Clinical trial NCT05074433
Conditions: Immunocompromised
Keywords: Non-response to COVID-19 vaccination COVID-19 Immunocompromised, weakened immune system
Sponsor: Regeneron Pharmaceuticals
Start date: 2021-10-25; Completion date: 2022-05-18
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of the study is to evaluate the effect of casirivimab+imdevimab, compared with placebo, in preventing symptomatic SARS-CoV-2 infection in immunocompromised participants.

The secondary objectives of the study are:

* To evaluate the safety and tolerability of repeated SC injections of casirivimab+imdevimab in the study population
* To characterize concentrations of casirivimab and imdevimab in serum over time
* To assess the immunogenicity of casirivimab and imdevimab

Detailed description:

Arms: arm 1: Initial subcutaneous (SC) dose, then SC dose every 4 weeks (Q4W) arm 2: SC dose Q4W arm 3: SC dose every 12 weeks (Q12W) arm 4: SC dose Q4W
Interventions: intervention 1: casirivimab+imdevimab intervention 2: Placebo
Intervention descriptions: intervention 1: Co-administered sequentially subcutaneous (SC) intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
IND: 148069 
EudraCT: 2021-005222-14 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY 
OF ANTI-SPIKE SARS-CoV-2 MONOCLONAL ANTIBODIES AS PRE-
EXPOSURE PROPHYLAXIS TO PREVENT COVID-19 IN 
IMMUNOCOMPROMISED PARTICIPANTS 
Compound: 
Casirivimab+Imdevimab 
Clinical Phase: 
3 
Protocol Number: 
R10933-10987-COV-2176 
Protocol Version: 
Amendment 2 US 
Amendment 2 US Date of Issue:  
See appended electronic signature page 
Amendment 1 (Not Implemented) 
N/A 
Original Date of Issue 
24 September 2021 
Medical /Study Director: 
 
 
 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
 
 
 
 
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AMENDMENT HISTORY 
Amendment 2 
The primary purpose of this amendment is to close the study. The procedures described in this 
amendment supersede those of the original protocol and site memorandum. 
Description of Change 
 
Brief Rationale   
Section(s) 
Added a new section with procedures specifying 
the study closure process, which includes the 
following: 
• Participants will be offered the option to receive a 
supplemental final dose of casirivimab+ 
imdevimab1200 mg SC 
• All participants, including those who do not 
consent to receive the optional final dose, will 
have a follow-up (end-of-study) telephone visit 
approximately 3 months from their last dose of 
investigational drug (casirivimab+imdevimab or 
placebo) to monitor safety 
• Participants with suspected COVID-19 may have 
an optional visit to evaluate signs and symptoms 
and to receive local and central laboratory testing 
for SARS-CoV-2 
• For participants who are SARS-CoV-2 positive, 
additional weekly visits can optionally occur until 
2 consecutive negative RT-qPCR tests are 
obtained 
• Safety collection will be broadened from original 
protocol to include treatment-emergent AEs 
considered by the investigator to be unrelated to 
baseline conditions and unrelated to treatments 
for baseline conditions. 
• Participants will be monitored for at least 60 
minutes after receiving study drug 
• Sites will ensure that an additional discussion 
about the potential risks and benefits to the 
participant and fetus is discussed as part of re-
consent for participants who become pregnant 
during the study 
• A modified statistical analysis plan has been 
summarized for participants who have already 
enrolled in the study 
To provide guidance to US 
sites regarding study close-
out procedures.  
 
Protocol Amendment 2 
Procedures 
Table 2 Schedule of Events for 
Study Close-Out (Applies to All 
Enrolled Participants Per 
Protocol Amendment 2) 
Section 9.1.2 Footnotes for the 
Schedule of Events (Protocol 
Amendment 2) 
 
 
 
 
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Site Memorandum 
This section describes changes to study conduct that were implemented by a site memorandum 
issued on 21 October 2021. 
Original Protocol  
Change / Additional Measures 
No Scheduled Safety Labs 
Measure absolute neutrophil count, platelet count, 
hemoglobin, ALT, AST, total bilirubin, and creatinine at the 
baseline visit as well as study visits days 29, 85 and 169 
Monitor for 15 minutes after first dose 
Monitor for 60 minutes after administration of study drug 
Report treatment emergent adverse events (TEAEs) 
that are grade ≥3 in severity 
Report all clinical and laboratory TEAEs that are not related 
to the patient’s underlying (non-COVID) disease and/or not 
related to treatments for the underlying conditions 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
CI 
Confidence interval 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
EC 
Ethics Committee 
EDC 
Electronic data capture 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HSCT 
Hematopoietic stem cell transplantation 
ICF 
Informed consent form 
ITT 
Intention-to-treat 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
mITT 
Modified intention-to-treat 
NAb 
Neutralizing antibody 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NP 
Nasopharyngeal 
PCSV 
Potentially clinically significant value 
PK 
Pharmacokinetic 
Q4W 
Every 4 weeks 
Q12W 
Every 12 weeks 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RBQM 
Risk-Based Quality Monitoring 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SCIG 
Subcutaneous immunoglobulin 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
Amendment 2 ...................................................................................................................................2 
Site Memorandum ............................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................4 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................12 
PROTOCOL AMENDMENT 2 PROCEDURES .........................................................................13 
1. 
INTRODUCTION ......................................................................................................16 
1.1. 
SARS-CoV-2 and COVID-19 ....................................................................................16 
1.2. 
Casirivimab+Imdevimab: A Combination of Two Non-Competing 
Monoclonal Antibodies that Target the SARS-CoV-2 S Protein RBD ......................16 
1.3. 
Monoclonal Antibody Therapy as Pre-Exposure Prophylaxis in 
Immunocompromised Individuals ..............................................................................16 
2. 
STUDY OBJECTIVES ..............................................................................................17 
2.1. 
Primary Objective .......................................................................................................17 
2.2. 
Secondary Objectives .................................................................................................17 
2.3. 
Exploratory Objectives ...............................................................................................17 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................18 
3.1. 
Hypotheses ..................................................................................................................18 
3.2. 
Rationale .....................................................................................................................18 
3.2.1. 
Rationale for Study Design .........................................................................................18 
3.2.1.1. 
Study Population .........................................................................................................18 
3.2.1.2. 
Double Blind Design ..................................................................................................19 
3.2.1.3. 
Clinical Efficacy .........................................................................................................19 
3.2.1.4. 
Virologic Efficacy ......................................................................................................20 
3.2.2. 
Rationale for Dose Selection ......................................................................................20 
3.3. 
Risk-Benefit ................................................................................................................21 
3.3.1. 
Summary of Efficacy and Safety Profile in Clinical Trials ........................................21 
3.3.2. 
Summary of Risks.......................................................................................................23 
3.3.3. 
Summary .....................................................................................................................24 
4. 
ENDPOINTS ..............................................................................................................25 
4.1. 
Primary Endpoint ........................................................................................................25 
4.2. 
Secondary Endpoints ..................................................................................................25 
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4.3. 
Exploratory Endpoints ................................................................................................25 
5. 
STUDY VARIABLES................................................................................................26 
5.1. 
Demographic and Baseline Characteristics ................................................................26 
5.2. 
Efficacy Variables ......................................................................................................26 
5.3. 
Safety Variables ..........................................................................................................26 
5.4. 
Pharmacokinetic Variables .........................................................................................26 
5.5. 
Immunogenicity Variables ..........................................................................................26 
6. 
STUDY DESIGN .......................................................................................................27 
6.1. 
Study Description and Duration .................................................................................27 
6.2. 
Evaluation of Symptomatic SARS-CoV-2 Infection ..................................................27 
6.3. 
Study Periods ..............................................................................................................28 
6.4. 
Monitoring and Management of Suspected COVID-19 .............................................29 
6.4.1. 
Monitoring for Suspected COVID-19 ........................................................................29 
6.4.2. 
Evaluation of Suspected COVID-19 ..........................................................................29 
6.4.3. 
Laboratory-Confirmed SARS-CoV-2 Infection Obtained Outside of the 
Study ...........................................................................................................................29 
6.4.4. 
Post-Infection Treatment for Participants with Confirmed Positive SARS-
CoV-2 RT-PCR ..........................................................................................................30 
6.4.5. 
Schedule of Events for Participants with Positive SARS-CoV-2 RT-PCR ................30 
6.4.6. 
Schedule of Events for Participants with Negative SARS-CoV-2 RT-PCR ..............31 
6.4.7. 
Management of Participants with Positive SARS-CoV-2 Infection at 
Baseline .......................................................................................................................31 
6.5. 
Study Stopping Rules .................................................................................................31 
6.6. 
End of Study Definition ..............................................................................................31 
6.7. 
Planned Interim Analysis ............................................................................................31 
6.8. 
Study Committees .......................................................................................................32 
6.8.1. 
Independent Data Monitoring Committee ..................................................................32 
6.8.2. 
Safety Monitoring Team .............................................................................................32 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PARTICIPANTS ........................................................................................................33 
7.1. 
Number of Participants Planned .................................................................................33 
7.2. 
Study Population .........................................................................................................33 
7.2.1. 
Inclusion Criteria ........................................................................................................33 
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7.2.2. 
Exclusion Criteria .......................................................................................................34 
7.3. 
Premature Withdrawal from the Study .......................................................................35 
7.4. 
Replacement of Participants .......................................................................................35 
8. 
STUDY TREATMENTS............................................................................................36 
8.1. 
Investigational and Reference Treatments ..................................................................36 
8.2. 
Background Treatment(s) ...........................................................................................36 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................36 
8.3.1. 
Dose Modification ......................................................................................................36 
8.3.2. 
Study Drug Discontinuation .......................................................................................36 
8.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................36 
8.4. 
Management of Acute Reactions ................................................................................37 
8.4.1. 
Acute Injection Reactions ...........................................................................................37 
8.4.1.1. 
Hypersensitivity Reaction (Systemic) ........................................................................37 
8.4.1.2. 
Local Injection Site Reactions ....................................................................................37 
8.5. 
Method of Treatment Assignment ..............................................................................37 
8.6. 
Blinding ......................................................................................................................37 
8.7. 
Emergency Unblinding ...............................................................................................38 
8.8. 
Treatment Logistics and Accountability .....................................................................39 
8.8.1. 
Packaging, Labeling, and Storage ..............................................................................39 
8.8.2. 
Supply and Disposition of Treatments .......................................................................39 
8.8.3. 
Treatment Accountability ...........................................................................................39 
8.8.4. 
Treatment Compliance ................................................................................................39 
8.9. 
Concomitant Medications and Procedures .................................................................39 
8.9.1. 
Prohibited Medications ...............................................................................................40 
8.9.2. 
Permitted Medications ................................................................................................40 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................40 
9.1. 
Schedule of Events .....................................................................................................40 
9.1.1. 
Footnotes for the Schedule of Events (Original Protocol) ..........................................44 
9.1.2. 
Footnotes for the Schedule of Events (Protocol Amendment 2) ................................45 
9.1.3. 
Early Termination Visit ..............................................................................................46 
9.1.4. 
Unscheduled Visits .....................................................................................................46 
9.2. 
Study Procedures ........................................................................................................46 
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9.2.1. 
Procedures Performed at Screening ............................................................................46 
9.2.1.1. 
Informed Consent .......................................................................................................46 
9.2.1.2. 
Medical History ..........................................................................................................46 
9.2.1.3. 
Weight and Height ......................................................................................................47 
9.2.1.4. 
Screening and Baseline Assessments for SARS-CoV-2 Infection .............................47 
9.2.2. 
Randomization ............................................................................................................47 
9.2.3. 
Study Drug Administration.........................................................................................47 
9.2.4. 
Efficacy Procedures ....................................................................................................47 
9.2.4.1. 
Post-Baseline Assessments for SARS-CoV-2 Infection .............................................47 
9.2.4.2. 
Clinician Assessment of COVID-19 Signs and Symptoms ........................................47 
9.2.4.3. 
COVID-19-Related Medically-Attended Visit Details, Immunocompromised 
Population Definition (Exploratory Outcome) ...........................................................49 
9.2.5. 
Safety Procedures .......................................................................................................49 
9.2.5.1. 
Vital Signs ..................................................................................................................49 
9.2.5.2. 
Adverse Event Monitoring .........................................................................................49 
9.2.5.3. 
Concomitant Medications and Procedures .................................................................49 
9.2.5.4. 
Pregnancy Test for Women of Childbearing Potential ...............................................50 
9.2.5.5. 
Pregnancy Status .........................................................................................................50 
9.2.5.6. 
Vital Status ..................................................................................................................50 
9.2.5.7. 
Safety Information in Newborns of Study Participants ..............................................50 
9.2.6. 
Drug Concentration and Measurements .....................................................................50 
9.2.7. 
Immunogenicity Measurements and Samples ............................................................50 
9.2.8. 
Pharmacodynamic/Biomarker Procedures ..................................................................50 
9.2.8.1. 
Serological Assays for Endogenous Anti-SARS-CoV-2 Antibodies .........................50 
9.2.8.2. 
Serum and Plasma for Exploratory Research .............................................................51 
9.2.8.3. 
Exploratory Virology and Viral Sequencing ..............................................................51 
9.2.9. 
Unused and Residual Biological Samples ..................................................................51 
9.2.10. 
Exploratory Immunology Sub-Study (Optional; Separate Protocol) ..........................51 
10. 
SAFETY EVALUATION AND REPORTING .........................................................52 
10.1. 
Recording and Reporting Adverse Events ..................................................................52 
10.1.1. 
General Guidelines .....................................................................................................52 
10.1.2. 
Reporting Procedure ...................................................................................................53 
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10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................53 
10.2. 
Definitions ..................................................................................................................54 
10.2.1. 
Adverse Event .............................................................................................................54 
10.2.2. 
Serious Adverse Event ................................................................................................54 
10.2.3. 
Adverse Events of Special Interest .............................................................................55 
10.2.4. 
Severity .......................................................................................................................55 
10.2.5. 
Causality .....................................................................................................................57 
10.3. 
Safety Monitoring .......................................................................................................58 
10.4. 
Notifying Health Authorities, Institutional Review Boards, and Investigators ..........58 
11. 
STATISTICAL PLAN................................................................................................59 
11.1. 
Statistical Hypothesis ..................................................................................................59 
11.2. 
Justification of Sample Size........................................................................................59 
11.3. 
Analysis Sets ...............................................................................................................60 
11.3.1. 
Efficacy Analysis Sets ................................................................................................60 
11.3.2. 
Safety Analysis Set .....................................................................................................61 
11.3.3. 
Pharmacokinetic Analysis Set ....................................................................................61 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................61 
11.4. 
Statistical Methods ......................................................................................................61 
11.4.1. 
Participant Disposition ................................................................................................61 
11.4.2. 
Demography and Baseline Characteristics .................................................................62 
11.4.3. 
Efficacy Analyses .......................................................................................................62 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................62 
11.4.4. 
Control of Multiplicity ................................................................................................63 
11.4.5. 
Safety Analysis ...........................................................................................................63 
11.4.5.1. 
Adverse Events ...........................................................................................................63 
11.4.5.2. 
Other Safety (Vital Signs and Laboratory Tests) .......................................................64 
11.4.5.3. 
Treatment Compliance ................................................................................................65 
11.4.6. 
Pharmacokinetics ........................................................................................................65 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................65 
11.4.7. 
Analysis of Immunogenicity Data ..............................................................................65 
11.5. 
Interim Analysis ..........................................................................................................66 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........66 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................67 
12.1. 
Data Management and Electronic Systems ................................................................67 
12.1.1. 
Data Management .......................................................................................................67 
12.1.2. 
Electronic Systems ......................................................................................................67 
12.2. 
Study Monitoring ........................................................................................................67 
12.2.1. 
Monitoring of Study Sites ...........................................................................................67 
12.2.2. 
Source Document Requirements ................................................................................68 
12.2.3. 
Case Report Form Requirements ................................................................................68 
12.3. 
Audits and Inspections ................................................................................................68 
12.4. 
Study Documentation .................................................................................................69 
12.4.1. 
Certification of Accuracy of Data ...............................................................................69 
12.4.2. 
Retention of Records ..................................................................................................69 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................69 
13.1. 
Good Clinical Practice Statement ...............................................................................69 
13.2. 
Informed Consent and Assent .....................................................................................69 
13.3. 
Participant Confidentiality and Data Protection .........................................................71 
13.4. 
Institutional Review Board / Ethics Committee .........................................................71 
13.5. 
Clinical Study Data Transparency ..............................................................................71 
14. 
PROTOCOL AMENDMENTS ..................................................................................71 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................72 
15.1. 
Premature Termination of the Study ...........................................................................72 
15.2. 
Close-out of a Site ......................................................................................................72 
16. 
CONFIDENTIALITY ................................................................................................72 
17. 
FINANCING AND INSURANCE .............................................................................72 
18. 
PUBLICATION POLICY ..........................................................................................72 
19. 
REFERENCES ...........................................................................................................73 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................75 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................76 
 
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LIST OF TABLES 
Table 1: 
Schedule of Events (No Longer Applicable as of Protocol Amendment 2) ...............41 
Table 2: 
Schedule of Events for Study Close-Out (Protocol Amendment 2; Applies to 
All Enrolled Participants) ...........................................................................................43 
Table 3: 
Broad Term Definition of COVID-19 Signs and Symptoms .....................................48 
Table 4: 
NCI-CTCAE Severity Grading System for Adverse Events (v5.0) ...........................55 
Table 5: 
NCI-CTCAE Severity Grading (v5.0) for Anaphylaxis, Allergic Reactions, 
and Injection-Site Reactions .......................................................................................56 
Table 6: 
Power and Sample Size Estimates to Demonstrate Antibody Efficacy at 
Overall α=0.025 (1-sided) ...........................................................................................60 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................27 
 
 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
As of protocol amendment 2 this study will close. Please refer to Protocol Amendment 2 
Procedures for further details. 
 
 
 
 
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PROTOCOL AMENDMENT 2 PROCEDURES 
Study R10933-10987-COV-2176 will be terminated early by the Sponsor due to evidence 
surrounding variants of concern and reduced neutralization potency of casirivimab+imdevimab 
against the Omicron variant. The study is not being terminated due to any safety concerns, nor 
from any data obtained in this study.  
The procedures described in amendment 2 should be implemented immediately at sites that have 
participants who are currently enrolled in the study.  
Optional Dose 
The Sponsor believes that casirivimab+imdevimab may continue to serve as an important pre-
exposure prophylaxis therapeutic among immunocompromised individuals in regions where 
Omicron is not the dominant variant or in regions where Omicron prevalence subsides. For this 
reason, participants will have the option to receive a 1200 mg SC dose of casirivimab+imdevimab 
as a final study dose. This optional dose may be administered to all participants regardless of 
treatment assignment at randomization. However, participants will not be eligible to receive this 
dose if they have already received casirivimab+imdevimab as post-infection treatment.  
Participants will be asked to return to the site for an unscheduled visit, during which they will be 
asked to consent to protocol amendment 2 and receive the final optional dose, if desired. This visit 
to receive the final optional dose should occur approximately 4 weeks after the most recent dose. 
Note that consent may be obtained remotely prior to this visit, if available and allowable by the 
study site. 
Procedures in the Event of Suspected COVID-19  
Participants with suspected COVID-19 may undergo an optional visit to evaluate symptoms by a 
study clinician (investigator or designee) and to undergo laboratory testing of SARS-CoV-2, as 
detailed in the new schedule of events (Table 2). This optional visit should occur as soon as 
possible (within 48 hours of symptom onset, if feasible). Note that clinician assessment of sign 
or symptoms may occur remotely. If remote assessment is performed, a confirmatory site visit for 
laboratory testing of SARS-CoV-2 can optionally occur after a clinician deems that the signs or 
symptoms are related to COVID-19. 
Clinical Evaluation. Signs and symptoms will be evaluated by a clinician (investigator or designee, 
evaluation may occur remotely) as described below. If the clinician confirms that at least one sign 
or symptom is potentially related to COVID-19, samples may be collected to perform both local 
and central testing for SARS-CoV-2 infection. 
Laboratory Testing of SARS-CoV-2. Local testing must be performed by RT-PCR using local 
sample collection and assay standards. A nasopharyngeal (NP) swab sample is the preferred 
sample type, but other samples (eg, nasal, oropharyngeal, saliva) adhering to local standards are 
acceptable. An additional NP swab sample will be collected for the purposes of central RT-qPCR 
testing. The samples will be collected prior to any administration of post-infection treatment 
(described below). The qualitative result of the central RT-qPCR will be reported back to the 
corresponding study site.  
SARS-CoV-2 viral genome sequencing will be performed using NP swab samples collected during 
the study that have been confirmed positive by RT-qPCR at the central laboratory. 
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Documentation of Clinical Evaluation. For each symptom, the start (onset) date, end date, and 
severity will be recorded (mild, moderate, severe) in the participant’s medical record (source 
document). It is important to record this information in the source document, to ensure that the 
temporal dimensions of each sign or symptom are captured. 
The following information may subsequently be recorded in EDC as applicable: 
• The sign or symptom, with start (onset) calendar date, end calendar date, and severity 
(mild, moderate, severe) 
• Confirmatory local RT-PCR test result and date of sample collection 
• Confirmatory central RT-qPCR test result and date of sample collection 
• Weekly central RT-qPCR test results and dates of sample collection 
• Record of any post-infection treatment with casirivimab+imdevimab administered 
Note that any sign or symptom considered by the investigator to be unrelated to baseline conditions 
and unrelated to treatments for baseline conditions will also be recorded and used for safety 
evaluation. 
Post-Infection Treatment. Participants with confirmed positive SARS-CoV-2 RT-PCR will be 
eligible for post-infection treatment (as described in Section 6.4.4) at any time prior to receipt of 
the optional 1200 mg SC dose (eg, during the 4 weeks between receipt of the last protocol-defined 
dose and the optional 1200 mg SC dose). Once this optional dose has been administered, post-
infection treatment will no longer be offered. Likewise, any participant who receives post-infection 
treatment will not be eligible to receive the optional 1200 mg SC dose. 
Participants with Positive SARS-COV-2 RT-PCR. Participants with a positive SARS-CoV-2 RT-
PCR may have additional assessments and sample collections, during unscheduled visits every 7 
days (±1 day) for central laboratory RT-qPCR analysis until 2 consecutive negative test results are 
obtained: 
• NP swab samples for RT-qPCR 
• COVID-19 signs and symptoms evaluated by the investigator or designee 
• Information regarding COVID-19-related medically-attended visits (MAVs; defined 
in Section 9.2.4.3)  
End-of-Study Visit 
All participants, including those who do not consent to receive the optional final dose, will have a 
follow-up (end-of-study) telephone visit approximately 85 days (3 months) from their last dose of 
investigational drug (casirivimab+imdevimab or placebo) to monitor safety. Study assessments for 
the 3-month follow-up visit will be limited to the collection of targeted adverse events, as detailed 
in the new schedule of events (Table 2).  
Sites will ensure that an additional discussion about the potential risks and benefits to the 
participant and fetus is discussed as part of re-consent for participants who become pregnant during 
the study. 
 
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Statistical Analysis Plan 
At the time that enrollment was paused, 66 participants had been enrolled in the study. Due to the 
early study closure and the resulting small sample size of enrolled participants, all analyses will 
be performed descriptively and only numeric comparisons will be performed. 
All safety endpoints (including AEs, TEAEs, AESIs, SAEs, and safety laboratory values) will be 
summarized. Selected efficacy, virology, PK, and/or immunogenicity data may also be analyzed 
descriptively. Additional details will be provided in the Statistical Analysis Plan (SAP). 
No interim analysis will be performed for this study, and no IDMC review meetings will occur. 
 
