Clinical trial NCT05081388
Conditions: SARS-CoV-2
Keywords: COVID-19 Non-hospitalized Low-risk Symptomatic Coronavirus disease 2019 (COVID-19) Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) coronavirus
Sponsor: Regeneron Pharmaceuticals
Start date: 2021-11-08; Completion date: 2022-06-30
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objectives Phase 1 (Safety and Tolerability)

• Evaluate the safety and tolerability of REGN14256+imdevimab and REGN14256 monotherapy, as measured by treatment-emergent adverse events (TEAEs), injection-site reactions (ISRs), and hypersensitivity reactions

Phase 1/2 (Virologic Efficacy) • Evaluate the virologic efficacy of REGN14256+imdevimab and REGN14256 monotherapy compared to placebo, as measured by time-weighted average (TWA) change from baseline in viral load through day 7

Phase 1/2/3 (Clinical Efficacy)

• Evaluate the clinical efficacy of REGN14256+imdevimab compared to placebo, as measured by COVID-19 symptoms resolution

Secondary Objectives Phase 1 (Safety and Tolerability) • Evaluate the safety and tolerability of REGN14256+imdevimab and REGN14256 monotherapy, as measured by treatment-emergent serious adverse events (SAEs)

Phase 2 and Phase 3 (Safety and Tolerability)

• Evaluate the safety and tolerability of REGN14256+imdevimab and REGN14256 monotherapy, as measured by TEAEs, ISRs, hypersensitivity reactions, and SAEs

Phase 1, Phase 2, and Phase 3 (Virologic Efficacy, Drug Concentration, and Immunogenicity)

* Evaluate additional indicators of virologic efficacy of REGN14256+imdevimab and REGN14256 monotherapy
* Characterize the concentration-time profile of REGN14256 administered in combination with imdevimab or alone as a monotherapy
* Assess the immunogenicity of REGN14256 administered in combination with imdevimab or alone as a monotherapy

Detailed description:

Arms: arm 1: Phase 1, Phase 2: Randomized 1:1:1:1:1 Phase 3: (≥18 Years): Randomized 1:1:1 Phase 3: (Open label) (≥12 and \<18 Years) arm 2: Phase 1, Phase 2: Randomized 1:1:1:1:1 arm 3: Phase 1, Phase 2: Randomized 1:1:1:1:1 arm 4: Phase 1, Phase 2: Randomized 1:1:1:1:1 Phase 3: (≥18 Years): Randomized 1:1:1 arm 5: Phase 1, Phase 2: Randomized 1:1:1:1:1 Phase 3: (≥18 Years): Randomized 1:1:1
Interventions: intervention 1: REGN14256 intervention 2: imdevimab intervention 3: casirivimab + imdevimab intervention 4: Placebo
Intervention descriptions: intervention 1: Sub-cutaneous (SC) single dose intervention 2: SC single dose intervention 3: SC single dose intervention 4: SC single dose

Protocol documents:
Prot_000.pdf: 
EudraCT: 2021-004760-10 
IND: 156846 
Regeneron Pharmaceuticals, Inc.
Clinical Study Protocol 
A PHASE 1/2/3 ADAPTIVE STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, AND EFFICACY OF REGN14256+IMDEVIMAB FOR THE 
TREATMENT OF COVID-19 PATIENTS WITHOUT RISK FACTORS FOR 
PROGRESSION TO SEVERE DISEASE 
Compound: 
REGN14256+Imdevimab 
Clinical Phase: 
1/2/3 
Protocol Number: 
R14256-COV-2149 
Protocol Version: 
Amendment 1  
Amendment 1 Date of Issue: 
See appended electronic signature page 
Original Date of Issue: 
26 Aug 2021 
Medical/Study Director: 
 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol 
 
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CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 1 
The primary purpose of this amendment is to update the study design based on health authority 
feedback as follows. 
Description of Change 
Brief Rationale  
Section(s) 
Changes Based on Health Authority Feedback 
The study design was changed from a phase 3 
study to an adaptive phase 1/2/3 protocol. 
• The first-in-human (FIH) phase 1 portion of the 
study will enroll approximately 100 patients to 
evaluate the safety and tolerability of 
REGN14256+imdevimab and REGN14256 
monotherapy. There will be 2 sentinel safety 
analyses by an independent data monitoring 
committee (IDMC), during each of which study 
enrollment will be paused. 
• Phase 2 portion of the study will assess the 
virologic efficacy of REGN14256+imdevimab 
and REGN14256 monotherapy (previously 
phase 3 part A).  
• Phase 3 portion of the study will assess the 
clinical efficacy of REGN14256+imdevimab 
(previously phase 3 part B).  
Change 
implemented per 
health authority 
feedback, with the 
aim of providing an 
enrollment pause 
for sentinel safety 
analysis during the 
FIH portion of the 
study  
Section 2.1 Primary Objectives 
Section 2.2 Secondary Objectives 
Section 3.2.1 Rationale for Study 
Design 
Section 3.2.2 Rationale for Dose 
Selection  
Section 4.1 Primary Endpoints 
Section 4.2 Secondary Endpoints  
Section 4.3 Exploratory Endpoints  
Section 6.1 Study Description and 
Duration  
Section 6.1.3 Sentinel Cohort (Part 
A) [removed] 
Figure 1 Study Flow Diagram: Phase 
1 [new] 
Figure 2 Study Flow Diagram: Phase 
2 
Figure 3 Study Flow Diagram: Phase 
3 
Table 1 Schedule of Events: Phase 1 
[new] 
Table 2 Schedule of Events: Phase 2 
Table 3 Schedule of Events: Phase 3 
Section 11.1 Statistical Hypothesis  
In addition to the oversight described in the 
original protocol, the IDMC will perform the 
following functions: 
• Sentinel safety analysis 1. In phase 1, after the 
first 40 patients reach study day 7 (6 days after 
dosing), the study will pause and the IDMC will 
review all unblinded safety data available at the 
time. After the IDMC evaluates these safety 
data, and if a positive recommendation to 
continue the study is provided, enrollment of the 
remaining phase 1 patients will begin. 
• Sentinel safety analysis 2. After phase 1 is 
fully enrolled and the last patient reaches study 
day 7, the study will pause and the IDMC will 
review all unblinded safety data available at the 
time. After the IDMC evaluates these safety 
data, and if a positive recommendation to 
continue the study is provided, enrollment in 
phase 2 will begin.  
Virologic and clinical efficacy data will remain 
blinded during the sentinel safety analyses by 
the IDMC, to facilitate subsequent phase 1/2 
and phase 1/2/3 analyses of virologic and 
clinical efficacy. 
• Planned interim safety analyses. In phase 2, 
the IDMC will perform interim safety analyses, 
To prospectively 
define sentinel 
safety analyses  
and planned 
interim safety 
analyses by the 
IDMC  
Section 3.2.1.2 Safety and Tolerability 
and the Phase 1 Sentinel Safety Group 
Section 6.3.1 Independent Data 
Monitoring Committee 
 
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CONFIDENTIAL 
Description of Change 
Brief Rationale  
Section(s) 
occurring (at minimum) after approximately 
half of the patients are enrolled and followed to 
study day 7. Based on these analyses, the IDMC 
may make recommendations on study conduct, 
including early study closure for safety. If phase 
2 enrollment is slow, the IDMC will perform 
the interim safety analysis when approximately 
200 patients have been enrolled in phase 2 and 
followed to day 7. Enrollment pauses are not 
planned during phase 2, unless otherwise 
indicated by review of ongoing phase 1 or phase 
2 safety data.  
Additional information will be provided in the 
IDMC charter. 
The occurrence of one of the following events at 
any time during the study will trigger a review 
by the Sponsor, and communication with the 
IDMC, to assess if the study should be temporarily 
paused (ie, pausing of screening, randomization, 
and dosing of study drug): 
• Three treatment-related serious adverse events 
(SAEs) or adverse events of special interest 
(AESIs), or 
• One treatment-related SAE with a fatal outcome 
To ensure adequate 
monitoring of 
safety-related 
events in the FIH 
portion of the study 
Section 6.4 Study Stopping Rules  
Grade ≥3 hypersensitivity reactions, rather than 
grade ≥2, will be reported as AESI through day 
29. 
Note that definitions of injection-site reactions 
(ISRs) and hypersensitivity reactions through day 
4 and day 29, respectively, were included in the 
original protocol in error and have been removed. 
While all ISRs and hypersensitivity reactions that 
occur anytime during or after subcutaneous 
injections will be recorded, only grade ≥3 ISRs 
through day 4 and grade ≥3 hypersensitivity 
reactions through day 29 will be reported as 
AESIs.  
NCI-CTCAE guidelines have been retained for 
severity evaluation of ISRs and hypersensitivity 
reactions. 
For consistency 
with other studies 
using SC route of 
administration 
within the 
casirivimab+imdev
imab clinical 
development 
program; and to 
provide clarity for 
AESI reporting  
Section 10.1.1 General Guidelines 
Section 10.1.3 Events that Require 
Expedited Reporting to Sponsor 
Section 10.2.4 Injection-Site Reactions 
and Hypersensitivity Reactions 
[removed] 
Additional information and clarifications have 
been provided: 
• Rationale for inclusion of REGN14256 and 
imdevimab monotherapy arms in phase 1/2  
• Rationale for performing the phase 2 primary 
analysis (virologic efficacy) in patients who are 
seronegative at baseline  
• Clarification that outcomes in the phase 3 
adolescent cohort will be analyzed descriptively 
and not be included in the primary clinical 
efficacy analysis  
• Clarification for the estimated sample size in 
phase 3 
• Clarification that all efficacy hypotheses are 
tested with respect to placebo 
To ensure accuracy 
and clarity in the 
statistical design 
Section 3.2.1.1 Study Population 
Section 3.2.1.2 Safety and Tolerability 
and the Phase 1 Sentinel Safety Group 
Section 3.2.1.3 Assessment of Efficacy
Section 3.2.1.4 Phase 3 Enrollment of 
Adolescents [new] 
Section 11.2 Justification of Sample 
Size 
Section 11.4.3 Efficacy Analyses 
Other Changes 
In phase 1, the proportion of patients with 
treatment-emergent SAEs will be assessed 
throughout the study as a secondary endpoint 
rather than primary. 
The primary 
endpoint for phase 
1 (all treatment-
emergent adverse 
events [TEAEs] 
through day 29) is 
Section 2.1 Primary Objectives 
Section 2.2 Secondary Objectives 
Section 4.1 Primary Endpoints 
Section 4.2 Secondary Endpoints  
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CONFIDENTIAL 
Description of Change 
Brief Rationale  
Section(s) 
inclusive of SAEs 
through this early 
time period. 
Optional future biomedical research sub-study was 
removed. 
Due to operational 
feasibility  
Table 1 Schedule of Events: Phase 1 
[new] 
Table 2 Schedule of Events: Phase 2 
Table 3 Schedule of Events: Phase 3 
Section 9.2.11 Future Biomedical 
Research (Optional) [removed] 
Minor clarifications for consistency and other 
minor updates (typographical, editorial, 
formatting, administrative) were made.  
To ensure clarity, 
accuracy, and 
consistency 
Throughout the document 
 
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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 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CDC 
US Centers for Disease Control and Prevention 
Cmax 
Maximum concentration 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOS 
End of study 
EQ-5D-5L 
European Quality of Life Five Dimension-5 Level 
EQ-5D-Y 
European Quality of Life Five Dimension-Youth 
ER 
Emergency room 
EUA 
Emergency Use Authorization 
FAS 
Full analysis set 
FDA 
US Food and Drug Administration 
FIH 
First-in-human 
GCP 
Good clinical practice 
IRB 
Institutional Review Board 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IDMC 
Independent data monitoring committee 
ISR 
Injection-site reaction 
IWRS 
Interactive web response system 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal antibody 
MAV 
Medically-attended visit 
mFAS 
Modified full analysis set 
NCI 
National Cancer Institute 
NLR 
Neutrophil-lymphocyte ratio 
NP 
Nasopharyngeal  
NT-proBNP 
N-terminal pro B-type natriuretic peptide 
OP 
Oropharyngeal  
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PRO 
Patient-reported outcome 
PT 
Preferred term  
RBD 
Receptor binding domain 
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Regeneron 
Regeneron Pharmaceuticals, Inc. 
RT-qPCR 
Quantitative reverse transcription polymerase chain reaction 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SE-C19 
Symptom Evolution of COVID-19 
SE-LC19 
Symptom Evolution of Long COVID-19 
SF-36 
Short Form-36 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TWA 
Time-weighted average 
VBM 
Variants Being Monitored 
VOC 
Variant of Concern 
VOHC 
Variant of High Consequence 
VOI 
Variant of Interest 
VUI 
Variant Under Investigation 
VUS 
Variants under surveillance 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
WPAI+CIQ 
Work Productivity and Activity Impairment and Classroom Impairment 
Questions 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................5 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................14 
1. 
INTRODUCTION ......................................................................................................22 
1.1. 
SARS-CoV-2 and COVID-19 ....................................................................................22 
1.2. 
Casirivimab+Imdevimab: A Combination of Two Non-Competing 
Monoclonal Antibodies that Target the SARS-CoV-2 S Protein RBD ......................22 
1.3. 
Emergence of SARS-CoV-2 Variants ........................................................................22 
1.4. 
A Randomized, Placebo-Controlled Study of REGN14256+Imdevimab in 
Non-Hospitalized, Low-Risk Patients with COVID-19 .............................................24 
2. 
STUDY OBJECTIVES ..............................................................................................24 
2.1. 
Primary Objectives .....................................................................................................24 
2.1.1. 
Phase 1 (Safety and Tolerability) ...............................................................................24 
2.1.2. 
Phase 1/2 (Virologic Efficacy) ...................................................................................24 
2.1.3. 
Phase 1/2/3 (Clinical Efficacy) ...................................................................................24 
2.2. 
Secondary Objectives .................................................................................................24 
2.2.1. 
Phase 1 (Safety and Tolerability) ...............................................................................24 
2.2.2. 
Phase 2 and Phase 3 (Safety and Tolerability) ...........................................................24 
2.2.3. 
Phase 1, Phase 2, and Phase 3 (Virologic Efficacy, Drug Concentration, and 
Immunogenicity) .........................................................................................................25 
2.3. 
Exploratory Objectives ...............................................................................................25 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................26 
3.1. 
Hypothesis ..................................................................................................................26 
3.2. 
Rationale .....................................................................................................................26 
3.2.1. 
Rationale for Study Design .........................................................................................26 
3.2.1.1. 
Study Population .........................................................................................................26 
3.2.1.2. 
Safety and Tolerability and the Phase 1 Sentinel Safety Group .................................27 
3.2.1.3. 
Assessment of Efficacy ...............................................................................................27 
3.2.1.4. 
Phase 3 Enrollment of Adolescents ............................................................................29 
3.2.1.5. 
Assessment of COVID-19 Symptoms During Acute COVID-19 (Through 
Day 29) .......................................................................................................................29 
3.2.1.6. 
Assessment of Long COVID (Day 30 to Day 169) ....................................................29 
3.2.2. 
Rationale for Dose Selection ......................................................................................29 
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3.3. 
Risk-Benefit ................................................................................................................31 
4. 
ENDPOINTS ..............................................................................................................32 
4.1. 
Primary Endpoints ......................................................................................................32 
4.1.1. 
Phase 1 (Safety and Tolerability) ...............................................................................32 
4.1.2. 
Phase 1/2 (Virologic Efficacy) ...................................................................................32 
4.1.3. 
Phase 1/2/3 (Clinical Efficacy) ...................................................................................32 
4.2. 
Secondary Endpoints ..................................................................................................32 
4.2.1. 
Phase 1 (Safety and Tolerability) ...............................................................................32 
4.2.2. 
Phase 2 and Phase 3 (Safety and Tolerability) ...........................................................32 
4.2.3. 
Phase 1, Phase 2, and Phase 3 (Virologic Efficacy; Drug Concentration and 
Immunogenicity) .........................................................................................................32 
4.3. 
Exploratory Endpoints ................................................................................................33 
5. 
STUDY VARIABLES................................................................................................34 
5.1. 
Demographic and Baseline Characteristics ................................................................34 
5.2. 
Efficacy Variables ......................................................................................................34 
5.3. 
Safety Variables ..........................................................................................................34 
5.4. 
Pharmacokinetic Variables .........................................................................................34 
5.5. 
Immunogenicity Variables ..........................................................................................34 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................34 
6. 
STUDY DESIGN .......................................................................................................34 
6.1. 
Study Description and Duration .................................................................................35 
6.1.1. 
Study Periods ..............................................................................................................35 
6.1.2. 
Electronic Questionnaires to Assess Patient-Reported Symptoms and 
Outcomes ....................................................................................................................36 
6.1.3. 
Adolescent Cohort (Phase 3) ......................................................................................37 
6.1.4. 
End of Study Definition ..............................................................................................41 
6.2. 
Planned Interim Analysis ............................................................................................41 
6.3. 
Study Committees .......................................................................................................41 
6.3.1. 
Independent Data Monitoring Committee ..................................................................41 
6.4. 
Study Stopping Rules .................................................................................................41 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............42 
7.1. 
Number of Patients Planned .......................................................................................42 
7.2. 
Study Population .........................................................................................................42 
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7.2.1. 
Inclusion Criteria ........................................................................................................42 
7.2.2. 
Exclusion Criteria .......................................................................................................43 
7.3. 
Premature Withdrawal from the Study .......................................................................45 
7.4. 
Replacement of Patient ...............................................................................................45 
8. 
STUDY TREATMENTS............................................................................................45 
8.1. 
Investigational and Reference Treatments ..................................................................45 
8.1.1. 
Phase 1 and Phase 2 ....................................................................................................45 
8.1.2. 
Phase 3 ........................................................................................................................46 
8.1.2.1. 
Patients Aged ≥18 Years ............................................................................................46 
8.1.2.2. 
Patients Aged ≥12 and <18 Years ..............................................................................46 
8.2. 
Background Treatment ...............................................................................................46 
8.3. 
Rescue Treatment .......................................................................................................46 
8.4. 
Dose Modification and Study Treatment Discontinuation/Termination Rules ..........47 
8.4.1. 
Dose Modification ......................................................................................................47 
8.4.2. 
Study Drug Discontinuation/Termination ..................................................................47 
8.5. 
Management of Acute Injection Reactions .................................................................47 
8.5.1. 
Systemic Injection Reactions ......................................................................................47 
8.5.2. 
Local Injection-Site Reactions ....................................................................................47 
8.6. 
Method of Treatment Assignment ..............................................................................47 
8.7. 
Blinding ......................................................................................................................47 
8.8. 
Emergency Unblinding ...............................................................................................48 
8.9. 
Treatment Logistics and Accountability .....................................................................49 
8.9.1. 
Packaging, Labeling, and Storage ..............................................................................49 
8.9.2. 
Supply and Disposition of Treatments .......................................................................49 
8.9.3. 
Treatment Accountability ...........................................................................................49 
8.9.4. 
Treatment Compliance ................................................................................................49 
8.10. 
Concomitant Medications and Procedures .................................................................49 
8.10.1. 
Prohibited Medications and Procedures .....................................................................50 
8.10.2. 
Permitted Medications and Procedures ......................................................................50 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................50 
9.1. 
Schedule of Events .....................................................................................................50 
9.1.1. 
Footnotes for the Schedule of Events .........................................................................57 
9.1.2. 
Early Termination Visit ..............................................................................................58 
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9.1.3. 
Unscheduled Visits .....................................................................................................59 
9.2. 
Study Procedures ........................................................................................................59 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................59 
9.2.1.1. 
Informed Consent .......................................................................................................59 
9.2.1.2. 
Diagnostic Test for SARS-CoV-2 ..............................................................................59 
9.2.1.3. 
Serology for Baseline Serostatus ................................................................................59 
9.2.1.4. 
Medical History ..........................................................................................................59 
9.2.1.5. 
Demographics .............................................................................................................59 
9.2.1.6. 
Weight and Height ......................................................................................................59 
9.2.2. 
Study Drug Administration.........................................................................................60 
9.2.3. 
Nasopharyngeal Swab Collection ...............................................................................60 
9.2.4. 
Patient-Reported Symptoms .......................................................................................60 
9.2.4.1. 
Symptom Evolution of COVID-19 (SE-C19), Patient Global Impression of 
Severity (PGIS), and Patient Global Impression of Change (PGIC) ..........................60 
9.2.4.2. 
Symptom Evolution of Long COVID-19 (SE-LC19) ................................................61 
9.2.4.3. 
Global Impression Items .............................................................................................63 
9.2.4.4. 
SF-36...........................................................................................................................63 
9.2.4.5. 
Work Productivity and Activity Impairment and Classroom Impairment 
Questions (WPAI+CIQ) .............................................................................................63 
9.2.4.6. 
EQ-5D-5L and EQ-5D-Y ...........................................................................................63 
9.2.5. 
Safety Procedures .......................................................................................................64 
9.2.5.1. 
Vital Signs ..................................................................................................................64 
9.2.5.2. 
Adverse Event Monitoring .........................................................................................64 
9.2.5.3. 
Record Concomitant Medications and Concomitant Procedures ...............................64 
9.2.5.4. 
Pregnancy Test for Women of Childbearing Potential ...............................................64 
9.2.5.5. 
Vital Status ..................................................................................................................64 
9.2.5.6. 
Pregnancy Status .........................................................................................................64 
9.2.5.7. 
Safety Information in Newborns of Study Participants ..............................................64 
9.2.5.8. 
Laboratory Testing ......................................................................................................65 
9.2.6. 
Drug Concentration and Measurements .....................................................................66 
9.2.7. 
Immunogenicity Measurements and Samples ............................................................66 
9.2.8. 
Exploratory Pharmacodynamic/Biomarker Analyses .................................................66 
9.2.8.1. 
Virology ......................................................................................................................66 
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9.2.8.2. 
Serological Immunoassays for Anti-SARS-CoV-2 Antibodies .................................67 
9.2.8.3. 
Serum and Plasma for Exploratory Research .............................................................67 
9.2.9. 
COVID-19-Related Medically-Attended Visit Details ..............................................67 
9.2.10. 
Wearable Device Data Collection ..............................................................................68 
9.2.11. 
Pharmacogenomic Analysis (Optional) ......................................................................68 
10. 
SAFETY EVALUATION AND REPORTING .........................................................69 
10.1. 
Recording and Reporting Adverse Events ..................................................................69 
10.1.1. 
General Guidelines .....................................................................................................69 
10.1.2. 
Reporting Procedure ...................................................................................................70 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................70 
10.2. 
Definitions ..................................................................................................................71 
10.2.1. 
Adverse Event .............................................................................................................71 
10.2.2. 
Serious Adverse Event ................................................................................................71 
10.2.3. 
Adverse Events of Special Interest .............................................................................72 
10.2.4. 
Severity .......................................................................................................................72 
10.2.5. 
Causality .....................................................................................................................73 
10.3. 
Safety Monitoring .......................................................................................................74 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics Committee, 
and Investigators .........................................................................................................74 
11. 
STATISTICAL PLAN................................................................................................75 
11.1. 
Statistical Hypothesis ..................................................................................................75 
11.2. 
Justification of Sample Size........................................................................................75 
11.3. 
Analysis Sets ...............................................................................................................77 
11.3.1. 
Efficacy Analysis Sets ................................................................................................77 
11.3.2. 
Safety Analysis Set .....................................................................................................77 
11.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................77 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................77 
11.4. 
Statistical Methods ......................................................................................................77 
11.4.1. 
Patient Disposition ......................................................................................................78 
11.4.2. 
Demography and Baseline Characteristics .................................................................78 
11.4.3. 
Efficacy Analyses .......................................................................................................78 
11.4.3.1. 
Phase 1/2: Primary Virologic Efficacy Analysis ........................................................78 
11.4.3.2. 
Phase 1/2/3: Primary Clinical Efficacy Analysis ........................................................79 
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11.4.4. 
Control of Multiplicity ................................................................................................79 
11.4.5. 
Safety Analysis ...........................................................................................................79 
11.4.5.1. 
Adverse Events ...........................................................................................................79 
11.4.5.2. 
Other Safety ................................................................................................................80 
11.4.5.3. 
Treatment Exposure ....................................................................................................80 
11.4.5.4. 
Treatment Compliance ................................................................................................80 
11.4.6. 
Analysis of Drug Concentration Data .........................................................................81 
11.4.7. 
Analysis of Immunogenicity Data ..............................................................................81 
11.5. 
Interim Analysis ..........................................................................................................81 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........82 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................82 
12.1. 
Data Management and Electronic Systems ................................................................82 
12.1.1. 
Data Management .......................................................................................................82 
12.1.2. 
Electronic Systems ......................................................................................................82 
12.2. 
Study Monitoring ........................................................................................................83 
12.2.1. 
Monitoring of Study Sites ...........................................................................................83 
12.2.2. 
Source Document Requirements ................................................................................83 
12.2.3. 
Case Report Form Requirements ................................................................................83 
12.3. 
Audits and Inspections ................................................................................................84 
12.4. 
Study Documentation .................................................................................................84 
12.4.1. 
Certification of Accuracy of Data ...............................................................................84 
12.4.2. 
Retention of Records ..................................................................................................84 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................85 
13.1. 
Good Clinical Practice Statement ...............................................................................85 
13.2. 
Informed Consent .......................................................................................................85 
13.3. 
Patients Confidentiality and Data Protection ..............................................................86 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................86 
13.5. 
Clinical Study Data Transparency ..............................................................................87 
14. 
PROTOCOL AMENDMENTS ..................................................................................87 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................87 
15.1. 
Premature Termination of the Study ...........................................................................87 
15.2. 
Close-out of a Site ......................................................................................................87 
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16. 
CONFIDENTIALITY ................................................................................................88 
17. 
FINANCING AND INSURANCE .............................................................................88 
18. 
PUBLICATION POLICY ..........................................................................................88 
19. 
REFERENCES ...........................................................................................................89 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................93 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................94 
 
LIST OF TABLES 
Table 1: 
Schedule of Events: Phase 1 .......................................................................................51 
Table 2: 
Schedule of Events: Phase 2 .......................................................................................53 
Table 3: 
Schedule of Events: Phase 3 .......................................................................................55 
Table 4: 
Symptoms Evaluated in the Symptom Evolution of COVID-19 (SE-C19) 
Instrument ...................................................................................................................61 
Table 5: 
Symptoms Evaluated in the Symptom Evolution of Long COVID-19 (SE-
LC19) Instrument ........................................................................................................62 
Table 6: 
NCI-CTCAE (v5.0) Severity Grading System for Adverse Events: General 
Guideline .....................................................................................................................72 
Table 7: 
NCI-CTCAE (v5.0) Severity Grading System for Anaphylaxis, Allergic 
Reactions and Injection-Site Reactions ......................................................................72 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram: Phase 1 ....................................................................................38 
Figure 2: 
Study Flow Diagram: Phase 2 ....................................................................................39 
Figure 3: 
Study Flow Diagram: Phase 3 ....................................................................................40 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 1/2/3 Adaptive Study to Evaluate the Safety, Tolerability, and Efficacy of 
REGN14256+Imdevimab for the Treatment of COVID-19 Patients Without Risk Factors for 
Progression to Severe Disease 
Site 
Locations 
The study will be conducted in approximately 80 sites in the United States and other countries. 
Principal 
Investigator To be determined 
Objectives 
 
