Clinical trial NCT04992273
Conditions: COVID-19
Keywords: Coronavirus disease 2019 (COVID-19) Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) coronavirus
Sponsor: Regeneron Pharmaceuticals
Start date: 2021-09-13; Completion date: 2022-06-01
Enrollment: 7 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to characterize the concentrations of casirivimab+imdevimab in serum over time after a single subcutaneous (SC) administration

The secondary objectives of the study are:

* To assess the safety and tolerability of SC or single administration of casirivimab+imdevimab
* To assess the occurrence of grade ≥3 injection site reactions and grade ≥3 hypersensitivity reactions, in participants treated with SC doses of casirivimab+imdevimab
* To assess the immunogenicity of casirivimab+imdevimab

Detailed description:

Arms: arm 1: SC administration arm 2: SC administration arm 3: SC administration arm 4: SC administration
Interventions: intervention 1: casirivimab+imdevimab
Intervention descriptions: intervention 1: Single dose administered based on weight

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
R10933-10987-COV-2121 Amendment 2 
Regeneron Pharmaceuticals, Inc. 
Page 1 
CONFIDENTIAL 
EudraCT: 2021-004590-30 
IND: 148069 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 2A, OPEN-LABEL STUDY ASSESSING 
PHARMACOKINETICS, SAFETY, TOLERABILITY, AND 
IMMUNOGENICITY OF SINGLE-DOSE SUBCUTANEOUS ANTI-
SPIKE (S) SARS-COV-2 MONOCLONAL ANTIBODIES (CASIRIVIMAB 
AND IMDEVIMAB) IN HIGH-RISK PEDIATRIC SUBJECTS UNDER 12 
YEARS OF AGE 
Compound: 
Casirivimab+Imdevimab 
Clinical Phase: 
2a 
Protocol Number: 
R10933-10987-COV-2121 
Protocol Version: 
Amendment 2 
Amendment 2 Date of Issue: 
Amendment 1 Date of Issue: 
See appended electronic signature page 
16 Sep 2021 
Original Date of Issue: 
30 Jun 2021 
Medical /Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
 
 
 
 
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NCT04992273


Clinical Study Protocol 
 
R10933-10987-COV-2121 Amendment 2 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 2 
The primary purpose of this amendment is to shorten the length of the follow-up period from 225 
days to 169 days (32 weeks to 24 weeks), and to add that the end of study visit (EOS) visit is 
required to be performed in person. 
Description of Change 
 
Brief Rationale   
Section(s) 
The length of the follow-up period 
for assessment of drug 
concentrations, safety, and 
immunogenicity has been shortened 
and the EOS date has been amended 
from day 225 to day 169 accordingly. 
Study visits scheduled for day 197 
and day 225 have been removed from 
the Schedule of Events. 
The reason for shortening the follow-
up period from day 225 to day 169 
was to align the duration of follow-up 
across pediatric studies as it relates to 
the current state of the COVID-19 
pandemic and the development 
program of casirivimab and 
imdevimab. The longer follow-up 
period of day 225 was initially 
intended to evaluate for antibody 
mediated enhancement of disease by 
casirivimab and imdevimab, however 
antibody mediated enhancement of 
disease has not been observed in the 
program. Additionally, antibody 
mediated enhancement of disease is 
no longer relevant while the Omicron 
variant is dominant because 
neutralization activity against 
Omicron by casirivimab and 
imdevimab was below the level of 
quantitation. A follow-up period of 
169 days is aligned with health 
authority agreements. 
Clinical Study Protocol Synopsis 
Section 3.2.1 Rationale for Study 
Design 
Section 6.1 Study Description and 
Duration 
Table 3 Schedule of Events 
Figure 1 Study Flow Diagram 
EOS visit at day 169 will be 
performed in person. 
Prior to this amendment (#2), the 
EOS visit day 225 was an in person 
visit, which is aligned with the key 
endpoint of safety in this early phase 
safety study in a new population 
(pediatric). The new end of study 
visit, day 169, will also be an in-
person visit, to maintain the overall 
study design. 
Figure 1 Study Flow Diagram 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #3 
Unused and residual biological 
samples collected during the study 
may be kept for use in assay 
development or validation, and/or for 
diagnostic test development or 
validation. 
Change implemented to provide 
flexibility for potential future use of 
unused and residual samples. 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #1 
Section 9.2.8.3 
Amendment 1 
The primary purpose of this amendment is to implement changes per health authority feedback, 
including the route of administration in subjects with lower body weight (subcutaneous rather than 
intramuscular), additional sample collections for drug concentration assessment at later time 
points, and addition of multisystem inflammatory syndrome in children (MIS-C) as an adverse 
event of special interest (AESI).
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Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
 
Description of Change 
 
Brief Rationale   
Section(s) 
Health Authority Requests 
All subjects will receive study drug by 
subcutaneous administration, including those 
who weigh <10 kg at the time of study 
enrollment. In the original protocol, subjects 
<10 kg were planned to receive intramuscular 
administration.  
Change implemented per 
health authority 
feedback, with the aim of 
utilizing a route of 
administration in the 
lowest weight pediatric 
subjects that has already 
been used in ongoing 
studies.  
 
Intramuscular 
administration has not 
yet been utilized in 
casirivimab+imdevimab 
clinical trials. 
Study Title 
Section 2.1 Primary Objective 
Section 2.2 Secondary Objectives 
Section 3.2.3.1 Overall 
Pharmacokinetics Objective of Study 
Section 3.2.3.3 Rationale for 
Intramuscular Dosing in Subjects 
Weighing Under 10 Kilograms 
[deleted] 
Section 4.2 Secondary Endpoints 
Section 8.1 Investigational Treatments 
Table 2 Weight-Tiered Dosing of 
Casirivimab+Imdevimab 
Section 8.3.1.1 Systemic Injection 
Reactions (Hypersensitivity) 
Section 11.2 Justification of Samples 
Size 
Section 11.4.4.1 Analysis of Drug 
Concentration Data 
Section 20 Investigator’s Agreement 
 
In addition to the previously-indicated time 
points, sample collection for drug 
concentration assessment will be performed on 
day 57 (schedule 1) and day 113 (schedule 2). 
Change implemented per 
health authority 
feedback, to ensure 
comprehensive collection 
of pharmacokinetics data 
Table 3 Schedule of Events 
Multisystem inflammatory syndrome in 
children (MIS-C) has been added as an 
adverse event of special interest (AESI): 
• MIS-C will be defined according the 
Centers for Disease Control (CDC, 2021c). 
• Occurrences of MIS-C will require 
expedited reporting. 
• MIS-C will not be evaluated as a secondary 
endpoint. 
For consistency with 
other Sponsor studies of 
casirivimab+imdevimab 
conducted in pediatric 
populations to ensure 
that a known 
complication of COVID-
19 in pediatric 
populations is 
expeditiously reported 
and captured. 
Section 2.2 Secondary Objectives 
Section 3.2.2.1 Risk Factors for Severe 
COVID-19 in the Pediatric Population 
Section 4.2 Secondary Endpoints 
Section 6.1 Study Description and 
Duration 
Section 6.6.2 Safety Monitoring Team 
Section 10.1.3 Events that Require 
Expedited Reporting to Sponsor 
The total sample size has been increased from 
24 to 28 subjects <12 years of age. 
Change implemented per 
health authority feedback 
Section 7.1 Number of Subjects 
Planned 
Enrollment will include minimum targets for 
the following weight categories: 
• ≥10 kg to <40 kg: at least 12 subjects 
• ≥3 kg to <10 kg: at least 12 subjects 
Change implemented per 
health authority 
feedback, to ensure 
adequate representation 
of body weight in study 
analyses. 
Section 7.1 Number of Subjects 
Planned 
Section 11.2 Justification of Samples 
Size 
 
Other Changes 
The following exclusion criterion has been 
added: 
• Treatment with another investigational (not 
authorized or approved) agent in the last 30 
days or within 5 half-lives of the 
investigational drug, whichever is longer, 
prior to the screening visit 
For consistency with 
other Sponsor studies of 
casirivimab+imdevimab  
Section 7.2.2 Exclusion Criteria, #14 
[new] 
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Description of Change 
 
Brief Rationale   
Section(s) 
The following prior medications will be 
recorded if they were given to a subject within 
6 months prior to their screening visit:  
• Other investigational (not authorized or 
approved) drugs 
• Investigational SARS-CoV-2 vaccines 
• Authorized or approved SARS-CoV-2 
vaccines 
• Investigational, authorized, or approved 
passive antibody for prophylaxis of SARS-
CoV-2 infection, including convalescent 
plasma, convalescent sera, hyperimmune 
globulin, or other monoclonal antibodies 
(eg, bamlanivimab and etesevimab, 
sotrovimab) 
To ensure relevant prior 
medications are captured, 
particularly in light of the 
anticipated availability of 
COVID-19 vaccination 
for individuals <12 years 
of age 
Section 9.2.1.3 Medication History 
[new] 
Visit windows of ±1 day have been added to 
day 2 and day 4 as follows:  
Day 2  
• For all subjects, the visit may occur on day 3 
• For subjects assigned to schedule 1, if the 
day 2 visit cannot occur on day 2 or day 3, 
subjects may have the day 2 blood draw for 
analysis of drug concentration on day 1, at 
least 4 hours after study drug administration. 
If this blood sample is collected, the day 2 
visit can be omitted. The day 2 visits should 
be scheduled for day 2 or day 3 whenever 
possible. 
Day 4 
• For all subjects the visit may occur on day 3 
or day 5 
To provide scheduling 
flexibility 
Table 3 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #14 
An Independent Data Monitoring Committee 
(IDMC) will be chartered to actively review 
safety data throughout the study. 
For consistency with 
other Sponsor studies of 
casirivimab+imdevimab 
conducted in pediatric 
populations; change not 
implemented due to any 
safety concerns related to 
casirivimab+imdevimab 
Section 6.6.1 Independent Data 
Monitoring Committee [new] 
Section 6.6.2 Safety Monitoring Team 
Analysis of neutralizing antibodies has been 
added to the analysis of immunogenicity 
For consistency with 
other Sponsor studies of 
casirivimab+imdevimab 
conducted in pediatric 
populations 
Section 4.2 Secondary Endpoints 
Section 5.4 Immunogenicity Variables 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #14 
Section 9.2.7 Immunogenicity 
Measurements and Samples 
Section 11.3.3 Immunogenicity 
Analysis Sets 
Section 11.4.5.1 Analysis of ADA Data 
Section 11.4.5.2 Analysis of NAb Data 
Clarified that interim reviews of PK and safety 
data may be performed before subjects 
complete the end of study. 
For consistency with the 
planned study analyses 
Section 6.7 Planned Interim Analysis  
Section 11.5 Interim Analysis 
Secondary endpoints related to adverse events 
have been rephrased to remove reference to 
“proportion of subjects”. 
To provide flexibility 
with respect to statistical 
analyses 
Section 4.2 Secondary Endpoints 
 
Corrected typographical error in footnote 10; 
the indicated blood samples may be collected 
at any point during the screening period; 
To ensure accuracy in the 
schedule of events. 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #10 
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Description of Change 
 
Brief Rationale   
Section(s) 
previous text indicated that screening 
collection could only occur on day -1. 
“Casirivimab and imdevimab” has been 
changed to “casirivimab+imdevimab” 
For nomenclature 
consistency with other 
Sponsor studies of 
casirivimab+imdevimab 
Throughout the document 
Minor clarifications for consistency and other 
minor updates (typographical, editorial, 
formatting) were made. 
To ensure clarity, 
accuracy, and 
consistency 
Throughout the document 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACE2 
Angiotensin-converting enzyme 2 
ADA 
Anti-drug antibody 
ADE 
Antibody-dependent enhancement 
AE 
Adverse event 
AESI 
Adverse event of special interest 
Casirivimab+imdevimab 
REGN10933 and REGN10987; also referred to by the 
proprietary name conditionally accepted by the FDA 
(REGEN-COV™) and by the EMA (RONPAPREVE®) 
CDC 
United States Centers for Disease Control and Prevention 
COVID-19 
Coronavirus disease 2019 
CPK 
Creatine phosphokinase 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVID 
Common variable immunodeficiency 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EUA 
Emergency Use Authorization 
FAS 
Full analysis set 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IM 
Intramuscular 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
IV 
Intravenous 
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LDH 
Lactate dehydrogenase 
MIS-C 
Multisystem inflammatory syndrome in children 
NAb 
Neutralizing antibody 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
PK 
Pharmacokinetic 
RBD 
Receptor binding domain 
RBQM 
Risk-Based Quality Monitoring 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
S protein 
Spike protein 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
XLA 
X-linked agammaglobulinemia 
 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
Amendment 2 ...................................................................................................................................2 
Amendment 1 ...................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................14 
1. 
INTRODUCTION ......................................................................................................17 
1.1. 
COVID-19 and the Role of Spike (S) Protein in SARS-CoV-2 Viral 
Pathogenesis ...............................................................................................................17 
1.2. 
Casirivimab+Imdevimab: Human Monoclonal Antibodies, Targeting 
SARS-CoV-2 S Protein, for the Treatment and Prevention of COVID-19 ................17 
1.3. 
An Open-Label Study to Assess the Pharmacokinetics and Safety Profile of 
Casirivimab+Imdevimab in High-Risk Pediatric Subjects .........................................18 
2. 
STUDY OBJECTIVES ..............................................................................................18 
2.1. 
Primary Objective .......................................................................................................18 
2.2. 
Secondary Objectives .................................................................................................18 
2.3. 
Exploratory Objectives ...............................................................................................18 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................19 
3.1. 
Hypothesis ..................................................................................................................19 
3.2. 
Rationale .....................................................................................................................19 
3.2.1. 
Rationale for Study Design .........................................................................................19 
3.2.2. 
Rationale for Target Population ..................................................................................20 
3.2.2.1. 
Risk Factors for Severe COVID-19 in the Pediatric Population ................................20 
3.2.2.2. 
Prophylaxis as a Complementary Approach to Vaccination in High-Risk 
Pediatric Populations ..................................................................................................20 
3.2.3. 
Rationale for Dose Selection ......................................................................................21 
3.2.3.1. 
Overall Pharmacokinetics Objective of Study ............................................................21 
3.2.3.2. 
Population Pharmacokinetics Modeling to Predict Exposure in Study 
Population ...................................................................................................................21 
3.3. 
Risk-Benefit ................................................................................................................22 
3.3.1. 
Summary of Efficacy and Safety Profile in Clinical Trials ........................................23 
3.3.2. 
Summary of Risks.......................................................................................................24 
3.3.3. 
Potential Benefit of Casirivimab+Imdevimab in the Study Population .....................25 
3.3.4. 
Summary .....................................................................................................................25 
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4. 
ENDPOINTS ..............................................................................................................25 
4.1. 
Primary Endpoint ........................................................................................................25 
4.2. 
Secondary Endpoints ..................................................................................................25 
5. 
STUDY VARIABLES................................................................................................26 
5.1. 
Demographic and Baseline Characteristics ................................................................26 
5.2. 
Safety Variables ..........................................................................................................26 
5.3. 
Pharmacokinetic Variables .........................................................................................26 
5.4. 
Immunogenicity Variables ..........................................................................................26 
5.5. 
Other Variables ...........................................................................................................26 
6. 
STUDY DESIGN .......................................................................................................26 
6.1. 
Study Description and Duration .................................................................................26 
6.2. 
Monitoring for Potential COVID-19 ..........................................................................27 
6.3. 
Management of Subjects With Suspected COVID-19 ...............................................27 
6.4. 
Study Stopping Rules .................................................................................................31 
6.5. 
End of Study Definition ..............................................................................................31 
6.6. 
Study Committees .......................................................................................................31 
6.6.1. 
Independent Data Monitoring Committee ..................................................................31 
6.6.2. 
Safety Monitoring Team .............................................................................................31 
6.7. 
Planned Interim Analysis ............................................................................................32 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF SUBJECTS ..............32 
7.1. 
Number of Subjects Planned ......................................................................................32 
7.2. 
Study Population .........................................................................................................32 
7.2.1. 
Inclusion Criteria ........................................................................................................32 
7.2.2. 
Exclusion Criteria .......................................................................................................33 
7.3. 
Premature Withdrawal from the Study .......................................................................34 
7.4. 
Replacement of Subjects .............................................................................................34 
8. 
STUDY TREATMENTS............................................................................................34 
8.1. 
Investigational Treatments ..........................................................................................34 
8.2. 
Dose Modification and Study Treatment Discontinuation Rules ...............................35 
8.2.1. 
Dose Modification ......................................................................................................35 
8.2.2. 
Study Drug Discontinuation .......................................................................................35 
8.3. 
Management of Acute Reactions ................................................................................35 
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8.3.1. 
Acute Injection Reactions ...........................................................................................35 
8.3.1.1. 
Systemic Injection Reactions (Hypersensitivity) ........................................................35 
8.3.1.2. 
Local Injection Site Reactions ....................................................................................35 
8.4. 
Method of Treatment Assignment ..............................................................................35 
8.5. 
Blinding ......................................................................................................................36 
8.6. 
Treatment Logistics and Accountability .....................................................................36 
8.6.1. 
Packaging, Labeling, and Storage ..............................................................................36 
8.6.2. 
Supply and Disposition of Treatments .......................................................................36 
8.6.3. 
Treatment Accountability ...........................................................................................36 
8.6.4. 
Treatment Compliance ................................................................................................36 
8.7. 
Concomitant Medications and Procedures .................................................................36 
8.7.1. 
Prohibited Medications ...............................................................................................37 
8.7.2. 
Permitted Medications and Procedures ......................................................................37 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................37 
9.1. 
Schedule of Events .....................................................................................................37 
9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................39 
9.1.2. 
Early Termination Visit ..............................................................................................40 
9.1.3. 
Unscheduled Visits .....................................................................................................40 
9.2. 
Study Procedures ........................................................................................................40 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................40 
9.2.1.1. 
Informed Consent and Assent .....................................................................................41 
9.2.1.2. 
Body Weight ...............................................................................................................41 
9.2.1.3. 
Medication History .....................................................................................................41 
9.2.1.4. 
Diagnostic Testing for SARS-CoV-2 at Screening and Baseline ...............................41 
9.2.2. 
SARS-CoV-2 Viral Testing in the Event of Suspected or Confirmed SARS-
CoV-2 Infection ..........................................................................................................42 
9.2.3. 
Study Drug Administration.........................................................................................42 
9.2.4. 
Safety ..........................................................................................................................42 
9.2.4.1. 
Vital Signs ..................................................................................................................42 
9.2.4.2. 
Targeted Physical Examination ..................................................................................42 
9.2.4.3. 
Concomitant Medications and Procedures .................................................................42 
9.2.4.4. 
Adverse Events ...........................................................................................................42 
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9.2.4.5. 
COVID-19 Signs and Symptoms ................................................................................42 
9.2.4.6. 
COVID-19-Related Medically-Attended Visits .........................................................43 
9.2.5. 
Laboratory Testing ......................................................................................................43 
9.2.6. 
Drug Concentration and Measurements .....................................................................44 
9.2.7. 
Immunogenicity Measurements and Samples ............................................................44 
9.2.8. 
Exploratory Biomarkers ..............................................................................................45 
9.2.8.1. 
Serological Assays for Endogenous Anti-SARS-CoV-2 Antibody Responses ..........45 
9.2.8.2. 
Serum and Plasma for Exploratory Research .............................................................45 
9.2.8.3. 
Unused and Residual Biological Samples ..................................................................45 
9.2.8.4. 
Viral Sequencing of Mid-Turbinate Nasal Swab Samples in SARS-CoV-2-
Positive Subjects .........................................................................................................45 
10. 
SAFETY EVALUATION AND REPORTING .........................................................45 
10.1. 
Recording and Reporting Adverse Events ..................................................................45 
10.1.1. 
General Guidelines .....................................................................................................45 
10.1.2. 
Reporting Procedure ...................................................................................................46 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................47 
10.2. 
Definitions ..................................................................................................................48 
10.2.1. 
Adverse Event .............................................................................................................48 
10.2.2. 
Serious Adverse Event ................................................................................................48 
10.2.3. 
Adverse Events of Special Interest .............................................................................48 
10.2.4. 
Severity .......................................................................................................................49 
10.2.5. 
Causality .....................................................................................................................51 
10.3. 
Safety Monitoring .......................................................................................................52 
10.4. 
Notifying Health Authorities, Institutional Review Boards, and Investigators ..........52 
11. 
STATISTICAL PLAN................................................................................................53 
11.1. 
Statistical Hypothesis ..................................................................................................53 
11.2. 
Justification of Sample Size........................................................................................53 
11.3. 
Analysis Sets ...............................................................................................................53 
11.3.1. 
Safety Analysis Set .....................................................................................................53 
11.3.2. 
Pharmacokinetic Analysis Set ....................................................................................53 
11.3.3. 
Immunogenicity Analysis Sets ...................................................................................53 
11.4. 
Statistical Methods ......................................................................................................54 
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11.4.1. 
Subject Disposition .....................................................................................................54 
11.4.2. 
Demography and Baseline Characteristics .................................................................54 
11.4.3. 
Safety Analysis ...........................................................................................................54 
11.4.3.1. 
Adverse Events ...........................................................................................................54 
11.4.3.2. 
Other Safety ................................................................................................................55 
11.4.3.3. 
Treatment Exposure ....................................................................................................55 
11.4.3.4. 
Treatment Compliance ................................................................................................55 
11.4.4. 
Pharmacokinetics ........................................................................................................55 
11.4.4.1. 
Analysis of Drug Concentration Data .........................................................................55 
11.4.5. 
Analysis of Immunogenicity Data ..............................................................................56 
11.4.5.1. 
Analysis of ADA Data ................................................................................................56 
11.4.5.2. 
Analysis of NAb Data .................................................................................................56 
11.4.6. 
Other Analyses ............................................................................................................56 
11.5. 
Interim Analysis ..........................................................................................................57 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........57 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................57 
12.1. 
Data Management and Electronic Systems ................................................................57 
12.1.1. 
Data Management .......................................................................................................57 
12.1.2. 
Electronic Systems ......................................................................................................57 
12.2. 
Study Monitoring ........................................................................................................58 
12.2.1. 
Monitoring of Study Sites ...........................................................................................58 
12.2.2. 
Source Document Requirements ................................................................................58 
12.2.3. 
Case Report Form Requirements ................................................................................58 
12.3. 
Audits and Inspections ................................................................................................59 
12.4. 
Study Documentation .................................................................................................59 
12.4.1. 
Certification of Accuracy of Data ...............................................................................59 
12.4.2. 
Retention of Records ..................................................................................................59 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................60 
13.1. 
Good Clinical Practice Statement ...............................................................................60 
13.2. 
Informed Consent and Assent .....................................................................................60 
13.3. 
Subjects Confidentiality and Data Protection .............................................................61 
13.4. 
Institutional Review Board .........................................................................................61 
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13.5. 
Clinical Study Data Transparency ..............................................................................61 
14. 
PROTOCOL AMENDMENTS ..................................................................................61 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................62 
15.1. 
Premature Termination of the Study ...........................................................................62 
15.2. 
Close-out of a Site ......................................................................................................62 
16. 
CONFIDENTIALITY ................................................................................................62 
17. 
FINANCING AND INSURANCE .............................................................................62 
18. 
PUBLICATION POLICY ..........................................................................................62 
19. 
REFERENCES ...........................................................................................................63 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................66 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................67 
 
