Conditions: COVID-19
Keywords: Post exposure COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1131
Healthy volunteers: no

Brief summary:
This study will assess the efficacy of AZD7442 for the post-exposure prophylaxis of COVID-19 in Adults.

Detailed description:
SARS-CoV-2 is the causative agent of the ongoing COVID-19 pandemic that, as of 29 September 2020, has resulted in a high death toll to date. Unlike the majority of coronaviruses that cause mild disease in humans and animals, SARS-CoV-2 can replicate in the lower respiratory tract to cause acute respiratory distress syndrome and fatal pneumonia. Effective interventions to prevent or treat COVID-19 remain limited in number and clinical experience is limited. Clinical management is limited to supportive care, consequently overwhelming resources of healthcare systems around the world. As a response to the ongoing pandemic, AstraZeneca is developing mAbs to the SARS-CoV-2 S protein. The SARS-CoV-2 spike protein contains the virus's RBD, which enables the virus to bind to receptors on human cells. By targeting this region of the virus's spike protein, antibodies can block the virus's attachment to human cells, and, therefore, is expected to block infection. Amino acid substitutions have been introduced into the antibodies to both extend their half-lives, which should prolong their potential prophylactic benefit, and decrease Fc effector function in order to decrease the potential risk of antibody-dependent enhancement of disease. AZD7442, a combination of 2 of these mAbs (AZD8895 and AZD1061), is being evaluated for administration to prevent and/or treat COVID-19. There is currently one ongoing Phase I study with AZD7442.

Arms:
arm 1: Participants will be randomized in a 2:1 ratio to receive a single dose (× 2 IM injections) of either 300 mg of AZD7442 (n = approximately 750) or saline placebo (n = approximately 375) on Day 1. arm 2: Participants will be randomized in a 2:1 ratio to receive a single dose (× 2 IM injections) of either 300 mg of AZD7442 (n = approximately 750) or saline placebo (n = approximately 375) on Day 1.

Interventions: intervention 1: AZD7442 intervention 2: Placebo
Intervention descriptions: intervention 1: Single dose (× 2 IM injections) of 300 mg of AZD7442 on Day 1. intervention 2: Single dose (× 2 IM injections) of saline placebo on Day 1.

Protocol document:
Prot_004.pdf: 
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Clinical Study Protocol 
IMP
AZD7442
Study Code
D8850C00003
Version
6.0
Date
12 March 2021
A Phase III Randomized, Double-blind, Placebo-controlled, Multi-center 
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
Sponsor Name: 
AstraZeneca AB
Legal Registered Address: 
151, 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s): 
IND number: 150712
EudraCT Number: 2020-004719-28
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: D8850C00003
Amendment Number: Amendment 5 
IMP: AZD7442 
Study Phase: Phase III
Short Title: Phase III Double-blind, Placebo-controlled Study of AZD7442 for Post-exposure 
Prophylaxis of COVID-19 in Adults
Acronym: STORM CHASER: COVID-19 Study to Optimally Reduce Morbidity in Care 
Homes and Sites with Enhanced Risk
Study Physician Name and Contact Information will be provided separately
International Co-ordinating Investigator: Dr. Myron J Levin


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Version 6.0 [Amendment 5]
12 March 2021
Version 5.0 [Amendment 4]
21 December 2020
Version 4.0 [Amendment 3]
16 December 2020
Version 3.0 [Amendment 2]
13 November 2020
Version 2.0 [Amendment 1]
26 October 2020
Original Protocol
07 October 2020
Version 6.0, 12 March 2021
Key amendment and rationale for change:
Highly efficacious vaccines against SARS-CoV-2 are being deployed on a mass scale in the 
participating countries, leading to substantially decreasing attack rates for COVID-19. 
Given that the probability of a participant being exposed to COVID-19 will diminish with 
increased vaccination roll-out, the primary analysis will be conducted 30 days after the 25th
primary endpoint event has been confirmed. This period, of 30 days, allows sufficient time 
for the 25th event to be monitored, and any other events occurring during this time interval 
will also be evaluated. To reflect this change in the timing of the primary analysis the 
interim analysis has been removed. Enrollment will be stopped after the 25th primary 
endpoint event has been confirmed, or after 1125 participants have been randomized, 
whichever comes first.
To provide data on AZD7442 for 5 half-lives, the study has been extended to 15 months 
allowing a safety assessment via a phone call and an optional serum sample for PK, ADA 
and nAb to be added at Day 457. Study endpoints have been adjusted accordingly. 
Synopsis, Sections 1.2 (Schema), 3 (Objectives and Endpoints), 4.1 (Overall Design), 
6.1.1 (Investigational Medicinal Products), 9.4 (Statistical Analysis), 9.4.3.1 (Primary 
Endpoint(s)), Table 1 (Schedule of Activities: Treatment and Follow-up Period – Main 
Study): To provide safety and PK assessments after 5 half-lives, the study has been 
extended from last visit on Day 366 to last visit on Day 457. Endpoints for safety and nAb 
have been adjusted to reflect this additional time point.
Synopsis, Sections 4.1 (Overall Design) and 6.3.1 (Randomization): Caps for Cohorts 1 
and 2, not to exceed 80% of the total participants randomized, have been removed. The 


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recruitment of participants from long term care facilities is no longer feasible with the 
increased availability of vaccinations to this population.
Synopsis, Sections 4.2.1 (Rationale for Study Endpoints): Recent attack rates for 
COVID-19 have substantially decreased and may continue to decrease with availability of 
vaccines to a broader population. To accommodate the changing attack rate the primary 
efficacy analysis will be conducted 30 days after the 25th event has been confirmed. 
Synopsis, Sections 9.1 (Statistical Hypotheses), 9.2 (Sample Size Determination), 9.4 
(Statistical Analyses), 9.4.2.1 (Primary Endpoint), 9.4.5 (Methods for Multiplicity 
Control), 9.5 (Interim Analyses), 9.6 (Data Safety Monitoring Board), and Appendix 
A5 (Committees Structure): The primary endpoint assumptions have been revised to 
reflect changing expectations regarding the attack rate. The primary analysis will be 
conducted 30 days after the 25th primary endpoint has been confirmed. The planned interim 
analysis and related activities have been removed. 
Table 1 (Schedule of Activities: Treatment and Follow-up Period – Main Study): 
During screening the eCRF is already capturing participant ECOG grade and therefore, for 
consistency, Performance Status has been added to Medical History. ECOG performance 
status grades have been included in Appendix G for reference.
Section 2.2.2 (Summary of Nonclinical Pharmacokinetics and Drug Metabolism):
Safety margins updated with emerging data from Phase I study. Results from cynomolgus 
monkey GLP toxicology study updated with week 8 data.
Section 6.5 (Concomitant Therapy) and Table 6 (Permitted, Restricted, and Prohibited 
Medications): Text updated to specify that any COVID-19 vaccination should be recorded 
by the investigator. The table has been updated for clarity and to avoid confusion at study 
sites. Allergy therapy should be allowed if participant has been receiving stable 
desensitization therapy for allergies for at least 30 days prior to Visit 1 and there are no 
anticipated changes during the treatment period. The stipulation that commercial biologics, 
prednisone, or immunosuppressive medications should not be administered on the same day 
of IMP has been removed. Clarification that blood/plasma donation restriction is for one 
year not 5 half-lives. 
Section 8.1.1 (Monitoring COVID-19 Symptoms): To ensure participants with qualifying 
COVID-19 symptoms are included in the Illness Visits as soon as possible, additional 
instructions to inquire about symptoms for the past 7 days have been added to the weekly 
phone calls. Furthermore, the investigators are instructed that participants with symptoms 
must be enrolled on Illness Visits immediately but no later than 3 days of those symptoms 
being identified.


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Previous amendments are summarized in Appendix I.


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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 ................................................................................................ 22
2.2
Background ...................................................................................................... 22
2.2.1
Summary of Nonclinical Pharmacology............................................................ 23
2.2.2
Summary of Nonclinical Pharmacokinetics and Drug Metabolism .................... 24
2.2.3
Summary of Toxicology ................................................................................... 25
2.3
Benefit/Risk Assessment................................................................................... 26
2.3.1
Risk Assessment............................................................................................... 26
2.3.2
Benefit Assessment........................................................................................... 27
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 27
3
OBJECTIVES AND ENDPOINTS................................................................... 28
4
STUDY DESIGN ............................................................................................. 30
4.1
Overall Design.................................................................................................. 30
4.2
Scientific Rationale for Study Design ............................................................... 31
4.2.1
Rationale for Study Endpoints .......................................................................... 31
4.3
Justification for Dose........................................................................................ 31
4.4
End of Study Definition.................................................................................... 32
5
STUDY POPULATION ................................................................................... 32
5.1
Inclusion Criteria .............................................................................................. 32
5.2
Exclusion Criteria ............................................................................................. 34
5.3
Lifestyle Considerations ................................................................................... 35
5.3.1
Lifestyle Restrictions ........................................................................................ 36
5.3.1.1
Women of Non Childbearing Potential.............................................................. 36
5.3.1.2
Women of Childbearing Potential ..................................................................... 36
5.3.1.3
Male Participants .............................................................................................. 37
5.4
Screen Failures ................................................................................................. 37
6
STUDY INTERVENTION............................................................................... 38
6.1
IMP(s) Administered ........................................................................................ 38
6.1.1
IMP .................................................................................................................. 38
6.2
Preparation/Handling/Storage/Accountability ................................................... 39


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6.2.1
Dose Preparation and Administration Instructions............................................. 39
6.2.1.1
Investigational Product Inspection .................................................................... 40
6.2.1.2
Dose Calculation............................................................................................... 40
6.2.1.3
Dose Preparation Steps ..................................................................................... 40
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 41
6.3.1
Randomization.................................................................................................. 41
6.3.2
Blinding............................................................................................................ 42
6.3.3
Procedures for Unblinding ................................................................................ 42
6.4
IMP Compliance............................................................................................... 42
6.5
Concomitant Therapy........................................................................................ 42
6.5.1
COVID-19 Vaccine .......................................................................................... 44
6.6
Dose Modification ............................................................................................ 45
6.7
Intervention After the End of the Study............................................................. 45
7
DISCONTINUATION OF IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 45
7.1
Discontinuation of Study IMP........................................................................... 45
7.2
Participant Withdrawal from the Study ............................................................. 45
7.3
Lost to Follow-up ............................................................................................. 46
7.4
Study Suspension/Early Termination ................................................................ 47
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 47
8.1
Efficacy Assessments........................................................................................ 48
8.1.1
Monitoring COVID-19 Symptoms.................................................................... 48
8.1.2
Severe or Critical Criteria ................................................................................. 49
8.1.3
Illness Visits ..................................................................................................... 50
8.1.4
SARS-CoV-2 Testing and Other Virology Assessments.................................... 50
8.1.5
Digital Health Device ....................................................................................... 50
8.1.6
Illness e-Diary .................................................................................................. 51
8.2
Safety Assessments........................................................................................... 51
8.2.1
Physical Examinations...................................................................................... 51
8.2.2
Vital Signs........................................................................................................ 52
8.2.3
Electrocardiograms........................................................................................... 52
8.2.4
Clinical Safety Laboratory Assessments............................................................ 52
8.2.4.1
Females Only.................................................................................................... 54
8.2.5
Injection Site Inspection.................................................................................... 54
8.2.5.1
Monitoring After IMP Administration............................................................... 54
8.3
Adverse Events and Serious Adverse Events..................................................... 55
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 55
8.3.2
Follow-up of AEs and SAEs ............................................................................. 55
8.3.3
Causality Collection.......................................................................................... 57
8.3.4
Adverse Events of Special Interest.................................................................... 57
8.3.5
Medically Attended Adverse Events ................................................................. 57
8.3.6
Adverse Events Based on Signs and Symptoms ................................................ 58
8.3.7
Adverse Events Based on Examinations and Tests............................................ 58


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8.3.8
Hy’s Law.......................................................................................................... 58
8.3.9
Reporting of Serious Adverse Events................................................................ 59
8.3.10
Pregnancy......................................................................................................... 59
8.3.10.1
Maternal Exposure............................................................................................ 60
8.3.10.2
Paternal Exposure............................................................................................. 60
8.3.11
Medication Error............................................................................................... 61
8.3.12
Device Deficiencies.......................................................................................... 61
8.4
Overdose .......................................................................................................... 61
8.5
Human Biological Samples............................................................................... 62
8.5.1
Pharmacokinetics Assessments ......................................................................... 62
8.5.1.1
Determination of Drug Concentration ............................................................... 63
8.5.2
Immunogenicity Assessments ........................................................................... 63
8.5.2.1
Anti-drug Antibody Assessments...................................................................... 63
8.5.2.2
SARS-CoV-2 Serology Assessments ................................................................ 64
8.5.2.3
Assessment of Mucosal Responses ................................................................... 64
8.5.2.4
Additional Serum Immunogenicity ................................................................... 64
8.5.3
Pharmacodynamics........................................................................................... 64
8.5.3.1
SARS-CoV-2 Neutralizing Antibody Assessments ........................................... 64
8.6
Human Biological Sample for Biomarkers........................................................ 64
8.6.1
Collection of mandatory samples for biomarker analysis................................... 64
8.6.1.1
Virologic Assessments...................................................................................... 65
8.6.1.2
Assessment of Viral Shedding .......................................................................... 65
8.6.2
Other Study-related Biomarker Research .......................................................... 65
8.7
Medical Resource Utilization and Health Economics........................................ 65
9
STATISTICAL CONSIDERATIONS............................................................... 65
9.1
Statistical Hypotheses....................................................................................... 65
9.2
Sample Size Determination............................................................................... 66
9.3
Populations for Analyses .................................................................................. 66
9.4
Statistical Analyses........................................................................................... 67
9.4.1
General Considerations..................................................................................... 68
9.4.2
Efficacy ............................................................................................................ 69
9.4.2.1
Primary Endpoint.............................................................................................. 69
9.4.2.2
Secondary Endpoint(s)...................................................................................... 70
9.4.2.3
Exploratory Endpoint(s).................................................................................... 70
9.4.3
Safety ............................................................................................................... 70
9.4.3.1
Primary Endpoint(s).......................................................................................... 70
9.4.3.2
Other Safety Endpoint(s) .................................................................................. 71
9.4.4
Pharmacokinetic and Anti-drug Antibody......................................................... 71
9.4.4.1
Pharmacokinetic ............................................................................................... 71
9.4.4.2
Anti-drug Antibody .......................................................................................... 71
9.4.5
Methods for Multiplicity Control ...................................................................... 72
9.4.6
Sensitivity Analyses.......................................................................................... 72
9.4.7
Subgroup Analyses ........................................................................................... 72
9.5
Interim Analyses............................................................................................... 72


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9.6
Data Safety Monitoring Board .......................................................................... 72
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 73
11
REFERENCES............................................................................................... 116
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 14
LIST OF TABLES
Table 1
Schedule of Activities: Treatment and Follow-up Period – Main Study.... 16
Table 2
Schedule of Activities: Illness Visits (Participants with Qualifying 
Clinical Symptoms) ................................................................................. 19
Table 3
Safety Margin Prediction for the Dose Levels in Phase I Study 
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Table 4
Objectives and Endpoints......................................................................... 28
Table 5
Highly Effective Methods of Contraception............................................. 34
Table 6
Investigational Products........................................................................... 38
Table 7
Permitted, Restricted, and Prohibited Medications ................................... 43
Table 8
COVID-19 Qualifying Symptoms............................................................ 48
Table 9
WHO Clinical Progression Scale ............................................................. 49
Table 10
Injection Site Inspection .......................................................................... 54
Table 11
Populations for Analysis .......................................................................... 67
Table 12
An Approach to Management of Anaphylactic, Hypersensitivity, and 
Post-injection Reactions........................................................................... 94
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 74
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 80
Appendix C
Handling of Human Biological Samples .................................................. 85
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 87
Appendix E
Anaphylaxis............................................................................................. 93


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Appendix F
e-Diary .................................................................................................... 97
Appendix G
ECOG Performance Status..................................................................... 105
Appendix H
Abbreviations ........................................................................................ 106
Appendix I
Protocol Amendment History................................................................. 109


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase III Randomized, Double-blind, Placebo-controlled, Multi-center 
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
Short Title: A Phase III Double-blind, Placebo-controlled Study of AZD7442 for 
Post-exposure Prophylaxis of COVID-19 in Adults
Rationale: AZD7442, a combination of 2 mAbs (AZD8895 and AZD1061) is being evaluated 
for the prevention or treatment of Coronavirus Disease 2019 (COVID-19). This Phase III 
study will assess the efficacy of AZD7442 for the post-exposure prophylaxis of COVID-19 in 
Adults.
Objectives and Endpoints:
Objective
Estimand Description/Endpoint
Primary
To estimate the efficacy of a single IM 
dose of AZD7442 compared to placebo 
for the prevention of COVID-19 
Population: Full analysis set
Endpoint: A binary response, whereby a participant is defined as a 
COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurs post dose of IMP and prior to Day 183.
Intercurrent events: For participants who become unblinded to properly 
consider vaccination for COVID-19, take COVID-19 vaccine or other 
COVID-19 preventive product prior to having met the criteria for the 
primary efficacy endpoint, data will be collected and analyzed regardless 
(ie, intercurrent events will be handled using treatment policy strategy).
Summary measure: Prophylactic efficacy, calculated as 1-relative risk. 
(Relative risk is the incidence of infection in the AZD7442 group relative 
to the incidence of infection in the control group).
To assess the safety and tolerability of a 
single IM dose of AZD7442 compared to 
placebo
AEs, SAEs, MAAEs, and AESIs post dose of IMP.
Key Secondary
To estimate the efficacy of a single IM 
dose of AZD7442 compared to placebo 
Population: Full analysis set
Endpoint: The incidence of SARS-CoV-2 RT-PCR-positive severe or 
critical symptomatic illness occurring after dosing with IMP.


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Objective
Estimand Description/Endpoint
for the prevention of severe or critical 
symptomatic COVID-19
Intercurrent events: For participants who become unblinded to properly 
consider vaccination for COVID-19, take COVID-19 vaccine or other 
COVID-19 preventive product prior to having met the criteria for this 
endpoint, data will be collected and analyzed regardless (ie, intercurrent 
events will be handled using treatment policy strategy).
Secondary
To estimate the efficacy of a single IM 
dose of AZD7442 compared to placebo 
for the prevention of SARS-CoV-2 
infection
The incidence of participants who have a post-treatment response 
(negative at baseline to positive at any time post-baseline) for SARS-
CoV-2 nucleocapsid antibodies.
To estimate the efficacy of a single IM 
dose of AZD7442 compared to placebo 
for the prevention of COVID-19-related 
death
The incidence of COVID-19-related death occurring after dosing with 
IMP.
To estimate the efficacy of a single IM 
dose of AZD7442 compared to placebo 
for the prevention of all-cause mortality
The incidence of all-cause mortality occurring after dosing with IMP.
To assess the pharmacokinetics of 
AZD7442 administered as a single dose 
of 300 mg IM
Serum AZD7442 concentrations.
PK parameters if data permit.
To evaluate ADA responses to AZD7442 
in serum
Incidence of ADA to AZD7442 in serum.
ADA, antidrug antibody; AE, adverse event; AESI, adverse event of special interest; COVID-19, coronavirus 
disease 2019; PK, pharmacokinetic; IM, intramuscular; IMP, investigational medicinal product; MAAE, 
medically attended adverse event; RT-PCR, reverse transcriptase polymerase chain reaction; SAE, serious 
adverse event; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2.
For Exploratory objectives, see Section 3.
Overall Design:
This is a Phase III, randomized, double-blind, placebo-controlled, multi-center study assessing 
the safety and efficacy of a single dose of AZD7442 (× 2 IM injections) compared to placebo 
for the prevention of COVID-19. Approximately 100 sites will participate in this study.
Participants will be adults ≥18 years of age with potential exposure, within 8 days, to a 
specific identified individual with laboratory-confirmed SARS-COV-2 infection, symptomatic 
or asymptomatic, who are therefore at appreciable risk of imminently developing COVID-19, 
based on available risk assessment at time of enrollment (see Section 5.1). Participants will be 
enrolled into one of 2 cohorts:

Cohort 1: Adults ≥ 60 years of age, living in long-term care facilities. In this context, 
long-term care facilities include skilled nursing facilities, assisted living facilities, and 
independent living facilities for senior adults. 


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
Cohort 2: Other adults ≥18 years of age with potential exposure to a specific identified 
individual with laboratory-confirmed SARS-COV-2 infection. Such individuals may 
include, but are not limited to, those living in institutional residences (military lodging, 
dormitories, etc.), household contacts, health care workers, long-term care facility 
workers, and workers in occupational or industrial settings in which close contact is 
common. 
The first 15 participants (Sentinel Cohort) will undergo safety monitoring for 4 hours post 
IMP administration before dosing further participants. The next 85 participants will undergo 
safety monitoring for 2 hours post IMP administration and, if no hypersensitivity reactions are 
observed, the remaining participants will undergo safety monitoring for one hour post IMP 
administration. Should hypersensitivity reactions be observed in the first 100 participants, all 
participants will be monitored for safety for at least 2 hours post IMP administration. 
Approximately 1125 participants will be randomized in a 2:1 ratio to receive a single dose (× 
2 IM injections) of either 300 mg of AZD7442 (n = approximately 750) or saline placebo 
(n = approximately 375) on Day 1. 
Following a screening evaluation, on the same day participants will receive a single dose (× 2 
IM injections) of IMP. After administration of the dose of IMP on Day 1, participants will 
undergo follow-up until Day 457. 
Disclosure Statement: This is a parallel-group preventive study with 2 arms that 
is double-blind.
Number of Participants: Enrollment of up to 1125 participants is planned. Enrollment will 
be stopped after the 25th primary endpoint event has been confirmed, or after 1125 participants
have been randomized, whichever comes first.
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, 
but are not randomly assigned in the study, are considered ‘screen failures’. 
Intervention Groups and Duration: Participants will be randomized in a 2:1 ratio to receive 
one single 300 mg dose of AZD7442 (divided in 2 sequential IM injections, one for each mAb 
component) or saline placebo. Investigational medicinal product will be administered on 
Day 1, and participants will be monitored until Day 457.
Data Safety Monitoring Board: An independent DSMB will review available safety and
efficacy data after the first 100 participants have been dosed, or after 4 weeks from first 
participant dosed, whichever comes first. Enrollment will not be paused pending the DSMB’s 


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review. Thereafter, the DSMB will review available safety and efficacy data monthly until the 
study is stopped. During the study, the benefit/risk assessment will be continuously monitored 
by the DSMB to ensure that the balance remains favorable.
If the study is suspended and does not proceed following evaluation of cumulative safety data 
from the first 100 participants enrolled, or after 4 weeks from first participant dosed, a 
protocol amendment will be submitted to Health Authorities.
Statistical Methods
Primary Endpoint: The primary efficacy endpoint is a binary response, whereby a 
participant is defined as a COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurs post dose of IMP and prior to Day 183.
Sample Size: Approximately 1125 participants will be randomized in a 2:1 ratio to receive a 
single IM dose of AZD7442 (divided into 2 sequential injections, one for each mAb 
component) (the active group, n = approximately 750) or saline placebo (divided into 2 
sequential injections) (the control group, n = approximately 375) on Day 1.
The sample size calculations are based on the primary efficacy endpoint and were derived 
following a modified Poisson regression approach (Zou 2004). The primary efficacy analysis 
will be conducted 30 days after the 25th primary endpoint has been confirmed. The study will 
have approximately 90% power to demonstrate that the lower bound of the 2-sided 95% CI for 
efficacy is greater than zero, assuming an attack rate of 4.5% in the placebo group and true 
efficacy of 75% (equating to an attack rate of 1.1% in the AZD7224 group). All participants 
will be followed for the entire duration of the study. 
1.2
Schematic
Figure 1
Study Design
a
Primary analysis to be conducted 30 days after the 25th event is observed.
Note: An independent DSMB will review available safety and efficacy data after the first 100 participants have 
been dosed, or after 4 weeks from first participant dosed, whichever comes first. Enrollment will not be paused 
pending the DSMB’s review.


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1.3
Schedule of Activities


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Table 1
Schedule of Activities: Treatment and Follow-up Period – Main Study 
Procedure
Screen and
Randomization
Follow-up Period
Early 
Discontinua
tion visit
For 
details, 
see 
section:
Day
1
8
29
58
92
183
366
457
Window (days)
NA
± 3
± 3
± 3
± 5
± 10
± 15
± 15
Informed consent
X (predose)
5.1
Assignment SID number
X (predose)
5.1
Confirmation of identified index SARS-
COV-2 case to which participant could 
have had potential exposure within 8 
days prior to Day 1a
X
Verify eligibility criteria
X (predose)
5.1
Demographics and Risk Categorization
X (predose)
5.1
Medical history and Functional Statusb
X (predose)
Complete physical examination, 
including height and weight
X (predose)
8.2.1
Targeted physical examination
X
X
X
X
X
X
X
8.2.1
Vital signs (including pulse oximetry)
X (pre and post 
dose)c
X
X
X
X
X
X
X
8.2.2
Triplicate 12-lead ECG 
X (predose)
X
X
8.2.3
Pregnancy test - urine (WOCBP only)d
X (predose)
Xd
Xd
Xd
Xd
Xd
Xd
Xd
8.2.4.1
FSH (suspected postmenopausal 
women, <50 years)e
X (predose)
8.2.4.1
Completed rapid point of care SARS-
CoV-2 serology testing using serum 
sample
X (predose)
8.5.2.2
Serum chemistry
X (predose)f
X
X
X
X
X
X
X
8.2.4


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Table 1
Schedule of Activities: Treatment and Follow-up Period – Main Study 
Procedure
Screen and
Randomization
Follow-up Period
Early 
Discontinua
tion visit
For 
details, 
see 
section:
Day
1
8
29
58
92
183
366
457
Window (days)
NA
± 3
± 3
± 3
± 5
± 10
± 15
± 15
Hematology
X (predose)f
X
X
X
X
X
X
X
8.2.4
Urinalysis
X (predose)f
X
X
X
X
X
X
X
8.2.4
Coagulation
X (predose)f
8.2.4
Concomitant medications
X (predose)
X
X
X
X
X
X
X
6.5
IMP administration
X
6.1
Efficacy assessments
Weekly telephone/email/text contacts -
monitoring for COVID-19 qualifying 
symptomsg
8.1.1
NP swab for SARS-CoV-2 RT-PCR 
(central laboratory)
X (predose)
8.6.1.1
Serum sample for SARS-CoV-2 
serology (anti-nucleocapsid) testing 
X (predose)
X
X
X
X
X
X
X
8.5.2.2
Pharmacokinetics, pharmacodynamics, and ADA assessments
Serum sample for AZD7442 
pharmacokinetic assessment
X(predose)
X
X
X
X
X
X
X
[optional]
X
8.5.1
Serum sample for AZD7442 ADA 
assessment
X
(predose)
X
X
X
X
X 
[optional]
X
8.5.2.1
Serum sample for SARS-CoV-2 nAbs
assessment
X
(predose)
X
X
X
X
X
X
X 
[optional]
X
8.5.3.1
Serum sample exploratory biomarkers 
X
(predose)
X
X
X
X
X
X
X
8.5.2.4


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Table 1
Schedule of Activities: Treatment and Follow-up Period – Main Study 
Procedure
Screen and
Randomization
Follow-up Period
Early 
Discontinua
tion visit
For 
details, 
see 
section:
Day
1
8
29
58
92
183
366
457
Window (days)
NA
± 3
± 3
± 3
± 5
± 10
± 15
± 15
Nasal adsorption for PK exploratory 
assessmentsh
X
X
X
X
X
X
X
8.5.2.3
Safety assessments
Check injection sitesi
X
8.2.5
AEsj
Xl
X
8.3
SAEs, MAAEs, and AESIsj
Xl
X
8.3
Telephone contact for safety 
monitoringk
8.3
a
See Inclusion criterion 2 for further details: Long-term care facilities; industrial setting; military setting; health care facility; university; college dormitories; 
household contact; other high-density inter-personal proximity. Exposure within 8 days should be confirmed, and investigator attestation that they were able 
to confirm the details of the potential exposure is required. Confirmation should be made either directly through the participant’s medical record or via 
official documentation from another source attesting to exposure (eg, letter from employer, notification from local health department, etc). A verbal/written 
statement from the participant, without independent substantiation, is not acceptable.
b
ECOG performance recorded at baseline only (Appendix G).
c
Vitals signs should be performed predose and 15 minutes (± 5 minutes) after both injections are complete.
d
If urine tests positive or indeterminate, a quantitative serum β-hCG will be performed for confirmation.
e
FSH will be analyzed at the screening visit to confirm postmenopausal status only in women < 50 years of age who have been amenorrhoeic for ≥ 12 
months. Until FSH is documented to be within menopausal range, the participant is to be considered of childbearing potential. For women aged ≥ 50 years, 
postmenopausal is defined as having a history of ≥ 12 months amenorrhea prior to randomization, without an alternative cause, following cessation of 
exogenous sex-hormonal treatment.
f
Baseline measure not part of eligibility assessment.
g
Weekly contact with participants to assess if they have qualifying symptoms.
h
When test supplies are available sampling should be performed. 
i
Perform immediately, 30 minutes (± 10 minutes) after both injections are complete, and prior to participant release.
j
The first 15 participants will be monitored for safety for 4 hours after IMP administration, the following 85 participants will be monitored for 2 hours after 
IMP administration, and the remaining participants for one hour after IMP administration. 
k
For the first 4 days after IMP administration, the first 15 participants will be contacted daily for safety monitoring followed by weekly contact. All other 
participants will be contacted weekly. 


