Conditions: SARS-CoV-2
Keywords: AZD7442 Monoclonal antibodies (mAb) COVID-19 EVUSHELD
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 46
Healthy volunteers: no

Brief summary:
This study will evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of AZD7442 administered intramuscularly (IM) or intravenously (IV) in pediatric participants aged ≥ 29 weeks GA to \< 18 years.

Detailed description:
This is a Phase I, open-label, uncontrolled, multi-country, multi-center, single-dose study. Initially, 2 cohorts of participants will be enrolled: 1) participants who are severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) negative at screening and have not knowingly been exposed to a SARS-CoV-2 positive individual (pre-exposure prophylaxis); and 2) participants who are SARS-CoV-2 RT-PCR positive at screening and have mild to moderate COVID-19 symptoms. A third cohort might be added for the treatment of severe COVID-19. If included, this third cohort will include participants who are SARS-CoV-2 positive at screening and have severe COVID-19.

Arms:
arm 1: All participants will receive a single dose of AZD7442 on Day 1, either IM (AZD8895 followed by AZD1061) or IV (AZD8895 + AZD1061 concurrently).

Interventions: intervention 1: AZD7442
Intervention descriptions: intervention 1: IM Administration: AZD8895 and AZD1061 (comprising AZD7442), must both be administered separately to the participant in a sequential order.

IV Administration: AZD7442 is dosed by co-administration of AZD8895 and AZD1061 in a single IV infusion.

Protocol document:
Prot_000.pdf: 
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ClinicalTrials.gov Identifier: 1&7 
Protocol Amendment No. : Final .0,  Oct 202 
Clinical Study Protocol – 5.0
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Clinical Study Protocol 
Study Intervention
AZD7442
Study Code
D8850C00006
Version
5.0
Date
25 October 2023
Open-label, Uncontrolled, Single dose Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of AZD7442 in 
Pediatric Participants Aged ≥ 29 Weeks Gestational Age to 
< 18 Years
Sponsor Name:
AstraZeneca AB
Legal Registered Address
151 85 Södertälje, Sweden.
Regulatory Agency Identifier Number(s):
IND number: 150712
EudraCT Number: 2021-006056-13
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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Protocol Number: D8850C00006
Amendment Number: 4
Study Intervention: AZD7442
Study Phase: I
Short Title: AZD7442 PK, PD, and safety evaluation in children aged ≥29 weeks gestational 
age to < 18 years
Study Physician Name and Contact Information will be provided separately
International Coordinating Investigator: PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4
Version 5.0
25 October 2023
Amendment 3
Version 4.0
22 September 2022
Amendment 2
Version 3.0
03 March 2022
Amendment 1
Version 2.0
16 December 2021
Amendment 4 [25 October 2023]
Overall Rationale for the Amendment:
The CSP was amended with the following substantial changes: last study visit changed from 
Day 457 to Day 366. Currently the totality of the available data in adults (15 months for 
AZD7442 in the PROVENT and TACKLE studies and interim analysis data from this TRUST 
study) suggest that it is possible to extrapolate or infer the safety of AZD7442 in pediatrics 
from the existing data up to 15 months, which represents 5 half-lives of AZD7442. Reducing 
the follow-up period in the TRUST study to 12 months (Day 366) would also alleviate further 
burden of being in the clinical trial.
Section No and Name
Description of Change
Brief Rationale
Global changes to protocol
Updated last study visit from 
Day 457 to Day 366, 
removing the safety follow-up 
at Day 457.
!
Feasible to extrapolate or infer the safety 
of AZD7442 in pediatrics from the 
existing data up to 15 months.
!
Lessen the overall burden on participants 
in the clinical trial by shortening the 
duration of the final study visit from Day 
457 to Day 366.
1.1 Synopsis; Overall 
Design
Changed inclusion of 
participants in the study from 
15 to 12 months following 
administration of IMP.
To be consistent with the change in the last 
study visit from Day 457 to Day 366.
1.1 Synopsis; Intervention 
Groups and Duration
Changed monitoring of 
participants from 15 to 12 
months after AZD7442 
administration
To be consistent with the change in the last 
study visit from Day 457 to Day 366.
1.2 Schematic; Figures 1 
and 2
Changed Day 457 to Day 366 
in Figure 1.
Changed Week 65 to Week 52 
in Figure 2.
To be consistent with the change in the last 
study visit from Day 457 to Day 366.


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Section No and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities; 
Tables 2 and 3
Deleted the column related to 
Day 457 safety follow-up 
assessment in both tables.
Deleted the footnote related to 
Day 457 safety follow-up 
assessment under both tables.
To be consistent with the change in the last 
study visit from Day 457 to Day 366.
4.1 Overall Design
Deleted “Follow-up will 
continue through Day 457 (± 
15 days) when participants 
will receive a telephone call to 
assess safety.”
Changed the maximum 
duration of the study for each 
participant, including 
screening, from 479 to 388 
days.
To be consistent with the change in the last 
study visit from Day 457 to Day 366.
4.2.1 Rationale for Choice 
of Endpoints
Changed the following (old 
information as strikethrough, 
new information in bold) 
“The revised study duration of 
366 days 456 day Follow up 
Period will allow follow-up of 
dosed participants through 
approximately 5 4 AZD7442 
half-lives,”
To be consistent with the change in the last 
study visit from Day 457 to Day 366.
6.1.1 Investigational 
Product
Changed the following (old 
information as strikethrough, 
new information in bold) All 
eligible participants will 
receive a single dose of 
AZD7442 on Day 1, either IM 
(AZD8895 followed by 
AZD1061 administered 
separately) or a single IV 
infusion (AZD8895 and 
AZD1061 co-administered), 
and participants will be 
monitored for 456 365 days 
after IMP administration
To be consistent with the change in the last 
study visit from Day 457 to Day 366.
7.4.1 Stopping Rules for an 
Individual Participant, at 
Any Time in the Study
Changed the following (old 
information as strikethrough, 
new information in bold) 
“Unless consent for follow-up 
is withdrawn, participants 
discontinued after receiving a 
To be consistent with the change in the last 
study visit from Day 457 to Day 366.


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Section No and Name
Description of Change
Brief Rationale
partial dose of IMP will be 
followed for the full study 
period (up to and including 
Day 457 366, 65 52 weeks 
after IMP dosing)”
CSP, Clinical Study Protocol; DSMB, Data Safety Monitoring Board; EUA, emergency use authorization; GA, 
gestational age; mo, month; IB, Investigator’s Brochure; IM, intramuscular(ly); IV, intravenous(ly); mAb, 
monoclonal antibody; PK, pharmacokinetics; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; 
wk, week.


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS ...................................................................................................... 6
1
PROTOCOL SUMMARY ................................................................................ 11
1.1
Synopsis ........................................................................................................... 11
1.2
Schematic ......................................................................................................... 14
1.3
Schedule of Activities ....................................................................................... 15
2
INTRODUCTION............................................................................................ 22
2.1
Study Rationale ................................................................................................ 23
2.2
Background ...................................................................................................... 23
2.3
Benefit/Risk Assessment................................................................................... 23
2.3.1
Risk Assessment ............................................................................................... 24
2.3.2
Benefit Assessment........................................................................................... 26
2.3.3
Overall Benefit:Risk Conclusion....................................................................... 27
3
OBJECTIVES AND ENDPOINTS................................................................... 27
4
STUDY DESIGN ............................................................................................. 28
4.1
Overall Design.................................................................................................. 28
4.2
Scientific Rationale for Study Design ............................................................... 32
4.2.1
Rationale for Choice of Endpoints .................................................................... 32
4.2.2
Rationale for Study Population ......................................................................... 33
4.2.3
Participant Input into Design............................................................................. 33
4.3
Justification for Dose........................................................................................ 33
4.4
End of Study Definition.................................................................................... 34
5
STUDY POPULATION.................................................................................... 35
5.1
Inclusion Criteria .............................................................................................. 35
5.2
Exclusion Criteria ............................................................................................. 37
5.3
Lifestyle Considerations ................................................................................... 39
5.4
Screen Failures ................................................................................................. 39
6
STUDY INTERVENTION ............................................................................... 39
6.1
Study Interventions Administered ..................................................................... 40
6.1.1
Investigational Product ..................................................................................... 40
6.2
Preparation/Handling/Storage/Accountability ................................................... 41
6.2.1
Storage and Handling Procedures...................................................................... 41
6.2.2
Preparation and Administration......................................................................... 42
6.2.2.1
Intramuscular Administration............................................................................ 42
6.2.2.2
Intravenous Administration............................................................................... 43
6.3
Measures to Minimize Bias: Randomization ..................................................... 47


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6.4
Study Intervention Compliance......................................................................... 47
6.5
Concomitant Therapy........................................................................................ 47
6.5.1
Receipt of COVID-19 Vaccines During the Study............................................. 50
6.6
Dose Modification ............................................................................................ 50
6.7
Intervention After the End of the Study............................................................. 50
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 50
7.1
Discontinuation of Study Intervention............................................................... 50
7.2
Participant Withdrawal from the Study.............................................................. 51
7.3
Lost to Follow-up ............................................................................................. 51
7.4
Stopping Rules, Progression to Next Study Part, and Termination of Study....... 52
7.4.1
Stopping Rules for an Individual Participant, at Any Time in the Study............. 52
7.4.2
Stopping Rules for a Whole Cohort, Progression to Next Study Part, and 
Termination of Study ........................................................................................ 52
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 54
8.1
Efficacy Assessments........................................................................................ 54
8.1.1
Monitoring COVID-19 Symptoms.................................................................... 54
8.1.2
Severe COVID-19 Criteria................................................................................ 55
8.2
Safety Assessments........................................................................................... 56
8.2.1
Physical Examinations...................................................................................... 56
8.2.2
Vital Signs ........................................................................................................ 57
8.2.3
Electrocardiograms........................................................................................... 57
8.2.4
Clinical Safety Laboratory Assessments............................................................ 57
8.2.4.1
Hematology...................................................................................................... 58
8.2.4.2
Serum Clinical Chemistry................................................................................. 58
8.2.4.3
Urinalysis ......................................................................................................... 58
8.2.4.4
Coagulation Tests.............................................................................................. 58
8.2.4.5
Pregnancy Testing............................................................................................. 59
8.3
Adverse Events and Serious Adverse Events..................................................... 59
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 59
8.3.2
Follow-up of AEs and SAEs ............................................................................. 59
8.3.3
Causality Collection.......................................................................................... 61
8.3.4
Adverse Events of Special Interest.................................................................... 61
8.3.4.1
Anaphylaxis and Hypersensitivity Reactions..................................................... 62
8.3.4.2
Injection and Infusion Site Reactions ................................................................ 62
8.3.4.3
Multisystem Inflammatory Syndrome - Children .............................................. 62
8.3.4.4
Cardiac and Thromboembolic Events................................................................ 63
8.3.5
Medically Attended Adverse Events.................................................................. 63
8.3.6
Adverse Events Based on Signs and Symptoms ................................................ 63
8.3.7
Adverse Events Based on Examinations and Tests ............................................ 63
8.3.8
Hy’s Law.......................................................................................................... 64
8.3.9
Reporting of Serious Adverse Events................................................................ 64
8.3.10
Pregnancy......................................................................................................... 65


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8.3.10.1
Maternal Exposure............................................................................................ 65
8.3.10.2
Paternal Exposure............................................................................................. 65
8.3.11
Medication Error, Drug Abuse, and Drug Misuse.............................................. 66
8.3.11.1
Timelines.......................................................................................................... 66
8.3.11.2
Medication Error............................................................................................... 66
8.3.11.3
Drug Abuse....................................................................................................... 66
8.3.11.4
Drug Misuse ..................................................................................................... 66
8.4
Overdose .......................................................................................................... 67
8.5
Human Biological Samples............................................................................... 67
8.5.1
Total Blood Volume .......................................................................................... 68
8.5.2
Pharmacokinetics.............................................................................................. 69
8.5.2.1
Determination of Drug Concentration in Serum ................................................ 69
8.5.2.2
Determination of Drug Concentration in Nasal Secretions................................. 70
8.5.3
Immunogenicity Assessments ........................................................................... 70
8.5.3.1
Anti-drug Antibody........................................................................................... 70
8.5.3.2
SARS-CoV-2 Serology ..................................................................................... 70
8.5.4
Pharmacodynamics: Neutralizing Antibody Assessments.................................. 70
8.5.4.1
SARS-CoV-2 Neutralizing Antibody Assessments ............................................ 70
8.6
Human Biological Sample Biomarkers ............................................................. 70
8.6.1
Virologic Assessments ...................................................................................... 70
8.6.2
Other Study-related Biomarker Research .......................................................... 71
8.7
Optional Genomics Initiative Sample................................................................ 71
8.8
Medical Resource Utilization and Health Economics ........................................ 71
9
STATISTICAL CONSIDERATIONS................................................................ 71
9.1
Statistical Hypotheses....................................................................................... 71
9.2
Sample Size Determination............................................................................... 71
9.3
Populations for Analyses................................................................................... 72
9.4
Statistical Analyses ........................................................................................... 73
9.4.1
General Considerations..................................................................................... 73
9.4.2
Pharmacokinetics.............................................................................................. 73
9.4.2.1
Primary Endpoint(s).......................................................................................... 73
9.4.3
Pharmacodynamics........................................................................................... 74
9.4.3.1
Secondary Endpoint: Neutralizing Antibody Titers............................................ 74
9.4.4
Safety ............................................................................................................... 75
9.4.5
Anti-drug Antibody........................................................................................... 75
9.5
Interim Analyses............................................................................................... 76
9.6
Data Monitoring Committee ............................................................................. 76
9.7
Cardiovascular Event Adjudication Committee................................................. 76
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ........................................................................................ 76
11
REFERENCES............................................................................................... 115


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LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 14
Figure 2
Recruitment and Safety Review During the Study.................................... 15
LIST OF TABLES
Table 1
Schedule of Activities: Screening Period (All Participants)...................... 15
Table 2
Schedule of Activities: Treatment and Follow-up Period for Neonates –
Main Study.............................................................................................. 17
Table 3
Schedule of Activities: Treatment and Follow-up Period for Participants 
Other Than Neonates – Main Study ......................................................... 19
Table 4
Objectives and Endpoints......................................................................... 27
Table 5
Minimum Number of Participants to be Enrolled for Each Cohort, Age 
Group, and Route of Administration ........................................................ 31
Table 6
Planned Doses in the Different Indications in the Pediatric PK/PD/Safety 
Study....................................................................................................... 34
Table 7
Investigational Product: AZD7442........................................................... 40
Table 8
Volume of AZD7442 for IM Administration by Participant Weight 
Range and Indication ............................................................................... 43
Table 9
Preparation of AZD7442 Admixture for IV Administration ..................... 44
Table 10
Doses and AZD7442 Admixture Concentration Selection per Cohort and 
Participant Weight Range for IV Administration...................................... 46
Table 11
Summary of Permitted, Prohibited, or Restricted Medications ................. 48
Table 12
Summary of Restricted Drugs of Abuse and Alcohol ............................... 49
Table 13
COVID-19 Qualifying Symptoms............................................................ 55
Table 14
WHO Clinical Progression Scale ............................................................. 56
Table 15
Injection/infusion Site Inspection............................................................. 62
Table 16
Blood Volume Estimates ......................................................................... 68
Table 17
Populations for Analysis .......................................................................... 72
Table 18
Clinical Features of Anaphylaxis in Children........................................... 99
Table 19
An Approach to Management of Anaphylactic, Hypersensitivity, and 
Post Injection/Infusion Reactions........................................................... 101


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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 77
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 84
Appendix C
Handling of Human Biological Samples .................................................. 90
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 92
Appendix E
Hospitalization Definition........................................................................ 98
Appendix F
Anaphylaxis............................................................................................. 99
Appendix G
Abbreviations ........................................................................................ 104
Appendix H
Protocol Amendment History................................................................. 107


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: Open-label, Uncontrolled, Single dose Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of AZD7442 in Pediatric Participants Aged 
≥29 Weeks Gestational Age to < 18 Years.
Short Title: AZD7442 PK, PD, and safety evaluation in pediatric participants aged 
≥29 weeks GA to < 18 years.
Rationale: This Phase I pediatric study will provide information on the AZD7442 PK profile, 
SARS-CoV-2-neutralizing antibody titers, effect on viral load, data on the safety and 
tolerability, and the generation of anti-drug antibodies to AZD7442, following a single IM or 
IV AZD7442 dose administration in different pediatric age groups.
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To evaluate the serum concentrations 
of AZD7442 after a single IM or IV 
dose in pediatric participants
•
Serum concentrations of AZD7442 at specified time 
points during the study period when administered as a 
single IM or IV dose
•
Serum PK parameters (if data permits): Cmax, tmax, t1/2, 
AUC0-last, AUC0-inf, tlast, %AUCex, and:
∀
for IM: CL/F, and Vz/F
∀
for IV: CL, and Vss
•
Model-derived predicted serum AZD7442 concentrations 
and AUC0-inf
•
To evaluate the safety and tolerability 
of AZD7442 after a single IM or IV 
dose in pediatric participants 
•
TEAEs, SAEs, and AESIs
•
Safety laboratory parameters (hematology, clinical 
chemistry, coagulation, and urinalysis); 12 lead safety 
ECG; vital signs (BP, pulse rate, tympanic membrane 
temperature, and respiratory rate); and physical 
examination
Secondary – All Cohorts
•
To evaluate the PD of AZD7442 after 
a single IM or IV dose in pediatric 
participants 
•
Titer of SARS-CoV-2 neutralizing antibodies 
•
To evaluate the immunogenicity 
profile of AZD7442 after a single IM 
or IV dose in pediatric participants 
•
Incidence of ADA and nAb to AZD7442 in serum 


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Objectives
Endpoints
Secondary – Cohort 1 (Prophylaxis)
•
To evaluate the incidence of SARS-
CoV-2 infections with or without 
COVID-19 symptoms after a single 
IM or IV dose of AZD7442 in 
pediatric participants 
•
Incidence of SARS-CoV-2 infections with and without 
COVID-19 symptoms
Secondary – Cohort 2 and Cohort 3 (Treatment)
•
To quantify SARS-CoV-2 viral loads 
after a single IM or IV dose of 
AZD7442 in pediatric participants 
•
Change from baseline to Day 8 in viral load as measured 
by qRT-PCR
•
To evaluate the proportion of 
participants with progression of 
COVID-19 after a single IM or IV 
dose of AZD7442 in pediatric 
participants 
•
Proportion of participants with progression of COVID-19 
through Day 29
•
To evaluate COVID-19-related death
after a single IM or IV dose of 
AZD7442 in pediatric participants 
•
The incidence of COVID-19-related death occurring after 
dosing with IMP through 90 days 
Secondary – Cohort 3 (Severe COVID-19)
•
To evaluate the time to sustained 
recovery from severe COVID-19 after 
a single IM or IV dose of AZD7442 in 
pediatric participants 
•
Time to sustained recovery (defined as being discharged 
from the index hospitalization, followed by being alive 
and home for 14 consecutive days)
%AUCex, percentage of AUC0-inf extrapolated to infinity; ADA, anti-drug antibodies; AESI, adverse event of 
special interest; AUC0-inf , area under the serum concentration versus time curve extrapolated to infinity; 
AUC0-last, area under the serum concentration versus time curve from time zero to time of last measurable 
concentration; BP, blood pressure; CL, systemic clearance; CL/F, apparent total clearance; Cmax, maximum 
serum concentration; COVID-19, Coronavirus disease-2019; ECG, electrocardiogram; IM, intramuscular; IMP, 
investigational medicinal product; IV, intravenous; nAb, neutralizing antibodies; MIS-C, multisystem 
inflammatory syndrome – children; PD, pharmacodynamics; PK, pharmacokinetics; qRT-PCR, quantitative real-
time polymerase chain reaction; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome 
coronavirus 2; t1/2, terminal half-life; tlast, time to last measurable concentration; tmax, time to reach maximum 
serum concentration; TEAE, treatment emergent adverse event; Vss, volume of distribution at steady state; Vz/F, 
apparent volume of distribution based on terminal phase.
For the exploratory objective and endpoint, see Section 3 of the protocol.
Overall Design
This is a Phase I, open-label, uncontrolled, multicenter, single dose study to evaluate the PK, 
PD, safety, and tolerability of AZD7442 administered IM or IV in pediatric participants aged 
≥29 weeks GA (infants born between gestational age of 29 weeks to full term) to < 18 years. 
Up to 3 cohorts of participants will be enrolled based on the adult indication and dose: 1) 
participants who are SARS-CoV-2 negative at screening and have not knowingly been 
exposed to a SARS-CoV-2 positive individual (pre-exposure prophylaxis); 2) participants who 
are SARS-CoV-2 positive at screening and have mild to moderate coronavirus disease 2019 
(COVID-19) symptoms; and 3) participants who are SARS-CoV-2 positive at screening and 


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have severe COVID-19. Both Cohorts 1 and Cohort 2 are required to be at increased risk of 
developing severe COVID-19. Recruitment will start with Cohort 1; Cohorts 2 and 3 will be 
added if the indications are progressed in adults. If a cohort is not opened, that cohort’s 
minimum number of participants will be re-allocated to available open cohorts in order for 
there to be a minimum of 6 participants receiving IV administration and a minimum of 6 
participants receiving IM administration of the IMP in each of the four main age categories. 
All participants will be included in the study for 12 months following administration of IMP.
Disclosure Statement: This is a sequential basic science study with one arm that is participant 
and treatment unblinded.
Number of Participants:
Approximately 120 participants will be enrolled such that a minimum of 100 evaluable 
participants are assigned to study intervention. Recruitment will be stratified to ensure that all 
pediatric age groups are represented.
Note: “Enrolled” means a participant's or their parent or legally acceptable representative’s 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility for 
the study, but are not assigned in the study, are considered “screen failures”, unless otherwise 
specified by the protocol.
Intervention Groups and Duration:
Eligible participants will receive a single dose of AZD7442 given via IM (AZD8895 followed 
by AZD1061 administered separately) or a single IV infusion (AZD8895 and AZD1061 
co-administered) based on the participant’s body weight (prophylaxis of COVID-19/treatment 
of mild to moderate COVID-19: 60 to 600 mg IM or 50 to 440 mg IV; treatment of severe 
COVID-19: 60 to 600 mg IV). Investigational medicinal product will be administered on 
Day 1, and participants will be monitored for up to 12 months after AZD7442 administration.
Data Safety Monitoring Board:
Yes
Statistical Methods:
All original and derived parameters as well as demographic and disposition data will be listed 
and described using summary statistics. All safety data (scheduled and unscheduled) will be 
presented in the data listings. Frequency counts (number of participants [n] and percentages) 
will be provided for each qualitative variable. Descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum) will be calculated for each quantitative variable. 
At least one interim analysis is planned after a minimum of 12 adolescent participants, age 
≥12 to # 18 years old, complete the Day 92 study visit. Additional interim analyses may be 


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conducted to support regulatory requirements or at the discretion of the Sponsor. No 
hypotheses are planned in this PK, PD, safety study so multiplicity is not a concern. All 
statistical analyses and production of tables, figures and listings will be performed using SAS®
version 9.4 or higher.
AZD7442 serum concentrations will be analyzed by non-compartmental analysis and PK 
parameters summarized descriptively. AZD7442 serum concentrations will also be analyzed 
by population methods and population PK parameter estimates presented.
1.2
Schematic
Figure 1
Study Design
a
The sentinel review will be conducted on the first 2 participants with 24 hours of safety data.
b
The first DSMB review will take place once 14 days of safety data are available for ≥6 participants.
c
The first interim analysis will take place once 92 days of safety data are available for ≥12 adolescents. All 
available PK and safety data from all age groups at the data cut-off date will be included in the analysis.
Cohort 1: Participants who are SARS-CoV-2 RT-PCR negative at screening and have not knowingly been 
exposed to a SARS-CoV-2 positive individual and who are at increased risk of developing severe COVID-19.
Cohort 2: Participants who are SARS-CoV-2 RT-PCR positive at screening and have mild to moderate 
COVID-19 and who are at increased risk of developing severe COVID-19. Cohort 2 will only start recruiting if 
this indication is progressed in adults.
Cohort 3: Participants who are SARS-CoV-2 RT-PCR positive at screening and have severe COVID-19. 
Cohort 3 will only start recruiting if this indication is progressed in adults.
Recruitment will be paused during the sentinel review but not during the DSMB reviews.
COVID-19, coronavirus disease 2019; DSMB, Data Safety Monitoring Board; Min, minimum; PK, 
pharmacokinetic; RT-PCR, reverse transcriptase polymerase chain reaction; SARS-CoV-2, severe acute 
respiratory syndrome coronavirus 2.


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Figure 2
Recruitment and Safety Review During the Study
a
Sentinel review: Two participants aged ≥2 to < 18 years from Cohort 1 will be dosed and monitored for 
24 hours post-dose (Sentinel Cohort). Recruitment will pause while the International Co-ordinating 
Investigator, the AstraZeneca Global Safety Physician, and the AstraZeneca Global Clinical Head review 
the safety data from the Sentinel Cohort. Once the 24 h safety data review of the Sentinel Cohort is 
complete, and the safety of AZD7442 is confirmed in the sentinel group, recruitment can start in the 
remaining pediatric participants, including those aged ≥29 weeks GA to < 2 years.
b
First DSMB Review: The review will be conducted when at least 6 participants from any age group 
(including the 2 sentinel participants) have at least 14 days of safety data (all available safety data from all 
participants will be included in the DSMB review). Recruitment will continue during the DSMB review.
c
Periodic DSMB Reviews: Cumulative safety data will be reviewed after the following number of 
participants have been recruited: 21, 36, 51, 66, 81, and 96. Recruitment will continue during the DSMB 
reviews.
DSMB, Data Safety Monitoring Board; GA, gestational age; pts, participants; h, hour.
1.3
Schedule of Activities
Table 1 summarizes the SoA at screening for all participants. Table 2 and Table 3 summarize 
the SoA during the main study for neonates (modified sample collection) and non-neonates, 
respectively.
Table 1
Schedule of Activities: Screening Period (All Participants)
Procedure/study day
Day -7 to Day 1 a
For details, see 
section:
Informed consent/assent
X
5.1
Assignment SID number b
X
6.3
Demographics and risk categorization
X
5.1
Medical history
X
NA
Complete physical examination, including 
height and weight
X
8.2.1
Vital signs (including pulse oximetry)
X
8.2.2
Triplicate 12-lead ECG
X
8.2.3
Serum chemistry, hematology, urinalysis c
X
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Table 1
Schedule of Activities: Screening Period (All Participants)
Procedure/study day
Day -7 to Day 1 a
For details, see 
section:
Coagulation
X
8.2.4
Urine pregnancy test (post-pubertal 
females only) d
X
8.2.4.5
Assessment of SAEs
X
8.3
Concomitant medications
X
6.5
Serum sample for SARS-CoV-2 serology 
(anti-nucleocapsid) testing (all participants 
other than neonates)
X
8.5.3.2
Verify eligibility criteria
X
5.1, 5.2
Screening criteria specific to each cohort
Cohort 1
Pre-exposure 
prophylaxis
Cohorts 2 and 3
Treatment of 
COVID-19
For details, see 
section:
Documented SARS-CoV-2 RT-PCR test 
taken ≤3 days before Day 1 e OR
Rapid SARS-CoV-2 antigen test (for 
assignment to study cohorts) per local 
standard of care authorized for screening or 
diagnosis
X (negative)
X (positive)
8.6.1
COVID-19 Symptom screen
NA
X (Yes)
5.1
a
Screening activities may be collected over more than one visit during the 7-day screening window if 
necessary; if screening and dosing occur at the same visit, only one evaluation is required, unless otherwise 
specified. The sample taken closest to dosing and prior to dosing is considered the baseline sample.
b
Assigned by the IRT system. See Section 6.3 for further information.
c
Collection of urine samples for urinalysis from participants who are unable to provide urine samples is not 
mandatory provided that a reasonable attempt has been made to collect the samples.
d
If urine tests positive or is indeterminate, a quantitative serum β-hCG will be performed for confirmation 
before the participant is enrolled in the study. Pregnancy testing is for baseline purposes only, and a 
participant with a positive urine pregnancy test can still participate in the study.
e
This test is not performed as part of the clinical study but may be available prior to enrollment. If a 
documented SARS-CoV-2 RT-PCR test is not available at screening, a rapid SARS-CoV-2 antigen test will 
be performed (to be sourced by the investigational site).
β-hCG, beta-human chorionic gonadotropin; COVID-19, coronavirus disease 2019; ECG, electrocardiogram; 
IRT, Interactive Response Technology; NA, not applicable; RT-PCR, reverse transcriptase polymerase chain 
reaction; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome-coronavirus 2; SID, 
subject identification.