Primary 
Phase 1 (Safety and Tolerability) 
• Evaluate the safety and tolerability of REGN14256+imdevimab and REGN14256 monotherapy, 
as measured by treatment-emergent adverse events (TEAEs), injection-site reactions (ISRs), and 
hypersensitivity reactions 
Phase 1/2 (Virologic Efficacy) 
• Evaluate the virologic efficacy of REGN14256+imdevimab and REGN14256 monotherapy 
compared to placebo, as measured by time-weighted average (TWA) change from baseline in 
viral load through day 7 
Phase 1/2/3 (Clinical Efficacy) 
• Evaluate the clinical efficacy of REGN14256+imdevimab compared to placebo, as measured by 
COVID-19 symptoms resolution 
Secondary 
Phase 1 (Safety and Tolerability) 
• Evaluate the safety and tolerability of REGN14256+imdevimab and REGN14256 monotherapy, 
as measured by treatment-emergent serious adverse events (SAEs) 
Phase 2 and Phase 3 (Safety and Tolerability) 
• Evaluate the safety and tolerability of REGN14256+imdevimab and REGN14256 monotherapy, 
as measured by TEAEs, ISRs, hypersensitivity reactions, and SAEs 
Phase 1, Phase 2, and Phase 3 (Virologic Efficacy, Drug Concentration, and Immunogenicity) 
• Evaluate additional indicators of virologic efficacy of REGN14256+imdevimab and REGN14256 
monotherapy  
• Characterize the concentration-time profile of REGN14256 administered in combination with 
imdevimab or alone as a monotherapy  
• Assess the immunogenicity of REGN14256 administered in combination with imdevimab or 
alone as a monotherapy  
Study 
Design 
The primary objective of the phase 1 first-in-human (FIH) portion of the study is to assess the safety 
and tolerability of REGN14256 alone and in combination with imdevimab. Phase 1 will include 2 
sentinel safety analyses (when the first 40 patients have reached study day 7 [6 days after dosing], then 
when all phase 1 patients have reached study day 7) during each of which study enrollment will pause 
for an unblinded IDMC review of all available safety data. Phase 2 enrollment will begin after the 
second sentinel safety analysis, if the IDMC provides a recommendation for the study to proceed.  
In phase 2, the virologic efficacy of REGN14256+imdevimab and REGN14256 monotherapy will be 
evaluated, and will include virologic data obtained in phase 1 which will remain blinded during that 
phase.  
In phase 3, the primary objective will be to assess the clinical efficacy, based on COVID-19 symptoms 
resolution, of REGN14256+imdevimab compared to placebo. Clinical efficacy analysis will include 
data obtained in all 3 study phases, as the symptoms data obtained in phase 1 and phase 2 will remain 
blinded during those phases. In addition to the adult patients, an adolescent cohort of 40 patients 
between ≥12 and <18 years of age will be enrolled during phase 3, where permitted by local 
requirements. 
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Study 
Periods 
Each phase of the study consists of 3 periods: a screening/baseline period, a treatment period, and a 
follow-up period. 
Screening/Baseline Period (Day -1 to Day 1 Before Dosing) 
Patients will be assessed for eligibility during the screening/baseline period, which may occur up to 1 
day prior to the baseline visit on study day 1. To be enrolled in the study, patients must have laboratory-
confirmed SARS-CoV-2 infection and experience COVID-19 symptoms. Patients cannot have 
received any COVID-19 vaccination, nor present any underlying medical condition or other factors 
associated with high risk for progression to severe COVID-19. Other eligibility criteria apply and are 
described in the main text.  
During this period, eligible patients will be randomized and dosed on day 1. Prior to study drug 
administration on day 1, patients will have nasopharyngeal (NP) swabs taken for SARS-CoV-2 RT-
qPCR testing and blood drawn for laboratory safety, drug concentration, immunogenicity, and 
biomarkers analyses. After study drug dosing, adult patients will have a post-dose blood collection for 
drug concentration at least 1 hour after study drug administration. In phase 1, and in phase 3 adolescent 
patients, patients will remain at the study site for at least 5 hours after study drug administration for 
additional safety monitoring and post-dose blood collection for drug concentration assessment.  
Treatment Period (Day 1 After Dosing Through Day 29) 
The treatment period through day 29 includes the key clinical efficacy and safety analyses. All patients 
will complete the Symptom Evolution of COVID-19 (SE-C19) electronic questionnaire through day 
29 for the key clinical efficacy assessment of COVID-19 symptoms. Also, within the treatment period, 
the key virologic efficacy analysis will be performed through day 7. NP swab samples will be collected 
according to the Schedule of Events: in phase 1 and phase 2, every other day (days 1 [pre-dose], 3, 5, 
and 7) for the first week then at day 29; in phase 3, on days 1 (pre-dose), 7, and 29.  
In addition, information regarding any concomitant medication use and any COVID-19-related 
medically-attended visits (MAVs; eg, hospitalization, ER visit, urgent care visit, physician’s office 
visit, or telemedicine visit, with the primary reason for the visit being COVID-19) will be recorded 
during this period and throughout the study. Patients will be asked to notify the investigator or study 
site personnel as soon as possible about such occurrences. Investigators and designated study site 
personnel must ensure that information about COVID-19-related symptoms and MAVs is collected as 
required. Patients will have blood samples at indicated visits according to the Schedule of Events for 
drug concentration, immunogenicity, and exploratory analyses. Safety will also be monitored 
throughout the study: In all study phases, all TEAEs and SAEs will be collected through the end of 
study, and select events (grade ≥3 ISRs through day 4 and grade ≥3 hypersensitivity reactions through 
day 29) will be reported to the Sponsor in an expedited manner as AESIs. 
Follow-Up Period (Day 30 Through Day 169) 
Following the treatment period, patients will enter a follow-up period of approximately 6 months 
through the end of study (EOS) on study day 169. In addition to safety monitoring and drug 
concentration data analysis, data and samples collected during this period will be used for research 
purposes related to long COVID. This will include electronic questionnaires such as the Symptom 
Evolution of Long COVID-19 (SE-LC19), NP swabs on days 120 and 169 to assess potential 
persistence of SARS-CoV-2 in the nasopharynx, blood draws on day 120, and queries regarding any 
COVID-19-related MAVs.  
On visit days when sample collection is not required (eg, when only electronic questionnaires are 
collected), the information indicated in the Schedule of Events may be collected by phone without an 
in-person visit. The EOS visit will take place approximately 6 months after study drug administration. 
Study 
Duration 
The duration of the study is approximately 170 days for each phase. 
End of 
Study 
Definition 
The end of study is defined as the date the last patient completes the last study visit, withdraws from 
the study, or is lost to follow-up (ie, the study patient can no longer be contacted by the investigator). 
Population 
 
Sample Size Up to approximately 1,359 patients are planned to be enrolled. 
• Phase 1 will enroll approximately 100 adult patients (≥18 years of age). 
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• Phase 2 will enroll approximately 610 adult patients. 
• Phase 3will enroll approximately 609 adult patients and an additional adolescent cohort of 40 
patients (≥12 and <18 years of age).  
Target 
Population This study will enroll non-hospitalized, low-risk, symptomatic patients with a baseline positive 
diagnostic test for SARS-CoV-2, and who have not previously received experimental, authorized or 
licensed COVID-19 vaccines. 
A patient must meet the following criteria to be eligible for inclusion in the study. Other criteria also 
apply and are described in the main text: 
• Is male or female between ≥18 and <65 years of age (or country’s legal age of adulthood) at 
randomization, or 
For the adolescent cohort in phase 3 only: Is male or female between ≥12 and <18 years of age 
at randomization 
Note: Adolescent cohort will only be enrolled where permitted by local requirements. 
• For the adolescent cohort in phase 3 only: Weighs ≥40 kg at randomization 
• Has SARS-CoV-2-positive antigen or molecular diagnostic test (by validated SARS-CoV-2 
antigen, RT-PCR, or other molecular diagnostic assay, using an appropriate sample such as 
nasopharyngeal [NP], nasal, oropharyngeal [OP], or saliva) ≤72 hours prior to randomization. A 
historical record of a positive result is acceptable as long as the sample was collected ≤72 hours 
prior to randomization 
• Has symptoms consistent with COVID-19 (as determined by the investigator) with onset ≤7 days 
before randomization, and doesn't have a medical condition or other factors associated with high 
risk for progression to severe COVID-19 as outlined in the exclusion criteria 
A patient who meets any of the following criteria will be excluded from the study. Other criteria also 
apply and are described in the main text: 
• Has a medical condition or other factors associated with high risk for progression to severe 
COVID-19:  
a. Cancer 
b. Cardiovascular disease (such as heart failure, coronary artery disease, cardiomyopathies, 
congenital heart disease or hypertension) 
c. Chronic lung disease including chronic obstructive pulmonary disease, asthma (moderate to 
severe), interstitial lung disease, cystic fibrosis, and pulmonary hypertension 
d. Chronic kidney disease at any stage 
e. Chronic liver disease (such as alcohol-related, nonalcoholic fatty liver disease, cirrhosis) 
f. Dementia or other chronic neurological condition 
g. Diabetes mellitus (type 1 or type 2) 
h. Immunodeficiency disease or taking immunosuppressive treatment  
i. Medical-related technological dependence [for example, tracheostomy, gastrostomy, or 
positive pressure ventilation (not related to COVID-19)] 
j. Neurodevelopmental disorder (for example, cerebral palsy) or other condition that confers 
medical complexity (for example, genetic or metabolic syndromes and severe congenital 
anomalies) 
k. Overweight (defined as BMI >25 kg/m2) or obesity (defined as BMI ≥30 kg/m2) 
l. Poorly controlled HIV infection or AIDS 
m. Pregnancy 
n. Sickle cell disease or thalassemia 
o. Stroke or cerebrovascular disease 
• Prior, current (at randomization) or planned use (within time period given per CDC guidance [90 
days]) of any authorized or approved vaccine for COVID-19 
• Was admitted to a hospital for COVID-19 prior to randomization, or is hospitalized (inpatient) for 
any reason at randomization 
• Has a known prior SARS-CoV-2 infection or positive SARS-CoV-2 serologic test  
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• Has a positive SARS-CoV-2 antigen or molecular diagnostic test from a sample collected >72 
hours prior to randomization 
• Prior, current, or any of the following treatments: COVID-19 convalescent plasma, mAbs against 
SARS-CoV-2, IVIG (any indication), systemic corticosteroids (any indication), or COVID-19 
treatments (authorized, approved, or investigational) 
Note: Prior use is defined as the past 30 days or within 5 half-lives of the investigational product 
(whichever is longer) from screening. 
Treatments Phase 1 and Phase 2 
Eligible patients will be randomized in a 1:1:1:1:1 allocation ratio to one of the following: 
• Co-administered REGN14256 and imdevimab combination therapy, 1200 mg (600 mg each of 
REGN14256 and imdevimab) SC single dose 
• REGN14256, 600 mg SC single dose 
• Imdevimab, 600 mg SC single dose 
• Co-administered casirivimab and imdevimab combination therapy, 1200 mg (600 mg each of 
casirivimab and imdevimab) SC single dose 
• Placebo SC single dose 
All patients will receive 4 SC injections of blinded study drug on day 1, each containing 2.5 mL (300 
mg) of active study drug or placebo.  
Phase 3 (≥18 Years) 
Eligible patients will be randomized in a 1:1:1 allocation ratio to one of the following: 
• Co-administered REGN14256 and imdevimab combination therapy, 1200 mg (600 mg each of 
REGN14256 and imdevimab) SC single dose 
• Co-administered casirivimab and imdevimab combination therapy, 1200 mg (600 mg each of 
casirivimab and imdevimab) SC single dose 
• Placebo SC single dose 
All patients will receive 4 SC injections of blinded study drug on day 1, each containing 2.5 mL (300 
mg) of active study drug or placebo.  
Phase 3 (≥12 and <18 Years) 
Eligible patients will receive open-label REGN14256+imdevimab (1200 mg; 600 mg each of 
REGN14256 and imdevimab) SC single dose on day 1. All patients will receive 4 SC injections of 
study drug on day 1, each containing 2.5 mL (300 mg) of active study drug. 
Endpoints 
 
Primary 
Phase 1 (Safety and Tolerability) 
• Treatment-emergent adverse events (TEAEs) and severity of TEAEs through day 29 
• Proportion of patients with injection-site reactions (ISRs) and severity of ISRs throughout the 
study  
• Proportion of patients with hypersensitivity reactions and severity of hypersensitivity reactions 
over time  
Phase 1/2 (Virologic Efficacy) 
• Time-weighted average (TWA) daily change from baseline in viral load (log10 copies/mL) from 
day 1 to day 7, as measured by SARS-CoV-2 quantitative reverse transcription polymerase chain 
reaction (RT-qPCR) in nasopharyngeal (NP) swab samples 
Phase 1/2/3 (Clinical Efficacy) 
• Time to COVID-19 symptoms resolution  
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Secondary 
Phase 1 (Safety and Tolerability) 
• Proportion of patients with treatment-emergent SAEs throughout the study 
Phase 2 and Phase 3 (Safety and Tolerability) 
• TEAEs and severity of TEAEs through day 29 
• Proportion of patients with ISRs and severity of ISRs throughout the study  
• Proportion of patients with hypersensitivity reactions and severity of hypersensitivity reactions 
over time  
• Proportion of patients with treatment-emergent SAEs throughout the study 
Phase 1, Phase 2, and Phase 3 (Virologic Efficacy, Drug Concentration, and Immunogenicity) 
• TWA change from baseline in viral load at each timepoint, as measured by RT-qPCR in NP 
samples (phase 1 and phase 2 only) 
• Change from baseline in viral load at each timepoint through day 7, as measured by RT-qPCR in 
NP samples 
• Proportion of patients with viral loads below the limit of detection at each visit  
• Concentrations of REGN14256 and imdevimab in serum over time 
• Incidence and titer of anti-drug antibodies (ADA) to REGN14256 and imdevimab over time 
Procedures 
and 
Assessments 
Procedures and assessments will include the following: 
• NP swabs for SARS-CoV-2 RT-qPCR 
• SE-C19 electronic questionnaire 
• Blood collection for serology 
• TEAEs through day 169 
• Treatment-emergent SAEs through day 169 
• Treatment-emergent adverse events of special interest (AESIs):  
o Grade ≥3 ISRs through day 4 
o Grade ≥3 hypersensitivity reactions through day 29  
• Blood collection for safety labs 
• Vital signs and concomitant medications 
• Vital status; pregnancy testing, pregnancy status, and pregnancy outcome (WOCBP only) 
• COVID-19-related MAVs details 
• Blood collection for biomarker, drug concentration, and immunogenicity analyses 
• Electronic questionnaires (SE-LC19, PGIS, PGIC, return to usual health, return to usual activities, 
SF-36, WPAI+CIQ, and EQ-5D-5L/Y)  
• Wearable device (phase 1 patients, and adult patients in phase 3 only) 
Statistical 
Plan 
 
Statistical 
Hypotheses Phase 1 
No formal hypothesis testing is planned for phase 1. The safety and tolerability objectives will be 
evaluated by estimating the proportion of patients with TEAEs and SAEs through day 29 and AESIs, 
which will include ISRs (grade ≥3) through day 4 and hypersensitivity reactions (grade ≥3) through 
day 29. 
Phase 1/2 
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There are two null hypotheses to be tested in phase 1/2 (ie, based on data from phase 1 and phase 2):  
• Ha1: There is no treatment difference between REGN14256 in combination with imdevimab 
compared to placebo in terms of time weighted average daily change from baseline in viral load 
(log10 copies/mL) from day 1 to day 7 for the seronegative patients. 
• Ha2: There is no treatment difference between REGN14256 alone compared to placebo in terms of 
time weighted average daily change from baseline in viral load (log10 copies/mL) from day 1 to 
day 7 for the seronegative patients.  
Phase 1/2/3 
The primary null hypothesis to be tested in phase 1/2/3 (ie, based on data from phase 1, phase 2, and 
phase 3) is: 
• Hb1: There is no difference in time to COVID-19 symptoms resolution for REGN14256 in 
combination with imdevimab compared to placebo for the seronegative patients.  
A hierarchical testing procedure will be applied to control for multiplicity and to maintain the study-
wise type I error rate at two-sided 0.05 level. 
Justification 
of Sample 
Size 
Phase 1  
Phase 1 will enroll approximately 100 patients (approximately 20 patients per arm) randomized to 5 
treatment groups.  
Phase 1/2 
The primary virologic efficacy analysis will be based on data from patients enrolled in phase 1 and 
phase 2. After the IDMC provides the recommendation to proceed with enrollment in phase 2, at least 
610 additional patients will be randomized in the phase 2 portion of the study, for a total sample size 
in phase 1 and 2 of at least 710 randomized patients.  
The sample size is based on the primary virologic endpoint of time-weighted average (TWA) daily 
change from baseline in viral load (log10 copies/mL) from day 1 to day 7 using a two-sample t-test at 
a two-sided significance of α=0.05, in patients who are seronegative and who have a positive RT-qPCR 
value at baseline. Assuming a standard deviation of 1.2 log10 copies/mL, a sample size per arm of 
n=85 seronegative patients with positive value on RT-qPCR at baseline provides at least 90% power 
to detect a difference of 0.6 log10 copies/mL in TWA daily change from baseline viral load between 
any treatment group and placebo.  
If approximately 60% of patients are seronegative and have a positive value on RT-qPCR at baseline, 
it is estimated that ~142 patients would be required to be randomized into each treatment arm in order 
to yield ~85 seronegative patients per group.  
During enrollment, if the proportion of seronegative patients is observed to be different from that 
initially assumed, the study will continue to enroll until the required number of seronegative patients 
are met for the assessment of the primary virology endpoint.  
Phase 1/2/3 
The total sample size for the study is based on having sufficient power to analyze the primary endpoint 
of time to COVID-19 symptoms resolution. The primary clinical efficacy analysis will be based on 
data from patients enrolled in phase 1, phase 2, and phase 3. 
Based on data from the seronegative mFAS patients from the COV-2067 study (defined as the subset 
of seronegative patients with a positive central-lab determined SARS-CoV-2 RT-qPCR result from NP 
swab samples at randomization), the difference in median time to symptoms resolution was 4 days (8.0 
days for casirivimab+imdevimab 2400 mg IV vs 12.0 days for placebo). Therefore, the sponsor 
conservatively assumes a difference in median time to symptoms resolution of 3.5 days for the 
comparison between co-administered REGN14256 and imdevimab combination therapy, 1200 mg 
(600 mg each of REGN14256 and imdevimab) SC single dose and placebo.  
Therefore, assuming a median time to COVID-19 symptoms resolution of 12 days for placebo, 354 
total events are needed to detect a difference in medians of 3.5 days with 90% power using a log-rank 
test (2 sided) with an overall type 1 error of 0.05, which corresponds to a median time to COVID-19 
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symptoms resolution of 8.5 days in the REGN14256 and imdevimab combination therapy group 
(HR=1.41).  
Assuming 29 days of follow up per patient, an accrual duration of 90 days, a total of 412 seronegative 
patients (206 per group) are required to achieve 354 total events in a pairwise comparison between 
REGN14256+imdevimab combination therapy and placebo. Given that phase 3 has 3 treatment arms 
with a 1:1:1 randomization ratio, 618 seronegative patients (206 per group) are required to be 
randomized. Furthermore, assuming approximately 60% of patients are seronegative and have a 
positive value on RT-qPCR at baseline, approximately 345 mFAS patients per arm in the relevant 
treatment groups will need to be randomized to have approximately 1035 patients for testing the 
clinical efficacy endpoint of time to COVID-19 symptoms resolution.  
Because 142 patients per group in the relevant treatment arms in phase1/2 will be contributing to the 
analysis of time to COVID-19 symptoms resolution, therefore, in phase 3, approximately 609 
additional patients (203 per group) are required to be randomized into the 3 arms in a 1:1:1 ratio in 
order to yield 345 patients per group for the statistical hypothesis testing. 
During enrollment, the number of events among seronegative patients will be monitored in a blinded 
manner to ensure that the comparison of time to symptoms resolution is adequately powered. The 
sample size for the phase 3 portion of the study will be adjusted accordingly if the design, objective 
and/or assumptions are changed.  
Statistical 
Methods 
All efficacy hypotheses are tested with respect to placebo. 
Phase 1/2: Primary Virologic Efficacy Analysis  
The primary virologic efficacy variable is time-weighted average change from baseline in viral load 
from day 1 to day 7, as measured by RT-qPCR in NP swab samples. The primary analysis will be 
conducted in the Seronegative mFAS population. The estimands for the primary hypotheses is the 
difference 
in 
means 
between 
the 
SARS-CoV-2 
combination 
mAb 
treatment 
(REGN14256+imdevimab) vs. placebo and the difference in means between REGN14256 vs. placebo. 
The analyses will be based on the observed data with no imputation for missing data except the 
following cases: uncertain viral load values with less than the lower limit of quantification of the PCR 
assay but with positive qualitative results are imputed with half of lower limit of quantification of the 
PCR assay; uncertain values with negative RNA are imputed with 0 log10 copies/mL if the reason for 
the uncertain values is not a failed test. The primary efficacy variable will be calculated using 
trapezoidal rule, ie, area under the curve for change from baseline at each time point from day 1 to last 
observation divided by the number of days from day 1 to day of last observation. More details are 
provided in the main text. 
Phase 1/2/3: Primary Clinical Efficacy Analysis  
COVID-19 symptoms included in the analysis are as follows: body aches such as muscle pain or joint 
pain, chest pain, chills, cough, diarrhea, dizziness, fatigue, feverish, headache, loss of appetite, loss of 
taste/smell, nausea, pressure/tight chest, red or watery eyes, runny nose, shortness of breath/difficulty 
breathing, sore throat, sputum/phlegm, and stomachache. 
Time to COVID-19 symptoms resolution will be defined as time from randomization to the first day 
during which the patient scored ‘no symptom’ (score of 0) on all of the above symptoms except cough, 
fatigue, and headache, which can be ‘mild/moderate symptom’ (score of 1) or ‘no symptom’ (score of 
0). Time to COVID-19 symptoms resolution will be analyzed using the log-rank test. The analyses 
will be performed in the seronegative mFAS. More details are provided in the main text. 
Control of 
Multiplicity 
 
A hierarchical testing procedure will be used to control the overall type I error rate at 0.05 for the 
testing of the primary virology endpoints (REGN14256 alone and in combination with imdevimab in 
comparison to the placebo arm) and the clinical endpoint (time to symptoms resolution in patients in 
the REGN14256+imdevimab arm in comparison to the placebo arm). The hierarchical testing order 
will be detailed in the SAP.  
Interim 
Analyses 
 
No formal interim analysis is planned.  
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At the time of primary virologic efficacy assessment, the Sponsor may conduct an administrative 
interim analysis for time to COVID-19 symptoms resolution in order to inform regulatory interactions 
and/or internal decision making.  
An alpha penalty of 0.001 will apply for the testing of the clinical endpoint of time to symptoms 
resolution if an administrative look occurs.  
To protect the integrity of study results, unblinding for the primary virology analyses will occur after 
all patients enrolled in phase 2 have reached day 29. Individuals unblinded to the patient-level data for 
the first step or any subsequent analysis will no longer be involved in the day-to-day conduct of the 
ongoing study. Patient-level results will not be released to any site-facing personnel or anyone who is 
directly involved in the conduct of the study. 
 