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l
At Day 457 AE/SAE/MAAE/AESI assessment may be made by telephone. 
Ab, antibody; ADA, antidrug antibody; AE, adverse event; AESI, adverse event of special interest; β-hCG, beta-human chorionic gonadotropin; MAAE, 
medically attended adverse event; NA, not applicable; nAb, neutralizing antibody; RT-PCR, reverse transcriptase polymerase chain reaction; SAE, serious 
adverse event; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2; US, United States; WOCBP, women of childbearing potential.
Table 2
Schedule of Activities: Illness Visits (Participants with Qualifying Clinical Symptoms)
Procedure a
Site Visit
Home/Self Collection by Participant
Site Visit for SARS-CoV-2 Positive 
Participants Onlyc
For 
details, see 
section:
Dayb
IL-D1
IL-D3
IL-D5
IL-D8
IL-D11
IL-D14
IL-D21
IL-D28
Window (days)
NA
± 1
± 1
± 2
± 2
± 2
± 2
± 2
Medical history 
X
X
X
X
Brief physical examination
X
X
X
X
8.2.1
Vital signs (including pulse oximetry)
X
X
X
X
8.2.2
Triplicate 12-lead ECG 
X
8.2.3
Concomitant medication
6.5
Efficacy assessments
Digital health deviced
8.1.5
Symptoms associated with COVID-19
(recorded daily by participant in Illness 
e-Diary)e
8.1.6
Self-collected anterior nasal swab for viral 
sheddinge
X
X 
X
X
X
X
X
X
8.6.1.2
Nasopharyngeal swab
SARS-CoV-2 RT-PCR (local laboratory)f
X
8.6.1.1
SARS-CoV-2 RT-PCR (central laboratory), 
sequencing, respiratory panel
X
X
X
X
8.6.1.1
Immunogenicity, Pharmacodynamics, and Pharmacokinetics


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Table 2
Schedule of Activities: Illness Visits (Participants with Qualifying Clinical Symptoms)
Procedure a
Site Visit
Home/Self Collection by Participant
Site Visit for SARS-CoV-2 Positive 
Participants Onlyc
For 
details, see 
section:
Dayb
IL-D1
IL-D3
IL-D5
IL-D8
IL-D11
IL-D14
IL-D21
IL-D28
Window (days)
NA
± 1
± 1
± 2
± 2
± 2
± 2
± 2
Serum sample for AZD7442 PK assessment
X
X
X
8.5.1
Serum sample for SARS-CoV-2 nAbs 
assessment
X
X
X
8.5.3.1
Nasal adsorption for SARS-CoV-2 mucosal 
responses and exploratory assessmentsg
X
X
X
8.5.2.3
Serum sample for exploratory assessments
X
X
X
8.5.2.4
Safety assessments
SAEs, MAAEs, and AESIs
8.3
Telephone contact for safety monitoring
X
X
Coagulation
X
X
X
8.2.4
a
Following availability of the SARS-CoV-2 RT-PCR results, only participants who test positive will continue with the Illness Visits, including any home 
collection requirements. Participants who test negative for SARS-CoV-2 will be instructed to stop all Illness Visit assessments and return the digital health 
device. 
b
To distinguish between illness episodes the visits will be labelled as follows. For the first episode illness visit day 1 = 1IL-D1, Illness Visit Day 3 = 1IL-
D3 etc, and for the second episode 2IL-D1, 2IL-D3 and so on as applicable.
c
Where supported, home or mobile visits by study staff may substitute for site visits.
d
Digital health device: A wearable health device with biosensor. Measures will include skin temperature, heart rate, respiratory rate, blood oxygen 
saturation, and physical activity.
e
Participants unable to self-collect are excluded from this assessment.
f
If an immediate test result is not available the participant should continue with the Illness Visit schedule until their result has been confirmed. Only if the 
local laboratory result is unavailable should the central laboratory result be used.
g
When test supplies are available sampling should be performed. 
Note: The Illness Visit schedule is to be performed in addition to the Main Study Visit schedule, where visits coincide all assessments from the Main Study 
schedule and Illness Visit schedule should be performed.


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Table 2
Schedule of Activities: Illness Visits (Participants with Qualifying Clinical Symptoms)
Procedure a
Site Visit
Home/Self Collection by Participant
Site Visit for SARS-CoV-2 Positive 
Participants Onlyc
For 
details, see 
section:
Dayb
IL-D1
IL-D3
IL-D5
IL-D8
IL-D11
IL-D14
IL-D21
IL-D28
Window (days)
NA
± 1
± 1
± 2
± 2
± 2
± 2
± 2
AESI, adverse events of special interest; COVID-19, coronavirus disease 2019; D, day; ECG, electrocardiogram; MAAE, medically attended adverse event; 
NA, not applicable; nAb, neutralizing antibody; NP, nasopharyngeal; PK, pharmacokinetic; RT-PCR, reverse transcriptase polymerase chain reaction; SAE,
serious adverse event; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2.


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2
INTRODUCTION
SARS-CoV-2 is the causative agent of the ongoing COVID-19 pandemic that, as of 
29 September 2020, has resulted in 33,206,004 confirmed cases of COVID-19, including 
999,239 deaths, reported to WHO (WHO 2020). Unlike the majority of coronaviruses that 
cause mild disease in humans and animals, SARS-CoV-2 can replicate in the lower respiratory 
tract to cause acute respiratory distress syndrome and fatal pneumonia. This is also a 
characteristic of the genetically-similar SARS-CoV and the more distantly related 
MERS-CoV, both of which were responsible for prior outbreaks in 2002 to 2003 and 2012, 
respectively (Gorbalenya et al 2020).
Effective interventions to prevent or treat COVID-19 remain limited in number and clinical 
experience is limited. Clinical management is limited to supportive care, consequently 
overwhelming resources of healthcare systems around the world.
As a response to the ongoing pandemic, AstraZeneca is developing mAbs to the SARS-CoV-2 
S protein. The SARS-CoV-2 spike protein contains the virus’s RBD, which enables the virus 
to bind to receptors on human cells. By targeting this region of the virus's spike protein, 
antibodies can block the virus’s attachment to human cells, and, therefore, is expected to block 
infection. Amino acid substitutions have been introduced into the antibodies to both extend 
their half-lives, which should prolong their potential prophylactic benefit, and decrease Fc 
effector function in order to decrease the potential risk of antibody-dependent enhancement of 
disease.
AZD7442, a combination of 2 of these mAbs (AZD8895 and AZD1061), is being evaluated 
for administration to prevent and/or treat COVID-19. There is currently one ongoing Phase I 
study with AZD7442.
For further details, please refer to the AZD7442 IB.
2.1
Study Rationale
AZD7442, a combination of 2 mAbs (AZD8895 and AZD1061) is being evaluated for 
administration to prevent or treat COVID-19. This Phase III study will assess the efficacy of 
AZD7442 for the post-exposure prophylaxis of COVID-19 in adults.
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 


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infection via different receptors (Li 2016). 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 
2020). It is the seventh coronavirus known to cause human infections and the third known to 
cause severe disease after SARS-CoV and MERS-CoV.
2.2.1
Summary of Nonclinical Pharmacology
AZD7442 neutralizes SARS-CoV-2 by mAbs AZD8895 and AZD1061 binding to unique, 
non-overlapping epitopes on the RBD of the viral S protein, which is responsible for receptor 
binding and cellular fusion. Both AZD8895 and AZD1061 bind the RBD with nanomolar 
affinity and are individually capable of sterically blocking the virus from engaging its cellular 
receptor human angiotensin-converting enzyme-2. This binding translates to potent inhibition 
of SARS-CoV-2 infection by AZD7742 in vitro, with half-maximal inhibitory concentration 
(IC50) values between 10 and 26 ng/mL. 
A combination mAb approach, like AZD7442, is advantageous because SARS-CoV-2 is an 
RNA virus capable of mutating, and the combination provides redundancy in case a viral 
mutation confers resistance to one of the mAbs. In vitro studies confirm that viruses with 
reduced susceptibility to AZD8895 or AZD1061 individually remain susceptible to the 
combination. The combination also demonstrated synergy in in vitro neutralization assays. 
The Fc region of both AZD8895 and AZD1061 has been engineered to include YTE and TM 
amino acid substitutions to extend t1/2 and reduce Fc effector function, respectively. These 
substitutions resulted in an expected increase in binding affinity to FcRn at pH 6.0 and 
reduced binding to FcγR and complement proteins involved in antibody-dependent 
cell-mediated cytotoxicity, complement-dependent cytotoxicity, and other antibody-directed 
effector functions. Importantly, incorporation of these YTE and TM substitutions did not alter 
the potency of AZD7442 in vitro. 
The parental mAbs of AZD8895 (COV2-2196) and AZD1061 (COV2-2130), which lack Fc 
substitutions, provided protection from SARS-CoV-2 infection in vivo. Prophylactic 
administration of the mAbs alone or in combination, at a 10 mg/kg dose, resulted in attenuated 
weight loss, as well as reduced viral RNA levels in the lungs of mice challenged with 
SARS-CoV-2. Similarly, reduced viral RNA levels were measured in the lungs of mice 
when mAbs were administered 12 hours after infection at a 20 mg/kg dose. The reduction in 
viral titers correlates with a reduction in proinflammatory cytokines and alveolar damage in 
the lungs of infected mice. 
Finally, intravenous administration of AZD7442 protected rhesus macaques from 
SARS-CoV-2 infection. NHPs that received an isotype mAb three days prior to SARS-CoV-2 
infection demonstrated mean viral sgmRNA in nasal mucosae and bronchoalveolar lavage that 
peaked at approximately 5 log10 copies/swab or 5 log10 copies/mL, respectively. In contrast, 


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NHPs prophylaxed with either a 4 or 40 mg/kg dose of AZD7442 had little or no detectable 
levels of viral sgmRNA in both nasal mucosae and lungs. In the treatment group of the study, 
intravenous administration of a 40 mg/kg dose of AZD7442 one day after SARS-CoV-2 
infection resulted in rapid resolution of virus infection in both the nasal mucosae and lungs of 
infected NHPs. While viral sgmRNA was detected up to 10 days after infection in control 
animals, AZD7442 administration resulted in undetectable levels of viral sgmRNA by Day 4 
post-infection in the lungs and Day 7 in the nasal mucosae, showing that AZD7442 can 
provide clinical benefit even with administration after virus infection.
Collectively, these data demonstrate that the mAbs that comprise AZD7442 potently 
neutralize SARS-CoV-2 in vitro and are efficacious in animal challenge models when 
administered prophylactically or therapeutically.
2.2.2
Summary of Nonclinical Pharmacokinetics and Drug Metabolism
A preliminary assessment of the PK properties of AZD8895 and AZD1061, the 2 component 
mAbs of AZD7442, was conducted by in vivo comparisons against a similar 
AstraZeneca-developed mAb, MEDI8897 (nirsevimab). Similar to AZD8895 and AZD1061, 
MEDI8897 is a human IgG1κ mAb directed against a viral fusion protein (F protein of RSV) 
and contains the YTE amino acid substitutions in its Fc region to prolong its t1/2. Unlike 
MEDI8897, AZD8895 and AZD1061 additionally contain a second triple amino acid 
substitution, L234F/L235E/P331S (TM), in their Fc regions, intended to inhibit FcγR binding. 
Following IV injection in Tg32 mice, the PK of MEDI8897+TM was similar to that of 
MEDI8897, indicating the TM did not significantly affect the PK of MEDI8897. The PK of 
AZD8895 and AZD1061 were similar to those of MEDI8897 and MEDI8897+TM. In the 8-
week cynomolgus monkey GLP toxicology study for AZD7442, high exposures were 
achieved and were consistent across animals and between males and females for both 
AZD8895 and AZD1061, for both the 300 mg/kg IV dose and the 75 mg/kg IM dose. The 
exposures were as expected since the AZD7442 TK was similar to the TK of nirsevimab in 
cynomolgus monkeys based on 1-week post single dose TK data available for nirsevimab.
Human efficacious doses for AZD7442 were evaluated using in vitro functional potency data 
(virus-neutralizing activity of AZD7442 against SARS-CoV-2) and PK data. In addition, a 
viral dynamic model was developed, which allowed for understanding of the 
pharmacodynamic effects of AZD7442 to inhibit a SARS-CoV-2 infection and the resulting 
immune response. The viral dynamic model indicates that virus entry inhibition greater than 
approximately 80% is sufficient to prevent infection. Therefore, doses were selected that result 
in concentrations in serum and the ELF of the lungs above the in vitro derived inhibition 
parameter of IC80 (inhibiting SARS-CoV-2 by 80%) of 104 ng/mL for a duration of at least 5 
months post dose. Assuming a partition ratio of 1% for lung ELF-to-serum and the IC80 of 104 
ng/mL, an IM dose of 300 mg is expected to provide prophylactic coverage at least 5 months 
and this dose would also be effective to treat active infection with significant reduction in


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peak viral load and complete suppression of viral load earlier than accomplished by the 
acquired immune response only.
The doses tested in the monkey toxicology study (75 mg/kg per antibody for IM and 
300 mg/kg per antibody for IV) were determined to be no-observed-adverse-effect level 
(NOAELs). These NOAELs were used to calculate the safety margins for the clinical doses in 
the FTIH study (Study D8850C00001) by dividing the NOAEL mean exposure (Cmax or AUC) 
over the first 56 days post dose in the monkeys by the geometric mean exposure (Cmax or 
AUC) over the first 60 days post dose for each clinical dose cohort. The calculated margins 
using either AUC or Cmax are shown in Table 3 for the IM clinical dose relative to the IM 
NOAEL and for the IV clinical doses relative to the IV NOAEL.
Table 3
Safety Margin Prediction for the Dose Levels in Phase I Study 
D8850C00001
Route of 
Administration in 
FTIH
FTIH AZD7442 
Dose (mg)
GLP Monkey 
Toxicology Study 
AZD7442 Dose 
(mg/kg)
Safety Margin 
AUC (0-60 days)
Safety Margin 
Cmax
IM
300
150
33
62
IV 
300
600
67
150
IV
1000
600
22
49
IV
3000
600
7.5
16
AUC, area under plasma concentration-time curve; Cmax, maximum plasma concentration; FTIH, first-time-in-
human; GLP, Good Laboratory Practice; IM, intramuscular; IV, intravenous; mAb, monoclonal antibody. 
2.2.3
Summary of Toxicology
Due to the foreign nature of the spike RBD antigen target for the 2 antibodies in AZD7442 
and lack of spike protein expression in human or animal tissues, no pharmacologically 
relevant species is available for nonclinical safety testing of AZD7442. Therefore, in 
accordance with ICH◦S6◦(R1), only a short term, ie, a single IV and IM dose, study of the 
combination (AZD7442) in cynomolgus monkeys with a 2- and 8-week follow-up, and a TCR 
study assessing binding of the combination (AZD7442) and the individual antibodies 
(AZD8895 and AZD1061) to the full list of human and cynomolgus monkey tissues are being 
conducted. The single dose study in cynomolgus monkeys is ongoing, and interim result 
summaries are available for Week 2 and Week 8 (end of study). At the Week 2 interim 
assessment, there were no AZD7442-related changes in clinical signs, injection site 
observations/dermal scoring, body weights, qualitative food consumption, ophthalmology, 
veterinary physical examinations, ECGs, neurologic examinations, blood pressure and heart 
rate, respiration rates, body temperature, clinical pathology parameters (hematology, 
coagulation, and urinalysis/urine chemistry), gross necropsy findings, organ weights, or 


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histopathologic examinations. Based on the Week 2 assessment, the single dose administration 
of AZD7442 via intravenous infusion was well tolerated in cynomolgus monkeys at a dose 
level of 600 mg/kg (combination of 300 mg/kg of AZD8895 and 300 mg/kg of AZD1061). A 
limited summary of the available Week 8 end of study data covering clinical signs, body 
weight, clinical pathology, organ weights, and macroscopic findings at necropsy, confirms the 
tolerability demonstrated at the Week 2 interim assessment. In the TCR study, the assessment 
of the combination (AZD7442), and the individual components AZD8895 and AZD1061, was 
completed on the full list of tissues from 3◦independent human and cynomolgus monkey 
donors. No binding to any tissues was observed, confirming the absence of target and off-
target binding in humans and cynomolgus monkeys.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD7442 is 
provided in the AZD7442 IB.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD7442 can be found in the AZD7442 IB.
2.3.1
Risk Assessment 
There are no identified risks associated with AZD7442. No observations are considered to 
represent expected adverse reactions that would form part of an emerging safety profile.
As of the data cut-off date of 03 November 2020, there have been no events of anaphylaxis or 
other serious allergic reactions in the FTIH Phase I Study D8850C00001. No injection site 
reactions occurred in participants dosed IM, 10 participants in the AZD7442 300 mg IM group 
and 2 participants in the placebo IM group.
AZD7442 is a combination of 2 human mAbs, with non-overlapping epitopes directed against 
RBD of the SARS-CoV-2 S protein for neutralization of the virus. Neither mAb has any 
human target. There are no potential risks based on mechanism of action.
Potential risks are associated with administration of any immunoglobulin, including 
polyclonal immunoglobulin preparations and mAbs.
The important potential risks associated with the administration or any immunoglobulin, 
include, but are not limited to, anaphylaxis and other serious hypersensitivity reactions
including immune complex disease.
Other potential risks include, but are not limited to, injection site reactions, infusion-related 
reactions, and ADE disease.


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Antibody-dependent enhancement of disease is a theoretical risk. Two different syndromes 
exist: 1) ADE, 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 ADE 
occurring via this mechanism should range from very low to none. 2) VAERD, which is 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 hyperresponsiveness, and attenuated cytolytic T cell activity (T 
helper 2 cell immune response). This mechanism, induced by vaccines, should not be 
provoked by mAbs.
2.3.2 Benefit Assessment
Recipients of AZD7442 do not have any guaranteed benefit, however, AZD7442 may be 
efficacious and offer participants protection from COVID-19. 
2.3.3 Overall Benefit: Risk Conclusion
Taking into account 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 participants at risk of COVID-19.


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3
OBJECTIVES AND ENDPOINTS
Table 4
Objectives and Endpoints
Objective 
Estimand Description/Endpoint
Primary
To estimate the efficacy of a single IM 
dose of AZD7442 compared to placebo 
for the prevention of COVID-19
Population: Full analysis set
Endpoint: A binary response, whereby a participant is defined as a 
COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurs post dose of IMPand prior to Day 183.
Intercurrent events: For participants who become unblinded to properly 
consider vaccination for COVID-19, take COVID-19 vaccine or other 
COVID-19 preventive product prior to having met the criteria for the 
primary efficacy endpoint, the data will be collected and analyzed 
regardless (ie, intercurrent events will be handled using treatment policy 
strategy).
Summary measure: Prophylactic efficacy, calculated as 1-relative risk. 
(Relative risk is the incidence of infection in the AZD7442 group relative 
to the incidence of infection in the control group).
To assess the safety and tolerability of a 
single IM dose of AZD7442 compared to 
placebo
AEs, SAEs, MAAEs, and AESIs post dose of IMP.
Key Secondary
To estimate the efficacy of a single IM 
dose of AZD7442 compared to placebo 
for the prevention of severe or critical 
symptomatic COVID-19
Population: Full analysis set
Endpoint: The incidence of SARS-CoV-2 RT-PCR-positive severe or 
critical symptomatic illness occurring after dosing with IMP.
Intercurrent events: For participants who become unblinded to properly 
consider vaccination for COVID-19, take COVID-19 vaccine or other 
COVID-19 preventive product prior to having met the criteria for this 
endpoint, data will be collected and analyzed regardless (ie, intercurrent 
events will be handled using treatment policy strategy).
Secondary
To estimate the efficacy of a single IM 
dose of AZD7442 compared to placebo 
for the prevention of SARS-CoV-2 
infection
The incidence of participants who have a post-treatment response 
(negative at baseline to positive at any time post-baseline) for SARS-
CoV-2 nucleocapsid antibodies.
To estimate the efficacy of a single IM 
dose of AZD7442 compared to placebo 
for the prevention of COVID-19-related 
death
The incidence of COVID-19-related death occurring after dosing with 
IMP.
To estimate the efficacy of a single IM 
dose of AZD7442 compared to placebo 
for the prevention of all-cause mortality
The incidence of all-cause mortality occurring after dosing with IMP.


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Table 4
Objectives and Endpoints
Objective 
Estimand Description/Endpoint
To assess the pharmacokinetics of 
AZD7442 administered as a single dose 
of 300 mg IM
Serum AZD7442 concentrations.
PK parameters if data permit.
To evaluate ADA responses to AZD7442 
in serum
Incidence of ADA to AZD7442 in serum.
Exploratory 
To evaluate the single dose 
pharmacokinetic concentrations of 
AZD7442 in nasal fluid
AZD7442 nasal concentrations. 
To determine anti-SARS-CoV-2 nAb 
levels in serum following a single IM 
dose of AZD7442 or placebo
Post-treatment GMTs and GMFRs from baseline value through Day 457 
after single IM dose in SARS-CoV-2 neutralizing antibodies (wild-type 
assay or pseudo neutralization assay).
To quantify SARS-CoV-2 viral loads in 
infected participants treated with a single 
IM dose of AZD7442 or placebo (Illness 
Visits)
Viral genome copies in NP swabs or blood collected at Illness Visits as 
determined by qRT-PCR.
To quantify duration of viral shedding in 
participants with symptomatic COVID-
19 treated with a single IM dose of 
AZD7442 or placebo (Illness Visits)
Duration of SARS-CoV-2 shedding in anterior nasal swabs over time. 
To characterize resistance to AZD7442 
(Illness Visits)
Genotypic analysis and biochemical and/or susceptibility analysis of 
SARS-CoV-2 variants to AZD7442.
To assess symptoms associated with 
COVID-19 using an e-Diary in 
participants treated with a single IM dose 
of AZD7442 or placebo (Illness Visits 
only)
Symptoms recorded by participants in an Illness e-Diary from Illness 
Visits Day 2 through Day 28. 
To assess additional immune responses 
following a single IM dose of AZD7442 
or placebo
Other exploratory assays for humoral, mucosal and cellular immune 
responses may be performed based upon emerging safety, efficacy, and 
pharmacodynamic data.
ADA, antidrug antibody; AE, adverse event; AESI, adverse event of special interest; COVID-19, coronavirus 
disease 2019; GMT, geometric mean titers, GMFR, geometric mean fold rises; IM, intramuscular; IMP, 
investigational medicinal product; nAb, neutralizing antibody; NP, nasopharyngeal; qRT-PCR, quantitative real-
time polymerase chain reaction; RT-PCR, reverse transcriptase polymerase chain reaction; SAE, serious adverse 
event; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2


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4
STUDY DESIGN
4.1
Overall Design
This is a Phase III, randomized, double-blind, placebo-controlled, multi-center study assessing 
the safety and efficacy of a single dose of AZD7442 (× 2 IM injections) compared to placebo 
for the prevention of COVID-19. Approximately 100 sites will participate in this study. 
Participants will be adults ≥18 years of age with potential exposure, within 8 days to a 
specific identified individual with laboratory-confirmed SARS-COV-2 infection, symptomatic 
or asymptomatic, who are therefore at appreciable risk of imminently developing COVID-19, 
based on available risk assessment at time of enrollment (see Section 5.1). Participants will be 
enrolled into one of 2 cohorts:

Cohort 1: Adults ≥ 60 years of age, living in long-term care facilities. In this context, 
long-term care facilities include skilled nursing facilities, assisted living facilities, and 
independent living facilities for senior adults. In this cohort, “potential exposure to a 
specific identified individual with laboratory-confirmed SARS-COV-2 infection" is 
defined to mean the occurrence of SARS-COV-2 infection, symptomatic or 
asymptomatic, in another resident of the facility or in a staff member of the facility.

Cohort 2: Other adults ≥18 years of age with potential exposure to a specific identified 
individual with laboratory-confirmed SARS-COV-2 infection. Such individuals may 
include, but are not limited to those living in institutional residences (military lodging, 
dormitories, etc.), household contacts, health care workers, long-term care facility 
workers, and workers in occupational or industrial settings in which close contact is 
common.
The first 15 participants (Sentinel Cohort) will undergo safety monitoring for 4 hours post 
IMP administration before dosing further participants. The next 85 participants will undergo 
safety monitoring for 2 hours pose IMP administration and, if no hypersensitivity reactions are 
observed, the remaining participants will undergo safety monitoring for one hour post IMP 
administration. Should hypersensitivity reactions be observed in the first 100 participants, all 
participants will be monitored for safety for at least 2 hours post IMP administration.
Up to 1125 participants will be randomized in a 2:1 ratio to receive a single dose (× 2 IM 
injections) of either 300 mg of AZD7442 (n = approximately 750) or saline placebo 
(n = approximately 375) on Day 1. Enrollment will continue until the 25th primary endpoint 
event has been confirmed, or until 1125 subjects have been randomized, whichever comes 
first. Formal efficacy assessment is intended at the primary analysis, 30 days after the 25th
primary endpoint has occurred. 


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Following a screening evaluation, on the same day participants will receive a single dose (× 2 
IM injections) of IMP. After administration of the dose of IMP on Day 1, participants will 
undergo follow-up as stated in the schedule of activities. All participants in the study will be 
assessed for efficacy with all data available through their last assessment up to visit Day 366
and PK, ADA, nAbs and safety will be assessed up to 15 months following the dose of IMP.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Endpoints
The primary efficacy endpoint is the first case of SARS-CoV-2 RT-PCR-positive symptomatic 
illness occurring post dose of IMP and prior to Day 183. Participants will be included in the 
primary endpoint if they have RT-PCR-confirmed SARS-CoV-2 and meet the qualifying 
symptoms (see Section 8.1.1). 
The efficacy endpoints in this study are designed to demonstrate clinically meaningful benefit 
in preventing COVID in acutely exposed populations, in a safe manner. These definitions have 
4 components: (1) a definition of clinical illness; (2) a method of respiratory specimen 
sampling for the detection of associated shedding of the relevant virus; (3) an assay method 
for laboratory confirmation; and (4) a defined surveillance period.
The primary efficacy analysis is to be conducted 30 days after the 25th primary endpoint has 
occurred or 30 days after 1125 participants have been randomized, whichever occurs first. 
This type of approach is warranted in a post-exposure setting, in which COVID-19 cases 
which will meet the primary endpoint definition should occur within a brief period of time 
after an index case is identified. The incubation period for COVID-19 has been characterized 
as typically ranging from 3 to 8 days (Xie et al 2020). Therefore, primary transmission from 
an index case should be apparent within 8 days, and most cases of secondary transmission 
should begin to occur within 2 weeks.
The key secondary efficacy endpoint assesses the efficacy of AZD7442 to prevent severe or 
critical symptomatic COVID-19. Severe or critical COVID has occurred with disproportionate 
frequency in elderly long-term care facility residents, is associated with enormous extra 
suffering, and cost. Preventing this outcome would result in significant benefit, and, in this 
study population, should be readily measurable. 
4.3
Justification for Dose
The dose level, 300 mg IM, selected for this study is based on PK and neutralizing titer results 
of the Phase I study of AZD7442, in which the 300 mg IM dose produced serum plaque 
reduction neutralizing titer-80 levels ranging from > 256 to > 1024. Neutralizing antibody titer 
level in this range should be sufficient to prevent illness.
For further details, please refer to the AZD7442 IB.


