Clinical trial NCT04852978
Conditions: Healthy Chronic Stable Illness
Sponsor: Regeneron Pharmaceuticals
Start date: 2021-04-29; Completion date: 2022-11-21
Enrollment: 295 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of the study are:

* To evaluate the extent of effect, if any, of REGN10933+REGN10987 administration on vaccine-induced neutralizing antibody responses to SARS-CoV-2 by Moderna mRNA-1273
* To evaluate the time interval required between REGN10933+REGN10987 administration and Moderna mRNA-1273 vaccination, to ensure no meaningful impact on vaccine-induced neutralizing antibody responses to SARS-CoV-2

The secondary objectives of the study are:

* To quantify the alteration of antigen specificity of vaccine-induced SARS-CoV-2 antibody responses when administered with different dose regimens of REGN10933+REGN10987
* To evaluate the safety and tolerability of REGN10933+REGN10987 and Moderna mRNA-1273 vaccine when administered in close succession
* To assess the concentrations of REGN10933 and REGN10987 in serum over time in participants who receive REGN10933+REGN10987 and Moderna mRNA-1273 vaccine
* To evaluate the immunogenicity of REGN10933 and REGN10987 over time

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None arm 10: None arm 11: None arm 12: None
Interventions: intervention 1: casirivimab+imdevimab intervention 2: Moderna mRNA-1273 vaccine
Intervention descriptions: intervention 1: Wave 1 Intravenous (IV) administration Wave 2 Subcutaneous administration intervention 2: Single intramuscular (IM) injection

Protocol documents:
Prot_000.pdf: 
IND: 148069 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 2 RANDOMIZED, OPEN-LABEL, PARALLEL GROUP 
STUDY TO ASSESS THE IMMUNOGENICITY, SAFETY, AND 
TOLERABILITY OF MODERNA mRNA-1273 VACCINE 
ADMINISTERED WITH CASIRIVIMAB+IMDEVIMAB IN HEALTHY 
ADULT VOLUNTEERS 
Compound: 
Casirivimab+Imdevimab (REGN10933+REGN10987) 
Clinical Phase: 
2 
Protocol Number: 
R10933-10987-COV-2118 
Protocol Version: 
Amendment 5 
Amendment 5 Date of Issue: 
See appended electronic signature page 
Amendment 4 Date of Issue: 
21 Jul 2021 
Amendment 3 Date of Issue: 
29 Apr 2021 
Amendment 2 Date of Issue: 
16 Apr 2021 
Amendment 1 Date of Issue: 
14 Apr 2021 
Original Date of Issue: 
05 Apr 2021 
Medical/Study Director: 
 
  
 
 
 
 
 
  
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
VV-RIM-00182647-1.0 Approved - 28 Jan 2022 GMT-5:00
NCT04852978


Clinical Study Protocol 
 
R10933-10987-COV-2118 Amendment 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00182647-1.0 Approved - 28 Jan 2022 GMT-5:00


Clinical Study Protocol 
 
R10933-10987-COV-2118 Amendment 5 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 3 
 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 5 
Change 
Rationale 
Section(s) Changed 
Sub-study has been included to allow 
subjects to opt to receive a booster dose of 
Moderna mRNA-1723 vaccine ≥5 months 
after completing the primary COVID-19 
vaccination series and >35 days before the 
end of the main study (ie, until study day 
345 for subjects in arms 1, 2, 3, 6a, 6c, 7 and 
8 and until study day 331 for subjects in 
arms 4, 5, 6b, 6d and 9). One visit was 
added for pre-booster blood sample 
collection and booster dose administration 
and a second visit was added for post-
booster blood sample collection. 
Nasopharyngeal swabs will be collected at 
each of the 2 visits. 
 
To accommodate the 
updated CDC guidance for 
COVID-19 booster vaccines. 
 
 
To assess immune responses 
to the booster dose. 
 
To test for SARS-CoV-2 
infection. 
Section 2.3 Exploratory 
objectives 
Section 6.1 Study Description 
and Duration 
Section 8.3.3 Vaccine Deferral or 
Discontinuation 
Section 9.1 Schedule of Events, 
Table 3, Table 4, Table 5 and 
Table 6 Schedule of Events for 
the Moderna mRNA-1273 
Vaccine Booster Sub-study [new] 
Section 9.1.1 Footnotes for the 
Schedule of Events 
Section 9.2.1.1 Informed Consent 
Section 9.2.10 Vaccine Booster 
Sub-Study (Optional) [new] 
Section 11.4.5 Adverse Events 
 
Vaccine booster analysis set definition and 
analysis of sub-study vaccine booster text 
included in the protocol. 
 
To define the vaccine 
booster analysis set and 
describe the possible 
analyses of the vaccine 
booster sub-study data. 
Section 11.3.3 Vaccine Booster 
Analysis Set [new section] 
Section 11.4.5 Analysis of Sub-
Study Vaccine Booster [new 
section] 
The observation period definitions were 
clarified and a post-booster vaccination 
period was included. 
To clarify the definitions of 
the different observation 
periods in the study. 
Section 11.4.6.1 Adverse Events 
Subjects will be allowed to receive COVID-
19 booster vaccinations during the study. 
Subjects can choose to receive a third 
COVID-19 vaccine in the optional vaccine 
booster sub-study or receive COVID-19 
vaccine boosters outside of the study which 
will then be recorded as a concomitant 
medication. 
To accommodate the 
updated CDC guidance for 
COVID-19 booster vaccines. 
Section 8.8.1 Prohibited 
Medications and Vaccines 
Text on offering an additional vaccine to 
subjects in the affected arms if group-level 
study data identified vaccine interference 
from REGN10933+REGN10987 in one or 
more arms was removed. 
An interim analysis which 
included wave 1 and 2 
subjects, the arms where the 
dose of REGEN-COV is the 
highest and thus at greatest 
risk for vaccine interference 
showed only a small 
difference in neutralizing 
mAb binding. Thus, 
significant vaccine 
interference by REGEN-
COV is unlikely.  
 
Section 6.1 Study Description 
and Duration 
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Page 4 
 
CONFIDENTIAL 
Change 
Rationale 
Section(s) Changed 
The CDC guidance has 
changed to allow all subjects 
to receive booster doses of 
vaccines.  
The requirements for reporting of Grade ≥3 
ISRs or Grade ≥2 hypersensitivity reactions 
related to Moderna mRNA-1273 
administered as a concomitant medication 
outside of the study was included. 
To clarify that Grade ≥3 
ISRs and Grade ≥2 
hypersensitivity reactions 
related to the Moderna 
mRNA-1273 vaccine 
administered outside the 
study should not be 
considered AESIs and do not 
require expedited reporting 
to the Sponsor.  
Section 10.1.3 Events that 
Require Expedited Reporting to 
Sponsor 
Clarified that causality should be assessed in 
relation to the Moderna mRNA-1273 
vaccine administered as part of the main 
study or sub-study, but not in relation to any 
vaccine administered as a concomitant 
medication outside of the study. 
This clarification is now 
required because the 
Moderna mRNA-1273 
booster shot administered as 
a concomitant medication is 
no longer prohibited. 
Section 10.2.5 Causality. 
Removed parenthetical referencing the post-
vaccination period in describing SAE 
reporting, and clarified that any SAE 
assessed by the investigator as related to the 
study drug that occur subsequent to the 
reporting period should also be reported. 
Reference to the reporting 
period being end of the post-
vaccination period was 
removed because the naming 
logic of the safety period has 
changed and post-booster 
vaccination period has been 
added. 
Section 10.1.1 General 
Guidelines 
Risks for the Moderna mRNA-1273 vaccine 
were updated. 
To align with the latest EUA 
Fact Sheet. 
Section 3.3.2 Risk-Benefit for 
Moderna mRNA-1273 Vaccine 
Text was added detailing mechanisms that 
could be implemented to ensure continuity 
of the study conduct and oversight due to 
COVID-19. 
To explicitly detail 
temporary or alternative 
mechanisms that could be 
utilized due to the COVID-
19 pandemic and to ensure 
appropriate documentation 
of any temporary or 
alternative mechanisms and 
deviation that may occur. 
Section 9.1. 
The risk-benefit information was updated to 
reflect the current investigator’s brochure.  
To provide current clinical 
data on 
REGN10933+REGN10987. 
Section 3.3.1 Risk-Benefit for 
REGN10933+REGN10987. 
Updates to relevant sections to include the 
current CDC guidelines, EUA for the Pfizer-
BioNTech vaccine and Moderna COVID-19 
vaccine fact sheet. 
To include current CDC 
guidelines and Moderna 
COVID-19 vaccine fact 
sheet 
Section 1 Introduction 
Section 3.2.1.2 Primary 
Objectives: Exploration of Time 
Intervals 
Section 3.3.2 Risk-Benefit for 
Moderna mRNA-1273 Vaccine 
Updates to the background information, 
minor clarifications for consistency, and 
other minor typographical and 
administrative updates were made. 
To include current CDC 
guidelines and include up to 
date references and to ensure 
Throughout the document 
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Page 5 
 
CONFIDENTIAL 
Change 
Rationale 
Section(s) Changed 
clarity, accuracy, and 
consistency 
 
Amendment 4 
Change 
Rationale 
Section(s) Changed 
Five additional study arms have been 
included: 
• Two study arms, with a third concurrent 
control arm, will simulate vaccination up 
through approximately 6 months 
following REGN10933+REGN10987 
administration. 
• One study arm, in addition to a 
concurrent control arm, will evaluate 
endogenous immune response to 
vaccination when the first vaccine dose is 
followed by REGN10933+REGN10987 
administration 6 days later. 
Enrollment in these arms will occur as two 
additional waves (wave 3 and wave 4). 
 
In total, 106 additional subjects (30 per 
REGN10933+REGN10987 treatment arms, 
and 8 per control arms) will be enrolled. The 
justification for samples size was updated 
accordingly. 
To better understand the 
temporal relationship 
between 
REGN10933+REGN10987 
and Moderna mRNA-1723 
vaccine with respect to 
endogenous immune 
response, by exploring larger 
time intervals between 
dosing, and by exploring the 
impact of immune “priming” 
prior to 
REGN10933+REGN10987 
treatment on 
immunogenicity 
Section 3.2.1.1 Primary 
Objectives: Potential Alteration 
of Endogenous Immune 
Responses 
Section 3.2.1.9 Use of Enrollment 
Waves 
Section 3.2.2 Rationale for Dose 
Selection 
Figure 1 Dose Administration by 
Study Arm 
Section 3.2.2.1 Study Arm 1 and 
Arm 9 (1200 mg IV) 
Section 3.2.2.2 Study Arm 2 (300 
mg IV), Arm 3 (150 mg IV), Arm 
7 (48 mg IV), and Arm 8 (12 mg 
IV)  
Table 1 Population 
Pharmacokinetics Modeling of 
Simulated Study Days Following 
1200 mg IV Dose 
Section 3.2.2.3 Study Arm 4 
(1200 mg SC) and Arm 5 (600 
mg SC) 
Section 6.1 Study Description 
and Duration 
Figure 2 Study Flow Diagram 
(Enrollment Waves 1 and 2) 
Figure 3 Study Flow Diagram 
(Enrollment Waves 3 and 4) 
[new] 
Section 7.1 Number of Subjects 
Planned 
Section 8.5 Method of 
Enrollment and Treatment 
Assignment  
Table 2 Study Treatment 
Assignment  
Table 3 Schedule of Events for 
Study Arms 1, 2, 3, and 6a 
(Enrollment Wave 1) and Arms 7, 
8, and 6c (Enrollment Waves 3) 
Table 4 Schedule of Events for 
Arms 4, 5, and 6b (Enrollment 
Wave 2) 
Table 5 Schedule of Events for 
Study Arms 9 and 6d (Enrollment 
Wave 4) [new] 
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CONFIDENTIAL 
Change 
Rationale 
Section(s) Changed 
Section 9.1.1 Footnotes for the 
Schedule of Events, #7, 10, and 
11 
Clinical history of myocarditis and/or 
pericarditis has been added as an exclusion 
criterion for study participation. 
To ensure an appropriate 
risk-benefit profile for the 
target population 
Section 7.2.2 Exclusion Criteria, 
#25 [new] 
Definitions of safety observation periods, 
statistical analysis sets, and analysis plans 
were updated.  
In addition, it was updated that formal 
interim analysis may be performed. 
To clarify methods of 
statistical analysis 
Section 6.2 Planned Interim 
Analysis 
Section 11 Statistical Plan 
Clarified that pregnancy testing is not 
required for women of childbearing 
potential (WOCBP) with documented 
bilateral tubal ligation. 
To avoid unnecessary 
pregnancy testing 
Section 9.1.1  Footnotes for the 
Schedules of Events 
Risk-benefit information was updated to 
reflect the current investigator’s brochure, as 
well as phase 3 clinical trials in the 
treatment and prevention of COVID-19. 
To provide current clinical 
data on 
REGN10933+REGN10987 
Section 3.3.1 Risk-Benefit for 
REGN10933+REGN10987 
Updates to background information, minor 
clarifications for consistency, and other 
minor typographical and administrative 
updates were made. 
To ensure clarity, accuracy, 
and consistency 
Throughout the document 
 
Amendment 3 
Change 
Rationale 
Section(s) Changed 
Vital signs will be assessed at screening, as 
abnormal blood pressure at screening visit 
is an exclusion criterion (#12). 
Updated to ensure accuracy of 
the Schedule of Events 
Table 3 Schedule of Events for 
Study Arms 1, 2, 3, and 6a 
Table 4 Schedule of Events for 
Study Arms 4, 5, and 6b 
 
Amendment 2 
Change 
Rationale 
Section(s) Changed 
Previously, it was specified that vaccine 
cards were to be dispensed to subjects only 
once their assigned study arm was deemed 
to have generated an appropriate vaccine 
response compared to the vaccine-only arm.  
 
This statement has been removed, and 
vaccine cards will be made available to all 
subjects upon receipt of the vaccine as per 
the current standard of care.  
Based on site feedback; 
vaccine cards indicate receipt 
of the vaccine, rather than 
generation of an appropriate 
vaccine response. 
Synopsis: Study Design 
Section 6.1 Study Description 
and Duration 
 
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CONFIDENTIAL 
Amendment 1 
Change 
Rationale 
Section(s) Changed 
Subjects with a positive serology test result 
for anti-SARS-CoV-2 antibodies at 
screening, tested either locally or by a 
central laboratory, will be excluded.  
 
Serology testing at baseline (central 
laboratory) will be used to exclude 
seropositive patients from the per-protocol 
set (PPS) for vaccine response analysis. 
Due to limited supply of rapid 
serology test kits, local testing 
may not be operationally 
feasible.  
Section 7.2.2 Exclusion 
Criteria, #2 
Table 3 Schedule of Events for 
Study Arms 1, 2, 3, and 6a 
Table 4 Schedule of Events for 
Study Arms 4, 5, and 6b 
Section 9.1.1  Footnotes for 
Table 2 and Table 3 Schedule 
of Event, footnote #5 
Procedural details regarding SARS-CoV-2 
serology tests were updated. 
Serology testing procedures 
were updated to remove 
unnecessary details or to 
ensure accuracy. 
Section 9.2.1 Procedures 
Performed at the 
Screening/Baseline Visit 
Section 9.2.1.3 SARS-CoV-2 
Serology 
Subjects with positive SARS-CoV-2 
diagnostic test result at any time prior to 
screening will be excluded from enrollment.  
Previous exclusion criterion of 
positive SARS-CoV-2 
infection needed to be updated 
for operational clarity.  
Section 7.2.2 Exclusion 
Criteria, #3 
Minor typographical and administrative 
updates 
For accuracy and consistency 
Throughout the protocol 
 
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CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACE2 
Angiotensin-converting enzyme 2 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
CDC 
Centers for Disease Control and Prevention 
COVID-19 
Coronavirus disease 19 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
EDC 
Electronic data capture 
EUA 
Emergency Use Authorization 
FBR 
Future biomedical research 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
HDL 
High-density lipoprotein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDL 
Low-density lipoprotein 
LFIA 
Lateral flow chromatographic immunoassay 
mAb 
Monoclonal antibody 
mFAS 
Modified full analysis set 
MIS 
Multisystem inflammatory syndrome 
NAb 
Neutralizing antibody 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
PBMC 
Peripheral blood mononuclear cell 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetic 
POC 
Point of care 
RBC 
Red blood cell 
RBD 
Receptor binding domain 
RBQM 
Risk-Based Quality Monitoring 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent adverse event 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 
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Clinical Study Protocol 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................8 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................16 
1. 
INTRODUCTION ......................................................................................................20 
2. 
STUDY OBJECTIVES ..............................................................................................21 
2.1. 
Primary Objectives .....................................................................................................21 
2.2. 
Secondary Objectives .................................................................................................22 
2.3. 
Exploratory Objectives ...............................................................................................22 
3. 
HYPOTHESES AND RATIONALE .........................................................................23 
3.1. 
Hypotheses ..................................................................................................................23 
3.2. 
Rationale .....................................................................................................................23 
3.2.1. 
Rationale for Study Design .........................................................................................23 
3.2.1.1. 
Primary Objectives: Potential Alteration of Endogenous Immune Responses ..........23 
3.2.1.2. 
Primary Objectives: Exploration of Time Intervals....................................................24 
3.2.1.3. 
Selection and Interpretation of Primary Endpoint ......................................................25 
3.2.1.4. 
Selection of Moderna mRNA-1273 for Vaccine Response Analysis .........................25 
3.2.1.5. 
Selection of Neutralizing Titer Assay .........................................................................26 
3.2.1.6. 
Secondary and Exploratory Analyses of Immune Response ......................................26 
3.2.1.7. 
Study Population .........................................................................................................27 
3.2.1.8. 
Safety and Tolerability ...............................................................................................27 
3.2.1.9. 
Use of Enrollment Waves ...........................................................................................27 
3.2.2. 
Rationale for Dose Selection ......................................................................................27 
3.2.2.1. 
Study Arm 1 and Arm 9 (1200 mg IV) .......................................................................28 
3.2.2.2. 
Study Arm 2 (300 mg IV), Arm 3 (150 mg IV), Arm 7 (48 mg IV), and Arm 
8 (12 mg IV) ...............................................................................................................28 
3.2.2.3. 
Study Arm 4 (1200 mg SC) and Arm 5 (600 mg SC) ................................................29 
3.3. 
Risk-Benefit ................................................................................................................29 
3.3.1. 
Risk-Benefit for REGN10933+REGN10987 .............................................................29 
3.3.2. 
Risk-Benefit for Moderna mRNA-1273 Vaccine .......................................................32 
3.3.3. 
Risk-Benefit for REGN10933+REGN10987 Administered With COVID-19 
Vaccines ......................................................................................................................33 
4. 
ENDPOINTS ..............................................................................................................34 
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4.1. 
Primary Endpoints ......................................................................................................34 
4.2. 
Secondary Endpoints ..................................................................................................34 
4.3. 
Exploratory Endpoints ................................................................................................35 
5. 
STUDY VARIABLES................................................................................................35 
5.1. 
Demographic and Baseline Characteristics ................................................................35 
5.2. 
Pharmacodynamic and Other Biomarker Variables ...................................................35 
5.3. 
Safety Variables ..........................................................................................................36 
5.4. 
Pharmacokinetic Variables .........................................................................................36 
5.5. 
Immunogenicity Variables ..........................................................................................36 
6. 
STUDY DESIGN .......................................................................................................37 
6.1. 
Study Description and Duration .................................................................................37 
6.1.1. 
Risk Minimization for SARS-CoV-2 Infection and Transmission .............................41 
6.1.2. 
Sample Collection and Visit Scheduling for Subjects with Suspected 
COVID-19 Symptoms or Positive SARS-CoV-2 Test ...............................................41 
6.1.3. 
Study Stopping Rules .................................................................................................41 
6.1.4. 
End of Study Definition ..............................................................................................42 
6.2. 
Planned Interim Analysis ............................................................................................42 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF SUBJECTS ..............42 
7.1. 
Number of Subjects Planned ......................................................................................42 
7.2. 
Study Population .........................................................................................................42 
7.2.1. 
Inclusion Criteria ........................................................................................................42 
7.2.2. 
Exclusion Criteria .......................................................................................................43 
7.3. 
Premature Withdrawal from the Study .......................................................................45 
7.4. 
Replacement of Subjects .............................................................................................45 
8. 
STUDY DRUG AND COVID-19 VACCINE ...........................................................45 
8.1. 
Investigational Treatment (Study Drug) .....................................................................45 
8.2. 
COVID-19 Vaccine ....................................................................................................45 
8.3. 
Dose Modification and Discontinuation Rules ...........................................................46 
8.3.1. 
Dose Modification ......................................................................................................46 
8.3.2. 
Study Drug Discontinuation .......................................................................................46 
8.3.3. 
Vaccine Deferral or Discontinuation ..........................................................................46 
8.4. 
Management of Acute Reactions ................................................................................46 
8.4.1. 
Acute Intravenous Infusion Reactions to the Study Drug ..........................................46 
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8.4.1.1. 
Interruption of the Intravenous Infusion .....................................................................47 
8.4.1.2. 
Termination of the Intravenous Infusion ....................................................................47 
8.4.2. 
Acute Injection Reactions to the Study Drug .............................................................48 
8.4.2.1. 
Systemic Injection Reactions ......................................................................................48 
8.4.2.2. 
Local Injection Site Reactions ....................................................................................48 
8.4.3. 
Acute Injection Reactions to the Vaccine ...................................................................48 
8.5. 
Method of Enrollment and Treatment Assignment ....................................................48 
8.6. 
Blinding ......................................................................................................................49 
8.7. 
Logistics and Accountability for Study Drug and Vaccine ........................................49 
8.7.1. 
Packaging, Labeling, and Storage ..............................................................................49 
8.7.2. 
Supply and Disposition of Study Drug .......................................................................49 
8.7.3. 
Study Drug and Vaccine Accountability ....................................................................50 
8.7.4. 
Study Drug and Vaccine Compliance .........................................................................50 
8.8. 
Concomitant Medications ...........................................................................................50 
8.8.1. 
Prohibited Medications and Vaccines ........................................................................50 
8.8.2. 
Permitted Medications ................................................................................................51 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................51 
9.1. 
Schedule of Events .....................................................................................................51 
9.1.1. 
Footnotes for the Schedules of Events........................................................................59 
9.1.2. 
Early Termination Visit ..............................................................................................61 
9.1.3. 
Unscheduled Visits .....................................................................................................61 
9.2. 
Study Procedures ........................................................................................................61 
9.2.1. 
Procedures Performed at the Screening/Baseline Visit ..............................................61 
9.2.1.1. 
Informed Consent .......................................................................................................61 
9.2.1.2. 
SARS-CoV-2 Rapid RT-PCR.....................................................................................61 
9.2.1.3. 
SARS-CoV-2 Serology ...............................................................................................61 
9.2.2. 
Study Drug and Vaccine Administration and Post-Administration 
Monitoring ..................................................................................................................61 
9.2.3. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................62 
9.2.3.1. 
SARS-CoV-2 Neutralization Assays ..........................................................................62 
9.2.3.2. 
SARS-CoV-2 Serology Characterization Assays .......................................................63 
9.2.3.3. 
Cellular Immunity Assays ..........................................................................................63 
9.2.3.4. 
Viral Sequencing ........................................................................................................63 
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9.2.3.5. 
Serum and Plasma for Exploratory Research .............................................................63 
9.2.4. 
Safety Procedures .......................................................................................................64 
9.2.4.1. 
Vital Signs ..................................................................................................................64 
9.2.4.2. 
Adverse Events Monitoring ........................................................................................64 
9.2.4.3. 
Concomitant Medications ...........................................................................................64 
9.2.4.4. 
Pregnancy Test ............................................................................................................64 
9.2.4.5. 
Targeted Physical Examination ..................................................................................64 
9.2.5. 
Laboratory Testing ......................................................................................................64 
9.2.6. 
Drug Concentration and Measurements .....................................................................66 
9.2.7. 
Immunogenicity Measurements and Samples ............................................................66 
9.2.8. 
Future Biomedical Research (Optional) .....................................................................66 
9.2.9. 
Pharmacogenomic Analysis (Optional) ......................................................................66 
9.2.10. 
Vaccine Booster Sub-Study (Optional) ......................................................................67 
10. 
SAFETY EVALUATION AND REPORTING .........................................................67 
10.1. 
Recording and Reporting Adverse Events ..................................................................67 
10.1.1. 
General Guidelines .....................................................................................................67 
10.1.2. 
Reporting Procedure ...................................................................................................68 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................68 
10.1.4. 
Reporting Adverse Events Following Vaccination ....................................................69 
10.2. 
Definitions ..................................................................................................................69 
10.2.1. 
Adverse Event .............................................................................................................69 
10.2.2. 
Serious Adverse Event ................................................................................................69 
10.2.3. 
Adverse Events of Special Interest .............................................................................70 
10.2.4. 
Severity .......................................................................................................................70 
10.2.5. 
Causality .....................................................................................................................73 
10.3. 
Safety Monitoring .......................................................................................................74 
10.4. 
Notifying Health Authorities, Institutional Review Board, and Investigators ...........74 
11. 
STATISTICAL PLAN................................................................................................75 
11.1. 
Statistical Hypothesis ..................................................................................................75 
11.2. 
Justification of Sample Size........................................................................................75 
11.3. 
Analysis Sets ...............................................................................................................76 
11.3.1. 
Vaccine Response Analysis Sets ................................................................................76 
11.3.2. 
Safety Analysis Set .....................................................................................................76 
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11.3.3. 
Vaccine Booster Analysis Set .....................................................................................76 
11.3.4. 
Pharmacokinetic Analysis Set ....................................................................................76 
11.3.5. 
Immunogenicity Analysis Sets ...................................................................................77 
11.4. 
Statistical Methods ......................................................................................................77 
11.4.1. 
Subject Disposition .....................................................................................................77 
11.4.2. 
Demography and Baseline Characteristics .................................................................77 
11.4.3. 
Analysis of Primary Vaccine Response Endpoint ......................................................77 
11.4.4. 
Analysis of Secondary Vaccine Response Endpoints ................................................78 
11.4.5. 
Analysis of Sub-Study Vaccine Booster .....................................................................78 
11.4.6. 
Safety Analysis ...........................................................................................................78 
11.4.6.1. 
Adverse Events ...........................................................................................................78 
11.4.6.2. 
Other Safety ................................................................................................................79 
11.4.6.3. 
Treatment Exposure ....................................................................................................79 
11.4.6.4. 
Treatment Compliance ................................................................................................80 
11.4.7. 
Pharmacokinetics ........................................................................................................80 
11.4.7.1. 
Analysis of Drug Concentration Data .........................................................................80 
11.4.8. 
Pharmacokinetics and Pharmacokinetics/Pharmacodynamics Analyses ....................80 
11.4.9. 
Analysis of Immunogenicity Data ..............................................................................80 
11.5. 
Interim Analysis ..........................................................................................................81 
11.6. 
Timing of Primary and Final Analyses .......................................................................81 
11.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........81 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................81 
12.1. 
Data Management and Electronic Systems ................................................................81 
12.1.1. 
Data Management .......................................................................................................81 
12.1.2. 
Electronic Systems ......................................................................................................82 
12.2. 
Study Monitoring ........................................................................................................82 
12.2.1. 
Monitoring of Study Sites ...........................................................................................82 
12.2.2. 
Source Document Requirements ................................................................................82 
12.2.3. 
Case Report Form Requirements ................................................................................82 
12.3. 
Audits and Inspections ................................................................................................83 
12.4. 
Study Documentation .................................................................................................83 
12.4.1. 
Certification of Accuracy of Data ...............................................................................83 
12.4.2. 
Retention of Records ..................................................................................................83 
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................84 
13.1. 
Good Clinical Practice Statement ...............................................................................84 
13.2. 
Informed Consent .......................................................................................................84 
13.3. 
Subjects Confidentiality and Data Protection .............................................................84 
13.4. 
Institutional Review Board .........................................................................................85 
13.5. 
Clinical Study Data Transparency ..............................................................................85 
14. 
PROTOCOL AMENDMENTS ..................................................................................85 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................86 
15.1. 
Premature Termination of the Study ...........................................................................86 
15.2. 
Close-out of a Site ......................................................................................................86 
16. 
CONFIDENTIALITY ................................................................................................86 
17. 
FINANCING AND INSURANCE .............................................................................86 
18. 
PUBLICATION POLICY ..........................................................................................86 
19. 
REFERENCES ...........................................................................................................87 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................91 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................92 
 