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1. 
INTRODUCTION 
1.1. 
SARS-CoV-2 and COVID-19 
Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel betacoronavirus, was 
initially identified in patients experiencing atypical pneumonia in Wuhan City, China, and later 
determined to be the pathogen responsible for coronavirus disease 2019 (COVID-19) 
(WHO, 2020) (Wu, 2020) (Zhu, 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 SARS-CoV-2 S protein facilitates membrane fusion and entry of the virus into susceptible cells 
(Hoffmann, 2020). The S protein is composed of two functional subunits: the S1 subunit, which 
contains the receptor binding domain (RBD) that binds ACE2, and the S2 subunit, which mediates 
virus-cell membrane fusion (Walls, 2020).  
1.2. 
Casirivimab+Imdevimab: A Combination of Two Non-Competing Monoclonal 
Antibodies that Target the SARS-CoV-2 S Protein RBD 
To address the emerging COVID-19 pandemic in early 2020, Regeneron Pharmaceuticals, Inc. 
(Regeneron) developed casirivimab and imdevimab, two non-competing recombinant monoclonal 
antibodies (mAbs) that bind simultaneously to the RBD and block its interaction with ACE2. As 
a co-administered combination therapy, casirivimab+imdevimab  has demonstrated efficacy as an 
antiviral agent for the treatment and prevention of COVID-19, across a variety of populations, and 
is generally well-tolerated with a favorable safety and tolerability profile. In the outpatient 
treatment setting, casirivimab+imdevimab enhances viral clearance and reduce rates of COVID-
19-related hospitalization or all-cause death (Weinreich, 2021). Casirivimab+imdevimab also 
reduces all-cause death in hospitalized patients (Horby, 2021). When given in a prophylaxis setting 
to household contacts of SARS-CoV-2-infected individuals, casirivimab+imdevimab reduces 
asymptomatic and symptomatic infections, produces faster viral clearance, and in those who 
develop symptoms, leads to shorter symptoms duration (O’Brien, 2021).  
Based on the demonstrated efficacy and safety profile, casirivimab+imdevimab has been 
approved, authorized, or conditionally authorized by a number of global health authorities for the 
treatment and/or prevention of COVID-19 (FDA, 2020a) (MHRA, 2021) (EMA, 2021). 
1.3. 
Emergence of SARS-CoV-2 Variants 
As an RNA virus, SARS-CoV-2 has a high mutation rate. New viral variants have evolved since 
the beginning of the pandemic with mutations that confer certain advantages to the virus, such as 
a higher infectivity rate or escape from the host immune response. In an effort to coordinate 
pandemic responses to emerging variants, the World Health Organization (WHO), United States 
(US) Centers for Disease Control and Prevention (CDC), and United Kingdom (UK) Public Health 
England have categorized SARS-CoV-2 variants based on important biological and 
epidemiological characteristics, including known or potential impact on disease severity, 
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transmissibility, or ability to resist treatments. Variants may be categorized differently by the 
WHO, US CDC, and/or Public Health England based on the evolving levels of public health threat 
in regions of interest. The US CDC variant categories represent an increasing degree of evidence 
that the variant represents a public health threat: variant being monitored (VBM), variant of interest 
(VOI), variant of concern (VOC), and variant of high consequence (VOHC), while the WHO 
recognizes variants under monitoring (VUM), VOI, and VOC (CDC, 2021c) (WHO, 2021a) . The 
United Kingdom (Public Health England) additionally categorizes variants under the labels variant 
under 
investigation 
(VUI) 
and 
monitoring, 
according 
to 
regional 
prevalence 
(PublicHealthEngland, 2021). Based on these differences in terminology, these variants are 
collectively referred to as variants under surveillance (VUS) by the Sponsor.  
While authorized vaccines are generally highly effective, there are data to suggest that some VUS 
may reduce vaccine effectiveness, highlighting that emerging viral variants pose a very real threat 
to natural and vaccine immunity and therapeutic efficacy (Brown, 2021) (Noori, 2021) 
(Wang, 2021) (Ministry of Health Israel, 2021). Additionally, these emerging circulating variants 
have already reduced the effectiveness of other mAbs and resulted in decisions to no longer 
distribute these other mAb therapeutics (Planas, 2021). 
Variants may arise through natural selection during circulation (eg, selection for enhanced 
transmissibility), but may also be driven by direct selective pressures such as expanding herd 
immunity, vaccine-induced immunity, and antiviral therapies with mutations that can promote 
treatment escape. In vitro studies have shown that individual mAb therapies directed at the RBD, 
as well as mAb combination therapies whose mAbs share competing RBD epitopes, are often 
susceptible to such escape mutants. These mutations appear to arise predominantly within the 
RBD, and in some cases, a single amino acid residue becomes the target of multiple unique amino 
acid substitutions (Baum, 2021) (Copin, 2021). These data suggest that strategic mAb therapy 
design, such as the simultaneous use of two highly potent, non-competing antibodies, may be 
required to effectively safeguard against the selection of treatment-emergent resistance variants 
and highlights the inherent risk of monotherapy against SARS-CoV-2.  
A key element in the development of casirivimab+imdevimab was the strategic decision to include 
a pair of non-competing antibodies that can simultaneously bind distinct epitopes of the SARS-
CoV-2 S protein to reduce the likelihood of drug resistant variants and provide coverage against 
circulating variants (Baum, 2020). Casirivimab+imdevimab has retained in vitro neutralization 
potency against all known VOI/VOCs, and an initial analysis of viral samples taken from clinical 
studies suggests that casirivimab+imdevimab does not lead to escape variants (Copin, 2021). 
However, some variants have emerged (eg, B.1.351 [Beta] and P.1 [Gamma] variants) that impact 
the potency of the casirivimab component of the casirivimab+imdevimab combination, creating a 
potential risk that casirivimab+imdevimab may behave functionally as a monotherapy against 
certain variants. Moreover, new variants may emerge in the future that carry a different resistance 
profile to vaccines and/or casirivimab+imdevimab. To mitigate this risk, active surveillance of 
circulating viruses and continued development of updated antibody combinations where multiple 
components maintain coverage against emerging variants should be an important focus for the 
future of antiviral mAb therapeutics. To ensure an effective combination of two antibodies that 
bind to non-competing epitopes of the S protein RBD, and where each component retains activity 
against circulating VOI/VOCs, the Sponsor is developing REGN14256 as a potential substitute 
for casirivimab at equivalent dose to form the basis of an updated combination therapy 
(REGN14256+imdevimab). REGN14256 is a human IgG1 mAb that has similar properties to 
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casirivimab with regard to its structure, potency, and manufacturing, except that it binds a distinct 
epitope from casirivimab, and retains neutralization potency against all known VOI/VOCs, 
including those that impact the activity of casirivimab.  
1.4. 
A Randomized, Placebo-Controlled Study of REGN14256+Imdevimab in Non-
Hospitalized, Low-Risk Patients with COVID-19 
This phase 1/2/3 adaptive study will evaluate the safety, tolerability, virologic efficacy, and clinical 
efficacy of REGN14256+imdevimab compared to placebo in non-hospitalized patients with 
COVID-19 who are at low risk of progressing to severe disease. Casirivimab+imdevimab will be 
included as a calibrator arm. To assess the contribution of individual components, the virologic 
efficacy of REGN14256 monotherapy and imdevimab monotherapy will also be evaluated during 
phase 2.  
For more information regarding the rationale for the study design and dose selection, refer to 
Section 3.2. Additional background information on REGN14256+imdevimab and the overall 
development program can be found in the Investigator’s Brochure. 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objectives 
2.1.1. 
Phase 1 (Safety and Tolerability) 
The primary objective is to evaluate the safety and tolerability of REGN14256+imdevimab and 
REGN14256 monotherapy, as measured by treatment-emergent adverse events (TEAEs), 
injection-site reactions (ISRs), and hypersensitivity reactions. 
2.1.2. 
Phase 1/2 (Virologic Efficacy) 
The primary objective is to evaluate the virologic efficacy of REGN14256+imdevimab and 
REGN14256 monotherapy compared to placebo, as measured by time-weighted average (TWA) 
change from baseline in viral load through day 7. 
2.1.3. 
Phase 1/2/3 (Clinical Efficacy) 
The primary objective is to evaluate the clinical efficacy of REGN14256+imdevimab compared 
to placebo, as measured by COVID-19 symptoms resolution. 
2.2. 
Secondary Objectives 
2.2.1. 
Phase 1 (Safety and Tolerability) 
The secondary objective is to evaluate the safety and tolerability of REGN14256+imdevimab and 
REGN14256 monotherapy, as measured by treatment-emergent serious adverse events (SAEs). 
2.2.2. 
Phase 2 and Phase 3 (Safety and Tolerability) 
The secondary objective is to evaluate the safety and tolerability of REGN14256+imdevimab and 
REGN14256 monotherapy, as measured by TEAEs, ISRs, hypersensitivity reactions, and SAEs. 
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2.2.3. 
Phase 1, Phase 2, and Phase 3 (Virologic Efficacy, Drug Concentration, and 
Immunogenicity) 
The secondary objectives are to: 
• Evaluate additional indicators of virologic efficacy of REGN14256+imdevimab and 
REGN14256 monotherapy  
• Characterize the concentration-time profile of REGN14256 administered in 
combination with imdevimab or alone as a monotherapy  
• Assess the immunogenicity of REGN14256 administered in combination with 
imdevimab or alone as a monotherapy  
2.3. 
Exploratory Objectives 
The exploratory objectives are to: 
• Evaluate SARS-CoV-2 variants at baseline and post-treatment 
• Evaluate the virologic efficacy of REGN14256 alone (as applicable) and in 
combination with imdevimab, compared to placebo, in reducing viral load of SARS-
CoV-2 variants under surveillance (VUS) 
• Evaluate the clinical efficacy of REGN14256 in combination with imdevimab, 
compared to placebo (phase 1 and phase 2, as applicable) 
• Evaluate additional indicators of clinical efficacy of REGN14256 in combination 
with imdevimab, compared to placebo (phase 3 only) 
• Evaluate the impact of REGN14256+imdevimab treatment, given during acute 
SARS-CoV-2 infection, on long COVID symptoms, compared to placebo 
• Explore the effects of REGN14256 alone (as applicable) and in combination with 
imdevimab on measures of SARS-CoV-2 infectivity as assessed in experimental 
laboratory assays 
• Explore biomarkers predictive of safety, efficacy, and/or disease progression and 
COVID-19 clinical outcomes of REGN14256 alone (as applicable) or in combination 
with imdevimab  
• Explore the underlying mechanisms of action and biology of REGN14256 alone (as 
applicable) and in combination with imdevimab, SARS-CoV-2, and COVID-19 
• Explore relationships between REGN14256 alone (as applicable) and in combination 
with imdevimab exposure and selected efficacy endpoints, safety endpoints, and/or 
biomarkers 
• Characterize the concentrations of casirivimab and imdevimab in serum over time 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
In non-hospitalized adult patients with symptomatic SARS-CoV-2 infection, treatment with 
REGN14256+imdevimab will reduce viral load and shorten COVID-19 symptoms duration. 
Information concerning statistical hypotheses is provided in Section 11.1. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This phase 1/2/3, randomized, double-blind, placebo-controlled adaptive study will assess the 
virologic and clinical efficacy, safety, tolerability, pharmacokinetics (PK), and immunogenicity of 
REGN14256+imdevimab in non-hospitalized, unvaccinated patients with symptomatic SARS-
CoV-2 infection who are at low risk for progressing to severe COVID-19.  
The study will utilize an adaptive design, which will allow for phase 3 adaptations as needed based 
on data obtained in phase 1 and phase 2 (Section 11.5). 
3.2.1.1. 
Study Population 
Casirivimab+imdevimab is currently authorized and available for individuals who are at higher-
risk for progression to severe COVID-19 (FDA, 2020a). Accordingly, a study population of 
symptomatic, non-hospitalized patients without such risk factors was selected to prevent higher-
risk patients from being randomized to the placebo control arm. Of note for an adequate assessment 
of virologic efficacy, study COV-2067 (an adaptive phase 1/2/3 efficacy and safety study in adult 
outpatients with mild to moderate COVID-19) showed that participants who had ≥1 risk factor for 
severe COVID-19 had a similar baseline viral load compared to those who did not have risk factors 
and a similar degree of improvement in the time to resolution of COVID-19 symptoms. 
The primary analysis population will consist of patients who are seronegative (ie, without 
endogenous antibodies against SARS-CoV-2) at baseline. The intent is to ensure that the 
assessment of virologic efficacy of REGN14256+imdevimab or REGN14256 monotherapy is 
reasonably similar to casirivimab+imdevimab. The assessment of the true pharmacological 
activity of the mAbs with respect to viral load reduction will be confounded if analyzed in patients 
with prior immunity due to either previous symptomatic or asymptomatic SARS-CoV-2 infection 
or to COVID-19 vaccination. Previous studies with casirivimab+imdevimab have shown that it is 
difficult to demonstrate treatment-related reductions in viral load in individuals that are 
seropositive at baseline, even though these patients may derive clinical benefit on outcomes. 
Previous 
studies 
have 
also 
shown 
that 
the 
virologic 
and 
clinical 
efficacy 
of 
casirivimab+imdevimab is greater in those who are seronegative at baseline compared with those 
who are seropositive (Weinreich, 2021) (O’Brien, 2021) (Horby, 2021).  Focusing phase 2 
analyses on the baseline seronegative population of patients allows greater precision with smaller 
sample sizes compared to analyzing all patients regardless of baseline serostatus. 
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3.2.1.2. 
Safety and Tolerability and the Phase 1 Sentinel Safety Group 
The first-in-human (FIH) phase 1 portion of the study will enroll approximately 100 patients 
(approximately 20 patients per arm) who will be randomized to 5 treatment groups that are also 
planned to be evaluated in phase 2. The aim of phase 1 will be to assess safety and tolerability, and 
there will be 2 sentinel safety analyses by an independent data monitoring committee (IDMC; 
Section 6.3.1):  
• After the first 40 patients reach study day 7 (6 days after dosing), the study will pause 
and the IDMC will review all unblinded safety data available at the time. After the 
IDMC evaluates these safety data, and if a positive recommendation to continue the 
study is provided, enrollment of the remaining phase 1 patients will begin. 
• After phase 1 is fully enrolled and the last patient reaches study day 7, the study will 
pause and the IDMC will review all unblinded safety data available at the time. After 
the IDMC evaluates these safety data, and if a positive recommendation to continue 
the study is provided, enrollment in phase 2 will begin.  
Virologic and clinical efficacy data will remain blinded during the sentinel safety analyses by the 
IDMC, to facilitate subsequent phase 1/2 and phase 1/2/3 analyses of virologic and clinical efficacy 
(Section 11).  
In all study phases, all TEAEs and SAEs will be collected through the end of study, and select 
events (grade ≥3 ISRs through day 4 and grade ≥3 hypersensitivity reactions through day 29) will 
be reported to the Sponsor in an expedited manner, ie, as AESIs (Section 10.1).  
3.2.1.3. 
Assessment of Efficacy 
Phase 2 will be powered to allow for a robust assessment of the virologic efficacy of 
REGN14256+imdevimab as a primary endpoint. To assess the contribution of individual 
components, during phase 2, the virologic efficacy of REGN14256 monotherapy and imdevimab 
monotherapy will also be evaluated. As new variants may emerge that carry a different resistance 
profile to current vaccines and/or therapies, understanding the key clinical characteristics of the 
individual mAb components will be an important criterion in defining future potential 
combinations. As such, the evaluation of individual monotherapy components will provide 
valuable data to inform the development of current and future therapies involving different 
combinations of individual antibodies. Of note, the Sponsor does not intend to pursue 
commercialization of monotherapy for the prevention or treatment of COVID-19. 
Finally, casirivimab+imdevimab combination therapy will be included as a calibrator arm given 
its established virologic and clinical efficacy, and the ongoing changes in the prevalence of 
circulating variant strains and disease morbidity.  
Combination therapy arms (REGN14256+imdevimab and casirivimab+imdevimab) and placebo 
will be continued into phase 3 and powered to allow for a robust determination of the impact of 
treatment on clinical outcomes, namely COVID-19 symptoms resolution. Assessment of viral load 
reduction, comparing active treatment arms with placebo, will also be performed during phase 3. 
Additionally, outcomes in the adolescent cohort will be analyzed descriptively and not included in 
the primary clinical efficacy analysis. 
Rationale for Virologic Efficacy Assessment 
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Virologic efficacy has been evaluated in all clinical efficacy studies and used as a proximal 
indicator of pharmacological activity, showing that the burden of disease following SARS-CoV-2 
infection is correlated with high viral load and consistently associated with clinical efficacy. For 
example, in the phase 3 portion of study COV-2067, placebo participants with a COVID-19-related 
hospitalization or all-cause death through study day 29 had a higher mean baseline viral load 
compared to placebo participants who did not experience an event (7.54 log10 copies/mL versus 
6.62 log10 copies/mL) and cleared virus slower (day 7 viral load 5.36 log10 copies/mL versus 3.60 
log10 copies/mL). Similarly, in study COV-2066 assessing the efficacy of casirivimab+imdevimab 
for the treatment of COVID-19 in hospitalized patients, a higher proportion of participants in the 
placebo group with high viral load at baseline progressed to death or mechanical ventilation 
(19.7% for subgroup with >104 copies/mL versus 0% for subgroup with <104 copies/mL).  
Overall, across all studies and in all populations analyzed, results from the change from baseline 
and TWA daily change from baseline show that casirivimab+imdevimab significantly and 
comparably reduced SARS-CoV-2 viral load compared to placebo over approximately 1 week 
across all populations. This was demonstrated in studies of non-hospitalized patients with 
asymptomatic SARS-CoV-2 infection that were presumed to have been recently infected and were 
at the earliest stages of their disease course (ie, in study COV-2069 cohort B [including those with 
known exposure to an infected household contact and positive for SARS-CoV-2 at baseline] and 
study COV-20145 [a dose-ranging study in outpatients with COVID-19]). 
Rationale for Clinical Efficacy Assessment 
Regeneron's COVID-19 antibody development program includes several controlled phase 3 
studies which have all shown consistent and substantial clinical benefit from treatment with 
casirivimab and imdevimab combination across the entire SARS-CoV-2/COVID-19 disease 
spectrum, spanning uninfected individuals to those with asymptomatic SARS-CoV-2 infection, 
and to outpatients and hospitalized patients with COVID-19. These studies have demonstrated 
efficacy on clinically-meaningful endpoints, including reduction in mortality (in patients 
hospitalized for COVID-19), in risk of COVID-19-related hospitalization and/or all-cause death 
through study day 29 (in outpatients with COVID-19), symptoms resolution, and risk of 
progression to symptomatic disease (in infected, asymptomatic individuals).  
This study will assess the time to COVID-19 symptoms resolution in patients who receive 
REGN14256+imdevimab, compared to placebo, as a primary endpoint (data collected using 
electronic questionnaires as described in Section 3.2.1.4, and analyzed at the end of the study based 
on data from patients enrolled in all 3 study phases, with the exception of the adolescent cohort). 
Findings from study COV-2067 showed that treatment with casirivimab+imdevimab was 
associated with a statistically significant and clinically meaningful 4-day reduction in time to 
symptoms resolution, where the median time to symptoms resolution was 10 days for both 1200 
mg and 2400 mg, versus 14 days for the placebo group (p<0.0001). Similar results for reduction 
in the duration of symptoms have been observed in patients with or without risk factors for severe 
COVID-19, where the median time to symptoms resolution was 9 days for 2400 mg versus 12 
days for the placebo group (p=0.0048). It is therefore assumed that similar effects will be observed 
here in patients without risk factors for severe COVID-19.  
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3.2.1.4. 
Phase 3 Enrollment of Adolescents 
Phase 3 of the study will also include an open-label adolescent cohort to assess the safety, 
tolerability, and PK of REGN14256+imdevimab in patients between ≥12 and <18 years of age. 
Outcomes in these adolescent patients will be analyzed descriptively and not included in the 
primary clinical efficacy analysis.  
3.2.1.5. 
Assessment of COVID-19 Symptoms During Acute COVID-19 (Through Day 
29) 
The types of COVID-19 related symptoms, as well as their duration and severity will be collected 
by patients through the use of electronic diaries/questionnaires, including the Symptom Evolution 
of COVID-19 (SE-C19) questionnaire. The SE-C19 instrument was developed by the Sponsor 
with the aim to better understand the symptomatic course of COVID-19 infection over time and is 
based on current available evidence on symptoms of COVID-19 (Arentz, 2020) (Chen, 2020a) 
(Chen, 2020b) (Huang, 2020) (Lapostolle, 2020) (Mizrahi, 2020) (Song, 2020) (Wang, 2020). The 
good measurement principles outlined in the FDA Patient-Reported Outcome (PRO) Guidance 
(FDA, 2009) and the four methodological Patient-Focused Drug Development guidance's were 
also considered in their design (FDA, 2020b). To aid interpretation, other questionnaires including 
the Patient Global Impression of Change (PGIC) and the Patient Global Impression of Severity 
(PGIS) scales will also be completed by patients. Refer to Section 9.2.4 for background and 
procedural information regarding these instruments.  
For the primary clinical efficacy analysis, the time in days to COVID-19 symptoms resolution will 
be assessed using SE-C19 through day 29 in all participants. Time to COVID-19 symptoms 
resolution will be defined as time from randomization to the first day during which the patient 
scores 0 (no symptom) on all 19 symptoms except cough, fatigue, and headache, for which the 
patient can have a score of 1 (mild symptom), 2 (moderate symptom), 3 (severe symptom) or 0 
(no symptom). To ensure that any observed recovery is likely to be a true treatment effect and not 
natural progression of disease, patients with a raw score of ≤3 at baseline will be censored at day 
0. Without this aspect of the definition, patients could potentially start the study already meeting 
the responder definition due to natural resolution of the disease.  
3.2.1.6. 
Assessment of Long COVID (Day 30 to Day 169) 
To understand better the biology of long COVID and the potential impact of prior treatment with 
REGN14256+imdevimab (during the acute phase of SARS-CoV-2 infection) on the development 
of long COVID symptoms, patients will be evaluated using measures including patient-reported 
outcomes questionnaires including the Symptom Evolution of Long COVID-19 (SE-LC19) 
questionnaire (Section 9.2.4), wearable device data collection (Section 9.2.10), and blood sample 
collections for biomarker analyses (Section 9.2.8.3.1). These analyses will be exploratory in 
nature. 
3.2.2. 
Rationale for Dose Selection  
This phase 1/2/3 adaptive study will evaluate 1200 mg SC of REGN14256+imdevimab (1:1 ratio, 
600 mg/mAb), 1200 mg SC of casirivimab+imdevimab (600 mg per mAb), 600 mg SC dose of 
REGN14256, and 600 mg SC dose of imdevimab.  
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The high-level dosing strategy in this study is to mirror the clinical dose (1200 mg SC) of 
casirivimab+imdevimab authorized in the US for treatment and post-exposure prophylaxis of 
COVID-19 (FDA, 2020a). The 1:1 ratio for REGN14256 + imdevimab is thought to be 
appropriate, as these are non-competing mAbs targeting non-overlapping epitopes of the RBD of 
the S protein of SARS-CoV-2, with comparable in vitro binding and neutralization properties. 
REGN14256 has similar in vitro potency to casirivimab, an improved resistance profile against 
known variants, given the pre-clinical PK data, and because both molecules target an exogenous 
protein, similar PK profiles for REGN14256 and casirivimab are anticipated.  
A 600 mg SC dose of each mAb (REGN14256 or imdevimab), either for the monotherapy arms 
or combination arms planned for this study was chosen based on extensive PK characterization of 
casirivimab and imdevimab combination therapy generated in the casirivimab+imdevimab clinical 
development program (ie, study COV-2067 and study COV-2069). Both antibodies (casirivimab 
and imdevimab) at a 1200 mg SC dose are present in significant excess [relative to the IC90 against 
the ancestral strain of SARS-CoV-2 virus and circulating variants (eg, E484K variant)], through 
day 29. The IV and SC doses (600 mg per mAb) for the combination of casirivimab and imdevimab 
have been shown to improve clinical outcomes in patients with COVID-19, when compared to 
placebo (Weinreich, 2021) (O’Brien, 2021) (FDA, 2020a). Given the measured IC90 for 
REGN14256 is similar or lower than that for imdevimab, especially against variants of concern 
such as L452R/T478K (Delta variant), and the similar expected PK profile for REGN14256 to that 
of casirivimab, the choice of 600 mg per mAb as the dose for the combination of REGN14256 and 
imdevimab to be given SC is also expected to provide robust efficacy against relevant VUS.  
For the monotherapy arms, the SC dose of each single mAb (600 mg) is matched to that in the 
combination, to facilitate a comparison for each single antibody and provide evidence of biological 
effect for the single mAbs, which are also predicted to be present in significant excess relative to 
relevant IC90’s for VUS. 
As the lower end of the proposed body weight range for adolescent subjects ≥12 years of age 
(40 kg) falls within the range of expected body weights for adult subjects, similar exposures are 
expected between these 2 populations for a single 1200 mg (600 mg of each mAb) SC dose of 
REGN14256+imdevimab. 
The lack of a dose effect between the 1200 mg IV and 1200 mg SC of 1:1 combination of 
casirivimab+ imdevimab in key clinical and virologic outcomes (COV-20145) and their similar 
safety profiles, irrespective of the route of administration, led to selection of SC injections as the 
only route to be employed this study. Intravenous (IV) administration requires access to a medical 
facility with trained medical professionals to set-up an IV infusion and determine appropriate 
dosing/infusion rate and time. In contrast, SC administration allows therapeutics to be self-
administered by patients or healthcare providers using a variety of different drug delivery systems. 
Because SC administration facilitates patient self-administration in home or outpatient clinical 
environments, SC administration provides a reduction in medical facility fixed costs. SC 
administration also provides flexibility in the anatomical infusion site, and SC infusion systems 
can be designed with smaller needle sizes, which may decrease pain during infusion. In studies 
comparing SC to IV administration, patients reported a higher preference for subcutaneous 
administration (88.9%) versus IV (9.6%) (Jin, 2015). 
The dosing regimen of REGN14256 (600 mg SC) is expected to be well tolerated and is supported 
by the results from a toxicology study in healthy cynomolgus monkeys with a NOAEL of 150 
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mg/kg IV and SC of REGN14256, the highest doses tested in the study. On a weight basis, this 
dose is approximately 20 times higher than the proposed clinical dose of 600 mg (or 7.5 mg/kg 
based on an 80 kg person). 
For additional information, refer to the Investigator’s Brochure. 
3.3. 
Risk-Benefit 
REGN14256 has not yet been administered to humans, alone or in combination with imdevimab. 
therefore, there is no evidence that it can provide clinical benefit and there are no identified risks 
with its clinical use in individuals with or without SARS-CoV-2 infection. However, imdevimab 
has been used in combination with casirivimab in other clinical studies, with an identified risk of 
hypersensitivity reactions (including anaphylaxis and ISRs).  
Preliminary results from nonclinical toxicology studies in nonhuman primates showed that 
REGN14256 was well tolerated without adverse findings. For individuals infected with SARS-
CoV-2, and for those at risk for infection due to exposure, neutralization of SARS-CoV-2 with 
REGN14256+imdevimab may provide clinical benefit by reduction of clinical disease severity and 
by post-exposure prevention.  
Currently there is no identified risk associated with REGN14256+imdevimab. The potential risks 
for REGN14256+imdevimab, as with all other mAbs, are systemic hypersensitivity reactions, 
clinical consequences of immunogenicity, and embryo-fetal toxicity.  
• As REGN14256 and imdevimab are fully human IgG1 mAbs, the risk of 
hypersensitivity (including ISRs) is expected to be low. Individuals with known allergy 
or hypersensitivity to study drug component(s) are excluded from clinical studies. In 
addition, this study protocol describes the process of monitoring and management 
guidelines (Section 8.5). 
• Protein therapeutics carry the potential risk of an immunogenic response in the form of 
anti-drug antibody (ADA) development following administration, with possible 
consequences on safety and efficacy. Therefore, blood samples for immunogenicity 
assessment will be collected during this study.  
• Reproductive and developmental toxicity studies have not been conducted at this stage; 
therefore, the effects of REGN14256+imdevimab on reproductive organs in males and 
females are unknown. Pregnant women are excluded from enrolling in this study. If a 
female patient was pregnant or were to become pregnant during this study, the 
pregnancy will be followed until outcome and any safety issue observed get reported 
(Section 10.1.3). There has been limited experience concerning pregnancy exposure 
from other clinical studies with imdevimab administered with casirivimab, in which 
pregnant women were not excluded. The limited safety data available from clinical 
studies to date, have not found any evidence of embryo-fetal toxicity. 
For additional information, refer to the Investigator’s Brochure. 
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4. 
ENDPOINTS  
4.1. 
Primary Endpoints 
4.1.1. 
Phase 1 (Safety and Tolerability) 
The primary safety endpoints of phase 1 are: 
• TEAEs and severity of TEAEs through day 29 
• Proportion of patients with ISRs and severity of ISRs throughout the study  
• Proportion of patients with hypersensitivity reactions and severity of hypersensitivity 
reactions over time  
4.1.2. 
Phase 1/2 (Virologic Efficacy) 
The primary endpoint is time-weighted average (TWA) daily change from baseline in viral load 
(log10 copies/mL) from day 1 to day 7, as measured by SARS-CoV-2 quantitative reverse 
transcription polymerase chain reaction (RT-qPCR) in nasopharyngeal (NP) swab samples. 
4.1.3. 
Phase 1/2/3 (Clinical Efficacy) 
The primary endpoint is time to COVID-19 symptoms resolution. 
4.2. 
Secondary Endpoints 
4.2.1. 
Phase 1 (Safety and Tolerability) 
The secondary endpoint is proportion of patients with treatment-emergent SAEs throughout the 
study. 
4.2.2. 
Phase 2 and Phase 3 (Safety and Tolerability) 
The secondary endpoints are: 
• TEAEs and severity of TEAEs through day 29 
• Proportion of patients with ISRs and severity of ISRs throughout the study  
• Proportion of patients with hypersensitivity reactions and severity of hypersensitivity 
reactions over time  
• Proportion of patients with treatment-emergent SAEs throughout the study 
4.2.3. 
Phase 1, Phase 2, and Phase 3 (Virologic Efficacy; Drug Concentration and 
Immunogenicity) 
The secondary endpoints are: 
• Time-weighted average change from baseline in viral load at each timepoint, as 
measured by RT-qPCR in NP samples (phase 1 and phase 2 only) 
• Change from baseline in viral load at each timepoint through day 7, as measured by 
RT-qPCR in NP samples 
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• Proportion of patients with viral loads below the limit of detection at each visit  
• Concentrations of REGN14256 and imdevimab in serum over time 
• Incidence and titer of anti-drug antibodies (ADA) to REGN14256 and imdevimab 
over time 
4.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
Virologic 
• SARS-CoV-2 sequence and variant classification in positive RT-qPCR samples  
• Viral load reduction in variants under surveillance (VUS) 
• Proportion of patients with positive SARS-CoV-2 test results after randomization 
through day 169 
• Change from baseline in viral load through day 29, and at day 120 and day 169, as 
measured by RT-qPCR in NP swab samples 
• Time-weighted average as measured by daily change from baseline in viral load 
(log10 copies/mL) from day 1 to day 7, as measured by RT-qPCR in NP swab samples 
(phase 3 only) 
Clinical 
• Proportion of patients with COVID-19-related hospitalization or all-cause mortality 
through day 29 and day 169 
• Proportion of patients with COVID-19-related hospitalization, emergency room (ER) 
visit, or all-cause mortality through day 29 and day 169 
• Proportion of patients with a COVID-19-related medically attended visit (MAV) 
through day 29 and day 169 
Note: COVID-19-related MAV is defined in Section 9.2.9.  
• Proportion of patients admitted to an intensive care unit (ICU) due to COVID-19 by 
day 29 and day 169 
• Proportion of patients requiring supplemental oxygen due to COVID-19 by day 29 
and day 169 
• Proportion of patients requiring mechanical ventilation due to COVID-19 by day 29 
and day 169 
• Total number of COVID-19-related MAVs through day 29 and 169 
• All-cause mortality by day 29 and day 169 
• Proportion of patients with ≥1 symptom from SE-LC19 Category A, B, C by day 169  
• Proportion of patients with ≥2 symptoms from SE-LC19 Category A, B, C by day 
169  
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Note: SE-LC19 symptom categories are provided in Table 5. Additional analyses 
related to psychometric validation of the SE-LC19 as well as potential biomarkers 
predicting long COVID will be outlined in separate statistical analysis plan(s).  
Drug Concentration 
• Concentrations of casirivimab and imdevimab in serum over time 
5. 
STUDY VARIABLES  
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height), disease 
characteristics, medical history, and medication history for each patient. 
5.2. 
Efficacy Variables 
Efficacy variables will differ according to study phase and will be defined in the SAP. Depending 
on the phase, efficacy variables may include viral load (log10 copies/mL), time to COVID-19 
symptoms resolution, number of patients with a COVID-19-related MAV, number of patients 
admitted to a hospital, ICU, or outpatient telemedicine visit, and number of patients requiring 
mechanical ventilation.  
5.3. 
Safety Variables 
Safety variables include incidence of TEAEs as described in Section 10.1.1.  
5.4. 
Pharmacokinetic Variables 
The PK variables are the concentration of REGN14256, casirivimab, and imdevimab in serum and 
time/visit. Samples will be collected according to the relevant Schedule of Events (Section 9.1). 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, and time/visit. Samples will be collected 
according to the relevant Schedule of Events (Section 9.1). 
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Exploratory variables may include, but are not limited to, parameters reported in hematology 
(including differential), blood chemistry, serology, SARS-CoV-2 sequencing, and PRO measures.  
These results may be reported outside of the clinical study report (CSR). 
6. 
STUDY DESIGN  
This is a phase 1/2/3, randomized, double-blind, placebo-controlled adaptive study to assess the 
safety, tolerability, virologic and clinical efficacy of REGN14256+imdevimab, compared to 
placebo, in non-hospitalized adults (≥18 years of age) with COVID-19. Additionally, this study 
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will evaluate the safety and tolerability of REGN14256+imdevimab in non-hospitalized 
adolescents (≥12 and <18 years of age) with COVID-19.  
The primary objective of the phase 1 FIH portion of the study is to assess the safety and tolerability 
of REGN14256 alone and in combination with imdevimab. Phase 1 will include 2 sentinel safety 
analyses (when the first 40 patients have reached study day 7 [6 days after dosing], then when all 
phase 1 patients have reached study day 7) during each of which study enrollment will pause for 
an unblinded IDMC review of all available safety data (Section 3.2.1.2). Phase 2 enrollment will 
begin after the second sentinel safety analysis, if the IDMC provides a recommendation for the 
study to proceed.  
In phase 2, the virologic efficacy of REGN142565+imdevimab and REGN14256 monotherapy 
will be evaluated, and will include virologic data obtained in phase 1 which will remain blinded 
during that phase (Section 11.4.3). In phase 3, the primary objective will be to assess the clinical 
efficacy, based on COVID-19 symptoms resolution, of REGN14256+imdevimab compared to 
placebo. Clinical efficacy analysis will include data obtained in all 3 study phases, as the symptoms 
data obtained in phase 1 and phase 2 will remain blinded during those phases. In addition to the 
adult patients, an adolescent cohort of 40 patients between ≥12 and <18 years of age will be 
enrolled during phase 3 (Section 6.1.3), where permitted by local requirements. 
6.1. 
Study Description and Duration 
Each phase of the study consists of 3 periods: a screening/baseline period, a treatment period, and 
a follow-up period.  
Refer to the study flow diagrams (Figure 1 for phase 1, Figure 2 for phase 2, and Figure 3 for phase 
3). The Schedule of Events is provided in Section 9.1 (Table 1 for phase 1, Table 2 for phase 2, 
and Table 3 for phase 3), and additional information on study procedures is provided in 
Section 9.2. 
6.1.1. 
Study Periods 
Screening/Baseline Period (Day -1 to Day 1 Before Dosing) 
Patients will be assessed for eligibility during the screening/baseline period, which may occur up 
to 1 day prior to the baseline visit on study day 1. To be enrolled in the study, patients must have 
laboratory-confirmed SARS-CoV-2 infection and experience COVID-19 symptoms. Patients 
cannot have received any COVID-19 vaccination, nor present any underlying medical condition 
or other factors associated with high risk for progression to severe COVID-19. Other eligibility 
criteria apply (Section 7.2.1 and Section 7.2.2).  
During this period, eligible patients will be randomized (Section 8.1) and dosed on day 1. Prior to 
study drug administration on day 1, patients will have nasopharyngeal (NP) swabs taken for SARS-
CoV-2 RT-qPCR testing and blood drawn for laboratory safety, drug concentration, 
immunogenicity, and biomarkers analyses. After study drug dosing, adult patients will have a post-
dose blood collection for drug concentration at least 1 hour after study drug administration. Phase 
1 patients, and phase 3 adolescent patients (Section 6.1.3), will remain at the study site for at least 
5 hours after study drug administration, for additional safety monitoring and post-dose blood 
collection for drug concentration assessment. 
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Treatment Period (Day 1 After Dosing Through Day 29) 
The treatment period through day 29 includes the key clinical efficacy and safety analyses. All 
patients will complete the Symptom Evolution of COVID-19 (SE-C19) electronic questionnaire 
through day 29 for the key clinical efficacy assessment of COVID-19 symptoms. Also, within the 
treatment period, the key virologic efficacy analysis will be performed through day 7. NP swab 
samples will be collected according to the Schedule of Events: in phase 1 and phase 2, every other 
day (days 1 [pre-dose], 3, 5, and 7) for the first week then at day 29; in phase 3, on days 1 (pre-
dose), 7, and 29.  
In addition, information regarding any concomitant medication use and any COVID-19-related 
medically-attended visits (MAVs; eg, hospitalization, ER visit, urgent care visit, physician’s office 
visit, or telemedicine visit, with the primary reason for the visit being COVID-19) will be recorded 
during this period and throughout the study. Patients will be asked to notify the investigator or 
study site personnel as soon as possible about such occurrences. Investigators and designated study 
site personnel must ensure that information about COVID-19-related symptoms and MAVs is 
collected as required. Patients will have blood samples at indicated visits according to the Schedule 
of Events for drug concentration, immunogenicity, and exploratory analyses. Safety will also be 
monitored throughout the study: In all study phases, all TEAEs and SAEs will be collected through 
the end of study, and select events (grade ≥3 ISRs through day 4 and grade ≥3 hypersensitivity 
reactions through day 29) will be reported to the Sponsor in an expedited manner as AESIs. Refer 
to Section 10.1 for AE recording and reporting requirements. 
Follow-Up Period (Day 30 Through Day 169) 
Following the treatment period, patients will enter a follow-up period of approximately 6 months 
through the end of study (EOS) on study day 169. In addition to safety monitoring and drug 
concentration data analysis, data and samples collected during this period will be used for research 
purposes related to long COVID. This will include electronic questionnaires such as the Symptom 
Evolution of Long COVID-19 (SE-LC19), NP swabs on days 120 and 169 to assess potential 
persistence of SARS-CoV-2 in the nasopharynx, blood draws on day 120, and queries regarding 
any COVID-19-related MAVs.  
On visit days when sample collection is not required (eg, when only electronic questionnaires are 
collected), the information indicated in the Schedule of Events may be collected by phone without 
an in-person visit. The EOS visit will take place approximately 6 months after study drug 
administration. 
6.1.2. 
Electronic Questionnaires to Assess Patient-Reported Symptoms and Outcomes 
To assess COVID-19 symptoms and other patient-reported outcomes, electronic questionnaires 
will be completed by patients throughout the study according to the Schedule of Events (Table 1 
for phase 1, Table 2 for phase 2, and Table 3 for phase 3). Refer to Section 9.2.4 for background 
and procedural information regarding these instruments. 
SE-C19. For assessment of COVID-19 symptoms during acute disease, the Symptom Evolution 
of COVID-19 (SE-C19) patient-reported questionnaire will be completed at baseline (study day 
1), then on a daily basis from study day 2 through 29 (inclusive).  
SE-LC19. Patients will complete the Symptom Evolution of Long COVID-19 (SE-LC19) 
developed by the Sponsor to evaluate the eventual occurrence of long COVID. This electronic 
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survey will be completed on a daily basis from study day 30 through 45 (inclusive), then at study 
days 60, 90, 120, and 169. Note that SE-LC19 will be completed on a daily basis during the week 
leading up to study day 120 (study day 114 through 120, inclusive) and during the week leading 
up to study day 169 (study day 163 through 169, inclusive).  
PGIS, return to usual health, and return to usual activities questionnaires. To aid 
interpretation of SE-C19 and SE-LC19, Patient Global Impression of Severity (PGIS) and surveys 
for return to usual health or activities will be completed at baseline (study day 1), on a daily basis 
from study day 2 through 45 (inclusive), then at study days 60, 90, 120, and 169. Note that Patient 
Global Impression of Change (PGIC), return to usual healthy survey, and return to usual activities 
survey will also be completed on a daily basis during the week leading up to study day 120 (study 
day 114 through 120, inclusive) and during the week leading up to study day 169 (study day 163 
through 169, inclusive).  
PGIC, SF-36, WPAI+CIQ, and EQ-5D-5L/EQ-5D-Y. Patient Global Impression of Change 
(PGIC), Short Form-36 (SF-36), Work Productivity and Activity Impairment and Classroom 
Impairment Questions (WPAI+CIQ), and European Quality of Life Five Dimension-5 Level 
(EQ-5D-5L)/European Quality of Life Five Dimension-Youth (EQ-5D-Y) will be completed 
according to the Schedule of Events. Note that all adult patients in part A and part B will complete 
EQ-5D-5L, while adolescent patients in part B will complete the youth version, EQ-5D-Y, instead. 
6.1.3. 
Adolescent Cohort (Phase 3) 
During the phase 3 portion of the study, a cohort of 40 adolescent patients (≥12 and <18 years of 
age) will be enrolled. These patients will receive open label REGN14256+indevimab with the 
primary goal of collecting safety and PK data. In addition, clinical outcomes data (eg, time to 
symptoms resolution) will also be collected. This group of adolescent cohort patients will have to 
meet all the same eligibility criteria as the adult patients enrolled in the study (Section 7.2).  
Patients enrolled in the adolescent cohort will follow the same Schedule of Events as adult patients 
enrolled in phase 3, unless otherwise noted. Outcomes in these adolescent patients will be analyzed 
descriptively and not included in the primary clinical efficacy analysis. 
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Figure 1: 
Study Flow Diagram: Phase 1 
 