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4.4
End of Study Definition
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.
The end of the study is defined as the date of the last scheduled procedure shown in the SoA 
for the last participant in the study globally.
5
STUDY POPULATION
Planned protocol deviations are not considered acceptable. A protocol deviation that is 
suspected or known to have the potential to significantly impact a participant’s safety, 
physical or mental integrity, or scientific value will be classified as a serious breach.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be ≥ 18 years of age at the time of signing the informed consent.
Type of Participant and Exposure Characteristics
2
Participants will be adults with potential exposure, within 8 days, to a specific identified 
individual with laboratory-confirmed SARS-COV-2 infection, symptomatic or 
asymptomatic, who are therefore at appreciable risk of imminently developing 
COVID-19, based on available risk assessment at time of enrollment, within any of the 
following settings:

Long-term care facilities, including skilled nursing homes, assisted living homes, 
independent living residences for the elderly. Residents, health care workers in such 
facilities, and other staff of such facilities are eligible under this criterion. For 
participants entering the study from these settings, “potential exposure to a specific 
identified individual with laboratory-confirmed SARS-COV-2 infection" is defined 
to mean the occurrence of SARS-COV-2 infection, symptomatic or asymptomatic, in 
another resident of the facility or in a staff member of the facility. 

Industrial settings shown to have been at high risk for SARS-COV-2 transmission, 
including but not limited to meatpacking plants. Workers in such facilities are 
eligible under this criterion.

Military settings including but not limited to barracks, ships, or other close-quarters 
working environments. Military and civilian personnel exposed in such settings are 
eligible.

Health care facilities. Health care workers and other staff exposed in such setting are 
eligible under this criterion.

University or college dormitories. Students exposed in such setting are eligible.


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
Household contacts. Any adult living in the same household as an index case are 
eligible under this criterion.

Other settings of similar close or high-density inter-personal proximity. The potential 
for exposure in such settings may be assessed on a case-by-case basis by 
investigators. Individuals exposed in such settings are eligible under this criterion.
3
Prior to enrollment, participants must not have had COVID-19 symptoms, as described in 
Table 8, within 10 days of dosing. 
4
Negative result from point of care SARS-CoV-2 serology testing at screening. 
Reproduction
5
Contraceptive use by men or women:
(a) Male Participants: Contraception for male participants is not required, however, to 
avoid the transfer of any fluids, all male participants must use a condom from Day 1 
and agree to continue through 365 days following administration of the IMP. 
(b) Female Participants

Women not of childbearing potential are defined as women who are either 
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Women will be considered 
postmenopausal if they have been amenorrhoeic for 12 months prior to the planned 
date of randomization without an alternative medical cause. The following age-
specific requirements apply:
o
Women < 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and FSH levels in the postmenopausal range.
o
Women ≥50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatment.

Female participants of childbearing potential must use one highly effective form of 
birth control. A highly effective method of contraception is defined as one that can 
achieve a failure rate of less than 1% per year when used consistently and correctly. 
Women of childbearing potential who are sexually active with a non-sterilized male 
partner must agree to use one highly effective method of birth control, as defined 
below, from Day 1 and agree to continue through 365 days following administration 
of the IMP. Cessation of contraception after this point should be discussed with a 
responsible physician. Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method are not acceptable methods of contraception. Female condom 
and male condom should not be used together. All women of childbearing potential 
must have a negative serum pregnancy test result at Visit 1 and throughout the study 
as indicated per the SoA (see Section 1.3).


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Examples of highly effective birth control methods are listed in Table 5.
Table 5
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
•
Intrauterine device
•
Intrauterine hormone-releasing system 
(IUS) a
•
Bilateral tubal occlusion
•
Vasectomized partner b
•
Sexual abstinence c
•
Combined (estrogen- and progestogen-containing 
hormonal contraception) associated with inhibition of 
ovulation

Oral (combined pill)

Intravaginal

Injectable

Transdermal (patch)
•
Progestogen-only hormonal contraception associated 
with inhibition of ovulation

Oral 

Injectable

Implantable
a
This is also considered a hormonal method.
b
Provided that partner is the sole sexual partner of the woman of childbearing potential study participant 
and that the vasectomized partner has received medical assessment of the surgical success. 
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the 
participant.
Informed Consent
6
Able to understand and comply with study requirements/procedures (if applicable, with 
assistance by caregiver, surrogate, or legally authorized representative) based on the 
assessment of the investigator. 
7
If able, signed informed consent. Ensure that participants who are considered by the 
investigator clinically unable to consent at screening and who are entered into the study 
by the consent of a legally acceptable representative show evidence of assent, as 
applicable in accordance with local regulations. See Appendix A for further details.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
History of laboratory-confirmed SARS-CoV-2 infection or SARS-CoV-2 seropositivity at 
screening.
2
History of infection with severe acute respiratory syndrome (SARS) or Middle East 
respiratory syndrome (MERS).


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3
Known history of allergy or reaction to any component of the study drug formulation.
4
Previous hypersensitivity, infusion-related reaction, or severe adverse reaction following 
administration of a mAb.
5
Any prior receipt of investigational or licensed vaccine or other mAb/biologic indicated 
for the prevention of SARS-CoV-2 or COVID-19 or expected receipt during the period of 
study follow-up.
6
Clinically significant bleeding disorder (eg, factor deficiency, coagulopathy, or platelet 
disorder), or prior history of significant bleeding or bruising following IM injections or 
venepuncture. 
7
Any other significant disease, disorder, or finding that, in the judgement 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/Concurrent Clinical Study Experience
8
Receipt of any IMP in the preceding 90 days or expected receipt of IMP during the period 
of study follow-up, or concurrent participation in another interventional study (see 
Table 7).
Other Exclusions
9
For women only - currently pregnant (confirmed with positive pregnancy test) or breast 
feeding.
10 Blood drawn in excess of a total of 450 mL (1 unit) for any reason within 30 days prior to 
randomization.
11 Employees of the Sponsor involved in planning, executing, 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.
12 In nations, states, or other jurisdictions that for legal or ethical reasons bar the enrollment 
of participants who lack capacity to provide their own informed consent, such subjects are 
excluded.
5.3
Lifestyle Considerations

Participants must follow the contraception requirements outlined in Section 5.1.

Restrictions relating to concomitant medications are described in Section 6.5.

Agree to wear digital health device if diagnosed with COVID-19 as described in 
Section 8.1.5.


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5.3.1
Lifestyle Restrictions
5.3.1.1
Women of Non Childbearing Potential
Women of non-childbearing potential are defined as female participants who are permanently 
surgically sterilized or postmenopausal.
Permanent sterilization includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy at least 6 weeks before screening. Bilateral oophorectomy alone is acceptable 
only when the reproductive status of the woman has been confirmed by follow-up hormone 
level assessment.
For women aged < 50 years, postmenopausal is defined as having both a history of ≥ 12 
months amenorrhea prior to randomization, without an alternative cause, following cessation 
of exogenous sex-hormonal treatment, and an FSH level in the postmenopausal range. Until 
FSH is documented to be within menopausal range, the participant is to be considered of 
childbearing potential.
For women aged ≥ 50 years, postmenopausal is defined as having a history of ≥ 12 months 
amenorrhea prior to randomization, without an alternative cause, following cessation of 
exogenous sex-hormonal treatment.
5.3.1.2
Women of Childbearing Potential
A woman is considered of childbearing potential, ie, fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Women of childbearing potential who 
are sexually active must agree to use, with their non-sterilized male partner, an approved 
method of highly effective contraception from the time of IMP administration until 365 days 
after the dose of IMP. In instances where a WOCBP participant, has a sterilized male partner, 
the vasectomized partner must have received a medical assessment of surgical success 
(Table 5). Women should be stable on their chosen method of birth control for at least one 
month before dosing.
Highly effective contraception is summarized in Table 5. 
Pregnancy Testing
Women of childbearing potential can be included only after a negative urine pregnancy test. 
Urine pregnancy testing will be done as per the SoA (see Section 1.3). If urine tests positive or 
indeterminate, a quantitative serum β-hCG will be performed for confirmation.
Pregnancy
If the participant becomes pregnant during the study, this should be reported to the PI. The PI 
should also be notified of pregnancy occurring during the study, but confirmed after 


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completion of the study. The pregnancy will be followed, and the status of mother and/or child 
will be reported to the Sponsor after delivery.
A pregnancy notification form and follow-up will be completed. Pregnancy occurring and 
reported during the study will be followed up for safety from the post dose administration to 
end of the study, or until term, to identify pregnancy outcome, whichever is later. Female 
participants who become pregnant after dosing will continue to have all safety PK (serum and 
nasal), ADA serum sample, and nAb samples collected. These do not represent a safety risk, 
and serum samples are already being collected as part of safety follow-up. Any complications 
during the planned follow-up of any pregnant participant (if any) will be discussed between 
the PI and AstraZeneca, and a decision to halt or continue any further sampling will be made 
on a case by case basis.
Ova Donation
Female participants should not donate ova for the duration of the study and for at least 
365 days after the IMP dose.
5.3.1.3
Male Participants
To avoid transfer of fluids to a sexual partner, all male participants must use a condom starting 
from the time of IMP administration until 365 days after dosing. Contraception for female 
partners of childbearing may be considered, but is not required for this protocol.
Sperm Donation
Male participants should not donate sperm for the duration of the study and for at least 365 
days after the dose of IMP.
Pregnancy
Participants will be instructed that if their partner becomes pregnant during the study, this 
should be reported to the PI. The PI should also be notified of pregnancy occurring during the 
study, but confirmed after completion of the study. In the event that a participant’s partner is 
subsequently found to be pregnant after the participant is included in the study, then consent 
will be sought from the partner and, if granted, any pregnancy will be followed, and the status 
of mother and/or child will be reported to the Sponsor after delivery.
A pregnancy notification form and follow-up will be completed.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to IMP. 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 


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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 re-consent for the study.
6
STUDY INTERVENTION
The IMP 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.
The third party medical device used for assessment of COVID-19 symptoms (ie, digital health 
device [Section 8.1.5]) is not considered a study intervention.
6.1
IMP(s) Administered
6.1.1
IMP
Participants will be randomized in a 2:1 ratio to receive one single 300 mg dose of AZD7442 
(divided in 2 sequential injections, one for each mAb component) or saline placebo (Table 6). 
Investigational medicinal product will be administered on Day 1, and participants will be 
monitored until Day 457 after IMP administration.
A dose of AZD7442 consists of 2 IM injections. If a participant experiences an immediate 
hypersensitivity reaction after receipt of the first IM injection, but before the second IM 
injection, the second IM injection should not be given. For details on the treatment of 
anaphylactic reactions after IMP IM injections see Appendix E. For further details on IMP 
discontinuation, see Section 7.1.
Table 6
Investigational Products
Intervention name
AZD7442 (AZD8895 + AZD1061)
Placebo (not to be matched to 
AZD7442)
Dose formulation
AZD7442 will be supplied as separate 
vials of AZD8895 and AZD1061 as 150 
mg colorless to slightly yellow, clear to 
opalescent solutions for injection. The 
solutions contain 100 mg/mL of active 
ingredient (AZD8895 or AZD1061) in 
20 mM L-histidine/L-histidine 
0.9% (w/v) saline 


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Table 6
Investigational Products
hydrochloride, 240 mM sucrose, and 
0.04% (w/v) polysorbate 80, at pH 6.0. 
The label-claim volume is 1.5 mL.
Unit dose 
strength(s)
300 mg AZD7442 consisting of 150 mg 
AZD8895 and AZD1061 at 100 mg/mL 
0.9% (w/v) saline solution for 
injection
Dosage level(s)
300 mg single dose of AZD7442
(150 mg of AZD8895 and 150 mg of 
AZD1061)
Single dose
Route of 
administration
2 IM injections of 1.5 mL each
2 IM injections of 1.5 mL each
Use
Experimental
Placebo-comparator
Sourcing
AZD7442 (AZD8895 + AZD1061): 
AstraZeneca.
0.9% (w/v) saline solution 
supplied by study site. 
Packaging and 
labeling
IMP will be provided in glass vials. Each 
glass vial will be labeled as required per 
country requirement.
Not applicable
IM, intramuscular; IMP, investigational medicinal product; w/v, weight per volume.
6.2
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IMP received, and any discrepancies are reported and 
resolved before use of the IMP.

Only participants enrolled in the study may receive IMP and only authorized site staff 
may supply or administer IMP. All IMP must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labelled 
storage conditions, with access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused IMPs are provided in 
the Pharmacy Manual or specified handling instructions. 
6.2.1
Dose Preparation and Administration Instructions 
Each vial selected for dose preparation should be inspected. If there are any defects noted with 
the IMP, the investigator and site monitor should be notified immediately.


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6.2.1.1
Investigational Product Inspection
AZD7442 IMP is comprised of 2 separate DPs, AZD8895 and AZD1061, to be administered 
sequentially. 
Liquid DP
The AZD8895 and AZD1061 DPs are each supplied as sterile, colorless to slightly yellow, 
clear to opalescent, solutions, with a label-claim of 150 mg at 100 mg/mL per vial. 
6.2.1.2
Dose Calculation
For AZD7442 (AZD8895 and AZD1061), the doses will be prepared directly from the 
AZD8895 and AZD1061 DP vials. AZD8895 and AZD1061 will be administered individually, 
using separate components. 
6.2.1.3
Dose Preparation Steps
The 2 DPs 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. The dose of AZD8895 must 
be administered first. The unblinded IMP Manager or other qualified professional should only 
remove the required DP vials for participant dosing from storage. No incompatibilities have 
been observed between AZD7442 and disposable polypropylene or polycarbonate syringes 
used for IM administration.
Dose Preparation and Administration for AZD7442 (AZD8895/AZD1061) 
The dose of AZD7442 (AZD8895 and AZD1061) for administration must be prepared by the 
investigator’s or site’s designated unblinded IMP Manager or other qualified professional 
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. Each AZD8895 
and AZD1061 vial must be used only once to prepare a single dose. AZD7442 (AZD8895 and 
AZD1061) does not contain preservatives, and any unused portion must be discarded.
Intramuscular AZD7442 doses should be prepared by accurately withdrawing 1.5 mL volume 
of DP (AZD8895 and AZD1061) into appropriately sized latex-free disposable polypropylene 
or polycarbonate syringes. Each DP should be administered sequentially as separate single 
injections, through a 22-25 gauge 1-1.5 in needle. Attach labels to the IM syringes to maintain 
blinding. AZD8895 and AZD1061 should be administered according to standard practice 


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procedures for IM injections, with one injection in each gluteal region. The IMP does not 
contain preservatives and any unused portion must be discarded.
Dose Preparation and Administration for Placebo
The dose of placebo (0.9% w/v saline solution) for administration must be prepared by the 
investigator’s or site’s designated unblinded IMP Manager or other qualified professional 
using aseptic technique. 
Use a separate disposable syringe with a 22 – 25 gauge and 1 – 1.5 in (25 – 38 mm) length 
needle for each placebo injection. Each injection should be administered as a separate single 
injection and administered sequentially. Intramuscular doses should be prepared by accurately 
withdrawing 1.5 mL volume of placebo into an appropriately sized latex-free disposable 
polypropylene or polycarbonate syringe. Attach labels to the IM syringes to maintain blinding. 
Placebo should be administered according to standard practice procedures for IM injections, 
with one injection in each gluteal region. Placebo does not contain preservatives and any 
unused portion must be discarded.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Randomization 
All participants will be centrally assigned to a randomized IMP using an IRT. Before the study 
is initiated, user guides, the log-in information, and directions for the IRT will be provided to 
each study site. Randomization will be maintained in a 2:1 ratio within each of the 2 cohorts:

Cohort 1: Adults ≥ 60 years of age, living in long-term care facilities. In this context, 
long-term care facilities include skilled nursing facilities, assisted living facilities, and 
independent living facilities for senior adults. 

Cohort 2: Other adults ≥18 years of age with who have been exposed to a specific 
identified individual with laboratory-confirmed SARS-COV-2 infection. Such individuals 
may include, but are not limited to those living in institutional residences (military 
lodging, dormitories, etc.), household contacts, health care workers, long-term care 
facility workers, and workers in occupational or industrial settings in which close contact 
is common. 
Where a participant does not meet all the eligibility criteria but incorrectly received IMP, the 
investigator should inform the Study Physician immediately, and a discussion should occur 
between the Study Physician and the investigator regarding whether to continue or discontinue 
the participant.


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6.3.2
Blinding 
Neither the participant nor any of the investigators or Sponsor staff who are involved in the 
treatment or clinical evaluation and monitoring of the participants will be aware of the IMP 
received. Since AZD7442 and placebo are visually distinct prior to dose preparation (due to 
differences in container closure), IMP will be handled by an unblinded pharmacist (or 
designee, in accordance with local and institutional regulations) at the study site. Syringe 
masking will be required in order to maintain the blind.
The IRT will provide the investigator(s) or pharmacists with a dose tracking number to be 
allocated to the participant at the dispensing visit. Routines for this will be described in the 
IRT user manual that will be provided to each study site.
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment 
randomization. The investigator documents and reports the action to the Sponsor, without 
revealing the treatment given to the participant to the Sponsor staff.
The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to the IMP and that potentially require expedited reporting to 
regulatory authorities. Randomization codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual participant have 
been made and documented.
6.3.3
Procedures for Unblinding 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, in 
which the knowledge of the specific blinded IMP will affect the immediate management of the 
participant’s condition (eg, antidote available), the investigator has the sole responsibility for 
determining if unblinding of a participants’ intervention assignment is warranted. Participant 
safety must always be the first consideration in making such a determination. If a participant’s 
intervention assignment is unblinded, the Sponsor must be notified within 24 hours after 
breaking the blind.
6.4
IMP Compliance
Dosing will take place under the guidance of study personnel, may occur at study sites, mobile 
units, or within long-term care facilities, and will be recorded in the eCRF.
Compliance will be assured by direct supervision and witnessing of the IMP administration. If 
a problem occurs during dosing, such as needle break, no re-dosing is permitted.
6.5
Concomitant Therapy
Permitted, restricted, and prohibited medications are summarized in Table 7.


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Any medication or vaccine (including COVID-19 vaccines, 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
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
Table 7
Permitted, Restricted, and Prohibited Medications
Use Category
Type of medication/treatment
Timeline/instructions
Permitted
Routine Vaccines 
Licensed influenza vaccines are permitted at any 
time.
All other routine vaccines are permitted beginning 
> 30 days after IMP dose.
Vaccines for the prevention of SARS-CoV-2 or 
COVID-19 are not considered routine vaccines in 
this protocol, (see Section 5.2).
Allergen immunotherapy 
Allowed if participant has been receiving stable 
desensitization therapy for allergies at least 30 days 
prior to Visit 1 and there are no anticipated changes
during the treatment period. Allergen 
immunotherapy should not be administered on the 
same day as IMP. Non-prescription over-the-counter 
treatments for allergies such as antihistamines, 
decongestants, and nasal steroids are permitted.
Commercial biologics, prednisone, 
immunosuppressive medications 
(eg, azathioprine, tacrolimus, 
cyclosporine, methotrexate, or 
cytotoxic chemotherapy)
Allowed, provided the participant is stable on 
maintenance dose (at steady state) prior to Visit 1.
•
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. 
•
Participants who develop COVID-19 after receiving IMP should be treated according 
to local standard of care, including investigational agents outside a clinical trial 
setting. 
Prohibited
Not applicable
Not applicable
Restricted
Contraceptive methods
See Section 5.1.


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Table 7
Permitted, Restricted, and Prohibited Medications
Use Category
Type of medication/treatment
Timeline/instructions
Blood/plasma donation
Participants must abstain from donating blood or 
plasma from the time of informed consent for one 
year after dose of study drug
COVID-19, coronavirus disease 2019; IMP, investigational medicinal product; SARS-CoV-2, severe acute 
respiratory syndrome-coronavirus-2.
6.5.1
COVID-19 Vaccine

For prospective participants for STORM CHASER who have not yet been dosed: 

In LTCFs in which an outbreak has been identified, and in which the residents have 
not been vaccinated, STORM CHASER could still be executed because a vaccine 
will not evoke immunity fast enough to protect participants in the post-exposure 
setting.

For STORM CHASER participants who have been dosed with investigational product, 
when an individual becomes eligible for the nationally deployed COVID-19 vaccine and 
the vaccine is locally available: 

Participants will be able to be unblinded if they request this, after a fully informed, 
objective discussion based on all available up-to-date information, and remain in the 
study. 
o
Unblinded participants who received placebo should be advised that no 
study-associated contraindication to receiving a vaccine exists. 
o
Unblinded participants who received AZD7442 should be advised that the 
300 mg dose may provide 6 to 9 months of protection, but that this has not been 
demonstrated. In these participants, there would be little or no urgency for 
receiving a vaccine. In addition, in the presence of adequate neutralizing 
antibody titers, an appropriate and effective response to the vaccine might be 
impaired. Such participants should be advised to consider waiting an appropriate 
length of time (6 to 9 months) before receiving an anti-SARS-CoV-2 vaccine. 
For AZD7442, 6 to 9 months will represent 2 or 3 elimination half-lives of the 
mAbs, after which the potential for the mAbs to protect against COVID-19 
should be reduced, and after which their potential interference with a vaccine 
may be reduced.

For participants who have received investigational product (blinded) and develop 
COVID-19, and are sick with it at some point in the study: 
o
There is no reason to believe that administration of a vaccine during acute 
COVID-19 will ameliorate the illness. 


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o
In almost all placebo recipients, and in most mAb recipients, an 
infection-induced immune response will occur, and this response should be 
protective. At this time, there is no reason to believe that the protection afforded 
by natural infection is less frequent or less robust than the protection provided by 
any vaccine, so the benefit of vaccination may be limited. 
o
The risk of receiving a vaccine after resolution of the illness should be low. 
6.6
Dose Modification
The IMP will be administered as described in Section 6.1.1. Dose modification is not 
permitted. 
6.7
Intervention After the End of the Study
There is no intervention after the end of the study (see definition in Section 4.4).
7
DISCONTINUATION OF IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study IMP
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
IMP. If IMP is permanently discontinued, the participant should remain in the study to be 
evaluated. See the SoA (see Section 1.3) for data to be collected at the time of discontinuation 
of IMP and follow-up, and for any further evaluations that need to be completed.
Note that discontinuation from IMP is NOT the same thing as a withdrawal from the study.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up, 
and for any further evaluations that need to be completed.
7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time 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 of withdrawal from the study, if possible, an Early Discontinuation Visit 
should be conducted, as shown in the SoA (see Section 1.3). See SoA for data to be 
collected at the time of study withdrawal and follow-up, and for any further evaluations 
that need to be completed.


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
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

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 requests withdrawal 
of 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 study 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 or not the participant wishes to and/or 
should continue in the study.

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 randomized, including 
those who did not receive IMP. 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.


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7.4
Study Suspension/Early Termination
The Sponsor reserves the right to temporarily suspend or permanently terminate this study or a 
component of the study at any time. The reasons for temporarily suspending the study may 
include, but are not limited to, the following:

Any death, SAE, or other safety finding assessed as related to IMP that, in the opinion of 
the Sponsor, may preclude further administration of IMP.

If one or more participant experiences a grade IV hypersensitivity reaction or 
hypersensitivity reaction classified as an SAE.

If two or more participants, within the first 100 participants, experiences a grade III or 
higher hypersensitivity reaction.

If two or more participants, within the first 100 participants, experiences a grade III or 
higher injection site reaction.
In such a situation, no additional participants will be randomized or treated with IMP until 
review by the DSMB is complete (see Appendix A 5).
If the study is suspended and does not proceed following evaluation of cumulative safety data 
from the first 100 participants enrolled, or after 4 weeks from first participant dosed, a 
protocol amendment will be submitted to Health Authorities.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.

Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
IMP.

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 timeframe defined in the SoA.


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8.1
Efficacy Assessments
8.1.1
Monitoring COVID-19 Symptoms
Study sites will contact participants weekly (telephone/email/text) through Day 366 with 
reminders to monitor for COVID-19 symptoms. During these weekly contacts the investigator 
will inquire about any COVID-19 symptoms (see Table 8) from the past 7 days and then 
initiate Illness Visits immediately within 3 days if such symptoms are reported. When a 
participant develops at least one of the COVID-19 qualifying symptoms listed in Table 8, the 
participant, his/her caretaker, or his/her legal representative must contact the study site. 
If a participant develops a COVID-19 qualifying symptom(s) after Day 1, nasopharyngeal 
swabs and anterior nasal swabs will be collected (see Section 8.6.1.1). If negative, the 
participant will be instructed to stop Illness Visits and continue with the main scheduled 
assessments (ie, Table 1). If one of these samples is positive for SARS-COV-2, the participant, 
his/her caretaker, or his/her legal representative, will be instructed to initiate Illness Visits, and 
the participant will have additional assessments per Table 2. 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 an AE.
Table 8
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
New onset confusion (only for participants ≥60 yo)
Appetite loss or decrease food intake (only for 
participants ≥60 yo)
Increased supplemental oxygen requirement (only for 
participants ≥60 yo on baseline supplemental 
oxygen)
Must be present for ≥2 days
Chills
Cough
Fatigue
Muscle aches
Body aches
Headache
New loss of taste
New loss of smell


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Table 8
COVID-19 Qualifying Symptoms
Participant must present with at least one of the following symptoms:
Duration
Symptom
Sore throat
Congestion
Runny nose
Nausea
Vomiting
Diarrhea
Adapted from (CDC 2020)
CDC, Centers for Disease Control and Prevention; yo, years old 
8.1.2
Severe or Critical Criteria
Severe COVID-19 is 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 9
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
(Marshall et al 2020)
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


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8.1.3
Illness Visits
Symptomatic participants (as defined in Section 8.1.1) will be instructed to visit the study site 
or to request study staff to visit their location for initiation of illness assessments (Table 2); 
where supported, home or mobile visits by qualified study staff may be substituted for the site 
visits. Symptomatic participants will complete the IL-D1 and will be instructed to continue 
with the home collection requirements. Local SARS-CoV-2 RT-PCR results will be available 
during the home collection period and participants will be informed of their status, which 
should also be reported to the participants’ primary care providers if applicable. Symptomatic 
participants will continue with the Illness Visits until a laboratory result is available. Only 
participants who test positive by the local laboratory results (or central laboratory results, if 
local not available) will be instructed to continue with the illness visits, including home 
collection requirements and digital health device and Illness e-Diary recordings. All devices 
and home lab kits should be brought to all subsequent illness visits. Participants who test 
negative for SARS-CoV-2 will be instructed to stop all illness visit assessments and return the 
digital health device. Participants will continue with follow-up visits per Table 1.
The Illness Visit schedule is to be performed in addition to the Main Study Visit schedule, 
where visits coincide, all assessments from the Main Study schedule and Illness Visit schedule 
should be performed.
To distinguish between the main study (Table 1) and the Illness Visits (Table 2), and to 
distinguish between illness episodes the visits will be labeled as follows: for the first episode 
illness visit Day 1 = 1IL-D1, illness visit Day 3 = 1IL-D3 etc, and for the second episode 
2IL-D1, 2IL-D3 and so on as applicable.
8.1.4
SARS-CoV-2 Testing and Other Virology Assessments
At the IL-D1, NP swabs will be collected for local and central laboratories and tested for 
SARS-CoV-2 by authorized RT-PCR assays (see Section 8.6.1.1).
Resistance monitoring as performed by genotypic and phenotypic characterization of virus 
isolated from illness visits may be conducted per the SoA (see Section 1.3 and Section 
8.6.1.1). Additionally, a respiratory panel to investigate the presence of additional viral 
pathogens may be carried out at time points per the SoA, and as outlined in Section 8.6.1.1.
Anterior nasal swabs may be self-collected during site Illness Visits and by self-collection at 
home throughout the Illness Visits to quantify duration of viral shedding (see Section 8.6.1.2). 
8.1.5
Digital Health Device
At IL-D1, participants will receive a wearable, digital health device (eg, Current Health 
Monitoring System) and be trained on use of the biosensor. The digital health device will 


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continuously track biophysical parameters, including, but not limited to, serial measurements 
of skin temperature, heart rate, respiratory rate, blood oxygen saturation, and physical activity.
Data will be obtained from the biosensor and transmitted via a wireless hub from the 
participant to the vendor platform. The investigator can monitor participant vital signs and 
receive alerts if there are clinically significant changes. The data from the device are intended 
to provide an early indication of worsening health status that would allow the investigator to 
provide appropriate follow-up. The data are not intended to substitute for protocol-mandated 
standard safety monitoring, participant self-reporting, or investigator oversight.
Along with the device, participants will be provided with a paper-based Quick Start Guide 
containing general instructions for the device as well as frequently asked questions. A 
reference copy of the document will be retained in the Site Master File.
8.1.6
Illness e-Diary
An Illness e-Diary (see Appendix F) will be used to collect self-reported information about 
COVID-19-associated symptoms per disease criteria (see Section 8.1.1).
At the Day 1 illness visit, participants (or, if applicable, their caregiver, surrogate, or legally 
authorized representative) will be given access to the Illness e-Diary and trained by study staff 
on how to record the information and assess the severity of the symptoms.
Participants who test positive for SARS-CoV-2 will be instructed to continue recording in the 
Illness e-Diary until symptoms resolve or until the Day 28 Illness Visit. Participants who test 
negative will be instructed to stop Illness e-Diary recording.
Study sites will monitor the health status of participants via Illness e-Diary responses after the 
Day 1 Illness Visit, and will call participants as needed based on these responses.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Physical Examinations
A complete physical examination will be performed at screening followed by targeted 
physical examinations as specified in the SoA (see 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.