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1. 
INTRODUCTION 
1.1. 
SARS-CoV-2 and COVID-19 
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a betacoronavirus determined to 
be the pathogen responsible for coronavirus disease 2019 (COVID-19) (WHO, 2020). 
The spike (S) protein of SARS-CoV-2 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 an 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 
Casirivimab and imdevimab are two non-competing recombinant monoclonal antibodies (mAbs), 
developed by Regeneron Pharmaceuticals, Inc., 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, and in hospitalized patients 
was shown to reduce all-cause death (Horby, 2021) (Weinreich, 2021b). 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, 
2021a) (refer to Section 3.3.1 for additional information).  
Casirivimab+imdevimab retains neutralization potency against all SARS-CoV-2 variants of 
concern/interest, including alpha (B.1.1.7; UK), beta (B.1.351; South Africa), delta (B.1.617.2; 
India) gamma (P.1; Brazil), lambda (C.37; Peru) and mu (B.1621; Colombia), and protects against 
the selection of drug resistant variants in vitro, in vivo, and in the clinical setting (REGEN-COV™ 
(casirivimab with imdevimab) [HCP Fact Sheet], 2021) (Copin, 2021). 
1.3. 
Monoclonal Antibody Therapy as Pre-Exposure Prophylaxis in 
Immunocompromised Individuals 
The available evidence indicates that some immunocompromised conditions, such as certain 
primary or secondary immunodeficiencies, can lead to a reduced production of endogenous 
antibodies against SARS-CoV-2. Individuals with such conditions may be at a greater risk of 
becoming infected or experiencing prolonged infection, potentially leading to increased morbidity 
and mortality, and may also have a significantly impaired protective immune response to COVID-
19 vaccination (Agha, 2021) (Babaha, 2020) (Boyarsky, 2021a) (Boyarsky, 2021b) (Deepak, 
2021) (Gao, 2020) (Herishanu, 2021) (Lewis, 2020) (Sonani, 2021). These at-risk individuals may 
benefit from the prophylactic use of exogenous anti-SARS-CoV-2 mAbs given prior to infection 
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or exposure to the virus (ie, pre-exposure prophylaxis), by providing an increased level of passive 
immunity to supplement an inadequate endogenous immune response from prior SARS-CoV-2 
infection or vaccination.  
This is a randomized, double-blind, placebo-controlled, phase 3 study in adults and adolescents to 
assess the safety and efficacy of casirivimab+imdevimab as prophylaxis against symptomatic 
COVID-19 in immunocompromised individuals, defined according to the primary and secondary 
immunodeficiencies outlined in the study eligibility criteria (Section 7.2).  
For more information regarding the rationale for the study design and dose selection, refer to 
Section 3.2. A summary of key efficacy and safety data from the casirivimab+imdevimab clinical 
development program is provided in Section 3.3. Additional background information on the study 
drug and the overall development program can be found in the Investigator’s Brochure.  
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the effect of casirivimab+imdevimab, compared 
with placebo, in preventing symptomatic SARS-CoV-2 infection in immunocompromised 
participants. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the safety and tolerability of repeated SC injections of 
casirivimab+imdevimab in the study population 
• To characterize concentrations of casirivimab and imdevimab in serum over time 
• To assess the immunogenicity of casirivimab and imdevimab 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To evaluate additional indicators of casirivimab+imdevimab clinical efficacy and 
disease prevention compared to placebo 
• To evaluate the effect of casirivimab+imdevimab, compared to placebo, in preventing 
SARS-CoV-2 infection with elevated viral load 
• To explore biomarkers predictive and/or indicative of safety and/or efficacy of 
casirivimab+imdevimab, COVID-19 vaccine response, SARS-CoV-2 infection and 
immune response, COVID-19 disease progression and clinical outcomes of 
casirivimab+imdevimab 
• To explore the effect of baseline immune response to COVID-19 vaccination on 
response to casirivimab+imdevimab and clinical outcomes 
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• To characterize viral variants by sequencing SARS-CoV-2 in participants who 
become infected post-baseline 
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
Pre-exposure prophylaxis with anti-SARS-CoV-2 mAbs (casirivimab+imdevimab) will prevent 
symptomatic SARS-CoV-2 infection in immunocompromised individuals who have not mounted 
an effective response to vaccination. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
3.2.1.1. 
Study Population 
In the absence of a universal clinical definition, this study will define an immunocompromised 
state according to a discrete set of primary and secondary immunodeficiencies used as eligibility 
criteria. These criteria can be found in Section 7.2. 
Immunocompromising Conditions. As described in Section 1, certain immunocompromising 
conditions can negatively impact the production of endogenous antibodies against SARS-CoV-2, 
particularly in response to vaccination. This study therefore aims to evaluate the use of anti-SARS-
CoV-2 mAb therapies, casirivimab+imdevimab, in immunocompromised individuals age ≥12 
years (Section 7.2).  
The definition of immunocompromised participants used for study enrollment (provided in 
Section 7.2.1) are consistent with criteria regarding conditions and treatments associated with 
moderate to severe immune compromise described at the August 2021 meeting of CDC Vaccine 
Recommendations of the Advisory Committee on Immunization Practices (ACIP). The criteria 
provided during this meeting were as follows (ACIP, 2021): 
• Active or recent treatment for solid tumor and hematologic malignancies 
• Receipt of solid-organ or recent hematopoietic stem cell transplants 
• Severe primary immunodeficiency 
• Advanced or untreated HIV infection 
• Active treatment with high-dose corticosteroids, alkylating agents, antimetabolites, 
tumor-necrosis (TNF) blockers, and other biologic agents that are immunosuppressive 
or immunomodulatory 
• Chronic medical conditions such as asplenia and chronic renal disease, some patients 
with these conditions may be associated with varying degrees of immune deficit 
The above criteria were presented in the context of identifying individuals that may be considered 
for a booster COVID-19 vaccine dose. The criteria described in this study (Section 7.2.1) are 
slightly modified, taking into consideration experience with study populations in the 
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casirivimab+imdevimab clinical development program, other government, academic, industry 
publications and presentations, advice from experts in the field, and other clinical trials.  
Prior Non-Response to COVID-19 Vaccination. To ensure that the enrolled study population 
has a demonstrated risk of future SARS-CoV-2 infection despite having been vaccinated, the study 
will require as a condition of enrollment that participants previously received a full course of 
COVID-19 vaccination (unless medically ineligible or contraindicated), and demonstrated a non-
response to COVID-19 vaccination (ie, a lack of circulating anti-S protein IgG antibodies) 
(Section 7.2.1).  
Non-response will be further evaluated retrospectively and quantitatively via central analysis of 
baseline samples, and the results of this analysis will be used to define the primary efficacy analysis 
population (modified intention-to-treat). A quantitative cutoff value will serve as the upper bound 
for non-response definition in the primary analysis, with a value derived from ongoing clinical 
trials evaluating immunologic response to COVID-19 booster vaccines (NCT05000216). 
Additional information regarding the assay and definition of the efficacy analysis population can 
be found in Section 9.2.8.1 and Section 11.3.1.  
As the study will be conducted in an at-risk population, additional treatment with 
casirivimab+imdevimab will be offered at sites to participants who become infected with SARS-
CoV-2 at any point during the study (Section 6.4.4).  
Focused Enrollment. The study will be conducted in regions where there is an ongoing COVID-
19 outbreak and active community transmission of COVID-19, further ensuring that the scientific 
aim of evaluating prevention in at-risk individuals can be attained.  
3.2.1.2. 
Double Blind Design 
The double-blind design serves to reduce potential bias introduced by knowing the study drug 
assignment. The comparator arm in this study will be placebo, as no approved or authorized pre-
exposure preventative treatments are currently available in the regions where the study is being 
conducted. 
3.2.1.3. 
Clinical Efficacy 
The primary endpoint of this study will evaluate the occurrence of symptomatic, laboratory-
confirmed SARS-CoV-2 infection (Section 4.1). This endpoint is similar to the primary endpoint 
utilized in COVID-19 vaccine trials (Baden, 2021) (Polack, 2020) (Sadoff, 2021) and is thus 
intended to evaluate efficacy in the pre-exposure prophylaxis setting.  
In this study, participants will be asked to promptly report any potential signs or symptoms of 
COVID-19, so that symptoms can be confirmed clinically prior to any laboratory testing for SARS-
CoV-2 infection (Section 6.4.2). However, it is possible that participants may obtain incidental 
testing outside of the study, either during that course of standard of care for their 
immunocompromising condition or for other personal reasons. The study will therefore 
accommodate participants who receive an outside positive test result for SARS-CoV-2 infection, 
and these participants will receive additional protocol-defined laboratory viral testing 
(Section 6.4.3). Since these participants may be asymptomatic at the time of laboratory-confirmed 
infection per protocol, the study will additionally evaluate (as an exploratory endpoint; 
Section 4.3) the occurrence of confirmed infection regardless of symptoms. 
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The casirivimab+imdevimab clinical development program includes several controlled phase 3 
studies that have shown consistent clinical benefit from treatment across the SARS-CoV-
2/COVID-19 disease spectrum, spanning uninfected individuals to those with asymptomatic 
SARS-CoV-2 infection to non-hospitalized and hospitalized patients with COVID-19. In the 
outpatient setting, treatment with casirivimab+imdevimab has demonstrated efficacy on clinically-
meaningful endpoints, including a reduction in risk in COVID-19-related hospitalization and/or 
all-cause death through study day 29 (Section 3.3.1). Although study participants will be offered 
additional casirivimab+imdevimab treatment at sites following laboratory-confirmed SARS-CoV-
2 infection (Section 6.4.4), it is nevertheless of interest to evaluate whether prior prophylactic 
dosing may confer subsequent clinical benefit post-infection. The study will therefore evaluate, as 
exploratory endpoints, several clinical outcome measures derived from the outpatient treatment 
setting.  
3.2.1.4. 
Virologic Efficacy 
The study will evaluate, in an exploratory manner, endpoints assessing viral load among 
participants who develop COVID-19 symptoms (Section 4.3). Virologic efficacy has been 
evaluated in all clinical efficacy studies in the casirivimab+imdevimab program, and has been 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 that casirivimab+imdevimab 
virologic efficacy is consistently associated with clinical efficacy (refer to Section 3.3.1 and 
references therein). 
3.2.2. 
Rationale for Dose Selection 
Three dosing regimens of casirivimab+imdevimab (co-administered casirivimab and imdevimab 
in a 1:1 ratio) will be evaluated in the current study: 1200 mg SC loading dose + 600 mg SC Q4W 
x 5 maintenance dose; 300 mg SC Q4W x 6; and 300 mg SC Q12W x 2. For post-exposure 
prophylaxis, a single 1200 mg SC casirivimab+imdevimab dose demonstrated a statistical and 
clinically-meaningful benefit in the prevention of SARS-CoV-2 infection (Section 3.3.1). In the 
chronic prevention setting, 1200 mg SC loading dose + 600 mg SC Q4W maintenance dose is 
authorized in the United States for post-exposure prophylaxis in individuals at high risk for 
progressing to severe COVID-19. The maintenance arm (600mg SC Q4W) is anticipated to 
maintain trough concentration at steady-state (Ctrough,ss) of casirivimab and imdevimab in serum, 
similar to the day 29 concentration after a single 1200 mg SC dose in study (as observed in COV-
2069). 
Concentrations of casirivimab+imdevimab combined in serum for a single 1200 mg SC dose are 
estimated to exceed the concentrations in serum required to achieve 90% neutralizing 
concentration (IC90) in respiratory tract fluid (Cs,target) against currently circulating variants of 
concern/variants of interest (alpha, beta, delta, gamma, kappa, lambda, and mu) as early as 4.8 
hours after dosing and through 28 days after dosing, using a conservative estimate of serum to 
respiratory tract fluid penetration of 1% (Magyarics, 2019) (Shah, 2013) (Wollacott, 2016). For 
the casirivimab+imdevimab 1200mg SC loading dose + 600mg SC Q4W maintenance dose 
regimen, population PK estimated median casirivimab+imdevimab combined Ctrough,ss is ~14x to 
35x the Cs,target against reference SARS-CoV-2 viruses (Wuhan, D614G) and currently circulating 
variants of concern/variants of interest. In outpatients with low risk for developing severe COVID-
19 (study COV-20145), time-weighted average change from baseline in nasopharyngeal (NP) viral 
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load from day 1 to day 7 was significantly and comparably reduced relative to placebo across all 
single IV (300, 600, 1200, and 2400 mg) and SC (600, 1200 mg) doses tested, indicating that all 
doses were on the plateau of the dose-response curve for NP viral load reduction. As all of these 
doses were maximally effective in lowering viral load in outpatients with COVID-19, these results 
warrant evaluation of lower doses in both the treatment and prevention settings. 
In addition to the 1200 mg SC loading dose + 600 mg SC Q4W x 5 maintenance dose regimen, 
two additional dosing regimens will be evaluated to understand whether a lower dose and/or a 
lower dose with an extended dosing interval will be efficacious in preventing SARS-CoV-2 
infection in immunocompromised individuals. For the intermediate dosing regimen of 300 mg SC 
Q4W x 6, the population PK estimated median casirivimab+imdevimab concentration in serum 12 
hours after the first dose exceeds the Cs,target against reference SARS-CoV-2 viruses and currently 
circulating variants of concern/variants of interest, with a predicted Ctrough,ss 50% of that for the 
1200 mg SC loading dose + 60 0mg SC Q4W maintenance dose regimen. Based on the in vitro 
potency of casirivimab+imdevimab against reference SARS-CoV-2 viruses and currently 
circulating variants of concern/variants of interest, and the modest reduction in exposure for 300 
mg SC Q4W x 6, it is expected that this intermediate dosing regimen will be efficacious in 
preventing SARS-CoV-2 infection. For the low dose regimen of 300 mg SC Q12W x 2, population 
PK estimated median casirivimab+imdevimab Ctrough,ss is ~7% of Ctrough,ss for the 1200 mg SC 
loading dose + 600 mg SC Q4W maintenance dose regimen, and is being explored to evaluate 
efficacy of a more convenient Q12W dose regimen. 
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 adults, similar exposures are expected 
between these 2 populations for each of the dosing regimens.  
3.3. 
Risk-Benefit 
The anticipated risks and benefits of casirivimab+imdevimab are informed by pre-clinical and 
clinical data, including data from phase 3 trials.  
For additional information concerning clinical and pre-clinical data, refer to the Investigator’s 
Brochure. 
3.3.1. 
Summary of Efficacy and Safety Profile in Clinical Trials 
Clinical trial data are summarized below. Overall, casirivimab+imdevimab has demonstrated 
efficacy as an anti-viral agent for the treatment and prevention of COVID-19, across a variety of 
populations, and is generally well-tolerated with an acceptable safety profile.  
Intravenous Administration of Casirivimab+Imdevimab in Clinical Trials.  
Outpatient Setting. In COV-2067 (R10933-10987-COV-2067), the phase 3 outpatient treatment 
trial, a single intravenous dose of casirivimab+imdevimab was shown (relative to placebo) to 
reduce COVID-19-related hospitalizations or all-cause death by 71.3% (2400 mg dose) and 70.4% 
(1200 mg dose), reduce symptom duration by 4 days (2400 mg and 1200 mg), and reduce viral 
load over the first 7 days. The incidence of serious adverse events was higher in the placebo group 
(4.0%) than in either of the active treatment groups (2400 mg, 1.1%; 1200 mg, 1.3%), and grade 
≥2 infusion-related reactions were infrequent (≤0.3% in all active treatment groups; 0% in placebo 
group) (Weinreich, 2021b). Similar virologic efficacy and a similar safety profile were observed 
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in the phase 1/2 portion of this trial, which evaluated casirivimab+imdevimab at 8000 mg and 2400 
mg IV doses (Weinreich, 2021a). 
Hospitalized Setting. COV-2066 was a randomized, placebo-controlled study evaluating single 
dose casirivimab+imdevimab 2400 mg IV and 8000 mg IV in hospitalized patients, with those 
requiring different baseline oxygen supplementation enrolled into separate cohorts. Among 
patients who were seronegative at baseline and did not require supplemental oxygen or required 
low-flow oxygen, the 2400 mg IV and 8000 mg IV doses (when analyzed together) exhibited a 
significantly greater reduction in viral load through day 7 relative to placebo, and exhibited a 
nominally significant reduction in the proportion of patients who died or were mechanically 
ventilated (relative risk reduction of 30.9%; nominal p=0.0212). Similar efficacy outcomes were 
observed when the 2400 mg and 8000 mg dose groups were analyzed separately, for either of the 
two cohorts (those who did not require supplemental oxygen and those who required low-flow 
oxygen at baseline). Both doses of casirivimab+imdevimab were well-tolerated, and safety 
findings were consistent with results from other studies in the development program. No new or 
serious safety concerns were observed. 
The controlled, open-label, platform study RECOVERY evaluated casirivimab+imdevimab 8000 
mg IV in hospitalized patients with varying baseline supplemental oxygen requirements (no 
oxygen, simple oxygen, non-invasive ventilation, mechanical ventilation). A single dose of 
casirivimab and imdevimab 8000 mg IV, when given in addition to usual care, reduced the 
incidence of death through day 28 (compared to usual care alone) by 20% in those who were 
seronegative for anti-SARS-CoV-2 antibodies at baseline (24% of patients died in the 
casirivimab+imdevimab group versus 30% in the usual care group). Among seronegative patients, 
the median duration of hospitalization was 4 days shorter in the casirivimab+imdevimab group (13 
days versus 17 days), and the proportion of patients discharged alive by day 28 was greater (64% 
versus 58%) (Horby, 2021). Among patients who were seropositive at baseline, neither clinical 
benefit nor evident clinical harm was observed following treatment with casirivimab+imdevimab. 
Safety information was collected within 72 hours of randomization to evaluate the effect of 
casirivimab+imdevimab on select parameters. No clinically meaningful differences were observed 
between the casirivimab+imdevimab group and the usual care group. There were minor numeric 
imbalances in specific targeted safety outcomes: the reported frequency of fever (4% versus 3%), 
sudden hypotension (4% vs. 2%), and thrombotic events (2% vs. 1%) was marginally higher in the 
casirivimab+imdevimab group versus the usual care group, while the frequency of sudden 
worsening in respiratory status (21% versus 22%) and clinical hemolysis (1% versus 2%) was 
marginally lower (Horby, 2021). Upon Sponsor review, these events were considered likely related 
to COVID 19-and its associated complications.  
In COV-2066, enrollment of patients requiring baseline high-intensity oxygen or mechanical 
ventilation was paused, following early imbalances in safety observed by the study IDMC (refer 
to the Investigator’s Brochure for additional information). These patient populations continued to 
enroll in RECOVERY, however, and within the larger RECOVERY dataset a similar safety signal 
was not observed. Instead, among seronegative patients, trends of clinical benefit were observed 
in subgroups across the different of respiratory support received (Horby, 2021). Subsequent review 
of complete follow-up data in COV-2066 did not show clear treatment-associated trends for death 
or mechanical ventilation among these participants, although the sample size was too small to draw 
definitive conclusions.  
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Subcutaneous Administration of Casirivimab+Imdevimab in Clinical Trials.  
Prophylaxis Setting. In COV-2069 (R10933-10987-COV-2069), the phase 3 prevention trial in 
those at high risk of infection by a household contact, a single subcutaneous dose of 
casirivimab+imdevimab (1200 mg) reduced (relative to placebo) symptomatic SARS-CoV-2 
infection by 81.4%, and reduced overall SARS-CoV-2 infection by 66.4%. The incidence of 
serious adverse events was similar between the active treatment group (1%) and placebo group 
(1%). Injection-site reactions were more common in the treatment group (4%) compared to the 
placebo group (2%), and were all mild to moderate with injection-site reactions in the study grade 
3 or above. The majority of injection site reactions occurred within one day and resolved within 
two days (O’Brien, 2021c).  
Among a sub-group of individuals in COV-2069 who were identified as SARS-CoV-2 positive 
but asymptomatic during screening, a single subcutaneous dose of casirivimab+imdevimab (1200 
mg) reduced (relative to placebo) progression to symptomatic disease by 31.5%, and reduced the 
duration of symptoms in those that developed symptomatic infections. Injection-site reactions 
were more common in the treatment group (4%) compared to the placebo group (1%), but no 
injection-site reactions in the study were grade 3 or above (O’Brien, 2021b).  
In COV-2069, efficacy results were similar in adolescents (age 12 to <18) as observed in adults: 
0% of subjects in the 1200 mg SC treatment group experienced symptomatic infection, compared 
with 9.3% of subjects in the placebo group. Safety data in adolescent subjects were also similar to 
that observed in adults. Injection site reactions were more common in the treatment group (5.9%) 
compared to the placebo group (1.6%), but none were grade 3 or above in any group.  
Adult Volunteers. In HV-2093 (R10933-10987-HV-2093), an adult volunteer study evaluating 
repeated doses of subcutaneously-administered casirivimab+imdevimab 1200 mg SC (monthly 
dosing over 6 months), casirivimab+imdevimab was well-tolerated with no unexpected safety 
findings. The incidence of treatment-emergent AEs was higher in the active treatment group 
(52.7%) compared to placebo (46.3%). This difference was primarily due to a higher incidence of 
injection-site reactions in the casirivimab+imdevimab group (34.6%, compared with 15.8% in the 
placebo group), but none were grade 3 or above in any group. All injection-site reactions were thus 
mild or moderate in severity and most events resolved without treatment. Although very few 
participants experienced symptomatic SARS-CoV-2 infection in the study, infection was less 
common within the active treatment group (0.4%; 3 participants) compared with placebo (5.0%; 
12 participants) 
3.3.2. 
Summary of Risks 
Identified Risks. As with other protein therapeutics, hypersensitivity reactions, including acute 
infusion-related reactions (intravenous administration) or injection site reactions (subcutaneous 
administration), may develop immediately or within a few hours to days after study drug 
administration. Hypersensitivity reactions, including infusion-related reactions or injection site 
reactions, have been observed in study participants who received casirivimab+imdevimab during 
ongoing clinical trials. 
Potential Risks. The potential risks of casirivimab+imdevimab are the clinical consequences of 
immunogenicity and embryo-fetal toxicity. 
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Protein therapeutics carry the potential risk of an immunogenic response in the form of anti-drug 
antibody (ADA) and neutralizing antibody (NAb) development following administration, with 
possible consequences on safety and efficacy. Therefore, blood samples for immunogenicity 
assessment will be collected during the studies.  
Reproductive and developmental toxicology studies have not been conducted, and the effects of 
casirivimab, imdevimab, or casirivimab+imdevimab combination therapy on the fetus and 
reproductive organs in males and females are unknown. There is also currently limited clinical 
experience in the use of casirivimab, imdevimab, or casirivimab+imdevimab combination therapy 
in females who are pregnant or breastfeeding. 
Human IgG1 antibodies are known to cross the placental barrier and are present in breast milk. 
Casirivimab and imdevimab combination therapy therefore has the potential to be transferred from 
the mother to the developing fetus or a breastfed child. Given the high affinity and specificity of 
casirivimab+imdevimab, off-target pharmacological effects are not anticipated in either the mother 
or the fetus, and no off-target binding of casirivimab or imdevimab was observed in any of the 
human or monkey tissues evaluated ex vivo in tissue cross-reactivity studies. However, it is 
unknown whether the potential transfer of casirivimab+imdevimab combination therapy provides 
any treatment benefit or risk to the developing fetus or a breastfed child. 
The combination of casirivimab+imdevimab therapy should be used during pregnancy or 
breastfeeding only if the potential benefit justifies the potential risk for the mother and the fetus or 
breastfed child considering all associated health factors. Pregnancy that occurs during this study 
will be reported and followed, including any complications and pregnancy outcome, as described 
in Section 10.1.3.  
Other Theoretical Risks. Theoretical risks of casirivimab+imdevimab include interference with 
the participant’s endogenous immune response to either SARS-CoV-2 infection or vaccination 
against COVID-19. This study will enroll individuals with a demonstrated non-response to 
COVID-19 vaccination (Section 7.2), regardless of prior passive antibody therapy. This theoretical 
risk is therefore unlikely to apply to the study population.  
Antibody-dependent enhancement (ADE) has been observed for some therapeutics targeting 
exogenous viral proteins. Clinical trials of casirivimab+imdevimab, including analyses of post-
treatment follow-up periods in studies COV-2069 and COV-2093. have not identified any 
evidence of an increase in reinfection corresponding to the waning effect of antibody treatment. 
To assess any potential ADE, a similar approach as that of COV-2069 and COV-2093 will be 
adopted in this study: All participants will have follow-up assessments during the drug elimination 
period (for over five half-lives), and participants will be monitored for any signal of ADE. 
3.3.3. 
Summary 
The available clinical and nonclinical data for casirivimab+imdevimab demonstrates anti-viral 
efficacy with a favorable safety profile. Based on these data, and given the current unmet need for 
prophylactic therapies to prevent SARS-CoV-2 infection and COVID-19 disease in 
immunocompromised individuals, it is the opinion of the Sponsor that the overall risk-benefit 
balance for casirivimab+imdevimab is acceptable to allow evaluation of casirivimab+imdevimab 
in the study population.  
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4. 
ENDPOINTS 
4.1. 
Primary Endpoint 
The primary endpoint is cumulative incidence of symptomatic (broad term), RT-PCR-confirmed 
SARS-CoV-2 infection cases during the efficacy assessment period (EAP). 
Note: definitions of symptomatic SARS-CoV-2 infection and the EAP are provided in Section 6.2. 
4.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Proportion of participants with grade ≥3 treatment-emergent adverse events (TEAEs), 
during the EAP and follow-up period 
• Proportion of participants with TEAEs leading to study drug discontinuation, during 
the EAP and follow-up period 
• Proportion of participants with treatment-emergent serious adverse events (SAEs) 
during the EAP and-follow up period 
• Incidence of adverse events of special interest (AESIs) during the EAP 
• Concentration of each mAb (as applicable to the treatment arm) over time 
• Incidence and titer of anti-drug antibodies (ADA), and incidence of neutralizing 
antibodies (NAb) to each mAb (as applicable to the treatment arm) over time 
4.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• Cumulative incidence of symptomatic (broad term), RT-PCR-confirmed SARS-CoV-
2 infection cases during the follow-up period 
• Cumulative incidence of RT-PCR-confirmed SARS-CoV-2 infection cases 
(regardless of symptoms) during the EAP 
• Proportion of participants with ≥1 moderate COVID-19 symptom (broad term) during 
the EAP and follow-up period 
• Duration of COVID-19 signs and symptoms in weeks (broad term) after diagnosis 
• Proportion of participants with COVID-19-related hospitalization, emergency room 
visit, urgent care center visit or death during the EAP and follow-up period 
• Proportion of participants with COVID-19-related hospitalization or death during the 
EAP and follow-up period  
• Proportion of participants requiring supplemental oxygen due to COVID-19 during 
the EAP and follow-up period 
• Proportion of participants admitted to an intensive care unit (ICU) due to COVID-19 
during the EAP and follow-up period 
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• Proportion of participants requiring mechanical ventilation due to COVID-19 during 
the EAP and follow-up period 
• Proportion of symptomatic (broad term) participants with viral load >4 log10 
copies/mL in NP swab sample collected at the time of COVID-19 diagnosis 
• Maximum SARS-CoV-2 RT-qPCR viral load (log10 copies/mL) in NP swab samples 
among individuals with ≥1 RT-qPCR positive test that has an onset during the EAP 
• Number of weeks of viral load >4 log10copies/mL in NP swab samples among 
symptomatic (broad term) participants during the EAP 
• Viral variant characteristics of SARS-CoV-2 in participants who become infected 
post-baseline 
5. 
STUDY VARIABLES  
A summary of study variables is provided below. A full accounting of variables will be provided 
in the statistical analysis plan (SAP). 
5.1. 
Demographic and Baseline Characteristics 
The variables for baseline characteristics include standard demography (eg, age, race, weight, 
height), medical history, vaccination history, and medication history. 
5.2. 
Efficacy Variables 
Efficacy variables include number of participants with symptomatic RT-qPCR-confirmed SARS-
CoV-2 infection and viral load (log10 copies/mL). 
5.3. 
Safety Variables 
Safety variables include recordings or measurements for individual participants of targeted 
TEAEs, vital signs, and laboratory test results. 
5.4. 
Pharmacokinetic Variables 
The PK variables are concentrations of casirivimab and imdevimab in serum and time. The 
sampling time points are specified in Table 1. 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, and NAb status at nominal sampling 
time/visit. Serum samples for ADA will be collected at the visits specified in Table 1. Samples 
positive in the ADA assays will be further characterized for ADA titers and for the presence of 
NAb. 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This is a randomized, double-blind, placebo-controlled, phase 3 study to assess the safety and 
efficacy of casirivimab+imdevimab as pre-exposure prophylaxis against symptomatic COVID-19 
in immunocompromised individuals, defined according to the primary and secondary 
immunodeficiencies outlined in the study eligibility criteria (Section 7.2). 
The study consists of three periods: a screening period of up to 14 days, an efficacy assessment 
period (EAP) of approximately 6 months (precise definition provided in Section 11.4.3.1), and a 
3-month follow-up period. A diagram depicting the study design is provided in Figure 1. The 
Schedule of Events is provided in Section 9.1. 
In addition to the main study, an optional immunology sub-study will be conducted outside of the 
protocol.  
 