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Table 2
Schedule of Activities: Treatment and Follow-up Period for Neonates – Main Study
Procedure
Treatment and follow-up period
Early 
discontinuation 
visit
For 
details, 
see 
section:
Visit 1
Visit 2
Visit 2A
Visit 3a
Visit 4a
Visit 5a
Visit 6a
Day
1
4, 8, 
11 or 
15b
8
31
92
183
366
Window (days)
NA
± 2
± 3
+ 5
± 5
± 10
± 15
Targeted physical examination
X
X
X
X
X
X
8.2.1
Vital signs (including pulse oximetry)
Xc
(post dose)
X
X
X
X
X
X
8.2.2
Triplicate 12-lead ECG 
X
X
8.2.3
Serum chemistry, hematology 
X
X
X
X
8.2.4
Coagulation tests
X
X
X
X
8.2.4
Urinalysisd
X
X
X
X
X
8.2.4
Concomitant medications
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
5.1, 5.2
IMP administration
X
Sample for SARS-CoV-2 RT-PCR 
(central laboratory)
Xe,f
(pre-dose)
Xf
8.6.1
Pharmacokinetics, pharmacodynamics, and ADA assessments
Serum sample for AZD7442 PK 
assessment
Only 
participants 
receiving 
AZD7442 
IV
(post 
doseg)
X
X
X
X
X
X
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ADA, anti-drug antibody; AE, adverse event; AESI, adverse event of special interest; COVID-19, Coronavirus disease-2019; ECG, electrocardiogram; FU, 
follow-up; IMP, investigational medicinal product; IV, intravenous; MAAE, medically attended adverse event; NA, not applicable; PK, pharmacokinetic; 
RT-PCR, reverse transcriptase polymerase chain reaction; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SoA, 
schedule of activities.
Table 3
Schedule of Activities: Treatment and Follow-up Period for Participants Other Than Neonates – Main Study
Procedure
Treatment and follow-up period
Early 
discontinuation 
visit
For 
details, see 
section:
Visit 1
Visit 2
Visit 2A
Visit 3
Visit 4
Visit 5
Visit 6
Day
1
4, 8, 11 
or 15a
8
31
92
183
366
Window (days)
NA
± 2
± 3
+ 5
± 5
± 10
± 15
Targeted physical examination
X
X
X
X
X
X
8.2.1
Vital signs (including pulse 
oximetry)
Xb
(post dose)
X
X
X
X
X
X
8.2.2
Triplicate 12-lead ECG 
X
X
8.2.3
Serum chemistry, hematology 
X
X
X
X
8.2.4
Coagulation tests
X
X
X
X
8.2.4
Urinalysisc 
X
X
X
X
X
8.2.4
Pregnancy test – urine (females of 
childbearing potential only)d
X
(pre-dose)
8.2.4
Concomitant medications
X
X
X
X
X
X
X
6.5
Verify eligibility criteria
X
5.1, 5.2
IMP administration
X
Sample for SARS-CoV-2 RT-PCR 
(central laboratory)e
Xf, g
(pre-dose)
Xg
8.6.1
Serum sample for SARS-CoV-2 
serology (anti-nucleocapsid) 
(Cohort 1 only)
X
X
X
X
X
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e
The type of sample (eg, saliva, blood, nasopharyngeal) should be consistent between all study visits for each participant, but particularly for the samples 
collected on Day 1 and Day 8 which will be used to estimate the change in viral load. For participants in cohort 1 that have COVID-19 qualifying symptoms 
(Table 13) at any time during the study, an unscheduled sample will be collected for SARS-CoV-2 RT-PCR to confirm the participant is SARS-CoV-2 
positive (Section 8.1.1).
f
Baseline sample, not a screening sample; results not needed prior to dosing.
g
All participants will have a sample collected for SARS-CoV-2 RT-PCR on Day 1. Only Cohorts 2 and 3 (treatment arms) will have a sample collected for 
quantitative RT-PCR on Day 1 and Day 8. For RT-PCR, the central laboratory should be used.
h
For participants who receive AZD7442 via an IV infusion, a serum sample should be taken at the end of the infusion (and from the opposite side to the one 
used for the infusion).
i
The first 2 participants aged ≥2 years to < 18 years in Cohort 1 (Sentinel Cohort) will undergo internal safety monitoring for 24 hours post IMP 
administration (including injection/infusion site reactions and other hypersensitivity or adverse reactions). Once the 24 h safety data review of the Sentinel 
Cohort is complete, recruitment can start in the remaining pediatric participants. All other participants will be monitored on site for general safety, including 
injection/infusion site reactions and other hypersensitivity reactions, for at least one hour after IMP administration (Section 8.3.1).
j
For the first 4 days after IMP administration, the sentinel participants (2 participants aged ≥2 to # 18 years) will be contacted daily for safety monitoring 
followed by weekly contact. All other participants will be contacted weekly starting from the time of IMP administration. During weekly contact the 
Investigator will enquire about any AEs, SAEs, MAAEs, and AESIs as well as any COVID-19 symptoms from the past 7 days.
If necessary, the visit windows in the SoA can be used to collect samples across a number of days. If it is not possible to obtain sufficient blood from a 
participant at a study visit, the order of the samples will be prioritized according to the key requirements of the study. The following hierarchy will be applied: 
safety (serum chemistry, hematology, and coagulation), PK, SARS-CoV-2 nAbs, and ADA (see Laboratory Manual).
ADA, anti-drug antibody; AE, adverse event; AESI, adverse event of special interest; β-hCG, beta-human chorionic gonadotropin; COVID-19, Coronavirus 
disease 2019; ECG, electrocardiogram; FU, follow-up; h, hour; IMP, investigational medicinal product; IV, intravenous; MAAE, medically attended adverse 
event; NA, not applicable; nAb, neutralizing antibody; PK, pharmacokinetic; RT-PCR, reverse transcriptase polymerase chain reaction; SAE, serious adverse 
event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SoA, schedule of activities.


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2
INTRODUCTION
Severe acute respiratory coronavirus 2, is a novel coronavirus that appears to have first 
emerged in China in late 2019 (Zhou et al 2020b) causing cases of atypical pneumonia, later 
named COVID-19 and being declared a pandemic by the WHO on 11 March 2020 (WHO 
2020). Since then, the COVID-19 pandemic has caused major disruption to healthcare systems 
with significant socioeconomic impacts. As of 5 August 2021, there have been over 
200 million confirmed cases of COVID-19, including 4.2 million deaths, reported to WHO 
(WHO 2021). With a basic reproduction number R0 value estimated between 2.43 to 3.10 
without intervention, SARS-CoV-2 is highly transmissible from person to person, which has 
contributed to its rapid dissemination worldwide (D’Arienzo and Coniglio 2020). The 
pandemic continues to evolve via the emergence of variants and their ability to increase the R0
value and potentially evade a vaccine only approach.
Relative to the total number of confirmed COVID-19 cases, the proportion of pediatric cases 
is estimated to be < 13% in Europe/United Kingdom (ECDC 2021) and < 12% in the USA 
(CDC 2021a), and the proportion of COVID-19-associated pediatric deaths is less than ≤1% 
of the total (ECDC 2021; CDC 2021a). COVID-19 in children is generally mild or 
asymptomatic and the prognosis is good, even inpatients who develop severe disease 
(including MIS-C) (CDC 2021d; Götzinger et al 2020; Swann et al 2020). Children with the 
greatest risk of poor outcomes with COVID-19 are those < 1 month of age, children of any 
age having, an underlying condition (including cardiovascular disease, malignancy, 
immunosuppression, chronic kidney disease, heart disease since birth, genetic, neurologic, or 
metabolic conditions), or being of black or Hispanic race (CDC 2021b; Götzinger et al 2020; 
Ludvigsson 2020; Swann et al 2020).
As a response to the ongoing pandemic, AstraZeneca has developed mAbs targeting the 
SARS-CoV-2 spike protein. The SARS-CoV-2 spike protein contains the RBD, which enables 
the virus to bind to ACE2 receptors on human cells. By targeting this region of the spike 
protein on the virus, antibodies can block the virus’s attachment to ACE2 receptors and, 
therefore, are expected to block infection. AZD7442 consists of 2 separate mAbs which bind 
to distinct, non-overlapping sites on the SARS-CoV-2 spike protein RBD. Binding to either of 
these sites blocks the virus’s ability to bind to ACE2 resulting in a blockade of virus entry, 
effectively neutralizing the SARS-CoV-2 virus. By blocking virus entry into human cells, 
AZD7442 stops virus replication, which stops infection, and is, therefore, being developed for 
the prophylaxis of COVID-19 and treatment of COVID-19.
AZD7442 retains full to nearly full neutralization activity against pseudoviruses and/or 
authentic SARS-CoV-2 variant strains harboring all spike substitutions identified in 
circulating variants of concern (including the Omicron BA.2 variant), variants of interest, 
variants alerts for further monitoring, and variants de-escalated from further monitoring. For 


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the Omicron BA.1 variant, independent laboratories have generated in vitro potency data 
showing that AZD7442 maintains neutralizing activity, although increases in IC50 compared to 
the original SARS-CoV-2 strain were observed (Dejnirattisai et al 2021; FNIH 2022; 
VanBlargan et al 2022; Zhou et al 2021). Virological surveillance is ongoing in the clinical 
studies to characterize how changes in potency observed in authentic SARS-CoV-2 or 
pseudotyped virus-like particle neutralization assays correlate with clinical outcomes.
On 08 December 2021, the FDA authorized AZD7442 as EVUSHELD™ (tixagevimab and 
cilgavimab administered together) for emergency use under an EUA for the pre-exposure 
prophylaxis of COVID-19 in adults and children (≥12 years weighing at least 40 kg) who are 
moderately to severely immunocompromised (Section 2.3.2).
A detailed and current description of the chemistry, pharmacology, efficacy, safety and 
marketing experiences of AZD7442 is provided in the latest version of the AZD7442 IB.
2.1
Study Rationale
This Phase I pediatric study will provide information on the AZD7442 PK profile, 
SARS-CoV-2-neutralizing antibody titers, effect on viral load, as well as data on the safety 
and tolerability and generation of ADAs to AZD7442, following a single IM or IV AZD7442 
dose administration in different pediatric age groups. This will be the first AZD7442 clinical 
study in pediatric participants aged ≥29 weeks GA to # 18 years.
2.2
Background
Coronaviruses are spherical, enveloped viruses with positive-sense, single-stranded RNA 
genomes. One fourth of their genome is responsible for coding structural proteins, such as the 
spike glycoprotein, envelope, membrane, and nucleocapsid proteins. Envelope, membrane, 
and nucleocapsid proteins are mainly responsible for virion assembly, while the spike protein 
is involved in receptor binding, mediating virus entry into host cells during coronavirus 
infection via different receptors (Li 2016). The SARS-CoV-2 belongs to the phylogenetic 
lineage B of the genus Beta-coronavirus, and it recognizes the ACE2 as the entry receptor 
(Zhou et al 2020a). It is the seventh coronavirus known to cause human infections and the 
third known to cause severe disease after SARS-CoV-1 and MERS-CoV.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD7442 is 
provided in the IB.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD7442 may be found in the IB and Participant/Parent Information Leaflet.


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2.3.1
Risk Assessment
There are no identified risks associated with AZD7442. To date, no observations are 
considered to represent expected adverse reactions that would form part of an emerging safety 
profile. In the FTIH Phase I dose escalation study (D8850C00001) in healthy adult volunteers, 
60 participants had received IMP by the data cut-off date for the interim analysis of 06 June 
2021. The results demonstrated an acceptable safety profile for AZD7442, including no 
observed infusion-related reactions (for IV administration), injection site reactions (for IM 
administration), or hypersensitivity reactions. No risks to date have been identified in the 
Phase III studies.
Due to observations in the adult population in the Phase III pre-exposure prophylaxis study 
PROVENT (n = 5197), cardiac ischemia, cardiac failure, and thrombotic events have been 
included as AESIs in this study. In PROVENT, a small numerical imbalance in SAEs in the 
Cardiac Disorders SOC was observed between the treatment groups. The number of 
participants with Cardiac Disorder SAEs adjusted by exposure (in patient-years) were 23 
(1.2%) in the AZD7442 group and 5 (0.5%) in the placebo group. There were no reports of 
severe COVID-19 or COVID-19-related deaths in those treated with AZD7442. In the placebo 
arm, there were 3 cases of severe COVID-19, which included 2 deaths. In STORM CHASER, 
a separate Phase III post-exposure prophylaxis study of AZD7442 in adults (n = 1121), which 
enrolled a younger population with fewer baseline cardiac risk factors than PROVENT, no 
Cardiac disorder SAEs were reported. In TACKLE, a Phase III treatment study of AZD7442 
in adults (n = 903), there were 2 (0.4%) SAEs in the Cardiac disorders SOC in the AZD7442 
group and 1 (0.2%) in the placebo group. None of the Cardiac disorder SAEs in the AZD7442 
group were considered related to the investigational product by the investigator. All 
participants in the Phase III studies who experienced cardiac disorder SAEs had numerous 
cardiac related risk factors and/or a prior history of CV disease at baseline. There was no clear 
temporal pattern, and a causal relationship between AZD7442 and these events has not been 
established. There was no signal for cardiac toxicity or thrombotic events identified in 
nonclinical studies.
AZD7442 is a combination of 2 human mAbs, with non-overlapping epitopes directed against 
RBD of the SARS-CoV-2 spike protein for neutralization of the virus. Neither mAb has any 
human target. There are no potential risks based on mechanism of action.
There are potential risks associated with the administration of any immunoglobulin, including 
polyclonal immunoglobulin preparations and mAbs. The potential risks include, but are not 
limited to injection site reactions, infusion-related reactions, and antibody-dependent 
enhancement of disease.
Injection site reactions may be observed and may manifest as local inflammation, redness, 
itching, pain, bruising, infection, or excessive bleeding at the site of injection. Clinical studies 


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with AZD7442 will closely monitor participants during and after IMP administration. These 
reactions should be managed according to standard clinical practice.
An infusion-related reaction is defined as any other reaction (other than hypersensitivity and 
anaphylaxis) occurring during infusion of IMP or felt to be temporally related to the infusion 
and occurring within 30 minutes to 2 hours after the initiation of first IMP infusion. However, 
though less frequent, infusion-related reactions can also occur later on within the first 24 hours 
from the start of infusion and are less common following subsequent exposures. Infusion-
related reactions may manifest with single or multiple signs and symptoms. Most are mild in 
intensity, but severe and even fatal reactions have been reported. Unlike infusion-related 
reaction, anaphylaxis is a rare event, usually occurring after subsequent exposure to an 
antigen, and is most commonly accompanied by severe systemic skin and/or mucosal 
reactions.
Antibody-dependent enhancement of disease is a theoretical risk. Two different syndromes 
exist:
1. Antibody-dependent enhancement of disease, which involves increased binding efficiency 
of virus-antibody complexes to Fc receptor bearing cells and which triggers virus entry. 
The mAbs in AZD7442 have been designed with a modification to prevent binding to 
cellular Fc receptors, so the risk of antibody-dependent enhancement of disease occurring 
via this mechanism should be very low to none.
2. Vaccine-associated enhanced respiratory disease: a distinct clinical syndrome that 
occurred in young children in the 1960s when whole inactivated virus vaccines for 
measles and RSV were tested. Immunizing with limiting doses of RSV antigen, especially 
with conformationally incorrect antigens, can result in 2 major types of immunological 
phenomena:
a) A relatively high ratio of antibody that binds, but does not neutralize, virus could 
potentially result in immunogenic cell death and complement activation (leading to 
inflammation and airway obstruction).
b) Immunization with whole inactivated virus vaccines can result in allergic 
inflammation characterized by, eg, increased mucus production, airway hyper-
responsiveness, and attenuated cytolytic T cell activity (T helper 2 cell immune 
response). This mechanism, induced by vaccines, should not be provoked by mAbs.
The potential risks in this study will be addressed by the following mitigation strategies:
!
Safety data from a Sentinel Cohort (of 2 participants aged ≥2 to # 18 years from 
Cohort 1) for at least 24 hours will be reviewed by the International Co-ordinating 
Investigator, the AstraZeneca Global Safety Physician, and the AstraZeneca Global 


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Clinical Head before the remaining participants in the study are dosed (Section 4.1). 
Recruitment will be paused during this review.
!
A DSMB will conduct a safety review of a minimum of 14 days of safety data from at 
least the first 6 participants enrolled in the study (Section 4.1). Subsequent DSMB 
meetings will review cumulative safety data after 21, 36, 51, 66, 81, and 96 participants 
have been dosed with AZD7442.
!
Participants will be monitored on site for adverse reactions for a minimum of one hour 
after IMP administration (Section 8.3.1).
!
Stopping rules (Section 7.4).
2.3.2 Benefit Assessment
This is the first study in pediatric participants so the benefits of AZD7442 in prophylaxis and 
treatment of COVID-19 in pediatrics is unknown. In both the PROVENT and STORM 
CHASER trials in adults, AZD7442 reduced the risk of developing symptomatic COVID-19 
by more than 70% compared with placebo in participants who were SARS-CoV-2 negative at 
baseline (see Section 2). In the TACKLE study (NCT04723394), AZD7442 reduced the risk 
of developing severe COVID-19 or death by 50% compared to placebo in non-hospitalized 
adults who had been symptomatic for 7 days or less, and the risk was reduced by 67% if 
participants were treated within 5 days of symptom onset. Importantly, 90% of trial 
participants were from populations at high risk for progressing to severe COVID-19. 
Additional adult studies for the treatment of mild to moderate COVID-19 and severe 
COVID-19 with AZD7442 are ongoing.
The FDA has authorized for emergency use under an EUA, AZD7442 as EVUSHELD
(tixagevimab and cilgavimab administered together) for the pre-exposure prophylaxis of 
COVID-19 in adults and children (≥12 years weighing at least 40 kg) who are moderately to 
severely immunocompromised due to an underlying immune disease or are taking 
immunosuppressive medications and therefore unable to mount an adequate immune response 
to COVID-19 vaccine. In addition, use is authorized in those with a history of severe adverse 
reaction to a COVID-19 vaccine, in whom COVID-19 vaccine is not recommended.
Despite the rollout of effective SARS-CoV-2 vaccines, a sizeable proportion of the general 
population remain unprotected and many young children are ineligible to receive a vaccine. 
There remains a clear unmet medical need to neutralize SARS-CoV-2 and ensure protection 
against emerging variants, particularly in those individuals not expected to mount an adequate 
response to complete active immunization (CDC 2021c), and those for whom vaccination is 
not suitable. AZD7442 remains the only prophylactic mAb to successfully neutralize the 
Omicron variant authentic virus (BA.1) in vitro (VanBlargan et al 2022).


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Recruitment will target pediatric participants aged ≥29 weeks GA to # 18 years who are likely 
to benefit from prophylaxis or treatment with AZD7442 because they either have severe 
COVID-19 or an underlying condition that increases their risk of developing severe 
COVID-19.
2.3.3 Overall Benefit:Risk Conclusion
Considering the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with AZD7442 are justified by the anticipated benefits that may 
be afforded to pediatric participants who have severe COVID-19 or who are at risk of 
developing severe COVID-19 if they contract SARS-CoV-2.
3
OBJECTIVES AND ENDPOINTS
Table 4 lists the objectives and endpoints for the study. The co-primary objectives are to 
evaluate the PK of AZD7442 and the safety and tolerability of AZD7442 administered as a 
single IM or IV dose to pediatric participants ≥29 weeks GA to < 18 years of age who either 
have severe COVID-19 or an underlying co-morbidity that increases their risk of developing 
severe COVID-19 (eg, immunosuppression).
Table 4
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To evaluate the serum concentrations 
of AZD7442 after a single IM or IV 
dose in pediatric participants
•
Serum concentrations of AZD7442 at specified time 
points during the study period when administered as a 
single IM or IV dose
•
Serum PK parameters (if data permits): Cmax, tmax, t1/2, 
AUC0-last, AUC0-inf, tlast, %AUCex, and:
∀
for IM: CL/F, and Vz/F
∀
for IV: CL, and Vss
•
Model-derived predicted serum AZD7442 concentrations 
and AUC0-inf
•
To evaluate the safety and tolerability 
of AZD7442 after a single IM or IV 
dose in pediatric participants 
•
TEAEs, SAEs, and AESIs
•
Safety laboratory parameters (hematology, clinical 
chemistry, coagulation, and urinalysis); 12 lead safety 
ECG; vital signs (BP, pulse rate, tympanic membrane 
temperature, and respiratory rate), and physical 
examination
Secondary – All Cohorts
•
To evaluate the PD of AZD7442 after 
a single IM or IV dose in pediatric 
participants 
•
Titer of SARS-CoV-2 neutralizing antibodies 
•
To evaluate the immunogenicity 
profile of AZD7442 after a single IM 
or IV dose in pediatric participants 
•
Incidence of ADA and nAb to AZD7442 in serum 


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Table 4
Objectives and Endpoints
Objectives
Endpoints
Secondary – Cohort 1 (Prophylaxis)
•
To evaluate the incidence of SARS-
CoV-2 infections with or without 
COVID-19 symptoms after a single 
IM or IV dose of AZD7442 in 
pediatric participants 
•
Incidence of SARS-CoV-2 infections with and without 
COVID-19 symptoms
Secondary – Cohort 2 and Cohort 3 (Treatment)
•
To quantify SARS-CoV-2 viral loads 
after a single IM or IV dose of 
AZD7442 in pediatric participants 
•
Change from baseline to Day 8 in viral load as measured 
by qRT-PCR.
•
To evaluate the proportion of 
participants with progression of 
COVID-19 after a single IM or IV 
dose of AZD7442 in pediatric 
participants 
•
Proportion of participants with progression of COVID-19 
through Day 29
•
To evaluate COVID-19-related death
after a single IM or IV dose of 
AZD7442 in pediatric participants
•
The incidence of COVID-19-related death occurring after 
dosing with IMP through 90 days
Secondary – Cohort 3 (Severe COVID-19)
•
To evaluate the time to sustained 
recovery from severe COVID-19 after 
a single IM or IV dose of AZD7442 in 
pediatric participants 
•
Time to sustained recovery (defined as being discharged 
from the index hospitalization, followed by being alive 
and home for 14 consecutive days)
Exploratory
•
To evaluate the concentrations of 
AZD7442 in nasal fluid after a single 
IM or IV dose in pediatric participants
•
Nasal concentrations of AZD7442 at specified time points 
during the study period when administered as a single IM 
or IV dose
%AUCex, percentage of AUC0-inf extrapolated to infinity; ADA, anti-drug antibodies; AESI, adverse event of 
special interest; AUC0-inf , area under the serum concentration versus time curve extrapolated to infinity; AUC0-
last, area under the serum concentration versus time curve from time zero to time of last measurable 
concentration; BP, blood pressure; CL, systemic clearance; CL/F, apparent total clearance; Cmax, maximum 
serum concentration; COVID-19, coronavirus disease 2019; ECG, electrocardiogram; IM, intramuscular; IMP, 
investigational medicinal product; IV, intravenous; nAb, neutralizing antibodies; MIS-C, multisystem 
inflammatory syndrome – children; PD, pharmacodynamics; PK, pharmacokinetics; qRT-PCR, quantitative real-
time polymerase chain reaction; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome 
coronavirus 2; tmax, time to reach maximum serum concentration; t1/2, terminal half-life; TEAE, treatment 
emergent adverse event; Vss, volume of distribution at steady state; Vz/F, apparent volume of distribution based 
on terminal phase.
4
STUDY DESIGN
4.1
Overall Design
This is a Phase I, open-label, uncontrolled, multicountry, multicenter, single dose study to 
evaluate the PK, PD, safety, and tolerability of AZD7442 administered IM or IV in pediatric 
participants aged ≥29 weeks GA (infants born between gestational age of 29 weeks to full 


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term) to < 18 years. Up to 3 cohorts of participants will be enrolled based on the adult 
indication and dose: 1) participants who are SARS-CoV-2 negative at screening and have not 
knowingly been exposed to a SARS-CoV-2 positive individual (pre-exposure prophylaxis); 2) 
participants who are SARS-CoV-2 RT-PCR positive at screening and have mild to moderate 
COVID-19; and 3) participants who are SARS-CoV-2 positive at screening and have severe 
COVID-19. Both Cohort 1 and Cohort 2 are required to be at increased risk of developing 
severe COVID-19. Recruitment will start with Cohort 1; Cohorts 2 and 3 will be added if the 
indications are progressed in adults. If recruitment in a cohort is not initiated, the minimum 
number of participants in the other cohort(s) will be increased such that there is a minimum of 
6 participants receiving IV administration and a minimum of 6 participants receiving IM 
administration of the IMP in each of the four main age categories. Approximately 33 sites will 
participate in this study.
To facilitate recruitment, participants will be assigned to a cohort and receive treatment based 
on the results of a documented RT-PCR test taken ≤3 days before Day 1 (if available) or a 
SARS-CoV-2 rapid antigen test at screening. A sample will also be taken on Day 1 for a pre-
dose SARS-CoV-2 RT-PCR test to be conducted at the central laboratory (baseline). 
Participants will continue in their assigned cohort even if the Day 1 pre-dose SARS-CoV-2 
RT-PCR test does not confirm the initial screening test results. Approximately 120 participants 
will be enrolled to ensure a minimum of 100 evaluable participants. If necessary, recruitment 
will be increased to replace participants who withdraw from the study.
Measures will be undertaken to ensure minimal SARS-CoV-2 exposure for site staff as well as 
study participants according to local requirements. Exclusion and withdrawal criteria are in 
place to ensure site staff and study participant safety. In Cohort 1 (prophylaxis), a post-
baseline SARS-CoV-2 positive result in participants who were SARS-CoV-2 negative at 
baseline and developed COVID-19 symptoms during the study will be reported as an AE. 
Measures will be applied at the discretion of the Investigator to minimize further 
SARS-CoV-2 exposure as much as possible. Guidance for management of participants who 
wish to receive or parents who wish for their child to receive an authorized vaccine for 
protection against SARS-CoV-2 during the study is provided.
The study flow chart is presented in Figure 1 and a graphical representation of the recruitment 
and safety reviews is presented in Figure 2. The SoA displaying assessments/tasks and time 
points is presented in Section 1.3. Following a screening evaluation, which can be conducted 
over one or more visits between Day -7 to Day 1, participants will receive a single dose of 
IMP. After administration of the dose of IMP on Day 1, participants will be monitored on site 
for at least one hour for general safety, including injection/infusion site reactions and 
hypersensitivity reactions (including anaphylaxis). Participants will undergo a follow-up until 
Study Day 366 for safety, including recording of AEs and SAEs, and collection of blood 
samples for PK, PD, and ADAs, and exploratory efficacy endpoints. The maximum duration 


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of the study for each participant, including screening, will be 388 days.
Participants will be stratified by age with a minimum number of participants to be assigned to 
each cohort and route of administration as shown in Table 5. These minimum numbers 
consider both FDA and European Medicines Agency Paediatric Committee (PDCO) feedback. 
In Cohorts 1 and 2, participants will receive IM AZD7442 (AZD8895 followed by AZD1061) 
unless they meet the inclusion criteria specified for IV administration (Section 5.1). 
Participants with severe COVID-19 in Cohort 3 will receive AZD7442 by IV infusion 
(AZD8895 and AZD1061 co-infusion). Proposed IM and IV AZD7442 doses for investigation 
by weight range for pediatric participants in Cohort 1 (prophylaxis) and Cohorts 2 and 3 
(treatment) are provided in Table 6. Interactive Response Technology will be used to ensure 
that all minimum targets are met and that each cohort and age group does not over-enroll by 
more than 20%.
Sentinel dosing will be applied to ensure participant safety. The first 2 participants aged ≥2 to 
# 18 years in Cohort 1 will undergo internal safety monitoring for at least 24 hours during 
which recruitment will be paused. After review of the Sentinel Cohort, the International
Co-ordinating Investigator, the AstraZeneca Global Safety Physician, and the AstraZeneca 
Global Clinical Head will decide whether recruitment can proceed for the rest of the study 
participants, including those aged ≥29 weeks GA to < 2 years (Figure 2).
The DSMB will conduct a review once at least 14 days of safety data are available from the 
first 6 participants recruited into the study (derived from any of the pediatric age groups). 
Recruitment will continue during the DSMB safety review. The DSMB may request 
recruitment to be stopped after that review. The minimum 14-day Follow-up Period for the 
DSMB safety review should provide adequate safety information for the review because 1) no 
binding to any tissues was observed in tissue cross-reactivity studies, confirming the absence 
of target and off-target binding in humans and cynomolgus monkey adult tissues and human 
fetal tissues, and 2) no safety concerns have been observed in adult studies to date. The 
DSMB will continue to meet to review cumulative safety data after 21, 36, 51, 66, 81, and 96 
participants have been recruited into the study.