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
A targeted physical examination will include areas suggested by the medical history. Each 
clinically significant abnormal finding following vaccination will be recorded as an AE.
All physical examinations will be performed by a licensed healthcare provider (eg, physician, 
physician assistant, or licensed nurse practitioner).
8.2.2
Vital Signs
Vital signs, including heart rate, pulse oximetry, blood pressure, and body temperature, will be 
performed as specified in the SoA (see Section 1.3). The participant should be resting prior to 
the collection of vital signs.
Data collected through the digital health device on heart rate, respiratory rate, temperature, 
and oxygen saturation level will be recorded as exploratory efficacy measurements and should 
not be reported as AEs, unless they result in an MAAE or SAE.
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 ECGs will be performed at time points specified in the SoA (see 
Section 1.3). A 12-lead safety ECG will be obtained after 5 minutes’ supine rest, using the 
sites own ECG machines.
The PI 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 PI. 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 PI may add extra 12-lead resting ECG safety assessments if there are any abnormal 
findings or if the PI 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 (see 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.


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The clinical chemistry, hematology, and urinalysis 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.
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)
Reticulocytes absolute count 
Serum Clinical Chemistry
Sodium
Alkaline phosphatase (ALP)
Potassium
Alanine aminotransferase (ALT)
Urea
Aspartate aminotransferase (AST)
Creatinine (and estimated glomerular filtration rate 
[eGFR])
Gamma glutamyl transpeptidase (GGT)
Albumin
Total Bilirubin
Calcium
Conjugated bilirubin
Phosphate
Creatine kinase
Glucose
C-reactive protein (CRP)
Urinalysis
Glucose
Blood
Protein
Microscopy (if positive for protein or blood): 
RBC, WBC, Casts (Cellular, Granular, Hyaline)
Coagulation
International normalized ratio (INR)
Prothrombin time (PT)
Activated partial thrombin time (aPTT)
Note: In case a participant shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN please refer 
to Appendix D. Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law, for 
further instructions.


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8.2.4.1
Females Only
Pregnancy test (women of childbearing potential only)
Serum human beta chorionic gonadotrophin 
Urine human beta chorionic gonadotrophin (pre-
and post dose)
Pregnancy test (suspected postmenopausal women < 50 years only)
Follicle-stimulating hormone (FSH)
If urine tests positive or indeterminate, a quantitative serum β-hCG will be performed for confirmation.
FSH will be analyzed at the screening visit to confirm postmenopausal status only in women < 50 years 
of age who have been amenorrhoeic for ≥ 12 months. Until FSH is documented to be within menopausal 
range, the participant is to be considered of childbearing potential. For women aged ≥ 50 years, 
postmenopausal is defined as having a history of ≥ 12 months amenorrhea prior to randomization, 
without an alternative cause, following cessation of exogenous sex-hormonal treatment.
8.2.5
Injection Site Inspection 
An injection site inspection will be performed according to Table 10 (see Section 1.3).
Table 10
Injection Site Inspection
Procedure/ Time after both injections 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
X
X
IMP, investigational medicinal product
Any AEs should be reported as described in Section 8.3.
8.2.5.1
Monitoring After IMP Administration
In addition to the injection site inspection, safety monitoring will be performed after IMP 
administration.
The first 15 participants (Sentinel Cohort) will undergo safety monitoring for 4 hours post 
IMP administration before dosing further participants. The next 85 participants will undergo 
safety monitoring for 2 hours pose IMP administration and, if no hypersensitivity reactions are 
observed, the remaining participants will undergo safety monitoring for one hour post IMP 
administration. Should hypersensitivity reactions be observed in the first 100 participants, all 
participants will be monitored for safety for at least 2 hours post IMP administration.


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For the first 4 days after IMP administration the Sentinel Cohort will be contacted daily to 
monitor AEs.
8.3
Adverse Events and Serious Adverse Events
The PI 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
All AEs and SAEs will be collected from the time of IMP administration throughout the study, 
up to and including the last visit.
SAEs will be recorded from the time of signing of the ICF.
If the investigator becomes aware of a 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 AE assessment 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 (verbatim)

The date and time when the AE started and stopped

Severity grade/maximum severity grade/changes in severity grade

Whether the AE is serious or not

Investigator causality rating against the IMP(s) (yes or no)

Action taken with regard to IMP


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
If the AE caused participant’s withdrawal from the 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

Date of discharge

Probable cause of death

Cause of death related to COVID-19 (yes/no/unknown) 

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
The following severity ratings will be used, adapted from the CTCAE v5.0 (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.
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.


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
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(s) 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
AESIs will be collected according to the time points specified in the SoA (see Section 1.3).
AESIs 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.
AESIs for AZD7442 are listed below. They include:

Anaphylaxis and other serious hypersensitivity reactions, including immune complex 
disease (see Appendix E).

Injection site reactions.
8.3.5
Medically Attended Adverse Events
MAAEs will be collected according to the time points specified in the SoA (see Section 1.3).
MAAEs 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 (medical doctor) for any reason. AEs, 
including abnormal vital signs, identified on a routine study visit or during the scheduled 
Illness Visits will not be considered MAAEs.


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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 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. Symptoms of COVID-19, confirmed 
SARS-CoV-2 infection, and/or diagnosis of COVID-19 will be collected and recorded in the 
eCRF as an AE.
8.3.7 Adverse Events Based on Examinations and Tests
The results from the protocol-mandated laboratory tests, vital signs, ECG, and other safety 
assessments 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 IMP, or are considered to be clinically relevant as judged 
by the investigator (which may include, but not limited to, consideration as to whether 
treatment or non-planned visits were required or other action was taken with the IMP, eg, dose 
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).
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 DUS.
8.3.8 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation. Any occurrences of AST or ALT ≥ 3 × ULN, together with TBL ≥ 2 × ULN and 
confirmed as a HL case should be reported as an SAE.
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 


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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 IMP 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.
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 the AstraZeneca 
drug. 
8.3.10
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca, except for:

If the pregnancy is discovered before the study participant has received any IMP.


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8.3.10.1
Maternal Exposure
The IMP should not be given to pregnant women.
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 
abnormalities/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 abnormality) 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 one 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 one 
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 
Male participants should refrain from fathering a child during the study and for 365 days 
following the dose.
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 
miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) 
should, if possible, be obtained and documented.
Please refer to Section 8.3.10 for further details.


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8.3.11
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs 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 works with the investigator to ensure that all 
relevant information is completed within one (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar day(s) if there is 
an SAE associated with the medication error (see Section 8.3.9) and within 30 days for all 
other medication errors.
The definition of a Medication Error can be found in Appendix B 4. 
8.3.12
Device Deficiencies
Any deficiency observed with the digital health device (third-party medical device) will be 
collected and reported to the manufacturer by the investigators or other site personnel within 
one day ie, immediately but no later than 24 hours of when he or she becomes aware of it.
A medical device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Medical device deficiencies include 
malfunctions, use errors, and information supplied by the manufacturer. The manufacturer’s 
medical device complaint report will be used to collect the deficiency.
8.4
Overdose
For this study, any dose of AZD7442 > 150 mg of either individual mAb will be considered an 
overdose.
AstraZeneca does not recommend a specific treatment for an overdose. Symptoms of overdose 
should be treated as per clinical judgement.

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 drug occurs in the course of the study, then the PI or 
other site personnel inform appropriate AstraZeneca representatives immediately, but no later 
than 24 hours of when he or she becomes aware of it.


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The designated AstraZeneca representative works with the PI to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 days for 
SAEs, and within 30 days for 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/repatriated. 

PK 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. 

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
Pharmacokinetics Assessments
Serum samples will be collected for measurement of serum concentrations of AZD7442 
(AZD8895 and AZD1061), as specified in Table 1 and Table 2.
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. 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.


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PK exposure (ie, AUCs) and other PK parameters, if data permit, may be calculated based on 
AZD7442 serum concentrations.
8.5.1.1
Determination of Drug Concentration
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. Full details of the analytical method used will be described in a separate Bioanalytical 
Report.
Placebo samples will not be analyzed, unless there is a need to confirm that correct treatment 
has been given to study participants. 
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Serum samples for immunogenicity assessments will be collected according to Table 1 and 
Table 2. Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual. Results for exploratory immunogenicity analyses may be reported separately from 
the CSR.
8.5.2.1
Anti-drug Antibody Assessments
Serum samples for determination of ADA will be conducted, on behalf of AstraZeneca, using 
a validated assay. Serum samples for determination of ADAs will be collected as specified in 
the SoA (see Section 1.3). Unscheduled samples for ADA analysis should be collected in 
response to suspected immune-related AEs.
The presence or absence of ADA will be determined in the serum samples using a validated 
bioanalytical method. A tiered testing scheme will be employed, with the first step being 
screening. Samples found positive in the screening step will be tested in the confirmatory step. 
Samples confirmed positive for ADA in the confirmatory step will undergo endpoint titer 
determination.
Full details of the analytical method and analyses performed will be described in a separate 
Bioanalytical Report.


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8.5.2.2
SARS-CoV-2 Serology Assessments
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels from 
all participants according to the SoA (see Section 1.3). A rapid point-of-care serology test will 
be utilized at screening to verify inclusion criteria. Baseline serostatus and the rate of 
SARS-CoV-2 infection in participants receiving AZD7442 versus placebo will be determined 
by seroconversion (negative to positive) in a validated SARS-CoV-2 nucleocapsid assay 
operated by an authorized laboratory. 
8.5.2.3
Assessment of Mucosal Responses
Nasal samples to evaluate PK or SARS-CoV-2 antigen-specific antibody responses in nasal 
secretions will be collected from participants according to the SoA (see Section 1.3). Nasal 
adsorption specimens will be collected, when test supplies are available, by synthetic 
absorptive matrix sampling as outlined in the Laboratory Manual. AZD7442 nasal 
concentrations may be assessed using an appropriately qualified bioanalytical assay. 
8.5.2.4
Additional Serum Immunogenicity
Residual serum samples may be used for exploratory immunogenicity evaluation. Serologic 
assessment to seasonal coronavirus antigens may also be assessed quantitatively using a 
qualified multiplexed meso scale discovery (MSD) immunoassay. Exploratory sera samples 
may be utilized to investigate additional humoral and cellular immune responses, as well as 
potential correlates of protection as determined by the Sponsor based upon emerging safety, 
efficacy, and immunogenicity data.
8.5.3
Pharmacodynamics
8.5.3.1
SARS-CoV-2 Neutralizing Antibody Assessments
Serum samples to measure SARS-CoV-2 nAb levels will be collected from participants 
according to the time points specified in the SoA (see Section 1.3). Authorized laboratories 
may measure neutralizing antibodies to SARS-CoV-2 using validated wild-type neutralization 
assay or pseudo-neutralization assays.
8.6
Human Biological Sample for Biomarkers
8.6.1
Collection of mandatory samples for biomarker analysis
By consenting to participate in the study, the participant consents to the mandatory research 
components of the study. 
Samples for biomarker research are required and will be collected from participants, as 
specified in the SoAs (see Section 1.3). Nasopharyngeal swabs will be collected for virologic 
assessments. Anterior nasal swabs may be collected at site Illness Visits and by the 
participants during the home-collection period. These biomarker measurements will support 
understanding of potential correlates of protection, duration of immune responses, and 


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correlations between pharmacodynamics and immunogenicity. Details for sample collection, 
processing, and testing will be provided in the Laboratory Manual.
Any results from such analyses may be reported separately from the CSR.
8.6.1.1
Virologic Assessments
Instructions for obtaining and processing NP swab samples are provided in the Laboratory 
Manual. NP swabs will be assessed by authorized RT-PCR assays for the detection of 
SARS-CoV-2 by local and central laboratories. Further details will be provided in the 
Virology Analysis plan.
Additionally, a validated multiplexed respiratory panel may be utilized to assess for the 
presence of other respiratory pathogens in NP swabs in a central laboratory operated on behalf 
of the Sponsor.
8.6.1.2
Assessment of Viral Shedding
Viral shedding may be assessed in self-collected anterior nasal swabs collected at site Illness 
Visits or self-collected at home, by an authorized RT-PCR assay for the qualitative and/or 
quantitative measurement of SARS-CoV-2 in participants whose medical condition allows. 
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, 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. 
8.7
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
The primary efficacy endpoint is a binary response, whereby a participant is defined as a 
COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurs post dose of IMP and prior to Day 183. Efficacy will be calculated as 1-relative risk, 
which is the incidence of infection in the AZD7442 group relative to the incidence of infection 
in the control group. The null hypothesis is: Efficacy of AZD7442 compared to placebo in 


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preventing COVID-19 is equal to zero. Whereas, the alternative hypothesis is: Efficacy of 
AZD7442 compared to placebo in preventing COVID-19 is not equal to zero. That is:

Null hypothesis: Efficacy = 0

Alternative hypothesis: Efficacy ≠ 0
The primary efficacy endpoint will be formally assessed at the primary analysis. The primary 
analysis will be conducted 30 days after the 25th primary endpoint event has occurred. 
Additional events may occur after the primary analysis. These will be evaluated and reported 
as exploratory endpoints at the end of study analysis. All participants will be followed for the 
entire duration of the study. Efficacy will be presented with a 2-sided CI, and statistical 
significance will be achieved if the 95% CI lower bound is > 0.
9.2
Sample Size Determination
Up to 1125 participants will be randomized in a 2:1 ratio to receive a single IM dose of 
AZD7442 (divided in 2 sequential injections, one for each mAb component) (the active group, 
n = approximately 750) or saline placebo (the control group, n = approximately 375) on 
Day 1.
The sample size calculations are based on the primary efficacy endpoint and were derived 
following a modified Poisson regression approach (Zou 2004). All participants will be 
followed for the entire duration of the study. The primary analysis will be conducted 30 days 
after the 25th primary endpoint event has occurred. The study will have approximately 90% 
power to demonstrate that the lower bound of the 2-sided 95% CI for efficacy is greater than 
zero, assuming an attack rate of 4.5% in the placebo group and true efficacy of 75% (equating 
to an attack rate of 1.1% in the AZD7224 group). 
To mitigate the uncertainty around these assumptions, a BSSR may be conducted prior to the 
primary analysis. The overall event rate, as well as the data from external sources (eg, 
prophylactic efficacy of other COVID-19 preventive mAbs), will be used in the sample size 
re-estimation and strictly no treatment information from this study will be used in the review. 
The summaries will not contain any information that would potentially reveal treatment 
assignments. The review may result in an adjustment of sample size when the observed attack 
rate is lower than expected. Since this review will be performed in a blinded fashion, no 
adjustment for the Type I error is needed. Full details will be in a BSSR plan.
9.3
Populations for Analyses
The following populations are defined:


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Table 11
Populations for Analysis
Population/Analysis set
Description
All participants analysis set
All participants screened for the study, to be used for reporting disposition 
and screening failures.
Full analysis set
All randomized participants who received at least one dose of IMP, 
irrespective of their protocol adherence and continued participation in the 
study. Participants will be analyzed according to their randomized treatment 
irrespective of whether or not they have prematurely discontinued, 
according to the intent-to-treat principle. 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
The safety analysis set consists of all participants who have received at least
one dose of IMP. Erroneously-treated participants (eg, those randomized to 
treatment A, but were actually given treatment B) are accounted for in this 
analysis set by assigning them to the treatment they actually received. A 
participant who has on one or several occasions received active IMP is 
classified as active. 
Pharmacokinetic 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.
IMP, investigational medicinal product; PK, pharmacokinetic
9.4
Statistical Analyses
The primary analysis will occur 30 days after 25 primary endpoint events have been observed 
across the active and control groups (see Section 9.4.2.1). The date for the DCO for this 
analysis will be calculated as date of onset of primary endpoint event (+30 days). All data 
collected during this interval including additional primary endpoints events will be evaluated. 
All participants in the study will be assessed for efficacy with all data available through their 
last assessment up to visit Day 366 and PK, ADA, nAbs and safety will be assessed up to 15 
months following the dose of IMP. A final analysis will occur when all participants have 
completed the study.
The SAP will be finalized prior to the primary DBL 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.
The study will initially be completely double-blind until the primary analysis (ie, blind for 
participants, investigators/site staff, and Sponsor/designated clinical research organization) at 
which time members of Sponsor/designated clinical research organization associated with the 
analysis, write-up and submission will be unblinded. To maintain the integrity of the study to 


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allow rigorous evaluation of efficacy and safety through the end of the study, the site 
personnel and participants will remain blinded to the treatment assignment until the end of the 
study. The primary analysis will be carried out by an unblinded analysis team at AstraZeneca 
(or its delegates) and the procedure will be detailed in an unblinding plan. Participant-level 
unblinding information will be kept strictly confidential and rationale for any unblinding will 
be documented. 
Categorical variables will be summarized using frequency and percentages, where the 
denominator for calculation is the underlying analysis set population, unless otherwise stated.
Continuous variables will be summarized with descriptive statistics of number of available 
observations, mean, standard deviation, median, minimum and maximum, and quartiles where 
more appropriate.
All point estimates will be presented with a 95% CI, unless otherwise stated. P-values, 
corresponding to a 2-sided test, will be presented for comparisons between treatments. 
Methods for controlling multiplicity across endpoints are discussed in Section 9.4.5.
9.4.1
General Considerations
The primary efficacy analysis will be based on the double-blind, placebo-controlled- phase of 
the study, and will compare participants randomized to receive a single IM dose of AZD7442 
(× 2 IM injections) against participants randomized to saline placebo. 
The primary estimand will be used for the analysis of the primary efficacy endpoint. It will be 
based on participants in the full analysis set, defined as all randomized participants who 
received at least one dose of IMP, analyzed according to their randomized treatment. For 
participants with multiple events, only the first occurrence will be used for the primary 
efficacy endpoint analysis. The set of intercurrent events for this estimand consists of 
participants who become unblinded to properly consider vaccination for COVID-19, take a 
COVID-19 vaccine or other COVID-19 preventive product prior to having met the primary 
efficacy endpoint. The intercurrent events will be handled using the treatment policy strategy. 
Absence of data following participants’ withdrawal prior to having met the primary efficacy 
endpoint will be treated as missing. Participants will be considered as not having the event 
through the time of last observation. Deaths that are caused by COVID-19 and 
hospitalizations that are characterized to be severe COVID-19 (Section 8.1.2) will also be 
considered as primary efficacy endpoints. 
Additional estimands will be specified for the primary efficacy endpoint to carry out 
sensitivity analyses for assessing the robustness of results. These sensitivity analyses will 
explore different methods for handling intercurrent events and different assumptions for 
missing data. Estimands will also be specified for the analysis of secondary endpoints. Full 
details will be provided in the SAP.


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Demography and baseline characteristics will be summarized by treatment for the full analysis 
set. If there are major differences between the full analysis set and the safety analysis set, the 
summaries will be repeated and presented for the safety analysis set.
9.4.2
Efficacy 
9.4.2.1
Primary Endpoint
The primary endpoint is the first case of SARS-CoV-2 RT-PCR -positive symptomatic illness 
occurring post dose of IMP and prior to Day 183. Participants will be included in the primary 
endpoint if they have RT-PCR-confirmed SARS-CoV-2 prior to Day 183 and meet the 
qualifying symptoms summarized in Table 8. If a participant’s first case of SARS-CoV-2 
RT-PCR positive symptomatic illness occurs after Day 183, the participant will be considered 
as not having met the primary endpoint. The primary efficacy endpoint is to be assessed 30 
days after the 25th event has occurred. A final analysis will also be conducted at end of study, 
the date of the last scheduled procedure shown in the SoA for the last participant, regardless of 
the number of events. This analysis will not be controlled for multiplicity and statistical 
hypotheses will be tested at a nominal 5% significance level (based on a 2-sided test). 
As the primary efficacy analysis, the plan is to use the primary estimand and a Poisson 
regression model with robust variance (Zou 2004) to analyze the primary efficacy endpoint, 
which will include the log of the follow-up time as an offset. If a participant’s first case of 
SARS-CoV-2 RT-PCR positive symptomatic illness occurs after Day 183, the participant will 
be considered as not having an event. The efficacy will be estimated from the model, which 
will give the RRR in the incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness. 
The efficacy is calculated as RRR = 100% × (1-relative risk), which is the incidence of 
infection in the AZD7442 group relative to the incidence of infection in the control group, 
expressed as a percentage. Model assumptions will be checked and the robustness of the 
primary analysis will be assessed. The Poisson regression model with robust variance has the 
flexibility for exploring multiple imputation approaches using, eg, the observed placebo attack 
rate to impute missing data. If the Poisson regression model with robust variance fails to 
converge, an alternative approach will be implemented. Full details will be documented in the 
SAP.
At the final analysis, the efficacy will also be estimated from a Poisson regression model with 
robust variance and offset including the log of the follow up time, which includes all 
SARS-CoV-2 RT-PCR positive symptomatic illness events, ie, including those that occurred 
after Day 183.
To support the primary analysis, a Cox proportional hazard model will be fitted to the data as 
well as Kaplan-Meier curves presented for the active and control groups, showing the 
cumulative incidence of the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurring post dose of IMP and prior to Day 183. In addition, the absolute risk reduction of 


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AZD7442 over placebo in preventing the incidence of the SARS-CoV-2 RT-PCR positive 
symptomatic illness will be presented, along with the 2-sided 95% CI using the Miettinen and 
Nurminen’s score method (Miettinen and Nurminen 1985). Full details will be documented in 
the SAP.
9.4.2.2
Secondary Endpoint(s)
The key secondary endpoint is the incidence of the first case of SARS-CoV-2 RT PCR-
positive and severe or critical symptomatic illness that occurs prior to Day 183. The criteria 
for determining this endpoint is the same as those for the primary efficacy endpoint (see 
Section 9.4.2.1). Details on multiplicity control are provided in Section 9.4.5.
Other secondary endpoints include the following summary measures, derived from binary 
outcomes:

The incidence of participants who have a post-treatment response (negative at baseline to 
positive at any time post-baseline) for SARS-CoV-2 nucleocapsid antibodies. 

The incidence of COVID-19-related death occurring after dosing with IMP.

The incidence of all-cause mortality occurring after dosing with IMP.
Following the same methodology outlined for the primary endpoint, each of these secondary 
endpoints will be analyzed by a separate Poisson regression model with robust variance (Zou 
2004). RRR will be estimated from each model, with a corresponding 95% CI. A p-value, 
corresponding to a 2-sided test, will be presented to compare AZD7442 against placebo. The 
key secondary efficacy endpoint (whose alpha is protected under a hierarchical framework) 
will be presented with 95% CIs and p-values for other secondary endpoints will be nominal, 
as they are not controlled for multiplicity. To support these analyses, descriptive statistics will 
be produced for the AZD7442 and control groups. Full details will be documented in the SAP.
9.4.2.3
Exploratory Endpoint(s)
Full details of the analyses for the exploratory endpoints will be specified in the SAP.
9.4.3
Safety
9.4.3.1
Primary Endpoint(s)
The safety of AZD7442 will primarily be assessed by:

Incidence of AEs 

Incidence of SAEs 

Incidence of MAAEs 

Incidence of AESIs 


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AE severity will be graded according to Appendix B and coded using the most recent version 
of the Medical Dictionary for Regulatory Activities. AEs 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.
9.4.3.2
Other Safety Endpoint(s)

Laboratory parameters (hematology, clinical chemistry, coagulation, and urinalysis)

12-lead safety ECG

Vital signs (blood pressure, pulse rate, oral temperature, and respiratory rate)

Physical examination
Laboratory assessments will be performed for hematology, clinical chemistry, coagulation, 
and urinalysis parameters. Laboratory parameters will be graded using the most recent version 
of the CTCAE. 
Additionally, per the SoA (see Section 1.3), all participants will be evaluated via ECG, vital 
signs, and a targeted physical examination. All parameters from laboratory, ECG, vital signs, 
and physical examination 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.
9.4.4
Pharmacokinetic and Anti-drug Antibody
9.4.4.1
Pharmacokinetic
Individual AZD7442 (AZD8895 and AZD1061) serum concentration data will be listed and 
tabulated by treatment group, along with descriptive statistics. Pharmacokinetic exposure (ie, 
AUCs) and other PK parameters may be estimated using non-compartmental analysis, if data 
permit. Potential correlation between PK exposure and efficacy/safety response may be 
explored. Population PK analysis may be performed and reported in a separate report.
9.4.4.2
Anti-drug Antibody
The incidence of ADA to AZD7442 will be assessed and summarized by number and 
percentage of participants who are ADA positive by treatment group. The ADA titer will be 


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listed by participant at different time points. The impact of ADA on PK, PD, efficacy, and 
association with AEs and SAEs, will be assessed. 
9.4.5
Methods for Multiplicity Control
If the primary endpoint achieves statistical significance a hierarchical approach will be used to 
control for multiplicity of the primary and key secondary efficacy endpoints. With that, the 
overall Type I error is controlled at 0.05. Therefore, no further multiplicity adjustment is 
necessary.
9.4.6
Sensitivity Analyses
Sensitivity analyses will be explored to assess the robustness of treatment effects for the 
primary efficacy endpoint, where different missing data mechanisms will be explored using 
multiple imputation approaches. Full details of the sensitivity analyses will be specified in the 
SAP, and documented prior to the DBL.
9.4.7
Subgroup Analyses
Subgroup analyses will be carried out to assess the consistency of the treatment effect across 
key, pre-defined, subgroups. These analyses will focus on the primary efficacy endpoint, and 
they may be performed on secondary and exploratory endpoints if deemed appropriate. The 
list of subgroups includes but may not be limited to: age, sex, race, ethnicity, comorbidity, and 
SARS-CoV-2 RT-PCR status at baseline. Full details of all subgroup analyses will be 
described in the SAP, including hypotheses that will be tested and the covariates and 
interaction terms to be included in the statistical models.
9.5
Interim Analyses 
Not applicable. 
9.6
Data Safety Monitoring Board
An independent DSMB will provide oversight, to ensure safe and ethical conduct of the study. 
The DSMB will meet monthly and make any necessary recommendations to the Sponsor 
based on their evaluations of emerging data. In particular, the evaluation of cumulative safety 
data from the first 100 participants enrolled will be performed by the DSMB, who will advise 
the Sponsor on whether it is appropriate to proceed. This evaluation will take place as soon as 
practical after randomization of the study’s 100th participant or after 4 weeks from first 
participant dosed, whichever comes first. Study enrollment will not be paused pending or 
during this evaluation by the DSMB. 
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.


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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 GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, 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 toward the safety of participants and the safety of 
the IMP 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 the IMP 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 Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.
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.
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 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 or their legally authorized representative 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.


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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 that would make the participant identifiable will not be transferred.

The participant 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. 

The participant 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 (DSMB)
An external DSMB will monitor and protect the safety of the participants throughout the 
double-blind treatment period of 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. Summaries of unblinded data 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 be held monthly until last participant last visit to 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 from the first 100 participants 
enrolled. This evaluation will take place as soon as practical after randomization of the study’s 
100th participant or after 4 weeks from first participant dosed, whichever comes first. Study 
enrollment will not be paused pending or during this evaluation by the DSMB. After 
completing this review, the DSMB will specifically advise the Sponsor on whether it is 
appropriate to continue the study. During any subsequent safety reviews by the DSMB, 


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participant enrollment can continue. The available unblinded safety data for the randomized 
participants will be evaluated by the DSMB. Safety and efficacy summaries will be prepared 
prior to each meeting. The efficacy summaries will be presented for safety review purposes. 
During the study, the benefit/risk assessment will be continuously monitored by the DSMB to 
ensure that the balance remains favorable. Specifically, the study may be paused for DSMB 
review if a statistically significantly higher risk ratio (> 1), at the 1-sided 5% significance 
level, is seen for cases of severe COVID-19 in the AZD7442 arm compared to the placebo 
arm. This assessment for a potentially increased risk ratio will begin after 8 cases of severe 
COVID-19 have accrued in the study and will occur during each monthly DSMB data review 
or sooner if there are 5 or more severe cases accrued compared to the previous assessment. 
Based on the output of the review, the study could be paused for further evaluation of the 
potential signal. 
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.
A 6
Dissemination of Clinical Study Data
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 in the 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 relevant study plans.


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
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).