Figure 1: 
Study Flow Diagram 
 
 
6.2. 
Evaluation of Symptomatic SARS-CoV-2 Infection 
The primary endpoint of the study will evaluate symptomatic SARS-CoV-2 infection cases. The 
conditions for symptomatic SARS-CoV-2 infection are as follows: 
• At least 1 sign or symptom (broad term definition) confirmed by a study clinician 
(investigator or designee) to be related to COVID-19, and  
• A positive SARS-CoV-2 RT-PCR result (local or central analysis), with 
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• The sign/symptom onset date and the date of collection for the positive sample 
occurring within ±7 days of one another 
The primary endpoint will analyze symptomatic SARS-CoV-2 infection during the efficacy 
assessment period (EAP), whose definition is provided in Section 11.4.3.1.  
Broad Term COVID-19 signs and symptoms include fever ≥38.0°C as well as 23 sign/symptoms 
designed to be consistent with the Symptom Evolution of COVID-19 (SE-C19) instrument 
developed by the Sponsor. Broad term signs and symptoms are listed in Table 3.  
 
6.3. 
Study Periods 
Screening/Baseline 
After participants provide informed consent, they will be assessed for study eligibility. Refer to 
Section 7.2 for detailed eligibility criteria and testing requirements. Screening will include 
negative test result by RT-PCR. Prior to dosing, a baseline nasopharyngeal swab sample will be 
collected for retrospective, central laboratory confirmation of SARS-CoV-2 negativity by RT-
qPCR. 
Participants who are unable to complete screening requirements within the screening period are 
allowed to be rescreened once, after consultation with the Sponsor. 
Treatment and Efficacy Assessment Period (EAP) 
On day 1, participants will be randomized to repeated subcutaneously-administered study drug or 
placebo as described in Section 8.1 and Figure 1. The method of randomization and stratification 
are described in Section 8.5.  
Study visits will occur every 4 weeks during the EAP. During these visits, dosing and collection 
of study information will occur, including an evaluation of any possible signs or symptoms of 
COVID-19. Signs and symptoms will be evaluated by a clinician (the investigator or designee) as 
described in Section 9.2.4.2, and will be used in the evaluation of the symptomatic SARS-COV-2 
infection (ie, the primary endpoint). 
Following the first dose, participants will be monitored for at least 15 minutes and then released 
from the study site, if medically appropriate. Dosing will continue for the duration of the EAP, 
with the last visit in the EAP occurring approximately one month after the final dose. 
Blood samples will be collected during select EAP visits, for evaluation of drug concentration, 
immunogenicity, serum antibody concentration, or for exploratory research.  
Follow-up Period  
Participants will continue to have visits every 4 weeks during the follow-up period. These visits 
may occur in person, by phone, or by other means of communication as necessary. These visits 
will be used to collect safety information and follow up on any COVID-19 signs/symptoms as 
described in the Schedule of Events. The final study visit will occur (by phone) at 9 months. 
 
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6.4. 
Monitoring and Management of Suspected COVID-19 
6.4.1. 
Monitoring for Suspected COVID-19 
Participants will be monitored for suspected COVID-19 symptoms throughout the study. 
Participants (or their caregivers, when applicable) will be provided with contact information for 
the clinical study site and will be given written and verbal instructions to call site personnel as 
soon as possible if the experience any changes in their health status. This could include any 
symptoms or signs potentially related to COVID-19 or if they observe any new sense of feeling 
unwell.  
6.4.2. 
Evaluation of Suspected COVID-19  
Participants with suspected COVID-19 will undergo an evaluation of symptoms by a study 
clinician (investigator or designee) as soon as possible (within 48 hours of symptom onset, if 
feasible). To ensure prompt evaluation, an unscheduled visit is highly preferred, unless a 
scheduled study visit is the soonest visit available.  
Signs and symptoms will be evaluated by a clinician (investigator or designee) as described in 
Section 9.2.4.2, and will be used for the analysis of symptomatic SARS-CoV-2 infection. If the 
clinician confirms that at least one sign or symptom is related to COVID-19, samples will be 
collected to perform both local and central testing for SARS-CoV-2 infection. 
Local testing must be performed by RT-PCR using local sample collection and assay standards. A 
nasopharyngeal (NP) swab sample is the preferred sample type, but other samples (eg, nasal, 
oropharyngeal, saliva) adhering to local standards are acceptable. An additional NP swab sample 
will be collected for the purposes of central RT-qPCR testing.  
The samples will be collected prior to any administration of post-infection treatment (described 
below). The qualitative result of the central RT-qPCR will be reported back to the corresponding 
study site. 
6.4.3. 
Laboratory-Confirmed SARS-CoV-2 Infection Obtained Outside of the Study 
If a site receives notification from a participant that a positive test result for SARS-CoV-2 infection 
was obtained outside of the study, the test result will be obtained and documented, and the 
participant will have an unscheduled study visit as soon as feasible. If the outside documented 
positive test utilized any assay type other than RT-PCR, the participant will have samples collected 
to perform local RT-PCR and central RT-qPCR testing for SARS-CoV-2 infection. If the outside 
test utilized RT-PCR, the participant will only require sample collection for central RT-qPCR 
testing. In all cases, participants will undergo an evaluation of COVID-19 signs and symptoms by 
the investigator or designee during the unscheduled visit.  
Test results outside of the study will qualify as laboratory-confirmed SARS-CoV-2 infection for 
the purposes of study analyses, but only if an RT-PCR assay was utilized. 
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6.4.4. 
Post-Infection Treatment for Participants with Confirmed Positive SARS-CoV-2 
RT-PCR 
Participants with a confirmed positive SARS-CoV-2 RT-PCR at any time during the study (local, 
central, or documented outside of the study) should be treated with standard of care per local 
practices and per the investigator’s judgment. In addition, casirivimab+imdevimab may be offered 
to the participant as post-infection treatment if medically appropriate in the investigator’s 
judgment. 
If post-infection treatment with casirivimab+imdevimab is deemed medically appropriate, the 
treatment should be provided through the most expeditious mechanism available. To this end, 
casirivimab+imdevimab may be given through mechanisms outside of the study in regions where 
it is approved or authorized. Where regionally approved or authorized, casirivimab+imdevimab 
should be administered at the approved or authorized dose.  
For participants who are able to receive post-infection care at a study site, casirivimab+imdevimab 
may also be offered to the participant as part of the study. This mechanism can be used, for 
example, if casirivimab+imdevimab is not regionally approved or authorized for treatment of 
SARS-CoV-2 infection, or if treatment cannot be made available in an expeditious manner via the 
approved or authorized mechanisms. 
The following investigational dose levels will be offered as part of the study, and may be provided 
if medically indicated in the investigator’s judgement:  
• Not hospitalized due to COVID-19 and does not require supplemental oxygen or an 
increase in baseline oxygen flow rate due to COVID-19: 1200 mg (600 mg per mAb), 
administered either intravenously or subcutaneously 
• Hospitalized due to COVID-19 and does not require supplemental oxygen due to 
COVID-19, or requires low-flow supplemental oxygen due to COVID-19: 2400 mg 
(1200 mg per mAb), administered intravenously 
• Hospitalized due to COVID-19 and requires either high-intensity supplemental 
oxygen due to COVID-19 or requires mechanical ventilation due to COVID-19: 
8000 mg (4000 mg per mAb), administered intravenously 
If feasible, treatment with casirivimab+imdevimab should be provided within 48 hours after a 
positive RT-PCR result is obtained. 
Administration of post-infection treatment with casirivimab+imdevimab will not require 
unblinding of the participant’s randomization assignment (Section 8.7).  
6.4.5. 
Schedule of Events for Participants with Positive SARS-CoV-2 RT-PCR 
Participants with a positive SARS-CoV-2 RT-PCR (from either local or central testing) will 
discontinue the study drug assigned at randomization and enter the follow-up period. This includes 
any participant for whom post-infection treatment with casirivimab+imdevimab was offered but 
was declined by the participant or investigator, or otherwise not received. 
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All participants with a positive SARS-CoV-2 RT-PCR will have additional assessments and 
sample collections, as noted in the Schedule of Events and summarized below): 
• NP swab samples will be collected during unscheduled visits every 7 days (±1 day) 
for central laboratory RT-qPCR analysis until 2 consecutive negative test results are 
obtained. During these visits, COVID-19 signs and symptoms will also be evaluated 
by the investigator or designee. 
• Information regarding COVID-19-related medically-attended visits (MAVs; defined 
in Section 9.2.4.3) will be recorded, and participants will be asked to notify study 
personnel as soon as possible about such occurrences.  
6.4.6. 
Schedule of Events for Participants with Negative SARS-CoV-2 RT-PCR 
Participants with a negative SARS-CoV-2 RT-PCR will continue to follow the Schedule of Events, 
and will continue to receive the treatment assigned to them at randomization. 
6.4.7. 
Management of Participants with Positive SARS-CoV-2 Infection at Baseline 
Participants who are negative for SARS-CoV-2 by local RT-PCR at screening but have a positive 
baseline (day 1) result for SARS-CoV-2 from the central laboratory RT-qPCR will be discontinued 
from the treatment assigned to them at randomization. These individuals will be eligible for post-
infection treatment with casirivimab+imdevimab as defined in Section 6.4.4. However, these 
participants will not be considered as having received post-infection treatment for the purposes of 
study analyses. 
Individuals who are positive at baseline will not undergo any protocol-defined assessments related 
to COVID-19 symptom evaluation or SARS-CoV-2 testing, but will directly enter the follow-up 
period and continue to be followed for safety according to the Schedule of Events.  
6.5. 
Study Stopping Rules 
An independent data monitoring committee (IDMC) will actively monitor interim data to review 
the ongoing safety of participants and may recommend to halt the study or implement changes in 
the study conduct as deemed necessary. Refer to Section 6.8.1 additional information regarding 
the IDMC. 
6.6. 
End of Study Definition  
The end of study is defined as the date the last participant completes the last study visit, withdraws 
from the study, or is lost to follow-up (ie, the participant can no longer be contacted by the study 
site). 
6.7. 
Planned Interim Analysis 
Refer to Section 11.5. 
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6.8. 
Study Committees 
6.8.1. 
Independent Data Monitoring Committee 
An IDMC will actively review data throughout the study to monitor participant safety and efficacy 
data. The IDMC can make recommendations about early study closure or changes to the study 
conduct. The IDMC will also perform planned interim analyses (Section 11.5), and make 
recommendations based on these analyses. 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 will 
conduct periodic data reviews as detailed in the IDMC charter. These data reviews will include all 
available safety data, including deaths, from all enrolled study participants up to the data cutoff 
date for the analysis. 
6.8.2. 
Safety Monitoring Team 
A safety monitoring team at Regeneron may meet periodically to review blinded safety data as 
needed. The team may be comprised of the medical directors, a Global Patient Safety 
representative, a Clinical Pharmacology representative and representatives from Biostatistics and 
Data Management, as well as representatives from Clinical Operations and Regulatory Affairs. 
The data to be reviewed include, but are not limited to:  
• Serious adverse events (SAEs) 
• Grade ≥3 injection-site reactions or grade ≥3 hypersensitivity reactions 
• Treatment-emergent adverse events that result in an early study withdrawal 
• Selected laboratory tests, as deemed appropriate by the safety monitoring team 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PARTICIPANTS 
7.1. 
Number of Participants Planned 
Approximately 8,752 participants will be enrolled in the study. Additional information on sample 
size can be found in Section 11.2. 
7.2. 
Study Population 
Participants enrolled in this study must have an immunocompromised condition, documented 
evidence of non-response to COVID-19 vaccination, a negative SARS-CoV-2 RT-PCR test result, 
and must have completed a full standard-of-care course (defined regionally) of COVID-19 
vaccination with documented evidence of non-response, unless medically ineligible or 
contraindicated. 
7.2.1. 
Inclusion Criteria  
A participant must meet the following criteria to be eligible for inclusion in the study: 
1. Is ≥12 years of age at randomization 
Note: participants <18 years of age will only be enrolled where permitted by local 
requirements. 
2. Meets ≥1 of the following criteria: 
a. Solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) recipients 
receiving immunosuppressive medication  
b. Active hematologic malignancies  
c. Solid organ malignancies receiving active treatment with T cell or B cell 
immunosuppressive therapy 
d. Primary immunodeficiency (such as hypogammaglobulinemia, common variable 
immune deficiency, severe combined immunodeficiency)  
e. HIV and CD4 <200 cells/microliter 
f. Patients with rheumatologic disease, autoimmune disease, or multiple sclerosis 
receiving immunosuppressive therapy that modulates Th1, Th17, anti-TNF such as 
infliximab, adalimumab, etanercept, or B cell responses 
g. Currently receiving any of the following immunosuppressant drugs: 
− T cell suppressing agents (eg, ≥5 mg prednisone equivalent/day during >3 weeks 
− Proteasome inhibitors (such as bortezomib, lenalidomide), alemtuzumab, anti-
thymocyte globulin, CAR-T therapy, calcineurin inhibitors) 
− Alkylating agents and anthracyclines  
− Antimetabolites and purine analogues, such as mycophenolate, fludarabine, or 
cladribine 
− B cell targeted therapies, such as rituximab, ocrelizumab, CD19/CD20, and BTK 
inhibitors 
− mTOR inhibitors 
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− JAK/STAT pathway inhibitors 
3. Has received a full course of standard-of-care COVID-19 vaccination per regional 
guidance, or is deemed medically ineligible or contraindicated to receiving a full course 
of standard-of-care COVID-19 vaccine 
4. Has a documented negative (based on test reference values) serology/antibody response 
in an anti-SARS-CoV-2 spike (S) protein IgG clinical test (including, but not limited to, 
RBD-specific tests), or ≤50 U/mL on the Elecsys® SARS-CoV-2 S Total Ig test. The test 
should be performed on a sample collected at least 2 weeks after the final dose of a 
COVID-19 vaccine and within 3 months prior to randomization 
Note: Lateral flow immunoassay (LFIA) results will not be accepted. Test should be 
considered acceptable for clinical use by local standards (approved or with EUA issued 
by the US FDA or by equivalent local health authority). 
5. Has SARS-CoV-2-negative RT-PCR from a sample collected ≤72 hours prior to 
randomization, using local assay and sample collection and assay standards  
Note: Historical record of negative result is acceptable, as long as the sample was 
collected ≤72 hours prior to randomization. Nasopharyngeal swab sample is highly 
preferred but other sample types (such as nasal, oropharyngeal [OP], or saliva) 
adhering to local standards are acceptable. 
6. Is willing and able to:  
a. Provide informed consent signed by study participant or legally acceptable 
representative 
b. Comply with clinic visits and study-related procedures, including providing samples 
for viral load testing 
7. Is judged by the investigator to be in stable health based on medical history, physical 
examination, vital sign measurements, and laboratory measurements performed at 
screening and/or other times prior to administration of study drug 
7.2.2. 
Exclusion Criteria  
A participant who meets any of the following criteria will be excluded from the study: 
1. Has a life expectancy of less than 2 years 
2. Weighs <40 kg (only applies to participants ≥12 to <18 years of age) 
3. Has any signs or symptoms consistent with COVID-19 (as determined by the 
investigator) 
4. Has a history of SARS-CoV-2 infection within 90 days prior to randomization 
5. Planned use of any investigational, authorized, or approved vaccine for COVID-19 
within 90 days (or per current CDC recommendations) of the last dose of study drug 
(CDC, 2021) 
6. Prior, current, or planned use of any of the following treatments: COVID-19 convalescent 
plasma, other monoclonal antibodies against SARS-CoV-2 (eg, bamlanivimab and 
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etesevimab, sotrovimab), or any COVID-19 treatment (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.  
7. Is planned to begin intravenous immunoglobulin (IVIG) or subcutaneous 
immunoglobulin (SCIG) therapy, is planned to have a change to existing IVIG or SCIG 
regimen, or has been on a chronic stable dose of their IVIG or SCIG regimen for less than 
90 days prior to screening. 
8. Has any known active acute respiratory infection 
9. Has no documented laboratory blood chemistry and hematology (including differential) 
results in the 6 months prior to randomization 
10. Has persistent (refractory to treatment for ≥14 days) bacterial or fungal infection  
11. Has known allergy or hypersensitivity to components of the study drugs 
12. Has been discharged, or is planned to be discharged, to a quarantine center  
13. Is a member of the clinical site study team or their immediate family member 
7.3. 
Premature Withdrawal from the Study 
A participant 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 participant from the study if it is no 
longer in the interest of the participant to continue in the study, or if the participant’s continuation 
in the study places the scientific outcome of the study at risk (eg, if a participant does not or cannot 
follow study procedures). An excessive rate of withdrawals would render the study 
uninterpretable; therefore, unnecessary withdrawal of participants should be avoided. 
Participants who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.1. 
Rules for permanent discontinuation of study treatment are discussed in Section 8.3.2. 
7.4. 
Replacement of Participants 
Participants will not be replaced.  
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8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
Eligible participants will be randomized in a 1:1:1:1 allocation ratio to: 
• Co-administered casirivimab+imdevimab combination therapy, 1200 mg (600 mg per 
mAb) on day 1, then 600 mg (300 mg per mAb) SC Q4W  
• Co-administered casirivimab+imdevimab combination therapy, 300 mg (150 mg per mAb) 
SC Q4W  
• Co-administered casirivimab+imdevimab combination therapy, 300 mg (150 mg per mAb) 
SC Q12W  
• Placebo SC Q4W 
In order to maintain blinding, additional placebo injections will be administered such that all 
participants receive the same number of injections and the same dosing frequency (Q4W). 
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 injection site reactions. 
Instructions on dose preparation are provided in the pharmacy manual.  
8.2. 
Background Treatment(s) 
Participants may self-administer non-prescribed medications and continue other concomitant 
medications with the exception of those prohibited in Section 8.9.1. Participants will continue 
current treatments for their baseline conditions. 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules 
8.3.1. 
Dose Modification 
Dose modification for an individual participant is not allowed. 
8.3.2. 
Study Drug Discontinuation 
Participants who permanently discontinue from study drug should be encouraged to remain in the 
study. Participants who permanently discontinue from study drug and who opt to withdraw from 
the study will be asked to complete study assessments, per Section 9.1.1. 
8.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Grade ≥3 injection-site reaction or grade ≥3 hypersensitivity reaction determined to be 
related to study drug 
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• Serious adverse event or other potentially life-threatening (grade 4) event that is 
determined to be related to study drug  
• Investigator’s clinical judgment, in coordination with principal investigator, that it is 
in the best interest of the participant  
• Receipt of a COVID-19 vaccine during the study 
• A positive baseline (day 1) result for SARS-CoV-2 from central laboratory RT-qPCR 
(however, eligible for additional treatment as defined in Section 6.4.7) 
• Receipt of post-infection treatment with casirivimab+imdevimab (Section 6.4.4) 
• Participant withdrawal of consent 
• Unblinding of participant  
8.4. 
Management of Acute Reactions  
8.4.1. 
Acute Injection Reactions 
8.4.1.1. 
Hypersensitivity Reaction (Systemic) 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use. Hypersensitivities must be reported as AESIs if they meet the severity criteria 
defined in Section 10.1.3. The corresponding NCI-CTCAE severity scale is provided in 
Section 10.2.4. 
Acute systemic reactions following SC injection of study drug should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.  
8.4.1.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AESIs if they meet the severity criteria defined 
in Section 10.1.3. The corresponding NCI-CTCAE severity scale is provided in Section 10.2.4. 
8.5. 
Method of Treatment Assignment 
Participants will be randomized according to a central randomization scheme using an interactive 
web response system (IWRS).  
Randomization will be stratified according to age categories (<18 years, ≥18 to ≤65 years, >65 
years), region (US, rest of world), and use of stable IVIG or SCIG regimen prior to screening (yes, 
no) 
8.6. 
Blinding 
An unblinded pharmacist or qualified personnel at the site, not otherwise associated with the 
conduct of the study, will reconstitute the drug for administration. The drug solution must be 
provided in identical form for active and placebo treatments, so that they remain indistinguishable 
to both study personnel and participants.  
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Study participants, 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 participant randomization assignments.  
Selected individuals from the Sponsor not involved in the conduct of the study may have access 
to unblinded data as needed for safety review or other data review. Any team performing interim 
data reviews will be separated from the ongoing study team. No study personnel involved in the 
day-to-day conduct of the study will have access to any unblinded data before the database is 
locked for this study.  
Drug concentration, serology and other blood-based biomarker results will not be communicated 
to the sites, and the Sponsor’s blinded operational team will not have access to results associated 
with participant identification until after the database is locked. 
8.7. 
Emergency Unblinding 
Unblinding of treatment assignment for a participant may be necessary due to a medical 
emergency, or any other significant medical event, when a treatment decision for that medical 
emergency/significant event is contingent upon knowing the participant's treatment assignment. 
Any participant who becomes RT-PCR positive during the study is eligible to receive 
post-infection treatment with casirivimab+imdevimab without unblinding. 
If unblinding is required: 
• The investigator will make the decision to unblind the treatment assignment, 
following consultation with the Sponsor or the global Principal Investigator 
• Only the affected participant 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 participant  
• 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 the Sponsor and/or designee as soon as possible after 
unblinding the participant 
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 participant'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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8.8. 
Treatment Logistics and Accountability 
8.8.1. 
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 participant. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC. Storage instructions will be 
provided in the pharmacy manual. 
8.8.2. 
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. 
8.8.3. 
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 participant 
• Returned from each participant (if applicable), and 
• Disposed of at the site or returned to the Sponsor or designee. 
All accountability records must be made available for inspection by the Sponsor and regulatory 
agency inspectors; photocopies must be provided to the Sponsor at the conclusion of the study. 
8.8.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the Sponsor 
and regulatory agency inspectors. 
8.9. 
Concomitant Medications and Procedures 
Any treatment or procedure administered from the time of the first dose of study drug to the final 
study visit will be recorded as concomitant medication or concomitant procedure. This includes 
medications or procedures that were started before the study and are ongoing during the study. 
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8.9.1. 
Prohibited Medications  
The following concomitant medications are prohibited and may result in permanent 
discontinuation of study drug: 
• Investigational, authorized, or approved COVID-19 vaccines within 90 days of the last 
dose of study drug (or per current CDC recommendations) (CDC, 2021) 
• Investigational or approved passive antibodies for SARS-CoV-2 infection (eg, 
convalescent plasma or sera, monoclonal antibodies, hyperimmune globulin), 
remdesivir, or other anti-SARS-CoV-2 agents when used as prophylaxis 
8.9.2. 
Permitted Medications  
Other than the prohibited medications listed in Section 8.9.1, concomitant medications are 
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 Sponsor medical monitor. 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following: phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures are to be 
documented as being related to COVID-19 and will remain in effect only for the duration of the 
public health emergency. 
Study assessments and procedures are presented by study period and visit in Table 1.
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Table 1: 
Schedule of Events (No Longer Applicable as of Protocol Amendment 2) 
Study Day 
Screening/Baseline1 
Efficacy Assessment Period2 
Follow-Up Period2 
Confirmatory 
Visit, 
Suspected 
COVID-193  
Post-
Infection 
Treatment 
Visit, Lab-
Confirmed 
Infection3 
ET 
-14 to 1 
1 
82 
29 57 85 113 141 169 
197 
(FU 1) 
225 
(FU 2) 
253 
(EOS) 
Screen Pre-
Dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
±3 ±7 ±7 ±7 ±7 ±7 
±7 
±14 
±14 
±14 
Screening/Baseline 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Locally-acceptable sample for SARS-CoV-2 RT-PCR (local)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NP swab sample for SARS-CoV-2 RT-qPCR (central)4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Study drug administration5 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Safety 
 