LIST OF TABLES 
Table 1: 
Population Pharmacokinetics Modeling of Simulated Study Days Following 
1200 mg IV Dose ........................................................................................................29 
Table 2: 
Study Treatment Assignment .....................................................................................49 
Table 3: 
Schedule of Events for Arms 1, 2, 3, and 6a (Enrollment Wave 1) and Arms 
7, 8, and 6c (Enrollment Wave 3) ...............................................................................52 
Table 4: 
Schedule of Events for Arms 4, 5, and 6b (Enrollment Wave 2) ...............................54 
Table 5: 
Schedule of Events for Study Arms 9 and 6d (Enrollment Wave 4) ..........................56 
Table 6: 
Schedule of Events for the Moderna mRNA-1273 Vaccine Booster Sub-
Study ...........................................................................................................................58 
Table 7: 
NCI-CTCAE (v5.0) Severity Grading System for Adverse Events: General 
Guideline .....................................................................................................................71 
Table 8: 
NCI-CTCAE (v5.0) Severity Grading System for Anaphylaxis, Allergic 
Reactions, Infusion-Related Reactions, and Injection Site Reactions ........................72 
 
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LIST OF FIGURES 
Figure 1: 
Dose Administration by Study Arm ...........................................................................28 
Figure 2: 
Study Flow Diagram (Enrollment Waves 1 and 2) ....................................................39 
Figure 3: 
Study Flow Diagram (Enrollment Waves 3 and 4) ....................................................40 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2 Randomized, Open-Label, Parallel Group Study to Assess the Immunogenicity, Safety, and 
Tolerability of Moderna mRNA-1273 Vaccine Administered with Casirivimab+Imdevimab in Healthy 
Adult Volunteers 
Site 
Locations 
The study will be conducted in approximately 5 sites in the United States. 
Principal 
Investigator To be determined 
Objectives 
 
Primary 
• To evaluate the extent of effect, if any, of REGN10933+REGN10987 administration on vaccine-
induced neutralizing antibody responses to SARS-CoV-2 by Moderna mRNA-1273 
• To evaluate the time interval required between REGN10933+REGN10987 administration and 
Moderna mRNA-1273 vaccination, to ensure no meaningful impact on vaccine-induced 
neutralizing antibody responses to SARS-CoV-2 
Secondary 
• To quantify the alteration of antigen specificity of vaccine-induced SARS-CoV-2 antibody 
responses when administered with different dose regimens of REGN10933+REGN10987 
• To evaluate the safety and tolerability of REGN10933+REGN10987 and Moderna mRNA-1273 
vaccine when administered in close succession 
• To assess the concentrations of REGN10933 and REGN10987 in serum over time in subjects who 
receive REGN10933+REGN10987 and Moderna mRNA-1273 vaccine 
• To evaluate the immunogenicity of REGN10933 and REGN10987 over time 
Study 
Design 
The study consists of 3 periods: a screening/baseline period, a vaccine response assessment period, 
and a follow-up period.  
Subjects will be assessed for eligibility during the screening/baseline period, which may occur up to 
21 days prior to day 1. To be eligible for the study, subjects must be confirmed negative for current or 
past SARS-CoV-2 infection by both RT-PCR and serology tests. 
During this period, subjects will also be assigned to one of four different enrollment waves. 
On day 1, subjects will be randomized to a study arm (1 of 12) within their assigned enrollment wave. 
Subjects randomized to study arms 1 through 5 or 7 through 9 will receive an IV infusion or SC 
injection of the study drug (REGN10933+REGN10987) on day 1 or day 7. Subjects in arms 6a to 6d 
(the control arms) will not receive any study drug. The first dose of the vaccine will be administered 
on day 1 or day 15, based on study arm assignment at randomization.  
All subjects will receive the second dose of the vaccine 28 days after their first dose of the vaccine in 
accordance with the EUA Fact Sheet.  
The vaccine response assessment period represents the time period of the primary analysis. For study 
arms 1, 2, 3, 7, 8, 6a, and 6c, this period includes up to study day 71; for study arms 4, 5, 9, 6b, and 
6d, the period includes up to day 57. Following this assessment period, subjects will enter a follow-up 
period lasting up to 10 months. 
Throughout the study, blood samples will be collected to assess whether the study drug impacts the 
ability of the vaccine to elicit neutralizing antibody titers against the SARS-CoV-2 S protein, and to 
understand any impact on vaccine-induced humoral and cellular immune responses to various S protein 
epitopes.  
Subjects will also have blood samples taken at select visits for drug concentration, immunogenicity, 
and exploratory analyses, and will be monitored for AEs (including AESIs) during in-person visits. 
For subjects in study arms 4 and 5 (receiving the study drug and vaccine on the same day), a phone 
call will be made within 24 hours following study drug and vaccine administration on day 1 for AE 
collection.  
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The last study visit will take place approximately 1 year after the first dose of the vaccine. 
Vaccine booster sub-study: All subjects will be offered an optional booster vaccination dose ≥5 
months after completing the primary COVID-19 vaccination series and >35 days (ie, until study day 
345 for subjects in arms 1, 2, 3, 6a, 6c, 7 and 8 and until study day 331 for subjects in arms 4, 5, 6b, 
6d and 9) before the end of the main study. Blood samples for possible analysis will be collected pre- 
and post-booster administration.   
Study 
Duration 
The duration of the study is approximately 401 days or 387 days, depending on the study arm 
assignment and length of the screening period. 
End of 
Study 
Definition 
The end of study is defined as the date the last subject completes the last study visit, withdraws from 
the study, or is lost to follow-up (ie, the study subject can no longer be contacted by the investigator). 
Population 
 
Sample Size Up to approximately 286 subjects are planned to be enrolled. 
Target 
Population Eligible subjects for this study consist of healthy adult volunteers over 18 years of age who are negative 
at screening for both SARS-CoV-2 infection and endogenous anti-SARS-CoV-2 antibodies. A 
complete listing of eligibility criteria is provided in the main text. 
Every effort should made to enroll older subjects, such that 30% to 50% of subjects enrolled at each 
site are ≥65 years of age. Efforts should also be made to enroll subjects representative of the 
demographics (eg, race and ethnic distribution) of those at risk for COVID-19 in the region where the 
study site is located. 
Treatments Site-managed assignment. At screening, eligible subjects will be assigned to an enrollment wave. 
The enrollment waves are intended to avoid or minimize the potential for unused doses of Moderna 
mRNA-1273 COVID-19 vaccine. Every effort should be made by sites to avoid unused doses of 
vaccine. 
Sites will manage the placement of subjects into each wave. Every effort should be made by the site 
to ensure balance of age (<65 years and ≥65 years) within each of the enrollment waves. 
Randomization. At baseline (day 1), subjects will be randomized to the corresponding study arms in 
each wave. Randomization will be stratified by age (<65 years versus ≥65 years). 
Study 
Arm 
Random-
ization 
Ratio 
Targeted 
Enrollment 
Co-administered REGN10933+REGN10987 
Combination Therapy 
Moderna mRNA-1273 
Vaccine 
Enrollment Wave 1 
1 
2 
30 
1200 mg (600 mg of each mAb) IV on day 1 
On day 15 and day 43 
2 
2 
30 
300 mg (150 mg of each mAb) IV on day 1 
On day 15 and day 43 
3 
2 
30 
150 mg (75 mg of each mAb) IV on day 1 
On day 15 and day 43 
6a 
1 
15 
None 
On day 15 and day 43 
Enrollment Wave 2 
4 
2 
30 
1200 mg (600 mg of each mAb) SC on day 1 
On day 1 and day 29 
5 
2 
30 
600 mg (300 mg of each mAb) SC on day 1 
On day 1 and day 29 
6b 
1 
15 
None 
On day 1 and day 29 
Enrollment Wave 3 
7 
15 
30 
48 mg (24 mg of each mAb) IV on day 1 
On day 15 and day 43 
8 
15 
30 
12 mg (6 mg of each mAb) IV on day 1 
On day 15 and day 43 
6c 
4 
8 
None 
On day 15 and day 43 
Enrollment Wave 4 
9 
15 
30 
1200 mg (600 mg of each mAb) IV on day 7 
On day 1 and day 29 
6d 
4 
8 
None 
On day 1 and day 29 
 
 
 
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Endpoints 
Primary 
• 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing antibodies to the SARS-CoV-
2 S protein assessed 56 days after the first dose of Moderna mRNA-1273 vaccine in individuals 
who receive high-dose (1200 mg) REGN10933+REGN10987 compared to vaccine alone 
• 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing antibodies to the SARS-CoV-
2 S protein assessed 56 days after the first dose of Moderna mRNA-1273 vaccine in individuals 
who receive submaximal dose levels of REGN10933+REGN10987 (less than 1200 mg) compared 
to vaccine alone 
Secondary 
• Absolute values, change from baseline, and percentage change from baseline in concentrations of 
vaccine-induced antibodies to the following SARS-CoV-2 antigens over time: 
− Anti-S protein 
− Anti-receptor binding domain (RBD) 
− Other S protein subdomains (including S1, S2, and NTD)  
• 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing antibodies to SARS-CoV-2 S 
protein assessed over time 
• Proportion of subjects with treatment-emergent adverse events (TEAEs) throughout the study  
• Proportion of subjects with treatment-emergent serious adverse events (SAEs) throughout the study 
• Proportion of subjects with infusion-related reactions (grade ≥2) to REGN10933+REGN10987 
through day 4 post-infusion  
• Proportion of subjects with injection site reactions (grade ≥3) to REGN10933+REGN10987 or each 
dose of Moderna mRNA-1273 vaccine through day 4 post-injection 
• Proportion of subjects with hypersensitivity reactions (grade ≥2) to REGN10933+REGN10987 or 
each dose of Moderna mRNA-1273 vaccine through day 29 post-infusion or post-injection (as 
applicable) 
• Concentrations of REGN10933 and REGN10987 in serum over time  
• Immunogenicity, as measured by anti-drug antibodies (ADA) and neutralizing antibodies (NAb) to 
REGN10933 and REGN10987 
Procedures 
and 
Assessments 
Procedures and assessments will include the following: 
• Nasopharyngeal (NP) swabs for SARS-CoV-2 rapid RT-PCR testing  
• Blood collection for rapid serology testing and/or central serology testing  
• Serum and whole blood collection for pharmacodynamic and exploratory analyses 
• Blood collection for safety labs 
• Pregnancy testing 
Statistical 
Plan 
 
Statistical 
Hypothesis No statistical hypothesis testing is planned in this study. Analyses of immunogenicity, safety, 
tolerability, and other data will be descriptive and exploratory in nature. 
Justification 
of Sample 
Size 
This study plans to enroll up to approximately 286 subjects, in order to achieve a target enrollment of 
up to approximately 30 subjects per Moderna mRNA-1273 + (REGN10933 and REGN10987) arm 
and 46 total Moderna mRNA-1273-alone subjects. Based on the calculations provided below, this 
sample size is considered appropriate to meet the aims of this phase 2 study, in that it is expected to 
provide adequate precision in quantifying the magnitude of effect for the primary endpoint, as well as 
allow for an assessment of the safety and tolerability of the Moderna mRNA-1273 vaccine when 
administered with REGN10933+REGN10987. 
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The assumed log10-scale standard deviation for the study is 0.30 log. This assumption is based on 
phase 1 data for the Moderna mRNA-1273 vaccine, taking the weighted average (ie, adjusting for 
sample sizes) across all doses (25,100, and 250 μg) and age groups (18 to 55, 56 to 70, and ≥71 years) 
for the neutralizing antibody titer ID50 endpoint at day 57 (Anderson, 2020) (Jackson, 2020). With a 
log-scale standard deviation of 0.30 for the primary endpoint and a sample size of 30 and 46 subjects 
per arm, the half-width of the 95% within-group confidence interval (CI) [ie, the minimal detectable 
difference] in this study is 0.11 log and 0.09 log respectively. For between-group comparisons, the 
half-width of the 95% between-group CI for any two Moderna mRNA-1273 + (REGN10933 and 
REGN10987) arms is 0.15 log. Additionally, the half-width of the 95% between-group CI in this study 
for any individual Moderna mRNA-1273 + (REGN10933 and REGN10987) arm and the total 
Moderna mRNA-1273 alone subjects is 0.14 log.  
The analysis set that will be used for assessment of vaccine response allows for subjects to be excluded 
from analysis if certain confounding criteria are met (see Section 11.3.1). If 50% of subjects are 
excluded from analysis (ie, 15 subjects are analyzed per individual Moderna mRNA-1273 + 
(REGN10933 and REGN10987) arm and 23 total Moderna mRNA-1273 alone subjects are analyzed), 
the half-width of the 95% between-group CI for any two Moderna mRNA-1273 + (REGN10933 and 
REGN10987) arms is 0.22 log. Additionally, the half-width of the 95% between-group CI for any 
individual Moderna mRNA-1273 + (REGN10933 and REGN10987) arm and Moderna mRNA-1273 
alone subjects is 0.20 log. Under this scenario, the minimal detectable difference still remains 
substantially smaller than the decrease in neutralization titers observed in a separate study of sera from 
recipients of the Moderna mRNA-1273 vaccine who were infected with South African variants (eg, 
B.1.351 v1, v2, and v3) (Garcia-Beltran, 2021) 
Statistical 
Analysis 
Analysis of Primary Vaccine Response Endpoint 
The primary endpoint is the 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing 
antibodies to SARS-CoV-2 pseudovirus, assessed on 56 days after the first dose of the vaccine. The 
56-day time point corresponds to study day 71 for study arms 1, 2, 3, 7, 8, 6a, and 6c, and study day 
57 for study arms 4, 5, 9, 6b, and 6d.  
An analysis of covariance (ANCOVA) model with treatment group as a fixed effect and age as a 
covariate will be fit to the data as the primary analysis.  
The least squares mean estimates for the endpoint will be presented for each treatment group, as well 
as for the differences between treatment groups. Associated 95% CIs will also be reported for each 
treatment group and for between-group comparisons.  
Data will be originally fitted in the log scale, and final outputs will be reported in geometric means 
and differences of the geometric means.  
Accompanying descriptive analyses will also be provided. The analyses will be conducted based on 
the observed data with no imputation for missing data. Values below the limit of quantification (LOQ) 
will be set to half of LOQ.  
Analysis of Secondary Vaccine Response Endpoints 
The secondary endpoints will be analyzed in a similar manner as described for the primary endpoint.  
For these secondary endpoints, the individual time points for assessments include all post-vaccine 
scheduled timepoints during the Vaccine Response Assessment Period as described in the Schedule of 
Events. 
Accompanying descriptive analyses for each endpoint at each individual time points will also be 
provided. 
Interim 
Analyses 
 
Data will be reviewed periodically to provide an understanding of vaccine response in different study 
arms. Formal interim analysis may be conducted. 
Timing of 
Primary  
and Final 
Analyses 
The primary vaccine response analysis will be conducted as a first-step analysis after all subjects have 
finished the primary endpoint visit (ie, 56 days after the first dose of the vaccine), in order to estimate 
the levels of neutralizing antibodies in each study arm. This analysis represents the final analysis of 
the primary endpoint and is not considered an interim analysis. The SAP will be issued prior to this 
analysis.  
After all subjects finish 1-year of follow-up, a final study analysis will be conducted. 
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1. 
INTRODUCTION 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel RNA betacoronavirus, 
initially identified in patients experiencing atypical pneumonia in Wuhan City, China (Zhu, 2020) 
and later identified as the causative pathogen of coronavirus disease 2019 (COVID-19) 
(WHO, 2020). 
Coronaviruses consist of an RNA genome packaged in nucleocapsid (N) protein. The resulting 
capsid is surrounded by an outer envelope 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. The S protein is essential for virus infectivity and is the main target of the humoral 
immune response, as demonstrated by serology analysis of recovered COVID-19 patients 
(Long, 2020). By mediating binding to the host receptor angiotensin-converting enzyme 2 (ACE2), 
the S protein facilitates membrane fusion and entry of the virus into susceptible cells 
(Hoffmann, 2020). The S protein is itself composed of 2 functional subunits: the S1 subunit, which 
contains the receptor binding domain (RBD) responsible for binding to ACE2 on host cells, and 
the S2 subunit, which mediates fusion of the viral and cellular membranes (Walls, 2020).  
Over 200 COVID-19 vaccines are currently in preclinical or clinical development, and many of 
these employ mechanisms involving S protein neutralization (WHO, 2021). On 11 Dec 2020, the 
Food and Drug Administration (FDA) issued the first Emergency Use Authorization (EUA) for a 
COVID-19 vaccine (Pfizer-BioNTech COVID‑19 Vaccine) in individuals ≥16 years old 
(FDA, 2020b). Similar authorizations were subsequently issued for mRNA-1273 (18 Dec 2020), 
a COVID-19 vaccine developed by Moderna, as well as a vaccine developed by Janssen 
Pharmaceuticals (27 Feb 2021), both in individuals ≥18 years old (Baden, 2020). On 03 Jan 2022, 
the EUA of the Pfizer-BioNTech vaccine was revised to include vaccination of individuals 5-11 
years old who have undergone solid organ transplantation or who are diagnosed with conditions 
that are considered to have an equivalent level of immunocompromise (FDA, 2022). Each of these 
vaccines elicit robust, dose-dependent neutralizing and other polyclonal antibodies against the S 
protein RBD (Polack, 2020) (Sadoff, 2021) (Jackson, 2020), and in phase 3 trials have shown over 
90% (Pfizer-BioNTech, Moderna) and over 60% (Janssen) efficacy in preventing symptomatic 
COVID-19 illness compared with placebo (Baden, 2020) (Polack, 2020) (Sadoff, 2021).  
Regeneron Pharmaceuticals, Inc. (Regeneron) has developed monoclonal antibodies (mAbs) 
directed against the RBD of the SARS-CoV-2 S protein. Casirivimab (REGN10933) and 
imdevimab (REGN10987) are human, IgG1 mAbs that bind simultaneously to the RBD and block 
interaction with ACE2. As a co-administered combination therapy, REGN10933+REGN10987 
(casirivimab+imdevimab; also referred to by the proprietary name conditionally accepted by the 
FDA, REGEN-COV™) is being evaluated for the treatment and prevention of SARS-CoV-2 
infection.  
REGN10933+REGN10987 exhibits potent SARS-CoV-2 neutralization in pseudovirus assays 
using wildtype Spike (Baum, 2020), and Spike sequences found in several variants of concern  
(UK B.1.1.7 [alpha], South Africa B.1.351 [beta], California B.1.429 [epsilon], India B.1.617.2 
[delta], and Brazil P.1 [gamma]) (REGEN-COV™ (casirivimab and imdevimab) [HCP Fact 
Sheet], 2022) (Weinreich, 2020) . The REGN10933+REGN10987 antibodies have significantly 
diminished potency and are not expected to be active against the recent Omicron variant 
(REGEN-COV™ (casirivimab and imdevimab) [HCP Fact Sheet], 2022).  
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The combination therapy is being evaluated for the treatment and prevention of SARS-CoV-2 
infection, and in phase 3 clinical trials was shown to be effective and well-tolerated in the treatment 
of outpatient and hospitalized adults with COVID-19, and in the prevention of SARS-CoV-2 
infection in adults and adolescents (Horby, 2021) (O’Brien, 2021a) (O’Brien, 2021b) 
(Weinreich, 2021b) (see Section 3.3.1 additional information). REGN10933+REGN10987 (1200 
mg IV or SC; 600 mg of each mAb) is currently authorized under EUA for the treatment of 
outpatients 12 years and older who are at high risk for developing severe COVID-19 
(FDA, 2020a).  
The Centers for Disease Control and Prevention (CDC) currently recommends deferring the 
receipt of a COVID-19 vaccine dose by 30 days following the use of passive antibody therapies 
for post-exposure prophylaxis and by 90 days following passive antibody therapies used for the 
treatment of COVID-19 (CDC, 2021). Currently, however, there are no published experimental 
data on potential pharmacodynamic interactions between anti-SARS-CoV-2 mAbs and COVID-
19 vaccines to inform this recommendation. Empirical assessment of the potential immunological 
impact of mAb administration on COVID-19 vaccination is thus urgently needed.  
This is a phase 2, randomized, open-label, parallel group study in healthy adult volunteers to assess 
the immunogenicity, safety, and tolerability of Moderna mRNA-1273 vaccine when administered 
with REGN10933+REGN10987. A central focus of the study will be to assess whether 
REGN10933+REGN10987 interferes with the ability of the Moderna mRNA-1273 vaccine to 
elicit neutralizing antibody titers against the SARS-CoV-2 S protein, and to gain a clearer 
mechanistic understanding of any observed alteration of vaccine-induced humoral and cellular 
immune responses to various S protein epitopes. The study is designed to replicate hypothetical 
clinical scenarios in which mAbs may be administered in conjunction with a COVID-19 vaccine, 
as well as simulate different time intervals between mAb and vaccine administration (using 
decreasing mAb dose concentrations as a proxy) to identify optimal dose timing in the event that 
interference with vaccine-induced immunity is observed. A detailed discussion of the rationale for 
the study design is provided in Section 3.2.  
Additional background information on REGN10933+REGN10987 and development program can 
be found in the Investigator’s Brochure. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The primary objectives of the study are:  
• To evaluate the extent of effect, if any, of REGN10933+REGN10987 administration 
on vaccine-induced neutralizing antibody responses to SARS-CoV-2 by Moderna 
mRNA-1273 
• To evaluate the time interval required between REGN10933+REGN10987 
administration and Moderna mRNA-1273 vaccination, to ensure no meaningful impact 
on vaccine-induced neutralizing antibody responses to SARS-CoV-2 
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2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To quantify the alteration of antigen specificity of vaccine-induced SARS-CoV-2 
antibody responses when administered with different dose regimens of 
REGN10933+REGN10987  
• To evaluate the safety and tolerability of REGN10933+REGN10987 and Moderna 
mRNA-1273 vaccine when administered in close succession 
• To assess the concentrations of REGN10933 and REGN10987 in serum over time in 
subjects who receive REGN10933+REGN10987 and Moderna mRNA-1273 vaccine 
• To evaluate the immunogenicity of REGN10933 and REGN10987 over time 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To explore circulating T cell and B cell responses to SARS-CoV-2 antigens in subjects 
who receive both REGN10933+REGN10987 and Moderna mRNA-1273 vaccine 
versus those who receive the vaccine alone 
• To explore the impact of REGN10933+REGN10987 as measured by the induction of 
vaccine-induced binding antibodies to SARS-CoV-2 receptor-binding domain (RBD) 
antigens post-Moderna mRNA-1273 vaccination that compete with the same epitopes 
recognized by REGN10933 and/or REGN10987 
• To explore how REGN10933+REGN10987 alters vaccine-induced neutralizing 
antibody responses, induced by Moderna mRNA-1273 vaccine, against SARS-CoV-2 
variants 
• To characterize viral variants by sequencing SARS-CoV-2 in subjects who become 
infected post-baseline  
• To explore the impact on vaccine responses and the mechanism of action of 
REGN10933+REGN10987 as measured by experimental laboratory assays and 
biomarkers after vaccination with Moderna mRNA-1273  
• To explore biomarkers and genomic factors associated with safety and immune 
responses after exposure to REGN10933+REGN10987 and Moderna mRNA-1273 
• To assess immune responses in subjects who receive booster vaccinations during the 
study 
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3. 
HYPOTHESES AND RATIONALE 
3.1. 
Hypotheses 
The clinical hypotheses of the study are that (1) REGN10933-REGN10987 does not alter the 
immunogenicity of Moderna mRNA-1273 vaccine and (2) REGN10933+REGN10987 and 
Moderna mRNA-1273, when administered in close succession, are well tolerated. 
There is no statistical hypothesis in this descriptive study (Section 11.1). 
3.2. 
Rationale 
3.2.1. 
Rationale for Study Design 
3.2.1.1. 
Primary Objectives: Potential Alteration of Endogenous Immune Responses 
Monoclonal antibody therapies such as REGN10933+REGN10987 will continue to play an 
important role in COVID-19 treatment and/or prevention, even as COVID-19 vaccination becomes 
more widespread. There is a theoretical risk, however, that mAb treatments may alter the vaccine-
induced immune responses, by binding to and thereby blocking key antigenic determinants that 
generate protective immunity. The primary objective of this study is thus to understand whether 
REGN10933+REGN10987, when administered in the setting of treatment or prevention of 
COVID-19, will alter the response to COVID-19 vaccines such as Moderna mRNA-1273. 
To accomplish the primary study objective, REGN10933+REGN10987 will be evaluated using 
dose levels that have either been authorized under EUA for the treatment of COVID-19 and/or for 
which clinical trial data indicate efficacy in treating or preventing COVID-19 (Section 3.2.2). The 
study is thus designed to mirror hypothetical clinical ‘use case’ scenarios, for which the two 
administration modalities of REGN10933+REGN10987 may be employed in close proximity to 
COVID-19 vaccination or mimic waiting for vaccination for up to 6 months after a 1200 mg dose 
of REGEN-COV.  
For the hypothetical treatment use case (ie, administration of REGN10933+REGN10987 1200 mg 
IV in a SARS-CoV-2-positive individual, followed by subsequent vaccination against future 
infection), Moderna mRNA-1273 will be administered 14 days after intravenous 
REGN10933+REGN10987. The use of an intervening period of time is based on public health 
recommendations to avoid COVID-19 vaccination during an active SARS-CoV-2 infection. The 
14-day 
interval 
was 
selected 
to 
ensure 
adequate 
time 
for 
the 
distribution 
of 
REGN10933+REGN10987 from the plasma compartment into tissues.  
For the hypothetical prophylaxis use case (ie, administration of REGN10933+REGN10987 1200 
mg SC in a SARS-CoV-2-negative individual for short-term protection against exposure, with 
administration of COVID-19 vaccination for long-term protection), REGN10933+REGN10987 
will be administered on the same day as Moderna mRNA-1273. Simultaneous administration of 
both antibody therapy and vaccination has been used as effective post-exposure prophylaxis for 
several pathogens, including rabies virus and hepatitis A virus (Manning, 2008) (Nelson, 2018). 
In addition to the above use case scenarios, the study will evaluate endogenous immune responses 
over time when 1200 mg IV of REGN10933+REGN10987 is administered 6 days after the first 
dose of Moderna mRNA-1273 (ie, study day 7). This interval was chosen to allow adequate 
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production and presentation of S protein antigens following vaccination and is thus intended to 
represent a scenario in which the immune system is “primed” prior to treatment with 
REGN10933+REGN10987. 
This 
will 
allow 
for 
assessment 
of 
safety 
of 
REGN10933+REGN10987 administration in close temporal proximity to vaccination. In the event 
REGN10933+REGN10987 is found to interfere with the endogenous immune response to 
vaccination when given prior to or concomitantly with vaccination, this will allow assessment of 
whether, in the prophylaxis setting, vaccination prior to REGN10933+REGN10987 administration 
will allow high risk subjects to receive both long term and short term protection from vaccination 
and REGN10933+REGN10987 administration followed shortly thereafter.  
3.2.1.2. 
Primary Objectives: Exploration of Time Intervals 
It is anticipated that REGN10933+REGN10987 will not alter the generation of endogenous, 
protective immune responses to Moderna mRNA-1273 vaccination. Vaccine responses are 
polyclonal, and the presence of mAb therapeutics may not alter neutralizing Ab generation to all 
S-protein epitopes. Additionally, we anticipate that presentation of peptides for T-cell priming will 
not be affected by mAb therapeutics. Finally, preliminary observations from subjects with SARS-
CoV-2 infection in treatment trials of REGN10933+REGN10987 have demonstrated intact IgG 
responses to SARS-CoV-2 antigens.  
However, it is possible that mAbs could meaningfully alter immune responses to vaccination. In 
light of this possibility, the other primary objective of this study is to understand the optimal time 
interval between mAb therapeutics and COVID-19 vaccinations. As a precautionary measure, 
the CDC has recommended a 90-day deferral period prior to vaccination in those who have 
received passive antibody therapy for COVID-19 treatment. The CDC has also recommended a 
30-day deferral period prior to vaccination in those who have received passive antibody therapy 
for post-exposure prophylaxis. These recommendations were based on the estimated half-life of 
such products and the anticipated period of protection against infection when receiving anti-SARS-
CoV-2 monoclonal antibodies for post-exposure prophylaxis or reinfection when receiving passive 
antibody therapy for treatment (CDC, 2021).  
In this study, several additional doses levels below 1200 mg will be administered at day 1 (Figure 1 
and Table 2). Sequentially lower dose levels were chosen as a means to vary the concentration of 
REGN10933+REGN10987 that exists at the time of Moderna mRNA-1273 vaccination. This 
method is intended to simulate various time intervals that could occur between administration of 
REGN10933+REGN10987 at 1200 mg and vaccination with Moderna mRNA-1273. This 
approach – altering the dose level rather than the time interval – was selected because 
REGN10933+REGN10987 concentration (and not time) is the key factor impacting the likelihood 
of altering vaccine responses. Moreover, the approach is operationally more feasible, and (by 
avoiding the need to test variable and potentially lengthy time intervals) lowers the likelihood of 
subjects becoming exposed to SARS-CoV-2 exposure during the study, which would confound 
the interpretation of results. Additional information regarding the selection of dose levels in this 
study is provided in Section 3.2.2. 
Taken together, the primary objectives in this study are intended to provide information that 
may guide physicians and public health agencies in making evidence-based recommendations on 
the usage of the 
Moderna mRNA-1273 COVID-19 vaccine in 
the setting of 
REGN10933+REGN10987 therapy or prevention. As COVID-19 vaccines employing S protein 
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neutralization as their mode of action are likely to produce comparable antibody responses and 
protective immunity (an assumption supported by some initial experimental data for some vaccines 
(Garcia-Beltran, 2021) it is anticipated that the data generated from this study can potentially be 
extrapolated to the general case of S-protein-based COVID-19 vaccines given in the setting of 
mAbs targeting the S protein RBD.  
3.2.1.3. 
Selection and Interpretation of Primary Endpoint 
Although quantitative correlates of protective immunity against SARS-CoV-2 are not yet 
established, the presence of serum neutralizing antibodies has been shown to correlate with 
protection from viral reinfection for other respiratory viruses, including influenza virus 
(Verschoor, 2015) and respiratory syncytial virus (Kulkarni, 2018). Neutralizing antibody titers 
are accepted as a general functional biomarker of the endogenous ability to block viral infection 
of target cells in vivo (Jackson, 2020). In the absence of clear correlates of vaccine-induced 
protection against COVID-19, reduced neutralization can serve as a useful benchmark to interpret 
any observed impact of mAb therapy on the development of an immune response to Moderna 
mRNA-1273 vaccine. Accordingly, the primary objective will be assessed by quantifying 
endogenous neutralizing antibody titers following vaccination administered with or without 
REGN10933+REGN10987. While the threshold of SARS-CoV-2-neutralizing antibody titers 
associated with meaningful clinical efficacy in treating or preventing COVID-19 are currently 
unknown, this study is designed with a sufficient sample size to provide a minimal detectable 
difference of 0.15 log (refer to Section 11.2). This precision is considered adequate to meet the 
aims of this phase 2 study (ie, to both quantify the magnitude of effect for the primary endpoint 
and to allow assessment of the safety and tolerability of the Moderna mRNA-1273 vaccine when 
administered with REGN10933+REGN1098). 
The primary endpoint will be assessed during the vaccine response assessment period, which 
includes the first 56 days after the first dose of Moderna mRNA-1273 (Section 4.1 and 
Section 6.1.1). SARS-CoV-2-neutralizing antibodies induced by Moderna mRNA-1273 vaccine 
can be detected as early as 2 weeks after the first vaccine dose, with titers peaking on day 36 (35 
days after the first dose and one week after the second dose of the vaccine), and remaining at peak 
levels at day 57 and day 119 (pseudovirus serum neutralizing infectious dose 50 [ID50] titers 
between 256 to 1024) (Jackson, 2020) (Widge, 2021). Assessing the primary endpoints after 56 
days of the first dose of vaccine will thus maximize the ability to detect the effect of mAb 
administration on vaccine responses (Jackson, 2020). Additional analyses of neutralizing antibody 
titers at approximately 6 months, 9 months, and 1 year after vaccine administration will assess 
long-term/memory immune response to SARS-CoV-2 following vaccination with Moderna 
mRNA-1273. 
An open-label design was chosen for this study, as it is considered appropriate and sufficient for 
achieving the primary objective, as well as the other pharmacodynamic objectives, of the study.  
3.2.1.4. 
Selection of Moderna mRNA-1273 for Vaccine Response Analysis 
The primary aim of this study is to evaluate the impact of REGN10933+REGN10987 on the 
induction of endogenous neutralizing immune responses to Moderna mRNA-1273. Moderna 
mRNA-1273 COVID-19 vaccine has demonstrated sufficient safety, tolerability and efficacy to 
receive EUA for active immunization against SARS-CoV-2 in individuals ≥18 years of age 
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(Moderna COVID-19 Vaccine [HCP Fact Sheet], 2022). The vaccine was shown to elicit robust, 
dose-dependent neutralizing titers against full-length S protein and against the S protein RBD, 
when measured using a pseudotyped lentivirus (PsVNA) assay (Jackson, 2020), and in a phase 3 
study of 30,420 volunteers, reduced the rates of symptomatic COVID-19 illness by over 90% 
compared to placebo (Baden, 2020). The robust neutralizing titers observed in clinical studies are 
anticipated to provide an opportunity for evaluating any impact of REGN10933+REGN10987 on 
immune response to vaccine. Any alteration of neutralization that may be observed in this trial will 
require further study. 
3.2.1.5. 
Selection of Neutralizing Titer Assay 
Serum neutralizing titers to Moderna mRNA-1273 vaccine will be assessed by a recombinant 
Vesicular Stomatitis Virus (rVSV) encoding SARS-CoV-2 S protein-based method 
(Vandergaast, 2020), similar to the assay reported in published reports of mRNA-1273 vaccine 
(Jackson, 2020) (Widge, 2021). The assay will be further validated with an additional anti-idiotype 
antibody step to block interference of REGN10933+REGN10987 in the measurement of the 
endogenous response to the vaccine. The impact of REGN10933+REGN10987 neutralizing Ab 
responses to S proteins from other viral variants may also be studied, if assays become available.  
3.2.1.6. 
Secondary and Exploratory Analyses of Immune Response 
It is possible that exogenous mAb treatments could skew or otherwise alter the antigen specificity 
of endogenous antibody responses elicited by Moderna mRNA-1273 vaccine. SARS-CoV-2 
binding antibody assessments to S-protein trimer and S1 RBD will be performed using a Meso 
Scale Diagnostics (MSD) kit that has been used to measure neutralizing antibody responses in 
Phase 3 vaccine trials with Moderna mRNA-1273. The assay will be adapted with an anti-idiotype 
step to block the interference of REGN10933+REGN10987 with the measurement of endogenous 
antibodies.  
In order to fully characterize the possible effects of REGN10933+REGN10987 on immune 
responses to Moderna mRNA-1273, we will evaluate cellular immune responses. Additional 
exploratory assays may be used to measure immunoglobulin titers to specific SARS-CoV-2 
antigens (such as further epitope mapping of endogenous vaccine response) following vaccination. 
Similarly, B-cell responses following vaccination could reveal subtle immunologic effects of mAb 
therapy on vaccine response. To this end, the study will explore circulating B cell response specific 
to SARS-CoV-2 S trimer protein, RBD, and other spike subdomains. Additional analyses of T cell 
immune responses to Moderna mRNA-1273 in the presence of REGN10933+REGN10987 will 
also be performed and may reveal important mechanistic insights into any observed immune 
interaction.  
Although the global emergence of variants has occurred only relatively recently in the history of 
the pandemic, emerging data suggest that they pose a significant threat to the clinical efficacy of 
some vaccines and therapies (AstraZeneca, 2021) (FDA, 2021). Recent evidence suggests that 
neutralizing humoral immunity induced by Moderna mRNA-1273 vaccination is reduced against 
specific SARS-CoV-2 variants (ie, B.1.351) (Garcia-Beltran, 2021). In this study, exploratory 
studies may be conducted to understand if REGN10933+REGN10987 alters the neutralization 
capacity seen with these viral variants after vaccination. 
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3.2.1.7. 
Study Population  
The population for this study includes healthy volunteers who are both seronegative and RT-PCR 
negative for SARS-CoV-2 at screening/baseline, as this will maximize the ability to measure any 
effects of REGN10933+REGN10987 on immune responses to Moderna mRNA-1273 vaccine. 
Randomization will be stratified by age (<65 years versus ≥65 years), as older individuals may be 
less likely to have robust humoral immunity following vaccination and more likely to benefit from 
mAbs in the prevention or treatment of COVID-19.  
3.2.1.8. 
Safety and Tolerability 
REGN10933+REGN10987, when given concomitantly or in temporal proximity to Moderna 
mRNA-1273, is reasonably expected to be well-tolerated in healthy volunteers (see Section 3.1). 
Nevertheless, this study will evaluate safety and tolerability of REGN10933+REGN10987 and 
Moderna mRNA-1273, including assessment of IRR (REGN10933+REGN10987) as well as ISR 
and hypersensitivity reactions (REGN10933+REGN10987 and Moderna mRNA-1273; see 
Section 4).  
As a precautionary safety measure, a follow-up phone call will be made within 24 hours after study 
drug and vaccine administration, for subjects receiving these concomitantly (see Section 9.2.2). 
3.2.1.9. 
Use of Enrollment Waves 
During the screening/baseline period, subjects will be assigned by each site to different enrollment 
waves, which are used to group study arms. The enrollment waves are staggered (eg, effort should 
be done so that study day 15 for wave 1 should occur on the same day as study day 1 for wave 2; 
see Figure 2). The primary intent of this staggering is to increase the number of study subjects who 
can be scheduled for vaccination on the same day at each site, and thus avoid or minimize the 
potential for unused doses of COVID-19 vaccine.  
Although assignment to enrollment waves will be performed by the sites, assignment to study arms 
within each wave will occur via randomization. To minimize the potential for bias in study arm 
assignment, each wave will include a separate vaccine-only control arm, included as part of the 
randomization scheme. In addition, sites will be instructed to make every effort to balance 
assignment into each wave according to age, the baseline characteristic that is considered to have 
the greatest potential impact on susceptibility of mAb-mediated interference to vaccine response. 
Refer to Section 8.5 for additional information on site-managed assignment to enrollment waves 
and subsequent randomization to study arms. 
3.2.2. 
Rationale for Dose Selection 
This parallel group study will utilize 12 study arms, of which 8 will receive single-dose 
administration of REGN10933+REGN10987 and administration of the Moderna mRNA-1273 
COVID-19 vaccine (Figure 1) before, after or concurrently with REGEN-COV administration. 
Study arms 6a, 6b, 6c and 6d will only receive the vaccine. 
For all study arms that include IV administration of REGN10933+REGN10987 followed by 
Moderna mRNA-1723, a 14-day interval was chosen to ensure that mAb concentrations in serum 
are in the post-distribution phase, and therefore representative of concentrations in equilibrium 
with relevant peripheral tissues (ie, the site of a potential immune interaction). 
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Figure 1: 
Dose Administration by Study Arm  
 