LIST OF TABLES 
Table 1: 
Predicted Exposure (Population PK Model) of Total Casirivimab 
(REGN10933) and Total Imdevimab (REGN10987) in Serum of Pediatric 
Subjects (<12 Years)...................................................................................................22 
Table 2: 
Weight-Tiered Dosing of Casirivimab+Imdevimab ...................................................35 
Table 3: 
Schedule of Events .....................................................................................................38 
Table 4: 
NCI-CTCAE Severity Grading (v5.0) for Anaphylaxis, Allergic Reaction, 
and Injection Site Reactions .......................................................................................50 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................30 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title  
A Phase 2a, Open-Label Study Assessing the Pharmacokinetics, Safety, Tolerability, and 
Immunogenicity of a Single Dose of Subcutaneous Anti-Spike SARS-CoV-2 Monoclonal 
Antibodies Casirivimab and Imdevimab in High-Risk Pediatric Subjects Under 12 Years of Age 
Site Locations The study will be conducted in approximately 8 sites in the United States. 
Principal 
Investigator 
To be determined 
Objectives 
 
Primary 
• To characterize the concentrations of casirivimab+imdevimab in serum over time after a single 
subcutaneous (SC) administration 
Secondary 
• To assess the safety and tolerability of SC single administration of casirivimab+imdevimab 
• To assess the occurrence of grade ≥3 injection site reactions and grade ≥3 hypersensitivity 
reactions, in subjects treated with SC doses of casirivimab+imdevimab 
• To assess the immunogenicity of casirivimab+imdevimab 
Study Design 
This is an open label, phase 2a study to assess the pharmacokinetics (PK), safety, tolerability, and 
immunogenicity of casirivimab+imdevimab in subjects <12 years old who are not infected with 
SARS-CoV-2 but are at high risk to develop severe COVID-19 if they become infected. 
Subjects will be assessed for eligibility during the screening period, which may occur up to 7 days 
prior to the day 1 (baseline) visit. To be eligible, subjects must not have symptoms consistent with 
COVID-19, and must be confirmed negative for SARS-CoV-2 infection prior to study drug 
administration according to the window specified in the exclusion criteria.  
This study will enroll subjects at baseline into two analysis groups, with each group defined 
according to body weight. All subjects will receive a single dose of casirivimab+imdevimab, 
adjusted for body weight. Each subject will be observed for one hour after completion of dosing, 
and the subject (or their parent or guardian) will be contacted by phone within 24 hours of dosing to 
assess for any potential adverse events (AEs).  
Following dose administration, subjects will be followed for approximately 24 weeks (169 days) to 
monitor for TEAEs. At each scheduled site visit, the Investigator or designee will assess and 
document the subject’s general health and AEs since the last contact. If a scheduled visit cannot be 
performed in person (for example, due to COVID-19 restrictions), or if no assessments or collections 
require the subject to be contacted in person, the visit may be conducted virtually (ie, by telemedicine 
or phone). Grade ≥3 injection site reactions and grade ≥3 hypersensitivity reactions that occur after 
study drug administration will be captured as AESIs, to allow for expedited reporting. Multisystem 
inflammatory syndrome in children (MIS-C) will also be captured as an AESI. 
During the first five weeks after study drug administration, subjects will have samples collected for 
clinical laboratory tests (hematology, blood chemistry), drug concentration, and immunogenicity. 
On day 1, subjects in group A and group B will each be assigned using an Interactive Web Response 
System (IWRS) to one of two staggered PK-ADA sampling schedules (schedule 1 and schedule 2). 
Subjects and their caregivers will be provided with contact information for the clinical study site and 
will be given written and verbal instructions to call site personnel with any changes in their health 
status. They will be asked to promptly notify site personnel by phone of any symptoms or signs 
potentially related to COVID-19. Additionally, subjects and their caregivers will be contacted 
regularly during the study for symptoms or signs of COVID-19.  
In the event of suspected COVID-19, subjects will continue in the study and undergo additional 
unscheduled visits, as described in the main text.  
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Study 
Duration 
The duration of the study is approximately 25 weeks, including up to 1 week of screening.  
End of Study 
Definition 
The end of study is defined as the date the last subject completes the last study visit, withdraws from 
the study, or is lost to follow-up (ie, the study subject can no longer be contacted by the Investigator). 
Population 
 
Sample Size 
Approximately 28 subjects are planned to be enrolled. This includes at least 12 subjects with body 
weight ≥10 kg and <40 kg, and at least 12 subjects with body weight ≥3 kg to <10 kg. 
Target 
Population 
The study will enroll subjects <12 years old who are not infected with SARS-CoV-2 but are at high 
risk to develop severe COVID-19 if they become infected.  
Subjects must meet the following criteria to be eligible for inclusion in the study. Other criteria also 
apply and are described in the main text: 
• Is <12 years of age and ≥3 kg to <40 kg at the time parental/guardian consent is signed  
• Has at least one risk factor for developing severe COVID-19 if they were to become infected, 
such as: 
a. Obesity (BMI [kg/m2] ≥95th percentile for age and sex based on CDC growth charts) 
b. Cardiovascular disease 
c. Chronic lung disease 
d. Type 1 or type 2 diabetes mellitus 
e. Chronic kidney disease, including those on dialysis 
f. Chronic liver disease 
g. Immunocompromised or immunodeficient, based on Investigator’s assessment (examples 
include cancer treatment, bone marrow or organ transplantation, immune deficiencies, 
HIV infection, sickle cell anemia, thalassemia, and prolonged use of immune-weakening 
medications) 
h. Medical complexities (examples include any underlying genetic condition, neurologic 
condition, metabolic condition, or congenital heart disease) 
i. Any other condition deemed by the Investigator to be a risk factor for severe COVID-19 
Subjects who meet any of the following criteria will be excluded from the study. Other criteria also 
apply and are described in the main text: 
• Has positive diagnostic test for SARS-CoV-2 infection from a sample collected during screening 
≤7 days prior to study drug administration 
Note: The sample for the test should be collected ≤7 days within study drug administration, and 
the result should be reviewed and confirmed negative prior to dosing. Historical records will not 
be accepted. 
• Has active respiratory or non-respiratory symptoms consistent with COVID-19 in the opinion of 
the investigator 
• Has subject-reported clinical history of COVID-19, as determined by Investigator, within the last 
90 days 
• Has subject-reported history of prior EUA/approved positive diagnostic test for SARS-CoV-2 
infection within the last 90 days 
• Is currently hospitalized or was hospitalized for >24 hours for any reason within 14 days of the 
screening visit 
Treatments 
Subjects will receive a single dose of co-administered casirivimab+imdevimab combination 
therapy subcutaneous single dose, administered as subcutaneous (SC) injections based on body 
weight: 
• ≥20 kg to <40 kg: 792 mg (396 mg per mAb)  
• ≥10 kg to <20 kg: 408 mg (204 mg per mAb) 
• ≥5 kg to <10 kg: 144 mg (72 mg per mAb) 
• ≥3 kg to <5 kg: 96 mg (48 mg per mAb) 
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Endpoints 
 
Primary 
• Concentrations of casirivimab and imdevimab in serum over time  
Secondary 
• 
Treatment-emergent adverse events (TEAEs), and severity of TEAEs, through end of study 
• 
Grade ≥3 injection site reactions and grade ≥3 hypersensitivity reactions through day 4  
• 
Immunogenicity as measured by anti-drug antibodies (ADA) to casirivimab and imdevimab 
over time 
Procedures 
and 
Assessments 
Procedures and assessments will include the following: 
• Blood collection for PK-ADA 
• Blood collection for SARS-CoV-2 serology status  
• Mid-turbinate swab sample collection for SARS-CoV-2 RT-qPCR 
• COVID-19-related medically-attended visits, signs and symptoms of COVID-19 
• Adverse events, including AESIs (grade ≥3 injection-site reactions, grade ≥3 hypersensitivity 
reactions, and multisystem inflammatory syndrome in children [MIS-C] as defined by the CDC) 
• Safety labs, vital signs, targeted physical examination, concomitant medications and procedures, 
and pregnancy test (all WOCBP, regardless of pregnancy status) 
Statistical Plan  
Statistical 
Hypothesis 
No formal hypothesis testing is planned in this study.  
Justification 
of Sample Size Analyses of PK, safety, tolerability, immunogenicity, and serology data will be descriptive. The 
sample size was chosen based on PK considerations and is consistent with early phase studies to 
assess PK.  
At least 12 subjects are needed to enroll in each weight group (Group A: ≥10 kg to <40 kg, and 
Group B: ≥3 kg to <10 kg) to assess drug concentration. The study plans to enroll approximately 28 
subjects in total.  
The sample size and dosing may be adjusted if planned SC dosing of casirivimab+imdevimab does 
not achieve concentrations in serum similar to, or higher than, that observed in adults (≥18 years of 
age) after casirivimab+imdevimab 1200 mg (600 mg per mAb) SC administration. PK will be 
evaluated on an ongoing basis to determine if dose adjustments are needed and whether more 
subjects are needed for analysis. 
Analysis of 
Drug 
Concentration 
Data 
Analysis will be performed according to two groups: 
• Group A: body weight ≥10 kg to <40 kg 
• Group B: body weight ≥3 kg to <10 kg 
The concentrations of total casirivimab and total imdevimab over time will be summarized by 
descriptive statistics for each weight group. 
Stratification of the analysis may be performed if subjects receive a treatment that has the potential 
to impact the pharmacokinetics of casirivimab+imdevimab (eg, IVIG)  
Interim 
Analyses 
 