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Table 5
Minimum Number of Participants to be Enrolled for Each Cohort, Age Group, and Route of 
Administration
Age
Cohort 1:
Pre-exposure prophylaxis of 
COVID-19a
Cohort 2:
Treatment of mild to moderate 
COVID-19b
Cohort 3:
Treatment of 
severe 
COVID-19c
Any 
cohortd
Total
IM
IV
IM
IV
IV
IM or IV
IM or IV
≥12 y to < 18 y
6
4
6
4
4
22
46
≥6 y to < 12 y
1e
6
1e
1
4
5
18
≥1 y to < 6 y
6e
1
1e
1
4
5
18
≥29 wk GA to < 1 y
6
1
6
1
4
0
18
•
≥1 mo to < 1 y
•
n = 2
•
n = 2
•
n = 4
•
≥29 wk GA to 
< 1 mof
•
n = 2g
•
n = 2g
•
n = 4
Total
19
12
14
7
16
32
100
a
Pediatric participants who are SARS-CoV-2 negative at baseline.
b
Pediatric participants who are SARS-CoV-2 positive at baseline and have mild to moderate COVID-19. Recruitment into this cohort will start if the 
indication is progressed in adults. If this cohort is not included in the study, the minimum number of participants in the other cohort(s) will be increased.
c
Pediatric participants who are SARS-CoV-2 positive at baseline and have severe COVID-19. Recruitment into this cohort will start if the indication is 
progressed in adults. If recruitment in this cohort is not initiated, the minimum number of participants in the other cohort(s) will be increased such that there 
is a minimum of 6 participants receiving IV administration of the IMP in each of the 4 main age categories.
d
Once the minimum number of participants has been reached in each cohort, the remaining participants can be derived from any of the applicable open 
cohorts and routes of administration.
e
In participants who weigh ≥15 to < 40 kg in Cohort 1 and Cohort 2, IM dosing is not feasible for prophylaxis and treatment indication due to the volume 
required for injection.
f
Born between gestational age of 29 weeks to full term, from birth up to 28 days of life (1 month).
g
May be administered by IM or IV route, depending on standard local practice for drug administration in neonates.
COVID-19, coronavirus disease 2019; GA, gestational age; IM, intramuscular; IMP, investigational medicinal product; IV, intravenous; mo, month; n, number of 
participants; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; wk, week(s); y, year(s).


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4.2
Scientific Rationale for Study Design
AZD7442 is being evaluated for prophylaxis of COVID-19 and treatment of COVID-19 in 
adults. This Phase I study will provide information on the PK profile, SARS-CoV-2-
neutralizing antibody titers and effect on viral load, as well as data on the safety and 
tolerability of AZD7442 and potential generation of ADAs to AZD7442 in pediatrics. This 
study will support the extrapolation of the efficacy and safety data observed in adults to 
children and determination of the therapeutic dose in children.
4.2.1
Rationale for Choice of Endpoints
The endpoints chosen for this Phase I PK/PD and safety study are consistent with those in 
AZD7442 studies in adults.
The primary study PK endpoints are those required to characterize the PK profile of AZD7442 
following a single IM or IV dose administered to pediatrics aged ≥29 weeks GA to # 18 years
(Day 1 through Day 366). Pharmacokinetic sampling will be kept to a minimum due to the age 
of the population under study: one sample on Day 1 for participants receiving an IV infusion, 
one sample during the first 2 weeks for all participants (at either Day 4, 8, 11, or 15, spread 
across participants), then one sample at Day 31, 92 , 183, and 366 (ie, the total number of 
samples per participant is up to 5 samples for IM administration and 6 samples for IV 
administration due to the additional sample taken at the end of the infusion on Day 1). 
Pharmacokinetic data will be analyzed by population methods and if data permit by non-
compartmental analysis approach. This sampling scheme also enables serum AZD7442 
concentration data to be obtained at the time points of primary efficacy endpoint evaluation 
for prophylaxis and treatment in the adult program. Pharmacokinetic profiles of AZD7442 are 
expected to be similar across the prophylaxis and treatment populations recruited because 
AZD7442 is cleared via nonspecific intracellular metabolism and will not be affected by 
binding to the exogenous target SARS-CoV-2. Therefore, PK data will be pooled across the 
cohorts within each age group.
The PD markers that are measured in this PK/PD and safety study will be used to support the 
assumption that the exposure-response relationship is similar for adults and children. In 
SARS-CoV-2 infected and non-infected children, the SARS-CoV-2 neutralizing antibody titer 
will be measured in a validated live neutralization assay. In addition, the neutralizing antibody 
titer will be correlated to the serum AZD7442 concentration. The correlation between drug 
level and neutralizing antibody titer in children will be compared to the correlation derived in 
adult serum samples.
The measures of viral load, disease progression or recovery, SARS-CoV-2 infections, and 
COVID-19-related death mirror the endpoints in the adult studies with AZD7442.


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Adverse events associated with exogenous immunoglobulins as a class, ie, infusion reactions, 
hypersensitivity reactions, including anaphylaxis, and injection site reactions, typically 
manifest within minutes to hours, and rarely after 24 hours. For such events, the 24 hours of 
monitoring assigned to the sentinel dosing group should be sufficient for detection. The safety 
endpoints are standard endpoints for safety assessment and include incidence of treatment-
emergent AEs, SAEs, and safety clinical laboratory measurements, with the addition of MIS-C 
as an AESI that is specific for SARS-CoV-2 infection in children. The presence of ADA and 
the potential impact of ADA on PK, PD, or safety will also be assessed.
The revised study duration of 366 -days will allow follow-up of dosed participants through 
approximately 4 AZD7442 half-lives, which is expected to provide sufficient safety follow-up 
and will also maximize the probability of detecting ADA to AZD7442.
4.2.2
Rationale for Study Population
Children of all ages are susceptible to SARS-CoV-2 infection and COVID-19 but many 
children will not develop severe disease; therefore, Cohorts 1 and 2 (prophylaxis and 
treatment of mild to moderate disease) will only include participants who have an underlying 
condition that increases their risk for developing severe COVID-19. Participants in Cohort 3 
(treatment of severe disease) require urgent treatment, so they are not required to have any 
pre-existing health conditions.
Participants will be stratified by age (≥29 weeks GA to < 1 year; ≥1 year < 6 years; ≥6 years 
to < 12 years; ≥12 years to < 18 years) to ensure that data are obtained from all pediatric age 
groups in the study. In addition, the youngest age category has been further stratified into 
2 subgroups (≥29 weeks GA to < 1 month and ≥1 month to < 1 year), to ensure that neonates 
are represented as they are particularly susceptible to COVID-19.
4.2.3 Participant Input into Design
Not applicable for a PK study.
4.3
Justification for Dose
The IM and IV doses to be investigated in this study were determined by simulations using the 
population PK model developed based on available data from the adult studies. The model 
used for the simulations included a weight-based allometric scaling of CL and volume as well 
as an age-based maturation function for CL to represent the entire range of the pediatric 
population. A dosing by body weight bands approach was chosen. Four weight band 
categories were considered: ≥1.5 to < 5 kg; ≥5 to < 15 kg; ≥15 to < 40 kg and ≥40 kg. The 
IM and IV doses in the respective body weight categories were selected so the predicted 
exposure in each weight category matches as closely as possible the exposure in adults at the 
highest authorized or investigated (if indication not yet approved) doses in each indication at 
the time of recruitment initiation in each cohort. In particular, pediatric prophylaxis doses 


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were selected such that the AZD7442 predicted serum concentrations were within the same 
range as adults at 6 months. The doses to be investigated in each weight category in the 
different indications are presented in Table 6. AZD7442 was investigated at doses up to 
3000 mg administered IV in adults in the Phase I FTIH study (D8850C00001), which is 5-fold 
higher than the maximum adult dose investigated in the Phase III adult studies.
Intramuscular injection is the preferred route of administration for outpatients (prophylaxis or 
treatment of mild to moderate disease) but for some participants, the IV route of 
administration will be more appropriate (see criteria for IV administration specified in the 
inclusion criteria in Section 5.1). Therefore, the IV route of administration has also been 
included for eligible participants in Cohorts 1 and 2. For patients who are hospitalized with 
severe COVID-19 in Cohort 3, IV administration is the route investigated in the clinical adult 
studies.
Table 6
Planned Doses in the Different Indications in the Pediatric 
PK/PD/Safety Study
Participant 
weight range
Prophylaxis 
(matching adult dose of 
600 mg IM)
Treatment – Outpatient
(matching adult dose of 
600 mg IM)
Treatment – Inpatient
(matching adult dose 
of 600 mg IV)
Planned IM 
dose (mg)
Planned IV 
dose (mg)
Planned IM 
dose (mg)
Planned IV 
dose (mg)
Planned IV 
dose (mg)
≥ 1.5 to < 5 kg
60
50
60
50
60
≥ 5 to < 15 kg
150
110
150
110
150
≥ 15 to < 40 kg
NAa
300
NAa
300
400
≥ 40 kg
600
440
600
440
600
a
In participants who weigh ≥ 15 to < 40 kg, IM dosing is not feasible for the treatment indication due to the 
maximum volume required for injection.
IM, intramuscular; IV, intravenous; PD, pharmacodynamic; PK, pharmacokinetic.
4.4
End of Study Definition
For the purpose of Clinical Trial Transparency, the definition of the end of the study differs 
under FDA and EU regulatory requirements:
European Union requirements define study completion as the last visit of the last subject for 
any protocol related activity.
Food and Drug Administration requirements define two completion dates:
Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure with 


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different completion dates, this term refers to the date on which data collection is completed 
for all of the primary outcomes.
Study Completion Date – the date the final participant is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures and 
AEs (for example, last participant’s last visit), whether the clinical study concludes according 
to the pre-specified protocol or is terminated.
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the SoA in Section 1.3.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age and Weight
1
Participant must be aged ≥29 weeks GA to < 18 years of age at the time of signing the 
informed consent (see Appendix A 3 for procedures around informed consent).
2
Participant must weigh a minimum of 1.5 kg.
Type of Participant and Disease Characteristics
COHORT 1: Participants who do not have COVID-19 and have not knowingly been exposed 
to a SARS-CoV-2 positive individual (pre-exposure prophylaxis):
3
At increased risk of severe COVID-19 for any of the following reasons:
(a) Immunocompromised state
(b) One or more comorbid conditions that increase the risk of severe COVID-19, 
eg, cardiovascular disease, including heart disease since birth, malignancy, chronic 
kidney disease, and genetic, neurologic, or metabolic conditions.
4
Medically stable defined as disease not requiring significant change in therapy or 
hospitalization for worsening disease during the one month prior to enrollment, with no 
acute change in condition at the time of study enrollment as judged by the Investigator.
5
Documented negative SARS-CoV-2 RT-PCR test collected ≤3 days prior to Day 1 or a 
negative rapid SARS-CoV-2 antigen test at screening.
6
Prior to enrollment, participants must not have had COVID-19 symptoms (Table 13) 
within 10 days of dosing.


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7
Increased risk for SARS-CoV-2 infection, defined as those whose locations or 
circumstances put them at appreciable risk of exposure to SARS-CoV-2 and COVID-19, 
based on available risk assessment at time of enrollment.
COHORT 2: Participants with COVID-19 and mild to moderate symptoms (treatment):
8
At increased risk of severe COVID-19 for any of the following reasons:
(a) Immunocompromised state
(b) One or more comorbid conditions that increase the risk of severe COVID-19 (see list 
in 3[b])
9
Medically stable defined as disease not requiring significant change in therapy or 
hospitalization for worsening disease during the one month prior to enrollment, with no 
acute change in condition at the time of study enrollment as judged by the Investigator.
10 Documented positive SARS-CoV-2 RT-PCR test collected ≤3 days prior to Day 1 or a 
positive rapid SARS-CoV-2 antigen test at screening.
11 Participants who are symptomatic must be dosed with IMP no more than 7 days from 
self-reported or observed onset of COVID-19-related symptoms or measured fever, 
defined as the self-reported date of first reported sign/symptom from the list in Table 13. 
One or more COVID-19 signs/symptoms must also be present within 24 hours prior to 
Day 1 to be eligible for inclusion.
12 Oxygenation saturation of ≥92% obtained at rest by study staff within 24 hours prior to 
Day 1, unless the potential participant regularly receives chronic supplementary oxygen 
for an underlying lung condition.
Note that Cohort 2 will only be included if the indication is progressed in adults.
COHORT 3: Participants with severe COVID-19 (treatment):
13 Patients hospitalized with COVID-19 with a time between onset of symptoms and dosing 
AZD7442 of ≤7 days
14 Documented positive SARS-CoV-2 RT-PCR test collected ≤3 days prior to Day 1 or a 
positive rapid SARS-CoV-2 antigen test at screening.
15 Spontaneous blood ALT/AST levels ≤5 times the ULN
16 Glomerular filtration rate ≥30 mL/min/1.73 m2
Note that Cohort 3 will only be included if the indication is progressed in adults.


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Route of Administration:
Participants will receive IM AZD7442 unless they meet any of the following criteria for IV 
administration:
17 The participant has severe COVID-19
18 IM dosing is contraindicated due to:
(a) Thrombocytopenia (# 120000 cells/mm3)
(b) Coagulation defects
(c) Any other condition that would compromise the absorption of AZD7442 or safety of 
the participant (eg, hypovolemic shock, myopathy, muscular atrophy, active infection 
other than SARS-CoV-2, cellulitis, and dermatitis at the injection site).
19 Any other participant for whom the enrolling physician considers an IV infusion the most 
appropriate route of administration.
Informed Consent
20 Provision of a signed and dated written informed consent form prior to any mandatory 
study specific procedures, sampling, and analyses. Informed assent is to be provided by 
participants who are capable of forming an opinion and assessing the information given to 
him or her; informed consent must be provided by the participant’s legal guardian.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Cohort 1: Significant infection or other acute illness, including fever > 100 °F (> 37.8 °C) 
on the day prior to or day of receiving AZD7442.
2
History of infection with SARS-CoV-1 or MERS-CoV.
3
Cohorts 1 and 2: Current need for immediate medical attention in an emergency room 
service in the clinical opinion of the site Investigator or current need for hospitalization 
(Appendix E) in the following circumstances:
(a) Due to progressive COVID-19 as this implies severe disease (an exception is 
participants hospitalized with mild-moderate COVID-19 as a precautionary measure 
for isolation/infection prevention or for the purpose of conducting study procedures).
(b) For any underlying medical condition that requires hospitalization (suggestive of an 
unstable medical condition) with the following exceptions:
∃
Neonates aged ≥29 weeks GA to < 1 month in their birth hospitalization when 
discharge is expected within 7 days after receiving AZD7442.


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∃
Children hospitalized for maintenance chemotherapy administration (induction, 
reinduction, relapse chemotherapy excluded). AZD7442 administration is to 
occur a minimum of 2 hours post chemotherapy administration (including any 
hydration or blood products) or post the institutional standards for observation 
after chemotherapy administration, whichever is longer. Only children who, in 
the opinion of the investigator, are at low risk for a hypersensitivity reaction to 
administration of chemotherapy or blood products should be considered for same 
day administration of AZD7442 during hospitalization for maintenance 
chemotherapy.
4
Requirement for mechanical ventilation or extracorporeal membrane oxygenation or 
anticipated impending need for mechanical ventilation at baseline for treatment of 
COVID-19 (CPAP and high flow O2 is permitted).
5
Known history of allergy or reaction to any component of the study drug formulation.
6
Previous hypersensitivity, injection/infusion-related reaction, or severe adverse reaction 
following administration of a mAb for any indication.
7
Any co-morbidity requiring surgery within 7 days prior to study entry, or that is 
considered life-threatening in the opinion of the site Investigator within 30 days prior to 
study entry.
8
Any other significant disease, disorder, or finding that, in the judgment of the 
Investigator, may significantly increase the risk to the participant because of participation 
in the study, affect the ability of the participant to participate in the study, or impair 
interpretation of the study data.
Prior Therapy (Before Enrollment)
9
Prior receipt of convalescent COVID-19 plasma/sera or hyperimmune globulin therapy.
10 Prior receipt of mAb/biologic indicated for the prevention or of SARS-CoV-2 or 
treatment of COVID-19 or expected receipt during the period of study follow-up.
11 Prior receipt of a COVID-19 vaccine ≤14 days before screening or plan to receive a 
COVID-19 vaccination ≤14 days after IMP administration at study Visit 1 (see 
Section 6.5.1). Receipt of a COVID-19 vaccine % 14 days before screening is allowed.
Other Exclusions
12 Employees of the Sponsor involved in the planning, execution, supervising, or reviewing 
the AZD7442 program, clinical study site staff, or any other individuals involved with the 
conduct of the study, or immediate family members of such individuals.
13 Judgment by the Investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.


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14 History of alcohol or drug abuse within the past 2 years that, according to the 
Investigator, might affect assessments of safety or ability of participant to comply with all 
study requirements.
15 Investigational Drugs or Devices: Treatment with investigational drug or device in 
another clinical trial within the last 30 days or 5 half-lives of the drug (whichever is 
longer) prior to screening. Note: Participation in observational studies (ie, studies that do 
not require medication, blood draws, or an additional intervention) is not exclusionary.
Interventional trials which do not include investigational drugs (only include approved 
therapies), or investigational treatment regimens may be considered if the blood draw 
requirements and study interventions are minimal and not deemed by the Investigator to 
interfere with completion of the planned study sampling and follow-up.
16 Vulnerable persons (eg, ward of the state, kept in detention).
5.3
Lifestyle Considerations
!
Restrictions related to concomitant medications and drugs of abuse and alcohol are 
described in Section 6.5.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened if the eligibility criterion that resulted in screen failure has changed in a manner 
that meets eligibility.
Only a single rescreening is allowed in the study. Rescreened participants should be assigned 
the same participant number as for the initial screening. Individuals who are rescreened do not 
need to reconsent for the study.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to or medical device(s) utilized by a study participant 
according to the study protocol.


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6.1
Study Interventions Administered
6.1.1
Investigational Product
All eligible participants will receive a single dose of AZD7442 on Day 1, either IM 
(AZD8895 followed by AZD1061 administered separately) or a single IV infusion (AZD8895 
and AZD1061 co-administered), and participants will be monitored for 365days after IMP 
administration (Table 7). Dose levels will be stratified by body weight range categories.
Age-appropriate quantities of all excipients are used within the AZD7442 formulation. All 
excipients are of pharmaceutical grade and are not considered to pose any safety issues for 
children at the anticipated exposure levels.
Table 7
Investigational Product: AZD7442
Intervention name
AZD7442 (AZD8895 + AZD1061) (AstraZeneca)
Type 
Biologic
Dose formulation
AZD7442 is comprised of 2 drug products supplied as 
separate vials of AZD8895 and AZD1061. Each vial contains 
a solution of 100 mg/mL active ingredient (AZD8895 or 
AZD1061), 20 mM histidine/histidine-HCl, 240 mM sucrose, 
0.04% (w/v) PS80, pH 6.0.
The label claim volume for each vial is 1.5 mL and each vial 
contains 150 mg (nominal) of active ingredient. 
Unit dose strength(s)
100 mg/mL of AZD8895 in a single vial
100 mg/mL of AZD1061 in a single vial
Dosage level(s)
The dose levels are stratified by body weight range categories 
as shown in Table 6 (prophylaxis of COVID-19/treatment of 
mild to moderate COVID-19: 60 to 600 mg IM or 50 to 
440 mg IV; treatment of severe COVID-19: 60 to 600 mg IV).
Route of administration
IM (AZD8895 followed by AZD1061) or a single IV infusion 
(AZD8895 and AZD1061 concurrently)
Use
Experimental
Sourcing
AstraZeneca 
Packaging and labeling
AZD7442 will be provided in glass vials. Each glass vial will 
be labeled as required per country requirement.
COVID-19, coronavirus 2019; IM intramuscular; IV, intravenous, w/v, weight per volume.
Details of the batch numbers will be included in the Trial Master File, and the final CSR. 
Labels will be prepared in accordance with GMP and local regulatory guidelines. The labels 
will fulfill GMP Annex 13 requirements for labeling.


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6.2
Preparation/Handling/Storage/Accountability
1
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the Investigator and authorized site staff.
2
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
6.2.1
Storage and Handling Procedures
AZD7442 vials (AZD8895 and AZD1061) are stored at 2 °C to 8 °C (36 °F to 46 °F) and must 
not be frozen. The Investigator, or an approved representative (eg, pharmacist), will ensure 
that all study intervention is stored in a secured area, in refrigerated temperatures (2 °C to 
8 °C; 36 °F to 46 °F) and in accordance with applicable regulatory requirements. A 
temperature log will be used to record the temperature of the storage area. Temperature 
excursions outside the permissible range listed in the clinical supply packaging are to be 
reported to the monitor upon detection. A calibrated temperature monitoring device will be 
used to record the temperature conditions in the drug storage facility. Storage conditions stated 
in the IB may be superseded by the label storage.
AZD7442 must be kept in original packaging until time of preparation to prevent prolonged 
light exposure.
AZD7442 is comprised of 2 drug products supplied as separate vials of AZD8895 and 
AZD1061. The product is a clear to slightly opalescent, colorless to slightly yellow solution.
Each vial selected for dose preparation should be inspected. If there are any defects noted with 
the IMP (ie, it is visually different to the description provided above), the Investigator and site 
monitor should be notified immediately.
The dose of AZD7442 (AZD8895 and AZD1061) for administration must be prepared by the 
Investigator’s or site’s designated IMP manager using aseptic technique. Total time from 
needle puncture of the vial to the start of administration must not exceed:
!
24 hours at 2 °C to 8 °C (36 °F to 46 °F)
!
4 hours at room temperature.
If the final product is stored at both refrigerated and ambient temperatures, the total time must 
not exceed 24 hours, otherwise a new dose must be prepared from new vials. AZD7442 


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(AZD8895 and AZD1061) does not contain preservatives; any unused portion of the vial must 
be discarded immediately after use.
No incompatibilities between AZD7442 (AZD8895 and AZD1061) and the following 
component materials of construction have been observed:
!
IV bags made of polyvinylchloride (PVC) or polyolefin (PO)
!
Polypropylene (PP) syringes
!
Filters made of polyethersulfone (PES)
AstraZeneca will be permitted upon request to audit the supplies, storage, dispensing 
procedures and records.
6.2.2
Preparation and Administration
6.2.2.1
Intramuscular Administration
The volumes for IM administration are provided by participant weight range and indication in 
Table 8. AZD8895 and AZD1061 (comprising AZD7442), must both be administered 
separately to the participant in sequential order, with no participant receiving doses of 
AZD8895 without also receiving the matching dose of AZD1061.
Accurately withdraw the required volume for each of the injections. Use a single disposable 
polycarbonate or polypropylene syringe for each of the injections.
Administer the injections of AZD7442 (comprised of AZD8895 and AZD1061) using a needle 
of appropriate gauge and length for each of the injections, according to standard procedures 
for IM injections for patients in each weight bracket. AZD8895 should be administered first in 
the anterolateral thigh followed by administration of AZD1061 in the alternate anterolateral 
thigh.


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Table 8
Volume of AZD7442 for IM Administration by Participant Weight 
Range and Indication
Participant 
weight range (kg)
Dose
Injection 
volume (mL) of 
AZD8895 
100 mg/mL
Injection 
volume (mL) of 
AZD1061 
100 mg/mL
Total injection 
volume (mL) of 
AZD7442 
100 mg/mL 
(AZD8895 + 
AZD1061)
Prophylaxis of COVID-19 (Cohort 1)/Treatment of mild to moderate COVID-19 (Cohort 2)
≥1.5 to < 5 kg
60 mg
(30 mg AZD8895 and 
30 mg AZD1061)
0.3
0.3
0.6
≥5 to < 15 kg
150 mg
(75 mg AZD8895 and 
75 mg AZD1061)
0.75
0.75
1.5
≥15 to < 40 kg
Participants in this weight range will be administered AZD7442 via IV infusion
≥40 kg
600 mg
(300 mg AZD8895 
and 300 mg 
AZD1061)
3
3
6
AZD8895 must be administered first followed by AZD1061.
COVID-19, coronavirus disease 2019; IM, intramuscular; IV, intravenous.
6.2.2.2
Intravenous Administration
AZD7442 is dosed by co-administration of AZD8895 and AZD1061 in a single IV infusion.
The dose volume to be administered to each participant depends on the weight of the 
participant, the indication (ie, prophylaxis, inpatient, or outpatient treatment), and the 
concentration of the prepared dilution as indicated in Table 9 and Table 10. The dose of 
AZD7442 (AZD8895 and AZD1061) should be administered as an admixture of AZD7442 
(AZD8895 and AZD1061) and diluent. The diluent is to be selected per the standard of care of 
the participant and may consist of 0.9% sodium chloride for injection or 5% dextrose for 
injection.
Dose Preparation
AZD7442 (AZD8895 and AZD1061) for administration should be prepared by combining the 
required volume of AZD7442 (AZD8895 and AZD1061) with an appropriate volume of 
diluent to give a final AZD7442 admixture with a concentration ranging from 10 mg/mL to 
50 mg/mL. Refer to Table 10 for recommended volumes for AZD7442 (AZD8895 and 
AZD1061) and diluent in order to achieve the required concentrations. The AZD7442 
admixture should be prepared by following the procedure below:


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!
Withdraw the AZD7442 (AZD8895 and AZD1061) dose volume into a suitable size 
syringe. Prepare a separate syringe containing required amount of diluent.
!
Transfer the AZD7442 (AZD8895 and AZD1061) solution into the diluent syringe; once 
capped (or secured with an attached needle), mix the solution using gentle inversion. Do 
not shake.
Table 9
Preparation of AZD7442 Admixture for IV Administration
Concentration 
of AZD7442 
Admixture 
(mg/mL)
Number of 
AZD8895 
(100 mg/mL) 
vials 
required
Number 
AZD1061 
(100 mg/mL) 
vials 
required
AZD8895 
Volume for 
Dilution 
(mL)
AZD1061 
Volume for 
Dilution 
(mL)
Diluent 
volume for 
dilution 
(mL)
Total 
volume 
post-
dilution 
(mL)a
10
1
1
1.5
1.5
27
30
20
1
1
1.5
1.5
12
15
50
1
1
1.5
1.5
3
6
50
2
2
3.0
3.0
6
12
a
The volume of the prepared diluted AZD7442 admixture will exceed the volume that will be required for 
dose administration
IV, intravenous.
Dose Administration
Following dilution, the required volume of the AZD7442 admixture for the intended dose will 
be drawn into an appropriately sized syringe or IV bag and administered intravenously. Refer 
to Table 10 for the volume of admixture to be administered.
The dose volumes, infusion rates, and infusion times for each weight range were determined 
by considering the maintenance fluid rate and maintenance volume requirements. It is not 
recommended to deviate from these values unless the participant has a particular medical 
requirement that deems it necessary to adjust.
!
AZD7442 (AZD8895 and AZD1061) infusion is to be administered through an IV 
administration set with a 0.2 or 0.22 μm low protein binding filter; acceptable 
configurations include an IV set containing an in-line filter or the attachment of a separate 
filter to the distal end of the IV tubing.
!
AZD7442 (AZD8895 and AZD1061) infusion can be administered through the same IV 
line as other medications when local practices for flushing the line with each 
administration are followed.
!
Administration set volume should not exceed 2 mL in order to minimize the flush 
volume.