3.2.2.1. 
Study Arm 1 and Arm 9 (1200 mg IV)  
REGN10933+REGN10987 1200 mg IV (600 mg per mAb) was selected as a potential use case 
scenario based on clinical efficacy data in treatment of COVID-19 (Section 3.3.1).  
The rationale for study arm 9 (administration of REGN10933+REGN10987 after the first dose of 
Modern mRNA-1723 vaccine) is provided in Section 3.2.1.1. 
3.2.2.2. 
Study Arm 2 (300 mg IV), Arm 3 (150 mg IV), Arm 7 (48 mg IV), and Arm 8 (12 
mg IV) 
As outlined in Section 3.2.1.3, one of the primary objectives of this study is to identify time 
intervals between administration of REGN10933+REGN10987 and Moderna mRNA-1273 that 
may mitigate any observed potential alteration of vaccine efficacy, and to utilize various dose 
levels as a means of simulating these time intervals. To this end, a preliminary population 
pharmacokinetics (PopPK) model was developed based on available REGN10933 and 
REGN10987 concentration data from studies COV-2067 and COV-2069. The PopPK model was 
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used to determine dose levels of REGN10933+REGN10987 that would achieve concentrations in 
serum on study day 15 (when Moderna mRNA-1723 is administered), that approximate particular 
time intervals following a 1200 mg IV dose (Section 3.2.1.2).  
Table 1 provides the estimated time intervals for each of the study arms used for these anchoring 
analyses. As an example of this simulation, 300 mg IV of REGN10933+REGN10987 administered 
on day 1, followed by the administration of the first dose of Moderna mRNA-1723 on day 15, 
simulates a scenario in which an individual receives a single 1200 mg IV dose of 
REGN10933+REGN10987, and then begins their vaccination with Moderna mRNA-1723 
approximately 60 days later. 
Table 1: 
Population Pharmacokinetics Modeling of Simulated Study Days Following 
1200 mg IV Dose 
REGN10933+REGN10987 Dose 
Administered 
Study Day of First Moderna 
mRNA-1723 Dose 
Simulated Study Day Following 
1200 mg IV Dose 
300 mg IV (150 mg per mAb) 
15 
57 
150 mg IV (75 mg per mAb) 
15 
85 
48 mg IV (24 mg per mAb) 
15 
113 
12 mg IV (6 mg per mAb) 
15 
169 
 
3.2.2.3. 
Study Arm 4 (1200 mg SC) and Arm 5 (600 mg SC) 
REGN10933+REGN10987 1200 mg SC (600 mg per mAb) was selected as a potential use case 
scenario based on clinical efficacy data in prevention of COVID-19. The 600 mg SC (300 per 
mAb) dose was also chosen as a potential use case, based on virologic efficacy observed at that 
dose level (Section 3.3.1). The rationale for concomitant administration of vaccine is provided in 
Section 3.2.1.1. 
3.3. 
Risk-Benefit 
Risk-benefit is provided separately for REGN10933+REGN10987 (Section 3.3.1), Moderna 
mRNA-1273 vaccine (Section 3.3.2), and REGN10933+REGN10987 administered with 
COVID-19 vaccines (Section 3.3.3). 
3.3.1. 
Risk-Benefit for REGN10933+REGN10987 
The anticipated risks and benefits of casirivimab and imdevimab are informed by pre-clinical and 
clinical data, including data from phase 3 trials. For additional information concerning clinical and 
pre-clinical data, refer to the Investigator’s Brochure. 
Intravenous Administration of Casirivimab+Imdevimab in Clinical Trials. In COV-2067, the 
phase 3 outpatient treatment trial, a single intravenous dose of casirivimab and imdevimab was 
shown (relative to placebo) to reduce COVID-19-related hospitalizations or all-cause death by 
71.3% (2400 mg dose) and 70.4% (1200 mg dose), reduce symptom duration by 4 days (2400 mg 
and 1200 mg), and reduce viral load over the first 7 days. Serious adverse events occurred more 
frequently in the placebo group (4.0%) than in either treatment group (2400 mg, 1.1%; 1200 mg, 
1.3%), and grade ≥2 infusion-related reactions were infrequent (<0.3% in all groups) 
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(Weinreich, 2021b). Similar virologic efficacy and a similar safety profile were observed in the 
phase 1/2 portion of this trial, which evaluated casirivimab and imdevimab at 8000 mg and 2400 
mg IV doses (Weinreich, 2021a). 
Subcutaneous Administration of Casirivimab+Imdevimab in Clinical Trials. In COV-2069, 
the phase 3 prevention trial in those at high risk of infection by a household contact, a single 
subcutaneous dose of casirivimab and imdevimab (1200 mg) reduced (relative to placebo) 
symptomatic SARS-CoV-2 infection by 81.4%, and reduced overall SARS-CoV-2 infection by 
66.4%. Serious adverse events occurred at similar frequencies in the treatment group (1%) and 
placebo group (1%). Injection-site reactions were more common in the treatment group (4%) 
compared to the placebo group (2%), but no injection-site reactions in the study were grade 3 or 
above. The majority of injection site reactions occurred within one day and resolved within two 
days (O’Brien, 2021b).  
Among a sub-group of individuals in COV-2069 who were identified as SARS-CoV-2 positive 
but asymptomatic during screening, a single subcutaneous dose of casirivimab and imdevimab 
(1200 mg) reduced (relative to placebo) progression to symptomatic disease by 31.5%, and 
reduced the duration of symptoms in those that developed symptomatic infections. Injection-site 
reactions were more common in the treatment group (4%) compared to the placebo group (1%), 
but no injection-site reactions in the study were grade 3 or above (O’Brien, 2021a).  
In COV-2069, efficacy results were similar in adolescents (age 12 to <18) as observed in adults: 
0% of subjects in the 1200 mg SC treatment group experienced symptomatic infection, compared 
with 9.3% of subjects in the placebo group. Safety data in adolescent subjects were also similar to 
that observed in adults. Injection site reactions were more common in the treatment group (5.9%) 
compared to the placebo group (1.6%), but none were grade 3 or above in any group.  
In COV-2093, the adult volunteer study evaluating multiple doses of subcutaneous administration 
of casirivimab+imdevimab (monthly dosing over 6 months), injection site reactions were more 
common in the casirivimab and imdevimab group (34.6%) compared with the placebo group 
(15.8%), but none were grade 3 or above in any group. 
Identified Risks. As with other protein therapeutics, hypersensitivity reactions, including acute 
infusion-related reactions (IV administration) or injection site reactions (SC administration), may 
develop after study drug administration. Hypersensitivity reactions, including anaphylaxis, 
infusion-related reactions or injection site reactions, have been observed in patients who received 
REGN10933+REGN10987. 
Potential or Theoretical Risks. The important potential risks of REGN10933+REGN10987 are 
the clinical consequences of immunogenicity, embryo-fetal toxicity and antiviral resistance. 
Protein therapeutics carry the potential risk of an immunogenic response in the form of anti-drug 
antibody (ADA) and neutralizing antibody (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, 
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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 females who are pregnant or breastfeeding. 
The combination of REGN10933+REGN10987 therapy should be used during pregnancy or 
breastfeeding only if the potential benefit justifies the potential risk for the mother and the fetus or 
breastfed child considering all associated health factors. If a female subject 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.  
REGN10933+REGN10987 combination therapy was strategically designed to be a combination 
therapy of 2 non-competing antibodies that can simultaneously bind distinct epitopes of the SARS-
CoV-2 S protein to reduce the likelihood of antiviral resistance and provide coverage against 
circulating variants. However, there is a potential risk of treatment failure due to circulating or 
treatment-emergent SARS-CoV-2 variants that are resistant to REGN10933+REGN10987 
combination. 
Ongoing sequencing analyses of nasopharyngeal swab samples from sponsor-conducted clinical 
studies have found no evidence that the clinical use of REGN10933+REGN10987 leads to the 
selection of escape (treatment emergent) variants in REGN10933+REGN10987-binding epitopes, 
within the RBD, or other regions of the S protein.  
The in vitro neutralization potency of REGN10933+REGN10987 and its individual components 
is continuously monitored against S protein variants, including VUS, variants identified in in vitro 
escape studies, and variants from publicly available SARS-CoV-2 genome data (eg, GISAID). 
REGN10933+REGN10987 demonstrates in vitro neutralization activity below the limit of 
quantitation against the Omicron variant, and it is unlikely that REGN10933+REGN10987 will be 
active against this variant. However, REGN10933+REGN10987 retains activity against the Alpha, 
Beta, Gamma, Delta, Epsilon, Iota, Kappa, and Mu variants. It is not known how in vitro 
neutralization data correlate with clinical outcomes.  
Decisions regarding the use of REGN10933+REGN10987 should take into consideration what is 
known about the characteristics of circulating variants including regional or geographical 
differences and available information on REGN10933+REGN10987 susceptibility patterns. 
There may also be a potential for the REGN10933+REGN10987 combination to interfere with an 
individual’s endogenous immune response to either SARS-CoV-2 infection or to effectiveness of 
vaccination against COVID-19. Refer to Section 3.3.3 for more information. 
Antibody-dependent enhancement (ADE) has been observed for some therapeutics targeting 
exogenous viral proteins. For antibody therapies, ADE is thought to occur when binding of 
antibody to the target viral protein enhances Fc gamma receptor (FcγR)-mediated host cell entry 
of the virus (Iwasaki, 2020). This could potentially lead to worsening of disease and, in the case 
of SARS, acute lung injury (Liu, 2019). REGN10933 and REGN10987 retain the Fc region, as 
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this may play a role in protecting against viral infection (Yasui, 2014), and 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 subjects receiving REGN10933+REGN10987 will have safety follow-up 
assessments during the drug elimination period. 
3.3.2. 
Risk-Benefit for Moderna mRNA-1273 Vaccine 
Always refer to the latest EUA Fact Sheet (Moderna COVID-19 Vaccine [Patient Fact Sheet], 
2022)  . Information from the current version of the Fact Sheet (dated 07 January 2022) is provided 
below: 
Benefit. In an ongoing clinical trial, Moderna mRNA-1273 vaccine has been shown to prevent 
COVID-19 following 2 doses given 1 month apart. The duration of protection against COVID-19 
is currently unknown. 
Risks.  
There is a remote chance that the Moderna COVID-19 Vaccine could cause a severe allergic 
reaction. A severe allergic reaction would usually occur within a few minutes to one hour after 
getting a dose of the Moderna COVID-19 Vaccine. For this reason, the vaccination provider may 
ask the vaccine recipients to stay at the place where they received the vaccine for monitoring after 
vaccination. Signs of a severe allergic reaction can include: 
• Difficulty breathing 
• Swelling of face and throat 
• A fast heartbeat 
• A bad rash all over body 
• Dizziness and weakness 
Myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the lining outside 
the heart) have occurred in some people who have received the Moderna COVID-19 Vaccine, 
more commonly in males under 40 years of age than among females and older males. In most of 
these people, symptoms began within a few days following receipt of the second dose of the 
Moderna COVID-19 Vaccine. The chance of having this occur is very low. The vaccine recipients 
should seek medical attention right away if they have any of the following symptoms after 
receiving the Moderna COVID-19 Vaccine: 
• Chest pain 
• Shortness of breath 
• Feelings of having a fast-beating, fluttering, or pounding heart 
Side effects that have been reported in a clinical trial with the Moderna COVID-19 Vaccine 
include: 
• Injection site reactions: pain, tenderness and swelling of the lymph nodes in the same 
arm of the injection, swelling (hardness), and redness 
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• General side effects: fatigue, headache, muscle pain, joint pain, chills, nausea and 
vomiting, fever and rash 
Side effects that have been reported during post-authorization use of the Moderna COVID-19 
Vaccine include: 
• Severe allergic reactions 
• Myocarditis (inflammation of the heart muscle) 
• Pericarditis (inflammation of the lining outside the heart) 
• Fainting in association with injection of the vaccine 
These may not be all the possible side effects of the Moderna COVID-19 Vaccine. Serious and 
unexpected side effects may occur. The Moderna COVID-19 Vaccine is still being studied in 
clinical trials. 
3.3.3. 
Risk-Benefit for REGN10933+REGN10987 Administered With COVID-19 
Vaccines  
To date, REGN10933+REGN10987 has not been studied systematically in the clinical 
development program with respect to concomitant (or temporally proximal) administration with 
vaccines (COVID-19 or otherwise). There are currently no published data on the safety and 
efficacy of COVID-19 vaccines in persons who received monoclonal antibodies as part of 
COVID-19 treatment. However, in a study of healthy adult subjects who received multiple SC 
doses of REGN10933+REGN10987 (R10933-10987-HV-2093), 54 subjects were noted (in 
blinded analysis) to have COVID-19 vaccination in close temporal proximity to study drug 
administration and thought to still be in therapeutic range for REGN10933+REGN10987. In this 
subset of subjects, no SAEs or hypersensitivity reactions were reported post vaccination. Similarly, 
study R10933-10987-COV-2069 (COV-2069) is a phase 3 randomized placebo-controlled trial 
assessing the safety and efficacy of REGN10933+REGN10987 in preventing COVID-19 after 
high risk exposure. During this study, 99 subjects received COVID-19 vaccination with few 
reported AE and no SAEs or hypersensitivity reactions. Although HV-2093 and COV-2069 were 
not systematically designed studies to assess vaccine-drug interaction, these results suggest that 
REGN10933+REGN10987 administered with a COVID-19 vaccine is reasonably expected to be 
well-tolerated in healthy adult subjects. 
Little or no impact is anticipated on the safety profile of the REGN10933+REGN10987 
combination when COVID-19 vaccine is given concomitantly or in temporal proximity, although 
safety and tolerability will nevertheless be evaluated in this study. Similarly, this study will also 
evaluate if concomitant administration (or administration in temporal proximity) may impact 
efficacy of COVID-19 vaccines to induce the desired immunologic response (positively or 
negatively). 
All risks described in the sections above for individual treatments (Section 3.3.1 and Section 3.3.2) 
are considered relevant for the administration of REGN10933+REGN10987 and Moderna mRNA-
1273 vaccine concomitantly or in temporal proximity. Theoretically, there may be a potential for 
the REGN10933+REGN10987 combination to interfere with an individual’s endogenous immune 
response to either SARS-CoV-2 infection or vaccination against COVID-19 in such setting. The 
objective of this study is to determine if this theoretical risk is identified and, if so, to quantify the 
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risk. To mitigate the potential risk of such interference, an allowance is provided for subjects to 
receive additional vaccination if interference is identified (Section 6.1). Similarly, there could be 
risk of hypersensitivity reactions when REGN10933+REGN10987 is administered within close 
proximity of Moderna mRNA-1273 vaccine. In this study, the risk of hypersensitivity will be 
monitored closely during study visits. Theoretical risk of ADE also remains applicable. However, 
currently ADE has not come up as a safety concern for REGN10933+REGN10987 in the long-
term safety follow-up in the ongoing clinical studies. We will continue to monitor ADE as a 
theoretical risk in this study like all other ongoing clinical studies. 
Summary. In summary, based on prior experience with other human mAbs against exogenous 
targets, the available preclinical data for REGN10933+REGN10987 to date, and the unmet need 
for a SARS-CoV-2 therapy that can be given concomitantly (or in temporal proximity) to COVID-
19 vaccination, it is the opinion of the Sponsor that the overall risk-benefit balance for 
REGN10933+REGN10987 given concomitantly with Moderna mRNA-1273 is acceptable to 
allow evaluation of this mAb combination in the adult population planned for this study. 
4. 
ENDPOINTS 
4.1. 
Primary Endpoints 
The primary endpoints are:  
• 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing antibodies to the 
SARS-CoV-2 S protein assessed 56 days after the first dose of Moderna mRNA-1273 
vaccine in individuals who receive high-dose (1200 mg) REGN10933+REGN10987 
compared to vaccine alone 
• 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing antibodies to the 
SARS-CoV-2 S protein assessed 56 days after the first dose of Moderna mRNA-1273 
vaccine 
in 
individuals 
who 
receive 
submaximal 
dose 
levels 
of 
REGN10933+REGN10987 (less than 1200 mg) compared to vaccine alone 
4.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Absolute values, change from baseline, and percentage change from baseline in 
concentrations of vaccine-induced antibodies to the following SARS-CoV-2 antigens 
over time: 
− Anti-S protein 
− Anti-RBD 
− Other S protein subdomains (including S1, S2, and NTD)  
• 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing antibodies to 
SARS-CoV-2 S protein assessed over time after the first dose of Moderna mRNA-1273 
vaccine 
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• Proportion of subjects with treatment-emergent adverse events (TEAEs) throughout the 
study  
• Proportion of subjects with treatment-emergent serious adverse events (SAEs) 
throughout the study 
• Proportion 
of 
subjects 
with 
infusion-related 
reactions 
(grade 
≥2) 
to 
REGN10933+REGN10987 through day 4 post-infusion 
• Proportion 
of 
subjects 
with 
injection 
site 
reactions 
(grade 
≥3) 
to 
REGN10933+REGN10987 or each dose of Moderna mRNA-1273 vaccine through day 
4 post-injection 
• Proportion 
of 
subjects 
with 
hypersensitivity 
reactions 
(grade 
≥2) 
to 
REGN10933+REGN10987 or each dose of Moderna mRNA-1273 vaccine through day 
29 post-infusion or post-injection (as applicable) 
• Concentrations of REGN10933 and REGN10987 in serum over time  
• Immunogenicity, as measured by anti-drug antibodies (ADA) and neutralizing 
antibodies (NAb) to REGN10933 and REGN10987 
4.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• Absolute percentages, change, and percentage change from baseline of blood-derived 
memory T cell responses specific to SARS-CoV-2 viral peptides over time 
• Absolute percentages, change, and percentage change from baseline of blood-derived 
B cell responses specific to SARS-CoV-2 S protein, RBD, and other S protein 
subdomains over time 
• Viral variant characteristics of SARS-CoV-2 in subjects who become infected 
post-baseline 
5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
medical history, and medication history for each subject. 
5.2. 
Pharmacodynamic and Other Biomarker Variables 
Primary, secondary, and exploratory endpoint variables may include, but are not limited to, the 
following: parameters reported in neutralization antibody titer assays to SARS-CoV-2 variants, 
binding antibody assays to SARS-CoV-2 antigens, virus-specific T cell and B cell assays, assays 
for detection of antibodies binding to RBD elicited post-vaccination that compete with 
REGN10933 and/or REGN10987, virology tests, and virus sequencing for variant determination. 
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5.3. 
Safety Variables 
Safety variables include recording, measurements, or laboratory test results for individual subjects 
of the following: Adverse events (AEs), vital signs (including temperature, blood pressure, heart 
rate, and respiratory rate), targeted physical examination findings, and results of laboratory tests 
(including hematology, blood chemistry, urinalysis, and pregnancy test). 
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 the Schedules of Events (Section 9.1). 
5.5. 
Immunogenicity Variables 
The study drug immunogenicity variables are ADA status, titer, NAb status, and time point/visit. 
Samples will be collected at the visits specified in the Schedules of Events (Section 9.1). 
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6. 
STUDY DESIGN 
This study is a phase 2, randomized, open-label, parallel group study in healthy adult volunteers 
to assess the immunogenicity, safety, and tolerability of Moderna mRNA-1273 vaccine when 
administered with REGN10933+REGN10987.  
6.1. 
Study Description and Duration 
The study consists of 3 periods: a screening/baseline period, a vaccine response assessment period, 
and a follow-up period. The study design is depicted in Figure 2 and Figure 3; study treatment 
assignment is depicted in Figure 1. The Schedules of Events can be found in Table 3 (enrollment 
wave 1 [study arms 1, 2, 3, and 6a] and enrollment wave 3 [arms 7, 8, and 6c]), Table 4 (enrollment 
wave 2 [study arms 4, 5, and 6b]), and Figure 3 (enrollment wave 4 [arms 9 and 6d]).  
Subjects will be assessed for eligibility during the screening/baseline period, which may occur 
up to 21 days prior to day 1. To be eligible for the study, subjects must be confirmed negative for 
current or past SARS-CoV-2 infection by both RT-PCR and serology tests (refer Section 7.2.2 for 
exclusion criteria).  
During this period, subjects will also be assigned to an enrollment wave, as described in 
Section 8.5).  
On day 1, eligible subjects will be randomized to a study arm (1 of 12) within their assigned 
enrollment wave. Subjects randomized to study arms 1 through 5 or 7 through 9 will receive an IV 
infusion or SC injection of the study drug (REGN10933+REGN10987) on day 1 or day 7. Subjects 
in arms 6a to 6d (the control arms) will not receive any study drug. The first dose of the vaccine 
will be administered on day 1 or day 15, based on study arm assignment at randomization 
(Figure 1).  
All subjects will receive the second dose of the vaccine 28 days after their first dose of the vaccine 
in accordance with the EUA Fact Sheet (Moderna COVID-19 Vaccine [HCP Fact Sheet], 2022) 
(refer to Section 3.2.1 for rationale). Refer to Section 8.5 for more information on dose levels and 
timing of administration. 
The vaccine response assessment period represents the time period of the primary analysis 
(Section 4.1). For study arms 1, 2, 3, 7, 8, 6a, and 6c, this period includes up to study day 71; for 
study arms 4, 5, 9, 6b, and 6d, the period includes up to day 57. Following this assessment period, 
subjects will enter a follow-up period lasting up to 10 months. 
Throughout the study, blood samples will be collected to assess whether the study drug impacts 
the ability of the vaccine to elicit neutralizing antibody titers against the SARS-CoV-2 S protein, 
and to understand any impact on vaccine-induced humoral and cellular immune responses to 
various S protein epitopes. Additional details are provided in Section 9.2.3. 
Subjects will also have blood samples taken at select visits for drug concentration, 
immunogenicity, and exploratory analyses, and will be monitored for AEs (including AESIs) 
during in-person visits (refer to Section 10.1 for recording and reporting requirements). For 
subjects in study arms 4 and 5 (receiving the study drug and vaccine on the same day), a phone 
call will be made within 24 hours following study drug and vaccine administration on day 1 for 
AE collection.  
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The last study visit will take place approximately 1 year after the first dose of the vaccine. 
Vaccine booster sub-study.  All subjects who have not already received the COVID-19 vaccine 
booster will be offered an optional booster vaccination dose ≥5 months after completing the 
primary COVID-19 vaccination series and >35 days (ie, until study day 345 for subjects in arms 
1, 2, 3, 6a, 6c, 7 and 8 and until study day 331 for subjects in arms 4, 5, 6b, 6d and 9) before the 
end of the main study. Blood samples for possible analysis will be collected pre- and post-booster 
administration.
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Figure 2: 
Study Flow Diagram (Enrollment Waves 1 and 2) 
 