No formal interim analysis is planned. Interim reviews of the PK and safety data may be performed 
before subjects complete the end of study. 
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1. 
INTRODUCTION 
1.1. 
COVID-19 and the Role of Spike (S) Protein in SARS-CoV-2 Viral Pathogenesis 
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 
2 (SARS-CoV-2), first emerged in December 2019 and was declared a global pandemic in March 
2020 (WHO, 2020) (Wu, 2020) (Zhu, 2020). 
Coronaviruses consist of an RNA genome packaged in nucleocapsid (N) protein. The resulting 
capsid is surrounded by an outer envelope comprised of membrane (M) protein and envelope (E) 
protein, which are involved in virus assembly, and spike (S) protein, which mediates entry into 
host cells. The S protein is essential for virus infectivity and is the main target of the humoral 
immune response, as demonstrated by serology analysis of recovered COVID-19 patients 
(Long, 2020). By mediating binding to the host receptor angiotensin-converting enzyme 2 (ACE2), 
the S protein facilitates membrane fusion and entry of the virus into susceptible cells 
(Hoffmann, 2020). The S protein is itself composed of 2 functional subunits: the S1 subunit, which 
contains the receptor binding domain (RBD) responsible for binding to ACE2 on host cells, and 
the S2 subunit, which mediates fusion of the viral and cellular membranes (Walls, 2020). COVID-
19 cases continue to rise globally, but there are no approved or recommended therapeutic options 
for pre- or post-exposure prophylaxis against SARS-CoV-2 infection (NIH, 2021). 
1.2. 
Casirivimab+Imdevimab: Human Monoclonal Antibodies, Targeting 
SARS-CoV-2 S Protein, for the Treatment and Prevention of COVID-19 
Regeneron Pharmaceuticals, Inc. (Regeneron) has developed monoclonal antibodies (mAbs) 
directed against the RBD of the SARS-CoV-2 S protein. Casirivimab (REGN10933) and 
imdevimab (REGN10987) are human, IgG1 mAbs that bind simultaneously to the RBD and block 
interaction with ACE2. As co-administered combination therapy, casirivimab+imdevimab, also 
referred to by the proprietary name conditionally accepted by the FDA (REGEN-COV™) and by 
the EMA (RONPAPREVE®), is being evaluated for the treatment and prevention of SARS-CoV-
2 infection and retains neutralization potency against circulating SARS-CoV-2 variants of concern 
(UK B.1.1.7 [alpha], South Africa B.1.351 [beta], California B.1.429 [epsilon], India B.1.617.2 
[delta], and Brazil P.1 [gamma]) and protects against the selection of resistant variants in vitro 
(Copin, 2021) (REGEN-COV™ (casirivimab with imdevimab) [HCP Fact Sheet], 2021). 
In phase 3 clinical trials, the combination of casirivimab+imdevimab was shown to be effective 
and well-tolerated in the treatment of outpatient and hospitalized adults with COVID-19, and in 
the prevention of SARS-CoV-2 infection in adults and adolescents (Horby, 2021) 
(O’Brien, 2021a) (O’Brien, 2021b) (Weinreich, 2021b) (see Section 3.3 for additional 
information). Casirivimab and imdevimab (1200 mg; 600 mg of each mAb) is currently authorized 
under Emergency Use Authorization (EUA) for the treatment of outpatients 12 years and older 
who are at high risk for developing severe COVID-19 (FDA, 2020).  
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1.3. 
An Open-Label Study to Assess the Pharmacokinetics and Safety Profile of 
Casirivimab+Imdevimab in High-Risk Pediatric Subjects  
This protocol describes a phase 2a, open-label study to assess the pharmacokinetics (PK), as well 
as safety, tolerability, and immunogenicity, of casirivimab+imdevimab in children under 12 years 
old who are uninfected but at high risk to develop severe COVID-19 if they become infected 
(CDC, 2021a).  
For more information regarding the rationale for the study design and dose selection, refer to 
Section 3.2. Additional background information on the study drug and the overall development 
program can be found in the Investigator’s Brochure.  
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to characterize the concentrations of casirivimab and 
imdevimab in serum over time after a single subcutaneous (SC) administration 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To assess the safety and tolerability of SC single administration of 
casirivimab+imdevimab 
• To assess the occurrence of grade ≥3 injection site reactions and grade ≥3 
hypersensitivity reactions in subjects treated with SC doses of 
casirivimab+imdevimab 
• To assess the immunogenicity of casirivimab and imdevimab  
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To assess the occurrence of COVID-19 during the study 
• To assess the occurrence of COVID-19-related medically-attended visits during the 
study 
• To assess the occurrence of SARS-CoV-2 seroconversion during the study  
• To identify biomarkers associated with the safety and exposure of 
casirivimab+imdevimab and/or SARS-CoV-2 infection 
• To assess viral genetic variation in SARS-CoV-2 in any subject with a positive 
SARS-CoV-2 RT-qPCR test 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
No formal statistical hypothesis will be tested. The pharmacokinetics hypothesis for this study is 
defined in Section 3.2.3.1. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This study will assess the PK, safety, tolerability, and immunogenicity of casirivimab+imdevimab 
in subjects <12 years old who are not infected with SARS-CoV-2 but are at high risk to develop 
severe COVID-19 if they were to become infected.  
Collection of Pharmacokinetics Data to Inform Efficacy Extrapolation. To date, the efficacy 
of casirivimab+imdevimab has not been evaluated in study participants under 12 years of age, 
either in the prophylaxis or treatment settings. The Sponsor proposes to utilize efficacy data 
collected in clinical trials of adult populations, in conjunction with a PK data in subjects under 
12 years of age, to extrapolate efficacy in the younger population. The Sponsor considers an 
extrapolation approach for pediatric efficacy to be justified by the similarities between adult and 
pediatric populations with respect to SARS-CoV-2 viral distribution, viral burden, and course of 
viral infection over time, and the corollary expectation that anti-viral response would be the same 
in these populations. 
The frequency of blood draws at early timepoints (Table 3) is required in order to achieve adequate 
sampling for PK analysis in the study population (<12 years of age and weighing <40 kg; 
Section 7.2.1) for which such data have not been previously collected. Staggered sampling 
schedules will be utilized to increase coverage of timepoints for PK analysis while simultaneously 
minimizing the frequency of blood draws in this younger population. Drug concentration data will 
be evaluated on a regular basis to inform whether sample size adjustments are required. 
Open-Label Design with No Placebo. Prior to this study, casirivimab+imdevimab have been 
administered in clinical trials to subjects 12 years and older, with an acceptable safety profile. The 
study utilizes an open label design with no placebo control group, a design is considered 
appropriate in light of the safety profile of casirivimab+imdevimab observed in subjects 12 years 
and older, as well as its demonstrated clinical efficacy as a prophylactic agent (Section 3.3.1), 
which may benefit the study target population in particular (Section 3.2.2). 
Length of Follow-up Period. Subjects will undergo a follow-up period of approximately 24 
weeks (six months) for assessment of drug concentrations, safety, and immunogenicity. In COV-
2069, a single 1200 mg SC dose resulted in an observed half-life of approximately 32.4 days 
(casirivimab) and 27.0 days (imdevimab). The duration of the follow-up period in the current study 
is thus intended to allow observation of drug concentration and safety in subjects for more than 
five half-lives (six months) following study drug administration. The length of the follow-up 
period may be modified based on drug concentration data observed in this study, as well as ongoing 
nonclinical data as they become available.  
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Collection of Serology for SARS-CoV-2 Serostatus. Subjects will be assessed for antibodies 
against SARS-CoV-2, which may include but not be limited to antibodies against spike (S) and/or 
nucleocapsid (N) protein, at the screening/baseline visit and (depending on the subject’s weight at 
the time of study drug administration) during scheduled and/or unscheduled visits following study 
drug administration. These assessments will allow detection of prior SARS-CoV-2 infection 
and/or seroconversion subsequent to a SARS-CoV-2 infection that occurs during the study. 
3.2.2. 
Rationale for Target Population 
3.2.2.1. 
Risk Factors for Severe COVID-19 in the Pediatric Population 
In this study, the target population consists of individuals <12 years of age with at least one risk 
factor for developing severe COVID-19. The suggested risk factors includes known risk factors 
and allows for any condition deemed by the Investigator to pose a risk for severe COVID-19 
(Section 7.2.1), and is intended to allow flexibility for study inclusion in light of the evolving 
understanding of risk factors in the pediatric population. 
Pediatric patients generally have asymptomatic or mild disease; however, certain pediatric 
populations are at high risk for developing severe COVID-19 (CDC, 2021a) (Bellino, 2020) 
(Graff, 2021). A study reviewing children with SARS-CoV-2 infection found that nearly half 
(45%) had at least 1 comorbid condition. The most common types of comorbid conditions 
identified were pulmonary (16.7%), gastrointestinal (10.8%), and neurologic disease (10.6%) 
(Graff, 2021). Other genetic conditions (eg, sickle cell disease) also put children at increased risk 
for severe disease (CDC, 2021a). 
A complication of COVID-19 in the pediatric population is the occurrence of multisystem 
inflammatory syndrome in children (MIS-C). A large observational study in the United States 
found that MIS-C cases, which occurred at an incidence of 2.1 cases per 100,000 individuals <21 
years of age, coincided with peak COVID-19 cases with a lag of 2 to 5 weeks. These data suggest 
that MIS-C occurs approximately 2 to 5 weeks after the initial COVID-19 infection. The incidence 
of MIS-C. In the study, a majority of children experiencing MIS-C had asymptomatic or mild 
COVID-19 infection initially. Most patients developed hypotension or shock, with about 60% 
being admitted for intensive care. Myocarditis, cardiac dysfunction, or coronary artery dilatations 
were reported in approximately 30% of patients. Currently, it is unknown if any preexisting 
condition presents a higher risk for MIS-C, and the pathophysiology of MIS-C is still being 
investigated (Belay, 2021). To ensure expeditious reporting of any MIS-C that may occur during 
this study, MIS-C will be captured as an AESI. 
In light of these and other risk factors for developing severe COVID-19, the pediatric population 
in this study may benefit from receipt of casirivimab+imdevimab as prophylaxis against SARS-
CoV-2 infection. 
3.2.2.2. 
Prophylaxis as a Complementary Approach to Vaccination in High-Risk 
Pediatric Populations 
Prophylaxis with casirivimab+imdevimab, which provides immediate protection against SARS-
CoV-2 infection (Section 3.3.1), may complement vaccination strategies, which require two weeks 
or more (and sometimes several doses) to generate protection. Casirivimab+imdevimab may be 
particularly useful to prevent infection in those at high risk of infection who may not mount a fully 
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protective immune response after receipt of a vaccine, or are otherwise unable to be vaccinated 
(for example, due to allergies to vaccine components) and therefore remain susceptible to infection 
(Boyarsky, 2021a) (Boyarsky, 2021b) (Cavanaugh, 2021) (Teran, 2021) . For example, pediatric 
patients with B-cell dysfunction/deficiency (eg, X-linked agammaglobulinemia [XLA], common 
variable immunodeficiency [CVID], X-linked hyper-IgM, severe combined immunodeficiency, 
Wiskott-Aldrich syndrome, and selective IgG class deficiency) and pediatric patients receiving B-
cell depleting therapies for conditions such as Crohn’s disease, Ulcerative Colitis, and certain 
pediatric autoimmune diseases are unlikely to respond to COVID-19 vaccines. Pediatric patients 
with B-cell dysfunction/deficiency may routinely receive IVIG, but it is unclear whether IVIG will 
contain protective antibodies to prevent SARS-CoV-2 infection.  
In summary, pediatric populations who have not yet received a vaccine against SARS-CoV-2, are 
unable to receive a vaccine, and/or who are not expected to develop protective immunity after 
vaccination, may benefit from prevention with casirivimab+imdevimab. 
3.2.3. 
Rationale for Dose Selection 
3.2.3.1. 
Overall Pharmacokinetics Objective of Study 
In this study, subjects will be evaluated separately in two groups, with each group defined 
according to body weight (Section 11.4.4.1). For each group, dosing will be adjusted by weight as 
described in Section 8.1. The target for dosing in the study population (<12 years of age and 
weighing <40 kg) is for ≥95% of subjects to achieve a similar or higher exposure of each antibody 
to that observed in adults (≥18 years of age) after a single SC dose of casirivimab+imdevimab 
1200 mg (600 mg per mAb). 
Hypothesis: In high-risk subjects <12 years old, a single body weight-adjusted dose of SC 
casirivimab+imdevimab will achieve serum concentrations similar to, or higher than, that observed 
in adults (≥18 years of age) after casirivimab+imdevimab 1200 mg (600 mg per mAb) SC 
administration, and will be well-tolerated. 
3.2.3.2. 
Population Pharmacokinetics Modeling to Predict Exposure in Study Population 
To predict exposure in the target population of the study, two 2-compartment population PK 
models with linear elimination and first-order absorption following SC dosing were developed for 
casirivimab+imdevimab. These models were based on observed data from COV-2069 (single SC 
dose for prevention in household contacts of SARS-CoV-2-infected individuals), COV-20145 
(single SC or IV dose for treatment in outpatients with low-risk or asymptomatic infection), and 
COV-2067 (single IV dose for treatment in outpatients, including those with risk factors) following 
IV and SC dosing in adults. Allometric scaling (with an exponent of 1 for volume and 0.75 for 
clearance) was applied on PK parameters to account for the effect of body weight in pediatric 
populations. In addition, age impact (gestational age + age) was applied on clearance to account 
for the effect of body size and age (on top of body weight) in pediatric populations (Robbie, 2012). 
Simulations of concentration vs. time were performed to predict exposure metrics for subjects in 
each weight category receiving casirivimab+imdevimab. The proposed doses are predicted to 
result in similar or higher exposure (Cmax, C28, AUC0-28) to adults in ≥95% of pediatric subjects 
within each weight tier (Table 1).  
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For subjects <12 years of age and weighing <40 kg, the 95th percentiles of predicted Cmax and 
AUC0-28 across the pediatric weight-tiered groups were 40% to 92% higher than the predicted 95th 
percentiles in adults after a single SC dose of 1200 mg (600 mg per mAb). However, the 95th 
percentiles of Cmax and AUC0-28 in pediatric weight-tiered groups were lower than the observed 
mean values following a single 2400 mg IV dose in adults, a dose with an acceptable safety and 
tolerability profile. 
PK will be evaluated on an ongoing basis to determine if dose adjustments are needed.  
Table 1: 
Predicted Exposure (Population PK Model) of Total Casirivimab 
(REGN10933) and Total Imdevimab (REGN10987) in Serum of Pediatric 
Subjects (<12 Years) 
Exposure 
Metrics 
Population 
Dose 
Casirivimab1 
Imdevimab1 
C28 (mg/L) 
Adult 
600 mg SC 
29.5 (19.4, 43.8) 
25.1 (16.9, 36.5) 
≥40 kg 
600 mg SC 
33.3 (20.8, 57.3) 
28.3 (18.1, 48.4) 
≥20 to <40 kg 
400 mg SC 
56.9 (37.0, 85.9) 
48.6 (32.2, 72.3) 
≥10 to <20 kg 
200 mg SC 
57.1 (36.3, 91.8) 
49.3 (31.8, 79.3) 
≥5 to <10 kg 
75 mg SC 
51.0 (32.2, 75.3) 
45.1 (28.9, 64.8) 
≥2.5 to <5 kg 
50 mg SC 
59.9 (41.0, 90.1) 
52.5 (36.9, 77.5) 
<2.5 kg 
25 mg SC 
49.0 (35.9, 71.4) 
42.9 (32.3, 61.2) 
Cmax (mg/L) 
Adult 
600 mg SC 
51.1 (33.4, 72.6) 
48.2 (32.2, 67.8) 
≥40 kg 
600 mg SC 
55.8 (32.4, 97.6) 
52.6 (31.2, 91.1) 
≥20 to <40 kg 
400 mg SC 
92.1 (58.2, 139.4) 
86.5 (55.6, 129.4) 
≥10 to <20 kg 
200 mg SC 
85.0 (54.6, 131.5) 
79.7 (52.1, 121.5) 
≥5 to <10 kg 
75 mg SC 
69.3 (42.9, 104.0) 
64.6 (40.8, 95.1) 
≥2.5 to <5 kg 
50 mg SC 
83.8 (54.4, 127.7) 
77.2 (51.5, 115.6) 
<2.5 kg 
25 mg SC 
71.2 (49.7, 107.0) 
65.0 (46.9, 96.3) 
AUC0-28 
(mg*day/L) 
Adult 
600 mg SC 
1093 (752, 1533) 
993 (708, 1361) 
≥40 kg 
600 mg SC 
1214 (738, 2087) 
1104 (693, 1868) 
≥20 to <40 kg 
400 mg SC 
2060 (1331, 3052) 
1865 (1238, 2714) 
≥10 to <20 kg 
200 mg SC 
1956 (1274, 3048) 
1775 (1180, 2746) 
≥5 to <10 kg 
75 mg SC 
1648 (1031, 2452) 
1508 (961, 2197) 
≥2.5 to <5 kg 
50 mg SC 
1976 (1298, 2980) 
1796 (1216, 2661) 
<2.5 kg 
25 mg SC 
1657 (1182, 2474) 
1497 (1107, 2200 
1 All values are represented as median (5th percentile, 95th percentile). 
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. 
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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. 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. 
Serious adverse events occurred more frequently in the placebo group (4.0%) than in either 
treatment group (2400 mg, 1.1%; 1200 mg, 1.3%), and grade ≥2 infusion-related reactions were 
infrequent (<0.3% in all groups) (Weinreich, 2021b). Similar virologic efficacy and a similar 
safety profile were observed in the phase 1/2 portion of this trial, which evaluated 
casirivimab+imdevimab at 8000 mg and 2400 mg IV doses (Weinreich, 2021a). 
In the controlled open-label platform study RECOVERY in hospitalized patients, a single dose of 
casirivimab+imdevimab 8000 mg given in addition to standard of care (compared to standard of 
care alone) reduced the incidence of death through day 28 by 20% in those who were seronegative 
at baseline (ie, those who had not yet mounted an immune response to SARS-CoV-2). Among 
seronegative patients, the median duration of hospitalization was 4 days shorter in the 
casirivimab+imdevimab group, and the proportion of patients discharged alive by day 28 was 
greater by 19%. The reported frequency of fever (4% versus 3%), sudden hypotension (4% versus 
2%), and thrombotic events (2% versus 1%) was slightly higher in the casirivimab+imdevimab 
group than the placebo group, while the frequency of sudden worsening in respiratory status (21% 
versus 22%) and clinical hemolysis (1% versus 2%) was slightly lower. There were 5 reports of 
SAEs believed to be treatment-related (Horby, 2021). These findings are consistent with 
preliminary data from a much smaller phase 1/2 study in hospitalized patients, which also 
demonstrated rapid reduction of viral load and trends for reducing the risk of death or mechanical 
ventilation, particularly in those who were seronegative at baseline (Regeneron, 2020). 
Subcutaneous Administration of Casirivimab+Imdevimab in Clinical Trials. 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%. Serious adverse events occurred at similar frequencies in the treatment 
group (1%) and placebo group (1%). Injection-site reactions were more common in the treatment 
group (4%) compared to the placebo group (2%), but no injection-site reactions in the study were 
grade 3 or above. The majority of injection site reactions occurred within one day and resolved 
within two days (O’Brien, 2021b).  
Among a sub-group of individuals in COV-2069 who were identified as SARS-CoV-2 positive 
but asymptomatic during screening, a single subcutaneous dose of casirivimab+imdevimab (1200 
mg) reduced (relative to placebo) progression to symptomatic disease by 31.5%, and reduced the 
duration of symptoms in those that developed symptomatic infections. Injection-site reactions 
were more common in the treatment group (4%) compared to the placebo group (1%), but no 
injection-site reactions in the study were grade 3 or above (O’Brien, 2021a).  
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In COV-2069, efficacy results were similar in adolescents (age 12 to <18) as observed in adults: 
0% of subjects in the 1200 mg SC treatment group experienced symptomatic infection, compared 
with 9.3% of subjects in the placebo group. Safety data in adolescent subjects were also similar to 
that observed in adults. Injection site reactions were more common in the treatment group (5.9%) 
compared to the placebo group (1.6%), but none were grade 3 or above in any group.  
In HV-2093 (R10933-10987-HV-2093), an adult volunteer study evaluating multiple doses of 
subcutaneous administration of casirivimab+imdevimab (monthly dosing over 6 months), 
injection site reactions were more common in the casirivimab+imdevimab group (34.6%) 
compared with the placebo group (15.8%), but none were grade 3 or above in any group. 
3.3.2. 
Summary of Risks 
Important 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 patients who received casirivimab+imdevimab during 
ongoing clinical trials. 
Important Potential Risks. The important potential risks of casirivimab+imdevimab are the 
clinical consequences of immunogenicity and embryo-fetal toxicity. 
Protein therapeutics carry the potential risk of an immunogenic response in the form of anti-drug 
antibody and neutralizing antibody 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 female patients who are pregnant or breastfeeding. 
Human IgG1 antibodies are known to cross the placental barrier and are present in breast milk. 
Casirivimab+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 or 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.  
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Other Theoretical Risks. Theoretical risks of casirivimab+imdevimab include interference with 
the patient’s endogenous immune response to either SARS-CoV-2 infection or vaccination against 
COVID-19. In this study, risk mitigation includes prohibition of SARS-CoV-2 vaccination for 90 
days after study drug administration (Section 8.7.1), consistent with current CDC guidance 
(CDC, 2021b). 
Antibody-dependent enhancement (ADE) has been observed for some therapeutics targeting 
exogenous viral proteins. For antibody therapies, ADE is thought to occur when binding of 
antibody to the target viral protein enhances Fc gamma receptor (FcγR)-mediated host cell entry 
of the virus (Iwasaki, 2020). This could potentially lead to worsening of disease and, in the case 
of SARS, acute lung injury (Liu, 2019). Casirivimab and imdevimab each retain the Fc region, as 
this may play a role in protecting against viral infection (Yasui, 2014), there is no strong evidence 
of ADE in other coronavirus models (Kam, 2007) (Liu, 2019) (Luo, 2018). To date, Fc-containing 
mAbs developed by the Sponsor for Ebola virus and MERS-CoV have demonstrated specificity to 
their exogenous targets with no significant unexpected safety findings in preclinical or clinical 
studies. All subjects will have follow-up assessments during the drug elimination period (for over 
five half-lives; Section 3.2.1), and subjects will be monitored for any signal of ADE.  
3.3.3. 
Potential Benefit of Casirivimab+Imdevimab in the Study Population 
As detailed in Section 3.2.2.2, the target population to be enrolled in this study represents an at-
risk population, who have an elevated risk of SARS-CoV-2 infection and either cannot be 
vaccinated or may not mount a protective immune response after vaccination. There is therefore a 
potential benefit to providing casirivimab+imdevimab to this population as prophylaxis against 
SARS-CoV-2 infection and development of COVID-19 that could potentially develop into severe 
disease. 
3.3.4. 
Summary 
Based on the available clinical and nonclinical data for casirivimab+imdevimab demonstrating 
anti-viral efficacy with an acceptable safety profile, as well as the unmet need for preventative 
therapy in the at-risk pediatric population to be enrolled in this study, it is the opinion of the 
Sponsor that the overall risk-benefit balance for casirivimab+imdevimab is acceptable to allow 
evaluation of this mAb combination in the study population.  
4. 
ENDPOINTS 
4.1. 
Primary Endpoint 
The primary endpoint is the concentrations of casirivimab and imdevimab in serum over time. 
4.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Treatment-emergent adverse events (TEAEs), and severity of TEAEs, through end of 
study 
• Grade ≥3 injection site reactions and grade ≥3 hypersensitivity reactions through day 4  
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• Immunogenicity as measured by anti-drug antibodies (ADA) and neutralizing 
antibodies (NAb) to casirivimab and imdevimab over time 
5. 
STUDY VARIABLES  
5.1. 
Demographic and Baseline Characteristics 
The variables for baseline characteristics include standard demography (eg, age, race, weight, 
height), medical history, and medication history. 
5.2. 
Safety Variables 
Safety variables include recording, measurements, or laboratory test results for individual subjects 
of the following: TEAEs, vital signs (including pulse rate, blood pressure, respiration rate, and 
body temperature), targeted physical examination findings, results of laboratory tests (including 
hematology, blood chemistry, pregnancy test), and diagnostic assay for SARS-CoV-2 infection (at 
baseline for all subjects; and at the time when signs of COVID-19 are identified in subjects). 
5.3. 
Pharmacokinetic Variables 
The PK variables are concentrations of casirivimab and imdevimab in serum and time. The 
sampling time points are specified in Table 3. 
5.4. 
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 3. Samples 
positive in the ADA assays will be further characterized for ADA titers and when feasible, NAb 
status. 
5.5. 
Other Variables 
Other variables include anti-SARS-CoV-2 serology test results and time, and COVID-19-related 
medically-attended visits. The sampling time points are specified in Table 3. 
6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This is an open label, phase 2a study to assesses the PK, safety, tolerability, and immunogenicity 
of casirivimab+imdevimab in subjects <12 years old who are not infected with SARS-CoV-2 but 
are at high risk to develop severe COVID-19 if they become infected. Risk factors are defined as 
inclusion criteria in Section 7.2.1). A diagram depicting the study design is provided in Figure 1. 
The Schedule of Events is provided in Section 9. 
Subjects will be assessed for eligibility during the screening period, which may occur up to 7 days 
prior to the day 1 (baseline) visit. To be eligible, subjects must not have symptoms consistent with 
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COVID-19, and must be confirmed negative for SARS-CoV-2 infection prior to study drug 
administration according to the window specified in the exclusion criteria.  
This study will enroll subjects into two analysis groups at baseline, with each group defined 
according to body weight (Section 11.4.4.1). All subjects will receive a single dose of 
casirivimab+imdevimab, adjusted for body weight as described in Section 8.1. Each subject will 
be observed for one hour after completion of dosing, and the subject (or their parent or guardian) 
will be contacted by phone within 24 hours of dosing to assess for any potential adverse events 
(AEs).  
Following dose administration, subjects will be followed for approximately 24 weeks (169 days) 
to monitor for TEAEs. At each scheduled site visit, the investigator or designee will assess and 
document the subject’s general health and adverse events since the last contact. If a scheduled visit 
cannot be performed in person (for example, due to COVID-19 restrictions), or if no assessments 
or collections require the subject to be contacted in person, the visit may be conducted virtually 
(ie, by telemedicine or phone). Grade ≥3 injection site reactions and grade ≥3 hypersensitivity 
reactions that occur after study drug administration will be captured as AESIs, to allow for 
expedited reporting. Multisystem inflammatory syndrome in children (MIS-C) will also be 
captured as an AESI. 
During the first five weeks after study drug administration, subjects will have samples collected 
for clinical laboratory tests (hematology, blood chemistry), drug concentration, and 
immunogenicity. On day 1, subjects in group A and group B will each be assigned using an 
Interactive Web Response System (IWRS) to one of two staggered PK-ADA sampling schedules 
(schedule 1 and schedule 2).  
6.2. 
Monitoring for Potential COVID-19 
Subjects and their caregivers will be provided with contact information for the clinical study site 
and will be given written and verbal instructions to call site personnel with any changes in their 
health status. They will be asked to promptly notify site personnel by phone of any symptoms or 
signs potentially related to COVID-19. Additionally, subjects and their caregivers will be 
contacted regularly during the study for symptoms or signs of COVID-19.  
In the event of suspected COVID-19, subjects will continue in the study and undergo additional 
unscheduled visits, as described in Section 6.3.  
6.3. 
Management of Subjects With Suspected COVID-19  
Unscheduled Visit to Confirm SARS-CoV-2 Infection and COVID-19 Symptoms. Subjects 
who have signs or symptoms consistent with COVID-19 will have an unscheduled visit to collect 
a mid-turbinate nasal swab sample for SARS-CoV-2 RT-qPCR testing and viral genome 
sequencing, evaluate signs and symptoms of COVID-19 (by the Investigator or designee), collect 
blood for drug concentration and immunogenicity, and (depending on the subject’s weight 
category) collect blood for serology and exploratory research (Table 3).  
Medical Management of SARS-CoV-2-Positive Subjects. Subjects with laboratory confirmed 
SARS-CoV-2 infection and/or the parent or guardian should be informed as soon as possible. Local 
or CDC guidance should be followed to reduce the risk of transmission. Subjects with acute illness 
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should be medically managed according to local standard of care and per the discretion of the 
treating physician.  
Continuation of the Schedule of Events for SARS-CoV-2-Positive Subjects. Subjects with 
confirmed SARS-CoV-2 infection will continue to follow the Schedule of Events as planned. If a 
scheduled visit cannot be performed in person (for example, due to COVID-19 restrictions), or if 
no assessments or collections require the subject to be contacted in person, the visit may be 
conducted virtually (ie, by telemedicine or phone). 
Additional Weekly Unscheduled Visits for Viral Testing of SARS-CoV-2-Positive Subjects. 
Subjects with confirmed SARS-CoV-2 infection will have weekly unscheduled visits to collect a 
mid-turbinate nasal swab sample for SARS-CoV-2 testing. These visits will include all 
assessments indicated in the ‘SARS-CoV-2 Confirmation’ visit in the Schedule of Events 
(Table 3). Note that these weekly visits will be held in addition to the visits that are planned as part 
of the study. If a weekly visit occurs within the same window as a planned visit, all assessments 
indicated in the ‘SARS-CoV-2 Confirmation’ visit must be performed during the planned visit. 
Assessments or samples that are indicated for both visits in the Schedule of Events will only be 
collected once. The weekly unscheduled visits will continue until two consecutive negative SARS-
CoV-2 test results are obtained from samples collected ≥24 hours apart. 
Additional Assessment of Adverse Events in SARS-CoV-2-Positive Subjects. Subjects with 
confirmed SARS-CoV-2 infection will be assessed by the Investigator or designee for adverse 
events (Section 10.1) and details of COVID-19-related medically-attended visits (Section 9.2.4.6). 
This assessment will occur at minimum on a weekly basis during the unscheduled visits described 
above. Subjects may be assessed for adverse events on a more frequent basis, if deemed clinically 
appropriate by the Investigator or designee. If more frequent assessments are performed, these will 
be reported as additional unscheduled visits. 
Requirements for SARS-CoV-2 Testing During Unscheduled Visits. Any SARS-CoV-2 test 
conducted during an unscheduled visit will be recorded as a concomitant procedure and associated 
with the adverse event “COVID-19”. The preferred method of SARS-CoV-2 testing is by central 
laboratory RT-qPCR using a mid-turbinate nasal swab sample. Central laboratory samples that 
have been confirmed positive for SARS-CoV-2 may be used for exploratory viral sequencing 
analysis (Section 9.2.8.4). 
Note: If a subject is unable or unwilling to visit the study site for SARS-CoV-2 testing as part of 
an unscheduled visit, central laboratory testing of a mid-turbinate swab sample may not be 
feasible. If this occurs, a local diagnostic assay (eg, molecular assay such as RT-PCR for SARS-
CoV-2), using an appropriate sample such as nasopharyngeal, nasal, oropharyngeal, or saliva, is 
allowable.  
The local diagnostic assay for SARS-CoV-2 must be considered acceptable for clinical use by local 
standards. If the test has not been approved or has not received authorization, such as EUA issued 
by the US FDA or authorization by the equivalent local health authority, the Sponsor must be 
consulted. The use of RT-PCR is highly recommended. 
In the event that the subject obtains SARS-CoV-2 testing at a facility not affiliated with the site, 
study site personnel will attempt to obtain and record all information from SARS-CoV-2 tests 
conducted in local laboratories that are associated with other medical facilities. This information 
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will include test results, name of the assay(s) utilized, and whether the laboratory or laboratories 
conducting the assay(s) are CLIA certified (or equivalent). 
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Figure 1: 
Study Flow Diagram 
 