 
 
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Figure 2: 
Study Flow Diagram: Phase 2 
 
 
 
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Figure 3: 
Study Flow Diagram: Phase 3 
 
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6.1.4. 
End of Study Definition 
The end of study is defined as the date when the last patient completes the last study visit, 
withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be contacted 
by the investigator).  
6.2. 
Planned Interim Analysis  
No formal interim analysis is planned. Refer to Section 11.5. 
6.3. 
Study Committees  
6.3.1. 
Independent Data Monitoring Committee 
An IDMC will actively review data throughout the study to monitor patient safety data during 
phases 1, 2 and 3, and clinical efficacy data during phase 3. The IDMC can make recommendations 
about early study closure or changes to the study conduct. This will prompt a review by the Sponsor 
who will decide to implement, modify, or reject the recommendation, and relevant health 
authorities will be notified. 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.  
In phase 1, the IDMC will review the initial safety data in 2 sentinel safety analyses, during each 
of which study enrollment will be paused as described in Section 3.2.1.2.  
In phase 2 and phase 3, the IDMC will perform interim safety analyses, occurring (at minimum) 
after approximately half of the patients are enrolled and followed to day 7. Based on these analyses, 
the IDMC may make recommendations on study conduct, including early study closure for safety 
(Section 6.4). If phase 2 and/or phase 3 enrollment is slow, the IDMC will perform the interim 
safety analysis when approximately 200 patients have been enrolled in a given phase and followed 
to day 7. Enrollment pauses are not planned during phase 2 or phase 3 unless otherwise indicated 
by review of ongoing safety data. 
The operation of the IDMC is governed by a charter describing further details, such as procedures 
(including but not limited to periodic safety monitoring) and requirements for reporting its 
observations to the Sponsor. The IDMC charter will be updated or amended as necessary, 
particularly at the time of initiation of the phase 3 portion study when planned interim efficacy 
analyses and criteria to stop the trial for futility will be defined. 
6.4. 
Study Stopping Rules 
An IDMC will actively monitor interim data to review the ongoing safety of patients and may 
recommend halting or pausing the study, or implementing changes in study conduct as deemed 
necessary. 
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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In addition, the occurrence of one the following events at any time during the study will trigger a 
review by the Sponsor, and communication with the IDMC, to assess if the study should be 
temporarily paused (ie, pausing of screening, randomization, and dosing of study drug): 
• Three treatment-related SAEs or AESIs (defined in Section 10.1.3), or 
• One treatment-related SAE with a fatal outcome 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
This study will enroll up to approximately 1,359 patients in total.  
• Phase 1 will enroll approximately 100 adult patients (≥18 years of age).  
• Phase 2 will enroll approximately 610 adult patients. 
• Phase 3 will enroll approximately 609 adult patients and an additional adolescent cohort 
of 40 patients (≥12 and <18 years of age).  
7.2. 
Study Population  
This study will enroll non-hospitalized, low-risk, symptomatic patients with a baseline positive 
diagnostic test for SARS-CoV-2, and who have not previously received experimental, authorized 
or licensed COVID-19 vaccines. 
7.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Is male or female between ≥18 and <65 years of age (or country’s legal age of adulthood) 
at randomization.  
or 
For the adolescent cohort in phase 3 only: Is male or female between ≥12 and <18 
years of age at randomization 
Note: Adolescent cohort will only be enrolled where permitted by local requirements.. 
2. For the adolescent cohort in phase 3 only: Weighs ≥40 kg at randomization 
3. Has SARS-CoV-2-positive antigen or molecular diagnostic test (by validated SARS-
CoV-2 antigen, RT-PCR, or other molecular diagnostic assay, using an appropriate 
sample such as nasopharyngeal [NP], nasal, oropharyngeal [OP], or saliva) ≤72 hours 
prior to randomization. A historical record of a positive result is acceptable as long as the 
sample was collected ≤72 hours prior to randomization 
4. Has symptoms consistent with COVID-19 (as determined by the investigator) with onset 
≤7 days before randomization, and doesn't have a medical condition or other factors 
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associated with high risk for progression to severe COVID-19 as outlined in the 
exclusion criteria 
5. Maintains O2 saturation ≥93% on room air 
6. Is willing and able to:  
a. Provide informed consent signed by study patient or legally authorized representative 
Note: Age-appropriate assent will be collected from the study patient according to 
local regulatory (competent authority/ethics) guidelines. 
b. Comply with clinic visits, study-related procedures, including completion of the 
electronic diary and providing samples for viral load testing 
c. Understand and complete study-related questionnaires  
7. Is judged by the investigator to be in good health based on medical history, physical 
examination, vital sign measurements, and ECG’s performed at screening and/or prior to 
administration of study 
7.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria will be excluded from the study: 
1. Has a medical condition or other factors associated with high risk for progression to 
severe COVID-19:  
a. Cancer 
b. Cardiovascular disease (such as heart failure, coronary artery disease, 
cardiomyopathies, congenital heart disease or hypertension) 
c. Chronic lung disease including chronic obstructive pulmonary disease, asthma 
(moderate to severe), interstitial lung disease, cystic fibrosis, and pulmonary 
hypertension 
d. Chronic kidney disease at any stage 
e. Chronic liver disease (such as alcohol-related, nonalcoholic fatty liver disease, 
cirrhosis) 
f. Dementia or other chronic neurological condition 
g. Diabetes mellitus (type 1 or type 2) 
h. Immunodeficiency disease or taking immunosuppressive treatment  
i. Medical-related technological dependence [for example, tracheostomy, gastrostomy, 
or positive pressure ventilation (not related to COVID-19)] 
j. Neurodevelopmental disorder (for example, cerebral palsy) or other condition that 
confers medical complexity (for example, genetic or metabolic syndromes and severe 
congenital anomalies) 
k. Overweight (defined as BMI >25 kg/m2) or obesity (defined as BMI ≥30 kg/m2) 
l. Poorly controlled HIV infection or AIDS 
m. Pregnancy 
n. Sickle cell disease or thalassemia 
o. Stroke or cerebrovascular disease 
2. Prior, current (at randomization) or planned use (within time period given per CDC 
guidance [90 days]) of any authorized or approved vaccine for COVID-19 
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3. Was admitted to a hospital for COVID-19 prior to randomization, or is hospitalized 
(inpatient) for any reason at randomization 
4. Has a known prior SARS-CoV-2 infection or positive SARS-CoV-2 serologic test  
5. Has a positive SARS-CoV-2 antigen or molecular diagnostic test from a sample collected 
>72 hours prior to randomization 
6. Has participated, or is participating, in a clinical research study evaluating COVID-19 
convalescent plasma, mAbs against SARS-CoV-2, or intravenous immunoglobulin 
(IVIG) within 3 months or within 5 half-lives of the investigational product (whichever is 
longer) prior to the screening visit 
7. Prior, current, or any of the following treatments: COVID-19 convalescent plasma, mAbs 
against SARS-CoV-2, IVIG (any indication), systemic corticosteroids (any indication), or 
COVID-19 treatments (authorized, approved, or investigational) 
Note: Prior use is defined as the past 30 days or within 5 half-lives of the investigational 
product (whichever is longer) from screening 
8. Has known active infection with influenza or other non-SARS-CoV-2 respiratory 
pathogen, confirmed by a diagnostic test 
9. Has known allergy or hypersensitivity to components of the study drugs 
10. Has been discharged, or is planned to be discharged, to a quarantine center 
11. Has participated, is participating, or plans to participate in a clinical research study 
evaluating any authorized, approved, or investigational vaccine for COVID-19 
12. Is a member of the clinical site study team or is an immediate family member of the site 
study team 
13. Is committed to an institution by virtue of an order issued either by the judicial or the 
administrative authorities 
14. For phase 1 only: 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 study drug administration 
Highly effective contraceptive measures include:  
a. Abstinence2,3 
b. 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 
c. Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
d. 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. 
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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. 
3Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception. Female condom and male condom should not be 
used together. 
7.3. 
Premature Withdrawal from the Study  
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or Sponsor have the right to withdraw a patient from the study if it is no 
longer in the interest of the patient to continue in the study, or if the patient’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow 
study procedures). An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of patients should be avoided. 
Patient who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.2. 
7.4. 
Replacement of Patient  
Patients prematurely discontinued from study will not be replaced. 
8. 
STUDY TREATMENTS  
8.1. 
Investigational and Reference Treatments 
Instructions on dose preparation are provided in the pharmacy manual. Refer to Section 9.2.2 for 
instructions on study drug administration. 
8.1.1. 
Phase 1 and Phase 2 
Eligible patients will be randomized in a 1:1:1:1:1 allocation ratio to one of the following: 
• Co-administered REGN14256 and imdevimab combination therapy, 1200 mg (600 
mg each of REGN14256 and imdevimab) SC single dose 
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• REGN14256, 600 mg SC single dose 
• Imdevimab, 600 mg SC single dose 
• Co-administered casirivimab and imdevimab combination therapy, 1200 mg (600 mg 
each of casirivimab and imdevimab) SC single dose 
• Placebo SC single dose 
All patients will receive 4 SC injections of blinded study drug on day 1, each containing 2.5 mL 
(300 mg) of active study drug or placebo.  
8.1.2. 
Phase 3  
8.1.2.1. 
Patients Aged ≥18 Years 
Eligible patients will be randomized in a 1:1:1 allocation ratio to one of the following: 
• Co-administered REGN14256 and imdevimab combination therapy, 1200 mg (600 
mg each of REGN14256 and imdevimab) SC single dose 
• Co-administered casirivimab and imdevimab combination therapy, 1200 mg (600 mg 
each of casirivimab and imdevimab) SC single dose 
• Placebo SC single dose 
All patients will receive 4 SC injections of blinded study drug on day 1, each containing 2.5 mL 
(300 mg) of active study drug or placebo.  
8.1.2.2. 
Patients Aged ≥12 and <18 Years 
Eligible patients will receive open-label REGN14256+imdevimab 1200 mg (600 mg each of 
REGN14256 and imdevimab) SC single dose on day 1. All patients will receive 4 SC injections 
of study drug on day 1, each containing 2.5 mL (300 mg) of active study drug.  
8.2. 
Background Treatment 
No background treatment will be allowed. Patients may self-administer non-prescribed 
medications (eg, antipyretics) and continue other concomitant medications unless they are 
prohibited in Section 8.10.1. 
8.3. 
Rescue Treatment 
There will be no specific protocol-defined rescue therapy. Patients with signs or symptoms 
suggestive of progression to severe COVID-19 may be treated according to local standard of care 
as per the discretion of the investigator or treating physician. Any rescue medication use should 
be captured in the concomitant medication eCRF. If possible, the treating physician should notify 
the Regeneron Medical monitor prior to implementing any rescue therapy. 
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8.4. 
Dose Modification and Study Treatment 
Discontinuation/Termination Rules 
8.4.1. 
Dose Modification 
This is a single dose study; dose modification is not allowed. 
8.4.2. 
Study Drug Discontinuation/Termination 
This is a single dose study; study drug discontinuation is not applicable.  
As study drug is administered in 4 consecutive SC injections, administration 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 
(severe confusion, loss of consciousness, severe paresthesia, paralysis, etc) or any other symptom 
or sign that, in the opinion of the investigator, warrants termination of study drug administration. 
If the study drug injections are interrupted for safety or any other reason (eg, mechanical failure 
of a syringe), the total volume of study drug that has been administered successfully will be 
recorded. 
8.5. 
Management of Acute Injection Reactions  
8.5.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use. 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.  
All injection reactions must be reported as AEs (as defined in Section 10.2.1) and graded using the 
grading scales as instructed in Section 10.2.4. Systemic reactions occurring through day 29 are 
considered adverse events of special interest (AESIs) and require expedited reporting to the 
Sponsor (Section 10.1.2). 
8.5.2. 
Local Injection-Site Reactions 
Local injection-site reactions must be reported as AEs and graded according to Section 10.2.4. 
Injection-site reactions occurring through day 4 are considered AESIs and require expedited 
reporting to the Sponsor (Section 10.1.2). 
8.6. 
Method of Treatment Assignment  
Patients will be randomized according to a central randomization scheme using an interactive web 
response system (IWRS).  
8.7. 
Blinding  
A pharmacist or qualified personnel at the site, not otherwise associated with the conduct of the 
study, will reconstitute the drug for SC administration. The drug infusion solution must be 
provided in identical form for active and placebo treatments, so that they remain indistinguishable 
to both study personnel and patients.  
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Study patients, the principal investigators, and study site personnel (with the exception of the 
unblinded pharmacist at each site) will remain blinded to all randomization assignments 
throughout the study. The Regeneron medical/study director, study monitor, and any other 
Regeneron and contract research organization (CRO) personnel who are in regular contact with 
the study site will remain blinded to all patient randomization assignments in all phases of the 
study.  
Selected individuals from the Sponsor not involved in the conduct of the study may have access 
to unblinded data as needed for safety review or other data review (see Section 6.2). The team 
performing the interim data reviews will be separate from the ongoing study team. No study 
personnel involved in the day-to-day conduct of the study will have access to any unblinded data 
before the database is locked for this study.  
Anti-drug antibody, drug concentration, and biomarker results will not be communicated to the 
sites, and the Sponsor’s blinded operational team will not have access to results associated with 
patient identification until after the database is locked. 
8.8. 
Emergency Unblinding  
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy) and when a treatment decision is contingent 
on knowing the patient's treatment assignment.  
If unblinding is required: 
• Only the investigator will make the decision to unblind the treatment assignment. 
• Only the affected patients will be unblinded. 
• Unblinding is performed using the IWRS, which will notify the Sponsor. The 
designated study pharmacist(s)/designee at the study site will provide the treatment 
assignment to the investigator. If the study pharmacist(s)/designee is not available, the 
investigator for the site will unblind the patient.  
• If the IWRS is unavailable, the investigator will ask the unblinded study 
pharmacist(s)/designee to perform manual unblinding. All manual unblinding 
procedure will be adequately documented, including the reason why the IWRS was not 
used. 
• The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient. 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency and when a treatment decision is contingent on knowing the patient's treatment 
assignment. In the event that there is no study pharmacist, the individual at the site fulfilling that 
role will be the only unblinded member of the site personnel. 
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8.9. 
Treatment Logistics and Accountability 
8.9.1. 
Packaging, Labeling, and Storage  
A medication numbering system will be used to label unblinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
The unblinded pharmacist will prepare the unblinded investigational product and dispense it in a 
blinded manner to the blinded study staff for administration to the patient. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC. Storage instructions will be 
provided in the pharmacy manual. 
8.9.2. 
Supply and Disposition of Treatments  
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed at the site with approval 
by the Sponsor or returned to the Sponsor or designee. 
8.9.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication 
• Dispensed to each patient 
• Disposed of at the site or returned to the Sponsor or designee 
All accountability records must be made available for inspection by the Sponsor and regulatory 
agency inspectors; photocopies must be provided to the Sponsor at the conclusion of the study. 
8.9.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the Sponsor 
and regulatory agency inspectors. 
8.10. 
Concomitant Medications and Procedures  
Any treatment or procedure administered from the first dose of study drug to the final study visit 
will be considered a concomitant medication or procedure. This includes medications and 
procedures that were started before the study and are ongoing during the study.  
For more information on recording of concomitant medications and procedures, refer to 
Section 9.2.5.3. 
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8.10.1. 
Prohibited Medications and Procedures  
Patients are not permitted to receive any medication specified in the exclusion criteria for study 
enrollment (Section 7.2.2) unless medically indicated. Patients may otherwise continue their 
normal regimen of medications and procedures. 
Based on CDC guidance and per protocol, the use of any authorized or approved COVID-19 
vaccine should be deferred for at least 90 days after dosing to reduce potential interference of the 
study drug with vaccine-induced immune responses. Refer to the latest CDC guidance 
(CDC, 2021a). 
8.10.2. 
Permitted Medications and Procedures 
Other than the prohibited medications and vaccines listed in Section 8.10.1, 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 
Study assessments and procedures are presented by study period and visit in Table 1 for phase 1, 
Table 2 for phase 2, and Table 3 for phase 3 . 
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 1: 
Schedule of Events: Phase 1 
Day 
Screening/Baseline1 
Treatment Period3 
Follow-Up Period3 
Day -1 to 1 
2 
3 
4 
5 
7 15 22 29 30 
45 
60 
90 114–
119 1208 163–
168 
1698 
EOS 
Screen Pre-
dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 
±3 
±3 
±3 
 
+7 or 
±74 
 
+7 or 
±74 
Screening/Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test for  
SARS-CoV-26 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology for serostatus (central lab)16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 symptoms) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration7 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virologic Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab for SARS-CoV-2 RT-qPCR 
(central lab) 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
Electronic Survey for Patient-Reported Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SE-C198 
X 
 
 
Daily 
 
 
 
 
 
 
 
 
Electronic Surveys for Exploratory Patient-Reported Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SE-LC198 
 
 
 
 
 
 
 
 
 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
PGIS8 
X 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
PGIC8 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Return to usual health8 
X 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
Return to usual activities8 
X 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
SF-368 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
WPAI+CIQ8 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
EQ-5D-5L8 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs2 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent AEs10 
 
 
 
← Continuous monitoring → 
Treatment-emergent SAEs 10 
 
 
 
← Continuous monitoring → 
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Day 
Screening/Baseline1 
Treatment Period3 
Follow-Up Period3 
Day -1 to 1 
2 
3 
4 
5 
7 15 22 29 30 
45 
60 
90 114–
119 1208 163–
168 
1698 
EOS 
Screen Pre-
dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 
±3 
±3 
±3 
 
+7 or 
±74 
 
+7 or 
±74 
Treatment-emergent grade ≥3 ISRs10 
 
 
 
←Continuous 
monitoring→ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥3 hypersensitivity 
reactions10 
 
 
 
← Continuous monitoring → 
 
 
 
 
 
 
 
 
Concomitant medications and procedures11 
X 
 
 
← Continuous monitoring → 
Pregnancy test (WOCBP)12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Vital status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pregnancy status12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Safety information (newborns of study 
participants)12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory Safety Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (including differential)  
X13 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry 
X13 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics and Immunogenicity Sampling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for drug concentration (PK)14 
X 
 
X15 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
 
 
Serum for immunogenicity (ADA)16 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Central Laboratory Biomarker Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for exploratory research17 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Plasma for exploratory research17 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Exploratory Patients Outcomes Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19-related MAV details18 
X 
 
 
← Continuous monitoring → 
Wearable device19 
X 
← Continuous monitoring → 
Pharmacogenomics (Optional Sub-Study) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for DNA5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2: 
Schedule of Events: Phase 2 
Day 
Screening/Baseline1 
Treatment Period3 
Follow-Up Period3 
Day -1 to 1 
2 
3 
4 
5 
7 15 22 29 30 
45 
60 
90 114–
119 1208 163–
168 
1698 
EOS 
Screen Pre-
dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 
±3 
±3 
±3 
 
+7 or 
±74 
 
+7 or 
±74 
Screening/Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test for  
SARS-CoV-26 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology for serostatus (central lab)16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 symptoms) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration7 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virologic Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab for SARS-CoV-2 RT-qPCR 
(central lab) 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
Electronic Survey for Patient-Reported Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SE-C198 
X 
 
 
Daily 
 
 
 
 
 
 
 
 
Electronic Surveys for Exploratory Patient-Reported Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SE-LC198 
 
 
 
 
 
 
 
 
 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
PGIS8 
X 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
PGIC8 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Return to usual health8 
X 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
Return to usual activities8 
X 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
SF-368 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
WPAI+CIQ8 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
EQ-5D-5L8 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs9 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent AEs10 
 
 
 
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Day 
Screening/Baseline1 
Treatment Period3 
Follow-Up Period3 
Day -1 to 1 
2 
3 
4 
5 
7 15 22 29 30 
45 
60 
90 114–
119 1208 163–
168 
1698 
EOS 
Screen Pre-
dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 
±3 
±3 
±3 
 
+7 or 
±74 
 
+7 or 
±74 
Treatment-emergent SAEs 10 
 
 
 
← Continuous monitoring → 
Treatment-emergent grade ≥3 ISRs10 
 
 
 
←Continuous 
monitoring→ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥3 hypersensitivity 
reactions10 
 
 
 
← Continuous monitoring → 
 
 
 
 
 
 
 