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:


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
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

Discontinuation of further IMP development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(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 multi-center studies only in their entirety and not as individual site data. In 
this case, a co-ordinating 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 an IMP 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 (eg, nausea, chest pain), or disease temporally 
associated with the use of an IMP, whether or not considered related to the IMP. 
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 IMP has been administered.
B 2
Definition of Serious Adverse Events
A 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 abnormality 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 
SAEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgement 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 fulfills 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 IMP 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 a 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 judgement 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 
judgement 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 (adapted from CTCAE v5.0):

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 


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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
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 Appendix B 2. 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 Appendix B 2.
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 limited or 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 DUS has deteriorated due to lack of effect should be 
classified as no reasonable possibility.
B 4
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an AstraZeneca IMP 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 intercepted before the 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, eg, 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 

Drug not stored as instructed, eg, kept in the fridge when it should be at room temperature 


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
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 that led 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

Errors related to background and rescue medication, or standard of care medication in 
open-label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.


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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 the 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 for the 
remainder of the sample lifecycle.
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 earlier.
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, 
and the action is documented and the study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING 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 that 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 PHL cases and 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 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; eg, 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 AE data (eg, 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 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
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in 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
If Central Laboratories are 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:

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 Section D 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results)
If Local Laboratories are Being Used:
The investigator, will without delay, review each new laboratory report and if the 
identification criteria are met will:

Determine whether the participant meets PHL criteria (see Section D 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF


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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 one day of PHL criteria being met, the investigator will report the case as an SAE 
of PHL; 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 change# 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.

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. 

Complete the 3 Liver eCRF Modules as information becomes available 
#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.
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.


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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 Lead 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 PHL 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.
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 PHL, (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 


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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 judgement. Any test results need to be 
recorded.
Hy’s Law Lab Kit for Central Laboratories 
Additional standard chemistry and coagulation 
tests
GGT (Gamma glutamyl transpeptidase)
LDH
Prothrombin time
INR
Viral hepatitis
IgM (immunoglobulin M) anti-HAV
HBsAg
IgM and IgG (immunoglobulin G) 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 antibody (Anti-
LKM)
Anti-Smooth Muscle antibody (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
a
HBV DNA is only recommended when IgG anti-HBc is positive


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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
Anaphylaxis
In adults, anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled:
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalised hives, pruritus or flushing, swollen lips, tongue and/or 
uvula)
AND AT LEAST ONE OF THE FOLLOWING:

Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxaemia)

Reduced BP (see number 3 below for definition) or associated symptoms of end-
organ dysfunction (eg, hypotonia [collapse], syncope, incontinence)
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
participant (minutes to several hours):

Involvement of the skin-mucosal tissue (eg, generalised hives, itch, flush, swollen 
lips, tongue and/or uvula)

Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxaemia)

Reduced BP (see number 3 below for definition) or associated symptoms (eg, 
hypotonia [collapse], syncope, incontinence)

Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3
Reduced BP after exposure to known allergen for that participant (minutes to several 
hours); for adults a systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline BP (taken at or immediately prior to start of the IMP 
administration), whichever BP is lower.
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).
To assist with the mitigation of these AEs, see Table 12, 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 SOC.


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Table 12
An Approach to Management of Anaphylactic, Hypersensitivity, and Post-injection Reactions
Severity of symptoms
Treatment
Investigational product
Mild local reactions (During and post injection 
and hypersensitivity)
Mild injection site reactions such as redness, mild 
swelling, pain at the injection site or headache, 
nausea, non-pruritic rash, or mild hypersensitivity 
reactions including localised 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 50 mg PO or equivalent 
and/or
•
Acetaminophen 500 to 650 mg or 
equivalent dose of paracetamol and/or
•
Topical antihistamines and/or low-potency 
topical corticosteroid preparations and/or
•
Anti-nausea medication, as needed.
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 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 (~500 to 1000 mL/hour 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.
Stop or hold additional IMP administration 
immediately.
At the discretion of the Investigator, resume 
current IMP administration under observation. 


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Table 12
An Approach to Management of Anaphylactic, Hypersensitivity, and Post-injection Reactions
Severity of symptoms
Treatment
Investigational product
Moderate hypersensitivity reactions
Reactions which may include generalised rash or 
urticaria, palpitations, chest discomfort, shortness 
of breath, hypo- or hypertension with
> 20 mmHg change in systolic BP
from pre-infusion measurement.
Evaluate participant, including close monitoring 
of vital signs.
Treat participant, for example, with:
•
Normal saline (~500 to 1000 mL/hour IV)
•
and/or
•
Diphenhydramine 50 mg IV or equivalent 
and/or
•
Acetaminophen 500 to 650 mg or 
equivalent dose of paracetamol and/or
•
IV corticosteroids, such as hydrocortisone 
100 mg or methylprednisolone 20 to 40 
mg.
Stop IMP administration immediately. 


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Table 12
An Approach to Management of Anaphylactic, Hypersensitivity, and Post-injection Reactions
Severity of symptoms
Treatment
Investigational product
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 (~500 to 1000 mL/hour IV)
•
Epinephrine for bronchospasm, 
hypotension unresponsive to IV fluids, or 
angioedema. Dose and route as per local 
SOC, example, epinephrine 1:1000, 0.5 to 
1.0 mL administered SC for mild cases and 
intramuscular for more severe cases
•
IV corticosteroids, such as hydrocortisone
•
100 mg or methylprednisolone 20 to 40 
mg
•
Diphenhydramine 50 mg IV or equivalent
•
Acetaminophen 500 to 650 mg or 
equivalent dose of paracetamol
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.


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Appendix F
e-Diary
Symptoms Associated with Covid-19
1
Record your temperature. If you take more than one temperature, record the highest one 
(ie, ____ °F/°C).
(a) Free text input
Move to Question 2
2
Have you experienced shortness of breath?
(a) No
(b) Yes
If No, move to Question 4
If Yes, move to Question 3
3
Grade the severity of shortness of breath based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 4
4
Have you experienced difficulty breathing?
(a) No
(b) Yes
If No, move to Question 6
If Yes, move to Question 5
5
Grade the severity of the difficulty breathing based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization


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Move to Question 6
6
Have you experienced chills?
(a) No
(b) Yes
If No, move to Question 8
If Yes, move to Question 7
7
Grade the severity of chills based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 8
8
Have you experienced a cough?
(a) No
(b) Yes
If No, move to Question 10
If Yes, move to Question 9
9
Grade the severity of cough based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 10
10 Have you experienced fatigue?
(a) No
(b) Yes
If No, move to Question 12


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If Yes, move to Question 11
11 Grade the severity of fatigue based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 12
12 Have you experienced muscle aches?
(a) No
(b) Yes
If No, move to Question 14
If Yes, move to Question 13
13 Grade the severity of muscle aches based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 14
14 Have you experienced body aches?
(a) No
(b) Yes
If No, move to Question 16
If Yes, move to Question 15
15 Grade the severity of body aches based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization


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Move to Question 16
16 Have you experienced headache?
(a) No
(b) Yes
If No, move to Question 18
If Yes, move to Question 17
17 Grade the severity of headache based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Repeated use of non-narcotic pain reliever
(c) 3 (Severe): Significant, any use of narcotic pain reliever or prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 18
18 Have you experienced new loss of taste?
(a) No
(b) Yes
If No, move to Question 20
If Yes, move to Question 19
19 Grade the severity of loss of taste based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 20
20 Have you experienced new loss of smell?
(a) No
(b) Yes


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If No, move to Question 22
If Yes, move to Question 21
21 Grade the severity of loss of smell based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 22
22 Have you experienced a sore throat?
(a) No
(b) Yes
If No, move to Question 24
If Yes, move to Question 23
23 Grade the severity of sore throat based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 24
24 Have you experienced congestion?
(a) No
(b) Yes
If No, move to Question 26
If Yes, move to Question 25
25 Grade the severity of congestion based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity


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(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 26
26 Have you experienced a runny nose?
(a) No
(b) Yes
If No, move to Question 28
If Yes, move to Question 27
27 Grade the severity of runny nose based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 28
28 Have you experienced nausea?
(a) No
(b) Yes
If No, move to Question 30
If Yes, move to Question 29
29 Grade the severity of nausea based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 30
30 Have you experienced vomiting?
(a) No


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(b) Yes
If No, move to Question 32
If Yes, move to Question 31
31 Grade the severity of vomiting based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
Move to Question 32
32 Have you experienced diarrhea?
(a) No
(b) Yes
If No, e-Diary can be submitted.
If Yes, move to Question 33
33 Grade the severity of diarrhea based on the descriptions below:
(a) 1 (Mild): No interference with activity
(b) 2 (Moderate): Some interference with activity
(c) 3 (Severe): Significant, prevents daily activity
(d) 4 (ER or hospital visit): ER visit or hospitalization
e-Diary can be submitted
For Patients ≥60 years of age ONLY: 
1
Have you felt as if you can’t think clearly?
(a) No
(b) Yes
2
Have you experienced any loss or decrease in your appetite?
(a) No
(b) Yes


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3
Do you take supplemental oxygen?
(a) No
(b) Yes
If No, e-Diary can be submitted.
If Yes, move to Question 4
4
Have you needed to increase your baseline intake?
(a) No
(b) Yes


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Appendix G
ECOG Performance Status
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead


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Appendix H
Abbreviations
Abbreviation or 
special term
Explanation
ADA
anti-drug antibody 
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase/transaminase
AST
aspartate aminotransferase/transaminase
AUC
area under the plasma concentration-time curve
β-hCG
beta-human chorionic gonadotropin
BSSR
blinded sample size re-estimation
CI
confidence interval
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CIOMS
Council for International Organizations of Medical Sciences 
CRO
Contract Research Organization
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DBL
database lock
DILI
Drug Induced Liver Injury
DP
drug product
DSMB
Data Safety Monitoring Board
DUS
Disease Under Study
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
ELF
epithelial lung fluid
Fc
fragment crystallizable region
FcγR
Fc gamma receptor(s)
FcRn
neonatal Fc receptor(s)
FTIH
first time in human
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HIV
human immunodeficiency virus


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Abbreviation or 
special term
Explanation
HL
Hy’s Law
IB
Investigator’s Brochure
IATA
International Airline Transportation Association
IC80
80% maximal inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IM
Intramuscular
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
Intravenous
LTCF
long-term care facilities
MAAE
medically attended adverse event
mAbs
monoclonal antibodies
MERS
Middle East respiratory syndrome
MERS-CoV
Middle East respiratory syndrome coronavirus
nAb
neutralizing antibody
NOAEL
no-observed-adverse-effect level
NP
Nasopharyngeal
PHL
Potential Hy’s Law
PI
Principal investigator 
PK
pharmacokinetic(s)
RBD
receptor binding domain
RNA
ribonucleic acid
RRR
relative risk reduction
RT-PCR
reverse transcriptase polymerase chain reaction
RTSM
Randomization and Trial Supply Management
S
Spike
SAE
serious adverse event 
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome-coronavirus 2
sgmRNA
subgenomic RNA


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Abbreviation or 
special term
Explanation
SoA
Schedule of Activities
t1/2
terminal half-life
TBL
total bilirubin level
TCR
tissue cross-reactivity
TM
triple mutation
ULN
upper limit of normal
WOCBP
women of childbearing potential
YTE
Immunoglobulin constant heavy chain substitution to modify the half-life of the 
antibody (M252Y/S254T/T256E)


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Appendix I
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Version 5.0, 21 December 2020
Key amendment and rationale for change:
After clarification in Amendment 3, on the use of SARS-CoV-2 vaccines in study 
participants, further clarification was required to ensure participant safety and statistical 
accountability for those unblinded participants considering vaccination for COVID-19. 
Synopsis, Sections 3 (Objectives and Endpoints), 9.4.1 (General Considerations): To 
account for increased availability of COVID-19, vaccines the definition of intercurrent 
events was expanded to include “become unblinded to properly consider vaccination for 
COVID-19”.
Table 1 (Schedule of Activities: Treatment and Follow-up Period – Main Study): 
Instructions added to footnote ‘a’ to define how exposure to COVID-19 should be 
confirmed. 
Section 6.5.1 (COVID-19 Vaccine): Changes made to the procedures required to allow 
potential and current study participants to receive a COVID-19 vaccine.
Section 9.4.2.1 (Primary Endpoint): Text added to clarify a final analysis will be 
conducted at end of study.
Version 4.0, 16 December 2020
Key amendments and rationale for change:
Highly efficacious vaccines against SARS-CoV-2 are being deployed on a mass scale. Top 
priority target populations for vaccine administration in both the UK and US include 
residents of LTCF. These LTCF residents are a key target population for this study, with up 
to 80% of the study population to be drawn from them. Given the extreme vulnerability of 
this population, and the apparently high efficacy of the vaccines in the elderly, our study 
should not delay or obstruct vaccine access to those who could benefit from it. Therefore, 
guidance for SARS-CoV-2 vaccine use has been added to the protocol. 
The sample size assumptions have been revised to reflect changing expectations regarding 
the attack rate and assumed efficacy. These changes are based on external information 


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concerning possible treatments, prevention of COVID-19 by vaccination or subject patterns 
of infection and prevention. 
Participants will be permitted to enter the study if they have previously received 
immunoglobulins, including mAbs, that have been approved for an indication other than 
COVID-19. AZD7442 and other mAbs will not be co-administered. Monoclonal antibodies 
approved for indications other than COVID-19 that have been administered prior to 
consideration for this trial with not disqualify a subject from participation in this study. 
After randomization, they are permitted at any point during the study other than the day of 
IMP administration.
Allowing the use of other mAbs during the study does not appear to pose any safety risk. 
AZD7442's mAbs bind specifically to the receptor binding domain of the Spike protein of 
SAR-CoV-2, but not to human targets. Published mAb-mAb interaction studies are rare. 
One clinical study of coadministration of pertuzumab and trastuzumab + docetaxel via 
separate infusions, which each bind to different epitopes on the HER2 receptor, illustrated 
that the PK of one mAb is not affected by the administration of the other (Cortés et al 
2013). Therefore, it is not expected that the action of AZD7442 will be affected by the 
presence of another mAb, including its PK parameters, clearance and elimination. Any 
potential impact on AZD7442 PK will be examined for any participants that have received a 
commercial mAb.
Due to the ongoing unprecedented situation caused by the COVID-19 pandemic, 
AstraZeneca believes the opportunity to participate in AZD7442 clinical studies should be 
available to employees and their family members who are not involved in the AZD7442 
development program. Therefore, the criterion excluding AstraZeneca employees has been 
amended to allow those employees and their family members not involved in AZD7442 
development to receive the IMP if eligible for the study. This change aligns this restriction 
with the exclusion criterion currently used in AstraZeneca’s clinical study of its 
anti-SARS-CoV-2 vaccine, and is therefore consistent with existing precedent.
Synopsis, Figure 1 (Study Design), Sections 4.1 (Overall Design), 9.1 (Statistical 
Hypotheses), 9.2 (Sample Size Determination), 9.4.2.1 (Primary Endpoint), 9.5
(Interim Analyses), and Appendix A5 (Committees Structure): Text changed to include 
an interim analysis after 25 events, a change from 45 events. The primary analysis has been 
changed to 50 events, a change from 90 events. These changes are in line with the updated 
sample size assumptions reflecting changing expectations regarding the attack rate and 
assumed efficacy rate, based on external information. 
Synopsis, Sections 4.1 (Overall Design) and 6.3.1 (Randomization): The proportion of 
total participant recruitment not to be exceeded in Cohort 2 was changed from 50% to 80%.


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Table 1 (Schedule of Activities: Treatment and Follow-up Period – Main Study): For 
clarity ‘early’ has been added to the discontinuation visit column header.
Table 1 (Schedule of Activities: Treatment and Follow-up Period – Main Study), Table 
2 (Schedule of Activities: Illness Visits), and Section 8.5.2.3 (Assessment of Mucosal 
Responses): To allow for logistical problems caused by the COVID-19 pandemic, text has 
been added to indicate that nasal adsorption sampling can be missed only if test supplies are 
not available. 
Section 2.3.1 (Risk Assessment): The date of the data cut-off for risk assessment has been 
changed to 03 November 2020 to reflect the ongoing Study D8850C00001.
Section 5.2 (Exclusion criteria): Criterion 8 ‘Receipt of blood products or 
immunoglobulins, including mAbs, within 6 months, or 5 antibody half-lives if longer than 
6 months, prior to screening (see Table 6)’ has been deleted per the rationale provided 
above.
Section 5.2 (Exclusion Criteria): Criterion changed from: ‘12. Employees of the Sponsor, 
clinical study site, or any other individuals involved with the conduct of the study, or 
immediate family members of such individuals’ to ‘11. Employees of the Sponsor involved 
planning, executing, 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’.
Table 6 (Permitted, Restricted, and Prohibited Medications): The instruction that any 
SARS-CoV-2 or COVID-19 vaccines should not be considered a routine vaccine, has been 
added. 
New Section 6.5.1 (COVID-19 Vaccine): New section added to describe the procedures 
required to allow potential and current study participants to receive a COVID-19 vaccine.
Section 8.1.2 (Severe or Critical Criteria): Severe COVID-19 definition updated to match 
all AZD7442 studies ‘either pneumonia (fever, cough, tachypnea, dyspnea, lung infiltrates)’ 
changed to ‘either pneumonia (fever, cough, tachypnea, or dyspnea, and lung infiltrates)’.
Section 8.1.3 (Illness Visits): Text added to confirm that qualified staff should conduct 
home visits. 
Section 8.2.4 (Clinical Safety Laboratory Assessments): For clarity regarding required 
laboratory tests the calculation of eGFR has been added.


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Section 9.4 (Statistical Analyses): Added clarification that Sponsor/designated clinical 
research organization associated with the analysis, write-up and submission will be 
unblinded if overwhelming efficacy is demonstrated during interim analysis.
Sections 9.4 (Statistical Analysis) and 9.5 (Interim Analyses): Changes to the text to 
reflect that the planned DSMB assessments will now include a separate unblinded analysis 
team, designated by the Sponsor, for the early efficacy and safety assessments. 
Corrected typos have not been listed above. 
Version 3.0, 13 November 2020
Key amendment and rationale for change:
Changes have been made to the protocol in response to health authority comments, which 
requested the inclusion of increased safety monitoring with particular emphasis on potential 
hypersensitivity reactions immediately after IMP administration. As of 14 September 2020 
no hypersensitivity reactions have been observed in the Phase I study. Health authority 
comments also recommended considering testing the null hypothesis of no difference 
between treatment groups without a specific lower bound to demonstrate statistical 
superiority over placebo.
Title Page: Updated to include study acronym.
Synopsis, Figure 1 (Study Design), Sections 4.1 (Overall Design), 9.4 (Statistical Analyses), 
9.4.2.1 (Primary Endpoint), and 9.5 (Interim Analyses): Sections updated to include an 
interim analysis after 50% of the total statistical information is available, approximately 45 
events.
Synopsis, Table 1 (Schedule of Activities: Treatment and Follow-up Period – Main 
Study), Section 4.1 (Overall Design), and New Section Added 8.2.5.1 (Monitoring After 
IMP Administration): To increase safety monitoring immediately after IMP administration 
a Sentinel Cohort has been included, so that the first 15 participants are dosed and observed 
for 4 hours before further participants are dosed. The next 85 participants will undergo 
safety monitoring for 2 hours pose IMP administration and, if no hypersensitivity reactions 
are observed, the remaining participants will undergo safety monitoring for one hour post 
IMP administration. Should hypersensitivity reactions be observed in the first 100 
participants, all participants will be monitored for safety for at least 2 hours post IMP 


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administration. In addition, the Sentinel Cohort will be contacted daily for the first 4 days 
after IMP administration. 
Synopsis, Section 9.2 (Sample Size Determination): Further details added on the sample 
size assumptions.
Synopsis, Section 9.6 (Data Safety Monitoring Board), and Appendix A5 (Committees 
Structure): Text added to clarify the frequency of the data review meeting, and confirm 
that there is only one formal efficacy look by DSMB with the potential for early stopping 
due to efficacy planned for this study (ie, the interim analysis). Added criteria for pausing 
the study for DSMB review to ensure safety oversight (ie, halting the trial if AZD7442 is 
harmful).
Table 1 (Schedule of Activities: Treatment and Follow-up Period – Main Study): The 
time frame for the index SARS-CoV-2 case to which participant could have had potential 
exposure changed from 2 weeks to 8 days prior to Day 1. Text added to specify that the first 
15 participants (Sentinel Cohort) will be contacted daily for safety monitoring during the 
first 4 days after IMP administration.
Table 1 (Schedule of Activities: Treatment and Follow-up Period – Main Study) and 
Section 8.2.5 (Injection Site Inspection): Instructions added to footnote to increase the 
number of times the injection site is inspected after IMP administration and in the main 
body a list of assessments to be performed described.
Table 1 (Schedule of Activities: Treatment and Follow-up Period – Main Study) and 
Section 5.1 (Inclusion Criteria): Addition of inclusion criterion and modification to 
schedule of events clarifying that a negative SARS-CoV-2 serology test result is required at 
screening for inclusion in the study. 
Table 2 (Schedule of Activities: Illness Visits): An additional self-collected nasal swab for 
viral shedding omitted from the original protocol added to IL-D11.
Table 2 (Schedule of Activities: Illness Visits), Sections 8.1.1 (Monitoring COVID-19 
Symptoms), and 8.1.3 (Illness Visits): Table headers updated for clarity. Footnotes added 
to clarify the use of local versus central laboratory results, to allow home visits if necessary, 
and to specify that the Illness Visit schedule should be completed in addition to the Main 
Study schedule. 
Section 5.2 (Exclusion Criteria): Addition of new criterion to exclude participants who 
lack capacity to provide their own informed consent in jurisdictions where this is not 
permitted.


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Section 6.1.1 (IMP): Text added to clarify that should a participant experience an 
immediate hypersensitivity reaction after receipt of the first IM injection, the second IM 
injection should not be given. Instructions for anaphylactic reactions added to Appendix E.
Section 6.3.1 (Randomization): A reference to stratification was incorrectly included in the 
original protocol, text updated to ‘randomization will be maintained in a 2:1 ratio within 
each of the 2 cohorts’.
Table 6 (Permitted, Restricted, and Prohibited Medications): Updated to specify that 
participants who develop COVID-19 after receiving IMP should be treated according to 
local standard of care, including investigational agents outside a clinical trial setting. 
Section 7.4 (Study Suspension/Early Termination): Section updated to include stopping 
rules which will be implemented should a grade IV or SAE hypersensitivity reaction occur. 
Furthermore, the study will be paused should a grade III hypersensitivity or a grade III 
injection site reaction(s) occur within the first 100 participants. Due to the age and 
comorbidity profile of the study population, the grade III hypersensitivity/injection site 
reaction stopping rules are limited to the first 100 participants, this is to reduce the 
likelihood of unrelated events temporarily stopping the study.
Section 8.1.2 (Severe or Critical Criteria): Modified to correctly correspond with severe 
or critical criteria for COVID-19 based on pneumonia or hypoxemia parameters and the 
WHO clinical progression scale. WHO clinical progression scale updated to the recently 
published 10-point guideline.
Sections 8.1.1 (Monitoring COVID-19 Symptoms) and 8.3.6 (Adverse Events Based on 
Signs and Symptoms): Clarified that symptoms of COVID-19, confirmed SARS-CoV-2 
infection, and/or diagnosis of COVID-19 will be collected and recorded in the eCRF as an 
AE.
Section 8.1.6 (Illness e-Diary) and New Appendix F (e-Diary): To allow for version 
control the e-Diary has been added to the appendices. 
Section 8.2.4.1 (Females Only): Footnotes added to clarify pregnancy and FSH testing. 
Section 8.3.2 (Follow-up of AEs and SAEs) and Appendix B2 (Definition of Serious 
Adverse Events): Severity ratings adjusted to align with CTCAE event grading.
Section 8.3.4 (Adverse Events of Special Interest) and New Appendix Added Appendix 
E (Anaphylaxis): Appendix E added to describe definition and management of anaphylaxis 
and other hypersensitivity/administration reactions. Injection site reaction(s) added as an 
AESI.


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Synopsis, Sections 9.1 (Statistical Hypotheses), 9.2 (Sample Size Determination), 
9.4.2.1 (Primary Endpoint), and 9.4.2.2 (Secondary Analysis): Removal of “lower bound 
of 2-sided 95% CI is required to be greater than 30%” constraint from the statistical 
significance criteria. The null hypothesis testing no difference between AZD7442 and 
placebo groups is considered sufficient for demonstrating statistical superiority over 
placebo in a more targeted population. 
Section 9.4.5 (Methods for Multiplicity Control): To reflect changes in CI the methods 
for multiplicity control were updated. 
Version 2.0, 26 October 2020
Key amendment and rationale for change:
Synopsis, and Section 7.4 (Study Suspension/Early Termination): Addition of wording 
that if the study is suspended and does not proceed following evaluation of cumulative 
safety data from the first 100 participants enrolled, or after 4 weeks from first participant 
dosed, a protocol amendment will be submitted to Health Authorities.
Version 1.0, 07 October 2020
Initial creation


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11
REFERENCES
CDC. (Centers for Disease Control and Prevention). Coronavirus Disease 2019 (COVID-19), 
Symptoms of Coronavrus. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-
testing/symptoms.html. Published 2020. Accessed 01 July 2020.
Cortés J, Swain SM, Kudaba I, Hauschild M, Patel T, Grincuka E et al. Absence of 
pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel. 
Anticancer Drugs. 2013;24(10):1084-92.
Gorbalenya A, Baker S, Baric R, de Groot R, Drosten C, Gulyaeva A et al. The species Severe 
acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-
CoV-2. Nature microbiology. 2020;5(4):536-44.
Li F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu Rev Virol. 
2016;3(1):237-61.
Marshall JC, Murthy S, Diaz J, Adhikari NK, Angus DC, Arabi YM et al. A minimal common 
outcome measure set for COVID-19 clinical research. The Lancet Infectious Diseases. 
2020;20(8):e192-e7.
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4(2):213-26.
NIH. (National Institutes of Health). Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. 
Published 2017. Accessed 11 November 2020.
WHO. WHO Coronavirus Disease (COVID-19) Dashboard.  2020.
Xie Y, Wang Z, Liao H, Marley G, Wu D, Tang W. Epidemiologic, clinical, and laboratory 
findings of the COVID-19 in the current pandemic: systematic review and meta-analysis. 
BMC Infect Dis. 2020;20(1):640.
Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W et al. A pneumonia outbreak 
associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-3.
Zou G. A modified poisson regression approach to prospective studies with binary data. Am J 
Epidemiol. 2004;159(7):702-6.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d8850c00003-csp-v6
Document Title:
D8850C00003 Clinical Study Protocol version 6
Document ID:
Doc ID-004386312
Version Label:
6.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
12-Mar-2021 20:30 UTC
Content Approval
12-Mar-2021 18:07 UTC
Management Approval
12-Mar-2021 21:48 UTC
Content Approval
12-Mar-2021 16:32 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
PPD
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SAP_005.pdf: 
Statistical Analysis Plan
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STATISTICAL ANALYSIS PLAN
D8850C00003
A PHASE III RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED,
MULTI-CENTER 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
AUTHOR:
VERSION NUMBER AND DATE: V3.1 APRIL 7, 2021
PPD


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MODIFICATION HISTORY
Unique 
Identifier for 
this Version
Date of the 
Document 
Version
Author
Significant Changes from 
Previous Version
1.0
29Dec2020
 