The EOS visit will be performed in person. In the case that the day 169 visit was conducted prior to Amendment #2, the subject should return to the clinical trial 
unit for 1 additional visit for the EOS visit as soon as possible after Amendment #2 is approved by local regulatory and ethics as required. 
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6.4. 
Study Stopping Rules 
The Sponsor will monitor safety data on an ongoing basis to assess the risk/benefit profile of 
casirivimab+imdevimab. The Sponsor team may be comprised of the medical/study directors, a 
Global Patient Safety representative, representatives from Biostatistics and Data Management, as 
well as representatives from Clinical Operations and Regulatory Affairs. The data to be reviewed 
will include, but are not limited to the following:  
• TEAEs that result in an early study drug discontinuation 
• Grade ≥3 TEAEs  
• Treatment-emergent SAEs 
• Treatment-emergent AESIs 
• Selected laboratory tests, as deemed appropriate  
If there are significant safety concerns, a recommendation may be made to temporarily pause, alter, 
or terminate the study. Appropriate action, if needed, will be taken based upon this review and in 
consultation with additional Sponsor team members, as needed. Applicable regulatory procedures 
will be adhered to as required by local laws in relation to any decisions related to a change in study 
conduct, temporary halt, study termination, or study restart. 
6.5. 
End of Study Definition 
The end of study is defined as the date the last subject completes the last study visit, withdraws 
from the study, or is lost to follow-up (ie, the subject can no longer be contacted by the 
Investigator).  
6.6. 
Study Committees 
6.6.1. 
Independent Data Monitoring Committee 
An IDMC (Independent Data Monitoring Committee) will actively review data throughout the 
study to monitor patient safety and efficacy data. The IDMC can make recommendations about 
early study closure or changes to the study conduct. The operation of the IDMC is governed by a 
charter describing further details, such as procedures (including but not limited to periodic safety 
monitoring) and requirements for reporting its observations to the Sponsor. 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 cutoff date 
for the analysis. 
6.6.2. 
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:  
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• Treatment-emergent adverse events that result in an early study withdrawal 
• Serious adverse events (SAEs) 
• Selected laboratory tests, as deemed appropriate by the safety monitoring team 
• Grade ≥3 injection-site reactions or grade ≥3 hypersensitivity reactions 
• Multisystem inflammatory syndrome in children (MIS-C) 
• Drug concentration 
Appropriate action, if needed, will be taken based upon this review and in consultation with the 
medical monitor.  
6.7. 
Planned Interim Analysis 
No formal interim analysis is planned for the study. Interim reviews of PK and safety data may be 
performed before subjects complete the end of study. 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
SUBJECTS 
7.1. 
Number of Subjects Planned 
The study will enroll approximately 28 subjects <12 years. This includes at least 12 subjects with 
body weight ≥10 kg and <40 kg, and at least 12 subjects with body weight ≥3 kg to <10 kg. Sample 
size and dosing may be adjusted based on PK analyses conducted (Section 3.2.3). 
Refer to Section 11.2 for justification of sample size. 
7.2. 
Study Population 
7.2.1. 
Inclusion Criteria 
Subjects must meet the following criteria to be eligible for inclusion in the study: 
1. Is <12 years of age and ≥3 kg to <40 kg at the time parental/guardian consent is signed  
2. Has at least one risk factor for developing severe COVID-19 if they were to become 
infected, such as: 
a. Obesity (BMI [kg/m2] ≥95th percentile for age and sex based on CDC growth charts) 
b. Cardiovascular disease 
c. Chronic lung disease 
d. Type 1 or type 2 diabetes mellitus 
e. Chronic kidney disease, including those on dialysis 
f. Chronic liver disease 
g. Immunocompromised or immunodeficient, based on Investigator’s assessment 
(examples include cancer treatment, bone marrow or organ transplantation, immune 
deficiencies, HIV infection, sickle cell anemia, thalassemia, and prolonged use of 
immune-weakening medications) 
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h. Medical complexities (examples include any underlying genetic condition, neurologic 
condition, metabolic condition, or congenital heart disease) 
i. Any other condition deemed by the Investigator to be a risk factor for severe 
COVID-19 
3. Is willing and able to comply with clinic visits and study-related procedures 
4. Has provided informed consent signed by subject or legally acceptable representative 
Note: Age-appropriate assent will be collected from the study subject according to local 
regulatory (competent authority/ethics) guidelines. 
7.2.2. 
Exclusion Criteria 
Subjects who meets any of the following criteria will be excluded from the study: 
1. Has positive diagnostic test for SARS-CoV-2 infection from a sample collected during 
screening ≤7 days prior to study drug administration 
Note: The sample for the test should be collected ≤7 days within study drug administration, 
and the result should be reviewed and confirmed negative prior to dosing. Historical 
records will not be accepted. 
2. Has active respiratory or non-respiratory symptoms consistent with COVID-19 in the 
opinion of the Investigator 
3. Has subject-reported clinical history of COVID-19, as determined by Investigator, within 
the last 90 days 
4. Has subject-reported history of prior EUA/approved positive diagnostic test for SARS-
CoV-2 infection within the last 90 days 
5. Is currently hospitalized or was hospitalized for >24 hours for any reason within 14 days 
of the screening visit 
6. Prior use (within 90 days prior to study drug administration) or current use of any 
investigational, authorized, or approved passive antibody for prophylaxis of SARS-CoV-2 
infection, including convalescent plasma, convalescent sera, hyperimmune globulin, or 
other monoclonal antibodies (eg, bamlanivimab and etesevimab, sotrovimab)  
7. Has initiated vaccination for SARS-CoV-2 with an investigational or approved vaccine, 
but has not completed the vaccine schedule as recommended by the vaccine manufacturer.  
8. Plans to receive an investigational or approved SARS-CoV-2 vaccine within 90 days after 
study drug administration, or per the recommended time frame from the current Centers 
for Disease Control vaccination guidelines (CDC, 2021b) 
9. Has participated, is participating, or plans to participate in a clinical research study 
evaluating any authorized, approved, or investigational vaccine for COVID-19 
10. Has a history of significant multiple and/or severe allergies (eg, latex gloves), or has had 
an anaphylactic reaction to prescription or non-prescription drugs or food 
Note: This is to avoid possible confounding of the safety analysis and not due to any 
presumed increased risk of these individuals to a reaction to the investigational product. 
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11. Has a known allergy or hypersensitivity to components of the study drug 
12. Has any physical examination findings, history of any illness, or any concomitant 
medications, that in the opinion of the investigator might confound the results of the study 
or pose an additional risk to the subject by their participation in the study 
13. Has received any live vaccine within 4 weeks prior to study drug administration 
14. Treatment with another investigational (not authorized or approved) agent in the last 30 
days or within 5 half-lives of the investigational drug, whichever is longer, prior to the 
screening visit 
7.3. 
Premature Withdrawal from the Study 
A subject has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The Investigator and/or Sponsor have the right to withdraw a subject from the study if it is no 
longer in the interest of the subject to continue in the study, or if the subject’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a subject does not or cannot follow 
study procedures). An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of subjects should be avoided. 
Subjects who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.2.2. 
7.4. 
Replacement of Subjects  
Subjects prematurely discontinued from study will not be replaced. 
8. 
STUDY TREATMENTS 
8.1. 
Investigational Treatments 
The following drug product will be provided. Instructions on dose preparation are provided in the 
pharmacy manual.  
Casirivimab+imdevimab, to be co-administered: 
• Casirivimab: supplied as a 120 mg/mL solution for SC injection 
• Imdevimab: supplied as a 120 mg/mL solution for SC injection 
Subjects will receive a single dose of casirivimab+imdevimab, administered as 1 to 4 subcutaneous 
(SC) injections based on body weight. Table 2 provides (according to body weight) the total dose, 
volume, route of administration, and number of injections that will be administered. This table also 
describes additional requirements and allowances for dose administration. 
For study drug administration which requires multiple SC injections, it is recommended to use 
different quadrants of the abdomen (avoiding navel and waist areas) and/or upper thighs. Each 
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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). A numbing 
cream may be used at the planned site(s) of injection.  
Table 2: 
Weight-Tiered Dosing of Casirivimab+Imdevimab 
Weight-Tiered 
Dose Group 
Total Dose (mg) 
Route of 
Administration 
Total Number 
of Injections 
Total Volume (mL) of 
Injection6 
≥20 kg to <40 kg 
792 (396 per mAb) 
SC3 
4 
6.6 (3.3 per mAb) 
≥10 kg to <20 kg 
408 (204 per mAb) 
SC3 
2 or 44 
3.4 (1.7 per mAb) 
≥5 kg to <10 kg1 
144 (72 per mAb) 
SC 
1 or 25 
1.2 (0.6 per mAb) 
≥3 kg to <5 kg2 
96 (48 per mAb) 
SC 
1 
0.8 (0.4 per mAb) 
1 Subjects between 5 and 10 kg should not receive an injection containing more than 1.25 mL. 
2 Subjects <5 kg should not receive an injection containing more than 1 mL. 
3 For SC injection, Investigators may use an infusion pump containing the combined volume with both mAbs. This 
may improve tolerability through administration of a single injection. 
4 Study drug may be administered as 2 injections (1.7 mL of casirivimab and 1.7 mL of imdevimab) or 4 injections 
(0.8 mL of casirivimab, 0.9 mL of casirivimab, 0.8 mL of imdevimab, and 0.9 mL of imdevimab).  
5 Study drug may be administered as 1 injection (1.2 mL total) or as 2 injections (0.6 mL of casirivimab and 0.6 mL 
of imdevimab).  
6 The total volume of study drug per syringe and the number of injections will be recorded in the eCRF. 
8.2. 
Dose Modification and Study Treatment Discontinuation Rules 
8.2.1. 
Dose Modification 
Dose modification for an individual subject is not allowed. 
8.2.2. 
Study Drug Discontinuation 
This is a single dose study; study drug discontinuation is not applicable.  
8.3. 
Management of Acute Reactions  
8.3.1. 
Acute Injection Reactions 
8.3.1.1. 
Systemic Injection Reactions (Hypersensitivity) 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use. All systemic injection reactions must be reported as AEs (as defined in 
Section 10.2.1) and graded using the grading scales as instructed in Section 10.2.4. 
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.  
8.3.1.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.2.4. 
8.4. 
Method of Treatment Assignment 
This is an open-label study; subjects will receive the study drug on day 1 as assigned. 
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8.5. 
Blinding 
This is an open-label study without blinding. 
8.6. 
Treatment Logistics and Accountability 
8.6.1. 
Packaging, Labeling, and Storage  
Open-label study drug will display the product lot number on the label. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.6.2. 
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. 
8.6.3. 
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 subject 
• Disposed of at the site or returned to the Sponsor or designee. 
All accountability records must be made available for inspection by the Sponsor and regulatory 
agency inspectors; photocopies must be provided to the Sponsor at the conclusion of the study. 
8.6.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the Sponsor 
and regulatory agency inspectors. 
8.7. 
Concomitant Medications and Procedures  
Any treatment administered during the on-treatment period (Section 11.4.3.1) will be considered 
concomitant medication. This includes medications that were started before the study and are 
ongoing during the study. 
All concomitant medications and procedures will be captured in the eCRF. 
Any positive SARS-CoV-2 test conducted during an unscheduled visit will be recorded as a 
concomitant procedure and associated with the COVID-19 AE. 
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8.7.1. 
Prohibited Medications  
The following are prohibited as concomitant medication (as defined in Section 8.7) when used as 
prophylaxis in SARS-CoV-2-negative individuals: 
• Other investigational drugs  
• Investigational SARS-CoV-2 vaccines  
• Authorized or approved SARS-CoV-2 vaccines (only prohibited within 90 days after 
study drug administration, or per the recommended time frame from current Centers 
for Disease Control vaccination guidelines) (CDC, 2021b) 
• Investigational, authorized, or approved passive antibody for prophylaxis of 
SARS-CoV-2 infection, including convalescent plasma, convalescent sera, 
hyperimmune globulin, or other monoclonal antibodies (eg, bamlanivimab and 
etesevimab, sotrovimab) (only prohibited within 90 days after study drug 
administration)  
Use of a prohibited medication during the on-treatment period may result in permanent 
discontinuation of a subject from the study.  
8.7.2. 
Permitted Medications and Procedures  
Other than the prohibited medications listed in Section 8.7.1, use of concomitant medications and 
procedures is permitted during the study. If there is any question regarding whether a concomitant 
medication or procedure may be used during the study, the study site should contact the medical 
monitor.  
Subjects with symptomatic laboratory-confirmed SARS-CoV-2 infection during the study will be 
treated according to local standard of care as per the discretion of the Investigator or treating 
physician.  
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 3. 
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Table 3: 
Schedule of Events 
Study Procedure 
Screening/Baseline1 
Follow Up2 
EOS
3 
Unscheduled Visits 
SARS-CoV-2 
Confirmation
4 
ET5 Other 
 