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Figure 3: 
Study Flow Diagram (Enrollment Waves 3 and 4) 
 
 
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6.1.1. 
Risk Minimization for SARS-CoV-2 Infection and Transmission 
To minimize the risk of acquiring or transmitting SARS-CoV-2 infection during the study, subjects 
will be asked to comply with all precautionary measures related to COVID-19 stipulated within 
site policies and local public health guidelines or requirements.  
Subjects will be provided with contact information for the clinical study site and will be given 
written and verbal instructions to call site personnel with any changes in their health status. They 
will be asked to promptly notify site personnel by phone of any positive SARS-CoV-2 testing 
results or symptoms/signs potentially related to COVID-19. Subjects presenting with acute illness 
should be medically managed according to local standard of care and per the discretion of the 
treating physician. Refer to Section 8.3.3 for additional guidance concerning COVID-19 vaccine 
deferral or discontinuation.  
Subjects with laboratory confirmed SARS-CoV-2 infection should be informed as soon as 
possible, and should undergo medical isolation per local guidelines and CDC guidance on medical 
isolation (CDC, 2021) , to prevent contact with others and reduce the risk of further transmission. 
6.1.2. 
Sample Collection and Visit Scheduling for Subjects with Suspected COVID-19 
Symptoms or Positive SARS-CoV-2 Test 
For subjects with signs or symptoms consistent with COVID-19, or those who obtain a positive 
SARS-CoV-2 RT-PCR test result from another testing location, every effort should be made to 
obtain a sample for SARS-CoV-2 rapid RT-PCR testing as soon as possible, either during an 
unscheduled visit or during a planned schedule visit (whichever is sooner). All subjects with 
suspected COVID-19 or laboratory-confirmed SARS-CoV-2 infection will continue to follow their 
respective Schedule of Events (Section 9.1), as feasible according to local guidelines, site policies, 
and/or CDC guidance on medical isolation (CDC, 2021) . Every effort should be made to obtain 
subsequent rapid RT-PCR testing samples as indicated in the Schedule of Events as feasible 
according to local guidelines, site policies, and/or CDC guidance on medical isolation 
(CDC, 2021) . Every effort should be made to obtain subsequent rapid RT-PCR testing samples as 
indicated in the Schedule of Events. These samples will be banked for viral sequencing. 
6.1.3. 
Study Stopping Rules 
A Regeneron team will monitor the safety data on an ongoing basis to assess the risk-benefit profile 
of REGN10933+REGN10987 administered with Moderna mRNA-1273 vaccine. The team may 
be comprised of the medical/study director, a Global Patient Safety representative, representatives 
from Biostatistics and Data Management, Clinical Operations, and Regulatory Affairs.  
The monitoring team will also include at least 2 medical officers from the National Institutes of 
Health (NIH). One officer will serve as the primary representative, with a second officer serving 
as an alternate representative as needed. 
If there are significant safety concerns, a recommendation may be made to temporarily pause, alter, 
or terminate the study. Appropriate action, if needed, will be taken based upon this review and in 
consultation with Regeneron Safety Oversight Committee (RSOC), which will include senior 
clinical, regulatory, and pharmacovigilance leaders at Regeneron. Applicable regulatory 
procedures will be adhered to as required by local laws in relation to any decisions related to a 
change in study conduct, temporary halt, study termination, or study restart. 
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Reasons for premature withdrawal from the study are described in Section 7.3. Study drug and 
vaccine discontinuation rules are described in Section 8.3.2 and Section 8.3.3. 
6.1.4. 
End of Study Definition 
The end of study is defined as the date the last subject completes the last study visit, withdraws 
from the study, or is lost to follow-up (ie, the study subject can no longer be contacted by the 
investigator).  
6.2. 
Planned Interim Analysis 
Formal interim analysis may be conducted. The Sponsor may view and report on the data as it is 
accumulated. 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
SUBJECTS 
7.1. 
Number of Subjects Planned 
Up to approximately 286 subjects are planned to be enrolled. Refer to Section 11.2 for the 
justification of sample size. 
7.2. 
Study Population 
Eligible subjects for this study consist of healthy adult volunteers who are between 18 years to 90 
years of age (inclusive) who are negative at screening for both SARS-CoV-2 infection and 
endogenous anti-SARS-CoV-2 antibodies. 
Every effort should made to enroll older subjects, such that 30% to 50% of subjects enrolled at 
each site are ≥65 years of age. Efforts should also be made to enroll subjects representative of the 
demographics (eg, race and ethnic distribution) of those at risk for COVID-19 in the region where 
the study site is located.  
7.2.1. 
Inclusion Criteria  
A subject must meet the following criteria to be eligible for inclusion in the study: 
1. 18 years to 90 years of age (inclusive) at the signing of informed consent 
2. Healthy or has chronic medical condition(s) that is (are) stable and well-controlled in the 
opinion of the investigator and that are not likely to require significant medical intervention 
through the end of study 
3. Willing and able to comply with study visits and study-related procedures, including 
compliance with site precautionary requirements related to SARS-CoV-2 infection and 
transmission 
4. Willing and able to provide signed informed consent  
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7.2.2. 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Positive RT-PCR test result for SARS-CoV-2 infection at screening and/or baseline 
2. Positive serology test result for anti-SARS-CoV-2 antibodies at screening  
3. COVID-19 diagnosis, positive SARS-CoV-2 diagnostic test result, or positive SARS-CoV-
2 serology test result at any time prior to screening 
4. Previously received an investigational, authorized, or approved coronavirus vaccine (eg, 
SARS-CoV-2 vaccine, MERS-CoV vaccine) 
5. Currently enrolled in, or has plans to enroll in, any interventional study to prevent or treat 
COVID-19 
6. Received investigational or approved passive antibodies for SARS-CoV-2 infection 
prophylaxis (eg, convalescent plasma or sera, mAbs, hyperimmune globulin)  
7. Received intravenous immunoglobulin (IVIG) or blood products in the last 3 months 
8. Any physical examination findings and/or history of any illness that, in the opinion of the 
study investigator, might confound the results of the study or pose an additional risk to the 
subject by study participation  
9. History of clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematological, psychiatric or neurological disease, as assessed by the 
investigator, that may confound the results of the study or pose an additional risk to the 
subject by study participation 
10. Medically attended acute illness or hospitalization (ie, >24 hours) for any reason within 30 
days prior to screening 
11. History of heart failure hospitalization, diagnosis of a myocardial infarction, stroke, 
transient ischemic attack, unstable angina, percutaneous or surgical revascularization 
procedure (coronary, carotid, or peripheral vascular), or intracardiac device placement 
(eg, pacemaker) within 6 months prior to screening  
12. Abnormal blood pressure (BP) at screening visit, as defined by diastolic BP >100 mm Hg 
and/or systolic BP >160 mm Hg 
Note: Blood pressure measurements may be repeated once during screening 
13. Active bleeding disorder considered a contraindication to subcutaneous or intramuscular 
injection or phlebotomy 
14. Regular alcohol consumption consistent with alcohol dependence or addiction, in the 
opinion of the investigator 
15. Any malignancy within the past 5 years, except for basal cell or squamous epithelial cell 
carcinomas of the skin or carcinoma in situ of the cervix or anus, that have been resected, 
with no evidence of metastatic disease for 3 years 
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16. Immunosuppressive or immunodeficient state, asplenia or recurrent severe infections that, 
in the opinion of the investigator may confound the results of the study or pose an additional 
risk to the subject by study participation 
17. Received systemic immunosuppressants or immune-modifying drugs for >14 days in total 
within 6 months prior to screening (for corticosteroids, ≥20 mg/day of prednisone 
equivalent) 
18. History of significant multiple and/or severe allergies (eg, latex gloves), or has had an 
anaphylactic reaction to prescription or non-prescription drugs or food.  
19. Known allergy or hypersensitivity to components of the study drug or vaccine 
20. Treatment with another investigational drug within 30 days or 5 half-lives of the 
investigational drug, whichever is longer, prior to screening 
21. Member of the clinical site study team and/or immediate family 
22. Pregnant or breastfeeding women 
23. Women of childbearing potential (WOCBP)1 who are unwilling to practice highly effective 
contraception prior to the initial dose/start of the first treatment and for at least 6 months 
after REGN10933+REGN10987 administration 
Highly effective contraceptive measures include:  
• Abstinence2,3 
• Stable use of combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation initiated 2 or more 
menstrual cycles prior to screening 
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
• Bilateral tubal ligation 
1WOCBP are defined as women who are fertile following menarche until becoming 
postmenopausal, unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
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 the Clinical Trial Facilitation 
Group (CTFG) guidance. Pregnancy testing and contraception are not required for women 
with documented hysterectomy or tubal ligation. 
2Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. 
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3Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not 
acceptable methods of contraception. Female condom and male condom should not be used 
together. 
24. Sexually active men who are unwilling to use the following forms of medically 
acceptable birth control during the study drug follow-up period and for 6 months after 
REGN10933+REGN10987 administration: vasectomy with medical assessment of 
surgical success OR consistent use of a condom. Sperm donation is prohibited during the 
study and for up to 6 months after REGN10933+REGN10987 administration. 
25. Clinical history of myocarditis and/or pericarditis. 
7.3. 
Premature Withdrawal from the Study  
A subject has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or Sponsor have the right to withdraw a subject from the study if it is no 
longer in the interest of the subject to continue in the study, or if the subject’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a subject does not or cannot follow 
study procedures). An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of subjects should be avoided. 
Subjects who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.2. 
Rules for discontinuation of study drug or vaccine are discussed in Section 8.3. 
7.4. 
Replacement of Subjects 
Subjects who do not receive their first dose of Moderna mRNA-1273 vaccine as assigned may be 
replaced. 
8. 
STUDY DRUG AND COVID-19 VACCINE  
8.1. 
Investigational Treatment (Study Drug) 
In this study, the study drug (REGN10933+REGN10987) will be administered intravenously or 
subcutaneously as described in Section 8.5. Instructions on dose preparation are provided in the 
pharmacy manual. Refer to Section 9.2.2 for information on drug administration. 
8.2. 
COVID-19 Vaccine 
In this study, the vaccine (Moderna mRNA-1273) will be prepared and administered as described 
in the latest EUA Fact Sheet (Moderna COVID-19 Vaccine [HCP Fact Sheet], 2022). Refer to 
Section 8.5 for dose levels and method of treatment allocation; refer to Section 9.2.2 for 
information on vaccine administration. 
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8.3. 
Dose Modification and Discontinuation Rules 
8.3.1. 
Dose Modification 
Dose modification for an individual subject is not allowed for REGN10933+REGN10987 or 
Moderna mRNA-1273.  
8.3.2. 
Study Drug Discontinuation 
Subjects receiving REGN10933+REGN10987 will receive a single dose of the study drug; study 
drug discontinuation is not applicable.  
8.3.3. 
Vaccine Deferral or Discontinuation 
In subjects who become infected, the timing of vaccine administration (either the first dose, second 
dose, or booster dose, as applicable) should be deferred according to the most recent CDC guidance 
(CDC, 2021) . Subjects who become pregnant will be counseled accordingly. 
For applicable vaccine discontinuation rules, always refer to the latest Moderna mRNA-1273 
vaccine EUA Fact Sheet (Moderna COVID-19 Vaccine [HCP Fact Sheet], 2022).  
Vaccination will be permanently stopped or not administered in the event of: 
• Serious 
or 
severe 
allergic 
reactions 
(grade 
≥3) 
considered 
related 
to 
REGN10933+REGN10987 or Moderna mRNA-1273 vaccine 
Note: In case of mild to moderate allergic reactions (grade ≤2) considered related to 
REGN10933+REGN10987 or Moderna mRNA-1273 vaccine, vaccine discontinuation 
is up to the investigator’s discretion.  
• Subject withdrawal of consent 
Subjects who permanently discontinue from Moderna mRNA-1273 vaccine should be encouraged 
to remain in the study. Those who agree and do not withdraw from the study will be asked to return 
to the clinic for all remaining study follow up visits per the Schedule of Events. 
Subjects who permanently discontinue and who opt to withdraw from the study will be asked to 
complete study assessments described in Section 9.1.2. 
If a subject requires a prohibited medication (Section 8.8.1) at any time during the study, the 
principal investigator should contact the Sponsor medical monitor (except for illness requiring 
prompt treatment). Based on the discussions, vaccination may either be continued or permanently 
discontinued. 
8.4. 
Management of Acute Reactions  
8.4.1. 
Acute Intravenous Infusion Reactions to the Study Drug 
Emergency equipment and medication for the treatment of infusion reactions must be available for 
immediate use. All infusion reactions must be reported as AEs (as defined in Section 10.1) and 
graded using the grading scales as instructed in Section 10.2.4. 
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8.4.1.1. 
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. 
8.4.1.2. 
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 
• 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) 
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• Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
8.4.2. 
Acute Injection Reactions to the Study Drug 
8.4.2.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use. All injection reactions must be reported as AEs (as defined in Section 10.1) 
and graded using the grading scales as instructed in Section 10.2.4. 
Acute systemic reactions following SC injection of study drug should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.  
8.4.2.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.2.4. 
8.4.3. 
Acute Injection Reactions to the Vaccine 
Appropriate medical treatment to manage immediate allergic reactions must be immediately 
available in the event an acute anaphylactic reaction occurs following administration of the 
vaccine. Always refer to the latest EUA Fact Sheet (Moderna COVID-19 Vaccine [HCP Fact 
Sheet], 2022) for additional information.  
8.5. 
Method of Enrollment and Treatment Assignment 
Site-managed assignment. At screening, eligible subjects will be assigned to an enrollment wave. 
The enrollment waves are intended to avoid or minimize the potential for unused doses of Moderna 
mRNA-1273 COVID-19 vaccine (refer to Section 3.2.1 for additional rationale). Every effort 
should be made by sites to avoid unused doses of vaccine. 
Sites will manage the placement of subjects into each wave. Every effort should be made by the 
site to ensure balance of age (<65 years and ≥65 years) within each of the enrollment waves.  
Randomization. At baseline (day 1), subjects will be randomized to the corresponding study arms 
in each wave as described in Table 2.  
Randomization will be performed according to a computer-generated randomization scheme 
provided by an interactive web response system (IWRS) to a designated study pharmacist or a 
qualified designee.  
Randomization will be stratified by age (<65 years versus ≥65 years). 
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Table 2: 
Study Treatment Assignment 
Study 
Arm 
Random-
ization 
Ratio 
Targeted 
Enrollment 
Co-administered REGN10933+REGN10987 
Combination Therapy 
Moderna mRNA-1273 
Vaccine* 
Enrollment Wave 1 
1 
2 
30 
1200 mg (600 mg of each mAb) IV on day 1 
On day 15 and day 43 
2 
2 
30 
300 mg (150 mg of each mAb) IV on day 1 
On day 15 and day 43 
3 
2 
30 
150 mg (75 mg of each mAb) IV on day 1 
On day 15 and day 43 
6a 
1 
15 
None 
On day 15 and day 43 
Enrollment Wave 2 
4 
2 
30 
1200 mg (600 mg of each mAb) SC on day 1 
On day 1 and day 29 
5 
2 
30 
600 mg (300 mg of each mAb) SC on day 1 
On day 1 and day 29 
6b 
1 
15 
None 
On day 1 and day 29 
Enrollment Wave 3 
7 
15 
30 
48 mg (24 mg of each mAb) IV on day 1 
On day 15 and day 43 
8 
15 
30 
12 mg (6 mg of each mAb) IV on day 1 
On day 15 and day 43 
6c 
4 
8 
None 
On day 15 and day 43 
Enrollment Wave 4 
9 
15 
30 
1200 mg (600 mg of each mAb) IV on day 7 
On day 1 and day 29 
6d 
4 
8 
None 
On day 1 and day 29 
*Moderna mRNA-1273 vaccine will be administered as described on the EUA Fact Sheet (Moderna COVID-19 Vaccine [HCP 
Fact Sheet], 2022). 
mAb=monoclonal antibody; SC=subcutaneous; IV=intravenous. 
8.6. 
Blinding 
This is an open-label study without blinding. 
8.7. 
Logistics and Accountability for Study Drug and Vaccine 
8.7.1. 
Packaging, Labeling, and Storage  
Study Drug (REGN10933+REGN10987) 
Open-label study drug will display the product lot number on the label. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; Storage instructions will be 
provided in the pharmacy manual. 
Vaccine (Moderna mRNA-1273) 
Vaccine will labeled and stored as described on the EUA Fact Sheet (Moderna COVID-19 Vaccine 
[HCP Fact Sheet], 2022).  
8.7.2. 
Supply and Disposition of Study Drug  
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 
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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. 
8.7.3. 
Study Drug and Vaccine Accountability 
All study drug and vaccine accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug and vaccine. 
These records should contain the dates, quantity, and study medication 
• Dispensed to each subject 
• 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. 
8.7.4. 
Study Drug and Vaccine Compliance 
All drug compliance records must be kept current and made available for inspection by the Sponsor 
and regulatory agency inspectors. 
8.8. 
Concomitant Medications  
Any treatment administered from the time of the first dose of Moderna mRNA-1273 Vaccine or 
REGN10933+REGN10987 (as applicable and whichever occurs first) 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. 
8.8.1. 
Prohibited Medications and Vaccines  
The use of the following concomitant medications and vaccines may not require withdrawal of the 
participant from the study but may determine a subject’s evaluability in the per-protocol analyses 
(Section 11.3): 
• Investigational drugs  
• Investigational or approved passive antibodies for SARS-CoV-2 infection prophylaxis 
(eg, convalescent plasma or sera, mAbs, hyperimmune globulin) 
• Any vaccine within 28 days prior to or after study drug administration, other than 
Moderna mRNA-1273 vaccine administered as part of this study 
Exceptions:  
- seasonal influenza vaccine is only prohibited within 14 days before or after study 
drug administration, or within 14 days before or after mRNA-1273 vaccine 
administration.  
- COVID-19 vaccine booster vaccinations are permitted. Subjects may receive a single 
booster vaccination (i.e. third COVID-19 vaccine administration) in the optional 
Vaccine Booster Sub-study (Section 6.1). COVID-19 vaccination boosters received 
outside of the study are permitted and should be recorded as a concomitant medication. 
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• Systemic medications that suppresses the immune system (as described in Section 7.2.2 
#17), except for the treatment of COVID-19 
8.8.2. 
Permitted Medications  
Other than the prohibited medications and vaccines listed in Section 8.8.1, treatment with 
concomitant medications is permitted during the study. If there is any question regarding whether 
a concomitant medication may be used during the study, the study site should contact the medical 
monitor. Any medications used by the study subject should be captured in the concomitant 
medication eCRF. 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms.  
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff.  Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures in response to 
COVID-19 are to be documented as being related to COVID-19 and will remain in effect only 
for the duration of the public health emergency. 
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Table 3: 
Schedule of Events for Arms 1, 2, 3, and 6a (Enrollment Wave 1) and Arms 7, 8, and 6c (Enrollment Wave 3)  
Visit Period 
Screening/Baseline 
Vaccine Response Assessment 
Follow-Up 
Unscheduled 
Visit 
ET  
Study Day 
-21 to 1 
151 
29 
431 
57 
71 
183 
267 380 
Screening Pre-
dose Dose1 Post-
Dose 
Days After the First Vaccine Dose 
 
 
 
 
 
14 
28 
42 
56 
168 
252 365 
Window (day) 
 
 
 
 
-1 to +3 
±2 
-1 to +3 
±2 
±2 
±7 
±14 ±14 
 
 
Screening/Baseline and Key Laboratory Testing 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for optional FBR sub-study2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for optional PGx sub-study2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP)3 
X3 
X3 
 
 
X 
 
X 
 
 
 
 
 
X 
 
SARS-CoV-2 rapid (local/POC) RT-PCR4 
X4 
X4 
 
 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
 
SARS-CoV-2 rapid serology5 
X5 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 serology (central lab)5 
 
X5 
 
 
 
 
 
 
 
 
 
 
X 
 
Enrollment Wave and Treatment Assignment 
Site-managed assignment6 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization6 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug and Vaccine Administration 
REGN10933+REGN10987 (arms 1, 2, 3, 7, and 8 only)7 
 
 
X7 
 
 
 
 
 
 
 
 
 
 
 
Moderna mRNA-1273 vaccine (arms 1, 2, 3, 7, 8, 6a, and 6c)7 
 
 
 
 
X7 
 
X7 
 
 
 
 
 
 
 
Biomarkers 
Serum for SARS-CoV-2 neutralization8 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum for serology characterization8 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood for PBMCs8 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum for exploratory research 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma for exploratory research 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety 
Vital signs9 
X 
X9 
 
X9 
X9 
 
X9 
 
 
 
 
 
 
 
Adverse events12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Targeted physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Testing (Central Lab) 
Hematology 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
Blood Chemistry 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug concentrations and Immunogenicity 
Drug concentration (PK) sample10 
 
X10 
 
X10 
X 
X 
X 
X 
X 
X 
 
 
 
 
Immunogenicity (ADA) sample11 
 
X11 
 
 
 
X 
 
 
 
X 
 
 
 
 
Pharmacogenomics (Optional) 
Whole Blood for DNA 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccine Booster Sub-Study (Optional)13 
Informed consent for vaccine booster sub-study2 
 
 
 
 
Refer to Table 6. 
 