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!
The IV line and catheter will be flushed according to local practices to ensure the full 
dose is administered. It is recommended to flush at the same rate as the drug infusion rate 
(listed in Table 10).
!
Important: The timing of the PK sample must be well coordinated such that the PK 
sample is immediately obtained after the full dose is delivered. Sampling should occur 
immediately after the IV line and catheter are flushed.
The approximate infusion time and target rates are listed in Table 10; however, if there are 
interruptions, the total allowed time must not exceed 4 hours with the infusion syringe 
maintained at room temperature, otherwise a new dose must be prepared from new vials.


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Table 10
Doses and AZD7442 Admixture Concentration Selection per Cohort and Participant Weight Range for IV 
Administration
Participant weight 
range (kg)
Dose of 
AZD7442 (mg)
Concentration of 
AZD7442 Admixture 
(mg/mL)a
Volume of AZD7442 
Admixture for 
administration (mL)
Infusion rate (mL/minute; 
mL/hour)
Approximate infusion 
time (minutes)b
Prophylaxis (Cohort 1)/Treatment – Outpatient (Cohort 2)
≥ 1.5 to < 5 kg
50
20
2.50
0.1 mL/min; 6.0 mL/hour
25
≥ 5 to < 15 kg
110
50
2.20
0.3 mL/min; 18 mL/hour
7
≥ 15 to < 40 kg
300
50
6.00
0.8 mL/min; 48 mL/hour
8
≥ 40 kg
440
50
8.80
1.0 mL/min; 60 mL/hour
9
Treatment – Inpatient (Cohort 3)
≥ 1.5 to < 5 kg
60
20
3.00
0.1 mL/min; 6 mL/hour
30
≥ 5 to < 15 kg
150
50
3.00
0.3 mL/min; 18 mL/hour
10
≥ 15 to < 40 kg
400
50
8.00
0.8 mL/min; 48 mL/hour
10
≥ 40 kg
600
50
12.00
1.0 mL/min; 60 mL/hour
12
a
Refer to Table 9 for instructions on preparation of the AZD7442 admixture.
b
Infusion time does not account for flush time
AZD7442 is to be administered as a single IV infusion (AZD8895 and AZD1061 co-administered).
IV, intravenous; min, minute.


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6.3
Measures to Minimize Bias: Randomization
This is an open-label study and all eligible participants will receive AZD7442.
For the PK sample collected post Day 1 during the first 14 days, participants will be 
randomized to have a blood sample collected on either Day 4, Day 8, Day 11, or Day 15 
(1:1:1:1) using the IRT.
The Investigator(s) will:
1
Obtain signed informed consent or assent from the potential participant, or their 
guardian/legal representative, before any study specific procedures are performed.
2
Determine participant eligibility.
3
Assign the eligible participant unique SID via the IRT.
4
Participants will be allocated to receive AZD7442 administered IM or IV
5
Participants will be assigned the Day of PK sampling (Day 4, Day 8, Day 11, or Day 15)
If a participant withdraws from the study, then his/her enrollment/SID cannot be reused. 
Withdrawn participants will not be replaced.
6.4
Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff.
Dosing will take place under the guidance of study personnel, and may occur at study sites, 
mobile units, or other health care facilities. The date, and time if applicable, of dose 
administered will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention. 
If a problem occurs during dosing, such as needle break, no re-dosing is permitted.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with:
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency


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The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
Permitted, prohibited, and restricted medications are summarized in Table 11. Restricted drugs 
of abuse and alcohol are summarized in Table 12.
Table 11
Summary of Permitted, Prohibited, or Restricted Medications
Use category
Type of 
medication/treatment
Timeline/instructions
Permitted
Routine vaccinesa
Licensed influenza vaccines are permitted at any time.
All other routine vaccines are permitted beginning 
> 30 days after IMP dose
COVID-19 vaccines are permitted before (> 14 days 
before study entry) and during the study, > 14 days after 
IMP administration study Day 1. For guidance during 
the study, see Section 6.5.1).
Allergen immunotherapy 
Allowed if participant has been receiving stable 
desensitization therapy for allergies for at least 30 days 
prior to Day 1 and there is no anticipated change during 
the treatment period. Allergen immunotherapy should 
not be administered on the same day as IMP. 
Non-prescription treatments for allergies such as 
antihistamines, decongestants, and nasal steroids are 
permitted.
Commercial biologics (except 
for COVID-19 prophylaxis or 
treatment), prednisone, 
immunosuppressive 
medications (eg, azathioprine, 
tacrolimus, cyclosporine, 
methotrexate, 
hydroxychloroquine, or 
cytotoxic chemotherapy)
Allowed, provided the participant is stable on 
maintenance dose (at steady state) prior to Day 1 and up 
to Day 29, OR
Allowed if participant is hospitalized for treatment of 
COVID-19
Biologics (eg, palivizumab) should not be administered 
on the same day as IMP
Participants may take concomitant medications prescribed by their primary care provider 
for management of chronic medical conditions and/or for health maintenance. Primary care 
providers, or where appropriate Investigators, should prescribe appropriate concomitant 
medications or treatments deemed necessary to provide full supportive care and comfort 
during the study. 


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Table 11
Summary of Permitted, Prohibited, or Restricted Medications
Use category
Type of 
medication/treatment
Timeline/instructions
Prohibited
Products indicated for the 
treatment or prevention of 
SARS-CoV-2 or COVID-19 
(including those under 
investigation or authorized 
under early access provisions)
Convalescent COVID-19 
plasma and sera
Note: For participants who become hospitalized with 
COVID-19, receipt of approved/licensed treatment 
options are permitted, and they should be treated 
according to local standard of care, including 
investigational agents under Emergency Use 
Authorization or equivalent regulations.
Hydroxychloroquine
Use of hydroxychloroquine is acceptable if used 
chronically for autoimmune disease, and the dose is 
stable prior to Day 1 and up to Day 29.
Chloroquine
Use of chloroquine is acceptable if used to treat a 
parasitic infection.
Ivermectin
Use of ivermectin is acceptable if used to treat a parasitic 
infection.
HIV protease inhibitors
HIV protease inhibitors are acceptable if used 
chronically for HIV infection, and the dose is stable prior 
to Day 1 and up to Day 29.
Hyperimmune globulin and 
immune globulin products
Previous use of hyperimmune globulin/ immune globulin 
is allowed if there is an adequate washout period prior to 
study start ≥5 half-lives of the drug with no plan to dose 
during the study period.
Restricted
Contraceptive methods
See Section 5.1
a
The potential impact of AZD7442 on COVID-19 vaccines is not known and has not been studied. See 
Section 6.5.1 for instructions on COVID-19 vaccinations.
COVID-19, coronavirus disease 2019; HIV, Human immunodeficiency virus; IMP, Investigational medicinal 
product; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Table 12
Summary of Restricted Drugs of Abuse and Alcohol
Amphetamine
Benzodiazepines
Ethanol
Methadone Metabolites
Cannabinoids
Barbiturates
Cocaine
Phencyclidine
Opiates 
Methamphetamines
Tricyclic anti-depressants (TCA)


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6.5.1
Receipt of COVID-19 Vaccines During the Study
Individual participants are encouraged to receive a COVID-19 vaccination when they become 
eligible and it is locally available. If a participant plans to receive a COVID-19 vaccine within 
14 days of study Day 1 (AZD7442 administration) they should delay starting in the study until 
> 14 days after their last dose of vaccine (Section 5.2). Available data suggests that AZD7442 
may provide 6 months of protection against pre-Omicron SARS-CoV-2 variants but due to a 
reduced in vitro neutralization against the Omicron variant, AZD7442 may provide a different 
duration of protection against Omicron. Protection has not yet been demonstrated in children.
Theoretically, in the presence of adequate neutralizing antibody titers, expected for the 
durations noted, an appropriate and effective response to the vaccine could be impaired. Data 
from animal studies reported that prior AZD7442 administration did not alter either the 
cellular or the humoral immune responses elicited by subsequent COVID-19 vaccinations. 
Based on these results, AZD7442 is not anticipated to interfere with vaccine efficacy. If the 
participant decides to receive the vaccination the participant can proceed and continue in the 
study. If a participant has a breakthrough case of COVID-19 during the study despite being 
previously vaccinated, they should be managed using standard of care.
For participants who have received IMP and develop symptomatic COVID-19 at some point 
in the study:
!
There is no reason to believe that administration of a vaccine during acute COVID-19 
illness will ameliorate the illness.
!
In most mAb recipients, an infection-induced immune response will occur, and this 
response should be protective.
!
The risk associated with receiving a vaccine after resolution of the illness should be low.
6.6
Dose Modification
The DSMB may recommend modifications to the doses outlined in Table 6 based on available 
safety and tolerability data. See Appendix A 5.
6.7
Intervention After the End of the Study
No intervention will be provided at the end of this study.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
Participants will receive a single IM dose of AZD7442 (administered as a single IM injection 
containing AZD8895 followed by a single IM injection containing AZD1061) or a single IV 


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dose of AZD7442 (administered by co-infusion of AZD8895 and AZD1061 in the same bag).
It may be necessary for a participant to temporarily interrupt their injection/infusion of IMP. If 
the injection of IMP is not resumed (ie, it is discontinued), the participant should remain in the 
study to be evaluated.
Note that discontinuation of IMP is NOT the same thing as withdrawal from the study.
7.2
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request, the request 
of their parent or legal guardian, or at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons. This is expected to be uncommon.
!
A participant who considers withdrawing from the study must be informed by the 
Investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).
!
At the time a participant withdraws consent or is withdrawn from the study, if possible, an 
Early Discontinuation visit should be conducted, as shown in the SoA (Table 3). See the 
SoA for data to be collected at the time a participant withdraws consent or is withdrawn 
from the study and follow-up and for any further evaluations that need to be completed.
!
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before consent was withdrawn.
!
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she withdraws consent 
for use of samples, destruction of any samples taken and not tested should be carried out 
in line with what was stated in the informed consent and local regulation. The Investigator 
must document the decision on use of existing samples in the site study records and 
inform the Global Study Team.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study.


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!
Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
!
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants enrolled, including 
those who did not get investigational product. Public sources may be searched for vital 
status information. If vital status is determined as deceased, this will be documented and 
the participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix A 9.
7.4
Stopping Rules, Progression to Next Study Part, and Termination 
of Study
7.4.1
Stopping Rules for an Individual Participant, at Any Time in the Study
Each participant in this study will receive a single dose of IMP. An individual participant will 
not receive IMP if any of the following occur in the participant in question:
!
Withdraws consent after signing informed consent.
!
Meets one or more of the exclusion criteria or fails to meet all inclusion criteria for study 
participation.
Each participant who has received IMP will be followed for the full study period unless 
consent is withdrawn specifically from further study participation, or the participant is lost to 
follow-up. Participants who have not received IMP, regardless of reason, will not be followed. 
Unless consent for follow-up is withdrawn, participants discontinued after receiving a partial 
dose of IMP will be followed for the full study period (up to and including Day 366, 52 weeks 
after IMP dosing) with all laboratory and clinical evaluations collected as defined in this CSP.
7.4.2
Stopping Rules for a Whole Cohort, Progression to Next Study Part, 
and Termination of Study
The Sponsor reserves the right to temporarily suspend or permanently terminate this study or a 
component of the study at any time.


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Stopping rules as detailed below (general, cardiovascular, laboratory, and AZD7442 specific).
General Criteria
The study will be put on temporary hold (defined as stop of enrollment of participants into the 
study) pending further safety data analysis if any of the following criteria occur in participants 
receiving AZD7442:
!
An SAE (including death) where there is a reasonable possibility that it is related to the 
IMP administration in any one participant.
!
A severe non-serious adverse reaction where there is a reasonable possibility that it is 
related to the IMP administration in 2 or more participants in the same cohort, 
independent of, within, or not within the same system organ class.
The risk to all participants will be evaluated thoroughly prior to a decision as to whether to 
terminate the study prematurely or continue dosing in agreement with the regulatory 
authorities.
The DSMB will carefully review the totality of data, taking into account moderate non-serious 
AEs where there is a reasonable possibility that the AE is related to the IMP administration, 
the number of participants in which the AE occurs, and concurrency of more than one AE 
within the same participant.
Cardiovascular Criteria
!
Two or more participants, that receive AZD7442, have QTc prolongation defined as 
QTcF > 500 ms, or a prolongation from baseline (pre-dose on Day 1) of > 60 ms, 
confirmed (persistent for at least 5 minutes) and determined post dose either during 
continuous 12 lead ECG monitoring or on a repeat 12 lead ECG.
Laboratory Findings
!
One or more participants, who receive AZD7442, fulfill Hy’s Law defined as “An 
increase in AST or ALT ≥3 × ULN and TBL ≥2 × ULN, where no other reason can be 
found to explain the combination of increases, eg, elevated serum ALP indicating 
cholestasis, viral hepatitis, another drug”. The elevations do not have to be at the same 
time or within a specified time frame (see Appendix D for follow-up procedures).
Study Specific Stopping Criteria Related to AZD7442
!
Anaphylactic reaction (Appendix F) considered related to the IMP in any participant.


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!
Any safety finding assessed as related to the IMP that, in the opinion of the Sponsor or 
the Investigator, warrants suspension of further dosing of participants until more fully 
assessed.
8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.
!
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness.
!
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
!
A hierarchy of blood tests and wide visit windows are defined in Section 8.5.1 to provide 
flexible blood collection schedules. This will allow Investigators to determine the blood 
volume that can be safely drawn from each child based on the child’s individual 
circumstances (eg, tests already conducted as part of the child’s routine clinical 
management) without exceeding local recommendations. Repeat or unscheduled samples 
may be taken for safety reasons or for technical issues with the samples.
8.1
Efficacy Assessments
8.1.1
Monitoring COVID-19 Symptoms
Progression of COVID-19 will be captured and recorded in the eCRF.
To determine the incidence of infection in Cohort 1, when a participant develops at least one 
of the COVID-19 qualifying symptoms listed in Table 13 after Day 1, the participant, his/her 
caretaker, or his/her legal representative must contact the study site. A sample will be collected 
for SARS-CoV-2 RT-PCR to confirm the participant is positive (see Section 8.6.1). COVID-
19 qualifying symptom(s), SARS-CoV-2 positive test results, and/or COVID-19 diagnosis will 
be collected and recorded in the eCRF as AEs.
In Cohorts 2 and 3, COVID-19 symptoms or signs listed in Table 13 will only be recorded as 


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AEs when any of the following occur:
!
The sign or symptom is serious according to the definition in Appendix B 2.
!
The participant discontinues the study due to the sign or symptom.
!
In the Investigator’s judgment, the sign or symptom is not considered COVID-19 related.
Table 13
COVID-19 Qualifying Symptoms
Participant must present with at least one of the following symptoms:
Duration
Symptom
No minimum duration
Fever
Shortness of breath
Difficulty breathing
Must be present for ≥2 days
Chills
Cough
Fatigue
Muscle aches
Body aches
Headache
New loss of taste
New loss of smell
Sore throat
Congestion
Runny nose
Nausea
Vomiting
Diarrhea
Abdominal pain
Poor appetite/feeding problems
CDC, Centers for Disease Control and Prevention; COVID-19, coronavirus disease 2019.
Adapted from CDC 2020.
8.1.2
Severe COVID-19 Criteria
In all cohorts, severe COVID-19 will be characterized by a minimum of either pneumonia 
(fever, cough, tachypnea, or dyspnea, and lung infiltrates) or hypoxemia (SpO2 < 90% in room 
air and/or severe respiratory distress) and a WHO Clinical Progression Scale score of 5 or 
higher (Table 14). Severe COVID-19 will be collected and recorded in the eCRF as an SAE.


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Table 14
WHO Clinical Progression Scale
Patient state
Descriptor
Score
Uninfected
Uninfected, no viral RNA detected
0
Ambulatory mild disease
Asymptomatic; viral RNA detected
1
Symptomatic; independent
2
Symptomatic; assistance needed
3
Hospitalized: moderate disease
Hospitalized; no oxygen therapya
4
Hospitalized; oxygen by mask or nasal 
prongs
5
Hospitalized: Severe Disease
Hospitalized; oxygen by NIV or high 
flow
6
Intubation and mechanical ventilation, 
pO2/FiO2 ≥150 or SpO2/FiO2 ≥200
7
Mechanical ventilation pO2/FiO2 < 150 
(SpO2/FiO2 < 200) or vasopressors 
8
Mechanical ventilation pO2/FiO2 < 150 
and vasopressors, dialysis, or ECMO 
9
Dead
Death
10
a
If hospitalized for isolation only, record status as for ambulatory patient.
ECMO, extracorporeal membrane oxygenation; FiO2, fraction of inspired oxygen; NIV, non-invasive ventilation; 
pO2, partial pressure of oxygen; SpO2, oxygen saturation, WHO, World Health Organization.
(Marshall et al 2020)
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations
A complete physical examination will be performed at screening followed by targeted 
physical examinations as specified in the SoA (Section 1.3).
!
A complete physical examination will include, but not be limited to, assessment of height, 
weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems. Each clinically significant 
abnormal finding at screening will be recorded in the medical history.
!
A targeted physical examination will include areas suggested by the medical history. Each 
clinically significant abnormal finding following IMP dosing will be recorded as an AE 
(Section 8.2).
All physical examinations will be performed by a licensed healthcare provider (eg, physician, 
physician assistant, or licensed nurse practitioner).


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8.2.2
Vital Signs
Vital signs, including heart rate, respiratory rate, pulse oximetry, BP, and body temperature, 
will be performed as specified in the SoA (Section 1.3). The participant should be resting prior 
to the collection of vital signs.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.7.
8.2.3
Electrocardiograms
A triplicate 12-lead ECG will be performed at time points specified in the SoA (Section 1.3). 
A 12-lead safety ECG will be obtained after 5 minutes’ supine rest, using the sites’ own ECG 
machines.
A pediatrician will judge the overall interpretation as normal or abnormal. If abnormal, it will 
be documented as to whether or not the abnormality is clinically significant by the 
Investigator. For neonates, ECGs must be evaluated by a physician who is experienced in 
reading neonatal ECGs. For all abnormalities (regardless of clinical significance), the specific 
type and nature of the abnormality will be documented. Clinically significant findings should 
also be documented on the AE page of the eCRF, if applicable.
The Investigator may add extra 12 lead resting ECG safety assessments if there are any 
abnormal findings or if the Investigator considers it is required for any other safety reason. 
These assessments should be entered as an unscheduled assessment.
All ECG readings will be digitally stored as source documents.
8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, hematology, coagulation, and 
urinalysis will be taken at the visits indicated in the SoA (Section 1.3).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units, and reference ranges) will 
be recorded on the appropriate eCRF.
The clinical chemistry, hematology, urinalysis, and coagulation will be performed at a central 
laboratory. Instruction for the collection and handling of the samples will be provided in the 
study-specific Laboratory Manual.
The following laboratory variables will be measured.


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8.2.4.1
Hematology
Hematology 
White blood cell (WBC) count
Neutrophils absolute count 
Red blood cell (RBC) count
Lymphocytes absolute count 
Hemoglobin (Hb)
Monocytes absolute count 
Hematocrit (HCT)
Eosinophils absolute count 
Mean corpuscular volume (MCV)
Basophils absolute count 
Mean corpuscular hemoglobin (MCH)
Platelets
Mean corpuscular hemoglobin concentration 
(MCHC)
8.2.4.2
Serum Clinical Chemistry
Serum Clinical Chemistry
Sodium
Alkaline phosphatase (ALP)
Potassium
Alanine aminotransferase (ALT)
Urea
Aspartate aminotransferase (AST)
Creatinine
Gamma glutamyl transpeptidase (GGT)
Albumin
Total bilirubin (TBL)
Calcium
Unconjugated bilirubin
Phosphate
Conjugated bilirubin
Glucose
Creatine Kinase
8.2.4.3
Urinalysis
Urinalysis
Glucose 
Protein
Blood
Microscopy (if positive for protein or blood): RBC, WBC, Casts (Cellular, Granular, Hyaline)
8.2.4.4
Coagulation Tests
Coagulation Tests
International normalized ratio (INR)
Activated partial thrombin time (aPTT)
Prothrombin Time (PT)


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8.2.4.5
Pregnancy Testing
Pregnancy test (Females of Childbearing Potential)
Serum human-beta chorionic gonadotrophin 
(screening)
Urine human-beta chorionic gonadotrophin 
(screening)
8.3
Adverse Events and Serious Adverse Events
The Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from the time of IMP administration throughout the study, up 
to and including the last visit. After IMP administration on Day 1, participants will be 
monitored on site for a minimum of one hour for general safety, including injection/infusion 
site reactions and hypersensitivity reactions (including anaphylaxis).
Serious adverse events will be recorded from the time of signing of the ICF throughout the 
study, up to and including the last visit.
If the Investigator becomes aware of an SAE with a suspected causal relationship to the IMP 
that occurs after the end of the clinical study in a participant treated by him or her, the 
Investigator shall, without undue delay, report the SAE to the Sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF. 
AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse Event Variables
The following variables will be collected for each AE:
!
AE diagnosis and description (verbatim)
!
The date and time when the AE started and stopped


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!
Severity grade/maximum severity
!
Whether the AE is serious or not
!
Investigator causality rating against the IMP(s) (yes or no)
!
Action taken with regard to the IMP(s)
!
AE caused participant to withdraw from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date Investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalization (if hospitalized)
!
Date of discharge
!
Probable cause of death (if death occurred)
!
Date of death (if death occurred)
!
Autopsy performed (if death occurred)
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
The following severity ratings will be used, adapted from the Common Terminology Criteria 
for Adverse Events version 5.0 (NIH 2017):
!
Grade 1: An event of mild intensity that is usually transient and may require only clinical 
or diagnostic observations. The event does not generally interfere with usual activities of 
daily living.
!
Grade 2: An event of moderate intensity that is usually alleviated with additional, specific 
therapeutic intervention, which is minimal, local, or non-invasive. The event interferes 
with usual activities of daily living, causing discomfort, but poses no significant or 
permanent risk of harm to the participant.
!
Grade 3: A severe event that requires intensive therapeutic intervention but is not 
immediately life-threatening. The event interrupts usual activities of daily living, or 
significantly affects the clinical status of the participant.
!
Grade 4: An event, and/or its immediate sequelae, that is associated with an imminent risk 
of death and urgent intervention is indicated.
!
Grade 5: Death, as result of an event.


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It is important to distinguish between serious and severe AEs:
!
Severity is a measure of intensity, whereas seriousness is defined by the criteria in 
Appendix B 2.
!
An AE of severe intensity need not necessarily be considered serious. For example, 
nausea that persists for several hours may be considered severe nausea, but not a SAE. On 
the other hand, a stroke that results in only a limited degree of disability may be 
considered a mild stroke but would be an SAE.
8.3.3 Causality Collection
The Investigator should assess causal relationship between IMP and each AE, and answer 
‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the 
event may have been caused by the IMP?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.
8.3.4
Adverse Events of Special Interest
Adverse events of special interest will be collected according to the time points specified in 
the SoA (Section 1.3).
Adverse events of special interest are events of scientific and medical interest, specific to the 
further understanding of the IMP safety profile, and require close monitoring and rapid 
communication by the Investigators to the Sponsor. An AESI can be serious or non-serious. 
All AESIs will be recorded in the eCRF. Serious AESIs will be recorded and reported as per 
Section 8.3.9. See also the AZD7442 IB, for additional information on AESIs.
Adverse events of special interest for AZD7442 are listed below. They include:
!
Anaphylaxis and other serious hypersensitivity reactions, including immune complex 
disease (Section 8.3.4.1).
!
Injection site and infusion site reactions (Section 8.3.4.2).
!
MIS-C (Section 8.3.4.3)
!
Thrombotic events, heart failure, and cardiac ischemia (Section 8.3.4.4)


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8.3.4.1
Anaphylaxis and Hypersensitivity Reactions
The definition and management of anaphylaxis and serious hypersensitivity reactions are 
provided in Appendix F. After IMP administration, participants will be monitored for at least 
one hour for general safety, including anaphylaxis and other hypersensitivity reactions 
(Section 8.3.1).
8.3.4.2
Injection and Infusion Site Reactions
An injection/infusion site inspection will be performed on Day 1 and at any in-person visits up 
to and including Day 6 (see SoA in Section 1.3 and Table 15). If evidence of injection or 
infusion site reaction persists, the site will be rechecked at each visit until no evidence of an 
active reaction remains. The inspection will include assessment of size, redness/erythema, 
swelling, itching/pruritis, pain or tenderness, induration, discoloration). Any injection/infusion 
site reaction will be recorded as an AE and a photograph taken, at the discretion of the 
Investigator, with visible measuring tape.
Table 15
Injection/infusion Site Inspection
Procedure/time after injections or infusions have 
been administered
Immediately 
after IMP 
administration
30 minutes 
(± 10 minutes)
Immediately 
prior to 
participant 
release
Visual inspection of site
X
X
X
Palpation of site
X
X
X
Participant will be asked:
Are you experiencing any discomfort?
X
X
X
If yes, has the feeling of discomfort changed 
since you received the injection?
NA
X
X
IMP, investigational medicinal product; NA, not applicable.
Any AEs should be reported as described in Section 8.3.
8.3.4.3
Multisystem Inflammatory Syndrome - Children
For this study, MIS-C is defined as follows (CDC 2021d):
!
Fever > 38.0 °C for ≥24 hours, or report of subjective fever lasting ≥24 hours, laboratory 
evidence of inflammation, and evidence of clinically severe illness requiring 
hospitalization, with multisystem (> 2) organ involvement (cardiac, renal, respiratory, 
hematologic, gastrointestinal, dermatologic or neurological); AND
!
No alternative plausible diagnoses; AND
!
Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen 
test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to 
the onset of symptoms.


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8.3.4.4
Cardiac and Thromboembolic Events
Cardiovascular AEs will be referred to a CV Event Adjudication Committee (Section 9.7). 
Only adjudicated events will be included as AESIs.
8.3.5
Medically Attended Adverse Events
Medically attended adverse events will be collected according to the time points specified in 
the SoA (Section 1.3).
Medically attended adverse events are defined as AEs leading to medically attended visits that 
were not routine visits for physical examination or vaccination, such as an emergency room 
visit, or an otherwise unscheduled visit to or from medical personnel (eg, a medical doctor or 
equivalent) for any reason. AEs, including abnormal vital signs, identified on a routine study 
visit will not be considered medically attended adverse events.
8.3.6 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or care provider or reported in response to 
the open question from the study site staff: ‘Have you/the child had any health problems since 
the previous visit/you were last asked?’, or revealed by observation will be collected and 
recorded in the eCRF. When collecting AEs, the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms. However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis 
and each sign or symptom will be recorded separately.
8.3.7 Adverse Events Based on Examinations and Tests
The results from the CSP mandated laboratory tests and vital signs will be summarized in the 
CSR.
Deterioration as compared to baseline in protocol-mandated safety assessments should 
therefore only be reported as AEs if they fulfill any of the SAE criteria, are the reason for 
discontinuation of treatment with the investigational product or are considered to be clinically 
relevant as judged by the Investigator (which may include, but are not limited to, 
consideration as to whether treatment or non-planned visits were required or other action was 
taken with the study intervention, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).


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Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.3.8 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with TBL ≥2 × ULN and 
confirmed as a Hy’s Law (HL) case should be reported as SAEs.
Occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, 
other than the IMP, can be found to explain the combination of increases, eg, elevated ALP 
indicating cholestasis, viral hepatitis, another drug should be evaluated. The elevation in 
transaminases must precede or be coincident with (ie, on the same day) the elevation in TBL, 
but there is no specified timeframe within which the elevations in transaminases and TBL 
must occur.
Please refer to Appendix D for further instruction on cases of increases in liver biochemistry 
and evaluation of HL.
8.3.9
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, Investigators or other site personnel will inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day, ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.


