 902 120 1692 
Screen Pre-Dose Dose Post-Dose 
Window (Days) 
 
 
 
 
 
 
 
 
±1 ±1 ±3 ±3 ±3 ±28 ±28 
 
 
 
 
Screening/Baseline Only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test for SARS-CoV-23 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 symptoms, if applicable )12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment  
Study drug administration 
 
 
X 
 
 
 
  
 
 
 
 
 
 
 
Efficacy  
Nasopharyngeal (NP) swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Safety  
Vital signs 
 
X4 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 IRRs5,6 
 
 
← cont. monitoring → 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥3 ISRs5,6 
 
 
← cont. monitoring → 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 hypersensitivity5reactions5,6 
 
 
← continuous monitoring → 
 
 
 
 
Treatment-emergent AEs5,6 
 
 
← continuous monitoring → 
 
 
 
 
Treatment-emergent grade 3 or 4 AEs5 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Treatment-emergent SAEs5,6 
 
 
← continuous monitoring → 
TEAEs that led to any hospitalization or emergency room visit5,6 
 
 
← continuous monitoring → 
Targeted concomitant medications5,6 
X 
 
← continuous monitoring → 
Pregnancy test (WOCBP)7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital status 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Pregnancy status7 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Safety information (newborns of study participants)7 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Central Laboratory Safety Testing and Serologic Testing 
Hematology (including differential)8 
X8 
 
 
 
 
 
X 
  
 
  
 
 
 
 
Blood chemistry8  
X8 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum for serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Concentration and Immunogenicity Testing 
Serum for drug concentration (PK)9 
X9 
 
X9 
X 
 
X 
X 
 
 
 
 
 
X 
 
Serum for immunogenicity (ADA)10 
X10 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Day 
Screening/Baseline1 
 Follow Up2 
EOS 
-1 to 1 
3 
4 
5 
7 
15 22 292 602 902 120 1692 
Screen Pre-Dose Dose Post-Dose 
Window (Days) 
 
 
 
 
 
 
 
 
±1 ±1 ±3 ±3 ±3 ±28 ±28 
 
 
 
 
Exploratory Patient Outcome Assessment 
COVID-19-related MAV details11 
 
 
← continuous monitoring → 
ADA, anti-drug antibodies; AE, adverse event; cont, continuous; EOS, end of study; IRR, infusion-related reaction; ISR, injection-site reaction; MAV, medically-
attended visit; PK, pharmacokinetics; SAE, serious adverse event; RT-qPCR, quantitative reverse transcription polymerase chain reaction; WOCBP, women of 
childbearing potential. 
For footnotes on the Schedule of Events, please see the protocol. 
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11.2. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Table 8: 
Criteria for Potentially Clinicially 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. 
 
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. 
 
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. 
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. 
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. 
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Parameter 
PCSV 
Comments 
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  
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  
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Parameter 
PCSV 
Comments 
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 
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 
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. 
Albumin 
≤25 g/L or ≤LLN (if LLN≤25 g/L) and baseline >25 g/L or 
>LLN (if LLN≤25 g/L) 
 
Hematology 
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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 race 
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. 
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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). 
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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 or >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 
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Parameter 
PCSV 
Comments 
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 
 
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11.3. 
SAS Code for Dose Response Modelling  
We utilize SAS code from the chapter on Classical Dose-Response Study from Modern Approaches to Clinical Trials Using SAS®: 
Classicial, Adaptive, and Bayesian Methods edited by Sandeep M. Menon and Richard C. Zink (page 185). We assume the data set 
data1 contains the response for each dose and use arbitrary initial values for demonstration purposes. 
*** Sigmoidal E_max model; 
proc nlmixed data=data1 alpha=0.05; 
*** set up initial values 
 
parms e0=10 emax=80 ed50=5.5 h=1 v=400; 
 
*** Specify that ed50 must be positive; 
 
bounds ed50>0; 
 
*** Define model; 
 
if dose=0 then eta = e0; 
 
else eta = e0 + (emax*dose**h) / (ed50**h+dose**h)); 
 
model resp ~ normal(eta, v); 
 
 
*** Estimate the difference in means; 
 
estimate “Diff Means (dose 2400 mg – placebo)” 
 
 
e0+((emax*2400**h)/(ed50**h+2400**h))-e0; 
 
estimate “Diff Means (dose 1200 mg – placebo)” 
 
 
e0+((emax*1200**h)/(ed50**h+1200**h))-e0; 
 
estimate “Diff Means (dose 600 mg – placebo)” 
 
 
e0+((emax*600**h)/(ed50**h+600**h))-e0; 
 
estimate “Diff Means (dose 300 mg – placebo)” 
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e0+((emax*300**h)/(ed50**h+300**h))-e0; 
 
 
predict eta out=etahat; 
 