 
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Visit Period 
Screening/Baseline 
Vaccine Response Assessment 
Follow-Up 
Unscheduled 
Visit 
ET  
Study Day 
-21 to 1 
151 
29 
431 
57 
71 
183 
267 380 
Screening Pre-
dose Dose1 Post-
Dose 
Days After the First Vaccine Dose 
 
 
 
 
 
14 
28 
42 
56 
168 
252 365 
Window (day) 
 
 
 
 
-1 to +3 
±2 
-1 to +3 
±2 
±2 
±7 
±14 ±14 
 
 
Sample collection and assessments 
 
 
 
 
 
 
 
 
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Table 4: 
Schedule of Events for Arms 4, 5, and 6b (Enrollment Wave 2) 
Visit Period 
Screening/Baseline 
Vaccine Response 
Assessment 
Follow-Up 
Unscheduled 
Visit 
ET  
Study Day 
-21 to 1 
15 
291 
43 
57 
169 
253 
366 
Screening 
Pre-
dose 
Dose1 
Post-
Dose 
Days After the First Vaccine Dose 
 
 
 
 
14 
28 
42 
56 
168 
252 
365 
Window (day) 
 
 
  
 
±2 
-1 to 
+3 
±2 
±2 
±7 
±14 
±14 
 
 
Screening/Baseline and Key Laboratory Testing 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for optional FBR sub-study2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for optional PGx sub-study2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP)3 
X3 
X3 
 
 
 
X3 
 
 
 
 
 
X 
 
SARS-CoV-2 rapid (local/POC) RT-PCR4 
X4 
X4 
 
 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
 
SARS-CoV-2 rapid serology5 
X5 
X5 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 serology (central lab)5 
 
X5 
 
 
 
 
 
 
 
 
 
X 
 
Enrollment Wave and Treatment Assignment 
 
Site-managed assignment6 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization6 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
Study Drug and Vaccine Administration 
 
REGN10933+REGN10987 (arms 4 and 5 only)7 
 
 
X7 
 
 
 
 
 
 
 
 
 
 
Moderna mRNA-1273 vaccine (arms 4, 5, and 6b)7 
 
 
X7 
 
 
X7 
 
 
 
 
 
 
 
Biomarkers 
 
Serum for SARS-CoV2 neutralization8 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum for serology characterization8 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood for PBMCs8 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum for exploratory research 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma for exploratory research 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety 
 
Vital signs9 
X 
X9 
 
X9 
 
X9 
 
 
 
 
 
 
 
Adverse events12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Targeted physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Testing (Central Lab) 
 
Hematology 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
X 
Blood Chemistry 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
X 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Drug concentrations and Immunogenicity 
 
Drug concentration (PK) sample10 
 
X10 
 
X10 
X 
X 
X 
X 
X 
 
 
 
 
Immunogenicity (ADA) sample11 
 
X11 
 
 
 
X 
 
 
X 
 
 
 
 
Pharmacogenomics (Optional) 
 
Whole Blood for DNA 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
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Visit Period 
Screening/Baseline 
Vaccine Response 
Assessment 
Follow-Up 
Unscheduled 
Visit 
ET  
Study Day 
-21 to 1 
15 
291 
43 
57 
169 
253 
366 
Screening 
Pre-
dose 
Dose1 
Post-
Dose 
Days After the First Vaccine Dose 
 
 
 
 
14 
28 
42 
56 
168 
252 
365 
Window (day) 
 
 
  
 
±2 
-1 to 
+3 
±2 
±2 
±7 
±14 
±14 
 
 
Vaccine Booster Sub-Study (Optional)14 
Informed consent for vaccine booster sub-study2 
 
 
 
 
Refer to Table 6. 
 
 
Sample collection and assessments 
 
 
 
 
 
 
 
 
 
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Table 5: 
Schedule of Events for Study Arms 9 and 6d (Enrollment Wave 4) 
Visit Period 
Screening/Baseline 
Vaccine Response Assessment 
Follow-Up 
Unscheduled 
Visit 
ET 
Study Day 
-21 to 1 
7 
15 291 43 
57 169 253 366 
Screening Pre-
dose 
Dose1 Post-
Dose 
Pre-
dose Dose1 Post-
Dose 
Days After the First Vaccine Dose 
 
 
 
 
 
 
 
14 
28 
42 
56 168 252 365 
Window (day) 
 
 
  
 
 
 
 
±2 -1 to 
+3 ±2 ±2 
±7 ±14 ±14 
Screening/Baseline and Key Laboratory Testing 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for optional FBR sub-study2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for optional PGx sub-study2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP)3 
X3 
X3 
 
 
X3 
 
 
 
X3 
 
 
 
 
 
X 
 
SARS-CoV-2 rapid (local/POC) RT-PCR4 
X4 
X4 
 
 
X4 
 
 
X4 X4 X4 X4 
X4 
X4 
X4 
X4 
 
SARS-CoV-2 rapid serology5 
X5 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 serology (central lab)5 
 
X5 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Enrollment Wave and Treatment Assignment 
Site-managed assignment6 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization6 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug and Vaccine Administration 
REGN10933+REGN10987 (arm 9 only)7 
 
 
 
 
 
X7 
 
 
 
 
 
 
 
 
 
 
Moderna mRNA-1273 vaccine (arms 9 and 6d)7 
 
 
X7 
 
 
 
 
 
X7 
 
 
 
 
 
 
 
Biomarkers 
Serum for SARS-CoV2 neutralization8 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum for serology characterization8 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood for PBMCs8 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum for exploratory research 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma for exploratory research 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety 
Vital signs9 
X 
X9 
 
X9 
X9 
 
X9 
 
X9 
 
 
 
 
 
 
 
Adverse events12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Targeted physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Testing (Central Lab) 
Hematology 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
X 
Blood Chemistry 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
X 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug concentrations and Immunogenicity 
Drug concentration (PK) sample10 
 
 
 
 
X10 
 
X10 
X 
X 
X 
X 
X 
 
 
 
 
Immunogenicity (ADA) sample11 
 
 
 
 
X11 
 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomics (Optional) 
Whole Blood for DNA 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccine Booster Sub-Study (Optional)14 
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Visit Period 
Screening/Baseline 
Vaccine Response Assessment 
Follow-Up 
Unscheduled 
Visit 
ET 
Study Day 
-21 to 1 
7 
15 291 43 
57 169 253 366 
Screening Pre-
dose 
Dose1 Post-
Dose 
Pre-
dose Dose1 Post-
Dose 
Days After the First Vaccine Dose 
 
 
 
 
 
 
 
14 
28 
42 
56 168 252 365 
Window (day) 
 
 
  
 
 
 
 
±2 -1 to 
+3 ±2 ±2 
±7 ±14 ±14 
Informed consent for vaccine booster sub-study2 
 
 
 
 
Refer to Table 6. 
 
 
Sample collection and assessments 
 
 
 
 
 
 
 
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Table 6: 
Schedule of Events for the Moderna mRNA-1273 Vaccine Booster Sub-Study  
Visit 
Vaccine Booster Administration 
Post-Booster Follow-Up 
Pre-Dose 
Dose1 
Post-Dose 
 
Visit Window 
≥5 months after the second dose of the vaccine (primary series), and >35 
days before end of the main study 
28 days ±7 days after the vaccine 
booster  
 
Informed 
consent for the 
booster sub-
study2 
X 
 
 
 
Moderna 
mRNA-1273 
vaccine booster 
shot 
 
X 
 
 
Pregnancy test 
(WOCBP)3 
X 
 
 
 
SARS-CoV-2 
rapid 
(local/POC) 
RT-PCR4 
X4 
 
 
X4 
Adverse 
events12 
X 
X 
X 
X 
Drug 
concentration 
(PK) sample10 
X 
 
 
X 
Serum for 
exploratory 
research 
X 
 
 
X 
Plasma for 
exploratory 
research 
X 
 
 
X 
Whole blood for 
PBMCs8 
X 
 
 
X 
 
 
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9.1.1. 
Footnotes for the Schedules of Events 
1. Throughout the study, study drug and/or vaccine administration will occur after all samples 
have been collected and all assessments have been performed. 
2. Separate consent is required for participation in the optional vaccine booster sub-study 
(Section 9.2.10), optional future biomedical research sub-study (Section 9.2.8), and 
optional pharmacogenomics sub-study (Section 9.2.9). For subjects consenting to the 
genomics sub-study, the blood sample for genomic DNA should be collected at baseline 
(day 1) but may be collected at any visit. 
3. All women of childbearing potential (WOCBP), with the exception of women with 
documented bilateral tubal ligation, will require pregnancy testing at screening, prior to 
study drug administration, and prior to COVID-19 vaccine administration. If a urine 
pregnancy test result is positive, a serum pregnancy test will be performed for confirmation. 
Subjects with confirmed pregnancy (by serum test) at screening will not be randomized. If 
the screening visit occurs on the same day as the baseline visit on day 1, pregnancy testing 
does not need to be repeated. Subjects with confirmed pregnancy at post-baseline dosing 
visits will be counseled according to Section 8.3.3. 
4. If the screening visit occurs on the same day as the baseline visit on day 1, SARS-CoV-2- 
rapid RT-PCR test does not need to be repeated. Nasopharyngeal swabs will be used for 
rapid RT-PCR testing. Refer to Section 6.1.2 for more information on sample collection 
and visit scheduling for subjects with suspected COVID-19 or positive RT-PCR test result. 
Post-baseline samples only: If the rapid RT-PCR test is positive at any time point post-
baseline, the samples will be banked for viral sequencing. 
Additional information is provided in Section 9.2.1.2. 
5. If a rapid serology test is used at the screening visit, and screening occurs on the same day 
as the baseline visit, the rapid serology test does not need to be repeated at baseline. 
Additional information about the rapid serology test is provided in Section 9.2.1.3. 
At screening, if the rapid serology test is not available locally, a rapid test may be 
performed at a central laboratory to determine eligibility, and a repeat of the test is not 
required at baseline.  
6. Subjects will receive site-managed assignment (at screening) and randomized treatment 
assignment (at baseline on day 1) according to Section 8.5. 
7. Note that not all subjects will receive study drug at randomization. Refer to Section 8.5 and 
Figure 1 for more information. 
Study arms 4 and 5: Subjects assigned to study arms 4 and 5 will receive both the study 
drug and vaccine on day 1. The study drug will be administered first, followed by the 
vaccine. There must be a minimum of 2 hours waiting period between administration of 
the study drug and subsequent vaccine administration. Approximately 24 hours after 
completion of the study drug and vaccine administration on day 1, subjects will be followed 
up by telephone for safety. Subjects should be monitored for at least 1 hour after study drug 
or vaccine administration. 
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Study arms 6a, 6b, 6c, and 6d only: Subjects assigned to one of these study arms will not 
receive study drug. These subjects will receive the vaccine only. These subjects should be 
monitored for at least 30 minutes after vaccine administration. 
Refer to Section 9.2.2 for additional information concerning administration and monitoring 
requirements following study drug and/or vaccine administration. 
8. Serology characterization assays will be used to assess antibodies against various 
SARS-CoV-2 antigens including: S protein, RBD, S1, and N protein. Refer to 
Section 9.2.3.1, Section 9.2.3.2, and Section 9.2.3.3 for more information on procedures 
and assays related to vaccine response assessment.  
9. Vital signs, including temperature, blood pressure, heart rate, and respiratory rate will be 
collected prior to and 30 minutes following each administration of the study drug or 
vaccine primary series (first and second dose) as described in Section 9.2.4.1.  
10. Actual dosing time and drug concentration sample collection times will be recorded. 
Study arms 1, 2, 3, 7, 8, and 9 (receiving IV infusion of study drug): At the indicated 
visit, blood for assessment of drug concentration in serum will be taken prior to dosing and 
within 60 minutes after the end of infusion (EOI). The EOI sample should be collected 
from the arm contralateral to that used for IV infusion. If not medically feasible, the EOI 
sample can be drawn from the same arm, but not from the infusion catheter.  
Study arms 4 and 5 (receiving SC injection of study drug): At the screening/baseline 
visit, blood for assessment of drug concentration in serum will be taken prior to dosing. 
The post-dose blood collection should occur at least 1 hour after study drug administration.  
Study arms 6a, 6b, 6c, and 6d (receiving no study drug): No blood for assessment of 
drug concentration in serum will be collected. 
11. The window for pre-dose ADA sample collection should be as close to administration of 
study drug as is reasonable. Actual dosing time and ADA sample collection times will be 
recorded.  
Study arms 6a, 6b, 6c, and 6d (receiving no study drug): No blood for ADA assessment 
will be collected. 
12. Adverse events will be continuously monitored as described in Section 10.1.1.  
13. For Arms 1, 2, 3, 6a, 6c, 7 and 8: For subjects receiving their COVID-19 vaccine booster 
as part of the sub-study, the vaccine booster may be administered at any time from 5 
months after their second vaccine dose until study day 345. The actual date the subject 
received their second vaccine dose should be used (as opposed to using study day 43) to 
determine when the booster window should begin. 
14. For Arms 4, 5, 6b, 6d, and 9: For subjects receiving their COVID-19 booster as part of 
the sub-study, the vaccine booster may be administered at any time from 5 months after 
their second vaccine dose until study day 331. The actual date the subject received their 
second vaccine dose should be used (as opposed to using study day 29) to determine 
when the booster window should begin. 
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9.1.2. 
Early Termination Visit 
Subjects who are withdrawn from the study before the primary endpoint visit (56 days after the 
first dose of the vaccine; day 71 for study arms 1, 2, 3, 6a, 7, 8, and 6c, and day 57 for study arms 
4, 5, 6b, 9, and 6d) will be asked to return to the clinic once for an early termination (ET) visit 
consisting of the end of study assessments (as described in the respective Schedules of Events).  
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep subjects on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed at the Screening/Baseline Visit 
Procedures to be performed for the purpose of determining study eligibility or characterizing the 
baseline population include: medical history, demographics (including age, sex, race, weight, 
height), and SARS-CoV-2 RT-PCR and serology tests. 
9.2.1.1. 
Informed Consent 
Informed consent must be obtained according to the requirements described in Section 13.2. 
Additional informed consent must be obtained if subjects choose to participate in the optional 
vaccine booster sub-study (Section 9.2.10), optional future biomedical research sub-study (refer 
to Section 9.2.8), or optional pharmacogenomics sub-study (refer to Section 9.2.9). 
9.2.1.2. 
SARS-CoV-2 Rapid RT-PCR  
At screening, the investigator or designee will verify that the subject has tested negative for 
SARS-CoV-2 by a rapid RT-PCR test. Historical test results will not be accepted. 
Subjects will also be tested for SARS-CoV-2 infection by the rapid RT-PCR test using 
nasopharyngeal (NP) swabs throughout the study according to the respective Schedules of Events. 
Any post-baseline virology samples that test positive for SARS-CoV-2 will be banked for viral 
sequencing Section 9.2.3.4.  
9.2.1.3. 
SARS-CoV-2 Serology  
The investigator or designee will verify that the subject has tested negative for circulating 
SARS-CoV-2-specific antibodies by a SARS-CoV-2 antibody test. 
The diagnostic antibody test may be performed using a rapid lateral flow chromatographic 
immunoassay (LFIA) intended for the qualitative detection and differentiation of IgM and IgG 
antibodies to SARS-CoV-2. If the LFIA assay is not available locally, the rapid LFIA test at the 
central laboratory will be used to determine study eligibility. 
9.2.2. 
Study Drug and Vaccine Administration and Post-Administration Monitoring 
Refer to Section 8.5 for treatment assignments. 
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SC and IM Injection Administration 
All subjects allocated to a SC regimen will receive either 4 (study arm 4) or 2 (study arm 5) 
injections of study drug on the day of administration. It is recommended that SC injection sites 
should be chosen among the different quadrants of the abdomen (avoiding navel and waist areas) 
and upper thighs. During study drug 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).  
All subjects will receive each Moderna mRNA-1273 vaccination dose through a single IM 
injection in the deltoid muscle (CDC, 2021) . 
Subjects should receive all doses of Moderna mRNA-1273 vaccine as assigned and as described 
in the EUA Fact Sheet (Moderna COVID-19 Vaccine [HCP Fact Sheet], 2022). 
Study arms 4 and 5 only: Subjects will receive both study drug and vaccine on day 1. The study 
drug will be administered first, followed by the vaccine. There must be a minimum of 2 hours 
waiting period between administration of the study drug and subsequent vaccine. Administration 
of the individual regimens should be performed as described above.  
Post-administration monitoring of study drug and vaccine 
Study arms 1 through 5 and 7 through 9: Subjects should be monitored for at least 1 hour after 
study drug or vaccine administration. Vaccine recipients should be monitored for the occurrence 
of acute reactions according to the latest CDC guidelines (CDC, 2021) . For study arms 4 and 5 
(receiving study drug and vaccine on the same day), approximately 24 hours after completion of 
the study drug and vaccine administration on day 1, subjects will be followed up by telephone for 
safety. 
Study arms 6a, 6b, 6c and 6d: Subjects assigned to each of these study arms will not receive 
study drug during this study. These subjects should be monitored for at least 30 minutes after 
vaccine administration. 
9.2.3. 
Pharmacodynamic and Exploratory Biomarker Procedures 
This section describes planned or potential pharmacodynamic and exploratory analyses, some of 
which may not be reported in the CSR. 
Note that any biological samples collected during the study which are not used for their planned 
purpose, or for which material remains after their planned analysis, may be kept for up 15 years 
after study completion (or for a shorter time period if required per regional laws and regulations) 
for use in exploratory research related to how the study drugs work and to study SARS-CoV-2, 
COVID-19, and immune responses to SARS-CoV-2 vaccination. 
9.2.3.1. 
SARS-CoV-2 Neutralization Assays 
Vaccine induced neutralizing antibody titers will be characterized using an assay to measure the 
ability of serum antibodies to block SARS-CoV-2 S protein-mediated infection of cells in vitro. 
(Vandergaast, 2020). Because REGN10933+REGN10987 will neutralize infection in this assay, 
anti-idiotype antibodies that block REGN10933 and REGN10987 neutralizing activity will be 
added, allowing for detection of vaccine-induced neutralizing antibodies generated in vivo 
post-vaccination. The ID50 (serum dilution that inhibits by 50% the transfection signal detected in 
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positive control wells) of neutralizing antibodies tested will be compared between the vaccine-only 
arm and each REGN10933+REGN10987 treatment group at time points in the Schedules of Events 
to measure the induction of neutralizing activity to the SARS-CoV-2 S protein.  
9.2.3.2. 
SARS-CoV-2 Serology Characterization Assays  
Serum binding antibodies to SARS-CoV-2 S protein trimer, RBD and other SARS-CoV-2 
subdomains (including S1 and nucleocapsid) will be assessed as secondary and exploratory 
objectives of this study. To explore whether or not mRNA-1273 vaccine-mediated humoral 
immunity to SARS-CoV-2 is affected by the administration of REGN10933+REGN10987, 
serological immunoassays will be used to detect antibodies against the SARS-CoV-2 S protein and 
subdomains at time points in the Schedules of Events. Because REGN10933+REGN10987 will 
interfere 
with 
these 
measurements, 
an 
anti-idiotype 
antibody 
that 
blocks 
REGN10933+REGN10987 will be included in the assay, allowing for detection of endogenous 
serum antibodies generated in vivo post-vaccination. Additional serological characterization 
related to antibody recognition of viral variants and further delineation of the epitope repertoire of 
vaccine-induced antibodies may be done if technically feasible and assays become available. 
9.2.3.3. 
Cellular Immunity Assays 
PBMCs will be processed at a central lab and may be stored for analysis. Both B cell and T cell 
immune responses will be studied. Assays for B cell responses may include, but not be limited to, 
quantification by flow-cytometry of circulating antigen-specific B cells or plasma cells using 
labeled S protein trimer, RBD and other SARS-CoV-2 subdomains, and quantification of SARS-
CoV-2 specific antibody responses in either primary ELISPOT assays or re-stimulation assays 
followed by ELISPOT. Studies focused on T cell responses may include, but may not be limited 
to, flow cytometry with isolated PBMCs to characterize immune subsets, quantify SARS-CoV-2 
specific T cell responses via ex vivo peptide stimulation assays with downstream flow cytometry 
and/or cytokine measurements. Cell profiling may include bulk RNA (transcriptome) sequencing, 
and T cell receptor or B cell receptor RNA or DNA sequencing. 
9.2.3.4. 
Viral Sequencing 
In order to monitor for possible SARS-CoV-2 infection post-REGN10933+REGN10987 treatment 
and/or post-vaccination and potential resistance, NP swabs will be collected for SARS-CoV-2 RT-
PCR testing at timepoints designated in the Schedules of Events. Viral genome sequencing will be 
performed on available post-baseline viral nucleic acid samples with a positive RT-PCR test result. 
Sequencing analyses will consist of the entire viral genome, including the full gene sequence that 
encodes the SARS-CoV-2 S protein. 
Viral variants suspected to confer decreased susceptibility to REGN10933 and/or REGN10987 or 
the mRNA-1273 vaccine will be evaluated in nonclinical work separate from this protocol. 
The results of viral sequencing will be reported separately from the CSR. 
9.2.3.5. 
Serum and Plasma for Exploratory Research 
Changes in circulating concentrations of serum/plasma biomarkers associated with COVID-19, 
SARS-CoV-2, REGN10933+REGN10987, vaccine-induced immunity, vaccine-drug interactions, 
host and viral biological pathways, and other mechanisms related to disease activity and clinical 
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outcome may be assessed in volunteers post-REGN10933+REGN10987 treatment and/or 
vaccination. The association between changes in biomarkers with clinical endpoints may be 
evaluated. 
9.2.4. 
Safety Procedures  
9.2.4.1. 
Vital Signs 
Vital signs will include temperature, blood pressure, heart rate, and respiratory rate. Vital signs 
will be measured after the subject has been resting quietly for at least approximately 5 minutes and 
may be obtained in seated or supine position. 
Vital signs will be collected prior to and approximately 30 minutes following each administration 
of the study drug or vaccine primary series (first and second vaccine dose). Vital signs may also 
be collected as needed, according to local standard of care and as per the discretion of the 
investigator.  
Blood pressure measurements may be repeated once during screening. 
9.2.4.2. 
Adverse Events Monitoring 
Adverse events listed in Section 10.1.1 will be recorded. 
9.2.4.3. 
Concomitant Medications 
Concomitant medications (as defined in Section 9.2.4.3) will be recorded. 
9.2.4.4. 
Pregnancy Test 
Urine pregnancy test will be performed for WOCBP at the time periods described in the Schedules 
of Events. If urine pregnancy test is positive, a serum pregnancy test will be performed for 
confirmation, and subjects should be counseled as described in Section 8.3.3. 
9.2.4.5. 
Targeted Physical Examination  
Targeted physical examination is required and will include examination of the oropharynx, skin, 
heart, lungs, and any other system(s) depending on complaints or concerns expressed by the 
subject. 
9.2.5. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and serum pregnancy testing samples will be analyzed by a 
central laboratory. Detailed instructions for blood sample collection are in the laboratory manual 
provided to study sites. Samples for laboratory testing will be collected at visits according to the 
Schedules of Events. 
Tests will include: 
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Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol* 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK) 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
*low-density lipoprotein (LDL) and high-density lipoprotein (HDL). 
Hematology 
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
 