 
Concomitant medications and procedures11 
X 
 
 
← Continuous monitoring → 
Pregnancy test (WOCBP)12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Vital status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pregnancy status12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Safety information (newborns of study 
participants)12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory Safety Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (including differential)  
X13 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry 
X13 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics and Immunogenicity Sampling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for drug concentration (PK)14 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
Serum for immunogenicity (ADA)16 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Central Laboratory Biomarker Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for exploratory research17 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Plasma for exploratory research17 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Exploratory Patient Outcomes Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19-related MAV details18 
X 
 
 
← Continuous monitoring → 
Pharmacogenomics (Optional Sub-Study) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for DNA5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3: 
Schedule of Events: Phase 3 
Day 
Screening/Baseline1 
Treatment Period3 
Follow Up Period3 
Day-1 to 1 
2 
3 
4 
7 15 22 29 30 
45 
60 
90 114–
119 1208 163–
168 
1698 
EOS 
Screen Pre-
dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 
±3 
±3 
±3 
 
+7 or 
±74 
 
+7 or 
±74 
Screening/Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent (or assent, as applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test for  
SARS-CoV-26 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology for serostatus (central lab)16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 symptoms) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration7 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virologic Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab for SARS-CoV-2 RT-qPCR 
(central lab) 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
Electronic Survey for Patient-Reported Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SE-C198 
X 
 
 
Daily 
 
 
 
 
 
 
 
 
Electronic Surveys for Exploratory Patient-Reported Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SE-LC198 
 
 
 
 
 
 
 
 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
PGIS8 
X 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
PGIC8 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Return to usual health8 
X 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
Return to usual activities8 
X 
 
 
Daily 
X 
X 
X8 
X8 
X8 
X8 
SF-368 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
WPAI+CIQ8 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
EQ-5D-5L (for patients ≥18 years of age)8 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
EQ-5D-Y (for patients <18 years of age)8 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs9 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Day 
Screening/Baseline1 
Treatment Period3 
Follow Up Period3 
Day-1 to 1 
2 
3 
4 
7 15 22 29 30 
45 
60 
90 114–
119 1208 163–
168 
1698 
EOS 
Screen Pre-
dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 
±3 
±3 
±3 
 
+7 or 
±74 
 
+7 or 
±74 
Treatment-emergent AEs10 
 
 
 
← Continuous monitoring → 
Treatment-emergent grade SAEs10 
 
 
 
← Continuous monitoring → 
Treatment-emergent grade ≥3 ISRs10 
 
 
 
←Continuous 
monitoring→ 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥3 hypersensitivity 
reactions10 
 
 
 
← Continuous monitoring → 
 
 
 
 
 
 
 
 
Concomitant medications and procedures11 
X 
 
 
← Continuous monitoring → 
Pregnancy test (WOCBP)12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Vital status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pregnancy status12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Safety information (newborns of study participants)12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory Safety Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (including differential)  
X13 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry 
X13 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics and Immunogenicity Sampling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for drug concentration (PK) for adult patients 
(≥18 years of age)14 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
Serum for drug concentration (PK) for adolescent 
patients (≥12 and <18 years)14 
X 
 
X15 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
 
 
Serum for immunogenicity (ADA) for all patients16 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Central Laboratory Biomarker Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for exploratory research17 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Plasma for exploratory research17 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Exploratory Patient Outcomes Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19-related MAV details18 
X 
 
 
← Continuous monitoring → 
Wearable device (≥18 years of age only)19 
X 
← Continuous monitoring → 
Pharmacogenomics (Optional Sub-Study) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for DNA5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.1.1. 
Footnotes for the Schedule of Events  
1. Screening visit may occur on the same day as the baseline visit (day 1), or the day prior to 
the baseline visit (day -1). 
2. In phase 1, on day 1, vital signs (as described in Section 9.2.5.1) will be measured at pre-
dose, approximately every 30 minutes during the first 2 hours after dose, at hour 3, and at 
hour 4. 
3. On visit days when sample collection is not required (eg, when only patient-reported 
questionnaires are collected), the information indicated in the Schedule of Events may be 
collected by phone without an in-person visit.  
4. For all day 120 and day 169 questionnaires, a visit window of +7 days will be applied. For 
all other day 120 and day 169 assessments and sample collections, a visit window of ±7 
days will be applied. 
5. Patients must provide separate consent to collect blood samples as part of the optional 
pharmacogenomics (PGx) sub-study. Blood sample for DNA should be collected at the day 
-1 or day 1 visit but may be collected at any visit. 
6. The investigator or sub-investigator will verify that the patient has tested positive for 
SARS-CoV-2, either at screening or by historical record of a positive antigen or molecular 
diagnostic test (by validated SARS-CoV-2 antigen, RT-PCR, or other molecular diagnostic 
assay, using an appropriate sample such as nasopharyngeal [NP], nasal, oropharyngeal 
[OP], or saliva) collected ≤72 hours prior to randomization. For local tests performed at 
screening, the local testing result, specimen type, assay type, and date of the test will be 
recorded in the eCRF.  
7. Refer to Section 9.2.2 for study drug administration instructions. 
8. On visit days when other assessments or sample collections are required, the site will verify 
that questionnaires have been completed prior to all other assessments or collections. The 
questionnaires should be completed in the order listed. On days when a certain 
questionnaire is not required, it will be skipped while the overall order of the other required 
questionnaires remains the same. Note that questionnaires will only be administered to 
patients in study sites if regionally available, and will only be administered to patients who 
are able to complete the questionnaires in the language available at their study site. Refer 
to Section 9.2.4 for additional information regarding these questionnaires. 
Long-COVID electronic surveys (ie, SE-LC19, PGIS, return to usual health, return to usual 
activities) must be completed as indicated in the Schedule of Events, then daily during the 
week leading up to day 120 visit, and daily during the week leading up to EOS visit on day 
169.  
9. On day 1, vital signs (as described in Section 9.2.5.1) will be collected once before study 
drug administration and once after study drug administration is completed.  
Phase 2: Patients will be monitored for at least 1 hour after study drug administration then 
released from the study site, if medically appropriate.  
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Phase 3 adult patients: After study drug administration, patients should be monitored 
according to local medical practice, as medically appropriate rather than a predefined 
period of time per the study protocol. 
Phase 3 adolescent cohort: Patients will be monitored for at least 1 hour after study drug 
administration. 
10. Refer to Section 10 for more information on safety reporting and recording requirements 
for. 
11. Concomitant medications and concomitant procedures will also be reviewed and recorded. 
Refer to Section 9.2.5.3 for more information. 
12. Pregnancy testing will be performed in women of childbearing potential (WOCBP) only. 
For WOCBP, negative pregnancy must be confirmed prior to study drug administration. 
Serum or urine pregnancy test are both acceptable. Note that a paper pregnancy report form 
must be completed for each patient who becomes pregnant and safety information in 
newborns of study participants will be collected. 
13. The indicated blood samples may be collected at either day -1 or day 1 (screening or pre-
dose) but must be collected prior to randomization. 
14. Actual dosing time and drug concentration (PK) sample collection times will be recorded. 
At the screening/baseline visit, blood for assessment of drug concentration in serum will 
be taken prior to dosing (either at day -1 or day 1).  
The post-dose blood collection on day 1, if indicated, should occur at least 1 hour after 
study drug administration.  
15. In phase 1 patients, and in adolescent cohort patients in phase 3, the post-dose blood 
collection on day 1 should occur at least 5 hours after study drug administration. 
16. The window for pre-dose ADA sample collection is as close to administration of study 
drug as is reasonable. Actual dosing time and ADA sample collection times will be 
recorded.  
17. Baseline serum SARS-CoV-2 serology assays will be performed centrally to determine 
serostatus retrospectively. Other serologic and plasma-based exploratory assays will be 
performed centrally post-treatment. 
18. COVID-19-related MAVs (defined as hospitalization, ER visit, urgent care visit, 
physician’s office visit, or telemedicine visit, with the primary reason for the visit being 
COVID-19) will be recorded in the eCRF. At minimum, details listed in Section 9.2.9 will 
be included. 
19. Wearable devices will be worn continuously, starting at least 15 minutes before study drug 
administration (preferably starting at screening). Refer to Section 9.2.10 for more 
information on the wearable device. 
9.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study before day 29 will be asked to allow an early 
termination visit consisting of day 29 assessments and sample collections. Patients who are 
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withdrawn from the study after day 29 will be asked to allow an early termination visit consisting 
of end-of-study assessments and sample collections. 
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for collection of NP swabs, 
blood, serum, or plasma, for follow-up of AEs, or for any other reason, as warranted. 
9.2. 
Study Procedures 
This section describes the procedures and sample collections that will be performed in this study. 
Procedures and sample collections will occur according to the Schedule of Events (Section 9.1). 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population.  
9.2.1.1. 
Informed Consent 
Informed consent (and assent, as applicable) must be obtained according to the requirements 
described in Section 13.2. Optional informed consent/assent may be obtained for participation in 
the pharmacogenomics sub-study (Section 9.2.11). 
9.2.1.2. 
Diagnostic Test for SARS-CoV-2 
The investigator or sub-investigator will verify that the patient has tested positive for SARS-CoV-
2, either at screening or by historical record (refer to Section 7.2.1 for detailed screening 
requirements). For tests performed at screening, the local testing result, specimen type, assay type, 
and date of the test will be recorded in the eCRF.  
9.2.1.3. 
Serology for Baseline Serostatus 
Serum serology assays will be performed to retrospectively determine baseline anti-SARS-CoV-2 
serostatus. 
9.2.1.4. 
Medical History 
Medical history will include, but not be limited to the following:  
• COVID-19 with start date as the date of onset of first symptoms related to COVID-19 
• Menopausal history 
• Pregnancy or breastfeeding status, if applicable  
9.2.1.5. 
Demographics 
Refer to Section 5.1. 
9.2.1.6. 
Weight and Height 
Weight and height will be recorded at the screening/baseline visit. 
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9.2.2. 
Study Drug Administration 
See Section 8.1 for treatments to be administered. 
For study drug administration which requires multiple SC injections, it is recommended to use 
different quadrants of the abdomen (avoiding navel and waist areas), front and upper outer sides 
of the thighs or the back side of the upper outer area of the arm. During the dose administration, 
each injection must be given in a different anatomical location (eg, 1 injection administered in the 
right lower quadrant of the abdomen, another in the left lower quadrant of the abdomen, etc). 
Numbing cream at the sites of injection should not be used as this will interfere with the safety 
assessment, ie, evaluation of ISRs.  
9.2.3. 
Nasopharyngeal Swab Collection 
Nasopharyngeal (NP) swab samples will be collected from patients to determine presence or 
absence of SARS-CoV-2 virus, including at baseline, and to measure viral load at different time 
points. Samples will be used for RT-qPCR analysis and viral RNA sequencing. Samples collected 
from patients may additionally be used for exploratory assays to study SARS-CoV-2. Additional 
details regarding sample collection and analysis can be found in the laboratory manual. 
In the event of a positive RT-qPCR, the investigator will be notified so that the patient may be 
informed of the result. Clinical management of a positive test result is deferred to the investigator 
or caring physician. As central laboratory test results may not be available in real time, any 
symptoms that may be related to acute COVID-19 infection should be tested and managed 
according to standard of care. 
9.2.4. 
Patient-Reported Symptoms 
This section describes planned patient-reported symptom analyses, some of which may not be 
reported in the CSR. Note that any symptoms collected by the instruments described below will 
not be considered AEs and will not be reconciled with any AEs. 
All questionnaires are self-reported using a compatible electronic device (eg, smartphone, tablet, 
laptop or personal computer). 
9.2.4.1. 
Symptom Evolution of COVID-19 (SE-C19), Patient Global Impression of 
Severity (PGIS), and Patient Global Impression of Change (PGIC) 
The Symptom Evolution of COVID-19 (SE-C19) instrument was developed de novo by 
Regeneron with the aim to better understand the symptomatic course of COVID-19 infection over 
time and is based on current available evidence on symptoms of COVID-19 (Arentz, 2020) 
(Chen, 2020a) (Chen, 2020b) (Huang, 2020) (Lapostolle, 2020) (Mizrahi, 2020) (Song, 2020) 
(Wang, 2020). Patients self-report symptoms are collected using a compatible electronic device 
(eg, smartphone, tablet, laptop or personal computer). Patients are presented with a list of 
symptoms and are asked to identify all those that they are experiencing.  
Patients rate each identified symptom as mild, moderate, or severe at the worst moment within the 
last 24 hours. An ‘other’ category is also available, where a free text field allows the addition of 
any symptom that is not on the list. Each score is assigned a numeric value: 0 (no symptom), 1 
(mild symptom), 2 (moderate symptom), or 3 (severe symptom). Table 4 provides the symptoms 
evaluated in the SE-C19.  
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Table 4: 
Symptoms Evaluated in the Symptom Evolution of COVID-19 (SE-C19) 
Instrument 
SE-C19 Symptoms Recorded and Planned for Analysis 
• Body aches such as muscle 
pain or joint pain 
• Chest pain 
• Chills 
• Confusion 
• Cough 
• Diarrhea 
• Dizziness 
• Fatigue 
• Feverish 
• Headache 
• Loss of appetite 
• Loss of taste / smell 
• Nausea 
• Pressure / tight chest 
• Rash 
• Red or watery eyes 
• Runny nose 
• Shortness of breath / difficulty 
breathing 
• Sneezing 
• Sore throat 
• Sputum / phlegm 
• Stomachache 
• Vomiting 
 
 
To aid interpretation, the SE-C19 is supplemented by the Patient Global Impression of Severity 
(PGIS) and the Patient Global Impression of Change (PGIC), which assess the overall subjective 
experience of symptom severity and change in symptoms over time. 
As a representation of the current available evidence of COVID-19 symptoms, the SE-C19 appears 
to have face validity for tracking symptom onset, severity, and recovery. Content validity was 
confirmed through an interview-based study of patients and clinicians, separate from this study.  
9.2.4.2. 
Symptom Evolution of Long COVID-19 (SE-LC19) 
To better understand the symptomatic course of long COVID, the Sponsor developed the Symptom 
Evolution of Long COVID-19 (SE-LC19). The SE-LC19 expands upon the SE-C19, which was 
developed with the aim of evaluating the acute phase of the disease course. The SE-LC19 consists 
of 40 symptoms, identified based on an evaluation of the currently-available literature on 
symptoms associated with long COVID (CDC, 2021b) (NHS, 2021) (WHO, 2021b).  
Participants are presented with a list of symptoms and are asked to identify all those that they are 
experiencing. Participants rate each symptom as mild, moderate, or severe at the worst moment 
within the last 24 hours. Each score is assigned a numeric value: 0 (no symptom), 1 (mild 
symptom), 2 (moderate symptom), or 3 (severe symptom). Table 5 lists the symptoms evaluated 
in the SE-LC19.
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Table 5: 
Symptoms Evaluated in the Symptom Evolution of Long COVID-19 (SE-
LC19) Instrument 
Symptom Evolution of Long COVID-19 (SE-LC19) 
All SE-LC19 Symptoms 
SE-LC19 Category A 
SE-LC19 Category B 
SE-LC19 Category C 
Altered or loss of smell  
Altered or loss of smell  
Altered or loss of smell  
Altered or loss of smell  
Altered or loss of taste  
Altered or loss of taste  
Altered or loss of taste  
Altered or loss of taste  
Body aches such as muscle pain 
or joint pain  
Body aches such as muscle 
pain or joint pain  
Body aches such as muscle 
pain or joint pain  
Body aches such as muscle 
pain or joint pain  
Cough  
Cough  
Cough  
Cough  
Fatigue  
Fatigue  
Fatigue  
Fatigue  
Headache  
Headache  
Headache  
Headache  
Shortness of breath or difficulty 
breathing  
Shortness of breath or 
difficulty breathing  
Shortness of breath or 
difficulty breathing  
Shortness of breath or 
difficulty breathing  
Chest pain 
 
Chest pain 
Chest pain 
Feeling depressed  
Symptoms Included: 7 
Feeling depressed  
Feeling depressed 
Rapid, strong or irregular 
heartbeat 
 
Rapid, strong or irregular 
heartbeat 
Rapid, strong or irregular 
heartbeat 
Brain fog  
 
 
Brain fog  
Diarrhea  
 
Symptoms Included: 10 
Diarrhea  
Dizziness  
 
 
Dizziness  
Feeling Anxious  
 
 
Feeling Anxious  
Fever  
 
 
Fever  
Loss of concentration  
 
 
Loss of concentration  
Memory problems  
 
 
Memory problems  
Pins and needles or numbness  
 
 
Pins and needles or numbness  
Pressure or tightness in chest  
 
 
Pressure or tightness in chest  
Rash  
 
 
Rash  
Sore throat  
 
 
Sore throat  
Stomachache  
 
 
Stomachache  
Chills 
 
 
 
Confusion 
 
 
Symptoms Included: 22 
Difficulty sleeping 
 
 
 
Earache 
 
 
 
Feeling irritable 
 
 
 
Feeling lightheaded 
 
 
 
Hair loss 
 
 
 
Hot flushes 
 
 
 
Inability to find the right words  
 
 
Loss of appetite 
 
 
 
Nausea 
 
 
 
Phlegm 
 
 
 
Red or watery eyes 
 
 
 
Ringing or buzzing in ears 
 
 
 
Runny nose  
 
 
 
Sneezing 
 
 
 
Sweats 
 
 
 
Vomiting  
 
 
 
 
 
 
 
Symptoms Included: 40 
 
 
 
Category A: Symptoms defined as “lingering” and identified across all three guidelines. 
Category B: identified across all three guidelines. 
Category C: identified across at least two or three guidelines. 
Guidelines: (CDC, 2021b) (NHS, 2021) (WHO, 2021b) 
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9.2.4.3. 
Global Impression Items 
The Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change 
(PGIC) questionnaires will assess the overall subjective experience of COVID-19 symptom 
severity and change in symptoms over time. The Return to Usual Health and Return to Usual 
Activities questionnaires will evaluate whether patients have returned to their usual health or 
activities prior to their COVID-19 illness. 
9.2.4.4. 
SF-36 
The SF-36 is a short-form, 36-question survey assessing health and quality of life. Questions are 
aggregated into eight scales, each of which measure a distinct aspect of health. A score from 0 to 
100 is generated for each scale, where higher scores represent less disability on the scale. The 
scales are further aggregated into two summary scores (also ranging from 0 to 100), which measure 
overall physical health and mental health.  
9.2.4.5. 
Work Productivity and Activity Impairment and Classroom Impairment 
Questions (WPAI+CIQ) 
Acute respiratory illnesses can lead to a significant economic burden owing to absenteeism and 
loss of workplace productivity (Li, 2007). The Work Productivity and Activity Impairment and 
Classroom Impairment Questions (WPAI+CIQ) questionnaire measures the effect of a specific 
health problem (eg, infection with SARS-CoV-2) on work productivity and activity impairment. 
The specific outcomes measured by the questionnaire are absenteeism (work time missed), 
presenteeism (impairment while working), overall work impairment (absenteeism plus 
presenteeism), and activity impairment (impairment in regular activities). Each score is 
represented as a percentage, with higher scores indicating less productivity or greater impairment. 
9.2.4.6. 
EQ-5D-5L and EQ-5D-Y  
The COVID-19 pandemic has resulted in a multisectoral global economic burden (Nicola, 2020), 
a significant portion of which is likely attributable to indirect costs related to school absenteeism, 
loss of workspace productivity, as well as health-related quality of life. Assessing the quality of 
life of individuals with SARS-CoV-2 is important, as it can aid in understanding the potential 
impact of interventions from the perspective of cost-utility analysis.  
The EQ-5D-5L is a validated and extensively published self-reported quality of life scale. The EQ-
5D-5L covers 5 health domains: mobility, self-care, usual activities, pain, and anxiety. Patients 
rate each domain on 5 level severity scale: having no problems, having slight problems, having 
moderate problems, having severe problems, and being unable to do/having extreme problems. In 
addition to the 5 domains, patients record their overall health on a visual analog scale, ranging 
from 0 (worst imaginable health state) to 100 (best imaginable health state).  
The EQ-5D-Y is a youth version of the adult scale designed and validated for use by children. It 
also includes 5 domains: mobility, looking after myself, doing usual activities, having pain or 
discomfort and feeling worried, sad or unhappy. 
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9.2.5. 
Safety Procedures  
9.2.5.1. 
Vital Signs 
Vital signs will include body temperature, blood pressure, heart rate (per minute), SpO2, and 
respiratory rate (per minute).  
Temperature may be measured using the following methods: axilla, oral, tympanic, or temporal. 
Body temperature should be measured using the same method each time. Temperature should be 
measured after at least 5 minutes of rest (supine or sitting). 
Blood pressure should be measured after the patient has been resting quietly for at least 5 minutes 
and may be obtained from a seated or supine position. 
SpO2 will be measured using a fingertip or similar non-invasive device following 5 minutes of rest 
(inactivity) while supine, semi-recumbent, or sitting and will only be measured in the presence of 
a good SpO2 wave form. 
9.2.5.2. 
Adverse Event Monitoring 
Treatment-emergent AEs (as defined in Section 10.1.1) will be recorded. 
9.2.5.3. 
Record Concomitant Medications and Concomitant Procedures 
Any concomitant medications or procedures will be recorded in the eCRF. In addition, any 
concomitant procedures used to treat an adverse event will be recorded in the eCRF. 
For more information on concomitant medications and procedures, refer to Section 8.10. 
9.2.5.4. 
Pregnancy Test for Women of Childbearing Potential 
Negative pregnancy test must be confirmed prior to study drug administration. Pregnancy testing 
may be satisfied by either serum pregnancy test (to be performed at a central laboratory) or by 
urine β-HCG test (to be performed at the local laboratory). Pregnancy tests are a requirement for 
WOCBP only and should be completed regardless of pregnancy status.  
Women of childbearing potential (WOCBP) are defined in Section 7.2.2 Exclusion Criterion #14. 
Information about pregnancy will be recorded as described in Section 10.1.3. 
9.2.5.5. 
Vital Status 
Vital status (whether the patient is dead or alive) will be recorded, as well as the date of death, 
when applicable. 
9.2.5.6. 
Pregnancy Status 
When applicable, date of pregnancy and status of the pregnancy will be recorded. Refer to 
Section 10.1.3 for reporting requirements. 
9.2.5.7. 
Safety Information in Newborns of Study Participants 
The incidence and outcome of any SARS-CoV-2 infection will be collected for newborn infants 
of patients who were treated in the study and were pregnant at randomization or became pregnant 
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at any time in the study. Note that this information is in addition to outcome reporting of all 
pregnancies (Section 10.1.3). 
9.2.5.8. 
Laboratory Testing 
Hematology, chemistry, and serum -HCG 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. 
Note that the laboratory tests listed below will only be performed based on samples that are 
collected according to the corresponding Schedules of Events (Section 9.1). 
Tests will include: 
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) 
 