Vital signs6 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Treatment-emergent grade ≥3 AEs7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Treatment-emergent AEs leading to study drug discontinuation7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Treatment-emergent SAEs7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Treatment-emergent grade 2 hypersensitivity reactions7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Treatment-emergent grade 3 ISRs7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Concomitant medications and procedures 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Pregnancy test, blood or urine (WOCBP only)  
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Pregnancy status 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Vital status 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Safety information (newborns of study participants) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Efficacy 
 
 
Clinician assessment of COVID-19 signs and symptoms 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X9 
Central Laboratory Pharmacodynamic/Biomarker Testing  
 
Serum for central anti-SARS-CoV-2 serological assays 
 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for exploratory research 
 
X8 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Plasma for exploratory research 
 
X8 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
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Study Day 
Screening/Baseline1 
Efficacy Assessment Period2 
Follow-Up Period2 
Confirmatory 
Visit, 
Suspected 
COVID-193  
Post-
Infection 
Treatment 
Visit, Lab-
Confirmed 
Infection3 
ET 
-14 to 1 
1 
82 
29 57 85 113 141 169 
197 
(FU 1) 
225 
(FU 2) 
253 
(EOS) 
Screen Pre-
Dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
±3 ±7 ±7 ±7 ±7 ±7 
±7 
±14 
±14 
±14 
Pharmacokinetics and Immunogenicity Sampling (first 600 enrollees at participating sites)10 
 
Serum for drug concentration (PK)10,11 
 
X8 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
Serum for immunogenicity (ADA)10,12 
 
X8 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Participants with suspected COVID-19 only13 
 
Clinician assessment of COVID-19 signs/symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Comprehensive vital sign assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X6 
 
Treatment-emergent grade ≥3 AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Treatment-emergent SAEs7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Concomitant medications and procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
If confirmed 
symptomatic13 
Locally-acceptable sample for SARS-CoV-2 
RT-PCR (local) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
NP swab for SARS-CoV-2 RT-qPCR (central) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
If  
SARS-CoV-2 
RT-PCR is 
positive13 
Post-infection treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinician assessment of COVID-19 
signs/symptoms 
 
 
 
 
Every 7 (±1) days until 2 consecutive negative RT-qPCR 
results13 
 
 
 
NP swab for SARS-CoV-2 RT-qPCR (central) 
 
 
 
 
X 
 
 
COVID-19-related MAV details 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ADA, anti-drug antibodies; AE; adverse event; EOS, end of study; FU, follow up; ISR, injection-site reactions; MAV, medically-attended visit; NP, nasopharyngeal; PK, 
pharmacokinetics; SAE, serious adverse event; RT-PCR, reverse transcription polymerase chain reaction; RT-qPCR, quantitative reverse transcription polymerase chain reaction; 
SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WOCBP, women of childbearing potential. 
 
 
 
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Table 2: 
Schedule of Events for Study Close-Out (Protocol Amendment 2; Applies to All Enrolled Participants) 
Study Visit 
Dose Visit 
Optional Confirmatory 
Visit(s), Suspected 
COVID-19 
End-of-Study 
Follow-Up Visit  
(Telephone) 
Timing of Visit 
28 Days After the Most 
Recent Dose 
Within 48 Hours of 
Symptom Onset, if 
Feasible 
85 Days After the Most 
Recent Dose1 
Window (Days) 
±7 
- 
±14 
Informed consent 
X2 
 
 
Optional study drug administration3 
X 
 
 
Vital signs4 
X 
 
 
Treatment-emergent AEs considered by the investigator to be unrelated to 
baseline conditions and unrelated to treatments for baseline conditions5 
X 
 
X 
Treatment-emergent AEs leading to study drug discontinuation5 
X 
 
X 
Treatment-emergent SAEs5 
X 
 
X 
Treatment-emergent grade 2 hypersensitivity reactions5 
X 
 
 
Treatment-emergent grade 3 injection site reactions (ISRs)5 
X 
 
 
Concomitant medications and procedures 
X 
 
X 
Pregnancy status 
 
 
X 
Vital status 
 
 
X 
Safety information (newborns of study participants) 
 
 
X 
Participants with suspected COVID-19 only (optional)6 
Clinician assessment of COVID-19 signs/symptoms7 
 
X6 
 
Comprehensive vital sign assessment8 
 
X6 
 
Treatment-emergent AEs considered by the investigator to be unrelated to 
baseline conditions and unrelated to treatments for baseline conditions5 
 
X6 
 
Treatment-emergent SAEs5 
 
X6 
 
Concomitant medications and procedures 
 
X6 
 
If confirmed 
symptomatic: 
Locally-acceptable sample for SARS-CoV-2 RT-PCR (local)9 
 
X6 
 
NP swab for SARS-CoV-2 RT-qPCR (central)9 
 
X6 
 
If SARS-CoV-2 
RT-PCR is 
positive: 
Clinician assessment of COVID-19 signs/symptoms 
 
Every 7 (±1) days until 2 
consecutive negative RT-
qPCR results6 
 
NP swab for SARS-CoV-2 RT-qPCR (central) 
 
 
COVID-19-related MAV details 
 
 
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9.1.1. 
Footnotes for the Schedule of Events (Original Protocol) 
1. The screening visit may occur up to 14 days prior to the baseline visit (day 1). For 
participants at sites with rapid RT-PCR testing, screening and baseline visits may occur on 
the same day.  
Participants who are unable to complete screening requirements within the screening 
period are allowed to be rescreened once, after consultation with the Sponsor. 
2. During all EAP and follow-up visits, the site will remind participants to call the site as soon 
as possible if they experience any changes in their health, including any symptoms possibly 
related to COVID-19, and ensure that participants have the correct contact information to 
notify the site. 
On visit days when sample collection or dosing is not required, the information indicated 
in the schedule may be collected remotely without an in-person visit.  
For participants who do not require blood samples collected for drug concentration (PK), 
the day 8 visit may be performed remotely. 
3. Participants will be offered post-infection treatment with casirivimab+imdevimab if the 
criteria provided in Section 6.4.4 are met. The post-infection treatment to be offered is also 
defined in Section 6.4.4. The confirmatory visit and post-infection treatment visit may 
occur on the same day. The confirmatory visit may also occur on the same day as a 
scheduled study visit. If visits occur on the same day, assessments for both visits must be 
collected (but not duplicated). 
4. Collection for screening test must fulfill the window specified in the eligibility criteria 
(Section 7.2.1). If collection is performed outside of this window, testing must be repeated 
prior to randomization. Refer Section 9.2.1.4 for requirements related to screening test and 
baseline tests for SARS-CoV-2 infection. Participants who were negative according local 
testing but positive by central testing will discontinue study drug and enter the follow-up 
period. Refer to Section 6.4.7 for more information.  
5. Dosing will be administered after all assessments and sample collections are completed. 
6. Vital signs (defined in Section 9.2.5.1) will be collected before study drug administration. 
On day 1, participants will be observed for at least 15 minutes after completion of study 
drug administration.  
7. Refer to Section 10.1 for AE monitoring and reporting guidelines.  
8. The indicated blood samples may be collected at either day -1 or day 1 but must be 
collected prior to drug administration.  
Samples for serological assays will be used for retrospective analysis (Section 9.2.8.1) and 
the results will not be reported to study sites. 
9. During any early termination visit, COVID-19 signs and symptoms will be assessed only 
for participants who were RT-PCR positive and entered follow-up without completing all 
study visits during the EAP. 
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10. Samples for drug concentration (PK) and immunogenicity (ADA) will only be collected 
in the first 600 participants who are enrolled at participating sites.  
11. Actual dosing time and drug concentration sample (PK) collection times will be recorded. 
For PK sample collection on dosing days, samples must be collected prior to dosing. 
12. The window for pre-dose immunogenicity (ADA) sample collection should be as close to 
administration of study drug as is reasonable. Actual dosing time and ADA sample 
collection times will be recorded.  
13. The assessments and procedures in this section only apply to participants with suspected 
COVID-19, confirmed COVID-19 symptoms, or laboratory confirmed SARS-CoV-2 
infection, as indicated. Note the following: 
− The collections and assessments indicated in this section will be performed in 
addition to collections and assessments indicated in the scheduled visits. 
− Refer to Section 6.4 for monitoring, evaluation, and additional procedures for 
participants with suspected COVID-19 or laboratory-confirmed SARS-CoV-2 
infection. 
− Comprehensive vital sign assessment includes standard vital sign assessment 
(defined in Section 9.2.5.1), SpO2, and respiratory rate.  
− NP swabs for central lab RT-qPCR testing are collected once every 7 days (±1 day) 
until 2 consecutive tests are negative. 
− Clinician assessment of COVID-19 signs and symptoms is performed every 7 days 
(±1 day) until 2 consecutive RT-qPCR tests are negative. Signs and symptoms will 
continue to be evaluated during the scheduled visits of the follow-up period. 
9.1.2. 
Footnotes for the Schedule of Events (Protocol Amendment 2) 
1. Approximately 85 days after the final dose of study drug (ie, the optional final dose of 
casirivimab+imdevimab defined in protocol amendment 2, or the final assigned 
casirivimab+imdevimab or placebo dose for participants who do not receive the optional 
dose). 
2. Informed consent may be obtained at the dosing visit, or at any time prior to the visit via 
remote consent (if available and allowable at the study site). 
3. Applicable to participants who consent to receive a final optional dose of 1200 mg SC 
casirivimab+imdevimab. The optional dose may be administered to all participants 
regardless of treatment assignment at randomization. However, participants will not be 
eligible to receive this dose if they have already received casirivimab+imdevimab as post-
infection treatment. The dose will be recorded. 
4. Vital signs (defined in Section 9.2.5.1) will be collected before study drug administration 
and at least 60 minutes after completion of study drug administration.  
5. Refer to Section 10.1 for AE monitoring and reporting guidelines. 
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6. Note that all assessments and procedures related to participants with suspected COVID-19 
are optional for both the study site and the study participant. Refer to Protocol Amendment 
2 Procedures for additional information. 
7. Clinician assessment of sign or symptoms may occur remotely. If remote assessment is 
performed, a confirmatory site visit for laboratory testing of SARS-CoV-2 can optionally 
occur after a clinician deems that the signs or symptoms are related to COVID-19.  
8. Comprehensive vital sign assessment includes standard vital sign assessment (defined in 
Section 9.2.5.1), SpO2, and respiratory rate.  
9. Note that samples for local and central laboratory testing of SARS-CoV-2 may be collected 
on the same day; the results of local testing are not required prior to sample collection for 
central testing. 
9.1.3. 
Early Termination Visit 
Participants who withdraw from the study will be asked to have an early termination (ET) visit 
consisting of the assessments indicated in the Schedule of Events. 
9.1.4. 
Unscheduled Visits 
All attempts should be made to keep participants on the study schedule. Unscheduled visits may 
be required for participants with suspected COVID-19; refer to Section 6.4 for additional 
information. 
Unscheduled visits may also be necessary to repeat testing following abnormal laboratory results, 
for collection of NP swabs, blood, serum, or plasma, for follow-up of treatment-emergent SAEs, 
treatment-emergent AESIs, or for any other reason, as warranted. 
9.2. 
Study Procedures 
This section describes the procedures and collections that will be performed in this study. 
Procedures and collections will occur according to the Schedule of Events. 
9.2.1. 
Procedures Performed at Screening 
The following procedures will be performed for the purpose of determining study eligibility or 
characterizing the baseline population: informed consent, medical history, demographics 
(including age, sex, race), weight, height, screening assessment for SARS-CoV-2 infection.  
9.2.1.1. 
Informed Consent 
Informed consent (and assent, as applicable) must be obtained according to the requirements 
described in Section 13.2.  
9.2.1.2. 
Medical History 
Medical history will include, but not be limited to the following:  
• Prior COVID-19 infection 
• COVID-19 vaccination record 
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• Menopausal history 
• Pregnancy or breastfeeding status, if applicable 
9.2.1.3. 
Weight and Height 
Body weight will be assessed using calibrated scales. During weight assessment, participants 
should not wear shoes. Body weight will be recorded to the nearest 0.1 kg.  
Height will also be recorded. 
9.2.1.4. 
Screening and Baseline Assessments for SARS-CoV-2 Infection  
During the screening period, the investigator or designee will verify that the participant has tested 
negative for SARS-CoV-2 within the time period specified in Section 7.2.1. The screening 
assessment for SARS-CoV-2 infection will be performed locally using an approved or authorized 
diagnostic RT-PCR assay, performed according to the study site’s standards and procedures.  
For local screening test, a nasopharyngeal (NP) swab sample is the preferred sample type, but other 
samples (eg, nasal, oropharyngeal, saliva) are acceptable if they are collected according to local 
standards. For tests performed at screening, the local testing result, specimen type, assay type, and 
date of the test will be recorded in the eCRF.  
Baseline SARS-CoV-2 RT-qPCR testing will be performed by a central laboratory NP swab test 
on day 1. The qualitative results of this baseline central SARS-CoV-2 RT-qPCR will be reported 
back to the corresponding study site but will not be required prior to study drug administration on 
day 1.  
9.2.2. 
Randomization 
Refer to Section 8.5. 
9.2.3. 
Study Drug Administration 
Refer to Section 8.1. 
9.2.4. 
Efficacy Procedures 
9.2.4.1. 
Post-Baseline Assessments for SARS-CoV-2 Infection 
Refer to Section 6.4 for additional information regarding post-baseline testing for SARS-CoV-2 
infection.  
9.2.4.2. 
Clinician Assessment of COVID-19 Signs and Symptoms 
COVID-19 signs and symptoms will be evaluated by a study clinician (investigator or designee) 
during each study visit as indicated in the Schedule of Events. Participants with suspected COVID-
19 will also undergo an evaluation of symptoms as soon as possible (within 48 hours of symptom 
onset, if feasible), and those with a positive SARS-CoV-2 RT-PCR will undergo weekly 
assessment of signs and symptoms (refer to Section 6.4 and the Schedule of Events for additional 
information). 
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Clinical Evaluation. The clinician (investigator or designee) will evaluate the participant for signs 
of COVID-19 and query participants and/or their parent(s) or guardian(s) for any symptoms of 
COVID-19.  
Information regarding symptoms should be obtained in an unsolicited fashion, allowing the 
participant and/or participant’s parent(s) or guardian(s) to spontaneously report events. Solicitation 
of specific symptoms should be avoided. 
Source Documentation. For each symptom, the start (onset) date, end date, and severity will be 
recorded (mild, moderate, severe) in the participant’s medical record (source document). It is 
important to record this information in the source document, to ensure that the temporal 
dimensions of each sign or symptom are captured. 
Event of Interest. A sign or symptom recorded in the source document will subsequently be 
recorded as an event of interest (EI) if it meets all of the following conditions: 
• The participant has laboratory-confirmed SARS-COV-2 infection (refer to 
Section 6.4 for details) 
• The sign or symptom falls within the broad term definition (Table 3) 
• The sign/symptom onset date and the date of collection for the positive sample 
occurring within ±7 days of one another 
For each EI, and during each visit for which signs and symptoms are evaluated, the following 
minimum information will be recorded: 
• The sign or symptom, with start (onset) calendar date, end calendar date, and severity 
(mild, moderate, severe) 
• Confirmatory local RT-PCR test result and date of sample collection 
• Confirmatory central RT-qPCR test result and date of sample collection 
• Weekly central RT-qPCR test results and dates of sample collection 
• Record of any post-infection treatment with casirivimab+imdevimab administered 
Note that any sign or symptom corresponding to a grade ≥3 TEAE will also be recorded and 
used for safety evaluation as described in Section 10.1.  
 