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If the EDC system is not available, then the Investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
For further guidance on the definition of a SAE, see Appendix B.
The reference document for definition of expectedness/listedness is the IB for AZD7442.
8.3.10
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except when 
the pregnancy is discovered before the study participant has received any IMP.
8.3.10.1
Maternal Exposure
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
anomalies/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly/birth defect) should be followed up and documented even if the 
participant was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.9) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
8.3.10.2
Paternal Exposure
In case of pregnancy of the partner of a male participant, the partner’s pregnancy should be 
reported on the pregnancy form (consent from the partner must be obtained before the 
pregnancy form is completed) following the same timeframe and routing as described for any 
participant’s pregnancy. Pregnancy of the participant’s partner is not considered to be an AE. 
These pregnancies will also be followed up, and the outcome of the pregnancy (spontaneous 


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miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) 
should, if possible, be obtained and documented.
8.3.11
Medication Error, Drug Abuse, and Drug Misuse
8.3.11.1
Timelines
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
Investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one calendar day, ie, immediately but no later than 24 hours of when they become aware of 
it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.9) and within 30 days for all other 
medication errors.
8.3.11.2
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.
The definition of a Medication Error can be found in Appendix B 4.
8.3.11.3
Drug Abuse
Events of drug abuse with IMP or AstraZeneca NIMP are collected in all studies where drug 
abuse is possible.
For guidance, refer to AstraZeneca SOP ‘Management of Individual Case Safety Reports 
(ICSR) in Clinical Trials’, SOP-0108717.
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B 4.
8.3.11.4
Drug Misuse
Events of drug misuse with IMP or AstraZeneca NIMP are collected in all studies where drug 
misuse is possible.
For guidance, refer to AstraZeneca SOP ‘Management of Individual Case Safety Reports 
(ICSR) in Clinical Trials’, SOP-0108717.


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Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, or 
for unauthorized IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
The full definition and examples of drug misuse can be found in Appendix B 4.
8.4
Overdose
For this study, any dose of AZD7442 greater than a planned weight-based dose presented in 
Table 6 will be considered an overdose.
AstraZeneca does not recommend a specific treatment for an overdose. Symptoms of overdose 
should be treated as per clinical judgment.
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study intervention occurs during the study, the Investigator 
or other site personnel inform appropriate AstraZeneca representatives immediately, but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for overdoses associated with an SAE (see Section 8.3.9) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific Laboratory Manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples see Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed.
!
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses.


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∃
Pharmacokinetic samples may be disposed of or anonymized by pooling. Additional 
analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.
!
Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years following issue of the CSR. Additional use includes but is not 
limited to further characterization of any ADAs, confirmation and/or requalification of 
the assay as well as additional assay development work. The results from future analysis 
will not be reported in the CSR.
8.5.1
Total Blood Volume
Blood volume estimates are provided in Table 16. For participants other than neonates, the 
total estimated blood volume to be collected during the study is approximately 73 mL per 
participant. For neonates, only safety and PK samples will be collected and the total estimated 
blood volume to be collected during the study is approximately 22 mL per participant. The 
total volume can be adjusted by age and the body weight of the participant per local ethics 
requirements. Where necessary, the visit windows in the SoA can be used to collect samples 
across a number of days. When sample collection occurs over ≥ 2 days for a given study visit, 
participants are required to visit the site at least once per study visit. If practical, additional 
sample collection can take place at home visits as long as the samples are obtained per 
protocol by qualified personnel. If it is not possible to obtain sufficient blood from a 
participant at a given study visit, the order of the samples will be prioritized according to the 
key requirements of the study and the following hierarchy will be applied: safety (ie, serum 
chemistry, hematology, coagulation), PK, SARS-CoV-2 neutralizing antibodies, and ADA (see 
Laboratory Manual). For participants receiving IV infusions of AZD7442, blood samples are 
to be collected from the opposite side of the body to the IV infusion at Visit 1.
Table 16
Blood Volume Estimates
Visit (study day ± visit window)
Estimated blood volume for 
neonatesa
Estimate blood volume for all 
other participantsb
Screening Visit (Day -7 to Day 0)
3.7 mL
6.3 mL
Visit 1 (Day 1 ± 0)
1.2 mL (IV only)
6.0 to 8.5 mLc, d
Visit 2 (Day 4 to 15 ± 2)
1.2 mL
2.5 mL
Visit 3 (Day 31 + 5)
4.9 mLe
14.8 mL
Visit 4 (Day 92 ± 5)
2.6 mLe
10.3 to 12.8 mLd
Visit 5 (Day 183 ± 10)
3.5 mLe
13.0 mL
Visit 6 (Day 366 ± 15)
4.9 mLe
14.8 mL
Total from screening to Day 366
20.8 to 22.0 mL
67.7 to 72.7 mL
a
For neonates, only safety and PK samples will be collected.


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b
For participants other than neonates, the following hierarchy will apply if it is not possible to obtain blood 
for all samples: (1) safety, (2) pharmacokinetics, (3) SARS-CoV-2 neutralizing antibodies, and (4) anti-drug 
antibodies.
c
At Visit 1, participants receiving AZD7442 IV will have an extra 2.5mL blood sample taken for post-dose 
PK sampling.
d
At Visit 4, participants in Cohort 1 will also have an additional 2.5mL taken for SARS-CoV-2 serology.
e
For Visits 3 to 6 blood samples should be taken on at least 2 different days and at least 24 h apart
Blood samples can be taken on different days within the sampling window specified in the Schedule of Activities 
(Section 1.3).
COVID-19, coronavirus disease 2019; IM, intramuscular; IV, intravenous; PK, pharmacokinetic; SARS-CoV-2, 
severe acute respiratory syndrome coronavirus 2.
Repeat blood samples may be collected for safety reasons.
8.5.2
Pharmacokinetics
!
Serum samples will be collected for measurement of serum concentrations of AZD7442 
(AZD8895 and AZD1061) at either Day 4, 8, 11, or 15 (one sample) and Days 31, 92, 
183, and 366 (one sample on each day), as specified in the SoA (Section 1.3). For 
participants who receive AZD7442 via an IV infusion, a serum sample should also be 
taken at the end of the infusion on Day 1 from the opposite side of the body. Serum 
samples should still be taken even if the participant is outside the visit window specified 
in the SoA.
!
Samples may be collected at additional time points during the study if warranted and 
agreed upon between the Investigator and the Sponsor, eg, for safety reasons. The timing 
of sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring.
!
Serum samples will be used to assess the PK of AZD7442 following IM and IV 
administration. Samples collected for analyses of AZD7442 serum concentration may 
also be used to evaluate safety or efficacy aspects related to concerns arising during or 
after the study.
!
Samples will be collected, labeled, stored, and shipped, as detailed in the Laboratory 
Manual.
!
AZD7442 PK parameters (eg, maximum serum concentration, AUC), if data permit, will 
be calculated based on AZD7442 serum concentrations following IM and IV 
administration.
8.5.2.1
Determination of Drug Concentration in Serum
Samples for determination of drug concentration in serum will be assayed by bioanalytical test 
sites operated on behalf of AstraZeneca, using an appropriately validated bioanalytical 
method. The bioanalytical sample results and the analytical method used will be described in a 


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separate Bioanalytical Report.
8.5.2.2
Determination of Drug Concentration in Nasal Secretions
Nasal samples to measure AZD7442 concentrations in nasal mucosa will be collected when 
test supplies are available and assessed using an appropriately qualified bioanalytical assay.
8.5.3
Immunogenicity Assessments
Serum samples for immunogenicity assessments will be collected according to the SoA 
(Section 1.3). Samples will be collected, labeled, stored, and shipped, as detailed in the 
Laboratory Manual.
8.5.3.1
Anti-drug Antibody
Blood samples for determination of ADA in serum will be assayed using an appropriately 
validated bioanalytical method. The results and the method details will be described in a 
separate report.
8.5.3.2
SARS-CoV-2 Serology
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels at 
baseline from all participants. Serostatus will also be collected from non-neonates in Cohort 1 
according to the SoA (Table 3). Baseline serostatus and time to seroconversion in participants 
receiving AZD7442 will be determined using a validated SARS-CoV-2 nucleocapsid antigen 
assay operated by an authorized laboratory. Serologic assessment to S (spike), RBD, and 
nucleocapsid antigens may also be assessed quantitatively using a validated multiplexed meso 
scale discovery immunoassay.
8.5.4
Pharmacodynamics: Neutralizing Antibody Assessments
8.5.4.1
SARS-CoV-2 Neutralizing Antibody Assessments
Serum samples to measure SARS-CoV-2 neutralizing antibody titers will be collected from 
participants according to the time points specified in the SoA (Section 1.3). Authorized 
laboratories may measure neutralizing antibodies to SARS-CoV-2 using validated wild-type 
live virus or pseudovirus neutralization assays.
For storage, re-use, and destruction of pharmacodynamic samples, see Section 8.5 and 
Appendix C.
8.6
Human Biological Sample Biomarkers
8.6.1
Virologic Assessments
Instructions for obtaining and processing samples for RT-PCR are provided in the Laboratory 
Manual. A SARS-CoV-2 rapid antigen test can be performed at each site at screening to enable 
same-day assignment to study cohorts. During the study, samples will also be assessed by 
authorized RT-PCR assays for the detection of SARS-CoV-2 by the central laboratories 


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according to the time points specified in the SoA (Section 1.3). Unscheduled RT-PCR testing 
may be performed in participants in Cohort 1 who present with COVID-19 qualifying 
symptom(s) (Section 8.1.1).
For Cohorts 2 and 3, viral load will be assessed in samples collected on Day 1 (at the site) and 
on Day 8 (at the site or at home) by an authorized RT-PCR assay for the quantitative 
measurement of SARS-CoV-2. The type of sample (eg, saliva, blood, nasopharyngeal) should 
be consistent between all study visits for each participant, but particularly for the samples 
collected on Day 1 and Day 8 which will be used to estimate the change in viral load.
8.6.2
Other Study-related Biomarker Research
Already collected samples may be analyzed for different biomarkers thought to play a role in 
COVID-19 severity or outcomes, including, but not limited to, serum, plasma or mucosal 
cytokines, quantification of RNA, micro-RNA, and/or non-coding RNA, using quantitative 
RT-PCR, microarray, sequencing, or other technology in blood, saliva, or mucosal specimens 
to evaluate their association with observed clinical responses to AZD7442. Other study-related 
biomarker research excludes genetic analysis.
For storage, re-use, and destruction of biomarker samples, see Section 8.5 and Appendix C.
8.7
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research are out of scope for pediatric 
studies.
8.8
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not applicable in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
No hypotheses are planned in this PK, PD, safety study.
9.2
Sample Size Determination
Approximately 120 participants will be screened/enrolled to achieve 100 evaluable 
participants.
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
can be rescreened once. If they are not subsequently assigned to receive AZD7442 in the 
study, they are considered “screen failures”.


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The total sample size of 100 participants across all pediatric age groups is the minimum 
number required to adequately characterize the AZD7442 safety profile in pediatric 
participants following IM or IV administration (based on FDA feedback). Furthermore, 
preliminary PK simulations based on adult PK data determined that with a minimum sample 
size of 24 participants (n = 6, per route of administration, in the 4 age groups from any 
cohort), and the proposed PK sampling scheme, 80% of the simulated trials estimated the 
geometric mean for CL with a 95% confidence interval that remained within 60% to 140% of 
the point estimate in each pediatric subgroup.
9.3
Populations for Analyses
The analysis populations are defined in Table 17.
Table 17
Populations for Analysis
Population/Analysis Set
Description
Screened population set
All participants who signed the ICF.
Unless otherwise stated, the enrolled set will be used for the presentation of 
disposition data.
Full Analysis Set
All participants who received IMP, irrespective of their protocol adherence 
and continued participation in the study. Participants who withdraw consent 
or assent to participate in the study will be included up to the date of their 
study termination.
Safety Analysis Set
All participants who have received IMP. 
PK Analysis Set
All participants who received AZD7442 and from whom PK blood samples 
are assumed not to be affected by factors such as protocol violations, and 
who had at least one quantifiable serum PK observation post-dose, will be 
included in the PK analysis dataset.
ADA Evaluable Analysis Set
All participants who are AZD8895 ADA evaluable and/or AZD1061 ADA 
evaluable.
A participant is AZD1061 ADA evaluable if they are in the Safety Analysis 
Set and have a non-missing baseline AZD1061 ADA result and at least one 
non-missing post-baseline AZD1061 ADA result.
A participant is AZD8895 ADA evaluable if they are in the Safety Analysis 
Set and have a non-missing baseline AZD8895 ADA result and at least one
non-missing post-baseline AZD8895 ADA result.
SARS-CoV-2 nAb Evaluable 
Analysis Set
All participants in the Safety Analysis Set from whom blood samples were 
assumed not to be affected by factors such as protocol violations and who 
had at least one quantifiable serum titer observation post dose. 
ADA, anti-drug antibodies; COVID-19, coronavirus disease 2019; ICF, informed consent form; IMP, 
investigational medicinal product; nAb, neutralizing antibody; PK, pharmacokinetic, SARS-CoV-2, severe acute 
respiratory syndrome coronavirus 2.


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9.4
Statistical Analyses
The SAP will be finalized before the first DSMB review and it will include a more technical 
and detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints.
9.4.1
General Considerations
The statistical methodology below describes the statistical analysis as it is foreseen when the 
study is being planned.
If circumstances should arise during the study rendering the analysis inappropriate, or if in the 
meantime improved methods of analysis should come to light, different analyses may be 
performed. Any deviations from the statistical methodology defined in this protocol, reasons 
for such deviations and all alternative/additional statistical analyses that may be performed 
will be described in the SAP. The verification and review of all statistical modeling 
assumptions will be documented appropriately.
All original and derived parameters as well as demographic and disposition data will be listed 
and described using summary statistics. All safety data (scheduled and unscheduled) will be 
presented in the data listings.
Frequency counts (number of participants [n] and percentages) will be produced for each 
qualitative variable. Descriptive statistics (n, mean, SD, median, minimum, and maximum) 
will be calculated for each quantitative variable (unless otherwise stated). Descriptive 
statistics will only be presented if n > 3. If no participants have data at a given time point, then 
only n = 0 will be presented. If n < 3, only the n, minimum and maximum will be presented, 
and if n = 3, only the n, median, minimum and maximum will be presented; the other 
descriptive statistics will be left blank.
All statistical analyses and production of tables, figures, and listings will be performed using 
SAS® version 9.4 or higher.
9.4.2
Pharmacokinetics
9.4.2.1
Primary Endpoint(s)
The serum AZD7442 mAbs (AZD8895 and AZD1061) concentrations and PK parameters 
following IM and IV administration will be listed and presented separately in tabular and 
graphical form.
Serum Concentration Data
For AZD7442 mAbs (AZD8895 and AZD1061), the serum concentrations for each scheduled 
time point will be summarized by weight categories, dose, and route of administration using 


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appropriate descriptive statistics, based on the PK analysis set. A listing of all serum 
concentration-time data, ie, PK scheduled times, actual sample collection times, sample actual 
relative times, as well as derived sampling time deviations will be presented by weight 
categories, dose, and route of administration for all participants in the Safety Analysis Set.
Individual serum concentration-time data will be graphically presented on linear and 
semi-logarithmic scales, for all participants in the PK analysis set. Combined individual serum 
concentration versus actual times will be plotted on both the linear and semi-logarithmic 
scales for all participants in the PK analysis set. Plots will be grouped by weight categories, 
dose, and route of administration. Figures for the geometric mean (± geometric SD) serum 
concentration-time data will be presented by weight categories, dose, and route of 
administration on both a linear and semi-logarithmic scale (no geometric SD presented), for 
all participants in the PK analysis set.
All plots will be based on the PK analysis set.
Serum Pharmacokinetic Parameters
All reportable AZD7442 (AZD8895 and AZD1061) PK parameters, obtained by non-
compartmental analysis method, including individual diagnostic and λz-related parameters, 
will be listed for each participant by weight categories, dose, and route of administration, 
based on the PK analysis set. All PK parameters will be summarized by weight categories, 
dose, and route of administration using appropriate descriptive statistics, based on the PK 
analysis set.
Population PK Analysis
Pharmacokinetic data from all age group/weight categories, doses, and route of administration 
will be analyzed simultaneously by population methods based on the PK analysis set. 
Population PK parameter estimates from the final model will be presented. Additionally, the 
post-hoc individual PK parameter estimates (including AUC0-inf) will be summarized by 
weight categories, dose, and route of administration using descriptive statistics, when 
appropriate.
Full details of the analyses to be performed will be provided in the SAP.
9.4.3
Pharmacodynamics
9.4.3.1
Secondary Endpoint: Neutralizing Antibody Titers
Samples will be collected for the evaluation of the functional inhibition of SARS-CoV-2 by 
AZD7442 concentrations in serum. Results will be listed for each participant and time point. 
Descriptive statistics for geometric mean titers and geometric mean fold rises will include 
number of participants, geometric mean, geometric SD, 95% CI, minimum, and maximum.


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9.4.4
Safety
The safety of AZD7442 will primarily be assessed by:
!
Incidence of AEs through end of study
!
Incidence of SAEs through end of study
!
Incidence of AESIs through end of study
Adverse event intensity will be graded according to Appendix B 2. Adverse events will be 
presented for each treatment group by system organ class and preferred term. Summaries will 
include the number and percentage of participants reporting at least one event, number of 
events, and exposure adjusted rates, where appropriate.
An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE and SAEs. Summaries will present the relationship to 
IMP as assessed by the Investigator, maximum intensity, seriousness, and death.
A listing will cover details for each individual AE. Full details of all AE analyses will be 
provided in the SAP.
Other safety endpoints include the following:
!
Laboratory parameters (hematology, clinical chemistry, coagulation, and urinalysis)
!
Vital signs (pulse rate, pulse oximetry, BP, and body temperature)
!
Physical examination
!
ECG
Laboratory assessments will be performed for hematology, clinical chemistry, coagulation, 
and urinalysis parameters.
All parameters from laboratory, vital signs, physical examination, and ECG assessments will 
be summarized with descriptive statistics based on data type (continuous, categorical, etc). No 
hypothesis testing or CIs will be performed or calculated, unless otherwise specified. Full 
details of safety endpoints analysis will be provided in the SAP.
9.4.5
Anti-drug Antibody
The results of the ADA assessments will be listed for each participant and time point. This will 
include the classification of the response (positive/negative) and the titers and neutralizing 
antibody status of the positive samples. Summary tables will be presented, by weight 
categories, dose, and route of administration as well as overall by route of administration, for 
the number and percentage of participants with positive/negative results at each time point, 


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based on the ADA evaluable analysis set.
In addition, the ADA titers (n, median, minimum, and maximum) will be summarized by 
weight categories, dose, and route of administration as well as overall by route of 
administration for all participants with a positive confirmatory assay result at each time point; 
this tabulation will include a summary of the highest titer across all time points for each 
participant.
The impact of ADA on PK, PD, and association with AEs and SAEs may be assessed.
9.5
Interim Analyses
At least one interim analysis is planned to be conducted in this study. The first will be 
conducted after a minimum of 12 adolescent patients, age ≥12 to # 18 years old, complete the 
Day 92 study visit. Additional interim analyses may be conducted to support regulatory 
requirements or at the discretion of the Sponsor. No hypotheses are planned in this PK, PD, 
safety study so multiplicity is not a concern.
9.6
Data Monitoring Committee
An independent DSMB will provide oversight, to ensure safe and ethical conduct of the study.
The DSMB will regularly meet and make any necessary recommendations to the Sponsor 
based on their evaluations of emerging data. In particular, the DSMB will conduct a safety 
evaluation as soon as practical after dosing of the study’s sixth participant plus 14 days. 
Subsequent DSMB meetings will review safety data after 21, 36, 51, 66, 81, and 96 
participants have been dosed with AZD7442.
For details on the DSMB, refer to Appendix A 5. Further details, composition, and operation 
of the independent DSMB will be described in a DSMB Charter.
9.7
Cardiovascular Event Adjudication Committee
An independent CV Event Adjudication Committee will provide an independent, external, 
systematic, and unbiased assessment of de-identified blinded data to systematically evaluate 
CV events. The adjudicated CV events will be included in descriptive analyses of safety data. 
Further details of the CV Event Adjudication Committee composition, operation, and listings 
of preferred terms to identify events are provided in a separate CV Event Adjudication 
Committee Charter.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∃
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
∃
Applicable ICH Good Clinical Practice (GCP) Guidelines
∃
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.
!
AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca.
!
The Investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations.
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
!
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators.
!
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary.
∃
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations


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!
An Investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the [IB or state other documents] and will notify the 
IRB/IEC, if appropriate according to local requirements.
Regulatory Reporting Requirements for Serious Breaches
!
Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.
∃
A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study.
!
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it.
!
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.
∃
AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the European Medicines Agency (EMA) Clinical 
Trial Information System (CTIS). It is important to note that redacted versions of 
serious breach reports will be available to the public via CTIS.
!
The investigator should have a process in place to ensure that:
∃
The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach
∃
A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca.
A 2
Financial Disclosure
Investigators and Sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for one year after completion of the study.


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A 3
Informed Consent Process
!
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.
!
Participants and their legally authorized representative must be informed that their 
participation is voluntary and they are free to refuse to participate and may withdraw their 
consent at any time and for any reason during the study. Participants will be required to 
provide their assent, where appropriate, and their legally authorized representative 
(defined as a parent or guardian) will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.
!
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
A participant who is rescreened is not required to sign another ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The Investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period.
A 4
Data Protection
!
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.
!
The participant and their legally authorized representative must be informed that his/her 
personal study-related data will be used by the Sponsor in accordance with local data 
protection law. The level of disclosure and use of their data must also be explained to the 
participant in the informed consent.


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!
The participant and their legally authorized representative must be informed that his/her 
medical records may be examined by Clinical Quality Assurance auditors or other 
authorized personnel appointed by the Sponsor, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
A 5
Committees Structure
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by Sponsor 
representatives in consultation with Patient Safety. Issues identified will be addressed; for 
instance, this could involve amendments to the CSP and letters to Investigators.
Data and Safety Monitoring Board 
An independent DSMB will monitor and protect the safety of the participants throughout the 
study. The DSMB members will be selected for their expertise. The voting members of the 
DSMB will be comprised of external individuals including the DSMB chair. Data summaries 
will be prepared and provided to the DSMB. To minimize the potential introduction of bias, 
DSMB members will not have direct contact with the study site personnel or participants. The 
data for review will be outlined in the DSMB Charter and will be agreed to in advance by the 
DSMB members. Data Review Meetings will review data relating to participant safety and 
quality of study conduct.
The DSMB will review safety data on a regular basis as set out in the DSMB Charter, 
including, but not limited to, reviewing cumulative safety data. These reviews will take place 
as soon as practical after 14 days of follow-up for the first 6 participants recruited into the 
study. Subsequent DSMB meetings will review safety data after 21, 36, 51, 66, 81, and 96 
participants have been dosed with AZD7442. Recruitment will continue during the safety 
review unless a pause is requested by the DSMB.
Safety summaries will be prepared prior to each meeting. During the study, the benefit/risk 
assessment will be continuously monitored by the DSMB to ensure that the balance remains 
favorable.
The DSMB can recommend modifications of the protocol to enhance participant safety and to 
recommend early termination of the study if there is strong evidence that AZD7442 or 
continuation of the study poses a safety concern to participants.
Morbidity Adjudication Committee
An independent Morbidity Adjudication Committee will provide an independent, external, 
systematic, and unbiased assessment of de-identified data to evaluate whether the causes of 
death for participants are considered COVID-19 associated. Only adjudicated deaths will be 
included in efficacy endpoints. All fatal events will be further assessed as part of safety 


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evaluation. Further details of this adjudication are provided in a separate Morbidity 
Adjudication Committee Charter.
Cardiovascular Event Adjudication Committee
An independent CV Event Adjudication Committee will provide an independent, external, 
systematic, and unbiased assessment of de-identified blinded data to systematically evaluate 
CV events. Further details of the CV Event Adjudication Committee composition, operation, 
and listings of preferred terms to identify events are provided in a separate CV Event 
Adjudication Committee Charter.
A 6
Dissemination of Clinical Study Data
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a half a year from global End of Trial Date in all participating countries, due to 
scientific reasons, as otherwise statistical analysis is not relevant.
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available. The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
A 7
Data Quality Assurance
!
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.
!
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.
!
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The Sponsor assumes accountability for actions delegated to other individuals (eg, 
CROs).


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!
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor.
A 8
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site.
!
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.
!
Definition of what constitutes source data can be found in the study monitoring plan.
A 9
Study and Site Start and Closure
The first act of recruitment is the first participant screened and will be the study start date.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:
!
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines
!
Inadequate recruitment of participants by the Investigator


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!
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy
!
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.
!
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfills one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalization or prolongation of existing hospitalization
!
Results in persistent or significant disability or incapacity
!
Is a congenital anomaly or birth defect
!
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above
Adverse events for malignant tumors reported during a study should generally be assessed as 
Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion 
should be used. In certain situations, however, medical judgment on an individual event basis 
should be applied to clarify that the malignant tumor event should be assessed and reported as 
a non-serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as non-serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.


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Life-threatening
“Life-threatening” means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. “Life-threatening” does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization
!
Development of drug dependency or drug abuse
Severity Rating Scale:
!
Grade 1: An event of mild intensity that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
!
Grade 2: An event of moderate intensity that is usually alleviated with additional, specific 
therapeutic intervention. The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the participant.


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!
Grade 3: A severe event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the clinical status of the 
participant.
!
Grade 4: An event, and/or its immediate sequelae, that is associated with an imminent risk 
of death.
!
Grade 5: Death as result of an event.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in this appendix. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in this appendix.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?
!
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.


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In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error, Drug Abuse, and Drug Misuse
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant.
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error.
!
Occurred
!
Was identified and participant received the drug
!
Did not occur, but circumstances were recognized that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
!
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet


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!
Drug not stored as instructed eg, kept in the refrigerator when it should be at room 
temperature
!
Wrong participant received the medication (excluding IRT/RTSM errors)
!
Wrong drug administered to participant (excluding IRT/RTSM errors).
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IRT/RTSM - including those which lead to one of the 
above listed events that would otherwise have been a medication error
!
Participant accidentally missed drug dose(s) eg, forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Participant failed to return unused medication or empty packaging
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used both 
if the drug abuse happened in a study participant or if the drug abuse involves a person not 
enrolled in the study (such as a relative of the study participant).
Examples of drug abuse include but are not limited to:
!
The drug is used with the intent of getting a perceived reward (by the study participant or 
a person not enrolled in the study)
!
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, or 
for unauthorized IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 


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misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant).
Examples of drug misuse include but are not limited to:
!
The drug is used with the intention to cause an effect in another person
!
The drug is sold to other people for recreational purposes
!
The drug is used to facilitate assault in another person
!
The drug is deliberately administered by the wrong route
!
Someone who is not enrolled in the study intentionally takes the drug.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples while at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent.
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analyzed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The Investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.