Not Applicable – First Version
2.0
26Mar2021
Given that the probability of a participant being 
exposed to COVID-19 will diminish with 
increased vaccination roll-out, the primary 
analysis will be conducted 30 days after the 25th
event has been confirmed. To reflect this change 
in the timing of the primary analysis the interim 
analysis and related activities have been removed.
Enrollment will be stopped after the 25th primary 
endpoint event has been confirmed, or after 1125 
participants have been randomized, whichever 
comes first.
To provide safety and PK assessments after 5 
half-lives, the study has been extended to 15 
months from last visit on Day 366 to last visit on 
Day 457. An optional serum sample for PK, ADA 
and nAb to be added at Day 457. Endpoints for 
safety and nAb have been adjusted to reflect this 
additional time point.
Caps for Cohorts 1 and 2, not to exceed 80% of 
the total participants randomized, have been 
removed. 
During screening the eCRF is already capturing 
participant ECOG grade and therefore, for 
consistency, Performance Status has been added 
to Medical History.
3.0
06Apr2021
The planned primary analyses and authoring of 
the SAP will no longer be conducted by the 
analysis team at IQVIA. Sections in 4.3 and 4.4 
have been revised to indicate AstraZeneca has 
assumed responsibility as the study sponsor for 
the primary analysis.
To clearly maintain the relationship between the 
RT-PCR sample and symptoms for the primary 
PPD
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endpoint durations were set around the 
assessment of qualifying symptoms. The 
durations have been adjusted from the previous 
version to have the Rt-PCR samples collected 
within 5 days prior or 10 days following the 
assessment of qualifying symptoms. See section 
16.1. 
To clarify the definition of “High risk for severe 
Covid-19” Appendix 6 was added specifying data 
sources to be used when programming each 
condition. 
3.1
06Apr2021
Added text to allow Anterior Nasal Swabs to be 
included in the RT-PCR tests used in the primary 
endpoint.
TABLE OF CONTENTS
1.
INTRODUCTION ...........................................................................................................8
2.
STUDY OBJECTIVES AND ESTIMANDS ..................................................................8
2.1.
Primary Objectives ...................................................................................................................................8
2.2.
Secondary Objectives................................................................................................................................8
2.3.
Exploratory Objectives.............................................................................................................................9
2.4.
Estimands................................................................................................................................................ 10
3.
STUDY DESIGN ...........................................................................................................21
3.1.
General Description ................................................................................................................................ 21
3.2.
Schedule of Events .................................................................................................................................. 22
3.3.
Changes to Analyses from Protocol ........................................................................................................ 22
4.
PLANNED ANALYSES................................................................................................22
4.1.
Data and Safety Monitoring Board......................................................................................................... 22
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4.2.
Interim Analysis...................................................................................................................................... 23
4.3.
Primary Analysis..................................................................................................................................... 23
4.4.
Final Analysis.......................................................................................................................................... 23
5.
ANALYSIS SETS..........................................................................................................23
5.1.
All Participants Analysis Set................................................................................................................... 23
5.2.
Full Analysis Set...................................................................................................................................... 23
5.3.
Safety Analysis Set.................................................................................................................................. 24
5.4.
Pharmacokinetic Analysis Set................................................................................................................. 24
5.5.
ADA Evaluable Analysis Set................................................................................................................... 24
5.6.
nAb Evaluable Analysis Set.................................................................................................................... 25
5.7.
Symptomatic COVID-19 Analysis Set.................................................................................................... 25
6.
GENERAL CONSIDERATIONS.................................................................................25
6.1.
Reference Start Date and Study Day...................................................................................................... 25
6.2.
Baseline ................................................................................................................................................... 25
6.3.
Unscheduled Visits, Retests, and Early Termination Data..................................................................... 26
6.4.
Windowing Conventions......................................................................................................................... 26
6.5.
Common Calculations............................................................................................................................. 28
7.
STATISTICAL CONSIDERATIONS..........................................................................29
7.1.
Sample Size Calculation.......................................................................................................................... 29
7.2.
Missing data............................................................................................................................................ 29
7.3.
Statistical Tests........................................................................................................................................ 30
7.4.
Multiple Comparisons/ Multiplicity ....................................................................................................... 30
7.5.
Multicenter Studies................................................................................................................................. 30
7.6.
Examination of Subgroups...................................................................................................................... 30
7.7.
Software Version..................................................................................................................................... 31


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8.
OUTPUT PRESENTATIONS ......................................................................................31
9.
DISPOSITION AND WITHDRAWALS......................................................................31
9.1.
Disposition............................................................................................................................................... 31
9.2.
Protocol Deviations ................................................................................................................................. 32
10.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.......................32
10.1.
Derivations .......................................................................................................................................... 33
11.
MEDICAL HISTORY...................................................................................................33
12.
CONCOMITANT ILLNESSES....................................................................................33
13.
MEDICATIONS............................................................................................................34
14.
EXPOSURE TO STUDY INTERVENTION ...............................................................34
15.
COMPLIANCE WITH STUDY INTERVENTION ....................................................34
16.
EFFICACY ENDPOINTS.............................................................................................34
16.1.
Primary Efficacy................................................................................................................................. 35
16.1.1.
Primary Efficacy Endpoint................................................................................................................. 35
16.1.2.
Missing Data Imputation Method for Primary Efficacy Endpoint........................................................ 36
16.1.3.
Primary Estimand.............................................................................................................................. 36
16.1.4.
Primary Analysis of Primary Efficacy Endpoint................................................................................. 37
16.1.5.
Sensitivity Analyses for Primary Efficacy Endpoint........................................................................... 38
16.1.6.
Supplementary Analyses for Primary Efficacy Endpoint .................................................................... 40
16.1.7.
Subgroup Analyses for Primary Efficacy Endpoint............................................................................. 40
16.1.8.
Additional Estimands for Primary Efficacy Endpoint ......................................................................... 40
16.2.
Secondary Efficacy.............................................................................................................................. 43
16.2.1.
Key Secondary Efficacy Endpoint...................................................................................................... 43
16.2.2.
Estimands for Key Secondary Efficacy .............................................................................................. 44
16.2.3.
Other Secondary Efficacy Endpoints.................................................................................................. 47
16.2.3.1.
The Incidence of Participants Who Have a Post-Treatment Response (Negative at Baseline to 
Positive at Any Time Post-Baseline) for SARS-CoV-2 Nucleocapsid Antibodies........................................... 47
16.2.3.2.
The incidence of COVID-19 related death occurring after dosing with IMP................................ 47
16.2.3.3.
The incidence of all-cause mortality occurring after dosing with IMP ......................................... 47
16.2.4.
Missing Data Imputation Method for Secondary Efficacy Endpoints .................................................. 48
16.2.5.
Analysis of Secondary Efficacy Endpoints......................................................................................... 48
16.2.6.
Sensitivity Analyses for Secondary Efficacy Endpoints...................................................................... 48
16.2.7.
Supplementary Analyses for Secondary Efficacy Endpoints ............................................................... 48
16.2.8.
Subgroup Analyses for Secondary Efficacy Endpoints ....................................................................... 48


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16.3.
Exploratory Efficacy........................................................................................................................... 48
16.3.1.
Exploratory Efficacy Endpoints......................................................................................................... 49
16.3.1.1.
Viral Genome Copies in NP Swabs Collected at Illness Visits as Determined by qRT-PCR......... 49
16.3.1.2.
Genotypic Analysis and Biochemical and/or Susceptibility Analysis of SARS-CoV-2 Variants to 
AZD7442 (Illness Visits Only)...................................................................................................................... 49
16.3.1.3.
Symptoms recorded by participants in an Illness e-Diary from Illness Visits Day 2 through Day 28
49
16.3.1.4.
Assessment of additional immune responses following a single IM dose of AZD7442 or placebo 50
16.3.2.
Missing Data Imputation Method for Exploratory Efficacy Endpoints ................................................ 50
16.3.3.
Sensitivity Analyses for Exploratory Efficacy Endpoints.................................................................... 50
16.3.4.
Supplementary Analyses for Exploratory Efficacy Endpoints............................................................. 50
17.
PHARMACOKINETIC, PHARMACODYNAMIC AND ADA ENDPOINTS ..........50
17.1.
Analysis of PK, PD and ADA Endpoints ............................................................................................ 51
17.1.1.
Serum AZD7442 Concentrations ....................................................................................................... 51
17.1.2.
The Incidence of ADA to AZD7442 in Serum.................................................................................... 51
17.1.2.1.
ADA Variables.......................................................................................................................... 51
17.1.2.2.
ADA Analysis ........................................................................................................................... 52
17.1.3.
AZD7442 Nasal Fluid Concentrations................................................................................................ 52
17.1.4.
Neutralizing Antibody Geometric Mean Titers and Geometric Mean Fold Rise .................................. 52
17.1.5.
Missing Data Imputation Method for PK, PD and ADA Endpoints..................................................... 53
17.1.6.
Sensitivity Analyses for Exploratory Efficacy Endpoints.................................................................... 54
17.1.7.
Supplementary Analyses for Exploratory Efficacy Endpoints............................................................. 54
18.
SAFETY ENDPOINTS .................................................................................................54
18.1.
Adverse Events.................................................................................................................................... 55
18.1.1.
Adverse Events and Serious Adverse Events...................................................................................... 55
18.1.1.1.
Severity for AEs ........................................................................................................................ 56
18.1.1.2.
Relationship to IMP/Other Medication/Study Procedure............................................................. 56
18.1.2.
AEs Leading to Discontinuation of IMP............................................................................................. 56
18.1.3.
AEs Leading to Discontinuation of Study........................................................................................... 56
18.1.4.
AEs with Outcome of Death .............................................................................................................. 57
18.1.5.
Medically Attended Adverse Events .................................................................................................. 57
18.1.6.
Adverse Events of Special Interest..................................................................................................... 57
18.2.
Deaths.................................................................................................................................................. 57
18.3.
Laboratory Evaluations ...................................................................................................................... 57
18.3.1.
CTCAE Toxicity Grades ................................................................................................................... 58
18.3.2.
Laboratory Normal Ranges................................................................................................................ 59
18.4.
Vital Signs............................................................................................................................................ 59
18.5.
ECG Evaluations................................................................................................................................. 60
18.5.1.
ECG Markedly Abnormal Criteria ..................................................................................................... 61
18.6.
Physical Examination.......................................................................................................................... 61
19.
OTHER DATA COLLECTED.....................................................................................61


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20.
REFERENCES..............................................................................................................62
APPENDIX 1.
PARTIAL DATE CONVENTIONS............................................................63
Algorithm for Prior / Concomitant Medications ............................................................................................... 63
APPENDIX 2.
PROGRAMMING CONVENTIONS FOR OUTPUTS .............................65
Dates & Times .................................................................................................................................................... 65
Spelling Format.................................................................................................................................................. 65
Paper Size, Orientation, and Margins................................................................................................................ 65
Fonts ................................................................................................................................................................... 65
Presentation of Treatment Groups .................................................................................................................... 65
Presentation of Nominal Visits........................................................................................................................... 66
Descriptive Statistics........................................................................................................................................... 67
Percentages......................................................................................................................................................... 67
p-values............................................................................................................................................................... 67
Listings ............................................................................................................................................................... 67
APPENDIX 3.
LABORATORY ASSESSMENTS..............................................................68
APPENDIX 4.
CTCAE TOXICITY GRADE, VERSION 5.0 ............................................69
APPENDIX 5.
CLINICAL ABNORMALITIES: VITAL SIGNS......................................73
APPENDIX 6.
HIGH RISK OF SEVERE COVID-19 AT BASELINE .............................74


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1. INTRODUCTION
This statistical analysis plan (SAP) describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for protocol D8850C00003. It describes the data to be summarized and analyzed, including 
specifics of the statistical analyses to be performed. 
This SAP is based on protocol version 6.0, dated 12Mar2021.
The term IMP (investigational medicinal product) is used throughout this SAP to include both treatment groups 
(AZD7442 and placebo). AZD7442 is specified when referring only to those who received active intervention.
2. STUDY OBJECTIVES AND ESTIMANDS
2.1.
PRIMARY OBJECTIVES
The primary objectives are:
!
To estimate the efficacy of a single intramuscular (IM) dose of AZD7442 compared to placebo for 
the prevention of coronavirus disease 2019 (COVID-19);
!
To assess the safety and tolerability of a single IM dose of AZD7442 compared to placebo.
2.2.
SECONDARY OBJECTIVES
The key secondary objective is:
!
To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of 
severe or critical symptomatic COVID-19.
The other secondary objectives are:
!
To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of 
severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection;
!
To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of 
COVID-19-related death;
!
To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of 
all-cause mortality;
!
To assess the pharmacokinetics (PK) of AZD7442 administered as a single dose of 300 mg IM;
!
To evaluate anti-drug antibody (ADA) responses to AZD7442 in serum.


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2.3.
EXPLORATORY OBJECTIVES
The exploratory objectives are:
!
To evaluate the single dose PK concentrations of AZD7442 in nasal fluid;
!
To determine anti-SARS-CoV-2 neutralizing antibody (nAb) levels in serum following a single IM 
dose of AZD7442 or placebo;
!
To quantify SARS-CoV-2 viral loads in infected participants treated with a single IM dose of 
AZD7442 or placebo (Illness Visits);
!
To quantify duration of viral shedding in participants with symptomatic COVID-19 treated with a 
single IM dose of AZD7442 or placebo (Illness Visits);
!
To characterize resistance to AZD7442 (Illness Visits) – not covered by this SAP;
!
To assess symptoms associated with COVID-19 using an e-Diary in participants treated with a single 
IM dose of AZD7442 or placebo (Illness Visits only);
!
To assess additional immune responses following a single IM dose of AZD7442 or placebo – not 
covered by this SAP.


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2.4.
ESTIMANDS
Table A:
List of Estimands - Primary
Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
The efficacy 
of a single IM 
dose of 
AZD7442 
compared to 
placebo for 
the 
prevention of 
COVID-19
Full analysis set, defined as all participants
who were randomized and received at least 
one of the planned injections of IMP. 
Targeted participants will have the 
following characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of imminently 
developing COVID-19, based on available 
risk assessment at time of enrollment
Single dose 
of 
AZD7442 
(× 2 IM 
injections, 
1 for each 
mAb 
component)
or placebo
A binary response, 
whereby a participant is 
defined as a COVID-19 
case if their first case of 
SARS-CoV-2 RT-PCR-
positive symptomatic 
illness occurs post dose
of IMP and prior to day 
183.
For participants who 
become unblinded to 
properly consider 
vaccination for COVID-19,
take COVID-19 vaccine or 
other COVID-19 preventive 
product prior to having met 
the criteria for the primary 
efficacy endpoint, the data 
will be collected and 
analyzed regardless  (i.e., 
intercurrent events will be 
handled using treatment 
policy strategy).
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.) 
The safety 
and 
tolerability of 
a single IM 
dose of 
Safety analysis set, defined as all 
participants who received at least one of the 
planned injections of IMP. Targeted 
participants will have the following 
Single dose 
of 
AZD7442 
(× 2 IM 
injections, 
Incidence of adverse 
events, serious adverse 
events, medically 
attended adverse events, 
and adverse events of 
Not Applicable
Descriptive 
statistics, including 
number and 
percentages of 
participants who 


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Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
AZD7442 
compared to 
placebo 
characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of imminently 
developing COVID-19, based on available 
risk assessment at time of enrollment
1 for each 
mAb 
component)
or placebo
special interest post dose 
of IMP.
have the incidence, 
and number of 
events.


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Table B:
List of Estimands – Key Secondary
Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/Endpoint
Intercurrent event handling 
strategy
Population-level 
summary measure
The efficacy of a 
single IM dose of 
AZD7442 
compared to 
placebo for the 
prevention of 
severe or critical 
symptomatic 
COVID-19
Full analysis set (see definition in 
primary estimands). Targeted 
participants will have the following 
characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of 
imminently developing COVID-19, 
based on available risk assessment at 
time of enrollment
Single dose 
of 
AZD7442 
(× 2 IM 
injections, 
1 for each 
mAb 
component)
or placebo
The incidence of 
SARS-CoV-2 RT-PCR-
positive severe or 
critical symptomatic 
illness occurring after 
dosing with IMP.
For participants who become 
unblinded to properly 
consider vaccination for 
COVID-19, take COVID-19 
vaccine or other COVID-19 
preventive product prior to 
having met the criteria for 
this endpoint, data will be 
collected and analyzed 
regardless (i.e., intercurrent 
events will be handled using 
treatment policy strategy)
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of severe 
or critical 
symptomatic illness
in the AZD7442 
group relative to the 
incidence of severe 
or critical 
symptomatic illness
in the control 
group.)


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Table C:
List of Estimands –Secondary
Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/Endpoint
Intercurrent event handling 
strategy
Population-level 
summary measure
The efficacy of a 
single IM dose of 
AZD7442 
compared to 
placebo for the 
prevention of 
SARS-CoV-2 
infection
Full analysis set (see definition in 
primary estimands). Targeted 
participants will have the following 
characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of 
imminently developing COVID-19, 
based on available risk assessment at 
time of enrollment
Single dose 
of 
AZD7442 
(× 2 IM 
injections, 
1 for each 
mAb 
component)
or placebo
The incidence of 
participants who have a 
post-treatment response 
(negative at baseline to 
positive at any time 
post-baseline) for 
SARS-CoV-2 
nucleocapsid 
antibodies.
For participants who become 
unblinded to properly 
consider vaccination for 
COVID-19, take COVID-19 
vaccine or other COVID-19 
preventive product prior to 
having met the criteria for 
this secondary efficacy 
endpoint, the data will be 
collected and analyzed 
regardless (i.e., intercurrent 
events will be handled using 
treatment policy strategy).
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.)


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Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/Endpoint
Intercurrent event handling 
strategy
Population-level 
summary measure
To estimate the 
efficacy of a 
single IM dose of 
AZD7442 
compared to 
placebo for the 
prevention of 
COVID-19-
related death
Full analysis set (see definition in 
primary objectives). Targeted 
participants will have the following 
characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of 
imminently developing COVID-19, 
based on available risk assessment at 
time of enrollment
Single dose 
of 
AZD7442 
(× 2 IM
injections, 
1 for each 
mAb 
component)
or placebo
The incidence of 
COVID-19-related 
death occurring after 
dosing with IMP
For participants who become 
unblinded to properly 
consider vaccination for 
COVID-19, take COVID-19 
vaccine or other COVID-19 
preventive product prior to 
having met the criteria for 
this secondary efficacy 
endpoint, the data will be 
collected and analyzed 
regardless (i.e., intercurrent 
events will be handled using 
treatment policy strategy).
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
COVID-19 related 
death in the 
AZD7442 group 
relative to the 
incidence of 
COVID-19 related 
death in the control 
group.)


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Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/Endpoint
Intercurrent event handling 
strategy
Population-level 
summary measure
To estimate the 
efficacy of a 
single IM dose of 
AZD7442 
compared to 
placebo for the 
prevention of all-
cause mortality
Full analysis set (see definition in 
primary estimands). Targeted 
participants will have the following 
characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of 
imminently developing COVID-19, 
based on available risk assessment at 
time of enrollment
Single dose 
of 
AZD7442 
(× 2 IM 
injections, 
1 for each 
mAb 
component)
or placebo
The incidence of all-
cause mortality 
occurring after dosing 
with IMP.
For participants who become 
unblinded to properly 
consider vaccination for 
COVID-19, take COVID-19 
vaccine or other COVID-19 
preventive product prior to 
having met the criteria for 
this secondary efficacy 
endpoint, the data will be 
collected and analyzed 
regardless (i.e., intercurrent 
events will be handled using 
treatment policy strategy).
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of death
(all-cause) in the 
AZD7442 group 
relative to the 
incidence of death
(all-cause) in the 
control group.)


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Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/Endpoint
Intercurrent event handling 
strategy
Population-level 
summary measure
The 
pharmacokinetics 
of AZD7442 
administered as a 
single dose of 
300 mg IM
Pharmacokinetic analysis set, defined as 
all participants who receive at least one 
of the planned injections of 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. Targeted 
participants will have the following 
characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of 
imminently developing COVID-19, 
based on available risk assessment at 
time of enrollment
Single dose 
of 
AZD7442 
(× 2 IM 
injections, 
1 for each 
mAb 
component)
or placebo
Serum AZD7442 
concentrations.
PK parameters if data 
permit.
Not Applicable
Individual 
AZD7442 
(AZD8895 and 
AZD1061) serum 
concentration data 
descriptive 
statistics; 
Pharmacokinetic 
exposure (i.e., 
AUCs) and other 
PK parameters may 
be estimated using 
non compartmental 
analysis, if data 
permit.


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Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/Endpoint
Intercurrent event handling 
strategy
Population-level 
summary measure
ADA responses 
to AZD7442 in 
serum
ADA evaluable analysis set, defined as 
all participants who received at least one 
of the planned injections of IMP and
who have a non-missing baseline 
AZD7442 ADA result and at least one 
non-missing post-baseline AZD7442 
ADA result. Targeted participants will 
have the following characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of 
imminently developing COVID-19, 
based on available risk assessment at 
time of enrollment
Single dose 
of 
AZD7442 
(× 2 IM 
injections, 
1 for each 
mAb 
component)
or placebo
Incidence of ADA to 
AZD7442 in serum.
Not Applicable
Descriptive statistics 
including the 
number and 
percentage of 
participants who 
have developed 
ADAs to AZD7442.


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Table D:
List of Estimands – Exploratory
Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/ 
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
The single dose 
pharmacokinetic 
concentrations of 
AZD7442 in 
nasal fluid
A subset of the pharmacokinetic analysis set, 
per available data, defined as all participants 
who receive at least one of the planned 
injections of AZD7442, from whom PK 
nasal fluid samples are assumed not to be 
affected by factors such as protocol 
violations, and who had at least one 
quantifiable nasal fluid PK observation post 
dose. Targeted participants will have the 
following characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of imminently 
developing COVID-19, based on available 
risk assessment at time of enrollment
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component)
AZD7442 nasal 
concentrations.
Not Applicable
Individual 
concentration data 
with descriptive 
statistics
Anti-SARS-
CoV-2 nAb 
levels in serum 
The nAb evaluable analysis set, defined as 
all participants who received at least one of 
the planned injections of IMP, from whom 
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
Post-treatment 
GMTs and 
GMFRs from 
Not Applicable
GMT and GMFR 
with descriptive 
statistics


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/ 
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
following a 
single IM dose 
of AZD7442 or 
placebo
blood samples are assumed not to be affected 
by factors such as protocol violations, and 
who had at least one quantifiable serum titer 
observation post dose. Targeted participants 
will have the following characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of imminently 
developing COVID-19, based on available 
risk assessment at time of enrollment
mAb component) or 
placebo
baseline value 
through Day 457
after single IM 
dose in SARS-
CoV-2 
neutralizing 
antibodies (wild-
type assay or 
pseudo 
neutralization 
assay).
SARS-CoV-2 
viral loads in 
infected 
participants 
treated with a 
single IM dose 
of AZD7442 or 
placebo (Illness 
Visits)
Symptomatic COVID-19 analysis set,
defined as all participants who were 
randomized, received at least one of the 
planned injections of IMP, did not have a 
prior SARS-CoV-2 RT-PCR-positive 
confirmed COVID-19 infection, and who 
met the criteria for symptomatic COVID-19 
and began Illness Visits following confirmed 
SARS-CoV-2 infection. Targeted 
participants will have the following 
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
Viral genome 
copies in NP 
swabs collected at 
Illness Visits as 
determined by 
qRT-PCR.
Not Applicable
Observed and 
change from 
baseline descriptive 
statistics


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/ 
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of imminently 
developing COVID-19, based on available 
risk assessment at time of enrollment.
Symptoms 
associated with 
COVID-19 using 
an e-Diary in 
participants 
treated with a 
single IM dose 
of AZD7442 or 
placebo (Illness 
Visits only)
Symptomatic COVID-19 analysis set (see 
definition above). Targeted participants will 
have the following characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of imminently 
developing COVID-19, based on available 
risk assessment at time of enrollment.
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
Symptoms 
recorded by 
participants in an 
Illness e-Diary 
from Illness Visits 
Day 2 through 
Day 28.
Not Applicable
Descriptive 
statistics, including 
number and 
percentage of 
participants with 
symptoms.


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3. STUDY DESIGN
3.1.
GENERAL DESCRIPTION
This is a Phase III, randomized, double-blind, placebo-controlled, multi-center study assessing the safety and 
efficacy of a single dose of AZD7442 (× 2 IM injections) compared to placebo for the prevention of COVID-19. 
Approximately 100 sites will participate in this study.
Participants will be adults ≥ 18 years of age with potential exposure, within 8 days to a specific identified individual 
with laboratory-confirmed SARS-CoV-2 infection, symptomatic or asymptomatic, who are therefore at appreciable 
risk of imminently developing COVID-19, based on available risk assessment at time of enrollment (see Protocol 
Section 5.1). Participants will be enrolled into one of 2 cohorts:
!
Cohort 1: Adults ≥ 60 years of age, living in long term care facilities. In this context, long-term care 
facilities include skilled nursing facilities, assisted living facilities, and independent living facilities 
for senior adults. In this cohort, “potential exposure to a specific identified individual with 
laboratory-confirmed SARS-CoV-2 infection" is defined to mean the occurrence of SARS-CoV-2 
infection, symptomatic or asymptomatic, in another resident of the facility or in a staff member of the 
facility. 
!
Cohort 2: Other adults ≥ 18 years of age with potential exposure to a specific identified individual 
with laboratory-confirmed SARS-CoV-2 infection. Such individuals may include, but are not limited 
to those living in institutional residences (military lodging, dormitories, etc.), household contacts, 
health care workers, long term care facility workers, and workers in occupational or industrial 
settings in which close contact is common. 
The first 15 participants (Sentinel Cohort), will undergo safety monitoring for 4 hours post IMP administration 
before dosing further participants. The next 85 participants will undergo safety monitoring for 2 hours pose IMP 
administration, and, if no hypersensitivity reactions are observed, the remaining participants will undergo safety 
monitoring for 1 hour post IMP administration. Should hypersensitivity reactions be observed, in the first 100 
participants, all participants will be monitored for safety for at least 2 hours post IMP administration.
Up to 1125 participants will be randomized in a 2:1 ratio to receive a single dose (× 2 IM injections) of either 300 
mg of AZD7442 (n = approximately 750) or saline placebo (n = approximately 375) on Day 1. Enrollment will 
continue until the 25th primary endpoint event has been confirmed, or until 1125 subjects have been enrolled, 
whichever comes first. Formal efficacy assessment is intended at the primary analysis, 30 days after the 25th primary 
endpoint has occurred. 
Following a screening evaluation, on the same day participants will receive a single dose (× 2 IM injections) of IMP. 
After administration of the dose of IMP on Day 1, participants will undergo follow-up as stated in the schedule of 
activities.  All participants in the study will be assessed for efficacy with all data available through their last 


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assessment up to visit Day 366 and PK, ADA, nAbs and safety will be assessed up to 15 months following the dose 
of IMP.
Figure A: Study Design
a
Primary analysis to be conducted 30 days after the 25th event is observed.
Note: An independent Data Safety Monitoring Board (DSMB) will review available safety and efficacy data after 
the first 100 participants have been dosed, or after 4 weeks from first participant dosed, whichever comes first. 
Enrollment will not be paused pending the DSMB’s review.
3.2.
SCHEDULE OF EVENTS
Schedule of events can be found in Section 1.3 of the protocol.
3.3.
CHANGES TO ANALYSES FROM PROTOCOL
There are no changes to the analyses planned in the protocol.
4. PLANNED ANALYSES
4.1.
DATA AND SAFETY MONITORING BOARD 
An independent DSMB will provide oversight, to ensure safe and ethical conduct of the study.
The DSMB will meet monthly and make any necessary recommendations to the Sponsor based on their evaluations 
of emerging data. 
In particular, the evaluation of cumulative safety data from the first 100 participants enrolled will be performed by 
the DSMB, who will advise the Sponsor on whether it is appropriate to proceed. This evaluation will take place as 


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soon as practical after randomization of the study’s 100th participant or after 4 weeks from first participant dosed, 
whichever comes first. Study enrollment will not be paused pending or during this evaluation by the DSMB.
Further details, composition, and operation of the independent DSMB will be described in a DSMB Charter.
4.2.
INTERIM ANALYSIS
No Interim Analysis is planned.
4.3.
PRIMARY ANALYSIS
The primary analysis will be conducted 30 days after 25 primary endpoint events have been observed across the 
active and control groups. The date for the Data Cutoff for this analysis will be calculated as date of onset of 
primary endpoint event (+30 days). 
All planned primary analyses are detailed in this SAP and will be performed by AstraZeneca or its delegates
following authorization of this SAP, authorization of the analysis sets, database lock (DBL), and analysis team
unblinding. The primary analysis will be carried out by an unblinded analysis team, and the procedure will be 
detailed in an unblinding plan; participant level unblinding information will be kept strictly confidential, and 
rationale for any unblinding will be documented.
4.4.
FINAL ANALYSIS 
The final analysis will be conducted at the end of the study, i.e., after the last participant dosed has completed the 
Day 457 visit, regardless of the number of events. This analysis will not be controlled for multiplicity and statistical 
hypotheses will be tested at a nominal 5% significance level (based on a 2-sided test).
All planned final analyses are detailed in this SAP and will be performed by AstraZeneca or its delegates following 
authorization of this SAP, authorization of the analysis sets, DBL, and general study unblinding.
5. ANALYSIS SETS
5.1.
ALL PARTICIPANTS ANALYSIS SET
The all participants analysis set (PAS) will contain all participants who provide informed consent for this study.
5.2.
FULL ANALYSIS SET
The Full Analysis Set (FAS) will contain all participants in the PAS who were randomized and received at least one 


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of the planned injections of IMP, irrespective of their protocol adherence and continued participation in the study. 
(Note: Per the protocol a dose is two injections, but any participant receiving at least one injection will be included 
in the FAS based on intent-to-treat (ITT) principle). Participants will be analyzed according to their randomized 
treatment irrespective of whether or not they have prematurely discontinued, according to the ITT principle. 
Participants who withdraw consent or assent to participate in the study will be included up to the date of their study 
termination.
For analyses and displays based on the FAS, participants will be classified according to randomized treatment 
regardless of what treatment they actually received.
5.3.
SAFETY ANALYSIS SET
The safety analysis set (SAF) will contain all participants in the PAS who received at least one of the planned 
injections of IMP. (Per the protocol a dose is two injections, but any participant receiving at least one injection will 
be included in the SAF to account for safety in all participants receiving any injection).     
For analyses and displays based on SAF, participants will be classified according to the actual treatment received.
Erroneously-treated participants (e.g., those randomized to treatment A, but were actually given treatment B) are 
accounted for in this analysis set by assigning them to the treatment they actually received. A participant who has 
once or on several occasions received active IMP will be classified as active.
5.4.
PHARMACOKINETIC ANALYSIS SET
The PK analysis set will contain all participants in the PAS who received at least one injection of AZD7442 
components 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. (Per the protocol a dose is two injections, but 
any participant receiving one injection will be accounted for in the corresponding individual mAb component).    
For analyses and displays based on PK analysis set, participants will be included according to the actual treatment 
received. Participants who received placebo will not be included. Summaries will be displayed by the individual 
mAb components, AZD8895 and AZD1061.
5.5.
ADA EVALUABLE ANALYSIS SET
The ADA evaluable analysis set will contain all participants who received at least one of the planned injections of
IMP and who have a non-missing baseline AZD7442 ADA result and at least one non-missing post-baseline 
AZD7442 ADA result.