Screen Pre-
Dose Dose 
Post
-
Dose 
 
 
 
 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
13 
 
 
 
Day (Week) 
-7 to 1  
(-1 to 1) 
1 (1) 
2 
(1)16 4 
(1) 8 (2) 15 
(3) 
22 
(4) 
29 
(5) 
57 
(9) 
85  
(13) 
113 
(17) 
141 
(21) 
169 
(25) 
 
 
 
Window (day) 
 
 
 
 
±1 ±1 ±1 ±3 ±3 
±3 ±3 ±3 
±3 
±3 
±3 
 
 
 
Screening/Baseline 
Informed consent (parent/guardian) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed assent (subject) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X1 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening test for SARS-CoV-2 infection  
(molecular diagnostic test)6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mid-turbinate nasal swab for SARS-CoV-2 
infection (RT-qPCR by central laboratory)6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
 
 
Pregnancy test (WOCBP only)7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Treatment 
Study drug administration8 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
Vital signs9 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Targeted physical examination 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Concomitant medications and procedures 
X 
X 
 
 
X 
X 
X X X 
X X X 
X 
X 
X 
X 
X 
X 
Adverse events4 
X 
X 
 
X 
X 
X 
X X X 
X X X 
X 
X 
X 
X 
X 
X 
COVID-19 signs and symptoms4 
X 
 
 
 
X 
X 
X X X 
X X X 
X 
X 
X 
X 
 
 
COVID-19-related medically-attended visit details 
 
 
 
 
X 
X 
X X X 
X X X 
X 
X 
X 
X 
 
 
Laboratory 
Hematology10 
X11 
 
 
 
 
 
 
 
X 
 
 
 
 
X12 
X12 
 
X 
Blood chemistry10 
X11 
 
 
 
 
 
 
 
X 
 
 
 
 
X12 
X12 
 
X 
Drug Concentration and Immunogenicity (all body weight tiers) 
Serum for PK-ADA (schedule 1)13,14 
 
X15 
 
 
X16 
 
X 
 
 
X15 X 
 
 
 
 
X 
X 
X 
Serum for PK-ADA (schedule 2)13,14 
 
X15 
 
 
 
X 
 
X 
 
 
 
X15 
X 
 
 
X 
X 
X 
Biomarkers (determined by body weight tier) 
≥20 kg 
Serum for SARS-CoV-2 serology 
X11 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Serum for exploratory research 
X11 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Plasma for exploratory research 
X11 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
≥10 kg to <20 kg Serum for SARS-CoV-2 serology 
X11 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
≥3 kg to <10 kg Serum for SARS-CoV-2 serology 
X11 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X17 
X 
 
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9.1.1. 
Footnotes for the Schedule of Events Table 
1. Screening visit may occur on the same day as the baseline visit. If screening and baseline 
visits occur on different days, assessments and collections marked for both screening and 
baseline visits will be performed on both days. If screening and baseline occur on the same 
day, assessments and collections marked for both visits may be performed once, on the 
same day. Samples and data may be used for exploratory research and/or diagnostic test 
development. 
2. If a scheduled visit cannot be performed in person (for example, due to COVID-19 
restrictions), or if no assessments or collections require the subject to be contacted in 
person, the visit may be conducted virtually (ie, by telemedicine or phone). 
3. The EOS visit will be performed in person. In the case that the day 169 visit was conducted 
prior to Amendment #2, the subject should return to the clinical trial unit for 1 additional 
visit for the EOS visit as soon as possible after Amendment #2 is approved by local 
regulatory and ethics as required. 
4. Subjects will be assessed for signs and symptoms related to COVID-19. Refer to 
Section 9.2.4.4 and Section 9.2.4.5 for additional information on recording of adverse 
events and signs/symptoms of COVID-19 associated with these adverse events.  
Subjects who have signs or symptoms consistent with COVID-19 will have an unscheduled 
‘SARS-CoV-2 Confirmation’ visit. If SARS-CoV-2 infection is confirmed, subjects will 
continue to follow the Schedule of Events and must have additional unscheduled visits. 
Refer to Section 6.3 for visit requirements for these subjects.  
5. Subjects who prematurely discontinue the study will have an early termination (ET) visit 
for sample collection and assessments as indicated.  
6. Refer to eligibility criteria (Section 7.2.2) for the acceptable sample collection window for 
screening test of SARS-CoV-2 infection. A confirmed local negative result is required prior 
to study drug administration.  
A mid-turbinate nasal swab will also be collected at baseline. For subjects whose screening 
and baseline visit occur on the same day, both the local molecular diagnostic assay and 
central mid-turbinate nasal swab assay will be performed.  
Refer to Section 9.2.1.4 for additional information regarding these collections. 
7. Urine pregnancy test will be performed for all women of childbearing potential (WOCBP), 
regardless of pregnancy status. If urine pregnancy test is positive, a serum pregnancy test 
will be performed for confirmation A pregnancy report form will be completed for each 
subject who becomes pregnant or is pregnant at the time the parent or guardian signs 
consent. 
8. Study drug will be administered after all sample collections and assessments are completed 
for the study visit.  
9. Vital signs will be recorded prior to study drug administration, and approximately 1 hour 
after study drug administration. Vital signs may additionally be recorded as needed per 
local standard of care and Investigator discretion.  
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10. In the event that limited availability of blood prevents the collection of all indicated blood 
samples for a given visit, PK-ADA sample collection (when applicable) will be prioritized 
over other blood samples. 
11. The indicated blood samples may be collected at either the screening or pre-dose visit, but 
must be collected prior to study drug administration. Efforts should be made to collect all 
screening/pre-dose blood samples on the same day, when feasible. 
12. Indicated hematology/blood chemistry sample collection is optional, and may be collected 
if considered clinically appropriate by the investigator or designee. 
13. On day 1, subjects in group A and group B will each be assigned using IWRS to one of 
two staggered PK-ADA sampling schedules (schedule 1 and schedule 2). 
14. Actual dosing time and sample collection times will be recorded for all drug 
concentration/immunogenicity (“PK-ADA”) samples. The pre-dose PK-ADA sample 
collection must be performed on the same day as study drug administration. The window 
for pre-dose PK-ADA sample collection is as close to administration of study drug as is 
reasonable. 
15. PK-ADA sample may be analyzed for ADA and NAb, if feasible, in samples collected pre-
dose, on day 29 (schedule 1), and on day 85 (schedule 2). 
16. Note that the day 2 visit may occur with a window of ±1 day. For all subjects, the day 2 
visit may occur on day 3 (+1 window). For subjects assigned to schedule 1, if the day 2 
visit cannot occur on day 2 or day 3, subjects may have the day 2 blood draw for analysis 
of drug concentration on day 1, at least 4 hours after study drug administration  
(-1 window). If this blood sample is collected, the day 2 visit can be omitted. The day 2 
visits should be scheduled for day 2 or day 3 whenever possible. 
17. Sample will only be collected if the ‘SARS-CoV-2 Confirmation’ visit occurs after study 
day 29.  
9.1.2. 
Early Termination Visit 
Subjects who prematurely discontinue the study will have an early termination (ET) visit as 
described in Table 3.  
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep subjects on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, for 
confirmation of suspected COVID-19, or for any other reason, as warranted. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
Procedures to be performed for the purpose of determining study eligibility or characterizing the 
baseline population include: informed consent and assent (as applicable), medical history, 
demographics, (including weight and height), and SARS-CoV-2 diagnostic testing. 
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9.2.1.1. 
Informed Consent and Assent 
Informed consent (and assent, as applicable) will be obtained according to the requirements 
described in Section 13.2.  
9.2.1.2. 
Body Weight 
Body weight will be assessed using calibrated scales. Subjects should void (empty bladder) prior 
to weight assessment. During weight assessment, subjects should be wearing undergarments only 
and should not wear shoes. Body weight will be recorded to the nearest 0.1 kg. 
9.2.1.3. 
Medication History 
The following prior medications will be recorded if they were given to a subject within 6 months 
prior to their screening visit:  
• Other investigational (not authorized or approved) drugs 
• Investigational SARS-CoV-2 vaccines 
• Authorized or approved SARS-CoV-2 vaccines 
• Investigational, authorized, or approved passive antibody for prophylaxis of SARS-
CoV-2 infection, including convalescent plasma, convalescent sera, hyperimmune 
globulin, or other monoclonal antibodies (eg, bamlanivimab and etesevimab, 
sotrovimab) 
9.2.1.4. 
Diagnostic Testing for SARS-CoV-2 at Screening and Baseline 
Screening. The Investigator or sub-Investigator will verify that the subject tests negative for 
SARS-CoV-2 by a local molecular diagnostic assay for SARS-CoV-2 virus (eg, RT-PCR) using 
an appropriate sample such as nasopharyngeal, nasal, oropharyngeal, or saliva. The local 
diagnostic assay for SARS-CoV-2 must be considered acceptable for clinical use by local 
standards. If the test has not been approved or has not received authorization, such as EUA issued 
by the US FDA or authorization by the equivalent local health authority, the Sponsor must be 
consulted. The use of RT-PCR is highly recommended. Antigen tests are not permitted for 
diagnostic testing. 
The local diagnostic test result, specimen type (eg, nasal swab), assay type, and date of test will be 
recorded in the eCRF. The sample type collected will depend on local lab requirements. Historical 
test results will not be accepted. 
Baseline. A mid-turbinate swab sample will be collected at baseline to test for SARS-CoV-2 by 
RT-qPCR using a central laboratory.  
Screening/Baseline Performed on the Same Study Visit. For subjects whose screening and 
baseline visit occurs on the same day, both the local molecular diagnostic assay and central mid-
turbinate assay will be performed.  
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9.2.2. 
SARS-CoV-2 Viral Testing in the Event of Suspected or Confirmed SARS-CoV-
2 Infection 
Samples will be collected during unscheduled visits in the event of suspected COVID-19 or 
confirmed SARS-CoV-2 infection that occurs after a subject receives study drug. Requirements 
for this testing are described in Section 6.3. 
9.2.3. 
Study Drug Administration  
Refer to Section 8.1. 
9.2.4. 
Safety  
9.2.4.1. 
Vital Signs 
Vital signs will include body temperature, blood pressure, pulse rate, and respiratory rate. Vital 
signs will be measured after the subject has been resting quietly for at least approximately 
5 minutes and may be obtained in seated or supine position. Refer to Section 9.1.1 for additional 
information concerning the timing of vital sign collection. 
9.2.4.2. 
Targeted Physical Examination  
Targeted physical examination will include examination of the oropharynx, skin, heart, lungs. 
Other system will be examined based on complaints or concerns expressed by the subject. 
9.2.4.3. 
Concomitant Medications and Procedures 
Concomitant medications and procedures will be recorded as defined in Section 8.7. 
9.2.4.4. 
Adverse Events 
Adverse events will be recorded at each visit indicated in the Schedule of Events (Table 3). This 
will include any adverse events that the subject is experiencing or has experienced since their last 
in-person or remote visit.  
Adverse events should be obtained in an unsolicited fashion, allowing the subject and/or subject’s 
parent(s) or guardian(s) to spontaneously report events. Solicitation of specific adverse events 
(eg, through the use of a checklist) should be avoided. 
All adverse events will be recorded and reported in the eCRF (Section 10.1). In addition, signs and 
symptoms related to COVID-19 will be recorded as described in Section 9.2.4.5. 
9.2.4.5. 
COVID-19 Signs and Symptoms 
On each visit when adverse events are recorded (Section 9.2.4.4), subjects and/or their parent(s) 
or guardian(s) will be queried for any signs and symptoms associated with these adverse events 
that may be related to COVID-19, as defined by the Centers for Disease Control (CDC, 2021d).  
For each sign or symptom, the start date, end date, and severity will be recorded (mild, moderate, 
severe) in the subject’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.  
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Subjects who experience signs or symptoms that are suspected to be related to COVID-19 will 
have an unscheduled visit to confirm SARS-CoV-2 infection, as described in Section 6.3. If the 
subject’s SARS-CoV-2 test result is positive, all signs and symptoms that were captured in the 
source documents and are confirmed to be temporally related to the positive test result will be 
recorded on a separate eCRF (individual sign or symptom with start date and end date, and 
associated severity). 
9.2.4.6. 
COVID-19-Related Medically-Attended Visits 
A COVID-19-related medically-attended visit will be defined as follows: hospitalization, 
emergency room (ER) visit, urgent care visit, physician’s office visit, or telemedicine visit, with 
the primary reason for the visit being COVID-19.  
COVID-19-related medically-attended visits will be recorded in the eCRF. During each indicated 
collection visit (Table 3), all previously unrecorded COVID-19-related medically-attended visits 
and details will be recorded. For subjects with confirmed SARS-CoV-2 infection will be queried 
for COVID-19-related medically-attended visits as described in Section 6.3. 
At a minimum, the following details will be recorded: 
• Nature of the visit (eg, hospitalization, emergency room visit) 
• Date and length of visit 
• Primary reason for the visit  
Note: the primary reason should also be recorded as an adverse event 
• Respiratory rate 
• Heart rate 
• Peripheral capillary oxygen saturation (SpO2) 
• Oxygen partial pressure (PaO2)/fractional inspired oxygen (FiO2) 
• Respiratory failure: needing high-flow oxygen, noninvasive ventilation, mechanical 
ventilation, extracorporeal membrane oxygenation (ECMO) 
• Systolic and diastolic blood pressure 
• Requiring vasopressors (yes/no)  
• Multiorgan dysfunction: Significant acute renal, hepatic, or neurologic dysfunction 
• Multisystem inflammatory syndrome in children (MIS-C)  
• Admission to an ICU 
9.2.5. 
Laboratory Testing 
Hematology, chemistry, and pregnancy testing samples will be analyzed by local laboratory. 
Detailed instructions for blood sample collection are in the laboratory manual provided to study 
sites. 
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Samples for laboratory testing will be collected at visits according to Table 3. Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Potassium 
Creatinine 
Chloride 
Blood urea nitrogen (BUN) 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Calcium 
Alanine aminotransferase (ALT) 
Glucose 
 Total bilirubin 
Albumin 
  