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!
Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
the action is documented, and study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf)
!
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content


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Appendix D
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
D 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than Drug Induced Liver Injury (DILI) caused by the IMP.
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
D 2
Definitions
Potential Hy’s Law
Aspartate aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 × Upper Limit of
Normal (ULN) together with Total Bilirubin (TBL) ≥2× ULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law
AST or ALT ≥3× ULN together with TBL ≥2× ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
D 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥3 × ULN
!
AST ≥3 × ULN
!
TBL ≥2 × ULN
Central Laboratories Being Used:
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the Investigator (also sent to 
AstraZeneca representative).
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the Investigator will:
!
Notify the AstraZeneca representative
!
Request a repeat of the test (new blood draw) by the central laboratory without 
delay
!
Complete the appropriate unscheduled laboratory eCRF module(s) with the 
original local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
!
Determine whether the participant meets PHL criteria (see Appendix D 2 for 
definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
Local Laboratories Being Used:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative


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!
Determine whether the participant meets PHL criteria (see Appendix D 2 for 
definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory eCRF
D 4
Follow-up
D 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the participant has not met PHL 
criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the CSP.
D 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the Investigator will:
!
Notify the AstraZeneca representative who will then inform the central Study Team
!
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ”Important medical event” and causality assessment 
”yes/related” according to CSP process for SAE reporting
!
For participants that met PHL criteria prior to starting IMP, the Investigator is not 
required to submit a PHL SAE unless there is a significant change1 in the participant’s 
condition
!
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data
!
Subsequent to this contact the Investigator will:
∃
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.
                                               
1 A ‘significant’ change in the participant’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in combination, or a clinically 
relevant change in associated symptoms. The determination of whether there has been a significant change will 
be at the discretion of the investigator, this may be in consultation with the Study Physician if there is any 
uncertainty.


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∃
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests available 
in the Hy’s Law lab kit should be used.
∃
Complete the 3 Liver eCRF Modules as information becomes available.
D 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days from 
date PHL criteria was met. The AstraZeneca Global Clinical Head or equivalent and Global 
Safety Physician will also be involved in this review together with other subject matter experts 
as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF
!
If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
!
Send updated SAE (report term “Hy’s Law”) according to AstraZeneca standard 
processes.
∃
The “Medically Important” serious criterion should be used if no other serious 
criteria apply
∃
As there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned.


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If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:
!
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now “Hy’s Law case”) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting.
!
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
D 6
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory. For studies using a local 
laboratory, the list may be modified based on clinical judgment. Any test results need to be 
recorded.
Hy’s Law Lab Kit for Central Laboratories
Additional standard chemistry and coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
HBsAg
IgM and IgG anti-HBc
HBV DNA a
IgG anti-HCV
HCV RNA b
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin) c
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)


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Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin c
Transferrin saturation
a
HBV DNA is only recommended when IgG anti-HBc is positive
b
HCV RNA is only recommended when IgG anti-HCV is positive or inconclusive
c
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly
D 7
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation


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Appendix E
Hospitalization Definition
Amid a rising number of COVID-19 hospitalizations across the world, leading to a shortage of 
hospital beds, temporary facilities are being utilized increasingly to manage severe COVID-19 
patients who would have usually been treated in a traditional hospital setting.
Please note that in this protocol, “hospitalization” is defined as ≥24 hours of acute care, in a 
hospital or similar acute care facility, including emergency rooms or temporary facilities 
instituted to address medical needs of those with severe COVID-19 during the COVID-19 
pandemic.
For the purposes of ascertaining an exclusion criterion or an endpoint event, individuals with 
COVID-19 will be considered “hospitalized” if they are:
1
Managed in an alternative care site set up or authorized by states, provinces, or equivalent 
jurisdictions or
2
Provided with acute hospital care at home meeting the criteria below:
(a) Physician determines the patient’s condition as being appropriate for “acute inpatient 
hospitalization”
(b) Treating physician should have appropriate screening protocols before care at home 
begins, to assess both medical and non-medical factors, including patient’s 
preference, working utilities and assessment of physical barriers
(c) Patients are evaluated daily either in person or remotely by a qualified health care 
provider/treating physician and are managed appropriately based on the patient’s 
treatment plan and local standards for COVID-19 management.
The appropriate WHO Clinical Progression Scale for COVID-19 score assigned to grade the 
participant’s condition would depend on the level of oxygen/ventilation support provided in 
these acute care settings.


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Appendix F
Anaphylaxis
Anaphylaxis is highly likely when either of the following criteria are fulfilled:
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips, tongue and/or 
uvula) plus features of anaphylaxis involving one or more system (Table 18) OR
2
Hypotension, bronchospasm, or upper airway obstruction
Table 18
Clinical Features of Anaphylaxis in Children
System
Features of anaphylaxis
Respiratory (most common in children)
Persistent cough
Wheeze, stridor, hoarse voice, difficulty talking or change in 
character of cry
Tongue swelling
Chest pain or dyspnoea
Subjective feeling of swelling, tightness or tingling the throat or 
mouth
Cardiovascular
Pale and floppy (infant)
Palpitations, tachycardia, bradycardia
Hypotension, pallor
Collapse with or without unconsciousness
Cardiac arrest
Neurological
Headache (usually throbbing)
Dizziness
Altered consciousness, confusion, sudden behavior change
Gastrointestinal
Nausea, vomiting, dysphagia
Diarrhoea
Abdominal or pelvic pain
Dermatological
Urticarial rash
Erythema, flushing, tearing
Angioedema
Pruritus (skin, eyes, nose, throat, mouth)
Source: RCH 2021.
The following definitions are provided for the purposes of this study:
Hypersensitivity reaction: An acute onset of an illness with involvement of the skin, mucosal 
tissue, or both after injection of IMP (but does not meet the definition of anaphylaxis 
described above).


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To assist with the mitigation of these AEs, see Table 19, which categorizes reactions by 
severity of symptoms and proposes severity-specific treatment and offers guidance on 
management of IMP. Final treatment is at the discretion of the Investigator and should reflect 
local standard of care.


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Table 19
An Approach to Management of Anaphylactic, Hypersensitivity, and Post Injection/Infusion Reactions
Severity of symptoms
Treatment
Investigational product
Mild local reactions (During and post 
injection/infusion and hypersensitivity)
Mild injection/infusion site reactions such as redness, 
mild swelling, pain at the injection site or headache, 
nausea, non-pruritic rash, or mild hypersensitivity 
reactions including localized at the injection site or 
generalized cutaneous reactions such as mild pruritus, 
flushing, rash, dizziness, headache, ≤20 mmHg 
change in systolic BP from pre-administration 
measurement.
Evaluate participant, including close monitoring 
of vital signs.
At the discretion of the Investigator, treat 
participant, for example, with:
Localized cold pack or heat to the injection site. If 
more generalized reaction:
•
Diphenhydramine or equivalent and/or
•
Acetaminophen or equivalent dose of 
paracetamol and/or
•
Topical antihistamines and/or low-potency 
topical corticosteroid preparations and/or
•
Anti-nausea medication, as needed.
Doses and route of administration as per local 
standard of care.
Pause or hold additional IMP injection 
immediately.
At the discretion of the Investigator, resume 
current IMP administration under observation. 
Moderate reactions (during or immediately post 
injection)
Injection/infusion site reaction such as those listed 
above under mild reactions but excluding moderate 
hypersensitivity reactions (see below).
Evaluate participant, including close monitoring 
of vital signs.
Treat participant, for example, with:
•
Normal saline IV and/or
•
Diphenhydramine 50 mg IV or equivalent 
and/or
•
Acetaminophen 500 to 650 mg or equivalent 
dose of paracetamol and/or
•
Anti-nausea and/or antiemetic intramuscular, 
as needed.
Doses and route of administration as per local 
standard of care.
Stop or hold additional IMP administration 
immediately.
At the discretion of the Investigator, resume 
current IMP administration under observation. 
Moderate hypersensitivity reactions
Reactions which may include generalized rash or 
urticaria, palpitations, chest discomfort, shortness of 
breath, hypo- or hypertension with
Evaluate participant, including close monitoring 
of vital signs.
Treat participant, for example, with:
•
Normal saline IV and/or
Stop IMP administration immediately. 


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Table 19
An Approach to Management of Anaphylactic, Hypersensitivity, and Post Injection/Infusion Reactions
Severity of symptoms
Treatment
Investigational product
> 20 mmHg change in systolic BP
from pre-infusion measurement.
•
Diphenhydramine or equivalent and/or
•
Acetaminophen or equivalent dose of 
paracetamol and/or
•
IV corticosteroids, such as hydrocortisone or 
methylprednisolone.
Doses and route of administration as per local 
standard of care.
Severe
Above plus fever with rigors, hypo- or hypertension 
with ≥40 mmHg change in systolic BP, signs of end-
organ dysfunction (eg, symptomatic hypotension such 
as hypotonia, syncope, incontinence, seizure) from 
pre-infusion measurement, or wheezing, angioedema, 
or stridor
OR
Life-threatening
Defined as a reaction that is
life-threatening and requires pressor and/or ventilator 
support or shock
associated with acidemia and
impairing vital organ function due to tissue 
hypoperfusion
Evaluate participant, including close monitoring 
of vital signs.
Maintain airway, oxygen if available.
Treat participant immediately, for example with:
•
Normal saline IV
•
Epinephrine for bronchospasm, hypotension 
unresponsive to IV fluids, or angioedema
•
IV corticosteroids, such as hydrocortisone
or methylprednisolone
•
Diphenhydramine or equivalent
•
Acetaminophen or equivalent dose of 
paracetamol
Doses and route of administration as per local 
standard of care.
Call emergency medical transport for transport to 
emergency hospital based on judgment of the 
Investigator.
Grade 3 wheezing, hypotension or angioedema is 
unresponsive to single dose of epinephrine
Grade 4 event
At the discretion of the Investigator
Stop IMP administration immediately. Do not 
resume current dosing. Permanently discontinue 
IMP administration.
Consider need for additional oral antihistamine 
administration or oral corticosteroid 
administration to prevent reoccurrence of 
symptoms over subsequent 2 to 3 days.
BP, blood pressure; IMP, investigational medicinal product; IV, intravenous;


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RCH 2021
The Royal Children’s Hospital (RCH) Melbourne. Clinical Practice Guidelines. Anaphylaxis. 
Available from: https://www.rch.org.au/clinicalguide/guideline_index/Anaphylaxis/ Accessed 
22 September 2021.


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Appendix G
Abbreviations
Abbreviation or 
special term
Explanation
ACE2
angiotensin converting enzyme 2
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase/transaminase
AST
aspartate aminotransferase/transaminase
AZ
AstraZeneca
AUC
area under the plasma concentration-time curve
AUC0-inf
area under the serum concentration versus time curve extrapolated to infinity
BP
blood pressure
CFR
Code of Federal Regulations
CI
confidence interval
CL
systemic clearance
COVID-19
coronavirus disease 2019
CPAP
continuous positive airway pressure 
CRO
Contract Research Organization
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTIS
Clinical Trial Information System
CV
cardiovascular
DES
Data Entry Site
DILI
drug-induced liver injury 
DSMB
Data Safety Monitoring Board
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EU
European Union
EUA
Emergency Use Authorization
Fc
fragment crystallizable region
FDA
Food and Drug Administration
FTIH
first time in human
GA
gestational age


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Abbreviation or 
special term
Explanation
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HL
Hy’s Law
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration or 50% inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IM
intramuscular
IMP
investigational medicinal product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
λz 
terminal disposition rate constant/terminal rate constant
mAb(s)
monoclonal antibody(ies)
MERS-CoV
Middle East respiratory syndrome coronavirus
MIS-C
multisystem inflammatory syndrome in children
NIMP
non-investigational medicinal product
PD
pharmacodynamic(s)
PHL
Potential Hy’s Law
PK
pharmacokinetic(s)
QT
ECG interval measured from the onset of the QRS complex to the J point
QTcF
QT interval corrected for heart rate using Fridericia’s formula
R0
basic reproduction number
RBD
receptor binding domain
RNA
ribonucleic acid
RSV
respiratory syncytial virus
RT-PCR
reverse transcriptase polymerase chain reaction
RTSM
Randomization and Trial Supply Management
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-1
severe acute respiratory syndrome coronavirus 1
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2


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Abbreviation or 
special term
Explanation
SD
standard deviation
SID
subject identification
SoA
Schedule of Activities
SUSAR
suspected unexpected serious adverse reactions
TBL
total bilirubin level
ULN
upper limit of normal
USA
United States of America
WHO
World Health Organization


















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11
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61.


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Document Name: d8850C00006-csp-v5
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STATISTICAL ANALYSIS PLAN
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STATISTICAL ANALYSIS PLAN
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D8850C00006
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Final 3.0
Date
31-Jul-2023
Open-label, Uncontrolled, Single dose Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of AZD7442 
in Pediatric Participants Aged ≥ 29 Weeks Gestational Age to 
< 18 Years


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TABLE OF CONTENTS
TITLE PAGE................................................................................................................1
TABLE OF CONTENTS..............................................................................................4
LIST OF ABBREVIATIONS .......................................................................................7
AMENDMENT HISTORY.........................................................................................10
1
INTRODUCTION....................................................................................12
2
CHANGES TO PROTOCOL PLANNED ANALYSES............................12
3
DATA ANALYSIS CONSIDERATIONS ................................................12
3.1
Timing of Analyses...................................................................................12
3.1.1
Interim Analysis .......................................................................................12
3.1.2
Data Safety Monitoring Board ..................................................................13
3.2
Analysis Populations.................................................................................13
3.3
General Considerations.............................................................................14
3.3.1
General Study Level Definitions ...............................................................14
3.3.2
Baseline....................................................................................................15
3.3.3
Change from Baseline...............................................................................15
3.3.4
Study Day.................................................................................................15
3.3.5
Handling of Missing Data.........................................................................15
3.3.6
Visit Window ...........................................................................................16
3.3.7
Handling of Unscheduled Visits................................................................16
3.3.7.1
For Tables, Listings and Figures ...............................................................16
3.3.7.2
For Pharmacokinetic Analysis...................................................................17
3.3.8
Multiplicity/Multiple Comparisons ...........................................................17
3.3.9
Handling of Protocol Deviations in Study Analysis...................................17
4
STATISTICAL ANALYSIS.....................................................................17
4.1
Study Population.......................................................................................17
4.1.1
Analysis Sets ............................................................................................17
4.1.1.1
Definitions and Derivations ......................................................................17
4.1.1.2
Presentation ..............................................................................................18
4.1.2
Subject Disposition and Completion Status...............................................18
4.1.2.1
Definitions and Derivations ......................................................................18
4.1.2.2
Presentation ..............................................................................................19
4.1.3
Protocol Deviations...................................................................................19
4.1.3.1
Definitions and Derivations ......................................................................19
4.1.3.2
Presentation ..............................................................................................19
4.1.4
Demographics...........................................................................................20
4.1.4.1
Definitions and Derivations ......................................................................20
4.1.4.2
Presentation ..............................................................................................20
4.1.5
Baseline Characteristics............................................................................20
4.1.5.1
Definitions and Derivations ......................................................................20
4.1.5.2
Presentation ..............................................................................................20
4.1.6
Disease Characteristics .............................................................................21


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4.1.6.1
Definitions and Derivations ......................................................................21
4.1.6.2
Presentation ..............................................................................................21
4.1.7
Medical History and Concomitant Disease................................................21
4.1.7.1
Definitions and Derivations ......................................................................21
4.1.7.2
Presentation ..............................................................................................22
4.1.8
Prior and Concomitant Medications ..........................................................22
4.1.8.1
Definitions and Derivations ......................................................................22
4.1.8.2
Presentation ..............................................................................................22
4.1.9
Study Drug Compliance............................................................................23
4.1.9.1
Definitions and Derivations ......................................................................23
4.1.9.2
Presentation ..............................................................................................23
4.2
Endpoint Analyses....................................................................................23
4.2.1
Primary PK Endpoints ..............................................................................25
4.2.1.1
Serum Concentration Data ........................................................................25
4.2.1.2
Figures for Serum Concentration Data ......................................................25
4.2.1.3
Serum Pharmacokinetic Parameters ..........................................................26
4.2.1.4
Final Population PK Model.......................................................................27
4.2.1.5
Evaluation of the Final Population PK Model ...........................................27
4.2.1.6
Handling of Missing Data and LLOQ .......................................................28
4.2.1.7
Population PK Analysis ............................................................................29
4.2.1.8
Final Population PK Model.......................................................................33
4.2.1.9
Evaluation of the Final Population PK Model ...........................................33
4.2.1.10
Subgroup Analyses ...................................................................................33
4.2.2
Primary Safety Endpoints .........................................................................33
4.2.2.1
Adverse Events.........................................................................................34
Serious Adverse Events...............................................................................................34
Adverse Event of Special Interest................................................................................34
Cardiovascular Events.................................................................................................35
Analysis of Adverse Events ........................................................................................35
4.2.2.2
Laboratory parameters ..............................................................................35
4.2.2.3
Vital Signs................................................................................................36
4.2.2.4
Physical Examination................................................................................36
4.2.2.5
ECG .........................................................................................................37
4.2.2.6
Subgroup Analyses ...................................................................................37
4.2.3
Secondary Endpoint – All Cohorts............................................................37
4.2.3.1
SARS-CoV-2 neutralizing antibodies........................................................37
4.2.3.2
ADA and nAb to AZD7442 in serum........................................................37
4.2.4
Secondary Endpoint – Cohort 1 (Prophylaxis)...........................................40
4.2.5
Secondary Endpoint – Cohort 2 and Cohort 3 (Treatment)........................41
4.2.5.1
Viral load..................................................................................................41
4.2.5.2
Progression of COVID-19.........................................................................41
4.2.5.3
COVID-19-related death...........................................................................41
4.2.6
Secondary Endpoint – Cohort 3 (Severe COVID-19) ................................42
4.2.6.1
Recovery ..................................................................................................42
4.2.7
Exploratory Endpoint................................................................................42
4.2.8
Other Endpoints........................................................................................42


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4.2.8.1
Exposure...................................................................................................42
4.2.8.2
Injection/Infusion site Inspection ..............................................................42
4.2.8.3
Potential Hy’s Law ...................................................................................42
5
INTERIM ANALYSIS .............................................................................43
6
APPENDICES..........................................................................................43


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LIST OF ABBREVIATIONS
Abbreviation or Specialized Term
Definition
%AUCext
percentage of AUC extrapolated 
ADA
anti-drug antibody
ADS1
AZD1061ADA Evaluable Analysis Set 
ADS2
AZD8895 ADA Evaluable Analysis Set 
ADS3
AZD7442 ADA Evaluable Analysis Set 
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase/transaminase
AST
aspartate aminotransferase/transaminase
AUC
area under the serum concentration-time curve
AUC(0-92d)
area under the serum concentration-time curve from time 
zero to day 92
AUC0-inf 
area under the serum concentration versus time curve zero 
to infinity
AUC0-last
area under the serum concentration versus time curve from 
time zero to time of last measurable concentration
AZD7442
the product under investigation (AZD8895 and AZD1061)
BP
blood pressure
CI
confidence interval
CL
systemic clearance
CL/F
apparent total clearance
Clast
Last observed (quantifiable) concentration
Cmax
maximum serum concentration
Ctrough
trough serum concentration 
COVID-19
Coronavirus disease-2019
CS
clinically significant
CV
Cardiovascular
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
FAS
Full Analysis Set
GA
gestational age
gCV
geometric coefficient of variation
ggt
Gamma glutamyl transpeptidase 
gmean
geometric mean
GMT
geometric mean titers


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gSD
geometric standard deviation
ICF
informed consent form
IM
intramuscular
IMP
investigational medicinal product
IPD
Important protocol deviation
IRT
Interactive Response Technology
IV
intravenous
LLOQ
lower limit of quantification
mAb
monoclonal antibody
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration 
MCV
Mean corpuscular volume
MedDRA 
Medical Dictionary for Regulatory Activities 
MIS-C
multisystem inflammatory syndrome in children
nAb
neutralizing antibody
NC
not calculated
NCS
not clinically significant
NQ
not quantifiable
NR
not reportable
NS
no sample
PD
pharmacodynamics
PK
pharmacokinetics
PKS
PK Analysis Set
PT
Preferred Term
qRT-PCR
quantitative real-time polymerase chain reaction
RBC
Red blood cell 
RT-PCR
reverse transcriptase polymerase chain reaction
SAE
serious adverse event
SAF
Safety Analysis Set
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
standard deviation
SES
SARS-CoV-2 nAb Evaluable Analysis Set
SOC
System Organ Class
SPS
Screened population set
t1/2
terminal half-life
t1/2λz
Half-life associated with terminal slope of a semi-
logarithmic concentration-time curve
TEAE
treatment-emergent adverse event
tmax
time to reach maximum serum concentration
VPC
Visual Predictive Checks
Vss
volume of distribution at steady state
Vz/F
apparent volume of distribution based on terminal phase


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WBC
White blood cell 
λz
Terminal disposition rate constant/terminal rate constant


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AMENDMENT HISTORY
CATEGORY
Change refers to:
Date
Description of change
In line with 
Clinical Study 
Protocol?
Rationale
Data presentation
26-Oct-2022
Removed reference to PK data for DSMB
Yes
Updated protocol
Other
26-Oct-2022
Minor text corrections
N/A
Typos and consistency
Data presentation
26-Oct-2022
Removed summary of AEs by maximum intensity
No
Sponsor request per AZD7442 
program-level shell changes
Data presentation
26-Oct-2022
Added confidence intervalls for percentage of subjects 
with AEs  
Yes
Sponsor request per AZD7442 
program-level shell changes
Data presentation
26-Oct-2022
Clarified ECG evaluation summary to be a shift table
Yes
Clarification of presentation per 
AZ standard shell
Other
26-Oct-2022
Demographics: correction of estimated gestational age 
for prematurely born infants at birth, not study entry
Yes
Correction
Data presentation
26-Oct-2022
COVID-19 incidence will be  summarized by weight 
categories, and route of administration, not by dose
Yes
Correction. This is a single-
dose study
Other
26-Oct-2022
ADA Evaluable Analysis Sets have been clearly 
distinguished, defining one set each for AZD1061, 
AZD8895, AZD7442  
Yes
Clarification
Other
26-Oct-2022
Mis-assignment to Cohort 1 via contradictory rapid and 
confirmatory COVID-19 test handling explained. 
Added separate analysis set and repetition of COVID-
19 incidence summary for this set.
Yes
Newly identified potential case 
of erroneous cohort assignment
Statistical analysis 
method for secondary 
endpoint(s)
26-Oct-2022
The SARS-CoV-2 viral loads will be log10-
transformed before summary.
Yes
Clarification on result 
presentation


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CATEGORY
Change refers to:
Date
Description of change
In line with 
Clinical Study 
Protocol?
Rationale
Statistical analysis 
method for secondary 
endpoint(s)
26-Oct-2022
Time-to-Event summaries will include quartiles.
Yes
Addition of statistic
Other
26-Oct-2022
Clarification of vaccinations status as captured in the 
eCRF at baseline.
Yes
Clarification of definition
Other
26-Oct-2022
Description of use of unscheduled and repeated 
assessments added.
Yes
Addition of information
Data presentation
26-Oct-2022
Presentation of descriptive statistics: quartiles, 
minimum, maximum updated for several variables and 
explicitly stated where applicable.
Yes
Sponsor request per AZD7442
program-level shell changes
Other
30-May-2023
Updated information on cohorts and early stop of 
recruitment.
Yes
Early discontinuation of patient 
recruitment
Data presentation
30-May-2023
Description of nAb data added.
Yes
Clarification


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1
INTRODUCTION
This Phase I pediatric study will provide information on the AZD7442 PK profile, 
SARS-CoV-2-neutralizing antibody titers, effect on viral load, data on the safety and 
tolerability and generation of ADAs to AZD7442, following a single IM or IV AZD7442 
dose administration in different pediatric age groups. This will be the first AZD7442 
clinical study in pediatric participants aged ≥ 29 weeks GA to < 18 years.
The analyses described in this SAP are based upon the following study documents:
1. Clinical Study Protocol, Version 1.0 (October 08, 2021)
2. Clinical Study Protocol Amendment 1 (December 16, 2021)
3. Clinical Study Protocol Amendment 2 (March 03, 2022)
4. Clinical Study Protocol Amendment 3 (September 22, 2022)
The content of this SAP is compatible with the International Council for 
Harmonization/Food and Drug Administration E9 Guidance documents.
2
CHANGES TO PROTOCOL PLANNED ANALYSES
A summary of adverse events by maximum intensity was planned in protocol Section 9.4.4. 
This was removed per AZD7442 program-level data presentation decision.
Enrolment into the study has been discontinued due to FDA feedback. No participant has 
been included for Cohort 3, and the full analysis set will contain 46 instead of 100
participants. Planned analyses for Cohorts with no participants will not be conducted.
3
DATA ANALYSIS CONSIDERATIONS
3.1
Timing of Analyses
3.1.1
Interim Analysis
At least one interim analysis is planned to be conducted in this study after a minimum of 
12 adolescent participants, age ≥ 12 to < 18 years old, complete the Day 92 study visit.
Additional interim analyses may be conducted to support regulatory requirements. No 
adjustment will be made for multiple hypotheses testing. 
Please see Section 5 Interim Analysis for details on the analysis content.


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3.1.2
Data Safety Monitoring Board
An independent DSMB will provide oversight to ensure safe and ethical conduct of the 
study. The DSMB will regularly meet and make any necessary recommendations to the 
Sponsor based on their evaluations of emerging data. In particular, the DSMB will conduct 
a safety evaluation once 14 days of safety data are available for 6 participants or more. 
Subsequent DSMB meetings will review safety data after 21, 36, 51, 66, 81 and 96 
participants have been dosed with AZD7442. Data summaries will be prepared and 
provided to the DSMB.
Details for the DSMB and summaries to be prepared will be outlined in a DSMB Charter 
and a DSMB analysis plan.
3.2
Analysis Populations
The study population of pediatric participants aged ≥ 29 weeks gestational age to < 18 
years are split into three cohorts by their COVID-19 status at study entry and dosed 
considering weight categories.
Cohorts
Cohort 1: Pediatric participants who are SARS-CoV-2 negative at baseline
Cohort 2: Pediatric participants who are SARS-CoV-2 positive at baseline and have mild to 
moderate COVID-19
Cohort 3: Pediatric participants who are SARS-CoV-2 positive at baseline and have severe 
COVID-19
In case a participant is assigned to Cohort 1 via a negative rapid COVID-19 test at 
screening, but the confirmatory test result is positive, the participant stays assigned to 
Cohort 1.
Cohort 3 will be empty due to discontinuation of enrolment. No change to enrolment in 
Cohort 1 and 2 was made.  
Route of IMP administration
IM: Participants will receive a single dose of AZD7442 given via IM (AZD8895 followed 
by AZD1061 administered separately)
IV: Participants will receive a single IV infusion (AZD8895 and AZD1061 co-
administered) based on the participant’s body weight


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Age groups
The participants’ ages will be categorized into the following categories using age 
information captured during the randomization procedure.
1. ≥ 12 years to < 18 years
2. ≥ 6 years to < 12 years
3. ≥ 1 years to < 6 years
4. ≥ 29 week gestational age to < 1year
a.
≥ 1 month to < 1 year
b. ≥ 29 week gestational age to < 1 month
Weight categories
1. ≥ 1.5 to < 5 kg
2. ≥ 5 to < 15 kg
3. ≥ 15 to < 40 kg
4. ≥ 40 kg
3.3
General Considerations
3.3.1
General Study Level Definitions
All original and derived parameters as well as demographic and disposition data will be 
listed and described using summary statistics. All safety data (scheduled and unscheduled) 
will be presented in the data listings.
Summaries will be based on the visit schedule, but unscheduled and repeated assessments 
captured will be used for definition of baseline or for identification of worst post-baseline 
evaluations. If there is an unscheduled and a scheduled assessment with the same date, the 
unscheduled assessment will be assumed to be a repetition and the scheduled result used for 
summaries.
Frequency counts (number of participants [n] and percentages) will be produced for each 
qualitative variable. Descriptive statistics (n, mean, SD, median, minimum and maximum) 
will be calculated for each quantitative variable (unless otherwise stated). Descriptive 
statistics will only be presented if n > 3. If no participants have data at a given time point, 
n = 0 will be presented. If n < 3, only the n, minimum and maximum will be presented, and 
if n = 3, only the n, median, minimum and maximum will be presented; the other 
descriptive statistics will be left blank.