Table 3: 
Broad Term Definition of COVID-19 Signs and Symptoms 
• Body aches such as muscle 
pain or joint pain 
• Chest pain 
• Chills 
• Confusion 
• Cough 
• Diarrhea 
• Dizziness 
• Fatigue 
• Feverish 
• Fever ≥38.0°C 
• 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 
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9.2.4.3. 
COVID-19-Related Medically-Attended Visit Details, Immunocompromised 
Population Definition (Exploratory Outcome) 
A COVID-19-related medically-attended visit (MAV) will be defined as follows: hospitalization, 
ER visit, urgent care visit, physician’s office visit, or telemedicine visit, with one of the reasons 
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 
• If hospitalized due to COVID-19, length of visit 
• Reason (list all COVID-19-related clinical manifestation[s] that prompted the 
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, remdesivir, baricitinib, etc) 
9.2.5. 
Safety Procedures 
9.2.5.1. 
Vital Signs 
Standard vital signs will include body temperature, blood pressure, and heart rate. Comprehensive 
vital sign assessment will additionally include SpO2 and respiratory rate.  
Vital signs will be measured after the participant has been resting quietly for at least approximately 
5 minutes and may be obtained in seated or supine position. 
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). 
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 
Refer to Section 10.1. 
9.2.5.3. 
Concomitant Medications and Procedures 
Concomitant medications and procedures will be recorded as defined in Section 8.9. 
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9.2.5.4. 
Pregnancy Test for Women of Childbearing Potential 
Pregnancy testing will be performed in women of childbearing potential (WOCBP) only. Serum 
or urine pregnancy test are both acceptable.  
Participants who become pregnant will remain in the study and will continue to follow the 
Schedule of Events as planned. Refer to Section 10.1.3 for more information regarding pregnancy 
reporting. 
9.2.5.5. 
Pregnancy Status 
Pregnancy status and date of pregnancy, as applicable, will be recorded. Refer to Section 10.1.3 
for reporting requirements. 
9.2.5.6. 
Vital Status 
Vital status (whether the participant is dead or alive) will be recorded, as well as the date of 
death, when applicable. 
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 participants who were treated in the study and were pregnant at randomization or became 
pregnant at any time in the study. Note that this information is in addition to outcome reporting of 
all pregnancies (Section 10.1.3). 
9.2.6. 
Drug Concentration and Measurements 
Samples will be collected at the timepoints listed in the Schedule of Events. For information 
concerning unused samples and exploratory research, refer to Section 9.2.9.  
9.2.7. 
Immunogenicity Measurements and Samples 
Samples for immunogenicity assessment will be collected at the timepoints listed in the Schedule 
of Events. For information concerning unused samples and exploratory research, refer to 
Section 9.2.9. 
9.2.8. 
Pharmacodynamic/Biomarker Procedures 
9.2.8.1. 
Serological Assays for Endogenous Anti-SARS-CoV-2 Antibodies 
Antibodies against the S protein RBD will be measured using the Elecsys® anti-SARS-CoV-2 S 
assay (anti-RBD total Ig, Roche) on samples collected at baseline. The results of this assay will be 
used to retrospectively analyze the data by the magnitude of baseline immune response to COVID-
19 vaccines (see efficacy analysis set definitions in Section 11.3.1). Neutralizing antibodies against 
SARS-CoV-2 will also be measured at baseline in all enrolled participants in order to determine if 
any measurable, endogenous humoral response was functional. 
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Additional anti-SARS-CoV-2 antibodies may also be measured on stored samples to further 
characterize participants’ baseline serostatus. Any assays used post-baseline to measure antibody 
immunity will have been demonstrated not to be susceptible to interference from study drug.  
9.2.8.2. 
Serum and Plasma for Exploratory Research 
Serum and plasma collected and banked for exploratory research may be used for studies related 
to COVID-19 disease or vaccination, SARS-CoV-2, casirivimab, imdevimab, host and viral 
biological pathways, and other mechanisms related to safety, drug exposure, disease activity and 
clinical outcomes. 
9.2.8.3. 
Exploratory Virology and Viral Sequencing 
In support of public health initiatives to track SARS-CoV-2 genetic variants pre and post-
treatment, viral genome sequencing will be performed on SARS-CoV-2 viral nucleic acid isolated 
from available nasopharyngeal (NP) swab samples collected during the study that have been 
confirmed positive by RT-qPCR for SARS-CoV-2 at the central laboratory. 
The results of viral sequencing and related analyses may be reported outside of the study CSR in 
a separate report. 
9.2.9. 
Unused and Residual Biological Samples 
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 
COVID-19 
disease 
or 
vaccination, 
SARS-CoV-2, 
casirivimab+imdevimab, host and viral biological pathways, and other mechanisms related to 
safety, drug exposure, disease activity and clinical outcomes. 
9.2.10. 
Exploratory Immunology Sub-Study (Optional; Separate Protocol) 
Whole blood samples may be collected as part of an optional sub-study at a select site(s) to study 
patients’ endogenous immune activity and responses to COVID-19 vaccination, SARS-CoV-2 
infection and infection by other pathogens such as, but not limited to, influenza. The samples 
may be used to characterize the cells and plasma to study immune function in these patients pre- 
and post-treatment using flow cytometry, RNA sequencing, cytokine profiling, and other 
methods. This sub-study will be described in a separate protocol and results will not be included 
in the CSR. 
 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
This study will collect and record the following targeted TEAEs: 
• Treatment-emergent grade ≥3 AEs 
• Treatment-emergent AEs leading to study drug discontinuation 
• Treatment-emergent SAEs 
• Treatment-emergent grade ≥2 hypersensitivity reactions 
• Treatment-emergent grade ≥3 injection-site reactions 
Note: throughout Section 10, the term “AE” refers to the targeted list above. 
10.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data 
collection, from the start of the pretreatment period to the end of on-treatment period (see 
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 an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
participant. Adverse events may be directly observed, reported spontaneously by the participant or 
parent, or by questioning the participant or parent at each study visit. Participants and parents 
should be questioned in a general way, without asking about the occurrence of any specific 
symptoms. The investigator must assess all AEs to determine seriousness, severity, and causality, 
in accordance with the definitions in Section 10.2. 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 SAEs (and AESIs) until they have resolved or are considered clinically stable; 
AEs should be followed until they are resolved or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available. If the signs and symptoms are distinct and do not suggest a 
common diagnosis, report them as individual entries of AE or SAE.  
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
Investigator to determine their clinical significance. Isolated abnormal laboratory results, vital sign 
findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported as 
AEs if they are symptomatic, lead to study drug discontinuation, dose reduction, require corrective 
treatment, or constitute an AE in the Investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization). A procedure is not 
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an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-planned (prior to 
signing the informed consent form) procedures, treatments requiring hospitalization for 
pre-existing conditions that do not worsen in severity, and admission for palliative or social care 
should not be reported as SAEs (see Section 10.2 for definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Any SAE that may occur after the on-treatment period that the Investigator assesses as related to 
study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3.  
10.1.2. 
Reporting Procedure  
All events (serious and non-serious) must be reported with Investigator’s assessment of the event’s 
seriousness, severity, and causality to the (when applicable: blinded) study drug. For SAEs and 
AESIs, a detailed narrative summarizing the course of the event, including its evaluation, 
treatment, and outcome should be provided on the AE 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: 
• SAEs 
• Adverse Events of Special Interest (AESI), defined as: 
− Grade ≥2 hypersensitivity reactions 
− Grade ≥3 injection-site reactions 
Note: refer to Table 5 for grading scale. 
• Pregnancy: Although pregnancy is not considered an AE, it is the responsibility of the 
Investigator to report to the Sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a study participants, during the study or within 8 months 
of the last dose of study drug. Any complication of pregnancy affecting a female 
participant, and/or fetus and/or newborn that meets the SAE criteria, must be reported 
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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. 
A pregnancy report form will be completed for each participant who becomes pregnant 
or is pregnant at the time the parent or guardian signs consent. 
10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a participant 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 participant is a passenger). 
• Is life-threatening – in the view of the Investigator, the participant 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 participant 
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.  
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10.2.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
interest specific to the Sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the Investigator to the Sponsor can be appropriate. Such an event might warrant 
further investigation in order to characterize and understand it.  
10.2.4. 
Severity 
The severity of adverse events (including test findings classified as adverse events) will be 
graded using the current version of the NCI-CTCAE v5.0 (DCTD, 2017).  
Treatment-emergent AEs, SAEs, or AESIs not listed in the NCI-CTCAE will be graded according 
to the scale in Table 4. The NCI-CTCAE severity grading scale for anaphylaxis, allergic reactions, 
and injection site reactions is provided in Table 5. 
Table 4: 
NCI-CTCAE Severity Grading System for Adverse Events (v5.0)  
Grade 
Severity 
Description 
1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
2  
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL)1 
3  
Severe 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL2 
4  
Life-threatening 
Life threatening consequences; urgent intervention indicated 
5  
Death 
Death related to adverse events 
1 Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
2 Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
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Table 5: 
NCI-CTCAE Severity Grading (v5.0) for Anaphylaxis, Allergic Reactions, and Injection-Site Reactions 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Anaphylaxis1 
Not applicable 
Not applicable 
Symptomatic bronchospasm, with 
or without urticaria; parenteral 
intervention indicated; allergy-
related edema/angioedema; 
hypotension 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Allergic reaction 
(hypersensitivity 
reaction)2 
Systemic intervention not 
indicated 
Oral intervention indicated 
Bronchospasm; hospitalization 
indicated for clinical sequelae; 
intravenous intervention indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Injection site 
reaction3 
Tenderness with or 
without associated 
symptoms (eg, warmth, 
erythema, itching) 
Pain; lipodystrophy; edema; 
phlebitis 
Ulceration or necrosis; severe 
tissue damage; operative 
intervention indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
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.  
Source: (DCTD, 2017) 
 
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10.2.5. 
Causality 
The Investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions. The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset versus time drug was administered 
• Nature of the reactions: immediate versus long term 
• Clinical and pathological features of the events  
• Existing information about the drug & same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation)  
• Response to rechallenge (re-introduction of the drug)  
• Participant’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, participant’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. 
• 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, participant’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
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Causality to the study conduct (protocol specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
participant’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, participant’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 participant at his/her site(s) as per the 
requirements of this protocol and consistent with current Good Clinical Practice (GCP). Any 
questions or concerns should be discussed with the Sponsor in a timely fashion. The Sponsor will 
monitor the safety data from across all study sites. The Medical/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Global Patient Safety; Biostatistics and Data Management). Safety monitoring 
will be performed on an ongoing basis (eg, individual review of SAEs) and on a periodic 
cumulative aggregate basis. 
10.4. 
Notifying Health Authorities, Institutional Review Boards, and 
Investigators 
During the study, the Sponsor and/or the contract research organization (CRO) will inform health 
authorities, Institutional Review Boards (IRBs)/Ethics Committees (ECs), 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.  
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 IRB/EC as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) of 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 interim analysis. 
11.1. 
Statistical Hypothesis  
For the primary objective (Section 2.1), the null hypothesis of the study is that the antibody 
efficacy (AbE) of casirivimab+imdevimab to prevent symptomatic SARS-CoV-2 infection, 
compared to placebo, is 0%.  
The statistical hypotheses (null and alternative) for any antibody arm can be stated as: 
H0: HR = 1 versus H1: HR < 1, where HR is the hazard ratio for antibody arm over placebo.  
Equivalently, the null and alternative hypotheses can be stated as: 
H0: AbE = 0% versus H1: AbE >0%, where AbE=100 x (1-HR).  
Antibody efficacy is thus defined as the percent reduction in hazard ratio for an antibody arm over 
that of placebo when comparing incidence of symptomatic SARS-CoV-2 infection, using a time-
to-event analysis approach.  
For the alternative hypothesis, the target antibody efficacy of arm 1 (casirivimab+imdevimab 1200 
mg (day 1) SC then 600 mg SC Q4W) is assumed to be at least 60% (ie, HR=0.4); AbE could be 
same or lower for the other 2 antibody arms, eg, 55% (HR=0.55), 45% (HR=0.45) (Table 6). 
11.2. 
Justification of Sample Size 
The sample size is driven by the number of cases to demonstrate the efficacy of the antibody arm, 
compared to placebo, in preventing symptomatic (broad term), RT-PCR-confirmed SARS-CoV-2 
infection in immunocompromised participants. 
The number of cases needed to detect the target antibody efficacy and corresponding power with 
log-rank test are provided in Table 6. These values assume that the time to symptomatic SARS-
CoV-2 infection is distributed exponentially in each group, with a COVID-19 incidence rate in the 
placebo arm of 4.02% over 6 months in the immunocompromised population.  
In this study, a total of 186 cases are targeted across all 4 treatment arms in the modified intention-
to-treat (mITT) set. Accordingly, a total of 8752 participants are planned to be randomized, based 
upon the following assumptions: 
• Study duration of 15 months, assuming 6 months follow-up for efficacy and accrual 
duration of 9 months,  
• Probability of participant dropouts by 6 months is 0.05 (ie, 5%), and 
• Approximately 10% participants at baseline will have failed to meet one (or both) of 
the conditions of the modified intent-to-treat (mITT) population (and will only be 
included in the ITT population; Section 11.3.1) 
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For the purpose of estimating events (sample size) for pairwise comparisons between antibody arm 
and placebo, it was assumed that there will be four interim looks at 20%, 33%, 50%, and 75% 
information fraction. Note, however, that actual number of interim looks conducted may vary. 
 
Table 6: 
Power and Sample Size Estimates to Demonstrate Antibody Efficacy at 
Overall α=0.025 (1-sided) 
Arm 
Group 
Target 
Antibody 
Efficacy 
Power 
Target 
Number of 
Cases 
(mITT)a 
6-month 
COVID-19 
incidence 
ratesb 
Number of 
participants, to 
randomize in 
1:1:1:1 ratioc 
- 
Total 
- 
- 
186 
- 
8752 
1 
Casirivimab+imdevimab 
1200 mg (day 1) SC then 
600 mg SC Q4W 
60% 
99.7% 
31 
1.628% 
2188 
2 Casirivimab+imdevimab 
300 mg SC Q4W 
55% 
98.7% 
35 
1.829% 
2188 
3 Casirivimab+imdevimab 
300 mg SC Q12W 
45% 
90% 
43 
2.231% 
2188 
4 Placebo 
- 
- 
77 
4.02% 
2188 
a Estimates based on log-rank test assuming at least 90% power for arm 3. 
b Assuming exponential distribution, placebo rate and hazard ratio for antibody arm. 
c Sample size adjusted upwards for 10% participants based on RT-qPCR and central lab serology test result at 
baseline (modified intent-to-treat [mITT] population). 
The power and sample size calculations were performed using EaST software. 
11.3. 
Analysis Sets  
11.3.1. 
Efficacy Analysis Sets 
The intent-to-treat (ITT) population is defined as all randomized participants. 
The primary analysis population for efficacy will be the modified intent-to-treat (mITT) 
population, defined as all randomized participants who received at least one dose of the study drug 
and at baseline (day 1):  
1. Have tested negative by RT-qPCR (central lab results), and  
2. Have central serology test result (Elecsys® anti-S RBD total Ig) ≤50 U/mL 
Participants who are deemed medically ineligible or contraindicated to receiving a full course of 
standard-of-care COVID-19 vaccine will also be included in the mITT. 
Analysis will be performed according to the study drug allocated (as randomized). 
Both, ITT and mITT populations will be used to summarize demographics and baseline 
characteristics of participants.  
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11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all participants 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, with details provided in the SAP. Treatment compliance/administration and all 
clinical safety variables will be analyzed using the SAF. 
11.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis population includes all participants who received any study drug and who had at 
least 1 non-missing result following the first dose of study drug. Participants will be analyzed 
based on the actual treatment received. 
Participants who test positive for SARS-CoV-2 infection during the treatment period and 
discontinue study drug may be analyzed separately. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis sets (AAS) includes all participants who received any amount of study drug 
(active or placebo [safety analysis set]) and had at least one non-missing ADA result following the 
first dose of the study drug. The AAS is based on the actual treatment received (as treated) rather 
than as randomized. 
The NAb analysis sets (NAS) includes all treated participants who received any study drug (active 
or placebo), have at least one non-missing ADA result following the first dose of study drug (active 
or placebo), and either tested negative at all ADA sampling times or tested positive for ADA with 
at least one non-missing NAb result after first dose of the study drug (active or placebo). 
Participants who are ADA negative are set to negative in the NAb analysis set. 
11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of participants 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. 
Subgroups will be defined by key baseline factors (e.g., demographics, disease characteristics). 
Subgroup analyses will be performed on efficacy endpoints and safety endpoints, as needed. 
Details will be described in the Statistical Analysis Plan (SAP). 
Statistical analyses will be performed using Statistical Analysis Software (SAS) Version 9.4 or 
higher. 
11.4.1. 
Participant Disposition 
The following will be provided: 
• The total number of screened participants who have signed informed consent 
• The total number of randomized participants: received a randomization number 
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• The total number of participants who discontinued the study, and the reasons for 
discontinuation 
• The total number of participants who discontinued from study treatment, and the 
reasons for discontinuation 
• A summary of analysis sets including ITT, mITT, SAF, PK, and AAS (see 
Section 11.3) 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all participants combined.  
11.4.3. 
Efficacy Analyses 
The mITT population will be the primary analysis population for efficacy. The ITT population 
will also be used for efficacy analysis. Participant data will be analyzed according to the group to 
which they were randomized. 
11.4.3.1. Primary Efficacy Analysis 
The primary endpoint of the study is cumulative incidence of symptomatic (broad term), RT-PCR-
confirmed SARS-CoV-2 infection cases during the efficacy assessment period (EAP). See 
Section 6.2 for the definition of a symptomatic SARS-CoV-2 infection.  
The EAP is defined as the day 2 to day 169 visit. The cumulative incidence of cases through the 
EAP will be estimated using the Kaplan-Meier method, and the antibody efficacy (AbE) will be 
estimated as the percent risk reduction (ie, 100 x [1-HR), where HR is the hazard ratio for 
comparison of the incidence of cases in the antibody arm versus placebo). A stratified Cox 
proportional hazard regression model with treatment group as a fixed effect, and adjusted for the 
stratification factors of age categories, region, and use of stable IVIG or SCIG regimen prior to 
screening, will be used to estimate the hazard ratio and 95% CI (2-sided).  
For the primary analysis, cases will be counted from day 2 through day 176 (ie, day 169 +7 days), 
to allow for cases to accrue until the end of the EAP visit window per the Schedule of Events. 
Time of symptomatic SARS-CoV-2 infection will be the earlier of the sign/symptom onset date or 
the sample collection date for which RT-PCR result (local or central) was positive.  
Two-sided p-values will be reported using the log-rank test for pairwise comparison between each 
antibody arm and placebo. See Section 11.4.4 and Section 11.5 for multiplicity adjustment. 
The primary analysis population will be the mITT population. ITT population will also be used to 
analyze the primary endpoint. 
Details of supportive analyses and subgroup analyses for the primary endpoint will be provided in 
the SAP. 
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11.4.4. 
Control of Multiplicity 
The overall type 1 error rate will be strictly controlled at 0.025 (1-sided) due to multiple hypothesis 
tests for each of the antibody arms versus placebo, planned interim analyses for efficacy, and other 
testing as detailed in the SAP.  
The hypothesis test for the primary endpoint will be performed first for comparison of arm 1 
(casirivimab+imdevimab 1200 mg SC [day 1], then 600 mg SC Q4W) versus placebo, and then 
for comparison of arm 2 (casirivimab+imdevimab 300 mg SC Q4W) and arm 3 
(casirivimab+imdevimab 300 mg SC Q12W) versus placebo. The overall testing strategy for all 
tests will be described in the SAP. 
The Lan-DeMets implementation of the O’Brien-Fleming alpha spending function will be applied 
to control the false positive error rate of 0.025 (1-sided) over the interim analyses for efficacy and 
primary analysis (see Section 11.5). 
11.4.5. 
Safety Analysis 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, the following observation periods are defined: 
• The pretreatment period is defined as the time from the signing of the ICF to before 
study drug administration. 
• The EAP is defined as the day from first dose of study drug to day 169 ± 7 days 
• The Follow-up period is defined as the end of the EAP to the end of the Follow-up 
Period (ie, the last study visit).  
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition.  
This study will collect data on the following targeted TEAEs (Section 10.1): Grade ≥3 AEs, AEs 
leading to discontinuation, SAEs, grade ≥2 hypersensitivity reactions, and grade ≥3 injection-site 
reactions. 
Analysis 
All AEs reported in this study will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®).  
The number and percentage (proportion) of participants will be summarized by group in the Safety 
Set.  
Summaries will be provided for the EAP, and combined across the EAP and Follow-up periods 
for the following: 
• Overview of TEAEs, ie, overall number (%) of participants with any TEAE, grade ≥3 
TEAE, Serious TEAE, AESI, serious AESI, TEAE leading to death, or TEAE leading 
to study discontinuation 
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• Grade 3 and Grade 4 TEAEs by primary system organ class (SOC) and preferred term 
(PT) 
• TEAEs leading to discontinuation by primary SOC and PT 
• TEAEs leading to death by primary SOC and PT 
• Treatment-emergent SAEs by primary SOC and PT, as well as by SOC, PT, and 
severity (according to the grading scale outlined in Section 10.2.4) 
In addition, following data will be analyzed: 
• Summary of Treatment-emergent AESIs by PT during the EAP 
• Incidence of Treatment-emergent AESIs by PT during the EAP 
− Grade ≥2 hypersensitivity reactions 
− Grade ≥3 injection-site reactions 
Deaths and other SAEs will be summarized by treatment group. 
11.4.5.2. Other Safety (Vital Signs and Laboratory Tests) 
Definitions 
The following definitions will be applied to laboratory parameters and vital signs: 
The potentially clinically significant value (PCSV) criteria are defined as abnormal values 
considered medically important by the Sponsor according to predefined criteria/thresholds based 
on literature review and defined by the Sponsor for clinical laboratory tests and vital signs. The 
PCSV criteria will be provided in the SAP. 
PCSV criteria will determine which subjects had at least 1 PCSV during the respective TEAE 
periods, taking into account all evaluations performed during the respective TEAE periods, 
including unscheduled or repeated evaluations. The number of all such subjects will be the 
numerator for the PCSV percentage.  
Analysis 
The incidence of PCSVs at any time during the TEAE period will be summarized regardless of the 
baseline level, and again in participants without PCSV in the corresponding category at baseline. 
Summary tables, 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. Summary of vital signs 
will be provided. 
Listings will be provided for subjects meeting PCSV criteria. 
Treatment Exposure 
The duration of study treatment exposure will be defined as day 1 through 4 weeks, ie, 28 days, 
after the last dose for a participant in the Q4W arms and day 1 through 12 weeks, ie, 84 days after 
the last dose for a participant in the Q12W arm. The duration of the study will be through the 
follow-up period defined as end of EAP through day 253 (±14 days). 
Treatment exposure and study duration will be evaluated in the SAF. 
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11.4.5.3. Treatment Compliance 
Participant treatment compliance in terms of total dose, number of doses, and number of SC 
injections will be summarized for each group. Compliance with study drug will be calculated as 
follows: 
Compliance (%) =100 ×
Number of actual injections
Number of planned injections. 
This will be presented by specific ranges for each group and the ranges of interest will be specified 
in the SAP. 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
The concentrations of casirivimab and imdevimab in serum over time will be summarized 
descriptively for each of the treatment groups by age group (subjects ≥12 years of age, ≥40 kg; 
and subjects ≥18 years of age). Associations between covariates that may impact PK of 
casirivimab and imdevimab and concentrations of the antibodies in serum may be evaluated as 
appropriate. 
No formal statistical hypothesis testing will be performed. 
11.4.7. 
Analysis of Immunogenicity Data 
The immunogenicity variables described in Section 5.5 will be summarized using descriptive 
statistics. Immunogenicity will be characterized by ADA status, ADA category, and maximum 
titer observed in participants in the AAS, and by NAb status observed in participants in the NSA. 
The ADA status of each participant 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 participant is classified as one of the following: 
• 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  
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Participants that are treatment-
emergent may be further categorized.  
The maximum titer category of each participant is classified as: 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000)  
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Listings of all ADA titer levels will be provided for participants with pre-existing, treatment-
emergent and treatment-boosted ADA response. The absolute occurrence (n) and percent of 
participants (%) with NAb status in the NAb analysis set will be provided by treatment groups. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on individual 
PK profiles evaluated. Assessment of impact of ADA and NAb on safety and efficacy may be 
provided. 
11.5. 
Interim Analysis 
This study will have planned interim analyses for efficacy. The primary objective of these interim 
analyses is the early detection of evidence of antibody efficacy (AbE) in arm 1, ie, 
casirivimab+imdevimab 1200 mg SC (day 1) then 600 mg SC Q4W compared to placebo and 
stopping for efficacy. 
To control the overall Type 1 error rate (false-positive rate) at 0.025 (1-sided) due to interim looks, 
the Lan-DeMets implementation of the O’Brien-Fleming alpha spending function will be used. 
The actual alpha spending will be based on the actual number of cases for the primary endpoint 
included in the analyses and the target total number of cases for the treatment arms being analyzed 
(see Table 6), as determined by the O’Brien-Fleming spending function at the time of interim 
analysis.  
An independent data monitoring committee (IDMC) will perform the interim analyses. If antibody 
efficacy is demonstrated at any interim analysis, the IDMC will inform the Sponsor’s management 
and may make recommendations to stop the study for efficacy. At the time of each interim analysis, 
a memo will be issued to document the data cutoff date. In the event that the first hypothesis test 
on the primary endpoint is met during interim or final analysis, all other pre-specified comparisons 
and endpoints will be analyzed at that time at all remaining alpha. 
In addition to the formal interim analyses for efficacy monitoring, the IDMC will also monitor for 
non-efficacy and safety, for which the guiding principles are stated in Section 6.5 and 
Section 6.8.1, with further details provided in the IDMC charter and the SAP. 
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study  
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE  
In accordance with ICH E6, the Sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.  
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, 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) system. 
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 – study drug supply 
• EDC system (data capture) – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
12.2. 
Study Monitoring  
12.2.1. 
Monitoring of Study Sites 
Regeneron uses a study-specific risk based approach to study monitoring and oversight, aligned 
with risk based quality principles, outlined in ICH E6 (R2) Guideline for Good Clinical Practice. 
Risk-Based Quality Monitoring (RBQM) methodology focuses on employing a fit-for-purpose 
monitoring strategy, supported either directly by Regeneron as Sponsor, or via our CRO partners. 
RBQM strategies include: reduced source data verification (SDV), targeted source data review 
(SDR), the use of off-site/remote and triggered on-site monitoring visits, and Centralized 
Monitoring to identify site level risks and study level trends. The Investigator must allow study-
related monitoring activities to occur. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of participants 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. 
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12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate participant records 
(source documents). The site is responsible to ensure quality within their records and systems and 
are accountable for ensuring that all source data and eCRF data are timely, accurate and complete. 
The Investigator must keep all source documents on file with the eCRF. Case report forms and 
source documents must be available at all times for inspection by authorized representatives of the 
Sponsor and regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (CRFs) within the EDC system by trained site personnel. All required eCRFs must be 
completed for each and every participant enrolled in the study. An unblinded site team member 
will enter study drug administration data in the EDC separately from blinded site team member, 
in order to maintain the blind. The Investigator must ensure the accuracy, completeness, and 
timeliness of the data reported to the Sponsor in the eCRFs. After review of the clinical data for 
each participant, the Investigator must provide an electronic signature. A copy of each participant 
eCRF casebook is to be retained by the Investigator as part of the study record and must be 
available at all times for inspection by authorized representatives of the Sponsor and regulatory 
authorities. 
Corrections to the eCRF will be entered in the eCRF by the Investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system. For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections  
This study may be participant 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 participant to audit or inspection include but are not limited to all source documents, 
eCRFs, medical records, correspondence, ICFs, IRB/EC files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities. Conditions of study material storage are also participant to 
inspection. In addition, representatives of the Sponsor may observe the conduct of any aspect of 
the clinical study or its supporting activities both within and outside of the Investigator's institution. 
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In all instances, the confidentiality of the data must be respected. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the Investigator. This signed declaration accompanies each set of participant’s 
final eCRF that will be provided to the Sponsor. 
12.4.2. 
Retention of Records 
The Investigator must retain all essential study documents, including ICFs, source documents, 
Investigator copies of eCRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The Investigator must obtain written approval from the Sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the Investigator's personal situation is such that archiving can no longer be ensured, the 
Investigator must inform the Sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
13. 
ETHICAL AND REGULATORY CONSIDERATIONS  
13.1. 
Good Clinical Practice Statement  
It is the responsibility of both the Sponsor and the Investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent and Assent 
The principles of informed consent are described in ICH guidelines for GCP. 
Due to disease severity, quarantine restrictions, and/or other reasons related to COVID-19, it may 
be necessary to implement temporary or alternative measures to obtain informed consent per 
procedures outlined in the investigator site file.  
The ICF used by the investigator must be reviewed and approved by the Sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the Sponsor before study drug will be shipped to the study site. 
Adult Participants 
For participants 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 
participant 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 participant in language that he/she can 
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understand. The ICF should be signed and dated by the participant and by the investigator or 
authorized designee who reviewed the ICF with the participant:  
• Participants who can write but cannot read will have the ICF read to them before 
signing and dating the ICF. 
• Participants 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 participant’s study record, and 
a copy of the signed ICF must be given to the participant. 
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 participants 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 participant’s study record and a copy must be given to the participant. 
Participants Under 18 Years of Age (or Under Country’s Legal Age of Adulthood) 
For participants 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 participant’s parent(s) or legal guardian(s) prior to the participant’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 participant’s parent(s) or legal guardian(s) can 
understand. The ICF should be signed and dated by the participant’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 
participant, as determined by the IRB/EC and in accordance with the local regulations and 
requirements: 
• Participants who can write but cannot read will have the assent form read to them before 
writing their name on the form 
• Participants 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 participant’s study 
record, and a copy of the signed assent form must be given to the participant’s parent(s) or legal 
guardian(s). 
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13.3. 
Participant Confidentiality and Data Protection 
The Investigator must take all appropriate measures to ensure that the anonymity of each study 
participant will be maintained. Participants should be identified by a participant identification 
number only, on eCRFs or other documents submitted to the Sponsor. Documents that will not be 
submitted to the Sponsor (eg, signed ICF) must be kept in strict confidence. 
The participant '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 participants 
(eg, advertising) before any participant may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the participant, 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 participants 
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.  
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15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The Sponsor has the right to terminate the study prematurely. Reasons may include efficacy, 
safety, or futility, among others. Should the Sponsor decide to terminate the study, the 
Investigator(s) will be notified in writing. 
15.2. 
Close-out of a Site 
The Sponsor and the Investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The Investigator must notify the Sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the Sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The Sponsor will notify the Investigator(s) of a decision to close-out a study site in writing. 
Reasons may include the following, among others:  
• The Investigator has received all items and information necessary to perform the study, 
but has not enrolled any participant 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 participants 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 participants’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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19. 
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784.e775. 
Horby PW, Mafham M, Peto L, Campbell M, Pessoa-Amorim G, Spata E, et al. Casirivimab and 
imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, 
controlled, open-label, platform trial. medRxiv 2021:2021.2006.2015.21258542. 
Lewis NM, Chu VT, Ye D, Conners EE, Gharpure R, Laws RL, et al. Household Transmission 
of SARS-CoV-2 in the United States. Clin Infect Dis 2020. 
Long QX, Liu BZ, Deng HJ, Wu GC, Deng K, Chen YK, et al. Antibody responses to SARS-
CoV-2 in patients with COVID-19. Nat Med 2020; 26(6):845-848. 
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Magyarics Z, Leslie F, Bartko J, Rouha H, Luperchio S, Schörgenhofer C, et al. Randomized, 
Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study of the Penetration of a 
Monoclonal Antibody Combination (ASN100) Targeting Staphylococcus aureus Cytotoxins in 
the Lung Epithelial Lining Fluid of Healthy Volunteers. Antimicrob Agents Chemother 2019; 
63(8). 
O’Brien MP, Forleo-Neto E, Musser BJ, Isa F, Chan K-C, Sarkar N, et al. Subcutaneous 
REGEN-COV Antibody Combination to Prevent Covid-19. New England Journal of Medicine 
2021a. 
O’Brien MP, Forleo-Neto E, Sarkar N, Isa F, Hou P, Chan K-C, et al. Subcutaneous REGEN-
COV Antibody Combination in Early SARS-CoV-2 Infection. medRxiv 
2021b:2021.2006.2014.21258569. 
O’Brien MP, Forleo Neto E, Musser BJ, Isa F, Chan K-C, Sarkar N, et al. Subcutaneous 
REGEN-COV Antibody Combination for Covid-19 Prevention. medRxiv 
2021c:2021.2006.2014.21258567. 
Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and Efficacy 
of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 2020; 383(27):2603-2615. 
REGEN-COV™ (casirivimab with imdevimab) [HCP Fact Sheet]. 2021; Regeneron 
Pharmaceuticals, Inc., Tarrytown, NY. https://www.regeneron.com/sites/default/files/treatment-
covid19-eua-fact-sheet-for-hcp.pdf. 
Sadoff J, Gray G, Vandebosch A, Cárdenas V, Shukarev G, Grinsztejn B, et al. Safety and 
Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N Engl J Med 2021; 
384(23):2187-2201. 
Shah DP, Ghantoji SS, Shah JN, El Taoum KK, Jiang Y, Popat U, et al. Impact of aerosolized 
ribavirin on mortality in 280 allogeneic haematopoietic stem cell transplant recipients with 
respiratory syncytial virus infections. Journal of Antimicrobial Chemotherapy 2013; 68(8):1872-
1880. 
Sonani B, Aslam F, Goyal A, Patel J,Bansal P. COVID-19 vaccination in immunocompromised 
patients. Clin Rheumatol 2021; 40(2):797-798. 
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT,Veesler D. Structure, Function, and 
Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 2020; 181(2):281-292.e286. 
Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, et al. REGEN-COV 
Antibody Cocktail in Outpatients with Covid-19. medRxiv 2021a:2021.2006.2009.21257915. 
Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, et al. REGEN-COV 
Antibody Cocktail Clinical Outcomes Study in Covid-19 Outpatients. medRxiv 
2021b:2021.2005.2019.21257469. 
WHO. Laboratory testing of 2019 novel coronavirus (2019-nCoV)in suspected human cases: 
interim guidance, 17 January 2020. https://www.who.int/publications/i/item/laboratory-testing-
of-2019-novel-coronavirus-(-2019-ncov)-in-suspected-human-cases-interim-guidance-17-
january-2020. Published 2020. 
Wollacott AM, Boni MF, Szretter KJ, Sloan SE, Yousofshahi M, Viswanathan K, et al. Safety 
and Upper Respiratory Pharmacokinetics of the Hemagglutinin Stalk-Binding Antibody VIS410 
Support Treatment and Prophylaxis Based on Population Modeling of Seasonal Influenza A 
Outbreaks. EBioMedicine 2016; 5:147-155. 
 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol, A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of Anti-Spike SARS-CoV-2 Monoclonal Antibodies as 
Pre-Exposure Prophylaxis to Prevent COVID-19 in Immunocompromised Participants, and agree 
to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved. I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
 (Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
 