Other Laboratory Tests 
Refer to Section 9.2.1.2 for information on the SARS-CoV-2 rapid RT-PCR test. 
 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.  
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.1. 
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9.2.6. 
Drug Concentration and Measurements 
Samples for drug concentration measurement will be collected at visits listed in the Schedules of 
Events. 
9.2.7. 
Immunogenicity Measurements and Samples 
Samples for study drug immunogenicity (ADA and NAb) assessment will be collected at time 
points listed in the Schedules of Events. 
9.2.8. 
Future Biomedical Research (Optional) 
Subjects who agree to participate in the future biomedical research (FBR) sub-study will be 
required to consent to this optional sub-study before samples are banked for FBR. Residual 
biomarker samples for study-related research, as well as unused PK and ADA samples, will be 
stored for up to 15 years after the final date of the database lock (or for a shorter time period if 
required per regional laws and regulations). The samples may be utilized for FBR that may or may 
not be directly related to the study, including being used as reference samples and assay 
development or validation. The results of these future biomedical research analyses will not be 
presented in the CSR. 
9.2.9. 
Pharmacogenomic Analysis (Optional) 
Subjects who agree to participate in the genomics sub-study will be required to consent to this 
optional sub-study before collection of the samples. Whole blood samples for DNA extraction 
should be collected on day 1/baseline (predose), but can be collected at a later study visit. DNA 
samples will be collected for pharmacogenomics analyses to understand the genetic determinants 
of efficacy and safety associated with the treatments in this study and the molecular basis of 
COVID-19 and related diseases. These samples will be single-coded as defined by the 
International Council for Harmonisation (ICH) guideline E15. Samples will be stored for up to 15 
years after the final date of the database lock (or for a shorter time period if required per regional 
laws and regulations). If there are specific site or country requirements involving the 
pharmacogenomic analyses which the Sponsor is unable to comply with, samples will not be 
collected at those sites.  
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to REGN10933+REGN10987, SARS-CoV-2 vaccination, other COVID-19 
clinical outcome measures and possible AEs. In addition, associations between genomic variants 
and prognosis or progression of COVID-19 as well as related diseases may also be studied. These 
data may be used or combined with data collected from other studies to identify and validate 
genomic markers related to the study drug, target pathway, SARS-CoV-2 vaccination or 
COVID-19.  
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions. Other methods, including whole-exome 
sequencing, whole-genome sequencing, and DNA copy number variation may also be performed. 
The list of methods may be expanded to include novel methodology that may be developed during 
the course of this study or sample storage period. Results from the genomic analyses will not be 
reported in the CSR. 
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9.2.10. 
Vaccine Booster Sub-Study (Optional) 
Subjects who have not already received the COVID-19 vaccine booster and who agree to 
participate in the vaccine booster sub-study will be required to consent to this optional sub-study 
before collection of the pre-dose blood sample and administration of the booster vaccination dose. 
Another blood sample will be collected approximately 28 days after the vaccine booster. These 
blood samples may be analyzed to supplement data regarding the potential immunological impact 
of mAb administration on COVID-19 vaccination. 
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 throughout the study  
• Treatment-emergent SAEs throughout the study 
• Treatment-emergent AESIs (defined in Section 10.1.3)  
The investigator must promptly record all clinical events occurring during the study data 
collection, from the time of signing the ICF to the end of the post-vaccination observation period 
(see Section 11.4.6.1). Medical conditions that existed or were diagnosed prior to the signing of 
the Informed Consent will be recorded as part of medical history. Abnormal laboratory values and 
vital signs observed at the time of Informed Consent should also be recorded as medical history. 
Any subsequent worsening (ie, any clinically significant change in frequency and/or intensity) of 
a pre-existing condition that is temporally associated with the use of the study drug should also be 
recorded as an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
subject. Adverse events may be directly observed, reported spontaneously by the subject, or by 
questioning the subject at each study visit. Subjects should be questioned in a general way, without 
asking about the occurrence of any specific symptoms. The investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.1.4. 
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 SAEs (and AESIs) until they 
have resolved or are considered clinically stable; AEs should be followed until they are resolved 
or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE 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 of AE or SAE.  
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 
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AEs if they are symptomatic, lead to study drug discontinuation, require corrective treatment, or 
constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization). A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-planned (prior to 
signing the informed consent form) 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 10.1.4 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 that the investigator assesses as related 
to study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3.  
10.1.2. 
Reporting Procedure  
All events (serious and non-serious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the study drug. For SAEs and AESIs, a detailed narrative 
summarizing the course of the event, including its evaluation, treatment, and outcome should be 
provided on the AE CRF. 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 CRF, 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 to REGN10933+REGN10987 through day 4  
− Grade ≥3 injection-site reactions to REGN10933+REGN10987 or each dose of 
Moderna mRNA-1273 vaccine through day 4 post-injection 
− Grade ≥2 hypersensitivity reactions to REGN10933+REGN10987 or each dose of 
Moderna mRNA-1273 vaccine through day 29 post-infusion or post-injection (as 
applicable) 
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• If subjects experience Grade ≥ 3 ISRs or Grade ≥2 hypersensitivity reactions related to 
Moderna mRNA-1273 administered as a concomitant medication outside of the 
study, these events are NOT to be considered as AESIs and do not require expedited 
reporting to Sponsor 
• 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, for 6 months after REGN10933+REGN10987 
administration. Any complication of pregnancy affecting a female study subject and/or 
fetus and/or newborn that meets the SAE criteria must be reported as an SAE. Outcome 
for all pregnancies should be reported to the Sponsor. 
10.1.4. 
Reporting Adverse Events Following Vaccination 
It is advised that healthcare providers administering Moderna mRNA-1273 vaccine should 
comply with CDC requirements for AE reporting, as outlined in the EUA Fact Sheet (Moderna 
COVID-19 Vaccine [HCP Fact Sheet], 2022). 
The vaccination provider is responsible for mandatory reporting of the following to the 
Vaccine Adverse Event Reporting System (VAERS): 
• Vaccine administration errors whether or not associated with an adverse event, 
• Serious adverse events* (irrespective of attribution to vaccination), 
• Cases of Multisystem Inflammatory Syndrome (MIS) in adults, and 
• Cases of COVID-19 that result in hospitalization or death. 
*Serious adverse events are defined as: Death; A life-threatening adverse event; Inpatient 
hospitalization or prolongation of existing hospitalization; A persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions; A congenital anomaly/birth 
defect; An important medical event that based on appropriate medical judgement may jeopardize the 
individual and may require medical or surgical intervention to prevent one of the outcomes listed 
above.  
10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a subject 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: 
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• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a subject is a passenger). 
• Is life-threatening – in the view of the investigator, the subject is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization 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 AE 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 subject or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An adverse event of special interest (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.  
AESI are defined for this study in Section 10.1.3. 
10.2.4. 
Severity 
The severity of adverse events (including test findings classified as AEs) 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 7. The grading systems for anaphylaxis, allergic reaction (hypersensitivity), 
infusion-related reaction, and injection-site reaction are provided in Table 8.  
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Table 7: 
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 8: 
NCI-CTCAE (v5.0) Severity Grading System for Anaphylaxis, Allergic Reactions, Infusion-Related Reactions, 
and Injection Site Reactions  
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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10.2.5. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the study drug and/or vaccine administered as part of the study caused the AE, 
based on evidence or facts, his/her clinical judgment, and the following definitions. Causality 
should be assessed separately for the study drug and for the vaccine. 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 vs time study drug and/or vaccine was 
administered 
• Nature of the reactions: immediate vs long term 
• Clinical and pathological features of the events  
• Existing information about study drug and/or vaccine and the same class of drugs or 
vaccines 
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when applicable  
• Subject’s medical and social history  
Causality to the study drug and/or vaccine (including study drug and/or vaccine administration): 
• Related: 
− The AE follows a reasonable temporal sequence from the study drug and/or vaccine 
administered as part of the study, and cannot be reasonably explained by the nature 
of the reaction, subject’s clinical state (eg, disease under study, concurrent diseases, 
concomitant medications), or other external factors. 
or 
− The AE follows a reasonable temporal sequence from the study drug and/or vaccine 
administered as part of the study, and is a known reaction to the drug or vaccine 
under study or its classes, or is predicted by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from the study drug and/or vaccine 
administered as part of the study, or can be reasonably explained by the nature of 
the reaction, subject's clinical state (eg, disease under study, concurrent diseases, 
and concomitant medications) or other external factors. 
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Causality to the study conduct (protocol specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
subject's clinical state (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol specified procedure, 
or can be reasonably explained by the nature of the reaction, subject'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 subject 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, 
GPS; 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 contract research organization (CRO) will inform health 
authorities, 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 REGN10933+REGN10987, 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 Institutional Review Board (IRB) unless delegated to the Sponsor. 
Event expectedness for study drug REGN10933+REGN10987 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 provides the basis for the statistical analysis plan (SAP) for the study. The SAP will 
be revised prior to the end of the study to accommodate amendments to the clinical study protocol 
and to make changes to adapt to unexpected issues in study execution and data that may affect the 
planned analyses. The final SAP will be issued before the first database lock. 
Endpoints are listed in Section 4. Analysis variables are listed in Section 5.  
11.1. 
Statistical Hypothesis  
No statistical hypothesis testing is planned in this study. Analyses of immunogenicity, safety, 
tolerability, and other data will be descriptive and exploratory in nature. 
11.2. 
Justification of Sample Size 
This study plans to enroll up to approximately 286 subjects, in order to achieve a target enrollment 
of up to approximately 30 subjects per Moderna mRNA-1273 + (REGN10933 and REGN10987) 
arm and 46 total Moderna mRNA-1273-alone subjects. Based on the calculations provided below, 
this sample size is considered appropriate to meet the aims of this phase 2 study, in that it is 
expected to provide adequate precision in quantifying the magnitude of effect for the primary 
endpoint, as well as allow for an assessment of the safety and tolerability of the Moderna mRNA-
1273 vaccine when administered with REGN10933+REGN10987. 
The assumed log10-scale standard deviation for the study is 0.30 log. This assumption is based on 
phase 1 data for the Moderna mRNA-1273 vaccine, taking the weighted average (ie, adjusting for 
sample sizes) across all doses (25,100, and 250 μg) and age groups (18 to 55, 56 to 70, and ≥71 
years) for the neutralizing antibody titer ID50 endpoint at day 57 (Anderson, 2020) (Jackson, 2020). 
With a log-scale standard deviation of 0.30 for the primary endpoint and a sample size of 30 and 
46 subjects per arm (in combined study drug/vaccine and vaccine-only arms, respectively), the 
half-width of the 95% within-group confidence interval (CI) [ie, the minimal detectable difference] 
in this study is 0.11 log and 0.09 log, respectively. For between-group comparisons, the half-width 
of the 95% between-group CI for any two Moderna mRNA-1273 + (REGN10933 and 
REGN10987) arms is 0.15 log. Additionally, the half-width of the 95% between-group CI in this 
study for any individual Moderna mRNA-1273 + (REGN10933 and REGN10987) arm and the 
total Moderna mRNA-1273 alone subjects is 0.14 log. 
The analysis set that will be used for assessment of vaccine response allows for subjects to be 
excluded from analysis if certain confounding criteria are met (see Section 11.3.1). If 50% of 
subjects are excluded from analysis (ie, 15 subjects are analyzed per individual Moderna mRNA-
1273 + (REGN10933 and REGN10987) arm and 23 total Moderna mRNA-1273 alone subjects 
are analyzed), the half-width of the 95% between group CI for any two Moderna mRNA-1273 + 
(REGN10933 and REGN10987) arms is 0.22 log. Additionally, the half-width of the 95% between 
group CI for any individual Moderna mRNA-1273 + (REGN10933 and REGN10987) arm and 
Moderna mRNA-1273 alone subjects is 0.20 log. Under this scenario, the minimal detectable 
difference still remains substantially smaller than the decrease in neutralization titers observed in 
a separate study of sera from recipients of the Moderna mRNA-1273 vaccine who were infected 
with South African variants (eg, B.1.351 v1, v2, and v3) (Garcia-Beltran, 2021) 
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11.3. 
Analysis Sets  
11.3.1. 
Vaccine Response Analysis Sets 
The modified full analysis set (mFAS) includes all randomized subjects who have been 
vaccinated with at least one dose and have a negative serology test result from the central 
laboratory test at baseline; it is based on the treatment received (as treated). 
The per protocol set (PPS) includes all randomized subjects who have been vaccinated with at 
least one dose and do not meet the PPS exclusion criteria; it is based on the treatment received (as 
treated). 
The PPS excludes subjects who: 
• Receive positive SARS-CoV-2 serology result based on central laboratory test at 
baseline  
• Do not receive the second dose of the vaccine 
• Receive a positive diagnostic test result for SARS-CoV-2 infection before 56 days 
after the first dose of the vaccine  
• Receive any dose of a coronavirus vaccine (refer to Section 8.8.1) outside of the study 
within 56 days after the first dose of the vaccine 
• Receive systemic immunosuppressants or immune-modifying drugs within 56 days 
after the first dose of the vaccine 
• Receive IVIG or blood products within 56 days after the first dose of the vaccine  
The SAP will document the finalized exclusion criteria for the PPS.  
The PPS is the primary analysis set for assessing vaccine response.  
11.3.2. 
Safety Analysis Set  
The safety analysis set (SAF) includes all randomized subjects who have been vaccinated with at 
least one dose or received any study drug; it is based on the treatment received (as treated). 
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
SAF. 
11.3.3. 
Vaccine Booster Analysis Set  
The vaccine booster analysis set includes all randomized subjects who signed the optional sub-
study informed consent and have been vaccinated with the study provided vaccine booster; it is 
based on the treatment received (as treated).  
11.3.4. 
Pharmacokinetic Analysis Set 
The PK analysis population includes all subjects who have received any study drug and who had 
at least 1 non-missing PK result following the first dose of study drug. Subjects will be analyzed 
based on the actual treatment received. 
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11.3.5. 
Immunogenicity Analysis Sets 
The ADA analysis sets include all subjects who received any study drug and had at least 1 
non-missing ADA result from the ADA assays after first dose of study drug. 
The NAb analysis sets include all subjects who received any study drug and who are either negative 
in the ADA assays or positive for ADA with at least one non-missing result in the NAb assays 
after first dose of the study drug. Subjects who are negative in the ADA assays are set to negative 
in the NAb analysis sets.  
Subjects will be analyzed according to the treatment actually received. 
11.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information: the number 
of subjects 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. 
11.4.1. 
Subject Disposition 
The following will be provided: 
• The total number of screened subjects who have signed the ICF 
• The total number of randomized subjects: received a randomization number 
• The total number of subjects who discontinued the study, and the reasons for 
discontinuation 
• The total number of subjects who discontinued from study treatment, and the reasons 
for discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all subjects combined.  
11.4.3. 
Analysis of Primary Vaccine Response Endpoint 
The primary endpoint is the 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing 
antibodies to SARS-CoV-2 pseudovirus, assessed on 56 days after the first dose of the vaccine (ie, 
the vaccine response assessment period). The 56-day time point corresponds to study day 71 for 
study arms 1, 2, 3, 7, 8, 6a, and 6c, and study day 57 for study arms 4, 5, 9, 6b, and 6d. 
An analysis of covariance (ANCOVA) model with treatment group as a fixed effect and age as a 
covariate will be fit to the data as the primary analysis.  
The least squares mean estimates for the endpoint will be presented for each treatment group, as 
well as for the differences between treatment groups. Associated 95% confidence intervals will 
also be reported for each treatment group and for between-group comparisons.  
Data will be fitted in the log scale, and final outputs will be reported in geometric means and 
differences of the geometric means.  
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Accompanying descriptive analyses will also be provided. The analyses will be conducted based 
on the observed data with no imputation for missing data. Values below the limit of quantification 
(LOQ) will be set to half of LOQ. 
11.4.4. 
Analysis of Secondary Vaccine Response Endpoints 
The secondary endpoints will be analyzed in a similar manner as described for the primary 
endpoint.  
For these secondary endpoints, the individual time points for assessments include all post-vaccine 
scheduled timepoints during the Vaccine Response Assessment Period as described in the 
Schedule of Events (Section 9.1). Accompanying descriptive analyses for each endpoint at each 
individual time points will also be provided. 
11.4.5. 
Analysis of Sub-Study Vaccine Booster  
Possible analysis includes assessment of vaccine immune responses over time among the vaccine 
booster analysis set. Accompanying descriptive statistics at individual time points will also be 
provided. 
11.4.6. 
Safety Analysis 
11.4.6.1. Adverse Events 
Definitions 
For safety variables, the following observation periods are defined: 
• The pre-vaccination period is defined as the time from study drug administration to 
the first primary series vaccine dose administration. 
• The primary series vaccination period is defined as the time from the first primary 
series vaccine dose administration to 28 days after the second primary series vaccine 
dose administration, and in subjects receiving only one dose of the primary series 
vaccine, 28 days after the first primary series vaccine dose administration. 
• The post primary series-vaccination period is defined as the time from the end of the 
primary series vaccination period to the end of the follow-up period in subjects who do 
not receive the sub-study provided vaccine booster. In subjects who receive the sub-
study provided vaccine booster dose, the post-primary series vaccination period is 
defined as the time from the end of the primary series vaccination period to the 
administration of the sub-study provided vaccine booster. 
• The post-booster vaccination period: is defined as the time from the sub-study 
provided vaccine booster to the end of the follow-up period. 
Treatment-emergent adverse events are defined as those that are not present at the time of the first 
dose of Moderna mRNA-1273 Vaccine or REGN10933+REGN10987 (as applicable and 
whichever occurs first) or represent the exacerbation of a pre-existing condition during the 
observation period. 
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Analysis 
All AEs reported in this study will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®).  
Summaries by treatment group will include the following: 
• The number (n) and percentage (%) of subjects with at least 1 TEAE by SOC and PT 
• The number (n) and percentage (%) of subjects with at least 1 treatment-emergent 
serious adverse events (SAEs) by SOC and PT 
• The number (n) and percentage (%) of subjects with at least 1 infusion-related reactions 
(grade ≥2) through day 4 by PT 
• The number (n) and percentage (%) of subjects with at least 1 injection-site reactions 
(grade ≥3) through day 4 by PT 
• The number (n) and percentage (%) of subjects with at least 1 hypersensitivity reactions 
(grade ≥2) through day 29 by PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.4), 
presented by SOC and PT 
• Treatment related TEAEs , presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and SAEs will be summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be 
summarized by treatment group. 
11.4.6.2. Other Safety 
Vital Signs 
Vital signs (temperature, blood pressure, heart rate, and respiratory 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 subjects with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test for all subjects 
and separately for subjects in whom the PCSV criterion was normal or missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
11.4.6.3. Treatment Exposure 
The derived variables, the summary tables and listings to be used to illustrate the extent of exposure 
to the investigational drug (characterized according to the number of subjects exposed, the duration 
of exposure and the dose to which they were exposed). 
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The associated medications in interaction studies or in studies where associated medication is 
specified as part of the investigational drug. 
11.4.6.4. Treatment Compliance 
Treatment compliance in terms of total dose and infusion interruption will be summarized. The 
analysis methods will be detailed in the SAP. 
11.4.7. 
Pharmacokinetics 
11.4.7.1. 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  
11.4.8. 
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. 
11.4.9. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA responses, titers, and NAb status observed in 
subjects 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 assay at all time points, 
regardless of any missing samples. 
• Pre-existing immunoreactivity, defined either an ADA positive response in the ADA 
assay at baseline with all post first dose ADA results negative, or a positive assay 
response at baseline, with all post first dose ADA assay 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 the baseline results are negative or missing. Treatment-emergent 
responses will be further characterized as Persistent, Indeterminate, or Transient. 
• Treatment-boosted ADA response, defined as a positive response in the ADA assay 
post first dose that is greater than or equal to 9-fold over baseline titer levels, when 
baseline results are positive.  
Titer categories (Maximum Titer values) 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤10,000) 
• High (titer >10,000)  
The following analysis will be provided: 
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• Number (n) and percent (%) of ADA-negative subjects by treatment groups 
• Number (n) and percent (%) of treatment-emergent ADA positive subjects by treatment 
groups and ADA titer categories 
• Number (n) and percent (%) of treatment-boosted ADA positive subjects by treatment 
groups and ADA titer categories 
A listing of all ADA titer levels will be provided for subjects with pre-existing, treatment-
emergent, and treatment-boosted ADA response. 
The absolute occurrence (n) and percent of subjects (%) with NAb status in the NAb analysis set 
will be provided by treatment groups.  
11.5. 
Interim Analysis  
Formal interim analysis may be conducted. 
11.6. 
Timing of Primary and Final Analyses 
The primary vaccine response analysis will be conducted as a first-step analysis after all subjects 
have finished the primary endpoint visit (ie, 56 days after the first dose of the vaccine, at study 
days listed in Section 11.4.3), in order to estimate the levels of neutralizing antibodies in each 
study arm. This analysis represents the final analysis of the primary endpoint and is not considered 
an interim analysis. The SAP will be issued prior to this analysis.  
After all subjects finish 1-year of follow-up, a final study analysis will be conducted.  
11.7. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. investigator and Sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE  
In accordance with ICH E6, the Sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.  
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). 
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A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history, physical examination findings) 
will be done using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC). 
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 and 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 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of subjects are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate subject 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 CRF data are timely, accurate and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). 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 (CRFs) within the EDC system by trained site personnel. All required CRFs must be 
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completed for each and every subject enrolled in the study. The investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the Sponsor in the CRFs. After 
review of the clinical data for each subject, the investigator must provide an electronic signature. 
A copy of each subject CRF 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 CRF will be entered in the CRF 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 or 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, CRFs, 
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. 
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 subject 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 CRFs, 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 
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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. 
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. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each subject 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 subject in 
language that he/she can understand. The ICF should be signed and dated by the subject and by 
the investigator or authorized designee who reviewed the ICF with the subject.  
• Subjects who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Subjects who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given. 
The original ICF must be retained by the investigator as part of the subject's study record, and a 
copy of the signed ICF must be given to the subject. 
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 subjects 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 subject’s study record and a copy must be given to the subject. 
13.3. 
Subjects Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
subject will be maintained. Subjects should be identified by a subject identification number only, 
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on CRFs 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 subject '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 
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 subjects 
(eg, advertising) before any subject 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 subject, 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 subjects 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 
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/EC-
approved amendment. Where required per local legislation, regulatory authority approval will also 
be sought.  
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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. 
Close-out 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 subject 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 subjects required for the study are enrolled earlier than expected 
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 
subjects’ 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. 
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FDA. Casirivimab and Imdevimab EUA Letter of Authorization. Food and Drug Administration 
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Hoffmann M, Kleine-Weber H,Pöhlmann S. A Multibasic Cleavage Site in the Spike Protein of 
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Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, et al. An mRNA 
Vaccine against SARS-CoV-2 — Preliminary Report. New England Journal of Medicine 2020; 
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Kam YW, Kien F, Roberts A, Cheung YC, Lamirande EW, Vogel L, et al. Antibodies against 
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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-
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O’Brien MP, Forleo-Neto E, Sarkar N, Isa F, Hou P, Chan K-C, et al. Subcutaneous REGEN-COV 
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Infection. 
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O’Brien MP, Forleo Neto E, Musser BJ, Isa F, Chan K-C, Sarkar N, et al. Subcutaneous REGEN-
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of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine 2020; 
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of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N Engl J Med 2021; 384(23):2187-
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Vandergaast R, Carey T, Reiter S, Lech P, Gnanadurai C, Tesfay M, et al. Development and 
validation of IMMUNO-COV™: a high-throughput clinical assay for detecting antibodies that 
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Verschoor CP, Singh P, Russell ML, Bowdish DM, Brewer A, Cyr L, et al. Microneutralization 
assay titres correlate with protection against seasonal influenza H1N1 and H3N2 in children. PLoS 
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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. 
 
Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, et al. REGEN-COV 
Antibody Cocktail in Outpatients with Covid-19. medRxiv 2021a:2021.2006.2009.21257915. 
 
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. 
 
Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, et al. REGEN-COV 
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WHO. 
Draft 
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Published 2021. Updated 16 Mar 2021. 
 
WHO. Laboratory testing of 2019 novel coronavirus (2019-nCoV)in suspected human cases: 
interim guidance, 17 January 2020.  https://www.who.int/publications/i/item/laboratory-testing-
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A PHASE 2 RANDOMIZED, OPEN-LABEL, PARALLEL 
GROUP STUDY TO ASSESS THE IMMUNOGENICITY, SAFETY, AND TOLERABILITY 
OF 
MODERNA 
mRNA-1273 
VACCINE 
ADMINISTERED 
WITH 
CASIRIVIMAB+IMDEVIMAB IN HEALTHY ADULT VOLUNTEERS 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 Randomized, Open-Label, Parallel Group Study to Assess the 
Immunogenicity, Safety, and Tolerability of Moderna mRNA-1273 Vaccine Administered with 
Casirivimab+Imdevimab in Healthy Adult Volunteers 
Protocol Number: 
R10933-10987-COV-2118 
Protocol Version:  
Amendment 5  
 
 
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-00182647 v1.0
Signature Page for VV-RIM-00182647 v1.0 Approved
Approval/eSignature
2 14:36:48 GMT+0000
Approval/eSignature
00
Approval/eSignature
2022 16:37:32 GMT+0000
Approval/eSignature
2022 17:28:21 GMT+0000
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SAP_001.pdf: 
REGENERON CONFIDENTIAL 
Page 1 of 49 
STATISTICAL ANALYSIS PLAN 
VERSION: 2.0 
Clinical Study Protocol Title: A Phase 2 Randomized, Open-Label, Parallel Group Study to 
Assess the Immunogenicity, Safety, and Tolerability of Moderna mRNA-1273 Vaccine 
Administered with Casirivimab+Imdevimab in Healthy Adult Volunteers  
Compound: 
REGN10933+REGN10987 
Protocol Number: 
R10933-10987-COV-2118 
Clinical Phase:  
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
  
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date:  
Version 2.00 / 23 September 2022 
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REGENERON CONFIDENTIAL 
Page 2 of 49 
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 
   
 
 
 
See appended electronic signature page 
 
 
 
 
See appended electronic signature page 
 
 
 
See appended electronic signature page 
 
 
 
 
See appended electronic signature page 
  
 
 
 
See appended electronic signature page 
 
 
 
 
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Page 3 of 49 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale ..................................................................................................8 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Exploratory Objectives .................................................................................................9 
1.2.4. 
Endpoints ....................................................................................................................10 
1.2.5. 
Modifications from the Statistical Section in the Final Protocol ................................11 
1.2.6. 
Revision History for SAP Amendments .....................................................................11 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ..............................................................................13 
2.2. 
Sample Size and Power Considerations .....................................................................14 
2.3. 
Study Plan ...................................................................................................................14 
3. 
ANALYSIS POPULATIONS ....................................................................................17 
3.1. 
Per Protocol Set Analysis Set (PPS) ...........................................................................17 
3.2. 
Modified Full Analysis Set (mFAS) ...........................................................................18 
3.3. 
Randomized Analysis Set ...........................................................................................18 
3.4. 
Safety Analysis Set (SAF) ..........................................................................................18 
3.5. 
Vaccine Booster Analysis Set .....................................................................................18 
3.6. 
The Pharmacokinetic Analysis Set .............................................................................18 
3.7. 
Immunogenicity Analysis Sets ...................................................................................18 
4. 
ANALYSIS VARIABLES .........................................................................................19 
4.1. 
Demographics and Baseline Characteristics ...............................................................19 
4.2. 
Medical History ..........................................................................................................19 
4.3. 
Prior / Concomitant Medication & Procedures ..........................................................19 
4.4. 
Prohibited Medication and Vaccine During Study .....................................................20 
4.5. 
Vaccine Response Variable ........................................................................................20 
4.5.1. 
Primary Vaccine Response Variable ..........................................................................20 
4.5.2. 
Secondary Vaccine Response Variables .....................................................................20 
4.5.3. 
Exploratory Vaccine Response Variables ..................................................................21 
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4.5.4. 
Additional Vaccine Response Variables ....................................................................21 
4.6. 
Safety Variables ..........................................................................................................21 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................21 
4.6.2. 
Adverse Events of Special Interest .............................................................................22 
4.6.3. 
Laboratory Safety Variables .......................................................................................22 
4.6.4. 
Vital Signs ..................................................................................................................22 
4.6.5. 
SARS-CoV-2 test results ............................................................................................22 
4.7. 
Pharmacokinetic Variables .........................................................................................23 
4.8. 
Immunogenicity Variables ..........................................................................................23 
5. 
STATISTICAL METHODS .......................................................................................24 
5.1. 
Demographics and Baseline Characteristics ...............................................................24 
5.2. 
Medical History ..........................................................................................................24 
5.3. 
Prior/Concomitant Medications & Procedures ...........................................................24 
5.4. 
Prohibited Medications ...............................................................................................24 
5.5. 
Subject Disposition .....................................................................................................24 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................24 
5.7. 
Analysis of Vaccine Response Variables ...................................................................25 
5.7.1. 
Analysis of Primary Vaccine Response Variable .......................................................25 
5.7.2. 
Analysis of Secondary Vaccine Response Variables .................................................26 
5.7.3. 
Analysis of Exploratory Vaccine Response Variables ...............................................26 
5.7.4. 
Analysis of Additional Vaccine Response Variables .................................................27 
5.7.5. 
Supplementary and Subgroup Analyses .....................................................................27 
5.7.6. 
Analysis of sub-study vaccine booster administration ...............................................27 
5.8. 
Analysis of Safety Data ..............................................................................................27 
5.8.1. 
Adverse Events ...........................................................................................................27 
5.8.2. 
Clinical Laboratory Measurements.............................................................................29 
5.8.3. 
Vital Signs ..................................................................................................................29 
5.9. 
Analysis of Pharmacokinetic Data ..............................................................................29 
5.10. 
Analysis of Immunogenicity Data ..............................................................................29 
5.10.1. 
Analysis of ADA Data ................................................................................................29 
5.10.2. 
Analysis of NAb Data .................................................................................................30 
5.10.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................31 
5.10.3.1. 
Immunogenicity and Exposure ...................................................................................31 
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5.10.3.2. 
Immunogenicity and Safety and Exposure .................................................................31 
6. 
DATA CONVENTIONS ............................................................................................32 
6.1. 
Definition of Baseline .................................................................................................32 
6.2. 
Data Handling Convention for Vaccine Response Variables .....................................32 
6.3. 
Data Handling Convention for Missing Data .............................................................32 
6.4. 
Analysis Windows ......................................................................................................33 
6.5. 
Unscheduled Assessments ..........................................................................................33 
7. 
INTERIM ANALYSIS ...............................................................................................34 
8. 
TIMING OF PRIMARY AND FINAL ANALYSES ................................................35 
9. 
SOFTWARE ...............................................................................................................36 
10. 
REFERENCES ...........................................................................................................37 
11. 
APPENDIX.................................................................................................................38 
11.1. 
Schedule of Events .....................................................................................................39 
11.2. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................45 
 
LIST OF TABLES 
Table 1: 
Study Treatment Assignment .....................................................................................13 
Table 2: 
Schedule of Events for Arms 1, 2, 3, and 6a (Enrollment Wave 1) and Arms 
7, 8, and 6c (Enrollment Wave 3) ...............................................................................39 
Table 3: 
Schedule of Events for Arms 4, 5, and 6b (Enrollment Wave 2) ...............................40 
Table 4: 
Schedule of Events for Study Arms 9 and 6d (Enrollment Wave 4) ..........................41 
Table 5: 
Schedule of Events for the Moderna mRNA-1273 Vaccine Booster Sub-
Study ...........................................................................................................................42 
 
LIST OF FIGURES 
Figure 1:     Study Flow Diagram (Enrollment Waves 1 and 2) ....................................................15 
Figure 2:     Study Flow Diagram (Enrollment Waves 3 and 4) ....................................................16 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
CI 
Confidence Interval 
CRF 
Case Report Form (electronic or paper) 
CTCAE 
Common Terminology Criteria for Adverse Events 
EUA 
Emergency Use Authorization 
FDA 
US Food and Drug Administration 
ICF 
Informed Consent Form 
ID50 
50% Inhibitory Dilution 
ICH 
International Council for Harmonisation 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
Modified Full Analysis Set 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
PCSV 
Potentially Clinically Significant Value 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
PT 
Preferred Term 
RBD 
Receptor-Binding Domain 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
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SI 
Standard International 
SMQ 
Standard MedDRA Query 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
ULOQ 
Upper Limit of Quantification 
VNT 
Viral Neutralizing Titer 
WHO 
World Health Organization 
 