Hematology 
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Other Test(s)  
-HCG pregnancy testing (serum) 
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 10.1.1. 
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9.2.6. 
Drug Concentration and Measurements 
Samples for assessment of drug concentration will be collected at the timepoints indicated in the 
corresponding Schedules of Events (Section 9.1). For information concerning unused samples and 
exploratory research, refer to Section 9.2.8. 
9.2.7. 
Immunogenicity Measurements and Samples 
Samples for assessment of immunogenicity will be collected at the timepoints indicated in the 
corresponding Schedules of Events (Section 9.1). For information concerning unused samples and 
exploratory research, refer to Section 9.2.8. 
9.2.8. 
Exploratory Pharmacodynamic/Biomarker Analyses 
This section describes planned exploratory pharmacodynamic/biomarker analyses, some of which 
may not be reported in the CSR.  
Also note that any biological samples collected during the study which are not used for their 
planned purpose, or for which material remains after their planned analysis, may be kept for up 15 
years after study completion (or for a shorter time period if required per regional laws and 
regulations) for use in exploratory research related to how the study drugs work and to study 
SARS-CoV-2. 
9.2.8.1. 
Virology 
Viral Sequencing 
In support of public health initiatives to track SARS-CoV-2 genetic variants, as well as to monitor 
for possible viral resistance, viral genome sequencing may be performed on viral nucleic acid 
isolated from nasopharyngeal swab samples, at baseline and in cases of a positive RT-qPCR result. 
Sequencing analyses will consist of the entire viral genome, including the full gene sequence that 
encodes the SARS-CoV-2 S protein. 
Viral sequencing may be performed on post-treatment samples to assess the emergence of 
sequence variants and to understand the potential relationship between genetic mutations and mAb 
functional activity. Viral sequencing may also be done on placebo controls to determine whether 
any genetic mutations observed in the mAb treatment group are naturally emergent genetic 
variants.  
Viral variants suspected to confer decreased susceptibility to REGN14256 and/or imdevimab will 
be evaluated in nonclinical work separate from this protocol. 
The results of viral sequencing will be reported separately from the CSR. 
Viral Infectivity 
To explore the effects of REGN14256 and imdevimab on infectivity of SARS-CoV-2, the Sponsor 
may use PFU, viral culture or viral subgenomic mRNA RT-qPCR or other assays to study SARS-
CoV-2. In vitro SARS-CoV-2 infectivity of cultured cells may be explored using NP samples. 
Infectivity of cells grown in culture may be assessed by PFU assays and/or immunofluorescence 
or other viral replication assays. The Sponsor may also use sub-genomic viral mRNA transcript 
assays, such as RT-qPCR or subgenomic mRNA sequencing, or other measures of in vivo 
infectivity potential. Viral sub-genomic mRNA is transcribed only in infected cells and is not 
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packaged into virions, and therefore may be an indicator of actively-infected cells. These data may 
be associated with RT-qPCR measuring viral load.  
The results of the viral infectivity assays may not be included in the CSR. 
9.2.8.2. 
Serological Immunoassays for Anti-SARS-CoV-2 Antibodies 
To explore the impact of baseline humoral activity against SARS-CoV-2 on the response to 
REGN14256+imdevimab, serological immunoassays will be used to detect antibodies at baseline 
against the SARS-CoV-2 spike protein RBD. Additional analyses of antibodies to other SARS-
CoV-2 antigens may also be performed. Neutralization assays may also be used to evaluate the 
function of endogenous baseline anti-SARS-CoV-2 antibodies. Associations will be evaluated 
with clinical outcomes. Measurement of antibodies against SARS-CoV-2 post-treatment may be 
tested for exploratory purposes. 
9.2.8.3. 
Serum and Plasma for Exploratory Research  
Research serum and plasma are being collected and banked for exploratory research related to 
COVID-19, SARS-CoV-2, REGN14256+imdevimab, host and viral biological pathways, and 
other mechanisms related to disease activity and clinical outcomes. These serum and plasma 
samples may be used for complement and/or cytokine analysis, and other related analyses. 
9.2.8.3.1. Long COVID 
Serum and plasma samples will be collected and banked for subsequent analyses. Such analyses 
may include, but are not limited to, multiplex proteomic profiling and serologic immunoassays to 
detect antibodies against SARS-CoV-2 among other assays.  
Serum and plasma-based analyses will be used to address scientific questions related to long 
COVID, such as the identification of prognostic biomarkers, understanding whether long COVID 
represents a single versus multiple unique pathologies and biological mechanisms, and associating 
biomarker profiles with patient-reported outcomes data. Analyses performed from banked samples 
may also be integrated with biomarker and other data from samples collected during the acute 
phase of SARS-CoV-2 infection. This will enable relationships between acute and long-term 
phases of COVID-19 to be explored, including better understanding the biology of COVID-19 
over time, and evaluating potential biomarkers during acute infection that may be predictive of 
REGN14256+imdevimab response during the long-term phase of disease. 
9.2.9. 
COVID-19-Related Medically-Attended Visit Details 
A COVID-19-related medically-attended visit will be defined as follows: hospitalization, 
emergency room (ER) visit, urgent care visit, physician’s office visit, or telemedicine visit, with 
the primary reason for the visit being COVID-19.  
Medically-attended visits related to COVID-19, as determined by the investigator, will be recorded 
in the eCRF. 
Details will include at minimum: 
• Type of visit (hospitalization, ER, urgent care, physician’s office visit, telemedicine) 
• Date of visit 
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• If hospitalized due to COVID-19, length of visit 
• Reason (list all COVID-19-related symptom[s] or clinical manifestation[s]) that 
prompted medically-attended visit) 
• If hospitalized due to COVID-19, whether ICU care was given 
• If hospitalized due to COVID-19, whether mechanical ventilation was required 
• Treatments given for COVID-19 (including, but not limited to supplemental oxygen, 
corticosteroids, COVID-19 convalescent plasma, remdesivir, monoclonal antibody, 
etc) 
9.2.10. 
Wearable Device Data Collection 
Exploratory parameters of pulse, respiratory rate, SpO2, physical activities and sleep will be 
measured using a wearable device. Patients will wear the device on the wrist, day and night 
according to the Schedule of Events. The devices will be worn continuously except during 
designated battery charging periods, bathing, and swimming.  
The wearable devices will be provided to study sites and appropriate training regarding patient use 
of these devices will be provided to the investigator and site staff.  
9.2.11. 
Pharmacogenomic Analysis (Optional)  
Patients 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 will 
be collected at the timepoints indicated in the corresponding Schedule of Events (Section 9.1.1) 
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 Harmonization (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 REGN14256 alone or in combination with imdevimab, or combination of 
casirivimab and imdevimab, 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, or COVID-19 and related diseases.  
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions. Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation may also be performed. The 
list of methods may be expanded to include novel methodology that may be developed during the 
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course of this study or sample storage period. Results from the genomic analyses will not be 
reported in the CSR. 
10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events  
10.1.1. 
General Guidelines 
Below TEAEs will be recorded: 
• Treatment-emergent adverse events (TEAEs) through day 169  
• Treatment-emergent serious adverse events (SAEs) through day 169 
• Treatment-emergent adverse events of special interest (AESIs):  
− Grade ≥3 injection-site reactions (ISRs) through day 4 
− Grade ≥3 hypersensitivity reactions through day 29  
The investigator must promptly report the above TEAEs occurring during the observation period 
(defined in Section 11.4.5.1). Medical conditions that existed or were diagnosed prior to the 
signing of the informed consent will be recorded as part of medical history. Abnormal laboratory 
values and vital signs observed at the time of Informed Consent should also be recorded as medical 
history. Any subsequent worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug 
should also be recorded as TEAE, provided that it fulfills the above criteria. 
Throughout the study, the investigator will determine whether any TEAEs occurred by evaluating 
the patient. These events may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit. Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms. The investigator must assess all TEAEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2. 
The investigator’s assessment must be clearly documented in the site’s source documentation with 
the investigator’s signature. The investigator should follow up on TEAEs until they have resolved 
or are considered clinically stable. 
Always report the diagnosis as the AE term. When a diagnosis is unavailable, report the primary 
sign or symptom as the AE term with additional details included in the narrative until the diagnosis 
becomes available. If the signs and symptoms are distinct and do not suggest a common diagnosis, 
report them as individual entries.  
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
Investigator to determine their clinical significance. Isolated abnormal laboratory results, vital sign 
findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported as 
AEs if they are symptomatic, require corrective treatment, or constitute an AE in the investigator’s 
clinical judgement. For events that are serious due to hospitalization, the reason for hospitalization 
must be reported as the serious adverse event (diagnosis or symptom requiring hospitalization). A 
procedure is not an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-
planned (prior to signing the informed consent form [ICF]) procedures, treatments requiring 
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hospitalization for pre-existing conditions that do not worsen in severity, and admission for 
palliative or social care should not be reported as SAEs (see Section 10.2 for definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Any SAE occurring subsequent to the reporting period (end of study) that the investigator assesses 
as related to study drug should be reported. In addition, any SAE resulting in death that occurs 
prior to study day 169 should also be reported, regardless of patient withdrawal or early 
termination. 
All treatment-emergent SAEs, AESIs, and pregnancies are to be reported according to the 
procedures in Section 10.1.3.  
Note that patient-reported outcomes data (eg, from patient-reported questionnaires, surveys, 
instruments, and wearable devices) are generally not reportable as individual AEs. However, if the 
investigator is made aware of any AE that (in his or her judgement) is related to study drug, the 
AE will be reported and recorded as described in Section 10.1.2. 
10.1.2. 
Reporting Procedure  
The TEAEs defined in Section 10.1.1 must be reported with investigator’s assessment of the 
event’s seriousness, severity, and causality to the blinded study drug. For SAEs and AESIs, 
detailed narratives summarizing the course of the event, including its evaluation, treatment, and 
outcome should be provided on the AE eCRF. Specific or estimated dates of event onset, treatment, 
and resolution should be included, when available. Medical history, concomitant medications, and 
laboratory data that are relevant to the event should also be summarized in the narrative. For fatal 
events, the narrative should state whether an autopsy was or will be performed and include the 
results if available. Information not available at the time of the initial report must be documented 
in a follow-up report. Source documents (including hospital or medical records, diagnostic reports, 
etc) will be summarized in the narrative on the AE eCRF and retained at the study center and 
available upon request.  
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up. 
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the Sponsor (or designee) within 24 hours of 
learning of the event: 
• Treatment-emergent SAEs 
• Treatment-emergent Adverse Events of Special Interest (AESI): Adverse events of 
special interest for this study include the following:  
− Grade ≥3 ISRs through study day 4 
− Grade ≥3 hypersensitivity reactions through study day 29 
• 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, 
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any pregnancy occurring in a female study patient during the study. A paper pregnancy 
report form must be completed for each patient who becomes pregnant.  
Any complication of pregnancy affecting a female study patient and/or fetus and/or 
newborn that meets the SAE criteria must be reported as an SAE. Outcome for all 
pregnancies should be reported to the Sponsor, including testing results for 
SARS-CoV-2 infection in the newborn, if performed. 
10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug (ICH 
E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an 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 patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events (Section 10.1.3). 
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10.2.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical interest specific to the Sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the Sponsor can be appropriate. Such an event might warrant further investigation in order to 
characterize and understand it.  
Adverse events of special interest for this study are defined in Section 10.1.3. 
10.2.4. 
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 6. The grading systems for anaphylaxis, allergic reaction (hypersensitivity), 
and injection-site reaction are provided in Table 7  
Table 6: 
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. 
Table 7: 
NCI-CTCAE (v5.0) Severity Grading System for Anaphylaxis, Allergic 
Reactions and Injection-Site Reactions  
Grade 
CTCAE Term 
Anaphylaxis1 
Allergic Reaction 
(hypersensitivity)2 
Injection-Site Reaction3 
1 
N/A 
Systemic intervention not 
indicated 
Tenderness with or without 
associated symptoms (eg, 
warmth, erythema, itching) 
2 
N/A 
Oral intervention indicated 
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 
Ulceration or necrosis; severe 
tissue damage; operative 
intervention indicated 
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4 
Life-threatening 
consequences; urgent 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
5 
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 an intense adverse reaction (usually immunologic) developing at the site of an injection. 
10.2.5. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions. The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
Include the following when applicable] For double blinded studies using an active comparator, the 
investigator should consider all study drugs in determining event causality.  
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset vs time drug was administered 
• Nature of the reactions: immediate vs. long term 
• Clinical and pathological features of the events  
• Existing information about the drug & same class of drugs  
• 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  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
(eg, disease under study, concurrent diseases, concomitant medications), or other 
external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration 
and is a known reaction to the drug under study or its class of drugs, or is 
predicted by known pharmacology. 
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• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol specified 
procedure and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol specified 
procedure or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications) or other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the Sponsor in a timely fashion. The Sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments (eg, 
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 /Ethics 
Committee, and Investigators 
During the study, the Sponsor and/or the CRO will inform health authorities, ECs/ IRBs, and the 
participating investigators of any SUSARs (Suspected Unexpected Serious Adverse Reactions) 
occurring in other study centers or other studies of the active study drug, as appropriate per local 
reporting requirements. In addition, the Sponsor and/or CRO will comply with any additional local 
safety reporting requirements. All notifications to investigators will contain only blinded 
information.  
Upon receipt of the Sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the IRB/EC unless delegated to the Sponsor. 
Event expectedness for study drug is assessed against the Reference Safety Information section of 
the Investigator’s Brochure that is effective for expedited safety reporting.  
At the completion of the study, the Sponsor will report all safety observations made during the 
conduct of the trial in the Clinical Study Report to health authorities and ECs/IRBs 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  
Phase 1 
No formal hypothesis testing is planned for phase 1. The safety and tolerability objectives will be 
evaluated by estimating the proportion of patients with TEAEs and SAEs through day 29 and 
AESIs, which will include ISRs (grade ≥3) through day 4 and hypersensitivity reactions (grade 
≥3) through day 29. 
Phase 1/2 
There are two null hypotheses to be tested in phase 1/2 (ie, based on data from phase 1 and phase 
2): 
• Ha1: There is no treatment difference between REGN14256 in combination with 
imdevimab compared to placebo in terms of time weighted average daily change from 
baseline in viral load (log10 copies/mL) from day 1 to day 7 for the seronegative 
patients. 
• Ha2: There is no treatment difference between REGN14256 alone compared to placebo 
in terms of time weighted average daily change from baseline in viral load (log10 
copies/mL) from day 1 to day 7 for the seronegative patients.  
Phase 1/2/3 
The primary null hypothesis to be tested in phase 1/2/3 (ie, based on data from phase 1, phase 2, 
and phase 3) is: 
• Hb1: There is no difference in time to COVID-19 symptoms resolution for 
REGN14256 in combination with imdevimab compared to placebo for the seronegative 
patients.  
A hierarchical testing procedure will be applied to control for multiplicity and to maintain the 
study-wise type I error rate at two-sided 0.05 level. 
11.2. 
Justification of Sample Size 
Phase 1  
Phase 1 will enroll approximately 100 patients (approximately 20 patients per arm) randomized to 
5 treatment groups.  
Phase 1/2 
The primary virologic efficacy analysis will be based on data from patients enrolled in phase 1 and 
phase 2. After the IDMC provides the recommendation to proceed with enrollment in phase 2 
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(Section 3.2.1.2), at least 610 additional patients will be randomized in the phase 2 portion of the 
study, for a total sample size in phase 1 and 2 of at least 710 randomized patients.  
The sample size is based on the primary virologic endpoint of time-weighted average (TWA) daily 
change from baseline in viral load (log10 copies/mL) from day 1 to day 7 using a two-sample t-test 
at a two-sided significance of α=0.05, in patients who are seronegative and who have a positive 
RT-qPCR value at baseline. Assuming a standard deviation of 1.2 log10 copies/mL, a sample size 
per arm of n=85 seronegative patients with positive value on RT-qPCR at baseline provides at 
least 90% power to detect a difference of 0.6 log10 copies/mL in TWA daily change from baseline 
viral load between any treatment group and placebo.  
If approximately 60% of patients are seronegative and have a positive value on RT-qPCR at 
baseline, it is estimated that ~142 patients would be required to be randomized into each treatment 
arm in order to yield ~85 seronegative patients per group.  
During enrollment, if the proportion of seronegative patients is observed to be different from that 
initially assumed, the study will continue to enroll until the required number of seronegative 
patients are met for the assessment of the primary virology endpoint.  
Phase 1/2/3 
The total sample size for the study is based on having sufficient power to analyze the primary 
endpoint of time to COVID-19 symptoms resolution. The primary clinical efficacy analysis will 
be based on data from patients enrolled in phase 1, phase 2, and phase 3. 
Based on data from the seronegative mFAS patients from the COV-2067 study (defined as the 
subset of seronegative patients with a positive central-lab determined SARS-CoV-2 RT-qPCR 
result from NP swab samples at randomization), the difference in median time to symptoms 
resolution was 4 days (8.0 days for casirivimab+imdevimab 2400 mg IV vs 12.0 days for placebo). 
Therefore, the sponsor conservatively assumes a difference in median time to symptoms resolution 
of 3.5 days for the comparison between co-administered REGN14256 and imdevimab combination 
therapy, 1200 mg (600 mg each of REGN14256 and imdevimab) SC single dose and placebo.  
Therefore, assuming a median time to COVID-19 symptoms resolution of 12 days for placebo, 
354 total events are needed to detect a difference in medians of 3.5 days with 90% power using a 
log-rank test (2 sided) with an overall type 1 error of 0.05, which corresponds to a median time to 
COVID-19 symptoms resolution of 8.5 days in the REGN14256 and imdevimab combination 
therapy group (HR=1.41).  
Assuming 29 days of follow up per patient, an accrual duration of 90 days, a total of 412 
seronegative patients (206 per group) are required to achieve 354 total events in a pairwise 
comparison between REGN14256+imdevimab combination therapy and placebo. Given that phase 
3 has 3 treatment arms with a 1:1:1 randomization ratio, 618 seronegative patients (206 per group) 
are required to be randomized. Furthermore, assuming approximately 60% of patients are 
seronegative and have a positive value on RT-qPCR at baseline, approximately 345 mFAS patients 
per arm in the relevant treatment groups will need to be randomized  to have approximately 1035 
patients for testing the clinical efficacy endpoint of time to COVID-19 symptoms resolution.  
Because 142 patients per group in the relevant treatment arms in phase1/2 will be contributing to 
the analysis of time to COVID-19 symptoms resolution, therefore, in phase 3, approximately 609 
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additional patients (203 per group) are required to be randomized into the 3 arms in a 1:1:1 ratio 
in order to yield 345 patients per group for the statistical hypothesis testing. 
During enrollment, the number of events among seronegative patients will be monitored in a 
blinded manner to ensure that the comparison of time to symptoms resolution is adequately 
powered. The sample size for the phase 3 portion of the study will be adjusted accordingly if the 
design, objective, and/or assumptions are changed. 
11.3. 
Analysis Sets  
11.3.1. 
Efficacy Analysis Sets 
The modified full analysis set (mFAS) includes all randomized patients with a positive central-
lab determined SARS-CoV-2 RT-qPCR result from NP swab samples at randomization and is 
based on the treatment received (as treated).  
The seronegative mFAS is the subset of patients in the mFAS population who are seronegative at 
baseline. The seronegative mFAS will be used for all efficacy and pharmacodynamic analyses. 
The seronegative mFAS is the primary analysis population; secondary analyses will be conducted 
in the overall mFAS population.  
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated). Determination of “as treated” will be based on the 
actual study drug received on day 1. Demographic and baseline characteristics, treatment 
compliance/administration and all clinical safety variables will be analyzed using the SAF. 
11.3.3. 
Pharmacokinetic Analysis Sets 
The drug concentration analysis population includes all randomized patients who received any 
study drug (SAF) and who had at least 1 non-missing result following the first dose of study drug. 
Patients will be analyzed based on actual treatment received. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis sets (AAS) include all patients who received any study drug and had at least 
one non-missing ADA result after first dose of the study drug.  
Samples positive in the ADA assays will be characterized further for ADA titers. Patients 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 patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
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11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients who have signed the ICF 
• The total number of randomized patients: received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.  
11.4.3. 
Efficacy Analyses 
All efficacy hypotheses are tested with respect to placebo. 
11.4.3.1. Phase 1/2: Primary Virologic Efficacy Analysis  
Note: the primary virologic efficacy analysis will be based on data from patients enrolled in phase 
1 and phase 2. 
The primary virologic efficacy variable is time-weighted average change from baseline in viral 
load from day 1 to day 7, as measured by RT-qPCR in NP swab samples. The primary analysis 
will be conducted in the Seronegative mFAS population. The estimands for the primary hypotheses 
is the difference in means between the SARS-CoV-2 combination mAb treatment 
(REGN14256+imdevimab) vs. placebo and the difference in means between REGN14256 vs. 
placebo.  
The analyses will be based on the observed data with no imputation for missing data except the 
following cases: uncertain viral load values with less than the lower limit of quantification of the 
PCR assay but with positive qualitative results are imputed with half of lower limit of 
quantification of the PCR assay; uncertain values with negative RNA are imputed with 
0 log10 copies/mL if the reason for the uncertain values is not a failed test. The primary efficacy 
variable will be calculated using trapezoidal rule, ie, area under the curve for change from baseline 
at each time point from day 1 to last observation divided by the number of days from day 1 to day 
of last observation. The variable is analyzed using an Analysis of Covariance (ANCOVA) model 
with treatment group as a fixed effect and baseline viral load and treatment by baseline interaction 
as covariates. 
The least squares means estimates for the TWA mean change from baseline in viral load at each 
visit, as well as the difference of these estimates between each treatment arm and placebo will be 
presented along with the corresponding p-value, standard error, and associated 95% confidence 
interval. Accompanying descriptive analyses will be provided at the individual timepoints used to 
calculate the TWA. 
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11.4.3.2. Phase 1/2/3: Primary Clinical Efficacy Analysis  
Note: the primary clinical efficacy analysis will be based on data from patients enrolled in phase 
1, phase 2, and phase 3. 
COVID-19 symptoms included in the analysis are as follows: body aches such as muscle pain or 
joint pain, chest pain, chills, cough, diarrhea, dizziness, fatigue, feverish, headache, loss of 
appetite, loss of taste/smell, nausea, pressure/tight chest, red or watery eyes, runny nose, shortness 
of breath/difficulty breathing, sore throat, sputum/phlegm, and stomachache. 
Time to COVID-19 symptoms resolution will be defined as time from randomization to the first 
day during which the patient scored ‘no symptom’ (score of 0) on all of the above symptoms except 
cough, fatigue, and headache, which can be ‘mild/moderate symptom’ (score of 1) or ‘no 
symptom’ (score of 0). Time to COVID-19 symptoms resolution will be analyzed using the log-
rank test. The analyses will be performed in the seronegative mFAS. Estimates of median times 
and associated 95% confidence intervals using the Kaplan-Meier method will be reported. The 
hazard ratio and 95% CI for time to COVID-19 symptoms resolution of COVID-19 symptoms 
endpoint will be estimated by the Cox regression model. Patients who do not experience resolution 
of symptoms will be censored at the last observation time point. Patients who died or had COVID-
19-related hospitalization prior to day 29 will be censored at day 29. Patients with a baseline raw 
score ≤3 will be censored at day 0. Patients with missing baseline assessment will not be included 
in the analysis.  
11.4.4. 
Control of Multiplicity 
A hierarchical testing procedure will be used to control the overall type I error rate at 0.05 for the 
testing of the primary virology endpoints (REGN14256 alone and in combination with imdevimab 
in comparison to the placebo arm) and the clinical endpoint (time to symptoms resolution in 
patients in the REGN14256+imdevimab arm in comparison to the placebo arm). The hierarchical 
testing order will be detailed in the SAP.  
11.4.5. 
Safety Analysis 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, 2 periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before study 
drug administration. 
• The observation period is defined as the time of study drug administration to the last 
study visit. 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the on-treatment period. 
Analysis 
All AEs reported in this study will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®).  
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Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• The number (n) and percentage (%) of patients with at least 1 treatment-emergent 
SAEs by SOC and PT 
• The number (n) and percentage (%) of patients with at least 1 injection-site reactions 
(grade ≥3) through day 4 by PT 
• The number (n) and percentage (%) of patients with at least 1 hypersensitivity 
reaction (grade ≥3) 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 other SAEs will be summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be 
summarized by treatment group. 
11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test for all patients 
and separately for patients in whom the PCSV criterion was normal or missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
11.4.5.3. Treatment Exposure 
The number and percentage of patients randomized and exposed to double-blind study drug, and 
duration of follow-up during the study will be presented by treatment group.  
11.4.5.4. Treatment Compliance 
Treatment compliance is not applicable for this study, since the study drug is administered once at 
the site. 
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11.4.6. 
Analysis of Drug Concentration Data 
All Patients in Phase 2 and Adolescent Patients in Phase 3 
The PK parameters may include, but are not limited to Cmax, Cmax/dose, tmax, and AUClast. 
The concentrations of REGN14256, imdevimab, and casirivimab in serum over time and selected 
pharmacokinetic parameters will be summarized descriptively for each of the treatment groups. 
Adult Patients in Phase 3 
The concentrations of REGN14256 and imdevimab in serum over time will be summarized 
descriptively for the REGN14256 and imdevimab treatment groups.  
11.4.7. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA status, ADA category, and maximum titer 
observed in patients in the ADA analysis set.  
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-emergent – A negative result or missing result at baseline with at least one 
positive post-baseline result in the ADA assay. 
− Treatment-emergent ADA response may be further characterized as persistent, 
transient, or indeterminate  
• 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.  
The maximum category of each subject is classified as: 
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤10,000) 
− High (titer >10,000)  
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers 
positivity presented by patient, time point, and dose cohort/group will be provided. Incidence of 
treatment-emergent ADA will be assessed as absolute occurrence (N) and percent of patients (%), 
grouped by study cohorts and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs on individual PK profiles 
evaluated. Assessment of impact of ADA on safety and efficacy may be provided. 
11.5. 
Interim Analysis  
No formal interim analysis is planned.  
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At the time of primary virologic efficacy assessment, the Sponsor may conduct an administrative 
interim analysis for time to COVID-19 symptoms resolution in order to inform regulatory 
interactions and/or internal decision making.  
An alpha penalty of 0.001 will apply for the testing of the clinical endpoint of time to symptoms 
resolution if an administrative look occurs. 
To protect the integrity of study results, unblinding for the primary virology analyses will occur 
after all patients enrolled in phase 2 have reached day 29. Individuals unblinded to the patient-
level data for the first step or any subsequent analysis will no longer be involved in the day-to-day 
conduct of the ongoing study. Patient-level results will not be released to any site-facing personnel 
or anyone who is directly involved in the conduct of the study.  
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study  
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and Sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE  
In accordance with ICH E6, the Sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.  
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, SAEs, baseline findings, medication, medical history) will be done using 
internationally recognized and accepted dictionaries. 
The eCRF data for this study will be collected with an electronic data capture (EDC) Medidata 
Rave. 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IWRS system – randomization, study drug supply 
• EDC system – data capture – Medidata Rave 
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• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
• Electronic clinical outcome assessment (eCOA) system – electronic patient diary and 
patient reported outcomes 
• Wearable devices 
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 patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and 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 
completed for each and every patient enrolled in the study. The investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the Sponsor in the CRFs. After 
review of the clinical data for each patient, the investigator must provide an electronic signature. 
A copy of each patient 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. 
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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/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities. Conditions of study material storage are also subject to inspection. In addition, 
representatives of the Sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
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 CRF/eCRF must be 
signed electronically by the investigator. This signed declaration accompanies each set of patient 
final eCRF that will be provided to the Sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of eCRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The investigator must obtain written approval from the Sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the Sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS  
13.1. 
Good Clinical Practice Statement  
It is the responsibility of both the Sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
An ICF can be defined as either a paper consent form or an electronically-delivered consent 
(eConsent). An eConsent may be provided only where allowable by local laws and regulations and 
by site policies.  
Due to disease severity, quarantine restrictions, and/or other reasons related to COVID-19, it may 
be necessary to implement temporary or alternative measures to obtain informed consent per 
procedures outlined in the investigator site file.  
Adult Patients 
The ICF used by the investigator must be reviewed and approved by the Sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the Sponsor before study drug will be shipped to the study site. 
For patients at or above the legal age of adulthood, it is the responsibility of the investigator or 
authorized designee (if acceptable by local regulations) to obtain informed consent from each 
patient prior to his/her participation in the study and after the aims, methods, objectives, and 
potential hazards of the study have been explained to the patient in language that he/she can 
understand. The ICF should be signed and dated by the patient and by the investigator or authorized 
designee who reviewed the ICF with the patient:  
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in the presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately. All study patients must be informed of the new information and provide their written 
consent if they wish to continue in the study. The original signed revised ICF must be maintained 
in the patient’s study record and a copy must be given to the patient. 
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Patients Under 18 Years of Age (or Under Country’s Legal Age of Adulthood) 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
For patients under the legal age of adulthood, it is the responsibility of the investigator or 
authorized designee (if acceptable by local regulations) to obtain written informed consent from 
the patient’s parent(s) or legal guardian(s) prior to the patient’s participation in the study and after 
the aims, methods, objectives, and potential hazards of the study have been explained to the fullest 
possible extent in language that the patient’s parent(s) or legal guardian(s) can understand. The 
ICF should be signed and dated by the patient’s parent(s) or legal guardian(s) and by the same 
investigator or designee who explained the ICF.  
Local law and site policies must be observed by the investigator in deciding whether the consent 
of 1 or both parents/guardians is required. If only 1 parent or guardian signs the ICF, the 
investigator must document the reason the other parent or guardian did not sign.  
The investigator (or authorized designee) may also be required to obtain assent from the patient,, 
as determined by the IRB/EC and in accordance with the local regulations and requirements: 
• Patients who can write but cannot read will have the assent form read to them before 
writing their name on the form 
• Patients who can understand but who can neither write nor read will have the assent 
form read to them by the person obtaining assent, who will sign and date the assent 
form to confirm that assent was given 
The original assent form must be retained by the investigator as part of the patient’s study record, 
and a copy of the signed assent form must be given to the patient’s parent(s) or legal guardian(s). 
13.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on 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 patient’s 's and investigator's personal data, which may be included in the Sponsor database, 
will be treated in compliance with all applicable laws and regulations. The Sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
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• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in 
which case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the Sponsor prior to shipment of drug supplies to the investigator. The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. Treatment codes will be disseminated to each investigation site 
thereafter. 
14. 
PROTOCOL AMENDMENTS 
The Sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment. Where required per local legislation, regulatory authority approval will also 
be sought.  
15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The Sponsor has the right to terminate the study prematurely. Reasons may include efficacy, 
safety, or futility, among others. Should the Sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
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 
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The Sponsor will notify the investigator(s) of a decision to close-out a study site in writing. 
Reasons may include the following, among others:  
• The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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PublicHealthEngland. SARS-CoV-2 Variants of Concern and Variants Under Investigation in 
England.Public 
Health 
England. 
https://www.gov.uk/government/publications/sars-cov-2-
variants-of-public-health-interest. Published 2021. 
 
Song F, Shi N, Shan F, Zhang Z, Shen J, Lu H, et al. Emerging 2019 Novel Coronavirus (2019-
nCoV) Pneumonia. Radiology 2020; 295(1):210-217. 
 
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT,Veesler D. Structure, Function, and 
Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 2020; 181(2):281-292.e286. 
 
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized 
Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020; 
323(11):1061-1069. 
 
Wang P, Nair MS, Liu L, Iketani S, Luo Y, Guo Y, et al. Increased Resistance of SARS-CoV-2 
Variants B.1.351 and B.1.1.7 to Antibody Neutralization. bioRxiv 2021:2021.2001.2025.428137. 
 
Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, et al. REGEN-COV 
Antibody Cocktail in Outpatients with Covid-19. medRxiv 2021:2021.2006.2009.21257915. 
 
WHO. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19).World 
Health Organization. 
https://www.who.int/docs/default-source/coronaviruse/who-china-joint-
mission-on-covid-19-final-report.pdf. Published 2020. Updated 24 Feb 2020. Accessed 30 Jun 
2020. 
 
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CONFIDENTIAL 
WHO. Tracking SARS-CoV-2 variants. https://www.who.int/en/activities/tracking-SARS-CoV-
2-variants/. Published 2021a. 
 
WHO. Update on Clinical long-term effects of COVID-19. https://www.who.int/docs/default-
source/coronaviruse/risk-comms-
updates/update54_clinical_long_term_effects.pdf?sfvrsn=3e63eee5_8. 
Published 
2021b. 
Accessed 28 Jun 2021. 
 
Wu Z,McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 
2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese 
Center for Disease Control and Prevention. JAMA 2020. 
 
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with 
Pneumonia in China, 2019. N Engl J Med 2020; 382(8):727-733. 
 