Hematology 
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Other Laboratory Tests 
Urine pregnancy test will be performed for all women of childbearing potential (WOCBP) prior 
to administration of study drug and at end of study, regardless of pregnancy status. If urine 
pregnancy test is positive, a serum pregnancy test will be performed for confirmation. 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the Investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.  
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the Investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.1.1. 
9.2.6. 
Drug Concentration and Measurements 
Samples for drug concentration measurement will be collected at visits listed in Table 3. For 
information concerning unused samples and exploratory research, refer to Section 9.2.8.3. 
9.2.7. 
Immunogenicity Measurements and Samples 
Samples for immunogenicity assessments will be collected at the timepoints listed in Table 3. For 
information concerning unused samples and exploratory research, refer to Section 9.2.8.3. 
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9.2.8. 
Exploratory Biomarkers 
9.2.8.1. 
Serological Assays for Endogenous Anti-SARS-CoV-2 Antibody Responses  
Antibodies against SARS-CoV-2 will be measured at baseline in all subjects. Antibodies may 
include, but may not be limited to, anti-S IgA and IgG and anti-N IgG antibodies measured using 
immunoassays. Anti-SARS-CoV-2 antibodies will be measured at timepoints post-baseline, as 
specified in the schedule of events, in order to explore the underlying prevalence of SARS-CoV-
2 antibody positivity, and seroconversion (compared to baseline) in the study population with 
casirivimab+imdevimab. The assays used post-baseline to measure antibody immunity will have 
been demonstrated to not be susceptible to interference from casirivimab+imdevimab and may 
include but may not be limited to anti-N IgG immunoassays. Neutralization assays that detect anti-
SARS-CoV-2 neutralizing antibodies may also be used to explore whether a positive anti-SARS-
CoV-2 antibody response was comprised of functionally neutralizing antibodies. 
9.2.8.2. 
 Serum and Plasma for Exploratory Research 
Serum and plasma for exploratory research will be collected and banked from subjects with 
bodyweight >20 kg for exploratory research related to COVID-19, 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. 
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 to 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, SARS-CoV-2, casirivimab+imdevimab, host 
and viral biological pathways, and other mechanisms related to safety, drug exposure, disease 
activity and clinical outcomes, or for assay development or validation, and/or for diagnostic test 
development or validation. 
9.2.8.4. 
Viral Sequencing of Mid-Turbinate Nasal Swab Samples in SARS-CoV-2-
Positive Subjects 
In support of public health initiatives to track SARS-CoV-2 genetic variants, viral genome 
sequencing may be performed on SARS-CoV-2 viral nucleic acid isolated from nasal swab 
samples that have been confirmed positive for SARS-CoV-2. 
10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
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 11.4.3.1). 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 
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signs observed at the time of informed consent should also be recorded as medical history. Any 
subsequent worsening (ie, any clinically significant change in frequency and/or intensity) of a pre-
existing condition that is temporally associated with the use of the study drug should also be 
recorded as an AE. 
At each visit, the Investigator will determine whether any AEs have occurred by evaluating the 
subject. Adverse events may be directly observed, reported spontaneously by the subject or parent, 
or by questioning the subject or parent at each study visit. Subjects 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 
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, 
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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): 
• Grade ≥3 injection-site reactions 
• Grade ≥3 hypersensitivity reactions 
Note: refer to Table 4 for grading scale. 
• Multisystem inflammatory syndrome in children (MIS-C) 
Note: MIS-C is defined according to the CDC (CDC, 2021c). All of the following 
criteria must be met to qualify: 
− An individual aged <21 years presenting with fever (≥38.0°C for ≥24 hours, or 
report of subjective fever lasting ≥24 hours) 
− Laboratory evidence of inflammation, including, but not limited to, one or more of 
the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation 
rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase 
(LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and 
low albumin 
− Evidence of clinically severe illness requiring hospitalization, with multisystem 
(≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, 
dermatologic or neurological) 
− No alternative plausible diagnoses 
− Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or 
antigen test; or COVID-19 exposure within the 4 weeks prior to the onset of 
symptoms 
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 subject, and/or fetus and/or newborn that meets the 
SAE criteria, must be reported as an SAE. Outcome for all pregnancies should be reported to the 
Sponsor. 
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A pregnancy report form will be completed for each subject 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 subject administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug (ICH 
E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a subject is a passenger). 
• Is life-threatening – in the view of the Investigator, the subject is at immediate risk of 
death at the time of the event. This does not include an AE that, had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
In-patient hospitalization is defined as a hospital admission (any duration) or an 
emergency room visit for longer than 24 hours. Prolongation of existing hospitalization 
is defined as a hospital stay that is longer than was originally anticipated for the event, 
or is prolonged due to the development of a new AE as determined by the Investigator 
or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).  
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
interest specific to the Sponsor’s product or program, for which ongoing monitoring and rapid 
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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 AEs (including test findings classified as AEs) and injection-site-related reactions 
will be graded using the current version of the NCI-CTCAE v5.0 (DCTD, 2017). The NCI-CTCAE 
severity grading systems for anaphylaxis, allergic reaction, and injection site reaction are 
specifically provided in Table 4. 
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Table 4: 
NCI-CTCAE Severity Grading (v5.0) for Anaphylaxis, Allergic Reaction, and Injection Site Reactions 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Only grade 3, 4, and 5 are reportable as AESI1 
Anaphylaxis2 
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)3 
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 
reaction4 
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 See details in Section 10.1.3. 
2 Definition: A 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 
3 Definition: A disorder characterized by an adverse local or general response from exposure to an allergen. 
4 Definition: A 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)  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
(eg, disease under study, concurrent diseases, concomitant medications), or other 
external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is predicted 
by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
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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, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol specified procedure, 
or can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
10.3. 
Safety Monitoring 
The Investigator will monitor the safety of study subject at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the Sponsor in a timely fashion. The Sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments 
(eg, 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, IRBs, and the participating Investigators of any SUSARs (Suspected Unexpected 
Serious Adverse Reactions) occurring in other study centers or other studies of the active study 
drug, as appropriate per local reporting requirements. In addition, the Sponsor and/or CRO will 
comply with any additional local safety reporting requirements.  
Upon receipt of the Sponsor’s notification of a SUSAR that occurred with the study drug, the 
Investigator will inform the Institutional Review Board (IRB) unless delegated to the Sponsor. 
Event expectedness for study drug is assessed against the Reference Safety Information section of 
the Investigator’s Brochure that is effective for expedited safety reporting.  
At the completion of the study, the Sponsor will report all safety observations made during the 
conduct of the trial in the Clinical Study Report to health authorities and IRB as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study. The SAP will 
be revised prior to the end of the study to accommodate amendments to the clinical study protocol 
and to make changes to adapt to unexpected issues in study execution and data that may affect the 
planned analyses. The final SAP will be issued before the first database lock. 
Endpoints are listed in Section 4. Analysis variables are listed in Section 5.  
11.1. 
Statistical Hypothesis  
No formal statistical hypothesis testing is planned in this study. The pharmacokinetics hypothesis 
for this study is defined in Section 3.2.3.1. 
11.2. 
Justification of Sample Size 
Analyses of PK, safety, tolerability, immunogenicity, and serology data will be descriptive. The 
sample size was chosen based on PK considerations and is consistent with early phase studies to 
assess PK.  
At least 12 subjects are needed to enroll in each weight group (Group A: ≥10 kg to <40 kg, and 
Group B: ≥3 kg to <10 kg) to assess drug concentration. The study plans to enroll approximately 
28 subjects in total. 
The sample size may be adjusted if planned SC dosing of casirivimab+imdevimab does not achieve 
concentrations in serum similar to, or higher than, that observed in adults (≥18 years of age) after 
casirivimab+imdevimab 1200 mg (600 mg per mAb) SC administration. PK will be evaluated on 
an ongoing basis to determine if dose adjustments are needed and whether more subjects are 
needed for analysis.  
11.3. 
Analysis Sets  
11.3.1. 
Safety Analysis Set 
The safety analysis set (SAF) includes all subjects who received any study drug; it is based on the 
treatment received (as treated). Treatment compliance/administration and all clinical safety 
variables will be analyzed using the SAF. 
11.3.2. 
Pharmacokinetic Analysis Set 
The PK analysis population includes all subjects who received any study drug and who had at least 
1 non-missing result following the first dose of study drug. Subjects will be analyzed based on the 
actual treatment received. 
11.3.3. 
Immunogenicity Analysis Sets 
The ADA analysis sets (AAS) include all subjects who received any study drug 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). 
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The NAb analysis sets (NAS) includes all subjects who received any study drug, have at least one 
non-missing result following the first dose of study drug, 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 study drug. Subjects 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 subjects reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
11.4.1. 
Subject Disposition 
The following will be provided: 
• The total number of screened subjects whose parent(s) or guardian signed the ICF 
• The total number of subjects who discontinued the study, and the reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by weight group and 
by all subjects combined.  
11.4.3. 
Safety Analysis 
11.4.3.1. Adverse Events 
Definitions 
For safety variables, 2 observation periods are defined: 
• The pretreatment period is defined as the time from the parent(s)/guardian(s) signing 
the ICF to before study drug administration. 
• The on-treatment period is defined as the time of study drug administration to the last 
study visit.  
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the on-treatment period. 
Analysis 
All AEs reported in this study will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®).  
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of subjects with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.4), 
presented by SOC and PT 
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• Treatment-related TEAEs presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Treatment-emergent adverse events leading to permanent treatment discontinuation will 
summarized by weight group. 
11.4.3.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of subjects with a potentially clinically significant value (PCSV) at any 
post-study drug administration time point will be summarized for each clinical laboratory test for 
all subjects and separately for subjects in whom the PCSV criterion was normal or missing at 
baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
11.4.3.3. Treatment Exposure 
The duration of study treatment exposure will be defined as 28 days after the last dose for a subject 
in SAF. 
11.4.3.4. Treatment Compliance 
Subject treatment compliance is not applicable for this study, since the study drug is administered 
once at the site and will be the same as treatment exposure. 
11.4.4. 
Pharmacokinetics 
11.4.4.1. Analysis of Drug Concentration Data 
Analysis will be performed according to two groups: 
• Group A: body weight ≥10 kg to <40 kg 
• Group B: body weight ≥3 kg to <10 kg 
The concentrations of total casirivimab and total imdevimab over time will be summarized by 
descriptive statistics for each weight group.  
Subjects who test positive for SARS-CoV-2 infection during the treatment period may be analyzed 
separately from the PK analysis population. 
Stratification of the analysis may be performed if subjects receive a treatment that has the potential 
to impact the pharmacokinetics of casirivimab+imdevimab (eg, IVIG)  
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No formal statistical hypothesis testing will be performed.  
11.4.5. 
Analysis of Immunogenicity Data 
11.4.5.1. Analysis of ADA Data 
The immunogenicity variables described in Section 5.4 will be summarized using descriptive 
statistics. Immunogenicity will be characterized by ADA status, ADA category, and maximum 
titer observed in patients in the ADA analysis sets. 
The ADA status of each patient 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 patient 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. Patients that are treatment-emergent 
may be further categorized.  
The maximum titer category of each patient is classified as: 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000)  
Listings of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
Plots of drug concentrations will be examined and the influence of ADAs on individual PK profiles 
evaluated. Assessment of impact of ADA on safety and efficacy may be provided. 
11.4.5.2. Analysis of NAb Data 
The absolute occurrence (n) and percent of patients (%) with NAb status in the NAb analysis sets 
will be provided by treatment groups. The NAb status is categorized as follows: 
• Negative: Samples tested negative in the ADA assay, or samples positive in the ADA 
assay but tested negative in the NAb assay. 
• Positive: Samples tested positive in the NAb assay. 
11.4.6. 
Other Analyses 
The number and percentage of baseline seronegative subjects with post-baseline 
anti-SARS-CoV-2 positive serology will be summarized for the entire study period. 
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The number and percentage of subjects with COVID-19-related MAVs will be summarized for the 
entire study period. 
11.5. 
Interim Analysis  
No formal interim analysis is planned. Interim reviews of PK and safety data may be performed 
before subjects complete the end of study. 
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study  
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and Sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE  
In accordance with ICH E6, the Sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.  
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, 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 – PK-ADA schedule assignment, study drug supply 
• EDC system (data capture) – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
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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 subjects are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate subject records (source 
documents). The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and 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 subject enrolled in the study. The Investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the Sponsor in the eCRFs. After 
review of the clinical data for each subject, the Investigator must provide an electronic signature. 
A copy of each subject 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. 
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12.3. 
Audits and Inspections  
This study may be subject to a quality assurance audit or inspection by the Sponsor or regulatory 
authorities. Should this occur, the Investigator is responsible for: 
• Informing the Sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the Sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the Sponsor immediately 
• Taking all appropriate measures requested by the Sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, 
eCRFs, medical records, correspondence, ICFs, IRB files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities. Conditions of study material storage are also subject to inspection. 
In addition, representatives of the Sponsor may observe the conduct of any aspect of the clinical 
study or its supporting activities both within and outside of the Investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the Investigator. This signed declaration accompanies each set of subject final 
eCRF that will be provided to the Sponsor. 
12.4.2. 
Retention of Records 
The Investigator must retain all essential study documents, including ICFs, source documents, 
Investigator copies of eCRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The Investigator must obtain written approval from the Sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the Investigator's personal situation is such that archiving can no longer be ensured, the 
Investigator must inform the Sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS  
13.1. 
Good Clinical Practice Statement  
It is the responsibility of both the Sponsor and the Investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent and Assent 
The principles of informed consent are described in ICH guidelines for Good Clinical Practice. 
The ICF used by the Investigator must be reviewed and approved by the Sponsor prior to 
submission to the appropriate IRB. A copy of the IRB -approved ICF and documentation of 
approval must be provided to the Sponsor before study drug will be shipped to the study site. 
It is the responsibility of the Investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each subject and his/her parent(s) or legal guardian(s) prior to the 
subject’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 subject and the 
parent(s) or legal guardian(s) can understand. The ICF should be signed and dated by the subject’s 
parent(s) or legal guardian(s) and the same Investigator or designee who explained the ICF. 
In the case of more than one parent or guardian, local law must be observed in deciding whether 1 
or both parent’s/guardian’s consent is required. If only 1 parent or guardian signs the consent form, 
the Investigator must document the reason the other parent or guardian did not sign. The subject 
may also be required to sign and date the ICF, as determined by the IRB and in accordance with 
the local regulations and requirements. 
• Subjects who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
• Subjects who can understand but who can neither write nor read will have the assent 
form read to them in presence of an impartial witness, who will sign and date the 
assent form to confirm that informed assent was given. 
The original ICF must be retained by the Investigator as part of the subject's study record, and a 
copy of the signed ICF must be given to the subject’s parent(s) or legal guardian(s). 
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 and assent form must be reviewed and 
updated appropriately. All study subjects and their parent(s) or legal guardian(s) must be informed 
of the new information and provide their written consent if they wish the subject to continue in the 
study. The original signed revised ICF must be maintained in the subject’s study record and a copy 
must be given to the subject’s parent(s) or legal guardian(s). 
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13.3. 
Subjects Confidentiality and Data Protection 
The Investigator must take all appropriate measures to ensure that the anonymity of each study 
subject will be maintained. Subjects should be identified by a subject identification number only, 
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 subject 's and Investigator's personal data, which may be included in the Sponsor database, 
will be treated in compliance with all applicable laws and regulations. The Sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
13.4. 
Institutional Review Board 
An appropriately constituted IRB, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the subjects 
(eg, advertising) before any subject may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the subject, in 
which case the IRB should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB should be informed of any event likely to affect the safety of subjects or the 
continued conduct of the clinical study. 
A copy of the IRB approval letter with a current list of the IRB members and their functions must 
be received by the Sponsor prior to shipment of drug supplies to the Investigator. The approval 
letter should include the study number and title, the documents reviewed, and the date of the 
review. 
Records of the IRB review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the Investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. Treatment codes will be disseminated to each investigation site 
thereafter. 
14. 
PROTOCOL AMENDMENTS 
The Sponsor may not implement a change in the design of the protocol or ICF without an IRB -
approved amendment. Where required per local legislation, regulatory authority approval will also 
be sought.  
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15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The Sponsor has the right to terminate the study prematurely. Reasons may include efficacy, 
safety, or futility, among others. Should the Sponsor decide to terminate the study, the 
Investigator(s) will be notified in writing. 
15.2. 
Close-out of a Site 
The Sponsor and the Investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The Investigator must notify the Sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the Sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The Sponsor will notify the Investigator(s) of a decision to close-out a study site in writing. 
Reasons may include the following, among others:  
• The Investigator has received all items and information necessary to perform the study, 
but has not enrolled any subject within a reasonable period of time 
• The Investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of subjects required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB and Health Authorities must be informed according to applicable 
regulatory requirements, and adequate consideration must be given to the protection of the 
subjects’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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19. 
REFERENCES 
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Temporal Distribution of US Children With Multisystem Inflammatory Syndrome During the 
COVID-19 Pandemic. JAMA Pediatrics 2021. 
 
Bellino S, Punzo O, Rota MC, Del Manso M, Urdiales AM, Andrianou X, et al. COVID-19 
Disease Severity Risk Factors for Pediatric Patients in Italy. Pediatrics 2020; 146(4). 
 
Boyarsky BJ, Werbel WA, Avery RK, Tobian AAR, Massie AB, Segev DL, et al. Antibody 
Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients. 
JAMA 2021a; 325(21):2204-2206. 
 
Boyarsky BJ, Werbel WA, Avery RK, Tobian AAR, Massie AB, Segev DL, et al. Immunogenicity 
of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients. 
JAMA 2021b; 325(17):1784-1786. 
 
Cavanaugh AM, Fortier S, Lewis P, Arora V, Johnson M, George K, et al. COVID-19 Outbreak 
Associated with a SARS-CoV-2 R.1 Lineage Variant in a Skilled Nursing Facility After 
Vaccination Program - Kentucky, March 2021. MMWR Morb Mortal Wkly Rep 2021; 
70(17):639-643. 
 
CDC. COVID-19 in Children and Teens. https://www.cdc.gov/coronavirus/2019-ncov/daily-life-
coping/children/symptoms.html#higher-risk. Published 2021a. Updated 17 Mar 2021. Accessed 
14 Jun 2021. 
 
CDC. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the 
United States.Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/covid-
19/info-by-product/pfizer/clinical-considerations.html. Published 2021b. Updated 05 Mar 2021. 
Accessed 21 Mar 2021 2021. 
 
CDC. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus 
Disease 2019 (COVID-19). https://emergency.cdc.gov/han/2020/han00432.asp. Published 2021c. 
Updated 14 May 2021. Accessed 14 September 2021. 
 
CDC. 
Symptoms 
of 
COVID-19. 
https://www.cdc.gov/coronavirus/2019-ncov/symptoms-
testing/symptoms.html. Published 2021d. Accessed 17 June 2021. 
 
Copin R, Baum A, Wloga E, Pascal KE, Giordano S, Fulton BO, et al. The monoclonal antibody 
combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and 
human studies. Cell 2021. 
 
DCTD. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.National Cancer 
Institute. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf. Published 2017. Accessed 2 Jul 2020. 
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FDA. Casirivimab and Imdevimab EUA Letter of Authorization.Food and Drug Administration 
(FDA). https://www.fda.gov/media/143891/download. Published 2020. Accessed 21 Nov 2020. 
 
Graff K, Smith C, Silveira L, Jung S, Curran-Hays S, Jarjour J, et al. Risk Factors for Severe 
COVID-19 in Children. Pediatr Infect Dis J 2021; 40(4):e137-e145. 
 
Hoffmann M, Kleine-Weber H,Pöhlmann S. A Multibasic Cleavage Site in the Spike Protein of 
SARS-CoV-2 Is Essential for Infection of Human Lung Cells. Mol Cell 2020; 78(4):779-784.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. 
 
Iwasaki A,Yang Y. The potential danger of suboptimal antibody responses in COVID-19. Nat Rev 
Immunol 2020:1-3. 
 
Kam YW, Kien F, Roberts A, Cheung YC, Lamirande EW, Vogel L, et al. Antibodies against 
trimeric S glycoprotein protect hamsters against SARS-CoV challenge despite their capacity to 
mediate FcgammaRII-dependent entry into B cells in vitro. Vaccine 2007; 25(4):729-740. 
 
Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H, et al. Anti-spike IgG causes severe acute lung 
injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight 2019; 
4(4). 
 
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. 
 