Study Title: 
 A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Anti-Spike SARS-CoV-2 Monoclonal Antibodies as Pre-Exposure 
Prophylaxis to Prevent COVID-19 in Immunocompromised Participants 
 
Protocol Number: 
R10933-10987-COV-2176 
Protocol Version:  
OriginalAmendment 2 US 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
                                        VV-RIM-00181183-1.0 Approved - 25 Jan 2022 GMT-5:00


Signature Page for VV-RIM-00181183 v1.0
Signature Page for VV-RIM-00181183 v1.0 Approved
Approval/eSignature
25-Jan-2022 15:24:05 GMT+0000
Approval/eSignature
25-Jan-2022 15:33:18 GMT+0000
Approval/eSignature
25-Jan-2022 16:34:45 GMT+0000
Approval/eSignature
25-Jan-2022 22:51:57 GMT+0000
                                        VV-RIM-00181183-1.0 Approved - 25 Jan 2022 GMT-5:00

SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
REGENERON CONFIDENTIAL 
Page 1 of 46 
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 3, Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy 
and Safety of Anti-Spike SARS-CoV-2 Monoclonal Antibodies as Pre-exposure Prophylaxis 
to Prevent COVID-19 in Immunocompromised Participants 
Compound: 
Casirivimab+Imdevimab (REGEN-COV; REGN10933+REGN10987) 
Protocol Number: 
R10933-10987-COV-2176 
Clinical Phase:  
Phase 3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Trial Manager: 
 
Study Medical Directors: 
 
 
Version/Date: 
Original (Version 1.0) / 15 JUN 2022 
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Regeneron Pharmaceuticals, Inc. 
 
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Statistical Analysis Plan 
 
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REGENERON CONFIDENTIAL 
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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 
 
 
 
 
See appended electronic signature page 
 
             
 
 
 
See appended electronic signature page 
 
  
 
 
 
 
See appended electronic signature page 
 
                           
 
 
 
See appended electronic signature page 
  
   
 
 
 
See appended electronic signature page 
 
                           
 
 
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Statistical Analysis Plan 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................7 
1.1. 
Background/Rationale ..................................................................................................7 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objectives .....................................................................................................11 
1.2.2. 
Secondary Objectives .................................................................................................11 
1.2.3. 
Exploratory Objectives ...............................................................................................11 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................12 
1.2.5. 
Revision History for SAP Amendments .....................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ..............................................................................13 
2.2. 
Sample Size and Power Considerations .....................................................................13 
2.3. 
Study Plan ...................................................................................................................13 
3. 
ANALYSIS POPULATIONS ....................................................................................14 
3.1. 
The Efficacy Analysis Sets .........................................................................................14 
3.2. 
Safety Analysis Set .....................................................................................................14 
3.3. 
Pharmacokinetic Analysis Set ....................................................................................14 
3.4. 
Immunogenicity Analysis Sets ...................................................................................14 
4. 
ANALYSIS VARIABLES .........................................................................................16 
4.1. 
Demographic and Baseline Characteristics ................................................................16 
4.2. 
Medical History ..........................................................................................................16 
4.3. 
Concomitant Medication/Procedures ..........................................................................16 
4.4. 
Prohibited Medication During Study and Post-Infection treatment ...........................17 
4.4.1. 
Prohibited Medication During Study ..........................................................................17 
4.4.2. 
Post-Infection treatment ..............................................................................................17 
4.5. 
Efficacy Variable ........................................................................................................18 
4.5.1. 
Primary Efficacy Variable ..........................................................................................18 
4.5.2. 
Other Efficacy Variable(s) ..........................................................................................19 
4.6. 
Safety Variables ..........................................................................................................20 
4.6.1. 
Adverse Events, Serious Adverse Events ...................................................................20 
4.6.2. 
Adverse Events of Special Interest .............................................................................20 
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4.6.3. 
Vital Signs and Laboratory Tests ...............................................................................20 
4.7. 
Pharmacokinetic Variables .........................................................................................20 
4.8. 
Immunogenicity Variables ..........................................................................................20 
5. 
STATISTICAL METHODS .......................................................................................21 
5.1. 
Demographics and Baseline Characteristics ...............................................................21 
5.2. 
Medical History ..........................................................................................................21 
5.3. 
Prior/concomitant Medications ...................................................................................21 
5.4. 
Prohibited Medications if applicable ..........................................................................21 
5.5. 
Subject Disposition .....................................................................................................21 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................22 
5.6.1. 
Measurement of Compliance ......................................................................................22 
5.6.2. 
Exposure to Investigational Product ...........................................................................22 
5.7. 
Analyses of Efficacy Variables ..................................................................................23 
5.7.1. 
Analysis of Primary Efficacy Endpoint ......................................................................23 
5.7.2. 
Analysis of Secondary Efficacy Endpoints ................................................................23 
5.7.3. 
Analysis of Other Exploratory Endpoints ...................................................................23 
5.7.4. 
Adjustment for Multiple Comparison .........................................................................24 
5.8. 
Analysis of Safety Data ..............................................................................................24 
5.8.1. 
Adverse Events ...........................................................................................................24 
5.8.2. 
Clinical Laboratory Measurements.............................................................................25 
5.8.3. 
Analysis of Vital Signs and Safety Laboratory Measures ..........................................25 
5.8.4. 
Analysis Other Safety Variables .................................................................................26 
5.9. 
Analysis of Pharmacokinetic Data ..............................................................................26 
5.10. 
Analysis of Immunogenicity Data ..............................................................................26 
5.10.1. 
Analysis of ADA data: ................................................................................................26 
5.10.2. 
Analysis of Neutralizing Antibody (NAb) Data .........................................................28 
5.11. 
Association of Immunogenicity with Exposure and Safety .......................................28 
5.11.1. 
Immunogenicity and Exposure ...................................................................................28 
5.11.2. 
Immunogenicity and Safety ........................................................................................28 
6. 
DATA CONVENTIONS ............................................................................................29 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................29 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................29 
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6.3. 
Data Handling Convention for Missing Data .............................................................29 
6.4. 
Visit Windows ............................................................................................................29 
6.5. 
Pooling of Centers for Statistical Analyses ................................................................31 
6.6. 
Statistical Technical Issues .........................................................................................32 
7. 
INTERIM ANALYSIS ...............................................................................................33 
8. 
SOFTWARE ...............................................................................................................34 
9. 
REFERENCES ...........................................................................................................35 
10. 
APPENDIX.................................................................................................................36 
10.1. 
Schedule of Time and Events .....................................................................................37 
10.2. 
Broad Term Definition of COVID-19 Signs and Symptoms .....................................45 
10.3. 
NCI-CTCAE Severity Grading (v5.0) for Anaphylaxis, Allergic Reactions, 
and Injection-Site Reactions .......................................................................................46 
 
LIST OF TABLES 
Table 1: 
Efficacy Analysis Windows for Unscheduled Visits with RT-qPCR or Viral 
Load Results ...............................................................................................................30 
Table 2: 
Global Analysis Windows for Data Other Than RT-qPCR Test ................................31 
Table 3: 
Schedule of Events (No Longer Applicable as of Protocol Amendment 2) ...............37 
Table 4: 
Schedule of Events for Study Close-Out (Protocol Amendment 2; Applies to 
All Enrolled Participants) ...........................................................................................42 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation  
Definition 
 
ADA   
 
Anti-drug antibody 
AE   
 
Adverse event 
AESI  
 
Adverse event of special interest 
CI  
 
 
Confidence interval 
CRF   
 
Case report form (electronic or paper) 
CRO   
 
Contract research organization 
EC   
 
Ethics Committee 
EDC   
 
Electronic data capture 
FDA   
 
US Food and Drug Administration 
GCP   
 
Good Clinical Practice 
ICF   
 
Informed consent form 
ITT   
 
Intention-to-treat 
ICH   
 
International Council for Harmonisation 
IRB   
 
Institutional Review Board 
IV  
 
 
Intravenous 
IVIG   
 
Intravenous immunoglobulin 
mITT  
 
Modified intention-to-treat 
NAb   
 
Neutralizing antibody 
NCI-CTCAE   
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NP   
 
Nasopharyngeal 
PCSV  
 
Potentially clinically significant value 
PK   
 
Pharmacokinetic 
Q4W   
 
Every 4 weeks 
Q12W  
 
Every 12 weeks 
Regeneron  
 
Regeneron Pharmaceuticals, Inc. 
RBQM  
 
Risk-Based Quality Monitoring 
SAE   
 
Serious adverse event 
SAP   
 
Statistical analysis plan 
SAS   
 
Statistical Analysis System 
SC  
 
 
Subcutaneous 
SCIG  
 
Subcutaneous immunoglobulin 
SOC   
 
System organ class 
SUSAR  
 
Suspected unexpected serious adverse reaction 
TEAE  
 
Treatment-emergent adverse event 
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Statistical Analysis Plan 
 
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1. 
OVERVIEW 
This is a randomized, double-blind, placebo-controlled, phase 3 study to assess the safety and 
efficacy of anti-SARS-CoV-2 mAb therapy, casirivimab+imdevimab as pre-exposure 
prophylaxis against symptomatic COVID-19 in immunocompromised individuals, defined 
according to the primary and secondary immunodeficiencies outlined in the study eligibility 
criteria. 
Regeneron decided to close enrollment of the COV-2176 Study on Dec 16 2021. This was based on 
several factors, including the recent Emergency Use Authorization of an alternative therapy in pre-
exposure prophylaxis as well as emerging evidence surrounding Variants of Concern (VOC). While 
casirivimab+imdevimab retains activity against other known VOCs, including Delta, which was the 
most prevalent variant in the U.S., it has diminished potency against Omicron. Consequently, 
Regeneron stopped recruitment into this study.  
 