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5.6.
NAB EVALUABLE ANALYSIS SET
The SARS-CoV-2 nAb evaluable analysis set will contain all participants in the SAF from whom blood samples are 
assumed not to be affected by factors such as protocol violations, and who had at least one quantifiable serum 
observation post dose.
5.7.
SYMPTOMATIC COVID-19 ANALYSIS SET
The symptomatic COVID-19 analysis set will include all participants in the FAS who met the criteria for 
symptomatic COVID-19 and began Illness Visits following confirmed SARS-CoV-2 infection.
6. GENERAL CONSIDERATIONS
6.1.
REFERENCE START DATE AND STUDY DAY
Study Day will be calculated from the reference start date and will be used to show start/stop day of assessments and 
events. Reference start date is defined as the day of the dose of IMP i.e., Day 1.
Study Day will be computed as follows:
!
Study Day = (Date of event –Date of dose of IMP) + 1 if the date of the event is on or after the date 
of the dose of IMP;
!
Study Day = (Date of event – Date of dose of IMP) if the date of the event is prior to the date of dose 
of IMP.
In the situation where the event date is partial or missing, Study Day and any corresponding durations will be 
displayed as missing in the listings.
For illness visits an illness study day will be calculated the reference start date is defined as the day of first illness 
assessment, i.e., illness visit Day 1. This will be calculated separately for each illness episode.
Illness Study Day will be computed as follows:
!
Illness Study Day = (Date of event –Date of illness visit Day 1) + 1.
6.2.
BASELINE
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to the dose of IMP. 
In the case where the last non-missing measurement and the date and time of the dose of IMP coincide or where 
time is missing, that measurement will be considered baseline, but adverse events (AEs) and medications 


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commencing on the date and time of the dose of IMP will be considered post-baseline.
Illness Visit baseline is defined as the first non-missing measurement taken on Illness Visit Day 1, for the first 
illness episode with laboratory confirmed positive reverse transcriptase polymerase chain reaction (RT-PCR) test 
result. For instances where Illness Visit Day 1 occurs on the same day as a main study Visit, and Illness Visit Day 1 
measurements are missing, then the measurements from the main study Visit will be used as Illness Visit baseline.   
Otherwise if there is still no available measurement for Illness Visit Day 1, Illness Visit baseline is considered as 
missing.  
6.3.
UNSCHEDULED VISITS, RETESTS, AND EARLY TERMINATION 
DATA
For by-visit summaries, data recorded at the nominal visit will be presented. That is, unscheduled, retest (same visit 
number assigned), and early termination measurements will not be included in by-visit summaries but might
contribute to the baseline timepoint and/or maximum value, where required (e.g. shift table). Visits for human 
biological samples data will follow a windowing convention as described in Section 6.4.
Listings will include scheduled, unscheduled, retest and early discontinuation data.
6.4.
WINDOWING CONVENTIONS 
A windowing convention will be used to determine the analysis value for a given study visit for human biological 
samples data analyses. The window definitions as following will be used for the following assessments:
!
Main study: serum sample for SARS-CoV-2 serology (anti-nucleocapsid testing)
!
Main study: serum sample for AZD7442 PK assessment;
!
Main study: serum sample for AZD7442 ADA assessment;
!
Main study: serum sample for SARS-CoV-2 nAbs assessment (pharmacodynamic [PD]);
!
Main study: serum sample exploratory biomarkers;
!
Main study: nasal adsorption for exploratory assessments (PK);
!
Illness visits schedule: self-collected anterior nasal sample for viral shedding;
!
Illness visits schedule: serum sample for AZD7442 PK assessment (PK);
!
Illness visits schedule: serum sample for SARS-CoV-2 nAbs assessment (PD);
!
Illness visits schedule: nasal adsorption for SARS-CoV-2 mucosal responses and exploratory assessments 
(PK);


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!
Illness visits schedule: serum sample for exploratory assessments.
The window for the visits following baseline will be constructed in such a way that the upper limit of the interval 
falls halfway between the two visits (the lower limit of the first post-baseline visit will be Day 2). If an even number 
of days exists between two consecutive visits, then the upper limit will be taken as the midpoint value minus 1 day
Table E:
Analysis windows for serum sample for SARS-CoV-2 serology testing, serum sample 
for AZD7442 PK assessment, serum sample for SARS-CoV-2 nAbs assessment (PD ) 
and serum sample exploratory biomarkers by Visit 
Visit
Day Relative to Dose 
Visit Window (Study Day)
Day 1
≤ 1
≤ 1
Day 8
8
2 - 18
Day 29
29
19 - 43
Day 58
58
44 – 74
Day 92
92
75 - 137
Day 183
183
138 - 274
Day 366
366
275 - 411
Day 457
457
≥ 412
Table F:
Analysis windows for serum sample for AZD7442 ADA assessment by Visit 
Visit
Day Relative to Dose 
Visit Window (Study Day)
Day 1
≤ 1
≤ 1
Day 29
29
2 - 60
Day 92
92
61 - 137
Day 183
183
138 - 274
Day 366
366
275 - 411
Day 457
457
≥ 412
Table G:
Analysis windows for serum sample for AZD7442 PK assessment, serum sample for 
nasal adsorption, serum sample for SARS-CoV-2 nAbs assessment (PD ) and serum 
sample exploratory biomarkers by Visit (Illness Visit Schedule)
Visit
Scheduled Illness Day
Visit Window (Illness Study Day)
Illness Day 1
≤ 1
≤ 1
Illness Day 14
14
8 – 21
Illness Day 28
28
22 - 35
Table H:
Analysis windows for Viral Shedding by Visit (Illness Visit Schedule)
Visit
Scheduled Illness Day
Visit Window (Illness Study Day)
Illness Day 1
≤ 1
≤ 1
Illness Day 3
3
2 - 3


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Illness Day 5
5
4 - 6
Illness Day 8
8
7 - 11
Illness Day 14  
14
12 - 17
Illness Day 21
21
18 - 24
Illness Day 28
28
25 - 35
Windows are applied only to the first illness episode with laboratory confirmed positive RT-PCR test results. One or 
more results for a particular human biological samples variable may be obtained in the same visit window. In such 
an event, the result with the date closest to the expected visit date will be used in the analysis. In the event that two 
observations are equidistant from the expected visit date, the later observation will be used in the analysis.
6.5.
COMMON CALCULATIONS
Change from baseline will be calculated as:
!
Change from baseline = Test value at post-baseline visit – Baseline value;
Percent change from baseline will be calculated as:
!
Percent change from baseline (%) = (Change from baseline at post-baseline visit / Baseline value) * 
100%;
Change from baseline for Illness Visits will be calculated as:
!
Change from baseline at Illness Visit Day 1 = Test value at Illness Visit Day 1 – Baseline value;
!
Change from baseline at Illness Visits after Illness Visit Day 1 = Test value at Visit post Illness Visit
Day 1– Illness Visit baseline value;
Percent change from baseline at Illness Visits will be calculated as:
!
Percent change from baseline Illness Visit Day 1 (%) = (Change from baseline at Illness Visit Day 1/ 
Baseline value) * 100%;
!
Percent change from baseline at Illness Visits after Illness Visit Day 1 (%) = (Change from baseline 
at Visit post Illness Visit baseline / Illness Visit Baseline value) * 100%.
If baseline is not available, the change from baseline and percent change from baseline will not be calculated and 
will remain missing.  


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7. STATISTICAL CONSIDERATIONS
For continuous data, descriptive statistics (i.e., n [number of participants with available data], mean, standard 
deviation [SD], median, minimum, maximum, and quartile values) will be presented by treatment group and visit, 
when applicable. For concentration data and log-transformed data, descriptive statistics (i.e., n [number of 
participants with available data], n < lower limit of quantification (LLOQ) [number of participants with results 
below the limit of quantification], geometric mean, arithmetic mean, SD, co-efficient of variation, median, min and 
max) will be presented by treatment group and visit, when applicable.
For categorical data, the number and percentages of participants in each category will be presented by treatment 
group and visit, when applicable. The denominator for percentage calculations is the underlying analysis set 
population N values unless otherwise stated.
7.1.
SAMPLE SIZE CALCULATION
Approximately 1125 participants will be randomized in a 2:1 ratio to receive a single IM dose of AZD7442 (divided 
in 2 sequential injections, one for each mAb component) (the active group, n = approximately 750) or saline placebo 
(the control group, n = approximately 375) on Day 1.
The sample size calculations are based on the primary efficacy endpoint and were derived following a modified 
Poisson regression approach (Zou 2004). All participants will be followed for the entire duration of the study. The 
primary analysis will be conducted 30 days after the 25th primary endpoint event has occurred. The study will have 
approximately 90% power to demonstrate that the lower bound of the 2-sided 95% CI for efficacy is  greater than 
zero, assuming an attack rate of 4.5% in the placebo group and true efficacy of 75% (equating to an attack rate of 
1.1% in the AZD7224 group). 
To mitigate the uncertainty around these assumptions, a blinded sample size re-estimation (BSSR) may be 
conducted prior to the primary analysis. The overall event rate, as well as the data from external sources (e.g., 
prophylactic efficacy of other COVID-19 preventive mAbs), will be used in the sample size re-estimation and 
strictly no treatment information from this study will be used in the review. The summaries will not contain any 
information that would potentially reveal treatment assignments. The review may result in an adjustment of sample 
size when the observed attack rate is greatly different than expected.  Since this review will be performed in a 
blinded fashion, no adjustment for the Type I error is needed. Full details will be in a BSSR plan.
A final analysis will be conducted at the end of the study, i.e., when the last participant dosed has completed the Day 
457 visit.
7.2.
MISSING DATA
Missing efficacy data will be handled as described in Sections 16.1.2, 16.2.4, and 16.3.2 of this analysis plan. 


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Partial or completely missing medication dates will be handled as described in APPENDIX 1.
7.3.
STATISTICAL TESTS
Unless stated otherwise, statistical tests will be conducted at the two-sided 5% significance level. Confidence 
Intervals (CIs) will be two-sided with 95% coverage.     
The null hypothesis is: There is no difference in efficacy between AZD7442 and placebo in preventing COVID-19 
(i.e. efficacy is equal to 0). Whereas, the alternative hypothesis is: There is a difference in efficacy between 
AZD7442 and placebo in preventing COVID-19 (i.e. efficacy is not equal to 0). That is:
•
Null hypothesis: No difference (i.e. Efficacy = 0)
•
Alternative hypothesis: There is a difference (i.e. Efficacy ≠ 0)
The primary efficacy endpoint will be formally assessed at the primary analysis. The primary analysis will be 
conducted 30 days after the 25th primary endpoint event has occurred. Additional events may occur after the primary 
analysis. These will be evaluated and reported as exploratory endpoints at the end of study analysis. All participants 
will be followed for the entire duration of the study. Efficacy will be presented with a 2-sided 95% CI, and statistical 
significance will be achieved if the 95% CI lower bound is > 0.
7.4.
MULTIPLE COMPARISONS/ MULTIPLICITY
If the primary endpoint achieves statistical significance a hierarchical approach will be used to control for 
multiplicity of the primary and key secondary efficacy endpoints. 
With that, the overall Type I error is controlled at 0.05. Therefore, no further multiplicity adjustment is necessary. 
7.5.
MULTICENTER STUDIES
This study will be conducted by multiple investigators at multiple centers internationally.  Data from all centers will 
be pooled together in the analyses and there are no plans to perform an analysis of homogeneity of the results across 
centers.
7.6.
EXAMINATION OF SUBGROUPS
Subgroup analyses will be conducted as stated in Sections 16.1.7. It should be noted that the study was not designed 
to detect treatment differences with high statistical power within subgroups.
The subgroups are:


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!
Categorical age (years) at informed consent (3 groupings 1: ≥60 years and < 60 years, 2: ≥ 65 years 
and < 65 years, 3: ≥ 75 years and < 75 years);
!
Sex (male and female);
!
Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific Islanders, White);
!
Ethnicity (Hispanic or Latino, Not Hispanic or Latino);
!
COVID-19 co-morbidities at baseline (at least one co-morbidity, no co-morbidity) (use the medical 
history electronic case report form (eCRF) page);
!
SARS-CoV-2 RT-PCR status at baseline (positive or negative).
!
High Risk for severe COVID-19 at baseline (History  of Obesity, Obese (BL BMI≥30), Morbid 
Obesity (BL BMI ≥40), Chronic kidney disease (CKD), Diabetes, Immunosuppressive disease,
Immunosuppressive treatment, Cardiovascular disease (CV disease), Chronic obstructive pulmonary 
disease (COPD), Chronic liver disease, Hypertension, Asthma, Cancer, Smoking, Sickle cell disease)
(yes/no; Refer to Appendix 6 for description of each condition);
If models of subgroup analysis do not converge due to sparse data, only descriptive counts and percentages will be 
presented.
7.7.
SOFTWARE VERSION
All analyses will be conducted using SAS version 9.4 or higher. 
8. OUTPUT PRESENTATIONS
APPENDIX 2 shows conventions for presentation of data in outputs. 
9. DISPOSITION AND WITHDRAWALS
All participants who provide informed consent will be accounted for in this study. 
9.1.
DISPOSITION
Number of participants screened will be presented overall for the PAS. Number and percentage of participants who 
with screen failure and reason for screen failure will also be presented overall based on the PAS. Number and 
percentage of participants randomized will be presented overall and by treatment group for the PAS.


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Number and percentages of participants ongoing in study (for primary analysis only) and who discontinued early 
from the study (including reason for withdrawal) will be provided overall and by planned treatment group based on 
the FAS.
The number of participants included and excluded from each analysis set (including reason for exclusion) will be 
summarized overall and by planned treatment group based on the FAS. A listing showing inclusion and exclusion of 
each participant from each analysis set, including reason for exclusion, will be provided.
9.2.
PROTOCOL DEVIATIONS
Number and percentage of participants with important protocol deviations, as identified by the study team in a 
blinded fashion before the DBL, will be provided overall and by planned treatment group based on the FAS for each 
category of protocol deviations specified in the Protocol Deviations Management Plan.
A listing of protocol deviations identified by the study team (important or not) will be provided.
10.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
The following demographic and other baseline characteristics will be reported for this study:
!
Age (years) – collected at informed consent;
!
Cohort (Cohort 1: Adults >= 60 residing in a long-term care facility Cohort 2: Other adults >= 18)  
!
Age groups ( >= 18 to < 60 years, >= 60 to < 70 years, >= 70 to <80 years and >= 80 years, 
>= 60 years, >= 65 years and >= 75 years);
!
Sex (refer to Section 7.6);
!
Race (refer to Section 7.6);
!
Ethnicity (refer to Section 7.6);
!
Weight (kg);
!
Height (cm);
!
Body Mass Index (BMI) (kg/m2);
!
BMI group (kg/m2) (< 18.5, ≥ 18.5 - < 25, ≥25 - < 30 , ≥ 30 - < 40 and ≥40)
!
Smoking status (current, former, never);
!
ECOG performance status (0,1 and >1);


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!
Home or other confinement status (yes/no);
!
High Risk for severe COVID-19 at baseline (History  of Obesity, Obese (BL BMI≥30), Morbid 
Obesity (BL BMI ≥40), CKD, Diabetes, Immunosuppressive disease, Immunosuppressive treatment,
CV disease, COPD, Chronic liver disease, Hypertension, Asthma, Cancer, Smoking, Sickle cell 
disease) (yes/no);
!
Subgroups specified in Section 7.6 and not previously listed above.
Continuous demographic and other baseline characteristics will be summarized using descriptive statistics overall 
and by planned treatment group based on the FAS. For categorical demographic and other baseline characteristics, 
number and percentage of participants in each category will be provided overall and by planned treatment group 
based on the FAS. If there are major differences between the FAS and the SAF, the summaries will be repeated and 
presented by actual treatment arm for the SAF. No statistical testing will be carried out for demographic or other 
baseline characteristics.
10.1. DERIVATIONS
BMI, in kg/m2, will be calculated as follows: 
!
BMI (kg/ m2) = weight (kg)/ [height (m)2].
11.
MEDICAL HISTORY
Medical history is defined as any medical conditions/diseases that started and stopped before the first dose of IMP. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 23.1 or 
higher, and will be summarized by System Organ Class (SOC) and Preferred Term (PT) overall and by planned 
treatment group based on the FAS.  A participant having more than one medical condition/disease within the same 
SOC/PT will be counted only once for that SOC or PT.
COVID co-morbidities are collected on the Medical history page of the eCRF.  The number and percentage of 
patients with each co-morbidities and also with any co-morbidities will be summarized overall and by planned 
treatment group based on the FAS.
All medical history will be listed.
12.
CONCOMITANT ILLNESSES
Concomitant conditions/illnesses are defined as any medical conditions/illnesses that started before the first dose of
IMP AND were ongoing at the time of the dose of IMP or ended on date of dose.


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Concomitant conditions/illnesses will be coded using the MedDRA, version 23.1 or higher, and will be summarized 
by SOC and PT overall and by planned treatment group based on the FAS. A participant having more than one 
medical condition/illness within the same SOC or PT will be counted only once for that SOC or PT.
All concomitant conditions/illnesses will be listed.
13.
MEDICATIONS
Prior medications are defined as any medication that started and stopped prior to the dose of IMP.
Concomitant medications are defined as:
!
Any medication that started before the dose of IMP AND was ongoing at the time of the dose of IMP
or ended on the date of dose of IMP;
!
Any medication that started on or after the dose of IMP.
Partially or completely missing medication start and stop dates will be handled as described in APPENDIX 1.
All medications will be coded using the World Health Organization (WHO) Drug Global dictionary, version B3 
March 2020, or a more recent version.
Prior and concomitant medications will be summarized by Anatomical Therapeutic Class (ATC) level 2 and 
preferred drug name overall and by planned treatment group based on the FAS. A participant having more than one 
medication within the same ATC Level 2 or preferred drug name will be counted only once for that ATC Level 2 or 
preferred drug name.
All collected prior and concomitant medications will be listed.
14.
EXPOSURE TO STUDY INTERVENTION
Due to the simplicity of dosing for this study, exposure is summarized in the participant disposition table. All 
exposure data will be listed.
15.
COMPLIANCE WITH STUDY INTERVENTION
Compliance will not be calculated since participants receive a single dose (2 IM injections) within clinic.
16.
EFFICACY ENDPOINTS
Unless otherwise indicated, all efficacy summaries and figures will be presented based on the FAS.


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16.1. PRIMARY EFFICACY
16.1.1.
PRIMARY EFFICACY ENDPOINT
The primary endpoint is the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post dose of 
IMP and prior to Day 183. The primary efficacy endpoint is to be to be assessed 30 days after the 25th event has 
occurred.
Participants will be included as an event in the primary endpoint if they have RT-PCR-confirmed SARS-CoV-2 
prior to Day 183 and present with at least one of the qualifying symptoms in Table I:. The onset of symptoms will
commonly occur between 2 and 8 days of infection with detectable virus typically up to 15 days. To maintain the 
relationship between the RT-PCR sample and symptoms the sample should be collected on or close to the symptom 
assessment but must be collected within 5 days prior or 10 days following the assessment of qualifying symptoms. 
This duration will allow subjects time to assess and confirm symptoms under medical supervision after the onset of 
symptoms, which will typically, but not always, occur at Illness Visit Day 1. A positive SARS-CoV-2 RT-PCR will 
be defined based on the central laboratory result whenever both central and local laboratory results are available for 
nasopharyngeal (NP) swabs, or if only a central laboratory result is available. If only a local NP swab laboratory 
result is available, then the local laboratory result will be used. If neither central nor local NP swab laboratory 
results are available, an anterior nasal sample will be used to determine the RT-PCR result. If no SARS-CoV-2 RT-
PCR sample is available, the participant will be considered as not having met the primary endpoint. Data from the 
eCRF will be used to determine if the participant met the qualifying symptoms. If a participant’s first case of SARS-
CoV-2 RT-PCR positive symptomatic illness occurs on or after Day 183, the participant will be considered as not 
having met the primary endpoint.


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Table I:
COVID-19 Qualifying Symptoms
Duration
Symptom
No minimum duration
Fever
Shortness of breath
Difficulty breathing
New onset confusion (only for participants ≥60 years old)
Appetite loss or decrease food intake (only for participants ≥60 years old)
Increased supplemental oxygen requirement (only for participants ≥60 years 
old on baseline supplemental oxygen)
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
Adapted from (CDC, 2020) 
CDC, Centers for Disease Control and Prevention
16.1.2.
MISSING DATA IMPUTATION METHOD FOR PRIMARY EFFICACY ENDPOINT
No missing data imputation method will be used for primary efficacy analysis. For participants who withdraw from 
the study prior to having met the criteria for the primary efficacy endpoint, absence of data following these 
participants’ withdrawal (or lost to follow-up, death not caused by SARS-CoV-2) will be treated as missing.
Participants will be considered as not having the event through the time of their last observation.
Sensitivity analyses will be explored to assess the robustness of treatment effects for the primary efficacy endpoint, 
where different missing data mechanisms will be explored using multiple imputation approaches. Full details of the 
sensitivity analyses are specified in Section 16.1.5.  
16.1.3.
PRIMARY ESTIMAND 
The treatment condition of interest is single dose of AZD7442 (two IM injections, one for each mAb component, 
AZD8895 and AZD1061). The alternative treatment condition to which comparison will be made is a placebo.
The population of participants targeted in the primary estimand includes adults at least 18 years of age with potential 


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exposure, within 8 days, to a specific identified individual with laboratory-confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are therefore at appreciable risk of imminently developing COVID-19, based on 
available risk assessment at time of enrollment.
The primary endpoint (variable) to be obtained is a binary response, whereby a participant is defined as a COVID-19 
case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurs post dose of IMP and prior to 
Day 183.
The primary estimand uses a treatment policy strategy. Data for participants who become unblinded to properly 
consider vaccination for COVID-19, take COVID-19 vaccine or other COVID-19 preventive product, prior to 
having met the criteria for the primary efficacy endpoint, are collected and analyzed regardless of the intercurrent 
event. 
The population-level summary measure is prophylactic efficacy, calculated as 1 - relative risk (RR). (RR is the 
incidence of infection in the AZD7442 group relative to the incidence of infection in the control group.)
16.1.4.
PRIMARY ANALYSIS OF PRIMARY EFFICACY ENDPOINT
The primary efficacy analysis of the primary endpoint will be performed on the FAS. The primary analysis occurs
30 days after the 25th event has occurred. For participants who withdraw from the study prior to having met the 
criteria for the primary efficacy endpoint, absence of data following these participants’ withdrawal (or lost to follow-
up, death not caused by SARS-CoV-2) will be treated as missing and participants will be considered as not having 
the event through the time of last observation. Participants with deaths that are caused by SARS-CoV-2 (death 
related to COVID marked on the death eCRF page) or hospitalizations that are characterized to be severe COVID-19
(defined in Section 16.2.1) will also be considered as having the event. 
A Poisson regression model with robust variance (Zou, 2004) adjusting for follow-up time, will be used as the 
primary efficacy analysis model to estimate the RR on the incidence of SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurring post dose of IMP between the AZD7442 and the placebo groups. The model contains 
the planned treatment group and the log of the follow-up time as an offset. Calculation of follow-up time is detailed 
as following: 
!
For participants who meet the primary endpoint before Day 183, the follow up time will be 
calculated as (Date of Onset of Primary Endpoint) – (Date of Dosing) + 1. The Date of Onset of 
Primary Endpoint is defined as the assessment date of qualifying COVID symptoms, if associated 
with a positive SARS-COV-2 RT-PCR lab test from a sample collected within 5 days prior or 10 
days after symptom assessment. In the case of death due to COVID-19 or hospitalization due to 
severe COVID-19, the Date of Onset of Primary Endpoint is the earliest date of death/date of 
hospital admission when a qualifying symptom assessment is not observed.
!
For participants who do not experience a primary endpoint event before Day 183, the efficacy 
follow-up time will be considered censored and determined based on the following: 


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o
If an end of study date occurs before Day 183, the efficacy follow-up time will be calculated as 
(Date of End of Study or Date of Last Assessment, whichever is later) – (Date of Dosing) + 1. 
o
If an end of study date occurs after Day 183, the efficacy follow-up will be censored at Day 183.
For participants who continue to participate in the study at the time of the primary analysis, the Data Cutoff date will 
be used as their last assessment date. For patients with no post-baseline visit data available, the date of IMP 
administration will be used i.e. follow-up will be 1 day.
Efficacy is the incidence of infection in the AZD7442 group relative to the incidence of infection in the placebo
group, expressed as a percentage. Efficacy will be calculated as relative risk reduction (RRR) = 100% x (1 - relative 
risk).
For the primary analysis, RRR and its corresponding 2-sided 95% CI will be estimated from the Poisson regression 
model with robust variance. In addition, the 2-sided p-value testing null hypothesis that there is no difference in 
efficacy between AZD7442 and placebo (i.e. efficacy is equal to 0) will be obtained from the model. Statistical 
significance will be achieved if the lower bound of the 95% CI for efficacy is > 0, which corresponds to an observed 
two-sided p-value < 0.05. For the final analysis nominal 95% CI’s will be presented.
The Poisson regression with robust variance analysis will be implemented by using the SAS PROC GENMOD 
procedure with the REPEATED statement for participant ID and logarithm link as well as OFFSET option. The 
estimated parameter  [i.e., log((RR) ̂)], 2-sided 95% CI for , and the 2-sided p- value will be obtained from the 
SAS outputs. The estimated RR and corresponding CI for the RR is given by exponentiating  and its confidence 
limits. Therefore, the percent of RRR is given by [(1 – exp()) * 100%]. The CI for the percent of RRR is given by 
([1 – exp(upper confidence limit for ) * 100%], [1 – exp(lower confidence limit for ) * 100%]).
If convergence cannot be achieved with the Poisson regression with robust variance analysis model, an Exact 
Poisson Regression model will be used as the primary analysis model to test the treatment effect on SARS-CoV-2 
RT-PCR-positive symptomatic illness between AZD7442 and placebo groups. SAS procedure of PROC GENMOD 
with EXACT statement will be used to perform the analysis. The RR of AZD7442 over placebo for the incidence of 
SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post dose and the 95% CI will be obtained from the 
SAS procedure. The percent of RRR and the 95% CI will be reported following the relationship of RRR (%) = (1-
RR) * 100%.
16.1.5.
SENSITIVITY ANALYSES FOR PRIMARY EFFICACY ENDPOINT
As a sensitivity analysis to the handling of missing data in the analysis of the primary efficacy endpoint, the primary 
analysis of the primary efficacy endpoint (refer to Section 16.1.4) will be repeated, without using log follow-up time 
as offset. For participants who do not have a SARS-CoV-2 RT-PCR-positive symptomatic illness status occurring 
post dose of IMP and withdraw from the study prior to the time of analysis, their event status will be imputed 
assuming the observed placebo attack rate using multiple imputation techniques as described in the following 
paragraphs. 