 
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CONFIDENTIAL 
20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Phase 1/2/3 Adaptive Study to Evaluate the Safety, 
Tolerability, and Efficacy of REGN14256+Imdevimab for the Treatment of COVID-19 Patients 
Without Risk Factors for Progression to Severe Disease and agree to abide by all provisions set 
forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the Sponsor or a 
partnership in which the Sponsor is involved. I will immediately disclose it in writing to the 
Sponsor if any person who is involved in the study is debarred, or if any proceeding for debarment 
is pending, or, to the best of my knowledge, threatened. 
This document contains confidential information of the Sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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CONFIDENTIAL 
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 1/2/3 Adaptive Study to Evaluate the Safety, Tolerability, and 
Efficacy of REGN14256+Imdevimab for the Treatment of COVID-19 Patients Without Risk 
Factors for Progression to Severe Disease 
Protocol Number: 
R14256-COV-2149 
Protocol Version:  
Amendment 1  
 
 
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-00168470 v1.0
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ESig Approval
21 13:41:09 GMT+0000
ESig Approval
2021 13:58:12 GMT+0000
ESig Approval
2021 14:49:11 GMT+0000
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
REGENERON CONFIDENTIAL 
Page 1 of 39 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL V1.0 
A PHASE 1/2/3 ADAPTIVE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
AND EFFICACY OF REGN14256+IMDEVIMAB FOR THE TREATMENT OF COVID-
19 PATIENTS WITHOUT RISK FACTORS FOR PROGRESSION TO SEVERE 
DISEASE 
Compound: 
REGN14256+Imdevimab 
Protocol Number: 
R14256-COV-2149 
Clinical Phase:  
Phase 1/2/3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
  
Version/Date: 
Original Statistical Analysis Plan (Version 1.0) / June 30, 2022 
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Statistical Analysis Plan 
 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
Study Biostatistician   
 
 
 
 
See appended electronic signature page 
Study Clinical Pharmacologist 
 
 
 
See appended electronic signature page 
Study Bioanalytical Scientist  
 
 
 
See appended electronic signature page 
Study Medical Director 
 
 
 
 
See appended electronic signature page 
Project Biostatistician  
 
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
 
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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. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.5. 
Revision History for SAP Amendments .....................................................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design and Randomization ..............................................................................11 
2.2. 
Sample Size and Power Considerations .....................................................................11 
2.3. 
Study Plan ...................................................................................................................11 
3. 
ANALYSIS POPULATIONS ....................................................................................12 
3.1. 
Efficacy Analysis Set ..................................................................................................12 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................12 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................12 
3.4. 
The Anti-drug Antibody (ADA) Analysis Set ............................................................12 
4. 
ANALYSIS VARIABLES .........................................................................................13 
4.1. 
Demographic and Baseline Characteristics ................................................................13 
4.2. 
Medical History ..........................................................................................................13 
4.3. 
Prior / Concomitant Medications or Procedures .........................................................13 
4.4. 
Rescue Medication/or Prohibited Medication During Study ......................................14 
4.4.1. 
Rescue Treatment .......................................................................................................14 
4.4.2. 
Prohibited Medications and Procedures .....................................................................14 
4.5. 
Efficacy Variable ........................................................................................................14 
4.5.1. 
Primary Efficacy Variable (s) .....................................................................................14 
4.5.2. 
Secondary Efficacy Variable(s) ..................................................................................15 
4.5.3. 
Exploratory Efficacy Variable(s) ................................................................................15 
4.6. 
Safety Variables ..........................................................................................................16 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................16 
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4.6.2. 
Adverse Events of Special Interest .............................................................................16 
4.6.3. 
Laboratory Safety Variables .......................................................................................17 
4.6.4. 
Vital Signs ..................................................................................................................17 
4.7. 
Pharmacokinetic Variables .........................................................................................18 
4.8. 
Exploratory Variables .................................................................................................18 
5. 
STATISTICAL METHODS .......................................................................................19 
5.1. 
Demographics and Baseline Characteristics ...............................................................19 
5.2. 
Medical History ..........................................................................................................19 
5.3. 
Prior/concomitant Medications and Procedures .........................................................19 
5.4. 
Prohibited Medications ...............................................................................................19 
5.5. 
Subject Disposition .....................................................................................................19 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................20 
5.6.1. 
Measurement of Compliance ......................................................................................20 
5.6.2. 
Exposure to Investigational Product ...........................................................................20 
5.7. 
Analyses of Efficacy Variables ..................................................................................20 
5.7.1. 
Analysis of Primary Efficacy Variable(s) ...................................................................20 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................20 
5.7.3. 
Analysis of Exploratory Variables ..............................................................................21 
5.7.4. 
Adjustment for Multiple Comparison .........................................................................21 
5.8. 
Analysis of Safety Data ..............................................................................................21 
5.8.1. 
Adverse Events ...........................................................................................................21 
5.8.2. 
Clinical Laboratory Measurements.............................................................................22 
5.8.3. 
Analysis of Vital Signs ...............................................................................................22 
5.8.4. 
Analysis of Drug Concentration Data .........................................................................23 
6. 
DATA CONVENTIONS ............................................................................................24 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................24 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................24 
6.3. 
Data Handling Convention for Missing Data .............................................................24 
6.4. 
Visit Windows ............................................................................................................24 
6.5. 
Unscheduled Assessments ..........................................................................................25 
6.6. 
Pooling of Centers for Statistical Analyses ................................................................25 
7. 
INTERIM ANALYSIS ...............................................................................................26 
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8. 
SOFTWARE ...............................................................................................................27 
9. 
REFERENCES ...........................................................................................................28 
10. 
APPENDIX.................................................................................................................29 
10.1. 
Schedule of Time and Events .....................................................................................29 
10.2. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................32 
 
LIST OF TABLES 
Table 1: 
Time Window for Summary of NP Swab for SARS-CoV-2 RT-qPCR 
(central lab) .................................................................................................................25 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram for Phase 1 ................................................................................11 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACE2 
Angiotensin-converting enzyme 2 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
ALP 
Aspartate aminotransferase 
Alkaline phosphatase  
CDC 
US Centers for Disease Control and Prevention 
Cmax 
Maximum concentration 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOS 
End of study 
EQ-5D-5L 
European Quality of Life Five Dimension-5 Level 
EQ-5D-Y 
European Quality of Life Five Dimension-Youth 
ER 
Emergency room 
EUA 
Emergency Use Authorization 
FAS 
Full analysis set 
FDA 
US Food and Drug Administration 
FIH 
First-in-human 
GCP 
Good clinical practice 
IRB 
Institutional Review Board 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IDMC 
Independent data monitoring committee 
ISR 
Injection-site reaction 
IWRS 
Interactive web response system 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal antibody 
MAV 
Medically-attended visit 
mFAS 
Modified full analysis set 
NCI 
National Cancer Institute 
NLR 
Neutrophil-lymphocyte ratio 
NP 
Nasopharyngeal  
NT-proBNP 
N-terminal pro B-type natriuretic peptide 
OP 
Oropharyngeal  
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PRO 
Patient-reported outcome 
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Statistical Analysis Plan 
 
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PT 
Preferred term  
RBD 
Receptor binding domain 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RT-qPCR 
Quantitative reverse transcription polymerase chain reaction 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SE-C19 
Symptom Evolution of COVID-19 
SE-LC19 
Symptom Evolution of Long COVID-19 
SF-36 
Short Form-36 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TWA 
Time-weighted average 
VBM 
Variants Being Monitored 
VOC 
Variant of Concern 
VOHC 
Variant of High Consequence 
VOI 
Variant of Interest 
VUI 
Variant Under Investigation 
VUS 
Variants under surveillance 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
WPAI+CIQ 
Work Productivity and Activity Impairment and Classroom Impairment 
Questions 
 
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Statistical Analysis Plan 
 
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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 study R14256-COV-2149 (hereafter referred to as 
COV-2149) of monoclonal antibodies (mAbs) for the treatment of non-hospitalized patients with 
COVID-19 who are at low risk of progressing to severe disease. The SAP is based on the 
Protocol Amendment 1 (dated 26-AUG-2021) of COV-2149. 
To address the COVID-19 pandemic and the predominant SARS-CoV-2 variants at the time 
(e.g., the Delta variant), the Sponsor (Regeneron) designed and implemented this phase 1/2/3 
adaptive COV-2149 study to evaluate the safety, virologic efficacy, and clinical efficacy of a 
new mAb R14256 alone or in combination with a previously evaluated mAb, imdevimab. 
Enrollment was subsequently prematurely closed on 16 December 2021 based on the reduced 
activity of R14256 and imdevimab against the newly emerging Omicron variant that had become 
the predominant circulating lineage variants in the US, and not due to any safety concerns.  
Therefore, enrollment was stopped during the phase 1 portion of the first-in-human (FIH) COV-
2149 study, and the phase 2/3 portions were never opened. Accordingly, the focus of this SAP is 
on the data collected in phase 1.   
All analyses will be descriptive in nature and will mainly pertain to the primary objectives of the 
phase 1 portion of the study, including: 
• Safety and tolerability (as measured by treatment-emergent adverse events, injection-
site reactions, and hypersensitivity reactions), and  
• Virologic efficacy (as measured by time-weighted average (TWA) change from 
baseline in viral load through day 7) 
Additional data pertaining to secondary objectives of the phase 1 will also be descriptively 
analyzed and selective exploratory outcome data will be provided in a brief clinical study 
report(CSR). 
This is the final statistical plan, and the SAP will be issued prior to data lock. In case of any 
unexpected issues prior to the data lock, any revisions to the SAP will be issued before code 
breaking of the blinded data. 
1.1. 
Background/Rationale 
COV-2149 was designed as a phase 1/2/3 randomized, placebo-controlled, adaptive study to 
evaluate the safety, tolerability, virologic efficacy, and clinical efficacy of 
REGN14256+imdevimab compared to placebo in non-hospitalized patients with COVID-19 who 
are at low risk of progressing to severe disease. Casrivimab+imdevimab, the mAb combination 
previously authorized for treatment of COVID-19 in non-hospitalized patients, was included as a 
calibrator arm. 
For more information regarding the rationale for the study design and dose selection, refer to 
Section 3.2 of the Protocol Amendment 1. Additional background information on 
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REGN14256+imdevimab and the overall development program can be found in the 
Investigator’s Brochure. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objectives of the phase 1 are to: 
• Evaluate the safety and tolerability of REGN14256+imdevimab and REGN14256 
monotherapy, as measured by treatment-emergent adverse events (TEAEs), injection-
site reactions (ISRs), and hypersensitivity reactions 
• Evaluate the virologic efficacy of REGN14256+imdevimab and REGN14256 
monotherapy compared to placebo, as measured by time-weighted average (TWA) 
change from baseline in viral load through day 7  
• Evaluate the clinical efficacy of REGN14256+imdevimab compared to placebo, as 
measured by COVID-19 symptoms resolution 
1.2.2. 
Secondary Objectives 
The secondary objectives of the phase 1 are to: 
• Evaluate the safety and tolerability of REGN14256+imdevimab and REGN14256 
monotherapy, as measured by treatment-emergent serious adverse events (SAEs) 
• Evaluate additional indicators of virologic efficacy of REGN14256+imdevimab and 
REGN14256 monotherapy  
• Characterize the concentration-time profile of REGN14256 administered in 
combination with imdevimab or alone as a monotherapy 
• Assess the immunogenicity of REGN14256 administered in combination with 
imdevimab or alone as a monotherapy 
1.2.3. 
Exploratory Objectives 
The exploratory objectives are to:  
• Evaluate the clinical efficacy of REGN14256 in combination with imdevimab, 
compared to placebo 
• Evaluate the impact of REGN14256+imdevimab treatment, given during acute 
SARS-CoV-2 infection, on long COVID symptoms, compared to placebo  
• Explore relationships between REGN14256 alone (as applicable) and in combination 
with imdevimab exposure and selected efficacy endpoints, safety endpoints, and/or 
biomarkers 
• Characterize the concentrations of casirivimab and imdevimab in serum over time 
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1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
Because enrollment was stopped prematurely during the phase 1 portion of Study COV-2149, the 
target sample size that the originally planned inferential analyses were based on would not be 
achieved. Therefore, due to a lack of sufficient statistical power to detect significant treatment 
differences, the inferential analyses planned in the final protocol will not be conducted. Instead, 
this study will descriptively analyze the endpoints mainly for phase 1 with no formal hypothesis 
testing to be performed. 
1.2.5. 
Revision History for SAP Amendments 
Not applicable 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a phase 1/2/3, randomized, double-blind, placebo-controlled adaptive study to assess the 
safety, tolerability, virologic and clinical efficacy of REGN14256+imdevimab, compared to 
placebo, in non-hospitalized adults (≥18 years of age) with COVID-19. Phase 1 of the study 
consists of 3 periods: a screening/baseline period, a treatment period, and a follow-up period. 
Refer to the phase 1 study flow diagram (Figure 1) for more details. The Schedule of Events is 
provided in Section 10.1.  
Figure 1: 
Study Flow Diagram for Phase 1 
 
2.2. 
Sample Size and Power Considerations 
Power calculations are not applicable as the enrollment was stopped at Phase 1. 
2.3. 
Study Plan 
The Study event table is presented in Section 10.1. 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis: 
3.1. 
Efficacy Analysis Set  
The full analysis set (FAS) includes all randomized patients and is based on the treatment 
allocated (as randomized). 
The modified full analysis set (mFAS) includes all randomized patients with a positive central 
lab determined SARS-CoV-2 RT-qPCR result from nasopharyngeal (NP) swab samples at 
randomization and is based on the treatment received (as treated). 
3.2. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it 
is based on the treatment received (as treated). Determination of “as treated” will be based on the 
actual study drug received on day 1. Demographic and baseline characteristics, treatment 
compliance/administration and all clinical safety variables will be analyzed using the SAF. 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) 
The pharmacokinetic (PK) analysis set is defined for each analyte separately. Each PK Analysis 
set includes all participants who received any study drug (SAF) and who had at least 1 non-missing 
result of respective analyte following the first dose of study drug. Subjects will be analyzed based 
on the actual treatment received. 
3.4. 
The Anti-drug Antibody (ADA) Analysis Set 
Not applicable as anti-drug antibody (ADA) analysis will not be performed due to early study 
discontinuation. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic variables will be summarized:  
• Age at screening (years) 
• Age range (quantitative and qualitative variable: 18 – 44, 45 – 64 years) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic/Latino, Not Hispanic/Latino) 
• Baseline Weight (kg) 
• Baseline Height (cm) 
• Baseline Body mass index (BMI) (kg/m2) calculated from weight and height 
• Baseline Obesity (BMI < 30 kg/m2, BMI ≥ 30 kg/m2) 
• Baseline Viral Load in nasopharyngeal swab samples (copies/mL, log10 copies/mL) 
• Baseline Viral Load Category (Below the Lower Detection Limit, <= 104 copies/mL, 
>104 copies/mL, >105 copies/mL, >106 copies/mL, >107 copies/mL) 
• Baseline SARS-CoV-2 diagnostic test result (Positive, Negative) 
• Baseline anti-SARS-CoV-2 serostatus (Negative, Positive, Other) 
• Baseline SARS-CoV-2 Spike Protein Antibody (U/mL) 
Additional baseline characteristics will be included if needed.  
4.2. 
Medical History 
Medical history Medical history will include, but not be limited to the following: 
• COVID-19 with start date as the date of onset of first symptoms related to COVID-19 
• Menopausal history 
• Pregnancy or breastfeeding status, if applicable 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
4.3. 
Prior / Concomitant Medications or Procedures  
Any treatment or procedure administered from the first dose of study drug to the final study visit 
will be considered a concomitant medication or procedure. Medications will be coded to the 
ATC level 2 (therapeutic main group) and ATC level 4 (chemical/therapeutic subgroup), 
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according to the latest available version of WHO Drug Dictionary (WHODD). Patients will be 
counted once in all ATC categories linked to the medication. 
Prior medications / procedures: medications taken or procedures performed prior to 
administration of the study drug. 
Concomitant medications / procedures: medications taken or procedures performed following 
the dose of study drug through the EOS visit. 
4.4. 
Rescue Medication/or Prohibited Medication During Study  
4.4.1. 
Rescue Treatment 
There will be no specific protocol-defined rescue therapy. Patients with signs or symptoms 
suggestive of progression to severe COVID-19 may be treated according to local standard of care 
as per the discretion of the investigator or treating physician. Any rescue medication use should 
be captured in the concomitant medication eCRF.  
4.4.2. 
Prohibited Medications and Procedures  
Patients are not permitted to receive any medication specified in the exclusion criteria for study 
enrollment (Section 7.2.2 of the Protocol Amendment 1) unless medically indicated. Patients 
may otherwise continue their normal regimen of medications and procedures.  
Based on CDC guidance and per protocol, the use of any authorized or approved COVID-19 
vaccine should be deferred for at least 90 days after dosing to reduce potential interference of the 
study drug with vaccine-induced immune responses. Refer to the latest CDC guidance (CDC, 
2021a). 
Other than the prohibited medications and vaccines listed above, treatment with concomitant 
medications is permitted during the study. Any medications used by the study subject should be 
captured in the concomitant medication eCRF. 
4.5. 
Efficacy Variable 
4.5.1. 
Primary Efficacy Variable (s) 
Virologic 
• Time-weighted average (TWA) daily change from baseline in viral load (log10 
copies/mL) from day 1 to day 7, as measured by SARS-CoV-2 quantitative reverse 
transcription polymerase chain reaction (RT-qPCR) in nasopharyngeal (NP) swab 
samples.  
Time-weighted average of change from baseline viral load in the nasopharyngeal (NP) swab 
samples from day 1 through day 7 will be calculated for each patient using the linear trapezoidal 
rule as the area under the curve for change from baseline at each time point divided by the time 
interval for the observation period. Accompanying descriptive analyses will be provided at the 
individual timepoints used to calculate the TWA. 
For example, the time-weighted average change from baseline in viral load in the nasopharyngeal 
(NP) swab samples till the last observation day tk will be calculated using formula 
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𝑇𝑊𝐴[0−𝑘] = [∑(𝑡𝑖
𝑘
𝑖=1
−𝑡𝑖−1) ∗(𝐷𝑖+ 𝐷𝑖−1)/2]/(𝑡𝑘−𝑡0) 
Where  
• k=3 refers to 3 post-baseline assessments through day 7 
• Di is the change from baseline in viral load value (log10 copies/mL) obtained at time 
ti, D0 =0 
• ti is the time (day) for which Di is measured, such as t0 = 1 (day) for baseline and 
{ti} = 3, 5, 7, for i=1 to 3 where the postbaseline assessment is taken. 
• If the Di is not available per protocol or missing due to failed test or other reasons, 
only the time points with non-missing values will be included into the calculation. For 
example, we will calculate the TWA till day 7. In this case, data is not available at 
day 1, 2, 4, and 6 per the protocol schedule of events. Suppose the scheduled 
assessment result is missing at day 5 due to a failed test but non-missing at day 3 and 
day 7, then 
𝑇𝑊𝐴[0−7] = [(𝑡3 −𝑡0) ∗(𝐷3 + 𝐷0)/2 + (𝑡7 −𝑡3) ∗(𝐷7 + 𝐷3)/2]/(𝑡7 −𝑡0) 
Baseline is defined as the last non-missing values prior to the study drug administration. Patients 
with missing baseline will be excluded from the analysis. 
4.5.2. 
Secondary Efficacy Variable(s) 
Virologic 
• Time-weighted average change from baseline in viral load at each timepoint, as 
measured by RT-qPCR in NP samples 
• Change from baseline in viral load at each timepoint through day 7, as measured by 
RT-qPCR in NP samples  
• Proportion of patients with viral loads below the limit of detection at each visit 
4.5.3. 
Exploratory Efficacy Variable(s) 
Virologic  
• Change from baseline in viral load through day 29 as measured by RT-qPCR in NP 
swab samples 
Clinical  
• Proportion of patients with COVID-19-related medically attended visits (MAVs) or 
all-cause mortality through day 29 and day 169  
Note: A COVID-19-related medically-attended visit will be defined as follows: 
hospitalization, emergency room (ER) visit, urgent care visit, physician’s office visit, 
or telemedicine visit, with the primary reason for the visit being COVID-19. Refer to 
Section 9.2.9 of the Protocol Amendment 1 for more information. 
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Drug Concentration  
• Concentrations of REGN14256, casirivimab and imdevimab in serum over time 
4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient administered a study 
drug which may or may not have a causal relationship with the study drug. All adverse events are 
to be coded to a “Preferred Term” and associated primary “System Organ Class (SOC)” 
according to the latest available version of Medical Dictionary for Regulatory Activities 
(MedDRA®). 
Treatment-emergent adverse events are defined as the AEs that are not present at baseline or 
represent the exacerbation of a pre-existing condition during the on-treatment period. A Serious 
Adverse Event is an AE that is classified as serious according to the criteria specified in Section 
10.2.2 of the Protocol Amendment 1. All TEAEs and SAEs will be collected through the end of 
study. 
4.6.2. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical interest specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator to the Sponsor can be appropriate. Adverse events of special interest for this study 
include the following: 
− Grade ≥3 injection-site reactions (ISRs) through study day 4  
− Grade ≥3 hypersensitivity reactions through study day 29 
All the adverse events define above in Section 4.6.1 and Section 4.6.2 must be reported with 
investigator’s assessment of the event’s seriousness, severity, and causality to the blinded study 
drug. 
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 6 of the Protocol Amendment 1. 
The grading systems for anaphylaxis, allergic reaction (hypersensitivity), and injection-site 
reaction are provided in Table 7 of the Protocol Amendment 1.  
The investigator must provide causality assessment as whether there is a reasonable possibility 
that the drug caused the adverse event, based on evidence or facts, his/her clinical judgment, and 
the following definitions. For more information regarding the causality assessment, refer to 
Section 10.2.5 of the Protocol Amendment 1.  
Laboratory results, vital signs, and other diagnostic results or findings (e.g., positive pregnancy 
test) should be appraised by the Investigator to determine their clinical significance. Isolated 
abnormal laboratory results, vital sign findings, or other diagnostic findings (i.e., not part of a 
reported diagnosis) should be reported as AEs if they are symptomatic, require corrective 
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treatment, or constitute an AE in the investigator’s clinical judgement. More details on the 
reporting of adverse events can be found in Section 10.1.1 of the Protocol Amendment 1. 
4.6.3. 
Laboratory Safety Variables 
Hematology, chemistry, and serum -HCG pregnancy testing samples will be analyzed by a 
central laboratory. The laboratory tests listed below will only be performed based on samples 
that are collected according to the corresponding Schedules of Events (Section 10.1). Tests will 
include:  
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) 
 
Hematology  
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Other Test(s) 
-HCG pregnancy testing (serum) 
4.6.4. 
Vital Signs 
The following vital signs parameters will be recorded at multiple time points according to 
Schedule of Time and Event Table (Section 10.1): 
• Respiratory rate (bpm) 
• Heart rate (bpm) 
• Systolic and diastolic blood pressures (mmHg) 
• SpO2 (%) 
• Body temperature (oC) 
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4.7. 
Pharmacokinetic Variables  
The PK variables are the concentrations of REGN14256, casirivimab and imdevimab in serum at 
each timepoint. These sampling timepoints are specified in the corresponding Schedule of Events 
(Section 10.1). 
4.8. 
Exploratory Variables 
Exploratory variables include, but not limited to, the patient-reported COVID-19 symptoms and 
outcomes assessed by electronic questionnaires (e.g., SE-C19), the exploratory parameters (e.g., 
physical activities) measured using wearable devices, and the parameters collected from viral 
sequencing tests, viral infectivity assays, serological immunoassays for Anti-SARS-CoV-2 
Antibodies, and serum and plasma samples for exploratory research. Refer to section 9.2.8 of the 
Protocol Amendment 1 for more information. These results may be reported outside of the 
clinical study report (CSR). 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, 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 summarized descriptively by treatment group, 
and by all groups combined using FAS, mFAS, and SAF. The corresponding subgroup 
summaries by baseline anti-SARS-CoV-2 serostatus will also be provided. 
5.2. 
Medical History 
Medical history will be summarized by primary SOC and PT by treatment group and all groups 
combined using SAF. The table will be sorted by decreasing frequency of SOC followed by PT 
based on the overall incidence across treated groups.  
5.3. 
Prior/concomitant Medications and Procedures  
Prior or concomitant medications/procedures will be summarized by treatment groups using 
SAF. Summaries will present patient counts (and percentages) for all medications, dictionary 
coded by WHODRUG, by decreasing frequency of the overall group incidence (or high dose 
group incidence in tables where the overall is not presented) of ATC followed by ATC level 2, 
ATC level 4 and preferred term.  
5.4. 
Prohibited Medications 
Prohibited medications will be summarized using SAF in a similar way as described above for 
concomitant medications. 
5.5. 
Subject Disposition 
The following summaries will be provided using FAS: 
• The total number of screened patients/subjects who have signed ICF  
• The total number of randomized patients: received a randomization number  
• The total number of screening phase discontinuation, and the reasons for 
discontinuation  
• The total number of patients randomized, patients randomized and treated, patients 
randomized but not treated, and patients treated but not randomized 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation  
• A summary of analysis sets including FAS, mFAS, SAF, and PKAS. 
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5.6. 
Extent of Study Treatment Exposure and Compliance 
5.6.1. 
Measurement of Compliance 
Treatment compliance is not applicable for this study since the study drug is administered once 
at the site.  
5.6.2. 
Exposure to Investigational Product 
Exposure to study drug will be examined for each patient as recorded on the Drug 
Administration - Injection CRF. The following variables will be analyzed by treatment group 
based on the SAF population:  
• Duration of injection  
• Total volume of drug administered (units: mL)  
• Number of patients with total planned dose administered (yes/no)  
• Number of patients with injection interruptions  
The number and percentage of patients randomized and exposed to double-blind study drug will 
be presented for each treatment group.  
5.7. 
Analyses of Efficacy Variables 
5.7.1. 
Analysis of Primary Efficacy Variable(s) 
Virology 
The primary virologic efficacy variable is time-weighted average (TWA) change from baseline 
in viral load from day 1 to day 7, as measured by RT-qPCR in NP swab samples. The primary 
virologic efficacy variable will be analyzed descriptively by treatment group, and by all groups 
combined in the mFAS population. The corresponding subgroup analyses by baseline anti-
SARS-CoV-2 serostatus will also be performed. 
The analyses will be based on the observed data with no imputation for missing data except the 
following cases: uncertain viral load values with less than the lower limit of quantification of the 
PCR assay but with positive qualitative results are imputed with half of lower limit of 
quantification of the PCR assay; uncertain values with negative RNA are imputed with 0 log10 
copies/mL if the reason for the uncertain values is not a failed test. The primary efficacy variable 
will be calculated using trapezoidal rule, i.e., area under the curve for change from baseline at 
each time point from day 1 to last observation divided by the number of days from day 1 to day 
of last observation.  
5.7.2. 
Analysis of Secondary Efficacy Variables 
Virology 
Time-weighted average change from baseline in viral load at each timepoint, as measured by 
RT-qPCR in NP samples, will be analyzed descriptively in a similar way as described above for 
the primary virologic efficacy variable.  
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To assess the time course of treatment effect in viral load, change from baseline in viral load at 
each timepoint through day 7, as measured by RT-qPCR in NP samples, will be analyzed 
descriptively in the mFAS population. The viral load at each visit up to day 7 along with the 
change from baseline in viral load (log10 copies/mL) will be summarized by treatment group 
with descriptive statistics. The line plot of mean (+/-se) viral load change from baseline in log10 
scale at each visit and the line plot of mean (+/-se) viral load in log10 scale at each visit will also 
be presented.  
Proportion of patients with viral loads below the limit of detection at each visit through day 29 
will be presented by treatment group. The percentage at each visit is derived using the number of 
patients with NP swab samples at the visit as the denominator. 
The corresponding subgroup analyses/graphs by baseline anti-SARS-CoV-2 serostatus will be 
performed for all the secondary virologic efficacy analyses.  
5.7.3. 
Analysis of Exploratory Variables 
Virology 
The analysis of change from baseline in viral load through day 29, as measured by RT-qPCR in 
NP swab samples, will be conducted referring to the previously detailed analysis of change from 
baseline in viral load at each timepoint through day 7.  
Clinical Outcomes 
The proportions of patients with medically attended visits (MAVs) due to COVID-19 or all-
cause death through Day 29 and Day 169 will be summarized with descriptive statistics. The 
analyses will be performed based on the observed data from the mFAS patients. Listings of 
COVID-19-related MAVs during the study will also be summarized and presented.  
5.7.4. 
Adjustment for Multiple Comparison 
There is no issue with multiplicity for the primary efficacy variable. 
5.8. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF, as defined in Section 3.2. 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations and vital signs. 
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables and vital 
signs are defined in Section 10.2.   
The summary of safety results will be presented for each treatment group. 
5.8.1. 
Adverse Events  
Definitions 
For safety variables, 2 periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before study 
drug administration.  
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• The observation period is defined as the time of study drug administration to the last 
study visit. Treatment-emergent adverse events are defined as those that are not 
present at baseline or represent the exacerbation of a pre-existing condition during the 
on-treatment period.  
Analysis  
All AEs reported in this study will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA®). 
Summaries of TEAEs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE through day 29 
and day 169 by SOC and PT  
• TEAEs by severity (according to the grading scale outlined in Section 10.2.4 of the 
Protocol Amendment 1), presented by SOC and PT 
• The number (n) and percentage (%) of patients with at least 1 TEAE related to study 
treatment through day 29 and day 169 by SOC and PT  
Summaries of SAEs and AESIs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 treatment-emergent 
SAE through day 169 by SOC, PT, and severity 
• The number (n) and percentage (%) of patients with at least 1 treatment-emergent 
SAE through day 169 by SOC, PT, and relationship to study drug 
• The number (n) and percentage (%) of patients with at least 1 AESI through day 29 
(defined with a PT or a prespecified grouping) 
Listings of deaths, SAEs, AESIs, and TEAEs leading to study discontinuation will be 
summarized and presented by treatment group. 
5.8.2. 
Clinical Laboratory Measurements  
Laboratory measurements include blood chemistry and hematology results and will be converted 
to standard international units and US conventional units. Patients with at least one post-baseline 
lab test result outside the normal range and patients with lab value status change from baseline to 
postbaseline will be summarized by each clinical laboratory test.  
Listings of patients with a potentially clinically significant value (PCSV) at any post-
randomization time point will be summarized and presented.  
5.8.3. 
Analysis of Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and by each scheduled assessment time with descriptive statistics. 
Listings of patients with a potentially clinically significant value (PCSV) at any post-
randomization time point will be summarized and presented.  
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5.8.4. 
Analysis of Drug Concentration Data  
Concentrations of REGN14256, casirivimab and imdevimab in serum over time will be 
measured and summarized descriptively in the PKAS population for each of the treatment 
cohorts.  
A non-compartmental analysis (NCA) will be performed on the concentration in serum and 
actual time data for REGN14256, casirivimab and imdevimab to obtain pharmacokinetic 
parameters, which may include but are not limited to the following: 
• AUClast – area under the curve (AUC) computed from time zero to the time of the 
last positive concentration 
• AUCinf - AUC from time zero extrapolated to infinity 
• Cmax – peak concentration 
• Tmax – time of peak concentration 
• Tlast - time of the last positive (quantifiable) concentration 
PK parameters will be summarized by standard descriptive statistics. No formal statistical 
hypothesis testing will be performed. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product.  
6.2. 
Data Handling Convention for Efficacy Variables  
Not applicable. 
6.3. 
Data Handling Convention for Missing Data 
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 5.7.1.  
For categorical variables, patients with missing data will be included in denominator for 
calculations of percentages. Number of patients with missing data will be presented. 
Medication missing/partial dates 
To determine whether a medication is prior, concomitant or post-treatment medication, the 
missing medication start date is estimated as early as possible up to randomization date, and the 
missing medication end date is estimated as late as possible up to Day 29. If the medication start 
date is missing, the onset day will not be imputed in medication listings. 
Adverse event 
If the severity of a SAE, AESI and grade 3 or 4 AEs is missing, it will be classified as “missing” 
in the frequency tables by CTC grade of SAE and AESIs. If the assessment of relationship of the 
investigational product is missing, it will be classified as “not reported” or “missing”. 
Date of injection 
Date of infection is the non-missing administration date filled in the Drug Administration – 
Injection CRF. If the first dose of study drug administration date is missing (even after site is 
queried), then the dosing date will be imputed with the randomization date. If any subsequent 
study drug administration date is missing, the date of dispensation of study drug from IRT will 
be used. 
6.4. 
Visit Windows 
Data analyzed by-visit-analysis will be summarized by the study scheduled visits described in 
Section 10.1, “Schedule of Events”. The analysis visit windows will be exhaustive so that all 
available values obtained from unscheduled visits, early termination visit (ETV) and end of study 
(EOS) have the potential to be summarized. No analysis visit windows will be applied for the 
study scheduled visits.  
The following analysis visit windows will be used to map the unscheduled visits, ETV and EOS 
visits for NP Swab for SARS-CoV-2 RT-qPCR, based on the study day during the double-blind 
period: 
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Table 1: 
Time Window for Summary of NP Swab for SARS-CoV-2 RT-qPCR (central 
lab) 
Visit Label Targeted Study Day Analysis Window in Study Day 
Baseline 
1 
≤ 1 
Day 3 
3 
[2, 3] 
Day 5 
5 
[4, 5] 
Day 7 
7 
[6, 18] 
Day 29  
29 
[19, 32] 
Day 120 
120 
[114, 144] 
Day 169 
169 
[145, 176] 
In the event of multiple measurements of the same test in the same window, if the measurements 
are from different categories, the priority order is scheduled, early termination visit then 
unscheduled visit. For the measurements in the same category, the value measured nearest to the 
target day will be assigned to the window; if they are at the same distance to the target day, the 
latest one will be used. Extra assessments (laboratory data or vital signs associated with 
non-protocol clinical visits or obtained in the course of investigating or managing adverse 
events) will be included in listings, but not summaries except for the endpoint determination. If 
more than one laboratory value is available for a given visit, the first observation will be used in 
summaries and all observations will be presented in listings. 
6.5. 
Unscheduled Assessments 
The determination of baselines and values at the end of treatment will be based on scheduled 
available assessments and unscheduled available assessments.  
For by visit summary, unscheduled visit will not be summarized unless otherwise specified. 
6.6. 
Pooling of Centers for Statistical Analyses 
Not applicable.  
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7. 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4. 
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9. 
REFERENCES 
1. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and  content of 
clinical study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
2. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
3. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
4. CDC. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently 
Authorized in the United States.Centers for Disease Control and Prevention. 
https://www.cdc.gov/vaccines/covid19/info-by-product/pfizer/clinical-
considerations.html. Published 2021a. Updated 05 Mar 2021. Accessed 21 Mar 2021 
2021. 
5. CDC. Post-COVID Conditions.CDC. https://www.cdc.gov/coronavirus/2019-ncov/long-
term-effects.html. Published 2021b. Updated 8 Apr 2021. Accessed 20 Jun 2021. 
6. NHS. Long-term effects of coronavirus (long COVID). 
https://www.nhs.uk/conditions/coronavirus-covid-19/long-term-effects-of-coronavirus-
long-covid/. Published 2021. Accessed 28 Jun 2021. 
7. WHO. Update on Clinical long-term effects of COVID-19. 
https://www.who.int/docs/default-source/coronaviruse/risk-comms-
updates/update54_clinical_long_term_effects.pdf?sfvrsn=3e63eee5_8. Published 2021b. 
Accessed 28 Jun 2021. 
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10. 
APPENDIX 
10.1. 
Schedule of Time and Events 
 