As a result of the early termination of the study, the objectives could not be achieved and none of the 
hypotheses are evaluable.  Although this SAP refers to primary and secondary endpoints and 
objectives based on their description in the protocol, these have all been designated exploratory due 
to the early termination. 
1.1. 
Background/Rationale 
Study R10933-10987-COV-2176 was terminated early by the Sponsor due to the high frequency 
of the Omicron variant and reduced neutralization potency of casirivimab+imdevimab against 
the Omicron variant. The study is not being terminated due to any safety concerns, nor from any 
data obtained in this study. The protocol amendment 2 followed the sponsor’s decision to close 
enrollment early and the study was revised to allow one optional dose and obtain final safety 
assessments.  
Optional Dose 
Casirivimab+imdevimab may continue to serve as an important pre-exposure prophylaxis 
therapeutic among immunocompromised individuals in regions where Omicron is not the 
dominant variant or in regions where Omicron prevalence subsides. For this reason, participants 
will have the option to receive a 1200 mg SC dose of casirivimab+imdevimab as a final study 
dose. This optional dose may be administered to all participants regardless of treatment 
assignment at randomization. However, participants will not be eligible to receive this dose if 
they have already received casirivimab+imdevimab as post-infection treatment. 
Participants will be asked to return to the site for an unscheduled visit, during which they will be 
asked to consent to protocol amendment 2 and receive the final optional dose, if desired. This 
visit to receive the final optional dose should occur approximately 4 weeks after the most recent 
dose. Note that consent may be obtained remotely prior to this visit, if available and allowable by 
the study site. 
Procedures in the Event of Suspected COVID-19 
Participants with suspected COVID-19 may undergo an optional visit to evaluate symptoms by a 
study clinician (investigator or designee) and to undergo laboratory testing of SARS-CoV-2, as 
detailed in the new schedule of events (protocol amendment 2 Table 2). This optional visit 
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should occur as soon as possible (within 48 hours of symptom onset, if feasible). Note that 
clinician assessment of sign or symptoms may occur remotely. If remote assessment is 
performed, a confirmatory site visit for laboratory testing of SARS-CoV-2 can optionally occur 
after a clinician deems that the signs or symptoms are related to COVID-19. 
Clinical Evaluation:  
Signs and symptoms will be evaluated by a clinician (investigator or designee, evaluation may 
occur remotely) as described below (in the Documentation of Clinical Evaluation section). If the 
clinician confirms that at least one sign or symptom is potentially related to COVID-19, samples 
may be collected to perform both local and central testing for SARS-CoV-2 infection. 
Laboratory Testing of SARS-CoV-2: 
Local testing must be performed by RT-PCR using local sample collection and assay standards. 
A nasopharyngeal (NP) swab sample is the preferred sample type, but other samples (eg, nasal, 
oropharyngeal, saliva) adhering to local standards are acceptable. An additional NP swab sample 
will be collected for the purposes of central RT-qPCR testing. The samples will be collected 
prior to any administration of post-infection treatment (described below). The qualitative result 
of the central RT-qPCR will be reported back to the corresponding study site. SARS-CoV-2 viral 
genome sequencing will be performed using NP swab samples collected during the study that 
have been confirmed positive by RT-qPCR at the central laboratory. 
Documentation of Clinical Evaluation. For each symptom, the start (onset) date, end date, and 
severity will be recorded (mild, moderate, severe) in the participant’s medical record (source 
document). It is important to record this information in the source document, to ensure that the 
temporal dimensions of each sign or symptom are captured. 
The following information may subsequently be recorded in EDC as applicable: 
• The sign or symptom, with start (onset) calendar date, end calendar date, and severity 
(mild, moderate, severe) 
• Confirmatory local RT-PCR test result and date of sample collection 
• Confirmatory central RT-qPCR test result and date of sample collection 
• Weekly central RT-qPCR test results and dates of sample collection 
• Record of any post-infection treatment with casirivimab+imdevimab administered 
Note that any sign or symptom considered by the investigator to be unrelated to baseline 
conditions and unrelated to treatments for baseline conditions will also be recorded and used for 
safety evaluation. 
Post-Infection Treatment. Participants with confirmed positive SARS-CoV-2 RT-PCR will be 
eligible for post-infection treatment (as described in protocol Section 6.4.4) at any time prior to 
receipt of the optional 1200mg SC dose (eg, during the 4 weeks between receipt of the last 
protocol-defined dose and optional 1200 mg SC dose). Once this optional dose has been 
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administered, post-infection treatment will no longer be offered. Likewise, any participant who 
receives post-infection treatment will not be eligible to receive the optional 1200 mg SC dose. 
Participants with Positive SARS-COV-2 RT-PCR. Participants with a positive SARS-CoV-2 RT-
PCR may have additional assessments and sample collections, including unscheduled visits 
every 7 
days (±1 day) for central laboratory RT-qPCR analysis until 2 consecutive negative test results 
are obtained: 
• NP swab samples for RT-qPCR 
• COVID-19 signs and symptoms evaluated by the investigator or designee 
• Information regarding COVID-19-related medically-attended visits (MAVs; defined in 
protocol Section 9.2.4.3) 
End-of-Study Visit 
All participants, including those who do not consent to receive the optional final dose, will have 
a follow-up (end-of-study) telephone visit approximately 85 days (3 months) from their last dose 
of investigational drug (casirivimab+imdevimab or placebo) to monitor safety. Study 
assessments for the 3-month follow-up visit will be limited to the collection of targeted adverse 
events, as detailed in the new schedule of events (protocol amendment 2 Table 2). 
Sites will ensure that an additional discussion about the potential risks and benefits to the 
participant and fetus is discussed as part of re-consent for participants who become pregnant 
during the study. 
Analysis Plan 
At the time that enrollment was closed, 66 participants had been enrolled in the study. Due to the 
early study closure and the resulting small sample size of enrolled participants, all analyses will 
be performed descriptively and only numeric comparisons will be performed. All safety 
endpoints (including AEs, TEAEs, AESIs, SAEs, and safety laboratory values) will be 
summarized. Selected efficacy, virology, PK, and/or immunogenicity data may also be analyzed 
descriptively.  No interim analysis will be performed for this study, and no IDMC review 
meetings will occur. 
The study consists of three periods: a screening period of up to 14 days, an efficacy assessment 
period (EAP) of approximately 6 months (precise definition below), and a 3-month follow-up 
period.  
The primary endpoint of the study will evaluate symptomatic SARS-CoV-2 infection cases. The 
conditions for symptomatic SARS-CoV-2 infection are as follows: 
• At least 1 sign or symptom (broad term definition) confirmed by a study clinician 
(investigator or designee) to be related to COVID-19, and  
• A positive SARS-CoV-2 RT-PCR result (local or central analysis), with 
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• The sign/symptom onset date and the date of collection for the positive sample 
occurring within ±7 days of one another 
The primary endpoint will analyze symptomatic SARS-CoV-2 infection during the efficacy 
assessment period (EAP).  
Broad Term COVID-19 signs and symptoms include fever ≥38.0°C as well as 23 symptoms 
designed to be consistent with the Symptom Evolution of COVID-19 (SE-C19) instrument 
developed by the Sponsor. 
Participants will be monitored for suspected COVID-19 symptoms throughout the study. Those 
with suspected COVID-19 will be evaluated by a study clinician for signs and symptoms of 
COVID-19 and will have RT-PCR testing to confirm SARS-CoV-2 infection. 
The double-blind design serves to reduce potential bias introduced by knowing the study drug 
assignment. The comparator arm in this study will be placebo, as no approved or authorized pre-
exposure preventative treatments were available at time of study initiation in the regions where 
the study is being conducted. 
Study Population 
In the absence of a universal clinical definition, this study will define an immunocompromised 
state according to a discrete set of primary and secondary immunodeficiencies used as eligibility 
criteria.  
Double Blind Design 
The double-blind design serves to reduce potential bias introduced by knowing the study drug 
assignment. The comparator arm in this study will be placebo, as no approved or authorized pre-
exposure preventative treatments are currently available at time of study initiation in the regions 
where the study is being conducted. 
Efficacy Analysis Sets 
The intent-to-treat (ITT) population is defined as all randomized participants. 
The primary analysis population for efficacy will be the modified intent-to-treat (mITT) 
population, defined as all randomized participants who received at least one dose of the study 
drug and at baseline (day 1):  
1. Have tested negative by RT-qPCR (central lab results), and  
2. Have central serology test result (ElecSys® anti-S RBD total Ig) ≤50 U/mL 
Participants who are deemed medically ineligible or contraindicated to receiving a full course of 
standard-of-care COVID-19 vaccine will also be included in the mITT. 
Primary Efficacy Analysis 
The EAP is defined as the day 2 to day 169 visit. The cumulative incidence of cases through the 
EAP will be estimated using the Kaplan-Meier method, and the antibody efficacy (AbE) will be 
estimated as the percent risk reduction (ie, 100 x [1-HR), where HR is the hazard ratio for 
comparison of the incidence of cases in the antibody arm versus placebo). A unstratified Cox 
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proportional hazard regression model with treatment group as a fixed effectwill be used to 
estimate the hazard ratio and 95% CI (2-sided).  
For the primary analysis, cases will be counted from day 2 through day 176 (ie, day 169 +7 
days), to allow for cases to accrue until the end of the EAP visit window per the Schedule of 
Events. Time of symptomatic SARS-CoV-2 infection will be the earlier of the sign/symptom 
onset date or the sample collection date for which RT-PCR result (local or central) was positive.  
Safety Analyses 
For safety variables, the following observation periods are defined: 
The pretreatment period is defined as the time from the signing of the ICF to before study drug 
administration. 
The EAP is defined as the day from first dose of study drug to day 169 ± 7 days 
The Follow-up period is defined as the end of the EAP to the end of the Follow-up Period (ie, the 
last study visit).  
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition.  
Per protocol amendment 2, this study will collect all clinical and laboratory TEAEs that are not 
related to the patient's underlying (non-COVID) disease and/or not related to treatments for the 
underlying conditions. 
Other Safety Analyses  
Vital Signs, Laboratory Tests, treatment exposure, and treatment compliance analyses will be 
performed.  
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective of the study is to evaluate the effect of casirivimab+imdevimab, compared 
with placebo, in preventing symptomatic SARS-CoV-2 infection in immunocompromised 
participants. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the safety and tolerability of repeated SC injections of 
casirivimab+imdevimab in the study population 
• To characterize concentrations of casirivimab and imdevimab in serum over time 
• To assess the immunogenicity of casirivimab and imdevimab 
1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
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• To evaluate additional indicators of casirivimab+imdevimab clinical efficacy and 
disease prevention compared to placebo 
• To evaluate the effect of casirivimab+imdevimab, compared to placebo, in preventing 
SARS-CoV-2 infection with elevated viral load 
• To explore biomarkers predictive and/or indicative of safety and/or efficacy of 
casirivimab+imdevimab, COVID-19 vaccine response, SARS-CoV-2 infection and 
immune response, COVID-19 disease progression and clinical outcomes of 
casirivimab+imdevimab 
• To explore the effect of baseline immune response to COVID-19 vaccination on 
response to casirivimab+imdevimab and clinical outcomes 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
Some exploratory efficacy endpoints listed in protocol amendment 2 will not be reported.  
1.2.5. 
Revision History for SAP Amendments 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a randomized, double-blind, placebo-controlled, phase 3 study to assess the safety and 
efficacy of anti-SARS-CoV-2 mAb therapy, casirivimab+imdevimab as pre-exposure 
prophylaxis against symptomatic COVID-19 in immunocompromised individuals, defined 
according to the primary and secondary immunodeficiencies outlined in the study eligibility 
criteria.  The study consists of three periods: a screening period of up to 14 days, an efficacy 
assessment period (EAP) of approximately 6 months and a 3-month follow-up period. A diagram 
depicting the study design is provided in the protocol. In addition to the main study, an optional 
immunology sub-study will be conducted outside of the protocol. 
Participants were randomized according to a central randomization scheme using an interactive 
web response system (IWRS).  
Randomization were stratified according to age categories (<18 years, ≥18 to ≤65 years, >65 
years), region (US only), and use of stable IVIG or SCIG regimen prior to screening (yes, no). 
Prior to closing enrollment early, 66 subjects (about 16~17 subjects per treatment group) were 
recruited and randomized from US sites. 
2.2. 
Sample Size and Power Considerations 
The trial was terminated by sponsor early and the actual sample size for the study was not driven 
by the number of cases to demonstrate the efficacy of the antibody arm, compared to placebo, in 
preventing symptomatic (broad term), RT-PCR-confirmed SARS-CoV-2 infection in 
immunocompromised participants. 
The planned number of cases needed to detect the target antibody efficacy and corresponding 
power with log-rank test are not reached for this study due to early study termination. There’s no 
interim analyses for this study. Study power may not be reached due to early termination.  
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. 
The Efficacy Analysis Sets 
The intent-to-treat (ITT) population is defined as all randomized participants. 
The primary analysis population for efficacy will be the modified intent-to-treat (mITT) 
population, defined as all randomized participants who received at least one dose of the study 
drug and at baseline (day 1):  
• Have tested negative by RT-qPCR (central lab results), and  
• Have central serology test result (Elecsys® anti-S RBD total Ig) ≤50 U/mL 
Analysis will be performed according to the study drug allocated (as randomized). 
ITT will be used to summarize demographics and baseline characteristics of participants.  
3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all participants 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,. Treatment compliance/administration and all clinical safety variables will 
be analyzed using the SAF. 
3.3. 
Pharmacokinetic Analysis Set 
The PK analysis set is defined for each study drug separately, includes all participants who 
received active study drug, and who had at least 1 non-missing result of each respective analyte 
following the first dose of respective study drug. Participants will be analyzed based on the 
actual treatment received (as treated) rather than as randomized. 
Participants who test positive for SARS-CoV-2 infection during the treatment period and 
discontinue study drug may be analyzed separately. 
3.4. 
Immunogenicity Analysis Sets 
The ADA analysis sets (AAS) are defined for each study drug separately and include all 
participants who received any amount of study drug (active or placebo [safety analysis set]) and 
had at least one non-missing ADA result following the first dose of the respective study drug or 
placebo. The AAS are based on the actual treatment received (as treated) rather than as 
randomized. 
The NAb analysis sets (NAbAS) are defined for each study drug separately and include all 
treated participants (active or placebo) that are included in the ADA analysis set and that tested 
negative at all ADA sampling times or tested positive at one or more post-dose ADA sampling 
times and had at least one non-missing post-dose NAb result (either imputed or analysis result). 
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Samples that tested negative for ADA are not assayed in the NAb assay and the corresponding 
NAb results are imputed as negative and included as such in the NAb analysis set. Participants in 
the NAbAS with multiple post-dose ADA results which consist of both imputed NAb-negative 
result(s) for ADA negative samples and only missing NAb results for all ADA-positive result(s), 
are set to NAb negative. Participants in the NAbAS that have at least one post-dose positive NAb 
analysis result are set to NAb positive even if other NAb results are missing. 
 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic variables will be summarized:  
• Age at screening (year) 
• Age groups for PK: ≥12 years and ≥40kg to <18 years; ≥18 years 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Region (US) 
• Ethnicity (Hispanic/Latino) 
• Baseline Weight 
• Baseline Body mass index (BMI) calculated from weight and height 
• Use of stable IVIG or SCIG regimen prior to screening  
• Baseline serology status and baseline median serology value from central lab  
• Baseline viral load from central lab (copies/ml; log10 copies/ml) 
• Baseline local RT-PCR qualitive results (U/mL) 
4.2. 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA®).Medical history will include, but not be limited to the following: 
• Prior COVID-19 infection 
• COVID-19 vaccination record 
• Menopausal history 
• Pregnancy or breastfeeding status, if applicable 
4.3. 
Concomitant Medication/Procedures 
Medications will be coded using the WHO Drug Dictionary (WHODD, Drug Global version 
SEP2020 B3).  
This includes medications that were started before the initiation of study treatment and are 
ongoing during the treatment-emergent EAP.  
. 
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4.4. 
Prohibited Medication During Study and Post-Infection treatment 
4.4.1. 
Prohibited Medication During Study 
The following concomitant medications are prohibited and may result in permanent 
discontinuation of study drug: 
• Investigational, authorized, or approved COVID-19 vaccines within 90 days of the 
last dose of study drug (or per current CDC recommendations 2021) 
• Investigational or approved passive antibodies for SARS-CoV-2 infection (eg, 
convalescent plasma or sera, monoclonal antibodies, hyperimmune globulin), 
remdesivir, or other anti-SARS-CoV-2 agents when used as prophylaxis 
4.4.2. 
Post-Infection treatment 
.The following investigational dose levels will be offered as part of the study, and may be 
provided if medically indicated in the investigator’s judgement:  
• Not hospitalized due to COVID-19 and does not require supplemental oxygen or an 
increase in baseline oxygen flow rate due to COVID-19: 1200 mg (600 mg per mAb), 
administered either intravenously or subcutaneously 
• Hospitalized due to COVID-19 and does not require supplemental oxygen due to 
COVID-19, or requires low-flow supplemental oxygen due to COVID-19: 2400 mg 
(1200 mg per mAb), administered intravenously 
• Hospitalized due to COVID-19 and requires either high-intensity supplemental 
oxygen due to COVID-19 or requires mechanical ventilation due to COVID-19: 
8000 mg (4000 mg per mAb), administered intravenously 
Administration of post-infection treatment with casirivimab+imdevimab will not require 
unblinding of the participant’s randomization assignment. 
Participants with a positive SARS-CoV-2 RT-PCR (from either local or central testing) will 
discontinue the study drug assigned at randomization and enter the follow-up period. This 
includes any participant for whom post-infection treatment with casirivimab+imdevimab was 
offered but was declined by the participant or investigator, or otherwise not received. 
All participants with a positive SARS-CoV-2 RT-PCR will have additional assessments and 
sample collections, as noted in the Schedule of Events and summarized below): 
• NP swab samples will be collected during unscheduled visits every 7 days (±1 day) 
for central laboratory RT-qPCR analysis until 2 consecutive negative test results are 
obtained. During these visits, COVID-19 signs and symptoms will also be evaluated 
by the investigator or designee. 
• Information regarding COVID-19-related medically-attended visits (MAVs) will be 
recorded, and participants will be asked to notify study personnel as soon as possible 
about such occurrences.  
 
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4.5. 
Efficacy Variable 
4.5.1. 
Primary Efficacy Variable  
Primary efficacy variable is cumulative incidence of symptomatic (broad term), RT-PCR-
confirmed SARS-CoV-2 infection cases during the efficacy assessment period (EAP).The 
conditions for symptomatic SARS-CoV-2 infection are as follows: 
• At least 1 sign or symptom (broad term definition) confirmed by a study clinician 
(investigator or designee) to be related to COVID-19, and  
• A positive SARS-CoV-2 RT-PCR result (local or central analysis), with 
• The sign/symptom onset date and the date of collection for the positive sample 
occurring within ±7 days of one another 
The primary endpoint will analyze symptomatic SARS-CoV-2 infection during the efficacy 
assessment period (EAP). The EAP is defined as the day 2 to day 169 +7 days . In addition, 
following rules will be applied to the primary analyses: 
• Time to first symptotic infection is defined as the first date of having either central or 
local lab deterimined positive test result.  
• Subjects do not experience any symptotic infection will be censored at last observed 
time point.  
• Subjects who die at any time in the study or discontinue the study earlier (did not get 
any infections) will be censored at the end of study in case of final database lock.  
• Subjects with COVID-19 symptoms that are missing a central lab determined RT-
qPCR test during the EAP  but have a positive SARS-COV-2 test from a local lab 
will be considered as having a symptomatic infection if any of the symptoms 
occurred within 7 days of the positive SARS-COV-2 test that was observed during 
the EAP.  
• If subjects took optional dose of 1200mg, all the data after the dose will be removed 
from the efficacy analyses.  
If subjects took investigational, authorized, or approved COVID-19 vaccines within 90 days of 
the last dose of study drug (or per current CDC recommendations) (CDC, 2021) or any covid-19 
treatment medications for prevention after starting study treatment (Anti SARS-CoV-2 
antibodies including Bamlanivimab/ Etesevimab, Casirvimab/ Imdevimab (REGEN-COV), 
Sotrovimab or Tixagevimab/ Cilgavimab (Evusheld); remdesivir; Nirmatrelvir/ Ritonavir 
(Paxlovid); Molnupiravir, all the efficacy data after these treatment will be removed from 
efficacy analyses. 
Broad Term COVID-19 signs and symptoms include fever ≥38.0°C as well as 23 sign/symptoms 
designed to be consistent with the Symptom Evolution of COVID-19 (SE-C19) instrument 
developed by the Sponsor. Broad term signs and symptoms are listed in the appendix 10.2 . 
 
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4.5.2. 
Other Efficacy Variable(s) 
The exploratory efficacy variables are: 
1. Cumulative incidence of symptomatic (broad term), RT-PCR-confirmed SARS-CoV-2 
infection cases during the follow-up period is defined as time to first symptomatic 
infection (RT-PCR-confirmed SARS-CoV-2 ) during the follow-up period. Similar rules 
to primary efficacy variable are applied to this variable.   
2. Cumulative incidence of RT-PCR-confirmed SARS-CoV-2 infection cases (regardless of 
symptoms) during the EAP is defined as time to first RT-PCR-confirmed SARS-CoV-2 
infection cases (regardless of symptoms) during the EAP. Similar rules to primary 
efficacy variable are applied to this variable. 
3. Proportion of participants with COVID-19-related hospitalization, emergency room visit, 
urgent care center visit or death during the EAP and follow-up period is defined as 
number of participants with COVID-19-related hospitalization, emergency room visit, 
urgent care center visit or death during the EAP and follow-up period divided by total 
number of participants of interest. 
4. Maximum SARS-CoV-2 RT-qPCR viral load (log10 copies/mL) in NP swab samples 
among individuals with ≥1 RT-qPCR positive test that has an onset during the EAP is 
defined as the maximum value of viral load (log10 copies/mL) among all the NP swab 
samples from individuals with ≥1 RT-qPCR positive test that has an onset during the 
EAP. 
5. Viral variant characteristics of SARS-CoV-2 in participants who become infected post-
baseline 
 
 
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4.6. 
Safety Variables 
4.6.1. 
Adverse Events, Serious Adverse Events  
For safety variables, the following observation periods are defined: 
•The pretreatment period is defined as the time from the signing of the ICF to before study drug 
administration. 
•The EAP is defined as the day from first dose of study drug to day 169 ± 7 days 
•The Follow-up period is defined as the end of the EAP to the end of the Follow-up Period (ie, 
the last study visit). 
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition. 
This study will collect data on the following targeted TEAEs: Grade ≥3 AEs, AEs leading to 
discontinuation, SAEs, grade ≥2 hypersensitivity reactions, and grade ≥3 injection-site reactions. 
4.6.2. 
Adverse Events of Special Interest  
Adverse Events of Special Interest (AESI) is defined as: 
− Grade ≥2 hypersensitivity reactions 
− Grade ≥3 injection-site reactions 
4.6.3. 
Vital Signs and Laboratory Tests 
Standard vital signs including body temperature, blood pressure, and heart rate, comprehensive 
vital sign assessment including additionally include SpO2 and respiratory rate will be collected. 
Temperature and SpO2 will be collected. Local safety laborary tests collect absolute neutrophil 
count, platelet count, hemoglobin, ALT, AST, total bilirubin, and creatineine at baseline visit as 
well as study visits days 29,85 and 169.  
4.7. 
Pharmacokinetic Variables  
The pharmacokinetic variables are concentrations of casirivimab and imdevimab in serum and 
time. The sampling time points are specified in Table 1 of the protocol. 
4.8. 
Immunogenicity Variables 
The immunogenicity variables include ADA status, titer, and NAb status at nominal sampling 
time/visit. Serum samples for ADA will be collected at the clinic visits specified in the protocol 
SOE. Samples positive in the ADA assay will be further characterized for ADA titers and for the 
presence of NAb. 
 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, 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 
The variables for baseline characteristics include standard demography and other baseline 
summaries of efficacy variables will be displayed for each treatment group and all participant 
combined.  
5.2. 
Medical History 
Summary for each treatment group and all participant combined will be provided. 
5.3. 
Prior/concomitant Medications  
Prior /concomitant illnesses and medications will be summarized based on the safety population. 
Any treatment or procedure administered from the time of the first dose of study drug to the final 
study visit will be recorded as concomitant medication or concomitant procedure. This includes 
medications or procedures that were started before the study and are ongoing during the study. 
Medications will be coded to the ATC level 2 (therapeutic main group) and ATC level 4 
(chemical/therapeutic subgroup) and summarized Subjects will be counted once in all 
ATC categories linked to the medication. Concomitant medications/procedures during EAP: 
medications taken or procedures performed in the period from the day of the first dose of study 
drug up to D176 or to the last visit if a subject discontinue from the study, whichever is earlier. 
This includes medications that were started before the initiation of study treatment and are 
ongoing during the EAP. Concomitant medications/procedures during the follow-up period: 
medications taken, or procedures performed from the day after the end of EAP to the final study 
visit or started during the treatment-emergent EAP and are ongoing after EAP. 
5.4. 
Prohibited Medications if applicable 
Prohibited medications will be summarized based on ITT under protocol deviations. Listing of 
prohibited medications described in the protocol will be provided for subjects under protocol 
deviations. 
5.5. 
Subject Disposition 
Subject study status will be summarized by treatment group and overall for the study. 
The following will be provided: 
• Number of screened subjects, defined as signed the ICF 
• Number of randomized subjects 
• Number of subjects randomized but who did not receive study treatment 
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• Number of subjects who discontinued the study, and the reasons for discontinuation 
• A listing of subjects treated but not randomized, subjects randomized but not treated, 
and subjects randomized but not treated as randomized 
• A listing of subjects prematurely discontinued from the study, along with reasons for 
Discontinuation 
• A summary of analysis sets including randomized subjects and randomized subjects 
by treatment groups, ITT,  mITT, SAF, PK, immunogenicity (AAS). 
5.6. 
Extent of Study Treatment Exposure and Compliance 
5.6.1. 
Measurement of Compliance 
Participant treatment compliance in terms of total dose, number of doses, and number of SC 
injections will be summarized for each group. Compliance with study drug will be calculated as 
follows: 
Compliance (%) =100 ×
Number of actual injections
Number of planned injections. 
This will be presented for SAF during EAP by each group and by all subjects combined.  
5.6.2. 
Exposure to Investigational Product 
The duration of study treatment exposure will be defined as day 1 through 4 weeks, ie, 28 days, 
after the last dose for a participant in the Q4W arms and day 1 through 12 weeks, ie, 84 days 
after the last dose for a participant in the Q12W arm. The duration of the study will be through 
the follow-up period defined as end of EAP through day 253 (±14 days). Treatment exposure and 
study duration will be evaluated in the SAF. 
 