****output estimations; 
 
****dataset est has output for estimate of the mean differences; 
 
****dataset parms has output for parameters: e0 emax ed50 h; 
 
ods output AdditionalEstimates=est ParameterEstimates=parms; 
run; 
 
*** Hyperbolic E_max model; 
proc nlmixed data=data1 alpha=0.05; 
*** set up initial values 
 
parms e0=10 emax=80 ed50=5.5 v=400; 
 
*** Specify that ed50 must be positive; 
 
bounds ed50>0; 
 
*** Define model; 
 
if dose=0 then eta = e0; 
 
else eta = e0 + (emax*dose) / (ed50+dose)); 
 
model resp ~ normal(eta, v); 
 
 
*** Estimate the difference in means; 
 
estimate “Diff Means (dose 2400 mg – placebo)” 
 
 
e0+((emax*2400)/(ed50+2400))-e0; 
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estimate “Diff Means (dose 1200 mg – placebo)” 
 
 
e0+((emax*1200)/(ed50+1200))-e0; 
 
estimate “Diff Means (dose 600 mg – placebo)” 
 
 
e0+((emax*600)/(ed50+600))-e0; 
 
estimate “Diff Means (dose 300 mg – placebo)” 
 
 
e0+((emax*300)/(ed50+300))-e0; 
 
 
predict eta out=etahat; 
 
****output estimations; 
 
****dataset est has output for estimate of the mean differences; 
 
****dataset parms has output for parameters: e0 emax ed50; 
 
ods output AdditionalEstimates=est ParameterEstimates=parms; 
run; 
 
*** Linear model; 
proc nlmixed data=data1 alpha=0.05; 
*** set up initial values 
 
parms e0=10 beta1=80 beta2=80  v=400; 
 
 
 
*** Define model; 
 
if dose=0 then eta = e0; 
 
else eta = e0 + beta1 * dose; 
 
model resp ~ normal(eta, v); 
                                        VV-RIM-00145959-1.0 Approved - 02 Mar 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-20145 
Statistical Analysis Plan 
 
Date: 01MAR2021 
 
CONFIDENTIAL 
Page 49 of 50 
 
 
*** Estimate the difference in means; 
 
estimate “Diff Means (dose 2400 mg – placebo)” 
 
 
e0+ beta1 * 2400 - e0; 
 
estimate “Diff Means (dose 1200 mg – placebo)” 
 
 
e0+ beta1 * 1200  - e0; 
 
estimate “Diff Means (dose 600 mg – placebo)” 
 
 
e0+ beta1 * 600 - e0; 
 
estimate “Diff Means (dose 300 mg – placebo)” 
 
 
e0+ beta1 * 300 - e0; 
 
 
predict eta out=etahat; 
 
****output estimations 
 
****dataset est has output for estimate of the mean differences; 
 
****dataset parms has output for parameters: e0 beta1; 
 
ods output AdditionalEstimates=est ParameterEstimates=parms; 
run; 
*** Exponential model; 
proc nlmixed data=data1 alpha=0.05; 
*** set up initial values 
 
parms e0=10 e1=1 delta=1; 
 
 
 
*** Define model; 
                                        VV-RIM-00145959-1.0 Approved - 02 Mar 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-20145 
Statistical Analysis Plan 
 
Date: 01MAR2021 
 
CONFIDENTIAL 
Page 50 of 50 
 
if dose=0 then eta = e0; 
 
else eta = e0 + e1 * (exp(dose/delta)-1); 
 
model resp ~ normal(eta, v); 
*** Specify that delta must be positive; 
 
bounds delta>0; 
 
 
*** Estimate the difference in means; 
 
estimate “Diff Means (dose 2400 mg – placebo)” 
 
 
e0+ e1* (exp(2400/delta)-1) - e0; 
 
estimate “Diff Means (dose 1200 mg – placebo)” 
 
 
e0+ e1* (exp(1200/delta)-1) - e0; 
 
estimate “Diff Means (dose 600 mg – placebo)” 
 
 
e0+ e1* (exp(600/delta)-1) - e0; 
 
estimate “Diff Means (dose 300 mg – placebo)” 
 
 
e0+ e1* (exp(300/delta)-1) - e0; 
 
predict eta out=etahat; 
 
****output estimations 
 
****dataset est has output for estimate of the mean differences; 
 
****dataset parms has output for parameters: e0 e1 delta; 
 
ods output AdditionalEstimates=est ParameterEstimates=parms; 
run; 
 
                                        VV-RIM-00145959-1.0 Approved - 02 Mar 2021 GMT-5:00


Signature Page for VV-RIM-00145959 v1.0
Signature Page for VV-RIM-00145959 v1.0 Approved
ESig Approval
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ESig Approval
                                        VV-RIM-00145959-1.0 Approved - 02 Mar 2021 GMT-5:00