Day 
Screening/Baseline1 
Treatment Period3 
Follow-Up Period3 
Day -1 to 1 
2 3 4 5 7 15 22 29 30 45 60 90 114–
119 1208 163–
168 
1698 
EOS 
Screen Pre-
dose Dose 
Post-
Dose 
Window (Day) 
 
 
 
 
     ±1 ±3 ±3 ±3 ±3 ±3 ±3 
 
+7 or 
±74 
 
+7 or 
±74 
Screening/Baseline 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent 
(optional)5 
X 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Antigen or molecular 
diagnostic test for  
SARS-CoV-26 
X 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Serology for serostatus 
(central lab)16 
X 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Medical history (including 
COVID-19 symptoms) 
X 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
      
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Study drug administration7 
 
 
X 
 
      
 
 
 
 
 
 
 
 
 
 
Virologic Outcomes 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab for 
SARS-CoV-2 RT-qPCR 
(central lab) 
X 
 
 
 X  X X  
 X  
 
 
 
 
X 
 
X 
Electronic Survey for Patient-Reported 
Symptoms 
 
      
 
 
 
 
 
 
 
 
 
 
SE-C198 
X 
 
 
Daily 
 
 
 
 
 
 
 
 
Electronic Surveys for Exploratory Patient-Reported 
Outcomes 
     
 
 
 
 
 
 
 
 
 
 
SE-LC198 
 
 
 
      
 
 Daily X X X8 
X8 
X8 
X8 
PGIS8 
X 
 
 
Daily 
X X X8 
X8 
X8 
X8 
PGIC8 
 
 
 
      
 X  
 
 
 
 
 
 
X 
Return to usual health8 
X 
 
 
Daily 
X X X8 
X8 
X8 
X8 
Return to usual activities8 
X 
 
 
Daily 
X X X8 
X8 
X8 
X8 
SF-368 
 
 
 
      
 
 X X X X 
 
X 
 
X 
WPAI+CIQ8 
X 
 
 
    X X X X  
 X X 
 
X 
 
X 
EQ-5D-5L8 
X 
 
 
    X X X X  
 X X 
 
X 
 
X 
Safety 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Vital Signs2 
X 
X 
 
X 
      
 
 
 
 
 
 
 
 
 
 
Treatment-emergent AEs10 
 
 
 
← Continuous monitoring → 
Treatment-emergent SAEs 10 
 
 
 
← Continuous monitoring → 
Treatment-emergent grade 
≥3 ISRs10 
 
 
 
←Continuous 
monitoring→ 
   
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00203598-1.0 Approved - 06 Jul 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R14256-COV-2149 
Statistical Analysis Plan 
 
Date: June 30, 2022 
 
REGENERON CONFIDENTIAL 
Page 30 of 39 
Day 
Screening/Baseline1 
Treatment Period3 
Follow-Up Period3 
Day -1 to 1 
2 3 4 5 7 15 22 29 30 45 60 90 114–
119 1208 163–
168 
1698 
EOS 
Screen Pre-
dose Dose 
Post-
Dose 
Window (Day) 
 
 
 
 
     ±1 ±3 ±3 ±3 ±3 ±3 ±3 
 
+7 or 
±74 
 
+7 or 
±74 
Treatment-emergent grade 
≥3 hypersensitivity 
reactions10 
 
 
 
← Continuous monitoring →  
 
 
 
 
 
 
 
Concomitant medications 
and procedures11 
X 
 
 
← Continuous monitoring → 
Pregnancy test (WOCBP)12 
X 
 
 
 
      
 
 
 
 
 
 
 
X 
 
X 
Vital status 
 
 
 
 
      
 
 
 
 
 X 
 
 
 
 
Pregnancy status12 
 
 
 
 
      
 
 
 
 
 X 
 
 
 
 
Safety information 
(newborns of study 
participants)12 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
X 
Central Laboratory Safety Testing 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Hematology (including 
differential)  
X13 
 
 
    X  
 
 
 
 
 
 
 
 
 
 
Blood Chemistry 
X13 
 
 
    X  
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics and Immunogenicity Sampling 
      
 
 
 
 
 
 
 
 
 
 
Serum for drug concentration 
(PK)14 
X 
 
X15 
X X   X  
 X  
 X X 
 
X 
 
 
Serum for immunogenicity 
(ADA)16 
X 
 
 
      
 X  
 
 
 
 
X 
 
 
Central Laboratory Biomarker Testing 
      
 
 
 
 
 
 
 
 
 
 
Serum for exploratory 
research17 
X 
 
 
      
 X  
 
 
 
 
X 
 
X 
Plasma for exploratory 
research17 
X 
 
 
      
 X  
 
 
 
 
X 
 
X 
Exploratory Patients Outcomes 
Assessments 
 
 
      
 
 
 
 
 
 
 
 
 
 
COVID-19-related MAV 
details18 
X 
 
 
← Continuous monitoring → 
Wearable device19 
X 
← Continuous monitoring → 
Pharmacogenomics (Optional 
Sub-Study) 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
Blood for DNA5 
X 
 
 
      
 
 
 
 
 
 
 
 
 
 
1. Screening visit may occur on the same day as the baseline visit (day 1), or the day prior 
to the baseline visit (day -1). 
2. In phase 1, on day 1, vital signs (as described in Section 9.2.5.1 of the Protocol 
Amendment 1) will be measured at pre-dose, approximately every 30 minutes during the 
first 2 hours after dose, at hour 3, and at hour 4. 
3. On visit days when sample collection is not required (e.g., when only patient-reported 
questionnaires are collected), the information indicated in the Schedule of Events may be 
collected by phone without an in-person visit.  
                                        VV-RIM-00203598-1.0 Approved - 06 Jul 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R14256-COV-2149 
Statistical Analysis Plan 
 
Date: June 30, 2022 
 
REGENERON CONFIDENTIAL 
Page 31 of 39 
4. For all day 120 and day 169 questionnaires, a visit window of +7 days will be applied. 
For all other day 120 and day 169 assessments and sample collections, a visit window of 
±7 days will be applied. 
5. Patients must provide separate consent to collect blood samples as part of the optional 
pharmacogenomics (PGx) sub-study. Blood sample for DNA should be collected at the 
day -1 or day 1 visit but may be collected at any visit. 
6. The investigator or sub-investigator will verify that the patient has tested positive for 
SARS-CoV-2, either at screening or by historical record of a positive antigen or 
molecular diagnostic test (by validated SARS-CoV-2 antigen, RT-PCR, or other 
molecular diagnostic assay, using an appropriate sample such as nasopharyngeal [NP], 
nasal, oropharyngeal [OP], or saliva) collected ≤72 hours prior to randomization. For 
local tests performed at screening, the local testing result, specimen type, assay type, and 
date of the test will be recorded in the eCRF.  
7. Refer to Section 9.2.2 of the Protocol Amendment 1 for study drug administration 
instructions. 
8. On visit days when other assessments or sample collections are required, the site will 
verify that questionnaires have been completed prior to all other assessments or 
collections. The questionnaires should be completed in the order listed. On days when a 
certain questionnaire is not required, it will be skipped while the overall order of the other 
required questionnaires remains the same. Note that questionnaires will only be 
administered to patients in study sites if regionally available, and will only be 
administered to patients who are able to complete the questionnaires in the language 
available at their study site. Refer to Section 9.2.4 of the Protocol Amendment 1 for 
additional information regarding these questionnaires. 
8. Long-COVID electronic surveys (i.e., SE-LC19, PGIS, return to usual health, return to 
usual activities) must be completed as indicated in the Schedule of Events, then daily 
during the week leading up to day 120 visit, and daily during the week leading up to EOS 
visit on day 169.  
9. On day 1, vital signs (as described in Section 9.2.5.1 of the Protocol Amendment 1) will 
be collected once before study drug administration and once after study drug 
administration is completed.  
10. Refer to Section 10 of the Protocol Amendment 1 for more information on safety 
reporting and recording requirements for. 
11. Concomitant medications and concomitant procedures will also be reviewed and 
recorded. Refer to Section 9.2.5.3 of the Protocol Amendment 1 for more information. 
12. Pregnancy testing will be performed in women of childbearing potential (WOCBP) only. 
For WOCBP, negative pregnancy must be confirmed prior to study drug administration. 
Serum or urine pregnancy test are both acceptable. Note that a paper pregnancy report 
form must be completed for each patient who becomes pregnant and safety information 
in newborns of study participants will be collected. 
                                        VV-RIM-00203598-1.0 Approved - 06 Jul 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R14256-COV-2149 
Statistical Analysis Plan 
 
Date: June 30, 2022 
 
REGENERON CONFIDENTIAL 
Page 32 of 39 
13. The indicated blood samples may be collected at either day -1 or day 1 (screening or pre-
dose) but must be collected prior to randomization. 
14. Actual dosing time and drug concentration (PK) sample collection times will be recorded. 
At the screening/baseline visit, blood for assessment of drug concentration in serum will 
be taken prior to dosing (either at day -1 or day 1).  
9. The post-dose blood collection on day 1, if indicated, should occur at least 1 hour after 
study drug administration.  
15. In phase 1 patients, the post-dose blood collection on day 1 should occur at least 5 hours 
after study drug administration. 
16. The window for pre-dose ADA sample collection is as close to administration of study 
drug as is reasonable. Actual dosing time and ADA sample collection times will be 
recorded.  
17. Baseline serum SARS-CoV-2 serology assays will be performed centrally to determine 
serostatus retrospectively. Other serologic and plasma-based exploratory assays will be 
performed centrally post-treatment. 
18. COVID-19-related MAVs (defined as hospitalization, ER visit, urgent care visit, 
physician’s office visit, or telemedicine visit, with the primary reason for the visit being 
COVID-19) will be recorded in the eCRF. At minimum, details listed in Section 9.2.9 of 
the Protocol Amendment 1 will be included. 
19. Wearable devices will be worn continuously, starting at least 15 minutes before study 
drug administration (preferably starting at screening). Refer to Section 9.2.10 of the 
Protocol Amendment 1 for more information on the wearable device. 
10.2. 
Criteria for Potentially Clinically Significant Values (PCSV) 
 
Parameter 
PCSV 
Comments 
Clinical Chemistry 
ALT* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 
ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be expressed in 
ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required; multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution across the 
different PCSV levels, additional shift table 
on ≤3, >3 to ≤5, > 5 to ≤10, >10 to ≤20, and 
> 20 category for baseline vs. post baseline 
may be provided  
                                        VV-RIM-00203598-1.0 Approved - 06 Jul 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R14256-COV-2149 
Statistical Analysis Plan 
 
Date: June 30, 2022 
 
REGENERON CONFIDENTIAL 
Page 33 of 39 
AST* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 
ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be expressed in 
ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution across the 
different PCSV levels, additional shift table 
on ≤3, >3 to ≤5, > 5 to ≤10, >10 to ≤20, and 
> 20 category for baseline vs. post baseline 
may be provided 
Alkaline 
Phosphatase 
>1.5 ULN and baseline ≤ 1.5 ULN 
Enzyme activity must be expressed in ULN, 
not in IU/L. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Total Bilirubin* >1.5 and ≤ 2 ULN and baseline ≤ 1.5 
ULN* 
>2 ULN and baseline ≤ 2.0 ULN 
Must be expressed in ULN, not in µmol/L or 
mg/L. Categories are cumulative. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution of 
significant level, additional shift table on 
≤1.5, >1.5 to ≤2.0 and > 2.0 category for 
baseline vs. post baseline may be provided 
Conjugated 
Bilirubin 
>35% Total Bilirubin and TBILI>1.5 
ULN, and baseline Total Bilirubin ≤ 
35% or TBILI ≤1.5 ULN 
Conjugated bilirubin determined on a case-
by-case basis. 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN, and 
baseline ALT ≤ 3 ULN or TBILI ≤ 
2ULN 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution of 
significant level, additional shift table on ≤3, 
>3 to ≤10, and > 10 category for baseline vs. 
post baseline may be provided 
                                        VV-RIM-00203598-1.0 Approved - 06 Jul 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R14256-COV-2149 
Statistical Analysis Plan 
 
Date: June 30, 2022 
 
REGENERON CONFIDENTIAL 
Page 34 of 39 
Creatinine 
≥150 μmol/L (Adults) or ≥ULN (if 
ULN≥150 μmol/L) and baseline < 150 
μmol/L or <ULN (if ULN≥150 μmol/L) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
3 independent criteria  
Creatinine 
Clearance 
(Cockcroft's 
formula) 
<15 ml/min and baseline ≥15 ml/min 
(end stage renal impairment) 
≥15 -<30 ml/min and baseline ≥30 
ml/min (severe renal impairment) 
≥30 - < 60 ml/min and baseline ≥60 
ml/min (moderate renal impairment) 
≥60 - < 90 ml/min and baseline ≥90 
ml/min (mild renal impairment) 
Use is optional. 
FDA draft guidance 2010 
Four independent criteria, will provide 
additional shift table if needed 
 
Uric Acid 
Hyperuricemia: 
 
Hypouricemia: 
 
>408 μmol/L or >ULN (if ULN≥408 
μmol/L) and baseline ≤408 μmol/L or 
≤ULN (if ULN≥408 μmol/L) 
<120 μmol/L or <LLN (if LLN≤120 
μmol/L) and baseline ≥ 120 μmol/L or 
≥LLN (if LLN≤120 μmol/L) 
Harrison- Principles of Internal Medicine 
17th Ed., 2008. 
Two independent criteria 
Blood Urea 
Nitrogen 
≥17 mmol/L or ≥ULN (if ULN≥17 
mmol/L) and baseline <17 mmol/L or 
<ULN (if ULN≥17 mmol/L) 
Two independent criteria 
Chloride 
                
Hypochloremia: 
 
               
Hyperchloremia: 
 
<80 mmol/L or <LLN (if LLN≤80 
mmol/L) and baseline ≥ 80 mmol/L or 
≥LLN (if LLN≤80 mmol/L) 
>115 mmol/L or >ULN (if ULN≥115 
mmol/L) and baseline ≤ 115 mmol/L or 
≤ULN (if ULN≥115 mmol/L) 
Two independent criteria  
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 
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Statistical Analysis Plan 
 
Date: June 30, 2022 
 
REGENERON CONFIDENTIAL 
Page 35 of 39 
Potassium 
                  
Hypokalemia 
 
                  
Hyperkalemia 
 
<3 mmol/L or <LLN (if LLN≤3 
mmol/L) and baseline ≥ 3 mmol/L or 
≥LLN (if LLN≤3 mmol/L) 
≥5.5 mmol/L or ≥ULN (if ULN≥5.5 
mmol/L) and baseline <5.5 mmol/L or 
<ULN (if ULN≥5.5 mmol/L) 
FDA Feb 2005. 
Two independent criteria 
Total Cholesterol ≥7.74 mmol/L or ≥ULN (if ULN≥7.74 
mmol/L) and baseline < 7.74 mmol/L or 
<ULN (if ULN≥7.74 mmol/L) 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L or ≥ULN (if ULN≥4.6 
mmol/L) and baseline < 4.6 mmol/L or 
<ULN (if ULN≥4.6 mmol/L) 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN and baseline < 3 ULN  
 
Amylasemia 
≥3 ULN and baseline < 3 ULN  
 
Glucose 
                
Hypoglycaemia 
 
               
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN and baseline 
>3.9 mmol/L or ≥ LLN  
≥11.1 mmol/L (unfasted); ≥7 mmol/L 
(fasted) and baseline < 11.1 mmol/L 
(unfasted); <7 mmol/L (fasted)  
 
ADA Jan 2008. 
HbA1c 
>8% and baseline ≤ 8%  
 
Albumin 
≤25 g/L or ≤LLN (if LLN≤25 g/L) and 
baseline >25 g/L or >LLN (if LLN≤25 
g/L) 
 
CRP  
>2 ULN or >10 mg/L (if ULN not 
provided) and 
baseline ≤2 ULN or ≤10 mg/L (if ULN 
not provided)  
FDA Sept 2005. 
                                        VV-RIM-00203598-1.0 Approved - 06 Jul 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R14256-COV-2149 
Statistical Analysis Plan 
 
Date: June 30, 2022 
 
REGENERON CONFIDENTIAL 
Page 36 of 39 
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. 
*The default criteria. Summary by race 
(black and Non-black) are optional. 
 
To be interpreted only if no differential count 
available. 
Lymphocytes 
>4.0 Giga/L or >ULN (if ULN≥4.0 
Giga/L) and baseline ≤ 4.0 Giga/L or 
≤ULN (if ULN≥4.0 Giga/L) 
 
Neutrophils 
<1.5 Giga/L or <LLN (if LLN≤1.5 
Giga/L) for Non-Black or <1.0 Giga/L 
or <LLN (if LLN≤1.0 Giga/L) for Black 
and baseline ≥1.5 Giga/L or ≥LLN (if 
LLN≤1.5 Giga/L) for Non-Black or 
≥1.0 Giga/L or ≥LLN (if LLN≤1.0 
Giga/L) for Black* 
 
<1.5 Giga/L or <LLN (if LLN≤1.5 
Giga/L) and baseline ≥1.5 Giga/L or 
≥LLN (if LLN≤1.5 Giga/L) (Non-
Black);  
<1.0 Giga/L or <LLN (if LLN≤1.0 
Giga/L) and baseline ≥1.0 Giga/L or 
≥LLN (if LLN≤1.0 Giga/L) (Black) 
 
<0.5 Giga/L regardless of baseline value 
or racce 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
*The default criteria. By race (black and 
Non-black) are optional. 
Monocytes 
>0.7 Giga/L or >ULN (if ULN≥0.7 
Giga/L) and baseline ≤ 0.7 Giga/L or 
≤ULN (if ULN≥0.7 Giga/L) 
 
Basophils 
>0.1 Giga/L or >ULN (if ULN≥0.1 
Giga/L) and baseline ≤ 0.1 Giga/L or 
≤ULN (if ULN≥0.1 Giga/L) 
 
                                        VV-RIM-00203598-1.0 Approved - 06 Jul 2022 GMT-5:00


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Statistical Analysis Plan 
 
Date: June 30, 2022 
 
REGENERON CONFIDENTIAL 
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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) for 
male or ≤95 g/L or ≤LLN (if LLN≤95 
g/L) for female and baseline > 115 g/L 
or >LLN (if LLN≤115 g/L) for male or > 
95 g/L or >LLN (if LLN≤95 g/L) for 
Female* 
 
≤115 g/L or ≤LLN (if LLN≤115 g/L) 
and baseline > 115 g/L or >LLN (if 
LLN≤115 g/L) for male; 
 ≤95 g/L or ≤LLN (if LLN≤95 g/L) and 
baseline > 95 g/L or >LLN (if LLN≤95 
g/L) for Female. 
 
≥185 g/L or ≥ULN (if ULN≥185 g/L) 
for male or ≥165 g/L or ≥ULN (if 
ULN≥165 g/L) for female and baseline 
<185 g/L or <ULN (if ULN≥185 g/L) 
for male or <165 g/L or <ULN (if 
ULN≥165 g/L) for Female* 
 
≥185 g/L or ≥ULN (if ULN≥185 g/L) 
and baseline <185 g/L or <ULN (if 
ULN≥185 g/L) for Male; 
≥165 g/L or ≥ULN (if ULN≥165 g/L) 
and baseline < 165 g/L or <ULN (if 
ULN≥165 g/L) for Female 
 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
*The default criteria. By gender (male and 
female) are optional. 
 
Criteria based upon decrease from baseline 
are more relevant than based on absolute 
value. Other categories for decrease from 
baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
                                        VV-RIM-00203598-1.0 Approved - 06 Jul 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R14256-COV-2149 
Statistical Analysis Plan 
 
Date: June 30, 2022 
 
REGENERON CONFIDENTIAL 
Page 38 of 39 
Hematocrit 
≤0.37 v/v or ≤LLN (if LLN≤0.37 v/v) 
for Male or ≤0.32 v/v or ≤LLN (if 
LLN≤0.32 v/v) for Female and baseline 
> 0.37 v/v or >LLN (if LLN≤0.37 v/v) 
for Male or > 0.32 v/v or >LLN (if 
LLN≤0.32 v/v) for Female* 
 
≤0.37 v/v or ≤LLN (if LLN≤0.37 v/v) 
and baseline > 0.37 v/v or >LLN (if 
LLN≤0.37 v/v) for Male ; ≤0.32 v/v or 
≤LLN (if LLN≤0.32 v/v) and baseline > 
0.32 v/v or >LLN (if LLN≤0.32v/v) for 
Female 
 
≥0.55 v/v or ≥ULN (if ULN≥0.55 v/v) 
for Male or ≥0.5 v/v or ≥ULN (if 
ULN≥0.5 v/v) for Female and baseline < 
0.55 v/v or <ULN (if ULN≥0.55 v/v) for 
Male < 0.5 v/v or <ULN (if ULN≥0.5 
v/v) for Female* 
 
≥0.55 v/v or ≥ULN (if ULN≥0.55 v/v) 
and baseline < 0.55 v/v or <ULN (if 
ULN≥0.55 v/v) for Male; ≥0.5 v/v or 
≥ULN (if ULN≥0.5 v/v) and baseline < 
0.5 v/v or <ULN (if ULN≥0.5 v/v) for 
Female 
Two Criteria are independent 
 
*The default criteria. By gender (male and 
female) are optional. 
RBC 
≥6 Tera/L or ≥ULN (if ULN≥6 Tera/L) 
and baseline < 6 Tera/L or <ULN (if 
ULN≥6 Tera/L) 
Unless specifically required for particular 
drug development, the analysis is redundant 
with that of Hb. 
Platelets 
<100 Giga/L or <LLN (if LLN≤100 
Giga/L) and baseline ≥100 Giga/L or 
≥LLN (if LLN≤100 Giga/L) 
≥700 Giga/L or ≥ULN (if ULN≥700 
Giga/L) and baseline < 700 Giga/L or 
<ULN (if ULN≥700 Giga/L) 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
Two independent criteria 
                                        VV-RIM-00203598-1.0 Approved - 06 Jul 2022 GMT-5:00


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Protocol: R14256-COV-2149 
Statistical Analysis Plan 
 
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REGENERON CONFIDENTIAL 
Page 39 of 39 
Urinalysis 
 
pH 
≤4.6 or ≤LLN (if LLN≤4.6) and baseline 
> 4.6 or >LLN (if LLN≤4.6) 
≥8 or ≥ULN (if ULN≥8) and baseline < 
8 or <ULN (if ULN≥8) 
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 
³ 5% increase from baseline 
³5% decrease from baseline 
FDA Feb 2007  
 
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