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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. 
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-2118 study. The current 
version of the SAP, version 2, was finalized after protocol amendment 5 to incorporate changes 
made to the protocol (see Section 1.2.6 for a summary of revisions). 
This plan may be revised during the study to accommodate protocol amendments and/or to make 
changes to adapt to unexpected issues in study execution and/or data that affect planned 
analyses. The original version of the analysis plan was issued prior to the first interim database 
lock. 
1.1. 
Background/Rationale 
This is a randomized, open-label, parallel group study to assess the immunogenicity, safety, and 
tolerability of Moderna mRNA-1273 vaccine administered with REGN10933+REGN10987 in 
healthy adult volunteers.  
The primary objectives are to understand whether REGN10933+REGN10987, when 
administered in the setting of treatment or prevention of COVID-19, will alter the response to 
COVID-19 vaccines such as Moderna mRNA-1273 and to evaluate the time interval between 
REGN10933+REGN10987 administration and Moderna mRNA-1273 vaccine administration to 
ensure no meaningful impact on vaccine-induced neutralizing antibody responses to SARS-CoV-
2. To accomplish the first primary study objectives, REGN10933+REGN10987 will be evaluated 
using a 1200 mg dose level that has been authorized under Emergency Use Authorization (EUA) 
for the treatment and post-exposure prophylaxis of COVID-19 and for which clinical trial data 
(conducted prior to the emergence of omicron-lineage variants) indicate efficacy for pre-
exposure prophylaxis of COVID-19  against susceptible variants  (Table 1). The study is thus 
designed to mirror hypothetical clinical ‘use case’ scenarios, for which the two routes of 
administration of REGN10933+REGN10987, intravenous and subcutaneous, may be employed 
in close proximity to COVID-19 vaccination or, to accomplish the second primary objective, 
mimic waiting for vaccination for up to 6 months after a 1200 mg dose of 
REGN10933+REGN10987.  
In this study, several additional dose levels below 1200 mg were to be administered at day 1 
(Figure 1 and Figure 2). Lower dose levels were chosen as a means to vary the concentration of 
REGN10933+REGN10987 that exists at the time of Moderna mRNA-1273 vaccination. This 
method was intended to simulate various time intervals that could occur between administration 
of REGN10933+REGN10987 at 1200 mg and vaccination with Moderna mRNA-1273. This 
approach – altering the dose level rather than the time interval – was selected because 
REGN10933+REGN10987 concentration (and not time) is the key factor impacting the 
likelihood of altering vaccine responses. Moreover, the approach is operationally more feasible, 
and (by avoiding the need to test variable and potentially lengthy time intervals) lowered the 
likelihood of subjects becoming exposed to SARS-CoV-2 exposure during the study, which 
would confound the interpretation of results. 
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To summarize, the primary objectives in this study are intended to provide information that may 
guide physicians and public health agencies in making evidence-based recommendations on the 
usage of the COVID-19 vaccines in the setting of REGN10933+REGN10987 therapy or 
prevention.  Since COVID-19 vaccines employing S protein neutralization as their mode of 
action are likely to produce comparable antibody responses and protective immunity (an 
assumption supported by some initial experimental data) as some vaccines (Garcia-Beltran, 
2021) it is anticipated that the data generated from this study can potentially be extrapolated to 
the general case of S-protein-based COVID-19 vaccines given in the setting of mAbs targeting 
the S protein RBD. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objectives of the study are:  
• To evaluate the extent of effect, if any, of REGN10933+REGN10987 administration 
on vaccine-induced neutralizing antibody responses to SARS-CoV-2 by Moderna 
mRNA-1273 
• To evaluate the time interval required between REGN10933+REGN10987 
administration and Moderna mRNA-1273 vaccination, to ensure no meaningful 
impact on vaccine-induced neutralizing antibody responses to SARS-CoV-2 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To quantify the alteration of antigen specificity of vaccine-induced SARS-CoV-2 
antibody 
responses 
when 
administered 
with 
different 
dose 
regimens 
of 
REGN10933+REGN10987  
• To evaluate the safety and tolerability of REGN10933+REGN10987 and Moderna 
mRNA-1273 vaccine when administered in close succession 
• To assess the concentrations of REGN10933 and REGN10987 in serum over time in 
subjects who receive REGN10933+REGN10987 and Moderna mRNA-1273 vaccine 
• To evaluate the immunogenicity of REGN10933 and REGN10987 over time 
1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To explore circulating T cell and B cell responses to SARS-CoV-2 antigens in 
subjects who receive both REGN10933+REGN10987 and Moderna mRNA-1273 
vaccine versus those who receive the vaccine alone 
• To explore the impact of REGN10933+REGN10987 as measured by the induction of 
vaccine-induced binding antibodies to SARS-CoV-2 receptor-binding domain (RBD) 
antigens post-Moderna mRNA-1273 vaccination that compete with the same epitopes 
recognized by REGN10933 and/or REGN10987 
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• To explore how REGN10933+REGN10987 alters vaccine-induced neutralizing 
antibody responses, induced by Moderna mRNA-1273 vaccine, against SARS-CoV-2 
variants 
• To characterize viral variants by sequencing SARS-CoV-2 in subjects who become 
infected post-baseline  
• To explore the impact on vaccine responses and the mechanism of action of 
REGN10933+REGN10987 as measured by experimental laboratory assays and 
biomarkers after vaccination with Moderna mRNA-1273  
• 
To explore biomarkers and genomic factors associated with safety and immune 
responses after exposure to REGN10933+REGN10987 and Moderna mRNA-1273 
• 
To assess immune responses in subjects who receive booster vaccinations during 
the study 
1.2.4. 
Endpoints 
Primary Endpoint 
The primary endpoint is the 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing 
antibodies to the SARS-CoV-2 S protein assessed 56 days after the first dose of Moderna mRNA 
1273 vaccine. 
This endpoint will be used in assessing both primary objectives. 
Secondary Endpoints 
• Absolute values, change from baseline, and percentage change from baseline in 
concentrations of vaccine-induced antibodies to the following SARS-CoV-2 antigens 
over time: 
− Anti-S protein 
− Anti-RBD 
− Other S protein subdomains (including S1, S2, and NTD) 
• 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing antibodies to 
SARS-CoV-2 S protein assessed over time after the first dose of Moderna 
mRNA-1273 vaccine 
• Proportion of subjects with treatment-emergent adverse events (TEAEs) throughout 
the study  
• Proportion of subjects with treatment-emergent serious adverse events (SAEs) 
throughout the study 
• Proportion 
of 
subjects 
with 
infusion-related 
reactions 
(grade 
≥2) 
to 
REGN10933+REGN10987 through day 4 post-infusion 
• Proportion 
of 
subjects 
with 
injection 
site 
reactions 
(grade 
≥3) 
to 
REGN10933+REGN10987 or each dose of Moderna mRNA-1273 vaccine through 
day 4 post-injection 
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• Proportion 
of 
subjects 
with 
hypersensitivity 
reactions 
(grade 
≥2) 
to 
REGN10933+REGN10987 or each dose of Moderna mRNA-1273 vaccine through 
day 29 post-infusion or post-injection (as applicable) 
• Concentrations of REGN10933 and REGN10987 in serum over time  
• Immunogenicity, as measured by anti-drug antibodies (ADA) and neutralizing 
antibodies (NAb) to REGN10933 and REGN10987 
Exploratory Endpoints 
• Absolute percentages, change, and percentage change from baseline of blood-derived 
memory T cell responses specific to SARS-CoV-2 viral peptides over time 
• Absolute percentages, change, and percentage change from baseline of blood-derived 
B cell responses specific to SARS-CoV-2 S protein, RBD, and other S protein 
subdomains over time 
• Viral variant characteristics of SARS-CoV-2 in subjects who become infected 
post-baseline 
1.2.5. 
Modifications from the Statistical Section in the Final Protocol 
Modifications in the Statistical Analysis Plan from the Statistical Section in the Final Protocol 
include the addition of Viral Neutralizing Titer and converted World Health Organization 
standard unit parameters as additional efficacy variables, further detailing of exclusion criteria 
for the Per Protocol Set and added exclusion details for the vaccine booster analysis set as subset 
of the Per Protocol Set. 
1.2.6. 
Revision History for SAP Amendments 
The revised SAP (version 2) is based on Protocol Amendment 5 dated January 28th 2022. 
Summary of Changes from Version 1 to Version 2 
Change and Rationale for Change 
Sections changed 
Edits and additions, due to protocol 
amendment and for added clarity. 
Section 1 
Secondary and exploratory objectives and 
endpoint wording updated to match changes in 
protocol amendment 
Section 1.2.2, 1.2.3, 1.2.4 
Section 4.5.2 
Section 4.5.3  
Clarify timeframe for criteria 7 of the Per 
Protocol Set  
Section 3.1 
Vaccine Booster Analysis Set is defined 
Section 3.5 
Clarify that the pharmacokinetics analysis sets 
Section 3.6 
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are defined for each study drug separately 
Clarify immunogenicity analysis sets and 
analysis of immunogenicity data 
Section 3.7 
Section 5.10.1, 5.10.2  
Add clarification that medications reporting to 
include standardized medication name 
Section 4.3 
Safety periods updated to match protocol 
amendment and reflect optional vaccine 
booster dose 
Section 4.6.1 
Added tabulation of subjects who receive 
vaccine booster dose along with time from 
completion of primary series of vaccine 
Section 5.6 
In alignment to other studies within the 
REGEN-COV program, handling rule for 
values above the upper limit of quantification 
(ULOQ) to be set to the ULOQ  
Section 5.7 
Section 6.2 
Noted an exploratory analysis that will be 
performed with data from a second 
neutralization assay and summarized in a 
separate report 
Section 5.7.3 
Addition of analyses for vaccine booster 
analysis set subjects  
Section 5.7.6 
Removal of text referencing noncompartmental 
analysis due to sampling schedule   
Section 5.9 
Schedule of events updated to reflect protocol 
amendment 
Section 11.1 
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2. 
 INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This study is a phase 2, randomized, open-label, parallel group study in healthy adult volunteers 
to assess the immunogenicity, safety, and tolerability of Moderna mRNA-1273 vaccine when 
administered with REGN10933+REGN10987.  
At screening, eligible subjects were to be assigned to an enrollment wave. The enrollment waves 
were intended to avoid or minimize the potential for unused doses of Moderna mRNA-1273 
COVID-19 vaccine (Protocol Section 3.2.1 for additional rationale). Every effort was made by 
sites to avoid unused doses of vaccine. 
Every effort was be made by the site to ensure balance of age (<65 years and ≥65 years) within 
each of the enrollment waves. At baseline (day 1), subjects were to be randomized to the 
corresponding study arms in each wave as described in Table 1. 
Randomization was performed according to a computer-generated randomization scheme 
provided by an interactive web response system (IWRS) to a designated study pharmacist or a 
qualified designee. 
Randomization was stratified by age (<65 years versus ≥65 years). 
Table 1: 
Study Treatment Assignment 
Study 
Arm 
Random-
ization 
Ratio 
Targeted 
Enrollment 
Co-administered 
REGN10933+REGN10987 Combination 
Therapy 
Moderna mRNA-
1273 Vaccine* 
Enrollment Wave 1 
1 
2 
30 
1200 mg (600 mg of each mAb) IV on day 
1 
On day 15 and day 43 
2 
2 
30 
300 mg (150 mg of each mAb) IV on day 1 On day 15 and day 43 
3 
2 
30 
150 mg (75 mg of each mAb) IV on day 1 
On day 15 and day 43 
6a 
1 
15 
None 
On day 15 and day 43 
Enrollment Wave 2 
4 
2 
30 
1200 mg (600 mg of each mAb) SC on day 
1 
On day 1 and day 29 
5 
2 
30 
600 mg (300 mg of each mAb) SC on day 1 On day 1 and day 29 
6b 
1 
15 
None 
On day 1 and day 29 
Enrollment Wave 3 
7 
15 
30 
48 mg (24 mg of each mAb) IV on day 1 
On day 15 and day 43 
8 
15 
30 
12 mg (6 mg of each mAb) IV on day 1 
On day 15 and day 43 
6c 
4 
8 
None 
On day 15 and day 43 
Enrollment Wave 4 
9 
15 
30 
1200 mg (600 mg of each mAb) IV on day 
7 
On day 1 and day 29 
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6d 
4 
8 
None 
On day 1 and day 29 
*Moderna mRNA-1273 vaccine will be administered as described on the US FDA EUA HCP Fact Sheet, 2021) 
mAb=monoclonal antibody; SC=subcutaneous; IV=intravenous. 
 
2.2. 
Sample Size and Power Considerations 
This study planned to enroll up to approximately 286 subjects, in order to achieve a target 
enrollment of up to approximately 30 subjects per Moderna mRNA-1273 + (REGN10933 and 
REGN10987) arm (resulting in 46 total Moderna mRNA-1273-alone subjects).  
The pooled standard deviation for the primary vaccine response endpoint of neutralizing 
antibody titer ID50 assessed 56 days after vaccination with Moderna mRNA 1273 (pooling across 
doses and age groups) is 0.30 (Anderson, 2020) (Jackson, 2020).  With a sample size of 30 and 
46 subjects per arm in combined study drug/vaccine and pooled vaccine-only arms, respectively, 
the half-widths of the 95% within-group confidence interval (CI) [ie, the minimal detectable 
difference] in this study are 0.11 and 0.09, respectively. For between-group comparisons, the 
half-width of the 95% between-group CI for any two Moderna mRNA-1273 + (REGN10933 and 
REGN10987) arms is 0.15. Additionally, the half-width of the 95% between-group CI in this 
study for any individual Moderna mRNA-1273 + (REGN10933 and REGN10987) arm and the 
total Moderna mRNA-1273 alone subjects is 0.14. 
If 50% of subjects are excluded from the Per Protocol Analysis Set (ie, 15 subjects are analyzed 
per individual Moderna mRNA-1273 + (REGN10933 and REGN10987) arm and 23 total 
Moderna mRNA-1273 alone subjects are analyzed), the half-width of the 95% between group CI 
for any two Moderna mRNA-1273 + (REGN10933 and REGN10987) arms is 0.22. Additionally, 
the half-width of the 95% between group CI for any individual Moderna mRNA-1273 + 
(REGN10933 and REGN10987) arm and Moderna mRNA-1273 alone subjects is 0.20. Note that 
it is not expected that 50% of subjects will be excluded from the Per Protcol Set (PPS); this 
precision statement is intended to be conservative.     
Note that the mean decrease in neutralization titers in sera from recipients of the Moderna 
mRNA-1273 vaccine who were infected with South African variants (eg, B.1.351 v1, v2, and v3) 
was 1.44 in log10 scale (Garcia-Beltran, 2021).  While this difference is not known to be 
clinically relevant, it provides a useful benchmark for results of this study. The vaccine still 
provided similar levels of protection against severe outcomes for infection with this variant 
(Chemaitelly, 2021).  
2.3. 
Study Plan 
Throughout the study, blood samples will be collected to assess whether the study drug impacts 
the ability of the vaccine to elicit neutralizing antibody titers against the SARS-CoV-2 S protein, 
and to understand any impact on vaccine-induced humoral and cellular immune responses to 
various S protein epitopes. Additional details are provided in Section 9.2.3 of protocol. 
Subjects will also have blood samples taken at select visits for drug concentration, 
immunogenicity, and exploratory analyses, and will be monitored for AEs [including Adverse 
Events of Special Interest (AESIs)] during in-person visits. For subjects in study arms 4 and 5 
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(receiving the study drug and vaccine on the same day), a phone call will be made within 24 
hours following study drug and vaccine administration on day 1 for AE collection. 
The last study visit will take place approximately 1 year after the first dose of the vaccine. 
 
Figure 1:     Study Flow Diagram (Enrollment Waves 1 and 2) 
 
 
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Figure 2:     Study Flow Diagram (Enrollment Waves 3 and 4) 
 
 
 
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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. 
In this study, “as treated” is defined as: (1) subjects who receive study drug will be grouped in 
the vaccine + study drug combination arms (2) subjects who receive vaccine only will be 
grouped into the vaccine alone arm within the same randomization wave (e.g. for a subject 
randomized to arm 1 who receives vaccine only, they will be grouped into arm 6a).   
3.1. 
Per Protocol Set Analysis Set (PPS) 
The per protocol set (PPS) includes all randomized subjects who have received both doses of 
vaccine and who do not meet the following exclusion criteria: 
1. Have a positive SARS-CoV-2 central serology result prior to the first dose of vaccine.  
2. Receive a positive Reverse Transcription Polymerase Chain Reaction (RT-PCR) 
diagnostic test result for SARS-CoV-2 infection at any time point prior to the scheduled 
visit 56 days after the first dose of vaccine. 
3. Receive any dose of investigational or approved passive antibodies for SARS-CoV-2 
infection prophylaxis (eg, convalescent plasma or sera, mAbs, hyperimmune globulin) 
outside of the study at any time point prior to the scheduled visit 56 days after the first 
dose of vaccine. 
4. Receive any other vaccine within 28 days prior to the study to the scheduled visit 56 days 
after the first dose of Moderna mRNA-1273 vaccine administered as part of this study.   
Exception: seasonal influenza vaccine is only prohibited within 14 days before or after 
study drug administration, or within 14 days before or after Moderna mRNA-1273 
vaccine administration. 
5. Receive systemic medications that suppresses the immune system (for corticosteroids, 
≥20 mg/day of prednisone equivalent) at any time point prior to the scheduled visit 56 
days after the first dose of vaccine.  
6. Receive IVIG or blood products at any time point prior to the scheduled visit 56 days 
after the first dose of vaccine.  
7. Subjects with incomplete infusions or injections of study drug or vaccine at any time 
point prior to the scheduled visit 56 days after the first dose of vaccine. 
8. Subjects with baseline neutralization antibody titer above the lower limit of quantification 
(LLOQ). 
The PPS is the primary analysis set for assessing vaccine response related endpoints. 
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3.2. 
Modified Full Analysis Set (mFAS) 
The modified full analysis set (mFAS) includes all randomized subjects who have been 
vaccinated with at least one dose and have a negative serology test result from the central 
laboratory test at baseline; it is based on the treatment received (as treated). 
3.3. 
Randomized Analysis Set 
The randomized analysis set includes all randomized subjects; it is based on the treatment 
allocated by the IWRS (as randomized).  
3.4. 
Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized subjects who have been vaccinated with at 
least one dose or received any study drug; it is based on the treatment received (as treated). 
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
SAF. 
3.5. 
Vaccine Booster Analysis Set 
The vaccine booster analysis set includes Per Protocol Set subjects who signed the optional sub-
study informed consent, have been vaccinated with the study-provided vaccine booster and did 
not have an adverse event of COVID (Preferred Terms of ‘COVID-19’, ‘Asymptomatic COVID-
19’, ‘SARS-CoV-2 test positive’, ‘COVID-19 pneumonia’) or a positive PCR test prior to the 
post-booster follow-up sample collection. 
3.6. 
The Pharmacokinetic Analysis Set  
The pharmacokinetics (PK) analysis sets (PKAS) are defined for each study drug separately and 
includes all subjects who received any study drug and who had at least 1 non-missing result 
following the first dose of the respective study drug. Subjects will be analyzed based on actual 
treatment received. 
3.7. 
Immunogenicity Analysis Sets   
The ADA analysis sets (AAS) are defined for each study drug separately and include all subjects 
who received any study drug (safety analysis set) and had at least one non-missing ADA result 
following the first dose of the respective study drug. The ADA analysis sets are based on the 
actual treatment received (as treated) rather than as randomized. 
The NAb analysis sets (NAbAS) are defined for each study drug separately and include all 
treated subjects that are included in the ADA analysis set and that tested negative at all ADA 
sampling times or tested positive at one or more post-dose ADA sampling times and had at least 
one non-missing post-dose NAb result (either imputed or analysis result). Samples that tested 
negative for ADA are not assayed in the NAb assay and the corresponding NAb results are 
imputed as negative and included as such in the NAb analysis set. Subjects in the NAbAS with 
multiple post-dose ADA results which consist of both imputed NAb-negative result(s) for ADA 
negative samples and only missing NAb results for all ADA-positive result(s), are set to NAb 
negative. Subjects in the NAbAS that have at least one post-dose positive NAb analysis result are 
set to NAb positive even if other NAb results are missing. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be obtained from the last available value up to the  
date of first dose of vaccine or REGN10933+REGN10987 (as applicable and whichever occurs 
first). 
The following demographic variables will be tabulated:  
• Age (years) 
• Age categories (≥18 to <45, ≥45 to <65, ≥65; and <65, and ≥65 years) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic/Latino) 
• Baseline Weight 
• Baseline Height 
• Baseline BMI 
• Baseline SARS-CoV-2 RT-PCR result (local lab) 
• Baseline SARS-CoV-2 serology results (central lab) 
Additional baseline characteristics will be included if needed. 
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated System Organ Class 
(SOC) according to Medical Dictionary for Regulatory Activities (MedDRA®). 
4.3. 
Prior / Concomitant Medication & Procedures 
Medications will be coded to an ATC Level 4, associated ATC Level 2, and standardized 
medication name according to the Anatomical Therapeutic Chemical Classification System. 
Procedures will be coded to a PT and associated SOC according to MedDRA®. 
Prior medications/procedures are defined as those that were started/performed prior to the first 
dose of vaccine or study drug (as applicable and whichever occurs first).  
On-treatment medications/procedures are defined those taken (or continued to be taken)/ 
performed following the first dose of vaccine or study drug (as applicable and whichever occurs 
first). 
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4.4. 
Prohibited Medication and Vaccine During Study 
The use of the following concomitant medications and vaccines may not require withdrawal of 
the participant from the study but may determine a subject’s evaluability in the analyses related 
to vaccine response (see Section 3.1).   
• Investigational drugs  
• Investigational or approved passive antibodies for SARS-CoV-2 infection 
prophylaxis (eg, convalescent plasma or sera, mAbs, hyperimmune globulin) 
• Any other vaccine within 28 days prior to or after study drug administration, other 
than Moderna mRNA-1273 vaccine administered as part of this study 
Exception: seasonal influenza vaccine is only prohibited within 14 days before or 
after study drug administration, or within 14 days before or after Moderna mRNA-
1273 vaccine administration. 
• Systemic medications that suppresses the immune system (for corticosteroids, ≥20 
mg/day of prednisone equivalent), except for the treatment of COVID-19 
4.5. 
Vaccine Response Variable 
4.5.1. 
Primary Vaccine Response Variable 
The primary endpoint is the 50% inhibitory dilution (ID50) neutralizing antibody titers of 
vaccine-induced neutralizing antibodies to SARS-CoV-2, assessed 56 days after the first dose of 
the vaccine (ie, the vaccine response assessment period). The 56-day time point corresponds to 
study day 71 for study arms 1, 2, 3, 7, 8, 6a, and 6c, and study day 57 for study arms 4, 5, 9, 6b, 
and 6d. 
The Neutralizing Antibody Assay (IMMUNO-COV REGN2118) is a functional assay that 
detects the presence of specific neutralizing antibodies capable of inhibiting vesicular stomatitis 
virus (VSV)- SARS2-Fluc. Infection by VSV-SARS2-Fluc results in the expression of firefly 
luciferase within Vero cells overexpressing the Ace-2 receptor (Vero-Ace-2). Luciferase 
substrate (d-luciferin) is added to assay plates to allow for a luminescence readout. The total 
luminescence (relative light units, RLU) corresponds to the extent of infection by VSV-SARS2-
Fluc. The ability of antibodies in human serum to block infection of Vero-Ace-2 cells by VSV-
SARS2-Fluc by 50% serves as a proxy readout for antibodies capable of neutralizing SARS-
CoV-2 infection. 
4.5.2. 
Secondary Vaccine Response Variables 
The secondary vaccine response variables in this study include: 
• Absolute values, change from baseline, and percentage change from baseline in 
concentrations of vaccine-induced antibodies to the following SARS-CoV-2 antigens 
over time: 
− Anti-S protein 
− Anti-RBD 
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− Other S protein subdomains (including S1, S2, and NTD)  
• 50% inhibitory dilution (ID50) neutralizing antibody titers of vaccine-induced 
neutralizing antibodies to SARS-CoV-2 S protein assessed over time after the first 
dose of Moderna mRNA 1273 vaccine 
The time points of the secondary vaccine response variables include 0, 6, 14, 28, 42, 56 days 
after the first dose of Moderna mRNA 1273 vaccine, except that day 56 is not applicable to the 
variable of 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing antibodies to 
SARS-CoV-2. In addition, variables associated with 6 days after the first dose of Moderna 
mRNA 1273 vaccine are only applicable to study arms 6d and 9, which corresponds to study day 
7 for these two arms. Variables will be reported in both BAU/mL and AU/mL units. 
4.5.3. 
Exploratory Vaccine Response Variables 
The exploratory vaccine response variables in this study include 
• Absolute percentages, change, and percentage change from baseline of blood-derived 
memory T cell responses specific to SARS-CoV-2 viral peptides over time 
• Absolute percentages, change, and percentage change from baseline of blood-derived 
B cell responses specific to SARS-CoV-2 S protein, RBD, and other S protein 
subdomains over time 
The time points of the exploratory vaccine response variables include 0, 6, 14, 28, 42, 56 days 
after the first dose of Moderna mRNA 1273 vaccine. In addition, variables associated with 6 
days after the first dose of Moderna mRNA 1273 vaccine are only applicable to study arms 6d 
and 9, which corresponds to study day 7 for these two arms. 
4.5.4. 
Additional Vaccine Response Variables 
World Health Organization (WHO) standard units (IU/mL) as well as Viral Neutralizing Titer 
(VNT) are collected and will be reported. 
4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to be coded to a 
PT and associated SOC according to the latest version of MedDRA®.  
For safety variables, the following observation periods are defined: 
• The pre-vaccination period is defined as the time from study drug administration to 
the first vaccine dose administration. 
• The primary series vaccination period is defined as the time from the first vaccine 
dose administration to 28 days after the second vaccine dose administration, and in 
subjects receiving only one dose of the vaccine, 28 days after the first vaccine dose 
administration. 
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• The post primary series vaccination period is defined as the time from the end of 
the primary series vaccination period to the end of the follow-up period in subjects 
who do not receive the sub-study provided vaccine booster. In subjects who receive 
the sub-study provided vaccine booster dose, the post-primary series vaccination 
period is defined as the time from the end of the primary series vaccination period to 
the administration of the sub-study provided vaccine booster. 
• The post-booster vaccination period is defined as the time from the sub-study 
provided vaccine booster to the end of the follow-up period. 
Treatment-emergent adverse events are defined as those that are not present at the time of the 
first dose of Moderna mRNA-1273 Vaccine or REGN10933+REGN10987 (as applicable and 
whichever occurs first) or represent the exacerbation of a pre-existing condition. 
4.6.2. 
Adverse Events of Special Interest 
AESIs 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): 
• Grade ≥2 infusion-related reactions to REGN10933+REGN10987 through day 4  
• Grade ≥3 injection-site reactions to REGN10933+REGN10987 or each dose of 
Moderna mRNA-1273 vaccine through day 4 post-injection 
• Grade ≥2 hypersensitivity reactions to REGN10933+REGN10987 or each dose of 
Moderna mRNA-1273 vaccine through day 29 post-infusion or post-injection (as 
applicable) 
4.6.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of blood chemistry, hematology, and urinalysis. 
Samples for laboratory testing will be collected at visits according to the Schedule of Events 
(Appendix 11.1). Samples will be analyzed by a central laboratory. The clinical laboratory data 
consists of blood chemistry, hematology, urinalysis and other specified in section 9.2.5 of the 
protocol. 
Clinical laboratory values will be presented in Standard International (SI) units.  
Potentially clinically significant value (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 collected include temperature, blood pressure, heart rate, and respiratory rate. PCSV 
ranges will be applied to corresponding vital sign parameter values according to (see PCSV 
criteria in Appendix 11.2). 
4.6.5. 
SARS-CoV-2 test results 
SARS-CoV-2 rapid RT-PCR testing will be conducted using nasopharyngeal swabs throughout 
the study according to the specific Schedules of Events for each enrolment wave. 
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SARS-CoV-2 rapid RT-PCR will be performed at unscheduled or planned scheduled visits for 
subjects with signs or symptoms consistent with COVID-19 or those who obtain a positive 
SARS-CoV-2 RT-PCR test result from the study site or another testing location. 
4.7. 
Pharmacokinetic Variables   
The pharmacokinetic variables are the concentrations of REGN10933 and REGN10987 in serum 
and time when a sample was collected. 
4.8. 
Immunogenicity Variables  
The immunogenicity variables are ADA response status, titer, and NAb status  at nominal 
sampling time/visit. Serum samples for immunogenicity analysis will be collected at the 
timepoints outlined in the Schedule of Events (Appendix 11.1). Samples positive in the ADA 
assays will be further characterized for ADA titers and for the presence of NAb. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of subjects 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum. For 
categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be tabulated by treatment group and overall for 
the PPS, mFAS and SAF analysis sets. 
Baseline is defined as the last available value prior to the first dose of Moderna mRNA-1273 
vaccine or REGN10933+REGN10987 (as applicable and whichever occurs first). 
5.2. 
Medical History 
Medical history will be tabulated by SOC and PT and by treatment group and overall for the 
SAF.  
5.3. 
Prior/Concomitant Medications & Procedures 
Prior medications and procedures will be tabulated by treatment group for the SAF.   
Concomitant medications will be tabulated by treatment group for the entire study period for the 
SAF. 
5.4. 
Prohibited Medications  
Prohibited medications will be tabulated by treatment group for the SAF.   
5.5. 
Subject Disposition 
Subject counts within each analysis set by treatment group and total will be presented. 
Additionally, the following will be tabulated: 
• Total number of screened subjects [defined as who signed the Informed Consent 
Form (ICF)] 
• Number of randomized subjects and number and reasons for subjects not randomized. 
• Number of subjects who discontinued from the study along with reason for study 
discontinuation 
If applicable, a listing of subjects treated but not randomized, subjects randomized but not 
treated, and subjects randomized but not treated as randomized will be provided. 
5.6. 
Extent of Study Treatment Exposure and Compliance 
The number of subjects whose infusion of REGN10933+REGN10987 or whose injection of 
vaccine was interrupted or incomplete will be tabulated by treatment group for the SAF.   
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The number of injections of primary series vaccine will be tabulated by treatment group for the 
SAF. Among those with more than one injection of vaccine, the time between first and second 
vaccination will be tabulated by treatment group for the SAF. The number of subjects with 
injections of booster vaccine will be tabulated by treatment group. Time from second injection of 
primary series vaccine to booster vaccine injection will be tabulated by treatment group for the 
SAF. 
 