Luo F, Liao FL, Wang H, Tang HB, Yang ZQ,Hou W. Evaluation of Antibody-Dependent 
Enhancement of SARS-CoV Infection in Rhesus Macaques Immunized with an Inactivated SARS-
CoV Vaccine. Virol Sin 2018; 33(2):201-204. 
 
NIH. 
Coronavirus 
Disease 
2019 
(COVID-19) 
Treatment 
Guidelines.NIH. 
https://www.covid19treatmentguidelines.nih.gov/. Published 2021. Accessed 23 Mar 2021. 
 
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 
2021a: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 
2021b:2021.2006.2014.21258567. 
 
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. 
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Regeneron. Regeneron Announces Encouraging Initial Data from COVID-19 Antibody Cocktail 
Trial in Hospitalized Patients on Low-Flow Oxygen.Regeneron Pharmaceuticals, Inc. 
https://investor.regeneron.com/news-releases/news-release-details/regeneron-announces-
encouraging-initial-data-covid-19-antibody. Published 2020. Updated 29 Dec 2020. Accessed 05 
May 2021. 
 
Robbie GJ, Zhao L, Mondick J, Losonsky G,Roskos LK. Population pharmacokinetics of 
palivizumab, a humanized anti-respiratory syncytial virus monoclonal antibody, in adults and 
children. Antimicrob Agents Chemother 2012; 56(9):4927-4936. 
 
Teran RA, Walblay KA, Shane EL, Xydis S, Gretsch S, Gagner A, et al. Postvaccination SARS-
CoV-2 Infections Among Skilled Nursing Facility Residents and Staff Members - Chicago, 
Illinois, December 2020-March 2021. MMWR Morb Mortal Wkly Rep 2021; 70(17):632-638. 
 
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. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19).World 
Health Organization. https://www.who.int/docs/default-source/coronaviruse/who-china-joint-
mission-on-covid-19-final-report.pdf. Published 2020. Updated 24 Feb 2020. Accessed 30 Jun 
2020. 
 
Wu Z,McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 
2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese 
Center for Disease Control and Prevention. JAMA 2020. 
 
Yasui F, Kohara M, Kitabatake M, Nishiwaki T, Fujii H, Tateno C, et al. Phagocytic cells 
contribute to the antibody-mediated elimination of pulmonary-infected SARS coronavirus. 
Virology 2014; 454-455:157-168. 
 
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with 
Pneumonia in China, 2019. N Engl J Med 2020; 382(8):727-733. 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Phase 2a, Open-Label Study Assessing Pharmacokinetics, 
Safety, Tolerability, and Immunogenicity of Single-Dose Subcutaneous Anti-Spike (S) SARS-
CoV-2 Monoclonal Antibodies (Casirivimab and Imdevimab) in High-Risk Pediatric Subjects 
Under 12 Years of Age and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the Sponsor or a 
partnership in which the Sponsor is involved. I will immediately disclose it in writing to the 
Sponsor if any person who is involved in the study is debarred, or if any proceeding for debarment 
is pending, or, to the best of my knowledge, threatened. 
This document contains confidential information of the Sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor. 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
A Phase 2a, Open-Label Study Assessing Pharmacokinetics, Safety, 
Tolerability, and Immunogenicity of Single-Dose Subcutaneous Anti-Spike 
(S) SARS-CoV-2 Monoclonal Antibodies (Casirivimab and Imdevimab) in 
High-Risk Pediatric Subjects Under 12 Years of Age 
Protocol Number: 
R10933-10987-COV-2121 
Protocol Version: 
Amendment 2 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
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Signature Page for VV-RIM-00189472 v1.0
Signature Page for VV-RIM-00189472 v1.0 Approved
Approval/eSignature
-2022 14:51:13 GMT+0000
Approval/eSignature
r-2022 15:58:44 GMT+0000
Approval/eSignature
22 19:15:50 GMT+0000
Approval/eSignature
000
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
REGENERON CONFIDENTIAL 
Page 1 of 30 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
Clinical Study Protocol Title: A PHASE 2A, OPEN-LABEL STUDY ASSESSING 
PHARMACOKINETICS, SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF 
SINGLE-DOSE SUBCUTANEOUS ANTI-SPIKE (S) SARS-COV-2 MONOCLONAL 
ANTIBODIES (CASIRIVIMAB AND IMDEVIMAB) IN HIGH-RISK PEDIATRIC 
PARTICIPANTS UNDER 12 YEARS OF AGE 
Compound: 
R10933-10987 
Protocol Number: 
R10933-10987-COV-2121 
Clinical Phase:  
Phase 2a 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date:  
Original Statistical Analysis Plan 23-JUN-2022 
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Regeneron Pharmaceuticals, Inc. 
 
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Statistical Analysis Plan 
 
Date: JUN 23, 2022 
 
REGENERON CONFIDENTIAL 
Page 2 of 30 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
Study Biostatistician  
 
 
 
See appended electronic signature page 
Study Pharmacokinetics 
 
 
 
See appended electronic signature page 
Study Bioanalytical Sciences 
 
 
 
See appended electronic signature page 
Study Medical Director 
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
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Statistical Analysis Plan 
 
Date: JUN 23, 2022 
 
REGENERON CONFIDENTIAL 
Page 3 of 30 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................7 
1.1. 
Background/Rationale ..................................................................................................7 
1.2. 
Study Objectives ...........................................................................................................7 
1.2.1. 
Primary Objectives .......................................................................................................7 
1.2.2. 
Secondary Objectives ...................................................................................................7 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ..................................7 
1.2.4. 
Revision History for SAP Amendments .......................................................................7 
2. 
INVESTIGATION PLAN ............................................................................................8 
2.1. 
Study Design .................................................................................................................8 
2.2. 
Sample Size and Power Considerations .......................................................................8 
2.3. 
Study Plan .....................................................................................................................8 
3. 
ANALYSIS POPULATIONS ......................................................................................9 
3.1. 
Safety Analysis Set .......................................................................................................9 
3.2. 
Pharmacokinetic Analysis Set ......................................................................................9 
3.3. 
Immunogenicity Analysis Sets .....................................................................................9 
4. 
ANALYSIS VARIABLES .........................................................................................10 
4.1. 
Demographic and Baseline Characteristics ................................................................10 
4.2. 
Medical History ..........................................................................................................10 
4.3. 
Pre-Treatment / Concomitant Medication ..................................................................10 
4.4. 
Rescue Medication/or Prohibited Medication During Study if Applicable ................11 
4.5. 
Efficacy Variable ........................................................................................................11 
4.5.1. 
Primary Efficacy Variable (s) .....................................................................................11 
4.5.2. 
Secondary Efficacy Variable(s) ..................................................................................11 
4.6. 
Safety Variables ..........................................................................................................11 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................11 
4.6.2. 
Adverse Events of Special Interest .............................................................................11 
4.6.3. 
Laboratory Safety Variables .......................................................................................11 
4.6.4. 
Vital Signs ..................................................................................................................12 
4.6.5. 
12-Lead Electrocardiography (ECG) ..........................................................................12 
4.6.6. 
Physical Examination Variables .................................................................................12 
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Statistical Analysis Plan 
 
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4.6.7. 
Other Safety Variables ................................................................................................12 
4.7. 
Pharmacokinetic Variables .........................................................................................12 
4.8. 
Immunogenicity Variables ..........................................................................................13 
5. 
STATISTICAL METHODS .......................................................................................14 
5.1. 
Demographics and Baseline Characteristics ...............................................................14 
5.2. 
Medical History ..........................................................................................................14 
5.3. 
Prior/concomitant Illnesses and Medications .............................................................14 
5.4. 
Prohibited Medications ...............................................................................................14 
5.5. 
Participant Disposition ................................................................................................15 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................15 
5.6.1. 
Measurement of Compliance ......................................................................................15 
5.6.2. 
Study Observation Duration .......................................................................................15 
5.7. 
Analyses of Efficacy Variables ..................................................................................15 
5.7.1. 
Analysis of Primary Efficacy Variable(s) ...................................................................15 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................15 
5.8. 
Analysis of Safety Data ..............................................................................................15 
5.8.1. 
Adverse Events ...........................................................................................................16 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................16 
5.8.3. 
Clinical Laboratory Measurements.............................................................................16 
5.8.4. 
Analysis of Vital Signs ...............................................................................................17 
5.8.5. 
Analysis of 12-Lead ECG ...........................................................................................17 
5.8.6. 
Physical Exams ...........................................................................................................17 
5.9. 
Analysis of Pharmacokinetic Data ..............................................................................17 
5.9.1. 
Analysis of Pharmacokinetic Data ..............................................................................17 
5.10. 
Analysis of Immunogenicity Data ..............................................................................17 
5.10.1. 
Analysis of ADA Data ................................................................................................17 
5.11. 
Association of Immunogenicity with Exposure and Safety .......................................18 
5.11.1. 
Immunogenicity and Exposure Data ..........................................................................18 
5.11.2. 
Immunogenicity and Safety ........................................................................................18 
6. 
DATA CONVENTIONS ............................................................................................20 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................20 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................20 
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Statistical Analysis Plan 
 
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6.3. 
Data Handling Convention for Missing Data .............................................................20 
6.4. 
Out of window visits ...................................................................................................20 
6.5. 
Unscheduled Assessments ..........................................................................................21 
6.6. 
Pooling of Centers for Statistical Analyses ................................................................21 
7. 
INTERIM ANALYSIS ...............................................................................................22 
8. 
SOFTWARE ...............................................................................................................23 
9. 
REFERENCES ...........................................................................................................24 
10. 
APPENDIX.................................................................................................................25 
10.1. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................25 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
Casirivimab+imdevimab 
REGN10933 and REGN10987; also referred to by the 
proprietary name conditionally accepted by the FDA 
(REGEN-COV™) and by the EMA (RONPAPREVE®) 
COVID-19 
Coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FDA 
U.S. Food and Drug Administration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
MIS-C 
Multisystem inflammatory syndrome in children 
NAb 
Neutralizing antibody 
PK 
Pharmacokinetic 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
 
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Protocol: R10933-10987-COV-2121 
Statistical Analysis Plan 
 
Date: JUN 23, 2022 
 
REGENERON CONFIDENTIAL 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the statistical methods to 
be used in the analysis of data for R10933-10987-COV-2121 study. 
The study was paused for new enrollment on December 28, 2021 due to the increasing 
prevalence of Omicron and the lack of neutralization of REGEN-COV to the Omicron variant. 
The participants who had been enrolled prior to the pause date were followed in the study 
according to the protocol. 
1.1. 
Background/Rationale 
This study assess the pharmacokinetics (PK), safety, tolerability and immunogenicity, of 
casirivimab and imdevimab in children under 12 years old who are uninfected but at high risk to 
develop severe COVID-19 if they become infected. 
1.2. 
Study Objectives 
1.2.1. 
Primary Objectives 
The primary objective of this study is to characterize the concentrations of casirivimab  and 
imdevimab serum over time after a single subcutaneous (SC) administration. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are:  
• To assess the safety and tolerability of SC single administration of casirivimab and 
imdevimab 
• To assess the occurrence of grade ≥3 injection site reactions and grade ≥3 
hypersensitivity reactions in participants treated with SC doses of casrivimab and 
imdevimab 
• To assess the immunogenicity of casirivimab and imdevimab 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
The NAb analysis specified in section 11.4.5.2 in protocol will not be performed. 
1.2.4. 
Revision History for SAP Amendments 
There is no revision history – this is original version of the SAP document. 
 
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Protocol: R10933-10987-COV-2121 
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REGENERON CONFIDENTIAL 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design  
This is a Phase 2a open label study with no placebo control to assess the PK, safety, tolerability, 
and immunogenicity of casrivimab and imdevimab in participants <12 years old who are not 
infected with SARS-CoV-2 but are at high risk to develop severe COVID-19 if they were to 
become infected.  In this study, participants will be evaluated separately in two groups with each 
group defined according to body weight (≥10 kg and <40 kg vs ≥3 kg to <10 kg). In each group, 
dosing will be adjusted by weight (Protocol Table 2). After a single SC dose of casrivimab and 
imdevimab, a total of 28 participants will be followed for approximately 24 weeks (6 months) for 
assessment of drug concentrations, safety, and immunogenicity. 
2.2. 
Sample Size and Power Considerations 
There are no formal hypotheses in this study. The sample size was chosen based on PK 
considerations and is consistent with early phase studies to assess PK.  
At least 12 participants are needed to enroll in each weight group (Group A: ≥10 kg to <40 kg, and 
Group B: ≥3 kg to <10 kg) to assess drug concentration. The study plans to enroll approximately 
28 participants in total. 
The sample size may be adjusted if planned SC dosing of casirivimab+imdevimab does not achieve 
concentrations in serum similar to, or higher than, that observed in adults (≥18 years of age) after 
casirivimab+imdevimab 1200 mg (600 mg per mAb) SC administration. PK will be evaluated on 
an ongoing basis to determine if dose adjustments are needed and whether more participants are 
needed for analysis.  
2.3. 
Study Plan 
The schedule of events is presented within Section 9.1 of the study protocol.  
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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. 
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). Treatment compliance/administration and all clinical safety 
variables will be analyzed using the SAF. 
3.2. 
Pharmacokinetic Analysis Set 
The pharmacokinetic (PK) analysis set is defined for each analyte separatly. Each PK Analysis set 
includes all participants who received any amount of study drug and who had at least 1 non-missing 
result of respective analyte following the first dose of study drug. Participants will be analyzed 
based on the actual treatment received. 
3.3. 
 Immunogenicity Analysis Sets 
The ADA analysis sets (AAS) is defined for each study drug separately and includes all treated 
participants who received any amount of study drug [safety data set] and had at least one non-
missing ADA result from the respective ADA assay following the first dose of the respective study 
drug.  
Neutralizing antibody (NAb) analysis will not be performed. 
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4. 
ANALYSIS VARIABLES 
 
4.1. 
Demographic and Baseline Characteristics 
The following demographic variables will be summarized: 
• Age at screening (year) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Baseline Weight 
• Baseline Height 
• Baseline Body mass index (BMI) calculated from weight and height 
Baseline measure is the last available value obtained prior to drug administration. 
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
4.3. 
Pre-Treatment / Concomitant Medication 
Medications/Procedures will be recorded from the day of informed consent until the end-of-study 
(EOS) visit. Medications will be coded to the ATC level 2 (therapeutic main group) and ATC 
level 4 (chemical/therapeutic subgroup), according to the latest available version of WHO Drug 
Dictionary (WHODD). Patients will be counted once in all ATC categories linked to the 
medication. Procedures will be coded to a Preferred Term (PT) and associated Primary System 
Organ Class (SOC) associated to the latest available version of MedDRA®. 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the study drug. 
Concomitant medications/procedures: medications taken or procedures performed following the 
dose of study drug through the EOS visit. 
For medications/procedures started prior to the administration of study drug, the study day onset 
is defined as (date of start - date of the drug administration); for medications/procedures started on 
or after treatment, the study day onset is defined as (date of start - date of the drug administration) 
+ 1. 
Any positive SARS-COV-2 test conducted during an unscheduled visit will be recorded as lab 
assessment: SARS-CoV2-Test Local Lab and associated with the COVID-19 AE. 
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4.4. 
Rescue Medication/or Prohibited Medication During Study if 
Applicable 
Prohibited medications are defined as any non-permitted medication as outlined within Section 8.7 
of the protocol. 
4.5. 
Efficacy Variable 
4.5.1. 
Primary Efficacy Variable (s) 
Not applicable. 
4.5.2. 
Secondary Efficacy Variable(s) 
Not applicable. 
4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events diagnosed by the investigators will be collected from 
the time of informed consent signature and then at each visit until the end of the study. All 
adverse events are to be coded to a “Preferred Term (PT)” and associated primary “System 
Organ Class (SOC)” according to the Medical Dictionary for Regulatory Activities (MedDRA). 
A Serious Adverse Event is an adverse event (AE) that is classified as serious according to the 
criteria specified in section 10.2.2 of the protocol. 
Laboratory results, vital signs, or ECG abnormalities are to be recorded as AEs if they are 
medically relevant: symptomatic, requiring corrective therapy, leading to treatment 
discontinuation and/or fulfilling a seriousness criterion. 
4.6.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner as described in the protocol. In 
this study, AESI are listed below, along with each AESI detailed definition: 
• Grade3 injection-site reactions 
• Grade3 hypersensitivity reactions 
• Multisystem inflammatory syndrome in children (MIS-C) 
These AESI variables are defined in protocol section 10.1.3 and recorded via eCRF specific tick 
box on AE page. In addition, hypersensitivity will also be summaried by SMQ hypersensitivity 
(narrow) and PTs. 
4.6.3. 
Laboratory Safety Variables 
The following laboratory tests will be collected and summarized: 
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Blood Chemistry 
Sodium 
Total protein, serum 
Potassium 
Creatinine 
Chloride 
Blood urea nitrogen (BUN) 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Calcium 
Alanine aminotransferase (ALT) 
Glucose 
 Total bilirubin 
Albumin 
  