 
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5.7. 
Analyses of Efficacy Variables 
The following null and alternate hypotheses will be tested for the primary endpoint unless 
otherwise specified: 
H0: There is no treatment difference between REGN10933+REGN10987 and placebo 
H1: There is a treatment difference between REGN10933+REGN10987 and placebo 
Primary efficacy variable will be analyzed and compared between REGN-COV arms vs placebo. 
5.7.1. 
Analysis of Primary Efficacy Endpoint 
The mITT population will be the primary analysis population for efficacy. The ITT population 
will also be used for primary efficacy analysis. Participant data will be analyzed according to the 
group to which they were randomized. 
The primary endpoint of the study is cumulative incidence of symptomatic (broad term), RT-
PCR-confirmed SARS-CoV-2 infection cases during the efficacy assessment period (EAP). See 
Section 4.5.1 for the definition of a symptomatic SARS-CoV-2 infection.  
The cumulative incidence of cases through the EAP will be estimated using the Kaplan-Meier 
method, and the antibody efficacy (AbE) will be estimated as the percent risk reduction (ie, 100 
x [1-HR], where HR is the hazard ratio for comparison of the incidence of cases in the antibody 
arm versus placebo). A unstratified Cox proportional hazard regression model with treatment 
group as a fixed effect, will be used to estimate the hazard ratio and 95% CI (2-sided). Nominal 
two-sided p-values will be reported for descriptive purpose using the log-rank test for pairwise 
comparison between each antibody arm and placebo. 
For the primary analysis, cases will be counted from day 2 through day 176 (ie, day 169 +7 
days), to allow for cases to accrue until the end of the EAP visit window per the Schedule of 
Events. Time of symptomatic SARS-CoV-2 infection will be the earlier of the sign/symptom 
onset date or the sample collection date for which RT-PCR result (local or central) was positive.  
5.7.2. 
Analysis of Secondary Efficacy Endpoints 
No secondary efficacy variables are collected for this study 
5.7.3. 
Analysis of Other Exploratory Endpoints 
The following exploratory endpoints will be summarized descriptively: 
1. Cumulative incidence of symptomatic (broad term), RT-PCR-confirmed SARS-CoV-2 
infection cases during the follow-up period 
2. Cumulative incidence of RT-PCR-confirmed SARS-CoV-2 infection cases (regardless of 
symptoms) during the EAP 
3. Proportion of participants with COVID-19-related hospitalization, emergency room visit, 
urgent care center visit or death during the EAP and follow-up period 
4. Maximum SARS-CoV-2 RT-qPCR viral load (log10 copies/mL) in NP swab samples 
among individuals with ≥1 RT-qPCR positive test that has an onset during the EAP 
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5. Viral variant characteristics of SARS-CoV-2 in participants who become infected post-
baseline 
5.7.4. 
Adjustment for Multiple Comparison 
Due to study early terminations, no multiple adjustments will be performed for any analyses.  
5.8. 
Analysis of Safety Data 
Secondary safety endpoints are 
1. Proportion of participants with grade ≥3 treatment-emergent adverse events (TEAEs), 
during the EAP and follow-up period  
2. Proportion of participants with TEAEs leading to study drug discontinuation, during the 
EAP and follow-up period 
3. Proportion of participants with treatment-emergent serious adverse events (SAEs) during 
the EAP and-follow up period 
4. Proportion of participants with adverse events of special interest (AESIs) during the EAP 
For safety variables, the following observation periods are defined: 
• The pretreatment period is defined as the time from the signing of the ICF to before 
study drug administration. 
• The EAP is defined as the day from first dose of study drug to day 169 ± 7 days 
• The Follow-up period is defined as the end of the EAP to the end of the Follow-up 
Period (ie, the last study visit). 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, and vital signs). The summary of AE results will be presented for each 
treatment group for each of three TEAE periods: treatment-emergent EAP (TEEAP), treatment-
emergent follow-up period (TEFUP), and overall study period (i.e., combined across the TEEAP 
and TEFUP). For laboratory and vital sign results they will be presented for each treatment group 
for each of three periods: EAP, follow-up, and overall study period.  
5.8.1. 
Adverse Events  
All AEs reported in this study will be reported by the preferred term (PT), and the primary 
system organ class (SOC). The number and percentage of subjects with TEAEs will be 
summarized by treatment group. 
Summaries will include: 
• Overview of TEAEs, i.e., overall number (%) of subjects with any TEAE, Serious 
TEAE, TEAE leading to death, TEAE leading to study withdrawn 
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• Overview of non-COVID TEAEs (not related to the patients’s underlying disease and/or not 
related to treatments for the underlying conditions), i.e., overall number (%) of subjects with any 
TEAE, Serious TEAE, TEAE leading to death, or TEAE leading to study withdrawn 
• Overview of AESI, i.e., overall number (%) of subjects with any AESI, grade 3 or greater 
injection site reactions, grade 2 or greater hypersensitivity reactions, AESI leading to death, or 
AESI leading to study drug withdrawn) 
• TEAEs by primary SOC and PT 
• TEAEs by severity (according to the grading scale appendix Section 10.3 ), presented by 
primary SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by primary SOC 
and PT 
• Treatment-emergent SAEs by primary SOC and PT 
• Treatment-emergent AESIs by primary SOC and PT 
• TEAEs leading to study withdrawn by primary SOC and PT 
• Treatment-emergent AESIs leading to study withdrawn by primary SOC and PT 
• Treatment-emergent AESIs by severity, presented by primary SOC and PT 
• Number of subjects who died during TEEAP, TEFUP, and the study period, 
respectively, and reason for death 
• TEAEs leading to death  
• AESIs leading to death by SOC and PT. 
In addition, the number (%) of subjects symptoms assessment collected in the COVID-19 
symptoms assessment eCRF will be summarized by treatment group. The descriptive statistics of 
the duration (days) of each COVID-19 symptom will also be presented. Subject listing of 
COVID-19 symptoms including the details such as the start date, end date, and duration of each 
symptom will be provided. In addition, subject listing of SAEs, AESI, TEAEs related to study 
drug, and TEAEs leading to study drug withdrawn will also be presented. 
5.8.2. 
Clinical Laboratory Measurements  
5.8.3. 
Analysis of Vital Signs and Safety Laboratory Measures 
Summary of vital signs including systolic blood pressure, diastolic blood pressure, heart rate, 
oxygen saturation, Temperature, Respiratory rate  will be provided. In addition, local labatory 
results will be summarized by abnormality(low/high) and normality. Listings will be provided 
for all the local laboratory results. 
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5.8.4. 
Analysis Other Safety Variables 
For subjects who become SARS-CoV-2 positive and require medically attended visits to the 
emergency department (ED), urgent care center (UCC), or hospitalization starting from the 
timepoint of SARS-CoV-2 RT-qPCR positive and through the end of the study, will have the 
following parameters or occurrences (worst or most abnormal finding) during the medically 
attended visit/stay collected (eCRF). 
A COVID-19-related medically-attended visit (MAV) will be defined as follows: hospitalization, 
ER visit, urgent care visit, physician’s office visit, or telemedicine visit, with one of the reasons 
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 
• If hospitalized due to COVID-19, length of visit 
• Reason (list all COVID-19-related clinical manifestation[s] that prompted the 
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, remdesivir, baricitinib, etc) 
A listing of subjects who have abnormal findings with any SARS-CoV-2 infection-related 
medically-attended visit will be provided including the corresponding study period information. 
5.9. 
Analysis of Pharmacokinetic Data 
The concentrations of casirivimab and imdevimab in serum over time will be summarized 
descriptively for each of the treatment groups by age group (subjects ≥12 years of age to <18 
years of age, ≥40 kg; and subjects ≥18 years of age). Associations between covariates that may 
impact PK of casirivimab and imdevimab and concentrations of the antibodies in serum may be 
evaluated as appropriate. No formal statistical hypothesis testing will be performed. 
5.10. 
Analysis of Immunogenicity Data 
5.10.1. 
Analysis of ADA data: 
The immunogenicity variables described in Section 4.8 will be summarized using descriptive 
statistics. Immunogenicity will be characterized per drug molecule by ADA status, ADA 
category and maximum titer observed in participants in the ADA analysis sets. For samples 
confirmed as drug specific ADA positive, but found negative at the lowest titer dilution, the 
lowest dilution in the titer assay is imputed. 
 
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The ADA status of each participants 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 participants is classified as: 
Treatment-boosted - A positive result at baseline in the ADA assay with at least one post 
baseline titer result ≥9-fold the baseline titer value  
Treatment-emergent - A negative result or missing result at baseline with at least one positive 
post baseline result in the ADA assay. Patients that are treatment-emergent will be further 
categorized as follows: 
Treatment-emergent is further sub-categorized as: 
Persistent - A positive result in the ADA assay detected in at least 2 consecutive post baseline 
samples separated by at least a 16-week post baseline period [based on nominal sampling 
time], with no ADA-negative results in-between, regardless of any missing samples 
Transient - Not persistent or indeterminate, regardless of any missing samples 
Indeterminate - A positive result in the ADA assay at the last collection time point only, 
regardless of any missing samples 
The maximum titer category of each participants is classified as: 
Low (titer <1,000) 
Moderate (1,000 ≤ titer ≤ 10,000) 
High (titer >10,000) 
The following will be summarized by treatment group and ADA titer level: 
• Number (n) and percent (%) of ADA-negative participants 
• Number (n) and percent (%) of pre-existing participants 
• Number (n) and percent (%) of treatment-emergent ADA positive participants 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
participants 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
participants 
− Number (n) and percent (%) of transient treatment-emergent ADA positive 
participants 
• Number (n) and percent (%) of treatment-boosted ADA positive participants 
Listing of all ADA titer levels will be provided for participants with pre-existing, treatment-
emergent and treatment-boosted ADA response. 
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5.10.2. 
Analysis of Neutralizing Antibody (NAb) Data 
The absolute occurrence (n) and percent of participants (%) with NAb status in the NAb analysis 
set will be provided by treatment groups.  The NAb status is categorized as follows: 
• Negative: Samples tested negative in the ADA assay, or samples positive in the ADA 
assay but tested negative in the NAb assay. 
• Positive: Samples tested positive in the NAb assay 
5.11. 
Association of Immunogenicity with Exposure and Safety 
5.11.1. 
Immunogenicity and Exposure 
Potential association between immunogenicity and systemic exposure to casirivimab and 
imdevimab will be explored by treatment groups. Plots of individual casirivimab and imdevimab 
concentration time profiles may be provided to examine the potential impact of ADA category, 
maximum titer category and NAb status on these profiles. 
5.11.2. 
Immunogenicity and Safety 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• Injection site reaction (serious or severe and lasting 24 hours or longer) 
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• Anaphylaxis (SMQ: Anaphylactic Reaction [Narrow]) 
The safety analyses mentioned above will be conducted using the following categories: 
− ADA Positive 
• Treatment-emergent 
• Treatment-boosted 
− Maximum post-baseline titer category in ADA positive participants 
− NAb positive  
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
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  
Rules for handling missing RT-qPCR test results for primary and secondary efficacy variables 
are described in Section 5.7 . 
6.3. 
Data Handling Convention for Missing Data 
This section includes the methods for missing data imputation and methods for missing 
mechanism exploration, if necessary. Missing data will not be imputed in listings. This section 
includes the methods for missing data imputation for some summary analyses, if necessary. 
Date and Time of Study Treatment Injections 
Since the study drug is administered at the site, the date and time of study drug administrations 
are filled in eCRF. No missing data is expected. The information is filled in eCRF. If a patient’s 
date of the last dose is totally missing or unknown, his/her last visit date will be substituted. 
Adverse Event 
If the severity of a TEAE is missing, it will be classified as “severe” or “Grade 3” in the 
frequency tables by intensity of TEAEs. If the assessment of relationship of a TEAE to the 
investigational product is missing, it will be classified as related to study drug. When the partial 
AE date/time information does not indicate that the AE started prior to study treatment or after 
the TEAE period, the AE will be classified as treatment-emergent. 
Medication/Procedure 
If a medication date or time is missing or partially missing and it cannot be determined whether 
it was taken prior or concomitantly or stopped prior to the first study treatment administration, it 
will be considered as concomitant medication/procedure by imputing the start date on the date of 
first study treatment administration. 
6.4. 
Visit Windows 
Assessments taken outside of protocol allowable windows will be displayed according to the 
case report form (CRF) assessment recorded by the investigator. Data analyzed by-visit-analysis 
will be summarized by the scheduled visit described in protocol Schedule of Events. Below are 
the definitions for the visit windows programmatically imposed on all available measures from 
unscheduled visits collected over the course of the study including early termination visit and 
end of study visit. No analysis visit windows will be applied for the study scheduled visits nor 
for drug concentration and immunogenicity data. The visit windows are constructed using ranges 
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applied to the number of days in study (study days) when the measure is collected. Below are the 
relevant definitions for the analysis visit windows: 
1. The first study treatment occurs on Study Day 1. 
2. Study day is defined as the number of days since the first study treatment administration+1. 
3. Since the protocol specifies that measurements be collected before study treatment is 
administered on a given day, it is appropriate that baseline include Day 1. 
4. For randomized but not treated subjects, Day 1 is the day of randomization. 
 
Table 1: 
Efficacy Analysis Windows for Unscheduled Visits with RT-qPCR or Viral 
Load Results 
Visit Label  
Targeted Study Day  
Window in Study Day 
Baseline  
1  
≤ 1 
Week 1  
8  
 [2, 11] 
Week 4  
29  
 [22, 36] 
Week 8 
57 
[50, 64] 
Week 12 
85 
[78, 92] 
Week 16 
113 
[106,120] 
Week 20 
141 
[134, 148] 
Week 24 
169 
[162,176] 
Week 28 
197 
[183, 211) 
Week 32 
225 
[211, 239)  
Week 36 
253 
[239, 267] 
If a subject has multiple efficacy assessment visits within an analysis visit window, the one with 
worst result (e.g., the positive test result will be used for analysis if one record is positive and the 
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other one is negative; the highest viral load result will be used if multiple viral load results are in 
the same analysis window.) will be selected. If the test results are all negative, the value of the 
latter visit will be used. If there are multiple positive RT-qPCR results within an analysis 
window, the record with the highest quantitative result will be used. 
 
Table 2: 
Global Analysis Windows for Data Other Than RT-qPCR Test 
Visit Label  
Targeted Study Day  
Window in Study Day 
Baseline  
1  
≤ 1 
Week 1  
8  
 [5, 11] 
Week 4  
29  
 [22, 36] 
Week 8 
57 
[50, 64] 
Week 12 
85 
[78, 92] 
Week 16 
113 
[106,120] 
Week 20 
141 
[134, 148] 
Week 24 
169 
[162,176] 
Week 28 
197 
[183, 211) 
Week 32 
225 
[211, 239)  
Week 36 
253 
>=239 
Unscheduled For efficacy, safety laboratory data, and vital signs, unscheduled visit 
measurements may be used to provide a measurement for a time point, including baseline, if 
appropriate according to their definitions. The measurements may also be used to determine 
abnormal values, AESIs 
6.5. 
Pooling of Centers for Statistical Analyses 
The randomization is stratified by region. Since there is only one country for the study, region 
variable as a fixed effect factor will not be included in the statistical analysis model. 
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6.6. 
Statistical Technical Issues 
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7. 
INTERIM ANALYSIS 
This study is terminated early and there’s no planned interim analysis. 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
 
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9. 
REFERENCES 
1. 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. 
 
 
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10. 
APPENDIX 
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10.1. 
Schedule of Time and Events 
Table 3: 
Schedule of Events (No Longer Applicable as of Protocol Amendment 2) 
Study Day 
Screening/Baseline1 
Efficacy Assessment Period2 
Follow-Up Period2 
Confirmatory 
Visit, 
Suspected 
COVID-193  
Post-
Infection 
Treatment 
Visit, Lab-
Confirme
d 
Infection3 
ET 
-14 to 1 1 
82 
29 57 85 113 141 169 
197 
(FU 1) 
225 
(FU 2) 
253 
(EOS) 
Screen Pre-
Dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
±3 ±7 ±7 ±7 ±7 ±7 
±7 
±14 
±14 
±14 
Screening/Baseline 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Locally-acceptable sample for SARS-CoV-2 RT-PCR (local)4 X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NP swab sample for SARS-CoV-2 RT-qPCR (central)4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
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Study Day 
Screening/Baseline1 
Efficacy Assessment Period2 
Follow-Up Period2 
Confirmatory 
Visit, 
Suspected 
COVID-193  
Post-
Infection 
Treatment 
Visit, Lab-
Confirme
d 
Infection3 
ET 
-14 to 1 1 
82 
29 57 85 113 141 169 
197 
(FU 1) 
225 
(FU 2) 
253 
(EOS) 
Screen Pre-
Dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
±3 ±7 ±7 ±7 ±7 ±7 
±7 
±14 
±14 
±14 
Study drug administration5 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Safety 
 
Vital signs6 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Treatment-emergent grade ≥3 AEs7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Treatment-emergent AEs leading to study drug 
discontinuation7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Treatment-emergent SAEs7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Treatment-emergent grade 2 hypersensitivity reactions7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Treatment-emergent grade 3 ISRs7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Concomitant medications and procedures 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Pregnancy test, blood or urine (WOCBP only)  
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Pregnancy status 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
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Study Day 
Screening/Baseline1 
Efficacy Assessment Period2 
Follow-Up Period2 
Confirmatory 
Visit, 
Suspected 
COVID-193  
Post-
Infection 
Treatment 
Visit, Lab-
Confirme
d 
Infection3 
ET 
-14 to 1 1 
82 
29 57 85 113 141 169 
197 
(FU 1) 
225 
(FU 2) 
253 
(EOS) 
Screen Pre-
Dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
±3 ±7 ±7 ±7 ±7 ±7 
±7 
±14 
±14 
±14 
Vital status 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Safety information (newborns of study participants) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Efficacy 
 
 
Clinician assessment of COVID-19 signs and symptoms 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X9 
Central Laboratory Pharmacodynamic/Biomarker 
Testing 
 
 
Serum for central anti-SARS-CoV-2 serological assays 
 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for exploratory research 
 
X8 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Plasma for exploratory research 
 
X8 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Pharmacokinetics and Immunogenicity Sampling (first 600 enrollees at participating sites)10 
 
Serum for drug concentration (PK)10,11 
 
X8 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
Serum for immunogenicity (ADA)10,12 
 
X8 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
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Study Day 
Screening/Baseline1 
Efficacy Assessment Period2 
Follow-Up Period2 
Confirmatory 
Visit, 
Suspected 
COVID-193  
Post-
Infection 
Treatment 
Visit, Lab-
Confirme
d 
Infection3 
ET 
-14 to 1 1 
82 
29 57 85 113 141 169 
197 
(FU 1) 
225 
(FU 2) 
253 
(EOS) 
Screen Pre-
Dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
±3 ±7 ±7 ±7 ±7 ±7 
±7 
±14 
±14 
±14 
Participants with suspected COVID-19 only13 
 
Clinician assessment of COVID-19 signs/symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Comprehensive vital sign assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X6 
 
Treatment-emergent grade ≥3 AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Treatment-emergent SAEs7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Concomitant medications and procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
If confirmed 
symptomatic1
3 
Locally-acceptable sample for SARS-CoV-2 
RT-PCR (local) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
NP swab for SARS-CoV-2 RT-qPCR (central)  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
If  
SARS-CoV-2 
RT-PCR is 
positive13 
Post-infection treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinician assessment of COVID-19 
signs/symptoms 
 
 
 
 
Every 7 (±1) days until 2 consecutive negative RT-qPCR 
results13 
 
 
 
NP swab for SARS-CoV-2 RT-qPCR (central)  
 
 
 
X 
 
 
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Study Day 
Screening/Baseline1 
Efficacy Assessment Period2 
Follow-Up Period2 
Confirmatory 
Visit, 
Suspected 
COVID-193  
Post-
Infection 
Treatment 
Visit, Lab-
Confirme
d 
Infection3 
ET 
-14 to 1 1 
82 
29 57 85 113 141 169 
197 
(FU 1) 
225 
(FU 2) 
253 
(EOS) 
Screen Pre-
Dose Dose Post-
Dose 
Window (Day) 
 
 
 
 
±3 ±7 ±7 ±7 ±7 ±7 
±7 
±14 
±14 
±14 
COVID-19-related MAV details 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
 
 
 
ADA, anti-drug antibodies; AE; adverse event; EOS, end of study; FU, follow up; ISR, injection-site reactions; MAV, medically-attended visit; NP, nasopharyngeal; PK, 
pharmacokinetics; SAE, serious adverse event; RT-PCR, reverse transcription polymerase chain reaction; RT-qPCR, quantitative reverse transcription polymerase chain reaction; 
SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WOCBP, women of childbearing potential. 
 
 
 
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Table 4: 
Schedule of Events for Study Close-Out (Protocol Amendment 2; Applies to All Enrolled Participants) 
Study Visit 
Dose Visit 
Optional Confirmatory 
Visit(s), Suspected 
COVID-19 
End-of-Study 
Follow-Up Visit  
(Telephone) 
Timing of Visit 
28 Days After the Most 
Recent Dose 
Within 48 Hours of 
Symptom Onset, if 
Feasible 
85 Days After the Most 
Recent Dose1 
Window (Days) 
±7 
- 
±14 
Informed consent 
X2 
Optional study drug administration3 
X 
Vital signs4 
X 
Treatment-emergent AEs considered by the investigator to be unrelated to baseline 
conditions and unrelated to treatments for baseline conditions5 
X 
X 
Treatment-emergent AEs leading to study drug discontinuation5 
X 
X 
Treatment-emergent SAEs5 
X 
X 
Treatment-emergent grade 2 hypersensitivity reactions5 
X 
Treatment-emergent grade 3 injection site reactions (ISRs)5 
X 
Concomitant medications and procedures 
X 
X 
Pregnancy status 
X 
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Study Visit 
Dose Visit 
Optional Confirmatory 
Visit(s), Suspected 
COVID-19 
End-of-Study 
Follow-Up Visit  
(Telephone) 
Timing of Visit 
28 Days After the Most 
Recent Dose 
Within 48 Hours of 
Symptom Onset, if 
Feasible 
85 Days After the Most 
Recent Dose1 
Window (Days) 
±7 
- 
±14 
Vital status 
X 
Safety information (newborns of study participants) 
X 
Participants with suspected COVID-19 only (optional)6 
Clinician assessment of COVID-19 signs/symptoms7 
X6 
Comprehensive vital sign assessment8 
X6 
Treatment-emergent AEs considered by the investigator to be unrelated to baseline 
conditions and unrelated to treatments for baseline conditions5 
X6 
Treatment-emergent SAEs5 
X6 
Concomitant medications and procedures 
X6 
If confirmed 
symptomatic: 
Locally-acceptable sample for SARS-CoV-2 RT-PCR (local)9 
X6 
NP swab for SARS-CoV-2 RT-qPCR (central)9 
X6 
Clinician assessment of COVID-19 signs/symptoms 
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Study Visit 
Dose Visit 
Optional Confirmatory 
Visit(s), Suspected 
COVID-19 
End-of-Study 
Follow-Up Visit  
(Telephone) 
Timing of Visit 
28 Days After the Most 
Recent Dose 
Within 48 Hours of 
Symptom Onset, if 
Feasible 
85 Days After the Most 
Recent Dose1 
Window (Days) 
±7 
- 
±14 
If SARS-CoV-2 
RT-PCR is 
positive: 
NP swab for SARS-CoV-2 RT-qPCR (central) 
Every 7 (±1) days until 2 
consecutive negative RT-
qPCR results6 
COVID-19-related MAV details 
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10.2. 
Broad Term Definition of COVID-19 Signs and Symptoms 
 
• Body aches such 
as muscle pain 
or joint pain 
• Chest pain 
• Chills 
• Confusion 
• Cough 
• Diarrhea 
• Dizziness 
• Fatigue 
• Feverish 
• Fever ≥38.0°C 
• 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 
                                        VV-RIM-00170603-1.0 Approved - 18 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2176 
Statistical Analysis Plan 
 
Date: 15 JUN 2022 
 
REGENERON CONFIDENTIAL 
Page 46 of 46 
 
10.3. 
NCI-CTCAE Severity Grading (v5.0) for Anaphylaxis, Allergic Reactions, and Injection-Site 
Reactions 
 
CTCAE Term Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Anaphylaxis1 
Not applicable 
Not applicable 
Symptomatic bronchospasm, 
with or without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Allergic 
reaction 
(hypersensitivit
y reaction)2 
Systemic intervention 
not indicated 
Oral intervention indicated 
Bronchospasm; hospitalization 
indicated for clinical sequelae; 
intravenous intervention 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Injection site 
reaction3 
Tenderness with or 
without associated 
symptoms (eg, warmth, 
erythema, itching) 
Pain; lipodystrophy; 
edema; phlebitis 
Ulceration or necrosis; severe 
tissue damage; operative 
intervention indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
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.  
 
                                        VV-RIM-00170603-1.0 Approved - 18 Jun 2022 GMT-5:00


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                                        VV-RIM-00170603-1.0 Approved - 18 Jun 2022 GMT-5:00