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The CI to a geometric mean will be determined by log-transforming the observations, 
calculating the 95% confidence limits to the arithmetic mean of the transformed data and 
back-transforming the confidence limits with the exponential function.
Percentages will be presented to one decimal place.  Percentages will not be presented for 
zero counts. Percentages will be calculated using n as the denominator. The denominator 
should be clearly presented in each table.
Rounding should be the last operation in the treatment of data. There should be no rounding 
of intermediate results during the calculation of any derived value. Zeros at the end of a 
number should be retained.
All statistical analyses and production of tables, figures, and listings will be performed 
using SAS® version 9.4 or higher. All other requirements and specifications for 
programming and presentation of TFLs will be specified in the TFL shells document.
3.3.2
Baseline
Unless otherwise specified, baseline is defined as the last non-missing measurement taken 
prior to the dose of IMP. These can be assessments from screening, Visit 1 or unscheduled 
or repeated assessments prior to IMP administration.
3.3.3
Change from Baseline
Change from baseline will be defined as the value post-dosing minus the baseline defined, 
for each timepoint.
Percent change from baseline will be calculated as:
Percent change from baseline = ([visit value – baseline value]/baseline value) ×100
3.3.4
Study Day
Study Day 1 is defined as the date of first dose of IMP.
For visits (or events) that occur on or after first dose of study treatment, study day is 
defined as (date of visit [event] – date of first dose of study treatment + 1). For visits (or 
events) that occur prior to first dose, study day is defined as (date of visit [event] – date of 
first dose of IMP). There is no study day 0 defined for this study.
3.3.5
Handling of Missing Data
In general, other than the below there will be no imputation of missing data unless 
explicitly stated. 


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In case of missing data in collection of AE start date or start time, that is not reported as 
unknown:
!
AEs with start date/time at the time of or after dosing (for each specific 
treatment/dose) until Follow-Up Visit will be assigned to the specific 
treatment/dose. 
!
AEs with completely unknown start dates will be imputed with the date and time of 
dosing, unless the end date is known and prior to dosing; in that case the start date 
will be imputed as the date of Screening and a time of 00:00.
!
AEs with unknown start times, but with start date known, will be imputed with a 
time of 00:00, unless the start date corresponds to the dosing date. In this case the 
start time will be imputed with the time of dosing. If this results in a start date/time 
after end date/time of the AE, then the time will also be imputed with 00:00.
!
Missing day: impute with the 1st of the month, unless the month and year in which 
the AE started is a month and year in which IMP was administered, then the day 
will be imputed with the first day on which IMP was administered in that month. If
this results in a start date after the end date, then the day will be imputed with the 
first day of the month.
!
Missing month: impute with the 1st month in which IMP was administered. If this 
results in a start date after the end date of the AE, then the month will be imputed 
with JAN. If the known year part is not a year in which IMP was administered, then 
the month will also be imputed with JAN.
!
Missing day and month: impute with the day and month of dosing. If this results in 
a start date after end date, then the day and month will be imputed with 01JAN. If 
the year is not a year in which IMP was administered, then the day and month will 
also be imputed with 01JAN.
!
Missing year: impute with the year of dosing
!
Missing times will be imputed as 00:00 h or with the time of dosing for events 
starting on a dosing day.
When imputing a start date, care should be taken to ensure the start date is sensible, ie, prior 
to the end date.
3.3.6
Visit Window
Scheduled visits will be analysed as captured in the electronic case report forms. Early 
discontinuation visits will be mapped to the chronologically closest not-performed visit.
3.3.7
Handling of Unscheduled Visits 
3.3.7.1
For Tables, Listings and Figures
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By-visit summaries will not include unscheduled visits. Across-visits summaries, eg, 
summaries of occurrences will include unscheduled assessments. 
3.3.7.2
For Pharmacokinetic Analysis
In case a serum PK sample is drawn at an unscheduled visit, PK analysis will include the 
unscheduled concentrations.
3.3.8
Multiplicity/Multiple Comparisons
No hypotheses are planned to be formally tested using inferential statistics in this study so 
multiplicity is not a concern.
3.3.9
Handling of Protocol Deviations in Study Analysis
Protocol deviations will be captured and presented as described in Section 4.1.3. The 
protocol deviations and their categorization to “important” or “non-important” are 
pre-defined as far as possible before inclusion of the first participant. Final categorization 
of protocol deviations and actions for analysis will be done continuously during the study 
but finalized prior to the final analysis and any interim analysis.
For details on definition of protocol deviations, please refer to the study-specific Protocol 
Deviation Specification.
4
STATISTICAL ANALYSIS
This section provides information on definitions, derivation and analysis/data presentation 
per domain.
4.1
Study Population
The domain study population covers subject disposition, analysis sets, protocol deviations, 
demographics, baseline characteristics, medical history, prior and concomitant medication, 
and study drug compliance. 
4.1.1
Analysis Sets
4.1.1.1
Definitions and Derivations
Before database lock for the final or interim analysis, protocol deviation categories and the 
analyses populations will be produced for review. An analysis set classification meeting 
will be arranged to discuss the outputs and to decide which participants and/or participant 
data will be excluded from certain analyses. Decisions made regarding the exclusion of 
participants and/or participant data from analyses will be documented and approved by the 
sponsor.


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Table 1: Analysis sets
Population/Analysis Set
Description
Screened Population Set (SPS)
All participants who signed the ICF. 
Unless otherwise stated, this set will be used for the presentation of 
disposition data.
Full Analysis Set (FAS)
All participants who received the IMP, irrespective of their protocol 
adherence and continued participation in the study. Participants who 
withdraw consent or assent to participate in the study will be included up to 
the date of their study termination.
Modified Full Analysis Set 
(mFAS)
All participants who are in the FAS, excluding participants who were 
assigned to Cohort 1 by rapid COVID-19 test, but have a positive 
confirmatory test.
Safety Analysis Set (SAF)
All participants who have received IMP.
PK Analysis Set (PKS)
All participants who received AZD7442 and from whom PK blood samples 
are assumed not to be affected by factors such as protocol violations, and 
who had at least one quantifiable serum PK observation post-dose, will be 
included in the PK analysis dataset.
AZD1061 ADA Evaluable 
Analysis Set (ADS1)
A participant is AZD1061 ADA evaluable if in the SAF and having a non-
missing baseline AZD1061 ADA result and at least one non-missing post-
baseline AZD1061 ADA result.
AZD8895 ADA Evaluable 
Analysis Set (ADS2)
A participant is AZD8895 ADA evaluable if in the SAF and having a non-
missing baseline AZD8895 ADA result and at least one non-missing post-
baseline AZD8895 ADA result.
AZD7442 ADA Evaluable 
Analysis Set (ADS3)
All participants who are AZD8895 ADA evaluable and/or AZD1061 ADA 
evaluable.
SARS-CoV-2 nAb Evaluable 
Analysis Set (SES)
All participants in the Safety Analysis Set from whom blood samples were 
assumed not to be affected by factors such as protocol violations, and who 
had at least one quantifiable serum titer observation post dose.
Generally, all listings will be prepared based on the SAF unless otherwise stated. 
Disposition data will be listed for the SPS. 
4.1.1.2
Presentation
A listing will be provided presenting each subject’s inclusion in each analysis set and 
cohort. The number of subjects in each analysis set will be summarized qualitatively by 
cohort.
4.1.2
Subject Disposition and Completion Status
4.1.2.1
Definitions and Derivations
A clear accounting of the disposition of all participants who enter the study will be 
provided, from screening to study completion including potential re-screening.


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For each subject, the dates for each visit they participated in will be listed.
4.1.2.2
Presentation
Participant disposition will be summarized and will include the following information: 
number of participants screened, randomized and dosed, number and percentage of 
participants completing the study and the number and percentage of participants who were 
withdrawn (including primary reason for withdrawal). The summary will be done overall 
and by cohort.
Participant discontinuations will be listed including the date of study exit, duration of 
participation and primary reason for discontinuation.
Participants and/or data excluded from the PK analysis set (see Section 4.1.1) will be listed 
including the reason for exclusion.
The analysis set to be used for these summaries and listings is the SPS (see Section 4.1.1).
4.1.3
Protocol Deviations
4.1.3.1
Definitions and Derivations
Important deviations from the protocol (IPDs) may lead to the exclusion of participants or 
data from the PKS or SES. Deviations will be assessed and classified during the study and 
finalized before database lock. IPDs include those deviations from the protocol that are 
likely to have an impact on the perceived safety of study treatments or outcome assessment.  
IPDs will include the following at a minimum:
!
Violation of key inclusion and/or exclusion criteria.
!
Administration of prohibited concomitant medications that are expected to influence 
the outcome of this study.
!
Deviations from planned dose or administration procedure of the IMP.
!
Relevant time window deviations expected to influence key safety and/or PK 
assessments.
All important protocol deviations will be listed. A qualitative summary table will be 
provided.
4.1.3.2
Presentation
IPDs will be listed including the deviation type. The number of participants with IPDs will 
be summarized qualitatively by deviation type. The denominator for percentages will be the 
number of participants in the FAS.


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4.1.4
Demographics
4.1.4.1
Definitions and Derivations
Demographics (age, age categories, estimated gestational age for prematurely born infants 
at birth, sex, race and ethnicity) will be listed and summarized for the SAF. 
Age
A participant’s age is captured during randomization in categories “≥ 29 week gestational 
age to < 1 month”, “≥ 1 month to < 1 year”, “1 year”, “2 years”, etc. to “17 years”. These 
categories will be integrated from the IRT into the study EDC system. 
Additionally, for participants younger than 1 year, age in weeks (for age from 1 week to 3 
months) or age in months (for age from four months to less than 1 year) will be captured. If 
the participant is prematurely born, the gestational age at birth in weeks is captured.
Age categories (1, 2, 3, 4, 4a and 4b) defined in Section 3.2 will be summarized by count 
and percent (relative to the number of participants in the analysis set) and age in years 
continuously for participants aged 0 to less than 12 years and 12 years or older separately.
In case transformations of units will need to be done, 4.3 weeks will amount to 1 month.
4.1.4.2
Presentation
The denominator for percentages will be the number of participants in the SAF. Summaries 
and listings will be done by cohort for the SAF.
Quantitative summary of age will be computed for each weight category separately.
A summary of demographics for those participants with a positively adjudicated 
Cardiovascular (CV) event will be presented.
4.1.5
Baseline Characteristics
4.1.5.1
Definitions and Derivations
Participant characteristics at baseline height [cm], weight [kg] and weight category and 
COVID-19 vaccination status at baseline will be listed and summarized.
Quantitative summary of height and weight will be computed by cohort and weight 
category.
4.1.5.2
Presentation
Both listings and summaries will be presented for the SAF.
A summary of demographics for those participants with a positively adjudicated 
Cardiovascular (CV) event will be presented.


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4.1.6
Disease Characteristics
4.1.6.1
Definitions and Derivations
COVID-19 status (Negative/Positive) will be determined at screening for all participants 
and severity for those assigned to Cohorts 2 and 3. A COVID-19 symptom screen is 
performed for occurrence and severity of COVID-19 symptoms (none, mild, moderate, 
severe, unknown). The symptom screen is also performed when Cohort 1 participants 
develop at least one of the below symptoms post Day 1.
!
Symptoms of any duration
o
Fever
o
Shortness of breath
o
Difficulty breathing
!
Symptoms present for 2 or more days
o
Chills
o
Cough
o
Fatigue
o
Muscle aches
o
Body aches
o
Headache
o
New loss of taste
o
New loss of smell
o
Sore throat
4.1.6.2
Presentation
Each symptom will be summarized qualitatively by category (none, mild, moderate, severe, 
unknown). For Cohorts 2 and 3, the summary will include only the screening visit. For 
subjects of Cohort 1, the summary will be calculated for occurrence at any time after Day 1.
4.1.7
Medical History and Concomitant Disease
4.1.7.1
Definitions and Derivations
Disease related medical history (past, ie, started and stopped before treatment and current, 
ie, started before study and ongoing at treatment visit) will be coded using MedDRA 
version 24.1 or higher. 


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4.1.7.2
Presentation
All related medical history will be listed including visit, description of the 
disease/procedure, MedDRA SOC, PT, start date and stop date (or ongoing, if applicable). 
Number of subjects with a history or concomitant condition will be counted by SOC and 
PT and by cohort.
A summary of medical history for those participants with a positively adjudicated 
Cardiovascular (CV) event will be presented.
4.1.8
Prior and Concomitant Medications
4.1.8.1
Definitions and Derivations
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study will be recorded along with:
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
Prior medications are those with start and stop date before the day of treatment.
Concomitant medications are any medications taken at least once between day of treatment 
(inclusively) and end of the follow-up period. Ie, medications with start date prior to Day 1 
and ongoing, medications with start date between Day 1 and day of Visit 6 (or early 
discontinuation).
The duration of the medication will be calculated as:
Duration = (end date/time) – (start date/time) +1
The duration may be presented in hours or days in the listing depending on the applicability 
to the emerging data. For medications with partial or completely missing start date/times
and/or end date/times, the duration will not be calculated.
Prior and concomitant medications will be coded using the AstraZeneca dictionary.
4.1.8.2
Presentation
Prior and concomitant medications will be listed by participant and will include the 
following information: reported name, preferred term, the route of administration, dose, 
frequency, start date/time, duration, and indication.


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The number of participants exposed to a medication will be presented for each occurring 
coded term of prior/concomitant medications. The percentage will be based on the number 
of subjects in each cohort in the SAF.
4.1.9
Study Drug Compliance
4.1.9.1
Definitions and Derivations
No analysis for study drug compliance is planned as the drug is only administered once.
4.1.9.2
Presentation
Not applicable.
4.2
Endpoint Analyses
This section covers details related to the endpoint analyses such as primary, secondary, 
other endpoints. Sensitivity analyses are done by repeating the endpoint analyses using a 
sensitivity analysis set if indicated in Table 2. The analysis sets shown are applicable to the 
tables of the endpoints. Listings may utilize other sets. All endpoint analyses will be 
descriptive qualitative or quantitative summaries.
Table 2: Analysis Endpoints
Objectives
Endpoints
Analysis Set
Primary
To evaluate the serum 
concentrations of 
AZD7442 after a single 
IM or IV dose in pediatric 
participants
Serum concentrations of AZD7442 at 
specified time points during the one-year 
study period when administered as a single 
IM or IV dose
PKS
Serum PK parameters (if data permits): 
Cmax, tmax, t1/2, AUC0-last , AUC0-inf , 
tlast, %AUCext, and:
!
for IM: CL/F, and Vz/F
!
for IV: CL, and Vss
PKS
Model-derived predicted serum AZD7442 
concentrations, Cmax and AUC0-inf
PKS
To evaluate the safety and 
tolerability of AZD7442 
after a single IM or IV 
dose in pediatric 
participants
TEAEs, SAEs, and AESIs (including 
anaphylaxis, injection/infusion site reactions, 
MIS-C).
SAF
Safety laboratory parameters (hematology, 
clinical chemistry, coagulation, and 
urinalysis); 12 lead safety ECG; vital signs 
(BP, pulse rate, tympanic membrane 
temperature, and respiratory rate), and 
physical examination.
SAF
Secondary – All Cohorts


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Objectives
Endpoints
Analysis Set
To evaluate the PD of 
AZD7442 after a single 
IM or IV dose
Titer of SARS-CoV-2 neutralizing 
antibodies
SES
To evaluate the 
immunogenicity profile of 
AZD7442
Incidence of ADA and nAb to AZD7442 in 
serum
ADS1/2/3
Secondary – Cohort 1 (Prophylaxis)
To evaluate the incidence 
of SARS- CoV-2 
infections with or without 
COVID-19 symptoms 
after a single IM or IV 
dose of AZD7442 in 
pediatric participants
Incidence of SARS-CoV-2 infections with 
and without COVID-19 symptoms
SAF, mFAS
Secondary – Cohort 2 and Cohort 3 (Treatment)
To quantify SARS-CoV-2 
viral loads after a single 
IM or IV dose of 
AZD7442 in pediatric 
participants
Change from baseline to Day 8 in viral load 
as measured by qRT-PCR.
SAF
To evaluate the proportion 
of participants with 
progression of COVID-19 
after a single IM or IV 
dose of AZD7442 in 
pediatric participants
Proportion of participants with progression 
of COVID-19 through Day 29
SAF
To evaluate COVID-19 
related death through 90 
days after a single IM or 
IV dose of AZD7442 in 
pediatric participants
The incidence of COVID-19-related death 
occurring after dosing with IMP up to study 
day 90
SAF
Secondary – Cohort 3 (Severe COVID-19)
To evaluate the time to 
sustained recovery from 
severe COVID-19 after a 
single IM or IV dose of 
AZD7442 in pediatric 
participants
Time to sustained recovery (defined as being 
discharged from the index hospitalization, 
followed by being alive and home for 14 
consecutive days)
SAF
Exploratory
To evaluate the 
concentrations of 
AZD7442 in nasal fluid 
after a single IM or IV 
Nasal concentrations of AZD7442 at 
specified time points during the one-year 
study period when administered as a single 
IM or IV dose
SAF


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Objectives
Endpoints
Analysis Set
dose in pediatric 
participants
4.2.1
Primary PK Endpoints
To evaluate the serum concentrations of AZD7442 after a single IM or IV dose in pediatric 
participants, the primary PK endpoints serum AZD7442 concentrations and PK parameters 
derived from these by non-compartmental analysis in accordance with AstraZeneca 
Pharmacokinetic Evaluations in Clinical Trials guideline will be listed and presented 
separately in tabular and graphical form.
Any serum concentrations for AZD7442 will be reported as the individual component 
concentrations AZD8895 and AZD1061 as well as the sum of the two individual 
component concentrations labelled as AZD7442.
The analysis of these endpoints will comprise of descriptive summary statistics stratified by 
cohort, route of administration (IM or IV) and weight categories (1, 2, 3, 4 and all).
For PK parameters other than tmax and tlast, the following descriptive statistics will be 
presented: n, gmean, gSD, 95% CI for the gmean, gCV, arithmetic mean, arithmetic SD, 
median, minimum, and maximum. For tmax and tlast, only n, median, minimum, and 
maximum will be presented.
4.2.1.1
Serum Concentration Data
For AZD7442 mAbs, the serum concentrations for each scheduled time point will be 
summarized based on the PKS. 
A listing of all serum concentration-time data, ie, PK scheduled times, actual sample 
collection times, sample actual relative times (ie, relative to time of administration of the 
IMP), as well as derived sampling time deviations (ie, difference between actual and 
scheduled time) will be presented for all participants in the SAF.
4.2.1.2
Figures for Serum Concentration Data
Individual serum concentration-time data (AZD7442, AZD8895 and AZD1061) will be 
graphically presented on linear and semi-logarithmic scales, for all participants in the PKS . 
Combined individual serum concentration versus actual times will be plotted on both the 
linear and semi-logarithmic scales for all participants in the PKS. Plots will be grouped by 
cohort, route of administration and weight categories. Figures for the gmean (±gSD) serum 
concentration-time data will be presented by cohort, route of administration and weight 
categories (1, 2, 3, 4 and all) on both a linear and semi-logarithmic scale (no gSD presented 
for the semi-logarithmic scale), for all participants in the PKS.


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4.2.1.3
Serum Pharmacokinetic Parameters
All reportable AZD7442, AZD8895 and AZD1061 PK parameters, obtained by 
non-compartmental analysis method, including individual diagnostic and λz-related 
parameters, will be listed for each participant by cohort, route of administration and weight 
categories, based on the PKS. All PK parameters will be summarized based on the PKS.
Table 3: PK Parameters
Parameter
Definition
Calculation
Cmax
Maximum observed serum (peak) 
drug concentration
Clast
Last observed (quantifiable) 
concentration
Ctrough
Observed drug concentration at the 
end of a specified time interval that is 
indication specific
For cohort 2 and 3 (treatment): 
concentration 28 days post-dose
For cohort 1 (prophylaxis): 
concentration 182 days post-dose
tmax
Time [days] to reach peak or 
maximum observed concentration 
following drug administration
AUC(0-92d)
area under the serum concentration-
time curve from time zero to day 92 
Using the linear up/log down 
trapezoidal rule
AUC0-last 
Area under the serum 
concentration-time curve from time 
zero to time of last quantifiable 
concentration
Using the linear up/log down 
trapezoidal rule
AUC0-inf
Area under serum concentration-time 
curve from time zero to infinity
Calculated by AUC(0-t) and then 
extrapolated by Clast/λz to infinity
tlast
Time of last quantifiable serum 
concentration [days]
%AUCext
percentage of AUC extrapolated 
λz
Terminal elimination rate constant
Estimated from linear regression of 
the terminal part of the log 
concentration versus time curve
t½ λz
Half-life associated with terminal 
slope (λz) of a semi-logarithmic 
concentration-time curve (final 
analysis only) [days]
ln 2/λz
MRT
Mean residence time
CL/F (for IM)
Apparent total body clearance of 
drug from serum after extravascular 
administration
Dose/AUC0-inf


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Parameter
Definition
Calculation
Vz/F (for IM)
Volume of distribution (apparent) 
following extravascular 
administration (based on terminal 
phase)
Dose/(λz * AUC0-inf)
CL (for IV)
Total body clearance of drug from 
serum after intravenous 
administration
DoseIV / AUC0-inf
Vss (for IV)
Volume of distribution at steady state 
after intravenous administration
MRT * CL
4.2.1.4
Final Population PK Model
At the end of covariate testing, alternative variance-covariance structures for Ω will be 
evaluated including partial and full block structures. Such a structure is deemed suitable if 
it provides a statistically significant (p < 0.001) improvement in the model OFV and if it 
improves model stability as measured by the condition number and/or a successful 
covariance step. The model that results from this step of the model building process is 
considered the final model.
Further criteria for accepting a model as the final run includes the following:
!
The minimization (for gradient methods) is successful.
!
There are no estimates close to a boundary.
!
Relative standard errors (RSE) of the estimates should be < 30% for fixed-effect 
parameters and < 50% for random-effect parameters.
!
There are no unacceptable trends in goodness-of-fit plots. 
!
The model allows for the goal of the analysis to be met.
!
The parameter shrinkage is acceptable.
!
Population PK parameter estimates from the final model will be presented, 
including bodyweight-adjusted clearance for each bodyweight category (adjusted to 
the mean bodyweight of each weight category). Additionally, the post-hoc 
individual PK parameter estimates (including AUC0-inf) will be summarized. 
4.2.1.5
Evaluation of the Final Population PK Model
Model qualification will be based on criteria including successful numerical convergence, 
acceptable goodness of fit plots with no indication of bias, adequate precision in parameter 
estimates evaluating shrinkage in important parameters (CL, V and Ka parameters). In 
addition, Visual Predictive Checks (VPCs) will be used to evaluate the predictive ability of 
the final model. Where applicable, VPCs will be performed with prediction correction. 
Plots of observed data distributions will be compared with simulated distributions to 
demonstrate the model’s ability to adequately predict the data on which the model was 
based. VPCs will be based on at least 500 simulations and will be stratified by covariates of 


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potential interest. Specifically, VPCs will be stratified by cohort, route of administration 
and weight category.
4.2.1.6
Handling of Missing Data and LLOQ
Individual concentrations below the Lower Limit of Quantification (LLOQ) of the 
bioanalytical assay will be reported as NQ (Not Quantifiable) in the listings with the LLOQ 
defined in the footnotes of the relevant tables, listings and figures. Individual serum 
concentrations that are Not Reportable will be reported as NR and those that are missing 
will be reported as NS (No Sample) in the listings. Serum concentrations that are NQ, NR 
or NS will be handled as follows for the provision of descriptive statistics:
!
Any values reported as NR or NS will be excluded from the summary tables and 
corresponding figures.
!
At a time point where less than or equal to 50% of the concentration values are NQ, 
all NQ values will be set to the LLOQ, and all descriptive statistics will be 
calculated accordingly.
!
At a time point where more than 50% (but not all) of the values are NQ, the gmean, 
gmean ± gSD and geometric coefficient of variation (gCV) will be set to NC. The 
maximum value will be reported from the individual data, and the minimum and 
median will be set to NQ.
!
If all concentrations are NQ at a time point, no descriptive statistics will be 
calculated for that time point. The gmean, minimum, median and maximum will be 
reported as NQ and the gCV and gmean ± gSD as NC.
!
The number of values below LLOQ (n < LLOQ) will be reported for each time
point together with the total number of collected values (n).
Three observations > LLOQ are required as a minimum for a serum concentration or PK 
parameter (eg, Cmax, Clast) to be summarized. Two observations > LLOQ are presented as 
minimum and maximum with the other summary statistics as NC.
For AZD7442 concentration derived as the sum of AZD1061 and AZD8895 concentrations, 
the following cases of < LLOQ or missing hold:


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AZD1061 
concentration
AZD8895 
concentration
Result of AZD7442 
concentration
< LLOQ
< LLOQ
< LLOQ
< LLOQ
XX
XX
YY
< LLOQ
YY
YY
XX
YY + XX
Missing
XX
Missing
YY
Missing
Missing
Missing
Missing
Missing
4.2.1.7
Population PK Analysis
Pharmacokinetic data from all cohorts, routes of administration and age group/weight 
categories will be analysed simultaneously by population PK approaches.
4.2.1.7.1
Dataset to Develop the Population PK Model
A population model based on adult studies are under development. The AZD7442 
population PK structural model will be developed based on serum concentration 
time- profile from the Phase I study (D8850C00001) conducted in healthy adult subjects, 
Phase III studies conducted in adult patients that will include at least studies D8850C00002, 
D8850C00003, D8851C00001 and ACTIV-3 and paediatric PK/PD/safety study 
D8850C00006, when data are available. Individuals will be defined as evaluable for the 
population PK analysis if they have at least one AZD7442 post-dose serum sample that are 
above the lower limit of quantification (LLOQ). Missing data will not be imputed. 
Concentrations below the LLOQ will be handled with the M3 method. Population PK data  
from this study as defined in section 4.2.1.7 will be added to the adult population PK 
dataset. A brief description of the minimum studies to be included in the dataset is provided 
in Table 5
Description of the studies to be included in the population PK analysis. in the
appendix.
4.2.1.7.2
Data analysis methods
The analysis will be carried out according to the FDA and EMA guidances “Guidance for 
Industry: Population Pharmacokinetics” and “Guidance on Reporting the Results of 
Population Pharmacokinetic Analyses”, respectively.
4.2.1.7.3
Covariates to be used in the analysis
This updated Population PK model will account for clinically relevant covariates and will 
include a weight-based allometric scaling of clearance and volume, with fix allometric 
exponents along with an age-based maturation function for clearance. Covariates in the 


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latest adult population PK model will be included such as age, body weight, sex, race and 
eGFR co-morbidity etc. Additional covariates such as body surface area (BSA), body mass 
index (BMI), albumin, anti-drug antibodies, hepatic function, renal function, SARS-CoV-2 
infected or not, viral load, severity of disease, asymptomatic or not, and different co-
morbidities may be evaluated as well if deemed appropriate. Co-linearity among covariates 
will be examined. For pairs with correlation > 80%, a determination will be made as to 
which variable to retain based on factors such as clinical relevance consistency of variable.
The covariates, whenever available, for the population PK analysis will be collected for all 
subjects who have received AZD7442 and had at least 1 valid serum concentrations. The 
assessment of each categorical covariate will be done if enough data are available to 
perform the test, ie if more than 20 subjects or more than 10% of subjects represent this 
subgroup of covariate. Race will be tested and potentially combined if deemed appropriate, 
such as combining all Asian populations. 
Demographics and baseline clinical chemistry covariates in consideration for 
investigation
!
Route of Administration (1 = IV Intra Venous; 2 = IM Intra Muscularly) 
!
Sex (SEX), 1 = males and 0 = females
!
Race (RACE), 1 = White; 2 = Black; 3 = Asian; 4 = Other
!
Age (AGE), year, weeks
!
Body weight (WT), kg
!
BMI (kg/m2)
!
Alanine Aminotransferase (ALT)
!
Aspartate aminotransferase (AST)
!
Estimated Glomerular Filtration Rate (eGFR)
!
Serum Creatinine (SCR)
!
Total Bilirubin (BIL)
!
Serum Albumin
!
Co-morbidity information
!
Viral Load
Covariates that change over time will be considered in order to obtain values that match the 
observation time of the dependent variable, such as age and body weight especially in the 
paediatric patients.
Derived covariates
!
Creatinine clearance (CrCL) (mL/min) is estimated depending on age using the 
following methods:
1. Original or Bedside Schwartz Equations for pediatric patients: 
eGFR  푘∗height in cm
SCR


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(a) Original Schwartz Equation for participants < 1 year of age:
!
k = 0.33 in preemie infants
!
k = 0.45 in term infants to 1 year of age
(b) Bedside Schwartz Equation for participants ≥ 1 to < 12 years of 
age: 
!
k = 0.413
2. Cockcroft and Gault method for adolescent subjects ≥12 years of 
age:
in males
in females
Where SCR = serum creatinine concentration.
!
Baseline Body Mass Index (kg/m²)
BMI = W/H2
Subject population   
!
Healthy volunteers
!
Subjects who do not have COVID-19
!
Subjects with mild/moderate COVID-19 
!
Subjects with severe COVID-19
4.2.1.7.4
Structural Population PK Model and Covariate Model Development
Based on prior experience, a 2-compartment model with fixed standard allometric 
exponents (0.75 for clearances and 1 for volumes) will be evaluated with the inclusion of an 
age-based maturation function for clearance to represent the paediatric population.
Random Effects in the Population PK Model
Inter-individual random effects on the parameters will be introduced and retained if their 
inclusion do not cause model instability and if their estimates are not close to zero. These 
will be modeled assuming a log-normal distribution as given by the following expression: 
휃	  휃 ∗푒
where θki denotes the parameter value for the ith subject, θk denotes the typical parameter value, and ηki
denotes the inter-individual random effect for the ith subject – assumed to have mean of 0 (zero) and 
variance ωk2. 
Collectively, the vector of random effects (across the parameters indexed by k) has the 
covariance matrix Ω. Covariance matrix structures including diagonal and blocked diagonal 
structures will be evaluated after the completion of covariate model building.