Hematology 
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
 
4.6.4. 
Vital Signs 
The following vital signs parameters will be recorded and summarized: 
• Body temperature 
• Blood pressure 
• Pulse rate 
• Respiration rate 
4.6.5. 
12-Lead Electrocardiography (ECG) 
12-Lead ECG parameters are not collected in this study. 
4.6.6. 
Physical Examination Variables 
Physical examination will be conducted at the protocol scheduled visits. If any abnormal findings 
during the screening period, they will be recorded in medical history eCRF form and AE eCRF 
form for any new or worsening abnormal findings during post-screening period.   
4.6.7. 
Other Safety Variables 
Not applicable. 
4.7. 
Pharmacokinetic Variables 
The PK variables  are concentrations of casirivimab and imdevimab in serum and sampling time. 
The sampling time points are specified in Table 3 in the protocol. 
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The analysis of PK will be documented in a separate document. 
4.8. 
Immunogenicity Variables 
The immunogenicity variables include ADA status and titer 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. 
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5. 
STATISTICAL METHODS 
Unless otherwise stated, the following conventions will be applied when presenting summary level 
statistics for data. 
Continuous variables will be summarized within each body weight group by presenting the 
following summary statistics: number of participants with an available value of the variable (n), 
mean, standard deviation, median, minimum, maximum, 1st quartile and 3rd quartile.   
Categorical data will be summarized within each body weight group by presenting the frequency 
(i.e. total number of participants within each level of the categorical variable in a given body 
weight group).  All levels of the categorical variable will be included. Percentages will also be 
calculated for each level of the categorical variables with respect to the total sample size of the 
respective treatment arm.   
In general, summaries will display grouping by weight group, and by all participants combined. 
Weight groups are defined according to protocol section 8.1. Weight group A: ≥10 kg to <40 kg, 
and weight group B: ≥3 kg to <10 kg. Within each weight group, sub groups are further defined 
in the SAP according to weight based dosing categories: weight group A1: ≥20 kg to <40 kg, 
weight group A2: ≥10 kg to <20 kg; weight group B1: ≥5 kg to <10 kg, and weight group B2: ≥3 
kg to <5 kg.  
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized via descriptive statistics based on 
SAF population. A participant listing will be provided. 
5.2. 
Medical History 
Medical history will be summarized by SOC then PT. A participant listing will be provided. 
5.3. 
Prior/concomitant Illnesses and Medications  
Medications and procedures will be summarized based on SAF using descriptive statistics.  
Prior/concomitant medications will be summarized by ATC level 2 and ATC level 4. 
Prior/concomitant procedures will be summarized by SOC and PT. 
Listings will also be provided. 
Participants who received COVID 19 vaccine and their time to first COVID 19 vaccine (days) 
from the study treatment administration  including the following categories: 90 days and >90 
days,  will be summarized using descriptive statistics.  
5.4. 
Prohibited Medications 
Prohibited medications is defined as any non-permitted medication as outlined within Section 8.7.1 
of the protocol. They will be reviewed and identified by the study clinician and reported in protocol 
deviations. 
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5.5. 
Participant Disposition 
Enrolled participants are defined as those who signed an informed consent form. Screen-failed 
participants are collected from participants screening status and eligibility eCRF form and 
summarized. Listing of participant discposition will be provided. 
Participant counts of those screened, enrolled, the completion status for the study (along with 
reason for any study withdrawal) will be summarized.  
5.6. 
Extent of Study Treatment Exposure and Compliance 
Exposure data will be summarized based on SAF using descriptive statistics. Listings will also be 
provided. Participants with a complete or delayed dose administration (completed SC dose 
administered) will be summarized.  
5.6.1. 
Measurement of Compliance 
Treatment compliance is not applicable as this is a single-dose study. 
5.6.2. 
Study Observation Duration 
Study observation duration (days) will be summarized and is defined as:  
Study observation duration = (date of the last study visit - date of study treatment administration) 
+ 1 
5.7. 
Analyses of Efficacy Variables 
5.7.1. 
Analysis of Primary Efficacy Variable(s) 
Not applicable 
5.7.2. 
Analysis of Secondary Efficacy Variables 
Not applicable. 
5.8. 
Analysis of Safety Data 
For safety variables, two observation periods are defined: 
• Pre-treatment period is defined as the time from signing the Informed Consent Form 
(ICF) to the time before administration of study drug 
• On-treatment period is defined as the time after administration of study drug until the 
end of study. 
Safety data will be summarized for all participants based on SAF using descriptive statistics unless 
noted otherwise.   
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5.8.1. 
Adverse Events  
All AEs reported in this study will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). The verbatim text, the PT, and the primary SOC will be listed in 
participant listings.  
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition during the on-treatment period.  
The focus of adverse event reporting in the clinical study report will be on TEAEs. A listing will 
be provided for COVID-19 Signs and Symptoms. 
For details on handling missing data and partial dates, see Section 6. 
Summaries of all TEAEs will include: 
• Overview of TEAEs 
• The number (n) and percentage (%) of participants with at least 1 TEAE by SOC and 
PT 
• TEAEs by severity (according to the grading scale outlines in protocol section 
10.2.4), presented by SOC and PT 
• Treatment-related TEAEs presented by SOC and PT 
• Treatment-emergent AESIs by SOC and PT 
• Treatment-emergent hypersensitivity events by SMQ hypersensitivity (narrow) and 
PT 
5.8.2. 
Analysis of Adverse Events of Special Interest 
Hypersensitivity events will be presented by SMQ hypersensitivity (narrow) and PT, as well as 
SOC and PT according to eCRF, respectively. Other treatment-emergent AESIs will be presented 
by SOC and PT. The summaries will be sorted by decreasing incidence of PT within each 
SOC/SMQ based on all participants combined column. 
5.8.3. 
Clinical Laboratory Measurements  
Individual participant laboratory parameter measurements will be evaluated by PCSV criteria (See 
Appendix 10.1), specifically identifying participants with at least one post-baseline measurement 
that meets the PCSV criteria. These laboratory parameters will be presented by the biological 
functions (e.g. red blood cells and platelets, white blood cells, and liver function, etc.). The 
incidence of PCSVs at any time including data from unscheduled visits during the study period 
will be summarized.  
Listings of laboratory measurements at all timepoints for the participants that meet PCSV criteria 
will be provided. Listings of all local laboratory measurements will also be provided. 
A listing of all women of childbearing potential with a confirmed serum pregnancy test during the 
study will be provided. 
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5.8.4. 
Analysis of Vital Signs 
Individual participant laboratory parameter measurements will be evaluated by PCSV criteria (See 
Appendix 10.1), specifically identifying participants with at least one post-baseline measurement 
that meets the PCSV criteria.  
Listings of vital sign measurements at all timepoints for the participants that meet PCSV criteria 
will be provided. Listings of vital signs for all participants will also be provided.  
5.8.5. 
Analysis of 12-Lead ECG 
There are no ECG data collected in this study. 
5.8.6. 
Physical Exams 
There is no specific physical exams data collected in this study. Any abnormal findings will be 
included in either medical history or TEAE summary depending on the timing of the abnormal 
findings.  
5.9. 
Analysis of Pharmacokinetic Data  
5.9.1. 
Analysis of Pharmacokinetic Data  
Analysis will be performed according to two groups: 
• Group A: body weight ≥10 kg to <40 kg 
• Group B: body weight ≥3 kg to <10 kg 
The concentrations of total casirivimab and total imdevimab over time will be summarized by 
descriptive statistics for each weight group.  
Participants who test positive for SARS-CoV-2 infection during the treatment period may be 
analyzed separately from the PK analysis population. 
Stratification of the analysis may be performed if participants receive a treatment that has the 
potential to impact the pharmacokinetics of casirivimab+imdevimab (eg, IVIG)  
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. 
The ADA status of each participant may be classified as one of the following:  
Positive 
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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: 
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. 
The maximum titer category of each participant 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. 
5.11. 
Association of Immunogenicity with Exposure and Safety  
5.11.1. 
Immunogenicity and Exposure Data  
Potential association between immunogenicity variables and systemic exposure to casirivimab 
and imdevimab may 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 and 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 on-treatment period:  
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• 
Injection site reaction (serious or severe and lasting 24 hours or longer) 
• 
Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
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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 study drug.  
6.2. 
Data Handling Convention for Efficacy Variables  
Not applicable as clinical efficacy variables are not collected within this study. 
6.3. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary.  
For categorical variables, participants with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of participants with missing 
data is presented. 
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 the investigational product. 
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. 
Potentially Clinically Significant Value (PCSV) 
For PCSVs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSV will be based 
only on the second condition. 
For a PCSV defined on a threshold and/or a normal range, this PCSV will be derived using this 
threshold if the normal range is missing; e.g., for eosinophils the PCSV is >0.5 giga/L or >ULN if 
ULN ≥0.5 giga/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSVs. 
6.4. 
Out of window visits 
Analysis will be based on nominal visits; analysis windows will not be defined. 
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6.5. 
Unscheduled Assessments 
Extra assessments (e.g. laboratory data or vital signs associated with non-protocol clinical visits 
or obtained in the course of investigating or managing AEs) will be included in listings and PCSV 
summaries.  For by visit summaries, only scheduled visit values will be included.  Both scheduled 
and unscheduled measurements will be considered for determining abnormal values from 
laboratory data, vital sign, as well as the baseline values. 
6.6. 
Pooling of Centers for Statistical Analyses 
No plan of pooling of centers for analysis. 
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7. 
INTERIM ANALYSIS 
No interim analysis is planned. 
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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. (1996, July 30). ICH Harmonized tripartite guideline: Structure and  content of 
clinical study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
2. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
3. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
                                        VV-RIM-00192515-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2121 
Statistical Analysis Plan 
 
Date: JUN 23, 2022 
 
REGENERON CONFIDENTIAL 
Page 25 of 30 
 
10. 
APPENDIX 
10.1. 
Criteria for Potentially Clinically Significant Values (PCSV) 
If baseline is missing, only post-baseline criteria will be considered. 
Parameter 
PCSV 
  
Comments 
Clinical chemistry 
ALT 
>3 and ≤5 ULN and baseline ≤3 ULN 
>5 and ≤10 ULN and baseline ≤5 ULN 
>10 and ≤20 ULN and baseline ≤10 ULN 
>20 ULN and baseline ≤20 ULN 
Enzymes activities must be expressed in ULN, 
not in IU/L.  
Each category is calculated independently. 
AST 
>3 and ≤5 ULN and baseline ≤3 ULN 
>5 and ≤10 ULN and baseline ≤5 ULN 
>10 and ≤20 ULN and baseline ≤10 ULN 
>20 ULN and baseline ≤20 ULN 
Enzymes activities must be expressed in ULN, 
not in IU/L.  
Each category is calculated independently. 
Alkaline Phosphatase 
>1.5 ULN and baseline ≤1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
 
Total Bilirubin 
>1.5 and ≤2 ULN and baseline ≤1.5 ULN 
>2 ULN and baseline ≤2.0 ULN 
Must be expressed in ULN, not in µmol/L or mg/L.  
Conjugated bilirubin 
>35% Total Bilirubin and TBILI >1.5 ULN, and baseline Total 
Bilirubin ≤35% or TBILI ≤1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI >2 ULN, and baseline ALT ≤3 ULN 
or TBILI ≤2ULN 
 
                                        VV-RIM-00192515-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2121 
Statistical Analysis Plan 
 
Date: JUN 23, 2022 
 
REGENERON CONFIDENTIAL 
Page 26 of 30 
Parameter 
PCSV 
  
Comments 
CPK 
>3 and ≤10 ULN and baseline ≤3ULN 
>10 ULN and baseline ≤10ULN 
 
Creatinine 
≥150 μmol/L (Adults) or ≥ULN (if ULN ≥150 μmol/L) and 
baseline <150 μmol/L or <ULN (if ULN ≥150 μmol/L)   
≥30% change from baseline 
≥100% change from baseline 
3 independent criteria 
Creatinine Clearance 
(Cockcroft's formula) 
<15 ml/min and baseline ≥15 ml/min (end stage renal 
impairment) 
≥15 to <30 ml/min and baseline ≥30 ml/min (severe renal 
impairment) 
≥30 to < 60 ml/min and baseline ≥60 ml/min (moderate renal 
impairment) 
≥60 to < 90 ml/min and baseline ≥90 ml/min (mild renal 
impairment) 
Four independent criteria 
Uric Acid 
Hyperuricemia: 
 
     
    Hypouricemia: 
 
>408 μmol/L or >ULN (if ULN ≥408 μmol/L) and baseline 
≤408 μmol/L or ≤ULN (if ULN ≥408 μmol/L)   
<120 μmol/L or <LLN (if LLN ≤120 μmol/L) and baseline 
≥120 μmol/L or ≥LLN (if LLN ≤120 μmol/L)   
Two independent criteria 
Blood Urea Nitrogen 
≥17 mmol/L or ≥ULN (if ULN ≥17 mmol/L) and baseline <17 
mmol/L or <ULN (if ULN≥17 mmol/L)   
Two independent criteria 
Chloride                        
   Hypochloremia: 
 
   Hyperchloremia: 
 
<80 mmol/L or <LLN (if LLN ≤80 mmol/L) and baseline ≥80 
mmol/L or ≥LLN (if LLN ≤80 mmol/L)   
>115 mmol/L or >ULN (if ULN ≥115 mmol/L) and baseline 
≤115 mmol/L or ≤ULN (if ULN ≥115 mmol/L)   
Two independent criteria  
                                        VV-RIM-00192515-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2121 
Statistical Analysis Plan 
 
Date: JUN 23, 2022 
 
REGENERON CONFIDENTIAL 
Page 27 of 30 
Parameter 
PCSV 
  
Comments 
Sodium 
   Hyponatremia: 
 
 
  Hypernatremia: 
 
≤129 mmol/L  or ≤LLN (if LLN ≤129 mmol/L) and baseline 
>129 mmol/L  or >LLN (if LLN ≤129 mmol/L)   
≥160 mmol/L  or ≥ULN (if ULN ≥160 mmol/L )  and baseline 
<160 mmol/L  or <ULN (if ULN ≥160 mmol/L )   
Two independent criteria 
Potassium 
   Hypokalemia 
 
 
   Hyperkalemia 
 
<3 mmol/L or <LLN (if LLN ≤3 mmol/L) and baseline ≥3 
mmol/L or ≥LLN (if LLN ≤3 mmol/L)   
≥5.5 mmol/L or ≥ULN (if ULN ≥5.5 mmol/L) and baseline 
<5.5 mmol/L or <ULN (if ULN ≥5.5 mmol/L) 
Two independent criteria 
Total Cholesterol 
≥7.74 mmol/L or ≥ULN (if ULN ≥7.74 mmol/L) and baseline 
<7.74 mmol/L or <ULN (if ULN ≥7.74 mmol/L) 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L or ≥ULN (if ULN ≥4.6 mmol/L) and baseline 
<4.6 mmol/L or <ULN (if ULN ≥4.6 mmol/L) 
Threshold for therapeutic intervention 
Glucose 
 Hypoglycemia 
 
 Hyperglycemia 
 
≤3.9 mmol/L and <LLN and baseline >3.9 mmol/L or ≥ LLN  
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) and baseline 
<11.1 mmol/L (unfasted); <7 mmol/L (fasted)  
 
 
HbA1c 
>8%  and baseline  ≤ 8%  
 
Albumin 
≤25 g/L or ≤LLN (if LLN≤25 g/L) and baseline >25 g/L or 
>LLN (if LLN ≤25 g/L)   
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) and 
baseline ≤2 ULN or ≤10 mg/L (if ULN not provided) 
 
Hematology 
                                        VV-RIM-00192515-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2121 
Statistical Analysis Plan 
 
Date: JUN 23, 2022 
 
REGENERON CONFIDENTIAL 
Page 28 of 30 
Parameter 
PCSV 
  
Comments 
WBC 
<3.0 Giga/L or <LLN (if LLN ≤3.0 Giga/L) and baseline ≥3.0 
Giga/L or ≥LLN (if LLN≤3.0 Giga/L) (Non-Black);  
<2.0 Giga/L or <LLN (if LLN ≤2.0 Giga/L) and baseline ≥2.0 
Giga/L or ≥LLN (if LLN≤2.0 Giga/L) (Black) 
 
≥16.0 Giga/L or ≥ULN (if ULN ≥16.0 Giga/L) and baseline < 
16 Giga/L or <ULN (if ULN ≥16.0 Giga/L) 
 
Lymphocytes 
>4.0 Giga/L or >ULN (if ULN ≥4.0 Giga/L) and baseline ≤4.0 
Giga/L or ≤ULN (if ULN ≥4.0 Giga/L) 
 
Neutrophils 
<1.5 Giga/L or <LLN (if LLN ≤1.5 Giga/L)  and baseline ≥1.5 
Giga/L or ≥LLN (if LLN ≤1.5 Giga/L) (Non-Black);  
 
<1.0 Giga/L or <LLN (if LLN ≤1.0 Giga/L)  and baseline ≥1.0 
Giga/L or ≥LLN (if LLN ≤1.0 Giga/L)  (Black) 
 
Monocytes 
>0.7 Giga/L or >ULN (if ULN ≥0.7 Giga/L) and baseline ≤0.7 
Giga/L or ≤ULN (if ULN ≥0.7 Giga/L)   
 
Basophils 
>0.1 Giga/L or >ULN (if ULN ≥0.1 Giga/L) and baseline ≤0.1 
Giga/L or ≤ULN (if ULN ≥0.1 Giga/L)   
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN ≥0.5 Giga/L) and baseline ≤0.5 
Giga/L or ≤ULN (if ULN ≥0.5 Giga/L) 
 
                                        VV-RIM-00192515-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2121 
Statistical Analysis Plan 
 
Date: JUN 23, 2022 
 
REGENERON CONFIDENTIAL 
Page 29 of 30 
Parameter 
PCSV 
  
Comments 
Hemoglobin 
≤115 g/L or ≤LLN (if LLN ≤115 g/L) and baseline >115 g/L or 
>LLN (if LLN ≤115 g/L) for male; ≤95 g/L or ≤LLN (if LLN 
≤95 g/L) and baseline >95 g/L or >LLN (if LLN ≤95 g/L) for 
Female. 
 
≥185 g/L or ≥ULN (if ULN ≥185 g/L) and baseline <185 g/L 
or <ULN (if ULN ≥185 g/L) for Male; ≥165 g/L or ≥ULN (if 
ULN ≥165 g/L) and baseline <165 g/L or <ULN (if ULN ≥165 
g/L) for Female 
 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
Hematocrit 
≤0.37 v/v or ≤LLN (if LLN ≤0.37 v/v) and baseline >0.37 v/v 
or >LLN (if LLN ≤0.37 v/v) for Male; ≤0.32 v/v or ≤LLN (if 
LLN ≤0.32 v/v) and baseline > 0.32 v/v or >LLN (if LLN 
≤0.32 v/v) for Female 
 
≥0.55 v/v or ≥ULN (if ULN ≥0.55 v/v) and baseline <0.55 v/v 
or <ULN (if ULN ≥0.55 v/v) for Male; ≥0.5 v/v or ≥ULN (if 
ULN ≥0.5 v/v) and baseline < 0.5 v/v or <ULN (if ULN ≥0.5 
v/v) for Female 
Two Criteria are independent 
 
RBC 
≥6 Tera/L or ≥ULN (if ULN ≥6 Tera/L) and baseline < 6 
Tera/L or <ULN (if ULN ≥6 Tera/L) 
 
Platelets 
<100 Giga/L or <LLN (if LLN ≤100 Giga/L) and baseline ≥100 
Giga/L or ≥LLN (if LLN≤100 Giga/L) 
 
≥700 Giga/L or ≥ULN (if ULN ≥700 Giga/L) and baseline 
<700 Giga/L or <ULN (if ULN ≥700 Giga/L)   
Two independent criteria 
                                        VV-RIM-00192515-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R10933-10987-COV-2121 
Statistical Analysis Plan 
 
Date: JUN 23, 2022 
 
REGENERON CONFIDENTIAL 
Page 30 of 30 
Parameter 
PCSV 
  
Comments 
Vital signs 
HR 
<45 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
 
SBP 
≤95 mmHg and decrease from baseline ≥20 mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
 
Footnote: Only data collected in this study will be applied to these criteria. 
 
                                        VV-RIM-00192515-1.0 Approved - 27 Jun 2022 GMT-5:00


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                                        VV-RIM-00192515-1.0 Approved - 27 Jun 2022 GMT-5:00