The extent of  follow-up (completing visit 56 days after the first vaccine dose,  visit 52 weeks 
after the first vaccine dose) will be tabulated by treatment group for the SAF. 
5.7. 
Analysis of Vaccine Response Variables 
For efficacy variables, baseline is defined as the last available value prior to the first dose of 
Moderna mRNA-1273 vaccine. The analyses will be conducted based on the observed data with 
no imputation for missing data. Values below the LLOQ will be set to half of LLOQ and values 
above the upper limit of quantification (ULOQ) will be set to the ULOQ. 
5.7.1. 
Analysis of Primary Vaccine Response Variable 
The primary endpoint is the 50% inhibitory dilution (ID50) neutralizing antibody titers of 
vaccine-induced neutralizing antibodies to SARS-CoV-2, assessed on 56 days after the first dose 
of the vaccine. The 56-day time point corresponds to study day 71 for study arms 1, 2, 3, 7, 8, 6a, 
and 6c, and study day 57 for study arms 4, 5, 9, 6b, and 6d.  For all analyses, the vaccine alone 
arms (i.e. arms 6a, 6b, 6c and 6d) will be pooled in the analysis.   
An analysis of covariance (ANCOVA) model with treatment group as a fixed effect and age as a 
continuous covariate will be run in order to perform the primary analysis for the PPS. The least 
squares mean estimates and associated 95% confidence interval for the endpoint will be reported 
for each treatment group, as well as for the relative differences between each combination of 
Moderna mRNA-1273 vaccine and REGN10933+REGN10987 arm (i.e. arms 1 - 5, and 7 - 9) 
and the pooled vaccine alone group. 
Data may be fitted in the log 2 scale, and final outputs of geometric means and relative 
differences of the geometric mean ratio will be reported through the back-transformation. 
Let  
, 
 denote the least squares mean estimates and  
, 
 , 
 denote the associated 
estimated variances and covariance for the endpoint of interest of treatment groups A and B, 
respectively. 
Geometric means and associated 95% confidence intervals for treatment groups A and B will be 
calculated as:  
, (
, 
), 
and  
, (
, 
). 
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Relative difference of the geometric mean ratio and associated 95% confidence interval for 
treatment groups A and B will be calculated as:  
)
, (
, 
). 
5.7.2. 
Analysis of Secondary Vaccine Response Variables 
Secondary vaccine response variables will also be analyzed using an ANCOVA model with 
treatment group as a fixed effect and age as a covariate in the model using the Per Protocol 
Analysis Set. 
The least square means estimates as well as the relative difference of these estimates between 
each combination of Moderna mRNA-1273 vaccine and REGN10933+REGN10987 group and 
the pooled vaccine alone group will be provided along with the associated 95% confidence 
interval.  
Data may be fitted in the log scale, and final outputs will be back-transformed to the original 
scale using the same method as described for the primary endpoint (see Section 5.7.1).  
For concentrations of vaccine-induced antibodies to the following SARS-CoV-2 antigens, if a 
log transformation is needed, modelling will use a log transformation with base 10: 
− Anti-S protein 
− Anti-RBD 
− Other S protein subdomains (including S1, S2, and NTD)  
For variables listed below, if a log transformation is needed, modelling will use a log 
transformation with base 2:  
• 50% inhibitory dilution (ID50) titers of vaccine-induced neutralizing antibodies to 
SARS-CoV-2 S protein assessed over time after the first dose of Moderna 
mRNA-1273 vaccine 
Numerical summaries of observed value, change from baseline, and percentage change from 
baseline will also be tabulated. 
5.7.3. 
Analysis of Exploratory Vaccine Response Variables 
Exploratory vaccine response variables will be analyzed in a similar manner as described for the 
secondary vaccine response variables.  
Accompanying descriptive analyses will be provided to all (primary/secondary/exploratory) 
vaccine response variables.   
The distribution of endpoint variables will be checked to ensure ANCOVA type analyses are 
appropriate.  If such modeling is deemed not appropriate, only raw data descriptions will be 
provided. 
On limited numbers of samples, an exploratory analysis will be performed with data from a 
second neutralization assay that will be summarized in a separate report.  
 
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5.7.4. 
Analysis of Additional Vaccine Response Variables 
VNT and WHO standard units will be analyzed in a similar manner as described for the primary 
vaccine response variable. Efficacy variables may also be explored using the mFAS. 
5.7.5. 
Supplementary and Subgroup Analyses 
Supplementary analysis: 
In order to assess the consistency of results due to concurrent randomization, analyses of the 
primary vaccine response variable may be performed separately within waves 1, 2 and within 
waves 3, 4, respectively.  
Subgroup analysis: 
The following subgroup analysis may be performed in Per Protocol Analysis Set in order to 
assess the consistency of results:  
• age groups: <65 vs ≥65 (if applicable)  
• gender: male vs female  
5.7.6. 
Analysis of sub-study vaccine booster administration 
Analysis to include assessment of vaccine immune responses over time among the vaccine 
booster analysis set. Accompanying descriptive statistics at individual time points will also be 
provided. 
5.8. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed within the SAF population.   
5.8.1. 
Adverse Events  
All AEs reported in this study will be coded using the currently available version of MedDRA®. 
Coding will be to lowest level terms. The PT and the primary SOC will be listed. 
All adverse events will be provided in a listing. Listing of deaths and other SAEs will also be 
provided.  
Tabulations by treatment group will include the following: 
All periods combined  
• Overview of TEAEs 
• TEAEs by SOC and PT 
• TEAEs by SOC and PT and Severity 
• Serious TEAEs by SOC and PT 
• Study Drug Related TEAEs by SOC and PT 
• Vaccine Related TEAEs by SOC and PT 
• Study Drug Related Infusion Related Reaction TEAEs by SOC and PT  
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• Study Drug Related Injection Site Reaction TEAEs by SOC and PT 
• Vaccine Related Injection Site Reaction TEAEs by SOC and PT 
• Study Drug Related Hypersensitivity Reaction TEAEs by SOC and PT 
• Vaccine Related Hypersensitivity Reaction TEAEs by SOC and PT 
• Treatment-Emergent AESIs by SOC and PT 
• TEAEs leading to permanent discontinuation of vaccine by SOC and PT 
• TEAEs leading to permanent discontinuation of study drug by SOC and PT 
• TEAEs leading to death by SOC and PT 
Pre-vaccination period 
• Overview of TEAEs 
• TEAEs by SOC and PT 
• TEAEs by SOC and PT and Severity 
• Serious TEAEs by SOC and PT 
• Study Drug Related TEAEs by SOC and PT 
• Study Drug Related Infusion Related Reaction TEAEs by SOC and PT 
• Study Drug Related Injection Site Reaction TEAEs by SOC and PT 
• Study Drug Related Hypersensitivity Reaction TEAEs by SOC and PT 
• TEAEs leading to permanent discontinuation of study drug by SOC and PT 
• TEAEs leading to death by SOC and PT 
Primary series vaccination period and Post-booster vaccination period 
• Overview of TEAEs 
• TEAEs by SOC and PT 
• TEAEs by SOC and PT and Severity 
• Serious TEAEs by SOC and PT 
• Study Drug Related TEAEs by SOC and PT 
• Vaccine Related TEAEs by SOC and PT 
• Study Drug Related Infusion Related Reaction TEAEs by SOC and PT 
• Study Drug Related Injection Site Reaction TEAEs by SOC and PT 
• Vaccine Related Injection Site Reaction TEAEs by SOC and PT 
• Study Drug Related Hypersensitivity Reaction TEAEs by SOC and PT   
• Vaccine Related Hypersensitivity Reaction TEAEs by SOC and PT 
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• TEAEs leading to permanent discontinuation of vaccine by SOC and PT 
• TEAEs leading to permanent discontinuation of study drug by SOC and PT 
• TEAEs leading to death by SOC and PT 
5.8.2. 
Clinical Laboratory Measurements  
Laboratory test results will be tabulated by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of subjects with potentially clinically significant value (PCSV) at any 
post-randomization time point will be tabulated for each clinical laboratory test for all subjects 
and separately for subjects 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, and respiratory rate) will be tabulated by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Graphs of mean (+/- SE) value may be provided.   
5.9. 
Analysis of Pharmacokinetic Data 
The concentrations of REGN10933 and REGN10987 in serum over time will be summarized 
descriptively for each of the treatment groups. No formal statistical hypothesis testing will be 
performed. 
5.10. 
Analysis of Immunogenicity Data 
5.10.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.8 will be summarized using descriptive 
statistics. Immunogenicity will be characterized per drug molecule by ADA status, ADA 
category, and maximum titer observed in subjects in the ADA analysis sets. 
The ADA status of each subject may be classified as one of the following: 
• Positive 
• Pre-existing – If the baseline sample is positive and all post baseline ADA titers are 
reported as less than 9-fold the baseline titer value 
• Negative – If all samples are found to be negative in the ADA assay. 
The ADA category of each positive subject is classified as: 
• Treatment-boosted – A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥9-fold the baseline titer value 
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• Treatment-emergent – A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Subjects that are treatment-emergent 
will be further categorized as follows: 
− Persistent – A positive result in the ADA assay detected in at least 2 consecutive 
post baseline samples separated by at least a 16-week post baseline period (based 
on nominal sampling time), with no ADA-negative results in-between, regardless 
of any missing samples 
− Transient – Not persistent or indeterminate, regardless of any missing samples 
− Indeterminate – A positive result in the ADA assay at the last collection time 
point only, regardless of any missing samples. 
The maximum titer category of each subject is classified as: 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
The following will be summarized by treatment group and ADA titer level: 
• Number (n) and percent (%) of ADA-negative subjects 
• Number (n) and percent (%) of pre-existing subjects 
• Number (n) and percent (%) of treatment-emergent ADA positive subjects 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
subjects 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
subjects 
− Number (n) and percent (%) of transient treatment-emergent ADA positive 
subjects 
• Number (n) and percent (%) of treatment-boosted ADA positive subjects 
 
Listing of all ADA titer levels will be provided for subjects with pre-existing, treatment-
emergent and treatment-boosted ADA response. 
5.10.2. 
Analysis of NAb Data  
The absolute occurrence (n) and percent of subjects (%) with NAb status in the NAb analysis 
sets will be provided by treatment groups. The NAb status is categorized as follows: 
• Negative: Samples tested negative in the ADA assays, or samples positive in the 
ADA assays but tested negative in the NAb assays, or ADA-positive results without 
Nab analysis results. 
• Positive: Samples tested positive in the NAb assays. 
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5.10.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
5.10.3.1. Immunogenicity and Exposure 
Potential association between immunogenicity and systemic exposure to REGN10933 and 
REGN10987 will be explored by treatment groups. Plots of individual REGN10933  and 
REGN10987 concentration time profiles may be provided to examine the potential impact of 
ADA category, maximum titer category and NAb status on these profiles. 
5.10.3.2. Immunogenicity and Safety and Exposure 
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 
o Treatment-emergent 
o Treatment-boosted 
• Maximum post-baseline titer category 
• NAb positive 
 
 
 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis. 
6.1. 
Definition of Baseline 
Unless otherwise specified, the baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of the first dose of Moderna 
mRNA-1273 vaccine or REGN10933+REGN10987  (as applicable and whichever occurs first). 
6.2. 
Data Handling Convention for Vaccine Response Variables  
Values below the LLOQ will be set to half of LLOQ and values above the upper limit of 
quantification (ULOQ) will be set to the ULOQ.  If two or more measurements correspond to the 
same visit, the lowest value will be used. 
6.3. 
Data Handling Convention for Missing Data 
Adverse Event 
If the severity of a TEAE is missing, it will be classified as severe in the frequency tables by 
intensity of TEAEs.  
If the assessment of relationship of a TEAE to either Moderna mRNA-1273 vaccine or 
REGN10933+REGN10987 is missing, following rules will be applied 
• If the relationship to Moderna mRNA-1273 vaccine is missing, the TEAE will be 
classified as related to Moderna mRNA-1273 vaccine if the TEAE occurs after the 
first dose of vaccine 
• If the relationship to REGN10933+REGN10987 is missing, the TEAE will be 
classified as related to REGN10933+REGN10987 if the TEAE occurs after the 
REGN10933+REGN10987 administration 
If the start time of an AE is completely missing, it will be assumed to have occurred on the time 
of the first dose of Moderna mRNA-1273 vaccine or REGN10933+REGN10987 (as applicable 
and whichever occurs first). When the partial AE time information does not indicate that in 
which period (pre-treatment/pre-vaccination/vaccination/post-vaccination) the AE starts,  the 
following rules will be applied (1) if the AE could happen either in pre-treatment or pre-
vaccination periods, the AE will be classified to the pre-vaccination period (applicable to arms 1, 
2, 3, 4, 5, 7, 8); (2) if the AE could happen either in pre-treatment or vaccination periods, the AE 
will be classified to the vaccination period (applicable to arms 6a – 6d and 9); (3) if the AE could 
happen either in pre-vaccination or vaccination periods, the AE will be classified to the 
vaccination period (applicable to arms 1, 2, 3, 4, 5, 7, 8); (4) if the AE could happen either in 
vaccination or post-vaccination periods, the AE will be classified to the vaccination period. If the 
end date of the AE is missing, then the date of the last follow-up will be used for imputation.  
Medication/Procedure 
If a medication time is missing or partially missing and it cannot be determined whether it was 
taken prior or concomitantly or stopped prior to the first dose of Moderna mRNA-1273 vaccine 
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or REGN10933+REGN10987 (as applicable and whichever occurs first), it will be considered as 
concomitant medication/procedure by imputing the start time on the time of first dose of 
Moderna mRNA-1273 vaccine or REGN10933+REGN10987 (as applicable and whichever 
occurs first). 
Potentially Clinically Significant Values 
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 tabulated or taken into account in 
the computation of PCSVs. 
6.4. 
Analysis Windows 
Assessments repeatedly collected during the study will be defined by the eCRF visit label for 
temporal tabulations and subject listings. 
6.5. 
Unscheduled Assessments 
For safety variables unscheduled visit measurements may be used to determine abnormal values, 
and PCSVs. 
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7. 
INTERIM ANALYSIS 
An interim analysis may be conducted after subjects within common enrollment waves have 
completed the primary endpoint visit (ie, 56 days after the first dose of the vaccine).  Such 
analyses represent an interim analyses of the primary endpoint variable and is not considered the 
final analysis of the primary endpoint. 
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8. 
TIMING OF PRIMARY AND FINAL ANALYSES 
The primary vaccine response analysis will be conducted after all subjects have finished the 
primary endpoint visit (ie, 56 days after the first dose of the vaccine).  This analysis represents 
the final analysis of the primary endpoint and is not considered an interim analysis.  
After all subjects finish 1-year of follow-up, the final long-term vaccine response, safety and 
biomarker data from this study will be reported.   
 
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9. 
SOFTWARE 
All statistical analyses will be done using SAS version 9.4 and R 3.5.3 or higher. 
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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. 
1. 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. 
2. 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. 
3. Division of Cancer Treatment and Diagnosis [DCTD]. Common Terminology Criteria for 
Adverse 
Events 
(CTCAE) 
version 
5.0. 
National 
Cancer 
Institute.https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTC
AE_v5_Quick_Reference_8.5x11.pdf. Published 2017. [Accessed] 2 July 2020. 
4. Garcia-Beltran WF, Lam EC, Denis KS, Nitido AD, Garcia ZH, Hauser BM, et al. 
Multiple SARSCoV-2 variants escape neutralization by vaccine-induced humoral 
immunity. medRxiv 2021:2021.2002.2014.21251704. 
5. Chemaitelly, H., Yassine, H.M., Benslimane, F.M. et al. mRNA-1273 COVID-19 
vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 
disease in Qatar. Nat Med 27, 1614–1621 (2021). 
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11. 
APPENDIX 
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11.1. 
Schedule of Events 
Table 2: 
Schedule of Events for Arms 1, 2, 3, and 6a (Enrollment Wave 1) and Arms 7, 8, and 6c (Enrollment Wave 3) 
 
 
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Table 3: 
Schedule of Events for Arms 4, 5, and 6b (Enrollment Wave 2) 
 
 
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Table 4: 
Schedule of Events for Study Arms 9 and 6d (Enrollment Wave 4) 
 
 
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Table 5: 
Schedule of Events for the Moderna mRNA-1273 Vaccine Booster Sub-Study 
 
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Footnotes for the Schedules of Events: 
1. 
Throughout the study, study drug and/or vaccine administration will occur after all samples have been collected and all assessments have been performed. 
2. 
Separate consent is required for participation in the optional vaccine booster sub-study (Protocol Section 9.2.10), optional future biomedical research sub-study (Protocol 
Section 9.2.8), and optional pharmacogenomics sub-study (Protocol Section 9.2.9). For subjects consenting to the genomics sub-study, the blood sample for genomic DNA 
should be collected at baseline (day 1) but may be collected at any visit. 
3. 
All women of childbearing potential (WOCBP), with the exception of women with documented bilateral tubal ligation, will require pregnancy testing at screening, prior to 
study drug administration, and prior to COVID-19 vaccine administration. If a urine pregnancy test result is positive, a serum pregnancy test will be performed for 
confirmation. Subjects with confirmed pregnancy (by serum test) at screening will not be randomized. If the screening visit occurs on the same day as the baseline visit on day 
1, pregnancy testing does not need to be repeated. Subjects with confirmed pregnancy at post-baseline dosing visits will be counseled according to Protocol Section 8.3.3. 
4. 
If the screening visit occurs on the same day as the baseline visit on day 1, SARS-CoV-2-rapid RT-PCR test does not need to be repeated. Nasopharyngeal swabs will be used 
for rapid RT-PCR testing. Refer to Protocol Section 6.1.2 for more information on sample collection and visit scheduling for subjects with suspected COVID-19 or positive 
RT-PCR test result. 
Post-baseline samples only: If the rapid RT-PCR test is positive at any time point postbaseline, the samples will be banked for viral sequencing. 
Additional information is provided in Protocol Section 9.2.1.2. 
5. 
If a rapid serology test is used at the screening visit, and screening occurs on the same day as the baseline visit, the rapid serology test does not need to be repeated at baseline. 
Additional information about the rapid serology test is provided in Protocol Section 9.2.1.3. 
At screening, if the rapid serology test is not available locally, a rapid test may be performed at a central laboratory to determine eligibility, and a repeat of the test is not 
required at baseline. 
6. 
Subjects will receive site-managed assignment (at screening) and randomized treatment assignment (at baseline on day 1) according to Protocol Section 8.5. 
7. 
Note that not all subjects will receive study drug at randomization. Refer to Protocol Section 8.5 and Protocol Figure 1 for more information. 
Study arms 4 and 5: Subjects assigned to study arms 4 and 5 will receive both the study drug and vaccine on day 1. The study drug will be administered first, followed by 
the vaccine. There must be a minimum of 2 hours waiting period between administration of the study drug and subsequent vaccine administration. Approximately 24 hours 
after completion of the study drug and vaccine administration on day 1, subjects will be followed up by telephone for safety. Subjects should be monitored for at least 1 hour 
after study drug or vaccine administration. 
Study arms 6a, 6b, 6c, and 6d only: Subjects assigned to one of these study arms will not receive study drug. These subjects will receive the vaccine only. These subjects 
should be monitored for at least 30 minutes after vaccine administration. 
Refer to Protocol Section 9.2.2 for additional information concerning administration and monitoring requirements following study drug and/or vaccine administration. 
8. 
Serology characterization assays will be used to assess antibodies against various SARS-CoV-2 antigens including: S protein, RBD, S1, and N protein. Refer to Protocol 
Section 9.2.3.1, Protocol Section 9.2.3.2, and Section 9.2.3.3 for more information on procedures and assays related to vaccine response assessment. 
9. 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate will be collected prior to and 30 minutes following each administration of the study drug or 
vaccine primary series (first and second dose) as described in Section 9.2.4.1. 
10. Actual dosing time and drug concentration sample collection times will be recorded. 
Study arms 1, 2, 3, 7, 8, and 9 (receiving IV infusion of study drug): At the indicated visit, blood for assessment of drug concentration in serum will be taken prior to 
dosing and within 60 minutes after the end of infusion (EOI). The EOI sample should be collected from the arm contralateral to that used for IV infusion. If not medically 
feasible, the EOI sample can be drawn from the same arm, but not from the infusion catheter. 
Study arms 4 and 5 (receiving SC injection of study drug): At the screening/baseline visit, blood for assessment of drug concentration in serum will be taken prior to 
dosing. The post-dose blood collection should occur at least 1 hour after study drug administration. 
Study arms 6a, 6b, 6c, and 6d (receiving no study drug): No blood for assessment of drug concentration in serum will be collected. 
11. The window for pre-dose ADA sample collection should be as close to administration of study drug as is reasonable. Actual dosing time and ADA sample collection times 
will be recorded. 
Study arms 6a, 6b, 6c, and 6d (receiving no study drug): No blood for ADA assessment will be collected. 
12. Adverse events will be continuously monitored as described in Protocol Section 10.1.1. 
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13. For Arms 1, 2, 3, 6a, 6c, 7 and 8: For subjects receiving their COVID-19 vaccine booster as part of the sub-study, the vaccine booster may be administered at any time from 5 
months after their second vaccine dose until study day 345. The actual date the subject received their second vaccine dose should be used (as opposed to using study day 43) 
to determine when the booster window should begin. 
14. For Arms 4, 5, 6b, 6d, and 9: For subjects receiving their COVID-19 booster as part of the sub-study, the vaccine booster may be administered at any time from 5 months after 
their second vaccine dose until study day 331. The actual date the subject received their second vaccine dose should be used (as opposed to using study day 29) to determine 
when the booster window should begin.
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11.2. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV 
For Studies in healthy subjects only 
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 
Enzymes activities must be expressed 
in ULN, not in IU/L. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008 
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.  
Concept paper on DILI – FDA draft 
Guidance Oct 2008 
Internal DILI WG Oct 2008 
Conjugated 
bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN, and 
baseline Total Bilirubin ≤ 35% or TBILI ≤1.5 ULN 
Conjugated bilirubin dosed 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 
Internal DILI WG Oct 2008 
CPK 
>3 and ≤ 10 ULN and baseline ≤ 3ULN 
>10 ULN and baseline ≤10ULN 
FDA Feb 2005 
Am J Cardio April 2006 
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 
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Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
Creatinine 
Clearance 
(Cockcroft's 
formula) 
<15 ml/min and baseline ≥15 ml/min (end 
stage renal impairment) 
≥15 -<30 ml/min and baseline ≥30 ml/min 
(severe renal impairment) 
≥30 - < 60 ml/min and baseline ≥60 ml/min 
(moderate renal impairment) 
≥60 - < 90 ml/min and baseline ≥90 ml/min (mild 
renal impairment) 
FDA draft guidance 2010 
Four independent criteria 
Uric Acid 
Hyperuricemia: 
 
       
Hypouricemia: 
 
>408 μmol/L or >ULN (if ULN≥408 μmol/L) 
and baseline ≤408 μmol/L or ≤ULN (if 
ULN≥408 μmol/L)   
<120 μmol/L or <LLN (if LLN≤120 μmol/L) and 
baseline ≥ 120 μmol/L or ≥LLN (if LLN≤120 
μmol/L)   
Harrison- Principles of Internal 
Medicine 17th Ed., 2008. 
Two independent criteria 
Blood Urea 
Nitrogen 
≥17 mmol/L or ≥ULN (if ULN≥17 mmol/L) 
and baseline <17 mmol/L or <ULN (if 
ULN≥17 mmol/L)   
Two independent criteria 
Chloride                
   
Hypochloremia: 
 
   Hyperchloremia: 
 
<80 mmol/L or <LLN (if LLN≤80 mmol/L) 
and baseline ≥ 80 mmol/L or ≥LLN (if 
LLN≤80 mmol/L)   
>115 mmol/L or >ULN (if ULN≥115 mmol/L) 
and baseline ≤ 115 mmol/L or ≤ULN (if 
ULN≥115 mmol/L)   
Two independent criteria  
Sodium 
   Hyponatremia: 
 
   Hypernatremia: 
 
≤129 mmol/L  or ≤LLN (if LLN≤129 mmol/L) 
and baseline > 129 mmol/L  or >LLN (if 
LLN≤129 mmol/L)   
≥160 mmol/L  or ≥ULN (if ULN≥160 mmol/L )  
and baseline <160 mmol/L  or <ULN (if ULN≥160 
mmol/L )   
Two independent criteria 
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 
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Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
Total Cholesterol 
≥7.74 mmol/L or ≥ULN (if ULN≥7.74 mmol/L) 
and baseline < 7.74 mmol/L or <ULN (if 
ULN≥7.74 mmol/L) 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L or ≥ULN (if ULN≥4.6 mmol/L) and 
baseline < 4.6 mmol/L or <ULN (if ULN≥4.6 
mmol/L) 
Threshold for therapeutic intervention 
Glucose 
   
Hypoglycaemia 
   
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN and baseline >3.9 
mmol/L or ≥ LLN  
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) and 
baseline < 11.1 mmol/L (unfasted); <7 mmol/L 
(fasted)  
 
ADA Jan 2008. 
HbA1c 
>8%  and baseline  ≤ 8%  
 
Albumin 
≤25 g/L or ≤LLN (if LLN≤25 g/L) and 
baseline >25 g/L or >LLN (if LLN≤25 g/L)   
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
and 
baseline ≤2 ULN or ≤10 mg/L (if ULN not 
provided) 
 FDA Sept 2005 
 
Hematology 
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. 
 
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)  
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) 
International Consensus meeting on 
drug-induced blood cytopenias, 
1991. 
 
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Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
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. 
Hemoglobin 
≤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) 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. 
Hematocrit 
≤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) 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 
 
RBC 
≥6 Tera/L or ≥ULN (if ULN≥6 Tera/L) and 
baseline < 6 Tera/L or <ULN (if ULN≥6 
Tera/L) 
 
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Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
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 
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 
Weight 
 5% increase from baseline 
5% decrease from baseline 
FDA Feb 2007  
 
 
 
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