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The residual error structure will be assumed to follow an proportional error model 
described by the following: 
푌	  퐶	 ∗1  휀1	
where Yij is the jth observed concentration for the ith subject, Cij is the corresponding predicted 
concentration, and 휀1ij (proportional) is the residual error under the assumption that 휀~N(0, σ2).
The residual error model will be optimized until no trends are visible in residual plots (in 
particular, absolute values of IWRES versus IPRED. 
Covariates in the latest adult population PK model will be included
The latest adult population PK model including covariates will serve as the base model. For 
additional covariate investigation, the covariate selection will be performed using a forward 
addition process followed by backward elimination process. The likelihood ratio test will 
be used to evaluate the significance of incorporating or removing fixed effects into the 
population model based on significance levels set a priori. For forward addition and 
backward elimination, significance levels of 0.01 and 0.001 are utilized, respectively. The 
improvement of the model relative to the base model is compared when each of the 
covariates is added univariately, and the model with the largest improvement is kept for the 
next evaluation step, given that there is an overall statistical significance supporting the 
inclusion of the respective covariate. During the backward elimination process, covariates 
are removed from the model one at a time if their deletion leads to insignificant model 
deterioration. The most insignificant covariate is removed first, and the procedure is 
repeated until no further insignificant covariate relationship is detected.
All continuous covariates are incorporated into the population model using a scaled 
structure based on either the median value of the covariate in the population or a reference 
value for the covariate (eg 70 kg for body weight, as was the case in the previous popPK 
model). This approach ensures that covariate effects are relative to an individual in the 
middle of the population distribution for that covariate. All categorical covariates are 
incorporated into the population model using a proportional structure with either the most 
common level of the covariate being the reference or a level specific to the analysis (eg 
healthy volunteer versus patient). This approach ensures that categorical covariate effects 
are relative to a reference group or category. The mathematical structures of the covariate 
models are shown below:
Continuous
Categorical
푃	  휃 ∗ 푋	
푀푋

푃	  휃 ∗1  휃

where Pki is the population estimate of the parameter Pk for subject i, Xij is the value of continuous 
covariate Xj for subject i, or an indicator variable for subject i for categorical covariate Xj with value 1 
for the nonreference category and 0 for the reference category, M(Xj) is the median of covariate Xj in the 
analysis dataset, θk is the typical value of the parameter Pk, and θj is a coefficient that reflects the effect 
of covariate Xj on the parameter. 
To ensure that the model emerging from the covariate testing process did not neglect any 
important covariate effects, random effects from the final model are plotted versus potential 
covariates and evaluated for residual trends in parameter covariate relationships.


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4.2.1.8
Final Population PK Model
At the end of covariate testing, alternative variance-covariance structures for Ω will be 
evaluated including partial and full block structures. Such a structure is deemed suitable if 
it provides a statistically significant (p < 0.001) improvement in the model OFV and if it 
improves model stability as measured by the condition number and/or a successful 
covariance step. The model that results from this step of the model building process is 
considered the final model.
Further criteria for accepting a model as the final run includes the following:
!
The minimization (for gradient methods) is successful.
!
There are no estimates close to a boundary.
!
Relative standard errors (RSE) of the estimates should be < 30% for fixed-effect 
parameters and < 50% for random-effect parameters.
!
There are no unacceptable trends in goodness-of-fit plots 
!
The model allows for the goal of the analysis to be met.
!
The parameter shrinkage is acceptable.
Population PK parameter estimates from the final model will be presented, including 
bodyweight-adjusted clearance for each bodyweight category (adjusted to the mean 
bodyweight of each weight category). Additionally, the post-hoc individual PK parameter 
estimates (including AUC0-inf) will be summarized.
4.2.1.9
Evaluation of the Final Population PK Model
Model qualification will be based on criteria including successful numerical convergence, 
acceptable goodness of fit plots with no indication of bias, adequate precision in parameter 
estimates evaluating shrinkage in important parameters (CL, V and Ka parameters). In 
addition, Visual Predictive Checks (VPCs) will be used to evaluate the predictive ability of 
the final model. Where applicable, VPCs will be performed with prediction correction. 
Plots of observed data distributions will be compared with simulated distributions to 
demonstrate the model’s ability to adequately predict the data on which the model was 
based. VPCs will be based on at least 500 simulations and will be stratified by covariates of 
potential interest. Specifically, VPCs will be stratified by cohort, route of administration 
and weight category. 
4.2.1.10
Subgroup Analyses
No analyses for a specific subgroup are planned. 
4.2.2
Primary Safety Endpoints
To evaluate the safety and tolerability of AZD7442 after a single IM or IV dose in pediatric 
participants, the primary safety endpoints will be used: TEAE, SAE, AESI, safety 
laboratory parameters, electrocardiogram (ECG), vital signs and physical examinations. 
The analysis of these endpoints will comprise of qualitative or quantitative summary 
statistics.


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All summaries of primary safety endpoints will be based on the SES, listings will be 
created for the SAF.
4.2.2.1
Adverse Events 
Adverse Events will be collected throughout the study from date of informed consent until 
the end of the follow-up. The MedDRA will be used to code the AEs using the latest 
available version.
Treatment-emergent AEs are those AEs with onset date/time at or after dosing.
A listing will cover details for each individual AE including MedDRA SOC, PT, reported 
term, seriousness, start and stop date/time, relatedness to IMP, intensity (mild, moderate, 
severe and CTCAE grade 1-5), actions taken, time from last dose, whether or not leading to 
withdrawal from the study, AESI identification and outcome.
Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
followup), that fulfills one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity
!
Is a congenital anomaly or birth defect
!
Is an important medical event that may jeopardize the participant or may require 
medical treatment to prevent one of the outcomes listed above 
Serious Adverse Events are identified as serious via the eCRF.
Adverse Event of Special Interest
An AESI includes any of the following TEAEs (categorized in the eCRF):
!
Anaphylaxis
!
Hypersensitivity
!
Serious Hypersensitivity Reaction including immune complex disease
!
Injection Site and Infusion Site Reactions (as identified by the investigator in the 
Adverse Event eCRF form. For the summary of injection/infusion site inspection, 
please see Section 4.2.8.2)
!
MIS-C


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!
Thrombotic events, heart failure and cardiac ischemia
Cardiovascular Events
Cardiovascular (CV) AEs are be referred to a CV Event Adjudication Committee. Only 
adjudicated events will be included as AESIs. 
CV events (cardiac ischemia, CV death, heart failure, stroke, thrombotic event) with their 
adjudication results will be listed and summarized:
!
Summary of CV adjudication results
!
time to onset of the event 
!
number of participants/events with positive adjudication
Demographics, baseline characteristics and medical history summaries will be repeated for 
those participants who experienced a positively adjudicated CV event.
Analysis of Adverse Events
The safety of AZD7442 will primarily be assessed by:
!
Incidence of TEAEs through end of study
!
Incidence of SAEs through end of study
!
Incidence of AESIs through end of study
Summaries of these incidences will include the number and percentage of participants 
reporting at least one event with the 95% exact Clopper-Pearson confidence interval for the 
percentage, number of events, exposure adjusted rates and presented by cohort and route of 
administration.
An overview of AEs will be presented for each cohort and route of administration, 
including the number and percentage of participants with any AE and SAEs. Summaries 
will present the relationship to IMP as assessed by the Investigator, seriousness, and deaths. 
4.2.2.2
Laboratory parameters
Hematology, clinical chemistry, coagulation, and urinalysis parameters will be summarized 
quantitatively by count, mean, SD and median, and listed by visit and cohort together with 
their changes from baseline.
The listings will include the following information: test name, date of measurement, 
reference range, result and flags for any measurements that are outside the reference range 
(eg, AstraZeneca, program, or laboratory ranges) and include repeat or unscheduled 
measurements. Clinical laboratory data will be reported in System International units.


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Table 4: Laboratory parameters
Hematology
White blood cell (WBC) count
Neutrophils absolute count
Red blood cell (RBC) count
Lymphocytes absolute count
Hemoglobin (Hb)
Monocytes absolute count
Hematocrit (HCT)
Eosinophils absolute count
Mean corpuscular volume (MCV)
Basophils absolute count
Mean corpuscular hemoglobin (MCH)
Platelets
Mean corpuscular hemoglobin concentration 
(MCHC)
Serum Clinical Chemistry
Sodium
Alkaline phosphatase (ALP)
Potassium
Alanine aminotransferase (ALT)
Urea
Aspartate aminotransferase (AST)
Creatinine
Gamma glutamyl transpeptidase (GGT)
Albumin
Total Bilirubin
Calcium
Unconjugated bilirubin
Phosphate
Conjugated bilirubin
Glucose
Creatine Kinase
Urinalysis
Glucose
Protein
Blood
Microscopy (if positive for protein or blood): RBC, WBC, Casts (Cellular, Granular, Hyaline)
Coagulation
International normalized ratio
Prothrombin Time
Activated partial thrombin time
4.2.2.3
Vital Signs
The results of heart rate, respiration rate, pulse rate, pulse oximetry, BP, and body 
temperature measurements will be listed by participant and time point including the 
date/time of the assessment, changes from baseline and repeat/unscheduled measurements.
Descriptive statistics (count, mean, SD and median) will be presented by time point for 
both observed values and changes from baseline.
4.2.2.4
Physical Examination
A Complete Physical Examination will include, but not be limited to, assessment of height, 
weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems.


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Abnormal baseline/results of the Physical Examination will be documented in medical 
history.
Any new or aggravated clinically relevant abnormal medical physical examination finding 
compared to the baseline assessment will be reported as an AE.
4.2.2.5
ECG
12-lead ECG results will be listed for each participant with overall evaluation by the 
investigator as Normal, Abnormal or Borderline including clinical significance (CS or 
NCS).
These evaluations will be summarized via a shift table showing the frequencies and 
percentages of the baseline evaluation versus the worst post-baseline overall evaluation. 
4.2.2.6
Subgroup Analyses
No analyses for a specific subgroup are planned. 
4.2.3
Secondary Endpoint – All Cohorts
4.2.3.1
SARS-CoV-2 neutralizing antibodies
To evaluate the PD of AZD7442 after a single IM or IV dose, titers of SARS-CoV-2 
neutralizing antibodies will be listed for the SAF and summarized for the SES at each time 
point.
Descriptive statistics for gmean titers (GMT) and geometric mean fold rises will include 
number of participants, gmean, gSD, 95% CI for the gmean, minimum, and maximum.
The GMTs for nAbs will be calculated for all participants in the SES as the antilogarithm of 
Σ(log2 transformed titer/n), ieas the antilogarithm transformation of the mean of the log-
transformed titer with base 2, where n is the number of participants with titer information. 
The gSD for GMT will be calculated as the antilogarithm transformation of the standard 
deviation of the log-transformed titer. The 95% CI will be calculated as the antilogarithm 
transformation of the upper and lower limits for a two-sided CI for the mean of the log-
transformed titers.
Summary tables will be generated by cohort and route of IMP administration, and 
separately by cohort, route of administration and COVID-19 vaccination status at baseline 
(as captured in the eCRF).
4.2.3.2
ADA and nAb to AZD7442 in serum
To evaluate the immunogenicity profile of AZD7442, the incidence of ADA and nAb to 
AZD7442 in serum will be assessed and summarized for the ADS (ie, ADS1 for AZD1061, 
ADS2 for AZD8895 and ADS3 for AZD7442).


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The ADA for AZD7442 will be assessed for the individual agents AZD8895 and AZD1061 
separately. The respective agent’s ADA Evaluable Analysis Set (see Table 1: Analysis sets) 
is to be used for the individual summary. The ADA titer of AZD7442 will be defined as the 
maximum of AZD8895 and AZD1061 titers at each time point.
Serum samples for AZD8895 and AZD1061 ADA assessments will be conducted utilizing 
a tiered approach (screen, confirm, titer), and ADA data will be collected at scheduled 
visits. The ADA results from each sample will be reported as either positive or negative. If 
the sample is positive in the confirmatory assay, the ADA titer will be reported as well. In 
addition, the presence of nAb will be tested for all ADA positive samples in the 
confirmatory assay. The nAb results will consist of a titer result and a subject status 
reported as positive or negative. Both of these results will be taken as received from the 
bioanalytical laboratory. A participant is defined as being ADA-positive if ADA evaluable 
and a positive ADA result in the confirmatory assay is available at any time, including
baseline and all post-baseline measurements; otherwise the participant is defined as ADA 
negative if ADA evaluable. 
Specifically for presentation of AZD7442, ADA-positive to AZD7442 is having a positive 
ADA result to AZD8895 and/or AZD1061 at any time, including baseline and all post-
baseline measurements. ADA-negative is having negative ADA results to all evaluable 
AZD8895 and AZD1061 results at all time, including baseline and all post-baseline 
measurements. Summaries will include only ADA evaluable subjects for the respective 
agent. 
In the evaluation of ADA results to AZD7442, if a component mAb (ieAZD8895 or 
AZD1061) is not ADA evaluable, all results from the component would be treated as 
missing.
ADA sample pos/neg status:
!
For a sample of a particular visit, AZD7442 is + for that visit if either AZD1061 
and/or AZD8895 is +
ADA subject pos/neg status:
!
For a subject, AZD7442 is + if either AZD1061 and/or AZD8895 is + at any visit
and if the subject is ADA evaluable for the mAb having the + result
Treatment-induced ADA+:
!
For AZD1061, ADA negative at baseline and ADA positive at ≥1 post-baseline 
assessments with ADA titer ≥80
!
For AZD8895, ADA negative at baseline and ADA positive at ≥1 post-baseline 
assessments with ADA titer ≥160


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!
AZD7442 is treatment-induced ADA+ if either AZD8895 and/or AZD1061 is 
treatment-induced ADA+
Treatment-boosted ADA+:
!
For AZD1061 or AZD8895, Baseline positive ADA titer that was boosted to ≥4 -
fold during study period 
!
AZD7442 is treatment-boosted ADA+ if either AZD8895 and/or AZD1061 is 
treatment-boosted ADA+
Treatment-emergent ADA+:
!
For AZD1061 or AZD8895, either treatment-induced ADA+ or treatment-boosted 
ADA+
!
AZD7442 is treatment- emergent ADA+ if either AZD8895 and/or AZD1061 is 
treatment- emergent ADA+
Persistently ADA+:
!
For AZD1061, participants who are Treatment-emergent ADA positive, and having 
ADA post-baseline positive with ADA titer ≥80 at ≥2 post-baseline assessments 
(with ≥16 weeks between first and last positive) or positive with ADA titer ≥80 at 
last post-baseline assessment
!
For AZD8895, participants who are Treatment-emergent ADA positive, and having 
ADA post-baseline positive with ADA titer ≥160 at ≥2 post-baseline assessments 
(with ≥16 weeks between first and last positive) or positive with ADA titer ≥160 at 
last post-baseline assessment
!
AZD7442 is persistently ADA+ if either AZD8895 and/or AZD1061 is persistently 
ADA+
Transiently ADA+
!
For AZD1061, participants who are Treatment-emergent ADA positive, and having 
at least one post-baseline ADA positive assessment with titer ≥80 and not fulfilling 
the conditions of persistently positive
!
For AZD8895, participants who are Treatment-emergent ADA positive, and having 
at least one post-baseline ADA positive assessment with titer ≥160 and not 
fulfilling the conditions of persistently positive
!
For AZD7442, treatment-emergent ADA positive and not fulfilling the conditions 
of persistently positive.
The number and percentage of AZD7442, AZD8895 and AZD1061 ADA-evaluable 
positive/negative participants in each cohort will be determined. The number of ADA-


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evaluable participants in the cohort will be used as the denominator for percentage 
calculation.
To evaluate the ADA responses to AZD7442, AZD8895 and AZD1061 in serum the 
following analyses will be presented:
!
The date and time of the blood samples collected for assessment of ADAs (samples 
to confirm the presence or absence of anti-AZD7442 (AZD8895 and AZD1061) 
antibodies from pre-dose Day 1 to Day 366, including the titer for samples 
confirmed positive for ADA) and neutralizing Antibodies (nAbs) will be listed. 
Tabulations will be provided for each cohort. The listings will be based on the SAF, 
the tabulations on the ADS1/2/3 respecively.
!
The results of the ADA assessments will be listed for each participant and time 
point. This will include the classification of the response (positive/negative) and the 
measured titers where appropriate. Summary tables will be presented, by weight 
categories, dose, and route of administration as well as overall by route of 
administration, for the number and percentage of participants with positive/negative 
results at each time point, based on the ADS1/2/3 respecively.
In addition, the ADA titers (n, median, minimum, and maximum) will be summarized by 
cohort, route of administration (IM or IV) and weight categories (1 to 4 and all) for all 
participants with a positive confirmatory assay result at each time point; this tabulation will 
include a summary of the highest titer across all time points for each participant.
The impact of ADA on PK, PD, and association with AEs and SAEs will be assessed using 
the graphical and/or tabular displays. 
For each cohort and by route of administration, spaghetti plots of individual PK 
concentration versus time profile by ADA subject status (positive or negative differentiated 
in the figure via color and/or line style) will be produced on semi-logarithmic scale. 
AZD7442, AZD8895 and AZD1061 concentrations will be presented separately.
For each cohort and by route of administration, spaghetti plots of nAb titer versus time 
profile by ADA subject status (positive or negative differentiated in the figure via color 
and/or line style) will be produced on semi-logarithmic scale.
4.2.4
Secondary Endpoint – Cohort 1 (Prophylaxis)
To evaluate the incidence of SARS-CoV-2 infections with or without COVID-19 
symptoms after a single IM or IV dose of AZD7442 in pediatric participants, when a 
participant develops at least one of the COVID-19 qualifying symptoms (see Section 
Disease Characteristics4.1.6), an unscheduled visit is performed and a SARS-CoV-2 RT-
PCR test is performed to confirm the participant is positive. Additionally, to identify 


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symptom-free SARS-CoV-2 infections, serology testing is performed at each visit. Any 
positive SARS-CoV-2 test result indicating infection as well as any symptoms will be 
reported as an AE.
Incidence will be determined by AE and summarized via frequency and proportion of 
participants in the SAF by weight categories and route of administration. SARS-CoV-2 
serology test results will be summarized by count and number of obervations for each 
timepoint and cohort. 
This summary will be repeated for participants in the mFAS.
4.2.5
Secondary Endpoint – Cohort 2 and Cohort 3 (Treatment)
4.2.5.1
Viral load
To quantify SARS-CoV-2 viral loads after a single IM or IV dose of AZD7442 in pediatric 
participants, the log10-transformed observed results and changes from baseline to Day 8 in 
log10-transformed viral load as measured by qRT-PCR will be summarized for the SAF by 
weight categories, dose, and route of administration. 
4.2.5.2
Progression of COVID-19
To evaluate the proportion of participants with progression of COVID-19 after a single IM 
or IV dose of AZD7442 in pediatric participants, the count and percentage of participants in 
the SAF with worsening of COVID-19 will be determined by occurrence of an increase in 
symptom severity (reported through AEs and the weekly contact) one or more new 
symptoms (reported through AEs and the weekly contact) or hospitalization or death related 
to COVID-19 up to day 29 (inclusive). The summary will be tabulated by cohort.
The time to (first) progression [date of AE – date of Day 1 +1] will also be listed and 
summarized via n, median, 1st and 3rd quartile, minimum, and maximum by weight 
categories, dose, and route of administration for the SAF.
4.2.5.3
COVID-19-related death
To evaluate COVID-19-related death through 90 days after a single IM or IV dose of 
AZD7442 in pediatric participants, the incidence of COVID-19-related death occurring 
after dosing with IMP up to study day 90 will be tabulated by cohort, weight categories, 
dose, and route of administration for the SAF. 
All fatal events will be further assessed as part of safety evaluation. Identification of deaths 
related to COVID-19 will be done based on the investigator’s judgement and captured in 
the death details eCRF.


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The time to death [date of death – date of Day 1 +1] will also be listed and summarized via 
n, median, 1st and 3rd quartile, minimum, and maximum by weight categories, dose, and 
route of administration for the SAF.
4.2.6
Secondary Endpoint – Cohort 3 (Severe COVID-19)
4.2.6.1
Recovery
To evaluate the time to sustained recovery from severe COVID-19 after a single IM or IV 
dose of AZD7442 in pediatric participants, the time from Day 1 to discharge from the index 
hospital, if and only if followed by being alive and home for 14 consecutive days, will be 
calculated. In case of multiple discharges due to re-hospitalization, only the first sustained 
recovery will be considered.
The time to sustained recovery will then be calculated as [date of discharge +14 days – date 
of Day 1 +1].
The time to sustained recovery will be listed and summarized via n, median, 1st and 3rd
quartile, minimum, and maximum by weight categories, dose, and route of administration 
for the SAF.
4.2.7
Exploratory Endpoint
To evaluate the concentrations of AZD7442 in nasal fluid after a single IM or IV dose in 
pediatric participants, nasal concentrations of AZD7442 for each visit will be listed and 
summarized quantitatively by cohort, route of administration and weight category (1 to 4 
and all) for the SAF.
4.2.8
Other Endpoints
4.2.8.1
Exposure
The IMP administration dates and times will be listed for each participant together with 
route of administration (IM or IV), planned dose, administered dose and any medication 
errors that might occur during administration, such as interruptions.
The listing will be created for the SAF.
4.2.8.2
Injection/Infusion site Inspection
The results of the inspection of the injection/infusions site will be listed for each participant 
presenting time of inspection, visual inspection of site, palpation of site, experience of 
discomfort and change in experience of discomfort. The results will be tabulated 
qualitatively by route of administration for the SAF.


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4.2.8.3
Potential Hy’s Law
In case of potential Hy’s Law, any liver risk factors, liver signs and symptoms and liver 
diagnostic investigation information will be listed.
5
INTERIM ANALYSIS
For interim analysis, a subset of the above analyses will be performed on all available data 
at time of the data snapshot. A database lock will be performed and all data cleaned for the 
data cut.
The interim analysis will include lisitings, tables and figures including: an overview over 
the patient population (disposition, demographics, baseline characteristics, medical history), 
important protocol deviations, safety information (adverse events, COVID related deaths, 
safety assessments, vital signs), as well as ADA and serum PK concentrations of AZD7442 
combined and its individual components and summaries of COVID-19 symptoms and 
infections, as data permits. Select data may also be presented by cohort, route of 
administration, weight categories or age groups.
The exact subset of the result tables, listings and figures generated for the interim analysis 
will be specified in the mock shells.
6
APPENDICES
Table 5
Description of the studies to be included in the population PK 
analysis.
Study description
Dose & PK sampling
Number 
of 
Subjects 
in PK 
dataset
Phase of 
Study and 
Study 
Population
D8850C00001 
A Phase I Double-blind, Placebo-
controlled Study to Evaluate the Safety, 
Tolerability and
Pharmacokinetics of AZD7442 in Healthy 
Adults.
Dose: 300 mg IM, 300 mg IV, 1000 mg 
IV, 3000 mg IV, 3000 mg IV –co-
administration
PK timepoints: 0, 8 hr, 24 hr, 3, 5, 7, 14, 
30, 60, 90, 150, 210, 270, and 360 days 
post-dose for IM route for both 
AZD8895 and AZD1061
0, 0.25h, 0.5h, 0.75h, 1h, 8 hr, 24h, 3, 5, 
7, 14, 30, 60, 90, 150, 210, 270, and 360 
days post-dose for IV route (AZD8895)
0, 0.75h, 1.5h, 2.25h, 3h, 8 hr, 24 hr, 3, 
5, 7, 14, 30, 60, 90, 150, 210, 270, and 
360 days post-dose for IV route 
(AZD1061)
50
Phase I, 
healthy 
subjects
D8850C00002
A Phase III Randomized, Double-blind, 
Placebo-controlled, Multi-centre Study in 
Adults to Determine the Safety and 
Efficacy of AZD7442, a Combination 
Product of Two Monoclonal Antibodies 
300 mg IM: PK samples collected on 0, 
7, 28, 57, 91, 182, and 365 days  post-
dose
~3333
Phase III, 
pre-exposure 
prophylaxis of
COVID-19 in 
Adults


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Study description
Dose & PK sampling
Number 
of 
Subjects 
in PK 
dataset
Phase of 
Study and 
Study 
Population
(AZD8895 and AZD1061), for Pre-
exposure Prophylaxis of COVID-19.
D8850C00003
A Phase III Randomized, Double-blind, 
Placebo-controlled, Multi-centre Study in 
Adults to Determine the Safety and 
Efficacy of AZD7442, a Combination 
Product of Two Monoclonal Antibodies 
(AZD8895 and
AZD1061), for Post-exposure Prophylaxis 
of COVID-19
300 mg IM: PK samples collected on 0, 
2,5, , 14,28, 57, 91, 182, and 365 days  
post-dose
~750
Phase III, 
Potential -
exposure 
(within 8 days) 
to SARS-
COV-2 in 
Adults
D8851C00001 
A Phase III Randomized, Double-blind, 
Placebo-controlled, Multi-centre Study to 
Determine the Safety and Efficacy of 
AZD7442 for the Treatment of COVID-19 
in Non-hospitalized Adults
ACTIV-3
A Multicenter, Adaptive, Randomized, 
Blinded Controlled Trial of the Safety and 
Efficacy of Investigational Therapeutics
for Hospitalized Patients with COVID-19 
(NIH funded)
D8850C00006
Open-label, Uncontrolled, Single dose 
Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, and Safety of 
AZD7442 in
Pediatric Participants Aged ≥ 29 Weeks 
Gestational Age to < 18 Years
600 mg IM: PK samples collected on 0, 
2, 5, 7, 14, 28, 58, 84, 92, 168, 365 days 
post-dose
600 mg IV: PK samples collected on 
Days 0, 5, 28, and 90
IM and IV; dose is dependent on cohort 
indication and participant’s weight. 
PK samples collected at end of infusion 
(IV only), on either 3, 7, 10 or 14 days 
post-dose, and then 28, 91, 182, and 365 
days post-dose
~850
~100a
Phase III, 
Treatment of 
COVID-19 in 
non-
hospitalized
Adults
Phase II and 
III, Treatment 
of COVID-19 
in hospitalized
Adults
Phase I,
pre-exposure 
prophylaxis, 
Treatment of 
COVID-19 in 
non-
hospitalized
participants, 
Treatment of 
COVID-19 in 
hospitalized 
participants
a The enrolment for this study was stopped early due to FDA feedback, therefore the full analysis set will only contain 46
participants.


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Document Name: d8850c00006-sap-ed-3
Document Title:
Statistical Analysis Plan Edition 3
Document ID:
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