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The primary analysis using Poisson regression with robust variance requires a participant-level dataset. A repeated 
imputation approach is introduced to impute the status of SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurring post dose of IMP for missing observations at the participant level for the model fitting. By incorporating 
the between-imputation variance, a reliable statistical inference in both hypothesis testing and CI estimation of the 
treatment effect is expected through the repeated imputation (Little and Rubin, 2002). In the primary analysis the 
missing outcome for participants who drop out (e.g., withdrawal, lost to follow-up, death not caused by SARS-CoV-
2, etc.) prior to reaching cut-off time for analysis without a SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurring post dose of IMP will be imputed using placebo event rate. The imputation and subsequent analysis will 
be carried out using SAS PROC MI (Monotone Logistic Regression Method) and SAS PROC MIANALYZE. The 
detailed imputation steps are described as follows. 
!
Step 1: For the participants in the AZD7442 arm who do not have a SARS-CoV-2 RT-PCR-positive 
symptomatic illness and are not followed through cut-off time of analysis, their treatment code of 
“AZD7442” will be substituted with “placebo” to ensure the placebo SARS-CoV-2 RT-PCR-positive 
symptomatic illness rate is applied in the imputation for the AZD7442 dropouts. Missing events in 
both arms will then be imputed with the placebo rate. The imputation will be executed using SAS 
Proc MI (e.g., logistic regression with the recoded treatment term). The random seed is 12345;
!
Step 2: The original treatment code will be restored after the SARS-CoV-2 RT-PCR-positive 
symptomatic illness statuses have been imputed. A complete dataset comprises the imputed SARS-
CoV-2 RT-PCR-positive symptomatic illness status and observed SARS-CoV-2 RT-PCR-positive 
symptomatic illness status;
!
Step 3: Analyze the complete dataset using a Poisson regression model with robust variance to 
estimate the RR on the incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness between 
AZD7442 and placebo, with the term of planned treatment group. The point estimate of log-
transformed RR and its variance will be extracted from the model;
!
Steps 2-3 will be repeated 20 times. SAS procedure PROC MIANALYZE will be used to combine 
inferences from the 20 completed datasets, that will result in a combined point estimate of log-
transformed RR and the variance. 
Additional sensitivity analysis will be carried out as given below 
!
Multiple imputation as described above using the observed event rate per treatment group for their 
event status. That is, the replacement of the treatment code in Step 1 and the restoration in Step 2 will 
be skipped. 
!
At the final analysis, the efficacy will also be estimated from a Poisson Regression model with robust 
variance and offset including the log of the follow-up time, which includes all SARS-CoV-2 RT-
PCR positive symptomatic illness events, i.e. including those that occurred on or after Day 183.


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16.1.6.
SUPPLEMENTARY ANALYSES FOR PRIMARY EFFICACY ENDPOINT
To support the primary analysis, time to event (i.e., the duration in days from dose to first event or censoring) 
analyses will be performed as follows. A Cox proportional hazard (PH) model, with treatment group as the only 
covariate, will be fitted to the data, and the Efron method will be used to control for ties. Kaplan-Meier curves with 
log-rank test p-values and estimates (hazard ratio, as well as the corresponding 95% CI) from the Cox PH model
will be presented for the AZD7442 and placebo groups based on observed events, showing the cumulative incidence 
of the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post dose of IMP and prior to Day 
183.
In addition, the absolute risk reduction of AZD7442 over placebo in preventing the incidence of the SARS-CoV-2 
RT-PCR positive symptomatic illness up to Day 183 will be presented, along with the 2-sided 95% CI using the 
Miettinen and Nurminen’s score method (Miettinen and Nurminen, 1985). The absolute risk reduction will be 
implemented using the SAS PROC FREQ procedure.
16.1.7.
SUBGROUP ANALYSES FOR PRIMARY EFFICACY ENDPOINT
Subgroup analysis will be performed for the primary efficacy endpoint, SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurring post dose of IMP and prior to Day 183. For subgroup analysis, FAS will be used. 
Treatment-by-subgroup interaction will be tested using the Poisson regression with robust variance model adjusting 
for follow-up time with the terms of planned treatment group, subgroup, and treatment-by-subgroup interaction, 
which will be implemented using PROC GENMOD procedure. If this full model does not achieve convergence, a 
reduced model of planned treatment group, subgroup, and treatment-by-subgroup interaction will be considered. 
Within each level of a subgroup, the RRR and its corresponding 95% CI will be estimated using a Poisson 
regression model with robust variance with the term of treatment. A forest plot of the RRR and the 95% CI will be 
presented. In the event that the Poisson regression model does not converge, an exact Poisson model will be used to 
generate the RRR and the corresponding 95% CI.
The subgroup analysis will be conducted for the subgroups in Section 7.6 on the FAS population.
If a subgroup corresponding to one of the factor levels included in the analysis model, the corresponding factor will 
not be included in the model.  
16.1.8.
ADDITIONAL ESTIMANDS FOR PRIMARY EFFICACY ENDPOINT
Additional estimands will also be used for the primary efficacy as shown in Table J:


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Table J:
List of Additional Estimands for Primary Efficacy 
Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/ Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
The efficacy 
of a single IM 
dose of 
AZD7442 
compared to 
placebo for 
the 
prevention of 
COVID-19 –
While on 
Treatment 
Estimand
Full analysis set, defined as all participants
who were randomized and received at least 
one of the planned injections of IMP. 
Targeted participants will have the 
following characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of imminently 
developing COVID-19, based on available 
risk assessment at time of enrollment
Single dose 
of AZD7442 
(× 2 IM 
injections, 1
for each 
mAb 
component)
or placebo
A binary response, 
whereby a participant is 
defined as a COVID-19 
case if their first case of 
SARS-CoV-2 RT-PCR-
positive symptomatic 
illness occurs post dose of 
IMP and prior to Day 183.
For participants who 
become unblinded to 
properly consider 
vaccination for COVID-19, 
take COVID-19 vaccine or 
other COVID-19 
preventive product prior to 
having met the criteria for 
the primary efficacy 
endpoint, only data prior to 
the intercurrent events (i.e.,  
up to the time of 
unblinding, or the vaccine 
or other preventative 
product is received, 
whichever comes first) 
will be considered (i.e., 
intercurrent events will be 
handled using while on 
treatment strategy).
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.) 
The efficacy 
A subset of the full analysis set, defined as 
Single dose 
A binary response, 
For participants who 
Prophylactic 


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Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/ Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
of a single IM 
dose of 
AZD7442 
compared to 
placebo for 
the 
prevention of 
COVID-19–
Per Protocol 
Estimand
all participants who were randomized,
received at least one of the planned 
injections of IMP, and who have no 
significant deviations from the protocol
prior to Day 183 or meeting the primary 
endpoint (whichever occurs first). Targeted 
participants will have the following 
characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of imminently 
developing COVID-19, based on available 
risk assessment at time of enrollment
of AZD7442 
(× 2 IM 
injections, 1
for each 
mAb 
component)
or placebo
whereby a participant is 
defined as a COVID-19 
case if their first case of 
SARS-CoV-2 RT-PCR-
positive symptomatic 
illness occurs post dose of 
IMP and prior to Day 183.
become unblinded to 
properly consider 
vaccination for COVID-19,
take COVID-19 vaccine or 
other COVID-19 
preventive product prior to 
having met the criteria for 
the primary efficacy 
endpoint, the data will be 
collected and analyzed 
regardless (i.e., intercurrent 
events will be handled 
using treatment policy 
strategy).
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.) 
 


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16.2. SECONDARY EFFICACY
The key secondary efficacy endpoint is:
!
The incidence of the first case of SARS-CoV-2 RT PCR-positive and severe or critical symptomatic illness that 
occurs prior to Day 183.
The other secondary efficacy endpoints are:
!
The incidence of participants who have a post-treatment response (negative at baseline to positive at 
any time post-baseline) for SARS-CoV-2 nucleocapsid antibodies;
!
The incidence of COVID-19-related death occurring after dosing with IMP;
!
The incidence of all-cause mortality occurring after dosing with IMP;
!
Please refer to Section 17 for other secondary endpoints related to PK and ADA data.
The analysis of the secondary efficacy endpoints will be performed on the FAS.
16.2.1.
KEY SECONDARY EFFICACY ENDPOINT
The key secondary endpoint is the incidence of the first case of SARS CoV-2 RT PCR-positive and severe or critical 
symptomatic illness that occurs prior to Day 183. The severity of COVID-19 will be evaluated in participants who 
test positive for SARS-CoV-2 by RT-PCR. A diagnosis of severe or critical COVID-19 will include laboratory-
confirmed COVID-19 (SARS-CoV-2 RT-PCR-positive symptomatic illness) plus meeting the severity criteria.
Participants with severe disease can be identified using the ‘COVID 19 Severity form’ eCRF page, and selecting 
those participants with either ‘Has the Subject Symptoms of Pneumonia’ or ‘Has the Subject Symptoms of 
Hypoxemia’ marked as ‘Yes’ and with a ‘WHO clinical progression scale’ score of 5 or higher. The date symptoms 
became severe will use the data populated in the ‘COVID 19 Severity form’ eCRF field ‘Date of Severity 
Assessment’. Any participants who experience death due to COVID-19 in the absence of a diagnosis of severe or 
critical COVID-19 will be included in this endpoint. Participants with hospitalizations that are characterized to be 
severe COVID-19 (as described above) will also be considered as having the event. The calculation of the follow up 
time (included as offset in model) will be calculated by using date symptoms become severe as the date of onset of 
endpoint, or date of death (as applicable), described in Section 16.1.4. Similar descriptive statistics as for the 
primary endpoint will be provided.
Severe COVID-19 is 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. 
The primary and the key secondary efficacy hypotheses will be assessed in a hierarchical order, 95% CI’s will be 


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presented as detailed for the primary endpoint. More details on multiplicity are provided in Section 7.4.
16.2.2.
ESTIMANDS FOR KEY SECONDARY EFFICACY
The treatment condition of interest is single dose of AZD7442 (two IM injections, one for each mAb component, 
AZD8895 and AZD1061). The alternative treatment condition to which comparison will be made is a placebo.
The population of participants targeted in the key secondary estimand includes adults at 18 years of age with 
potential exposure, within 8 days, to a specific identified individual with laboratory-confirmed SARS-CoV-2 
infection, symptomatic or asymptomatic, who are therefore at appreciable risk of imminently developing COVID-
19, based on available risk assessment at time of enrollment. 
The key secondary endpoint (variable) to be obtained is a binary response, whereby a participant is defined as a 
COVID-19 severe or critical case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic illness that 
meets the severity criteria occurs post dose of IMP that occurs prior to Day 183.
The estimand for the key secondary efficacy endpoint uses a treatment policy strategy. Data for participants who 
become unblinded to properly consider vaccination for COVID-19, take COVID-19 vaccine or other COVID-19 
preventive product, prior to having met the criteria for the key-secondary efficacy endpoint, are collected and 
analyzed regardless of the intercurrent event.
The population-level summary measure is prophylactic efficacy, calculated as 1 - relative risk. (Relative risk is the 
incidence of infection in the AZD7442 group relative to the incidence of infection in the control group.)
Additional estimands will also be used for the key secondary efficacy as shown in Table K:.


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Table K:
List of Additional Estimands for Key Secondary Efficacy 
Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/ Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
The efficacy 
of a single IM 
dose of 
AZD7442 
compared to 
placebo for the 
prevention of 
severe or 
critical 
symptomatic 
COVID-19 –
While on 
treatment 
Estimand
Full analysis set, defined as all 
participants who were randomized and 
received at least one of the planned 
injections of IMP. Targeted participants 
will have the following characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of 
imminently developing COVID-19, based 
on available risk assessment at time of 
enrollment
Single dose 
of AZD7442 
(× 2 IM 
injections, 1
for each 
mAb 
component)
or placebo
The incidence of SARS-
CoV-2 RT-PCR-positive 
severe or critical 
symptomatic illness 
occurring after dosing 
with IMP.
For participants who 
become unblinded to 
properly consider 
vaccination for COVID-19,
take COVID-19 vaccine or 
other COVID-19 
preventive product prior to 
having met the criteria for 
the primary efficacy 
endpoint, only data prior to 
the intercurrent events (i.e., 
up to the time of 
unblinding, or the vaccine 
or other preventative 
product is received, 
whichever comes first) 
will be considered (i.e., 
intercurrent events will be 
handled using while on 
treatment strategy).
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.) 
The efficacy 
A subset of the full analysis set, defined 
Single dose 
The incidence of SARS-
For participants who
Prophylactic 


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Label
Attributes
Definition Population
Treatment 
Condition 
of Interest
Variable/ Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
of a single IM 
dose of 
AZD7442 
compared to 
placebo for the 
prevention of 
severe or 
critical 
symptomatic 
COVID-19 –
Per Protocol 
Estimand
as all participants who were randomized,
received at least one of the planned 
injections of IMP, and who have no 
significant deviations from the protocol
prior to Day 183 or meeting the key 
secondary endpoint (whichever occurs 
first). Targeted participants will have the 
following characteristics:
Adults ≥ 18 years of age with potential 
exposure, within 8 days, to a specific 
identified individual with laboratory-
confirmed SARS-CoV-2 infection, 
symptomatic or asymptomatic, who are 
therefore at appreciable risk of 
imminently developing COVID-19, based 
on available risk assessment at time of 
enrollment
of AZD7442 
(× 2 IM 
injections, 1
for each 
mAb 
component)
or placebo
CoV-2 RT-PCR-positive 
severe or critical 
symptomatic illness 
occurring after dosing 
with IMP.
become unblinded to 
properly consider 
vaccination for COVID-19, 
take COVID-19 vaccine or 
other COVID-19 
preventive product prior to 
having met the criteria for 
the primary efficacy 
endpoint, the data will be 
collected and analyzed 
regardless (i.e., intercurrent 
events will be handled 
using treatment policy 
strategy).
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.) 
 


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16.2.3.
OTHER SECONDARY EFFICACY ENDPOINTS
The following endpoints will be presented along with 95% CIs and p-values, these will be nominal, as they are not 
controlled for multiplicity.
16.2.3.1.
The Incidence of Participants Who Have a Post-Treatment Response (Negative at 
Baseline to Positive at Any Time Post-Baseline) for SARS-CoV-2 Nucleocapsid Antibodies
A secondary endpoint is the incidence of participants who have a post-treatment response for SARS-CoV-2 
nucleocapsid antibodies.
Serum samples will be collected as per the schedule of events (refer to protocol Section 1.3) for SARS-CoV-2 
serology testing to monitor participants for infection. To be considered post-baseline positive in the endpoint 
analysis, the participant should have a positive result from the validated assay performed at the central laboratory.
The calculation of the follow up time (included as offset in model) will be calculated by using date of first positive 
response.
In addition, the proportion of participants who have a post-treatment response (negative at baseline to positive post 
treatment with study intervention) for SARS-CoV-2 nucleocapsid antibodies will be summarized by treatment 
group, visit and overall.
16.2.3.2.
The incidence of COVID-19 related death occurring after dosing with IMP
A secondary endpoint is the incidence of participants who have a COVID-19 related death after dosing with IMP.
The number and percentage of participants who died due to COVID-19 as primary cause of death will be 
summarized by nominal visit and actual treatment group based on the FAS. The incidence of COVID-19 related 
deaths will be analyzed in the same way as the primary endpoint.  The calculation of the follow up time (included as 
offset in model) will be calculated by using date of death as the date of onset of endpoint, described in Section 
16.1.4.
16.2.3.3.
The incidence of all-cause mortality occurring after dosing with IMP
Incidence of all-cause mortality is collected on the Death eCRF form. The number and percentage of participants 
who died due to any cause will be summarized by nominal visit and actual treatment group based on the FAS. The 
incidence of COVID-19 related deaths will be analyzed in the same way as the primary endpoint.  The calculation of 
the follow up time (included as offset in model) will be calculated by using date of death as the date of onset of 
endpoint, described in Section 16.1.4.


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16.2.4.
MISSING DATA IMPUTATION METHOD FOR SECONDARY EFFICACY ENDPOINTS
No imputation method will be used for the analysis of the key or other secondary efficacy endpoints.
Imputations will be made for sensitivity analyses of the key secondary efficacy endpoint, described in Section 
16.2.6.
16.2.5.
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS
The key secondary efficacy endpoint will be analyzed as described in Section 16.2.1.
All other secondary efficacy endpoints described in the Section 16.2.3 will be analyzed in the same manner as the 
primary analysis of the primary efficacy endpoint (refer to Section 16.1.4).
The key secondary efficacy endpoint will be assessed by a hierarchical order. More details on multiplicity control 
are described in Section 7.4. For the other secondary efficacy endpoints, the 95% CIs and p-values will be nominal 
as they are not controlled for multiplicity.
16.2.6.
SENSITIVITY ANALYSES FOR SECONDARY EFFICACY ENDPOINTS
For the key secondary efficacy endpoint, the same sensitivity analyses as for the primary efficacy endpoint will be 
performed (refer to Section 16.1.5).
No sensitivity analysis will be performed for the other secondary efficacy endpoints.
16.2.7.
SUPPLEMENTARY ANALYSES FOR SECONDARY EFFICACY ENDPOINTS
For the key secondary efficacy endpoint, the same supplementary analyses as for the primary efficacy endpoint will 
be performed (refer to Section 16.1.6). However, these supplementary analyses will be limited by the number of key 
secondary efficacy events. If the number of events is too low, these analyses may not be performed. 
16.2.8.
SUBGROUP ANALYSES FOR SECONDARY EFFICACY ENDPOINTS
Subgroup analyses for secondary endpoints will be conducted if their sample is sufficient. The same methodology 
for the primary endpoint will be employed.  If the model will not converge because the sample is too small, then 
only descriptive statistics such as counts and percentages and where applicable continuous summary statistics will 
be presented. 
16.3. EXPLORATORY EFFICACY
The exploratory efficacy endpoints are:


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!
Viral genome copies in nasopharyngeal (NP) swabs collected at Illness Visits as determined by qRT-
PCR (Illness Visits only);
!
Duration of SARS-CoV-2 shedding in over time (Illness Visits only);
!
Genotypic analysis and biochemical and/or susceptibility analysis of SARS-CoV-2 variants to 
AZD7442 (Illness Visits only);
!
Symptoms recorded by participants in an Illness e-Diary from Illness Visits Day 2 through Day 28;
!
Assessment of additional immune responses following a single IM dose of AZD7442 or placebo.
Only nominal p-values will be provided for exploratory efficacy endpoints (see Section 7.4). See Section 17 for 
details on exploratory endpoints for PK, PD and ADA data.
16.3.1.
EXPLORATORY EFFICACY ENDPOINTS
16.3.1.1.
Viral Genome Copies in NP Swabs Collected at Illness Visits as Determined by qRT-
PCR 
An exploratory efficacy endpoint is the viral genome copies in NP swabs which will be collected via SARS-CoV-2 
RT-PCR test at central laboratory at Illness visits as described in protocol section 1.3. The analysis will be 
performed on a subset of the pharmacokinetic analysis set, defined as all participants who receive at least one of the 
planned injections of AZD7442, 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. Observed and change 
from baseline for Illness Visits (as defined in Section 6.5) in viral load will be summarized by planned treatment 
group and time points for the Illness Visits. Illness visits with corresponding positive RT-PCR test will be used for 
the summary.
A listing will be provided for all viral genome copy data, regardless of RT-PCR result. Indicators will be included in 
listings of illness visits to distinguish those with positive RT-PCR results from those with negative RT-PCR results.
16.3.1.2.
Genotypic Analysis and Biochemical and/or Susceptibility Analysis of SARS-CoV-2 
Variants to AZD7442 (Illness Visits Only)
An exploratory efficacy endpoint is the Genotypic analysis and biochemical and/or susceptibility analysis of SARS-
CoV-2 from NP swabs collected at Illness Visit baseline. This analysis will not be covered in this SAP.
16.3.1.3.
Symptoms recorded by participants in an Illness e-Diary from Illness Visits Day 2 
through Day 28
A group of exploratory endpoints are symptoms collected by participants in an illness e-Diary. Symptoms from the 
first SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post dose will be summarized. Illness visits with 


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corresponding positive RT-PCR test will be used for the summary. The number and percentage of participants with 
these symptoms, onset study day of these symptoms, and the duration days will be summarized by treatment group
for the symptomatic COVID-19 analysis set. Percentage is based on the number of participants with illness visits
corresponding to a positive RT-PCR result. The analysis will be based on participants in FAS.
All symptoms from each illness visit will be listed, regardless of RT-PCR result. Indicators will be included in 
listings of illness visits to distinguish those with positive RT-PCR results from those with negative RT-PCR results.
16.3.1.4.
Assessment of additional immune responses following a single IM dose of AZD7442 or 
placebo
An exploratory efficacy endpoint is assessment of additional immune responses following a single IM dose of 
AZD7442 or placebo. This analysis will not be covered in this SAP.
16.3.2.
MISSING DATA IMPUTATION METHOD FOR EXPLORATORY EFFICACY ENDPOINTS
No imputation method will be used for exploratory efficacy endpoints.
16.3.3.
SENSITIVITY ANALYSES FOR EXPLORATORY EFFICACY ENDPOINTS
No sensitivity analysis will be performed for the exploratory efficacy endpoints.
16.3.4.
SUPPLEMENTARY ANALYSES FOR EXPLORATORY EFFICACY ENDPOINTS
No supportive analysis will be performed for the exploratory efficacy endpoints.
17.
PHARMACOKINETIC, PHARMACODYNAMIC AND ADA
ENDPOINTS
The PK and ADA secondary endpoints are:
!
Serum AZD7442 concentrations;
!
PK parameters, if data permit;
!
The incidence of ADA to AZD7442 in serum.
The exploratory PD and ADA endpoints are:
!
AZD7442 nasal fluid concentrations;
!
Post-treatment geometric mean titers (GMTs) and geometric mean fold rises (GMFRs) for nAbs to 
SARS-COV-2 from baseline value through Day 457 after single IM dose in SARS-CoV-2 


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neutralizing antibodies (wild-type assay or pseudo neutralization assay).
Other exploratory assays for humoral, mucosal and cellular immune responses may be performed based upon 
emerging safety, efficacy and PD data.
17.1. ANALYSIS OF PK, PD AND ADA ENDPOINTS
17.1.1.
SERUM AZD7442 CONCENTRATIONS
Individual AZD7442 (AZD8895 and AZD1061) serum concentration data will be listed and tabulated by mAb 
component, along with descriptive statistics for the PK analysis set. A figure of serum concentrations by mAb 
component will also be presented.
Pharmacokinetic exposure (i.e., AUCs) and other PK parameters may be estimated using non-compartmental 
analysis; this will be optional if data permit. Potential correlation between PK exposure and efficacy/safety response 
may optionally be explored. Population PK analysis may be performed by the Sponsor and reported in a separate 
report. The analysis is not covered in this SAP.
17.1.2.
THE INCIDENCE OF ADA TO AZD7442 IN SERUM
17.1.2.1.
ADA Variables
Serum samples for ADA assessments will be conducted utilizing a tiered approach (screen, confirm, titer), and ADA 
data will be collected at scheduled visits shown in protocol section 1.3. ADA result from each sample will be 
reported as either positive or negative. If the sample is positive, the ADA titer will be reported as well. In addition, 
the presence of nAb will be tested for all ADA-positive samples. The nAb results will be reported as positive or 
negative. A participant is defined as being ADA-positive if a positive ADA result is available at any time, including 
baseline and all post-baseline measurements; otherwise the participant is defined as ADA negative.
The number and percentage of ADA-evaluable participants in the following ADA categories in each treatment group 
will be determined. The number of ADA-evaluable participants in the treatment group will be used as the 
denominator for percentage calculation.
!
ADA positive at any visit (at baseline and/or post-baseline). The percentage of these participants in a population 
is known as ADA prevalence;
!
Treatment-induced ADA positive (positive post-baseline and not detected at baseline);
!
Treatment-boosted ADA positive (baseline ADA titer that was boosted by ≥4-fold following drug 
administration);
!
Treatment-emergent ADA (TE-ADA) positive (either treatment-induced ADA positive or treatment-boosted 


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ADA positive). The percentage of these participants in a population is known as ADA incidence;
!
ADA positive post-baseline and positive at baseline;
!
ADA positive at baseline and not detected post-baseline;
!
TE-ADA persistently positive, defined as TE-ADA positive participants having at least 2 post-baseline ADA 
positive measurements with at least 16 weeks (112 days) between the first and last positive measurement, or an 
ADA positive result at the last available assessment;
!
TE-ADA transiently positive, defined as TE-ADA positive participants having at least one post-baseline ADA 
positive measurement and not fulfilling the conditions for TE-ADA persistently positive;
!
nAb (to AZD7442) positive at any visit (at baseline and/or post-baseline).
17.1.2.2.
ADA Analysis
A summary of the number and percentage of participants who developed detectable ADA to AZD7442 (ADA 
results to AZD8895 and AZD1061 will be reported separately) by ADA categories (Section 17.1.2.1) in different 
treatment groups will be presented based on the ADA evaluable analysis set. Descriptive statistics of the maximum 
titer will also be presented by ADA category. ADA results and titers will be summarized by visit and treatment 
group. ADA results will be listed for all participants in the safety analysis set regardless of ADA-evaluable status. 
ADA titer and nAb data will be presented for samples confirmed positive for the presence of ADA to AZD7442. 
AEs in ADA positive participants by ADA positive category will be listed.
The effect of ADA on PK, safety, and efficacy will be examined by descriptive summaries if data allow.
17.1.3.
AZD7442 NASAL FLUID CONCENTRATIONS
Individual AZD7442 (AZD8895 and AZD1061) nasal fluid concentration data will be listed and tabulated by mAb 
component, along with descriptive statistics appropriate for concentration data, for the subset of participants in the 
PK analysis set who have at least one quantifiable nasal fluid PK observation post-dose.
17.1.4.
NEUTRALIZING ANTIBODY GEOMETRIC MEAN TITERS AND GEOMETRIC MEAN 
FOLD RISE
Geometric mean titers (GMTs) and geometric mean fold rises (GMFRs) for nAbs will be calculated for the active 
and control groups and will be summarized at each scheduled visit as per protocol section 1.3. GMT and GMFR 
summaries will be based on the nAb evaluable analysis set.
Descriptive statistics for GMTs and GMFRs will include number of participants, geometric mean, geometric 
standard deviation (GSD), 95% CI, minimum and maximum. 


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The GMT will be calculated as the antilogarithm of Σ(log transformed titer/n), i.e. as the antilogarithm 
transformation of the mean of the log-transformed titer, 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 anti-logarithm transformation of the upper and lower limits 
for a two-sided CI for the mean of the log-transformed titers.
The fold rise is calculated as the ratio of the post-dose titer level to the pre-dose titer level. GMFR will be calculated 
as anti-logarithm of Σ (log transformed (post-dose titer/ pre-dose titer)/n). The GSD and 95% CIs for GMFR will be 
calculated similarly to those for GMT.
17.1.5.
MISSING DATA IMPUTATION METHOD FOR PK, PD AND ADA ENDPOINTS
The PK descriptive analyses of serum AZD7442 concentrations (Section 17.1.1) and AZD7442 nasal fluid 
concentrations (Section 17.1.3) will use the following imputation methods: Individual concentrations below the 
LLOQ of the bioanalytical assay will be reported as Not Quantifiable (NQ) in the listings with the LLOQ defined in 
the footnotes of the relevant tables, figures, and listings (TFLs). Individual plasma concentrations that are Not 
Reportable (NR) will be reported as NR and those that are missing will be reported as No Sample (NS) in the 
listings. Plasma 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 geometric mean, geometric mean ± 
GSD and geometric coefficient of variation (gCV%) will be set to Not Computed (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 
geometric mean, minimum, median, and maximum will be reported as NQ and the gCV% and geometric mean 
± 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 plasma concentration or PK parameter (e.g. Cmax, 
Cmin, Clast) to be summarized. Two observations > LLOQ are presented as minimum and maximum with the other 
summary statistics as NC.
The analysis for the incidence of ADA to AZD7442 in serum (Section 17.1.2) will use the following imputation 
method: ADA titers values below the limit of detection (LOD) are negative results, hence they are not imputed and 
are excluded from calculation of summary statistics. Titer values of positive ADA samples reported as ≤ LOD are 


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imputed as LOD in the calculation of summary statistics on ADA titer.
The analysis of neutralizing antibody geometric mean titers and geometric mean fold rise (Section 17.1.4) will use 
the following imputation method: a titer value measured below the LLOQ will be imputed to a value that is half of 
the LLOQ in summaries and analyses, but will be listed as reported in the raw data. Titer values measured as above 
the upper limit of quantification (ULOQ) will be imputed at the ULOQ value.
17.1.6.
SENSITIVITY ANALYSES FOR EXPLORATORY EFFICACY ENDPOINTS
No sensitivity analysis will be performed for the PK, PD and ADA endpoints.
17.1.7.
SUPPLEMENTARY ANALYSES FOR EXPLORATORY EFFICACY ENDPOINTS
No supportive analysis will be performed for the PK, PD and ADA endpoints.
18.
SAFETY ENDPOINTS
The safety of AZD7442 will primarily be assessed by:
!
Incidence of AEs post dose of IMP;
!
Incidence of SAEs post dose of IMP;
!
Incidence of medically attended adverse events (MAAEs, defined in Protocol Section 8.3.5) post 
dose of IMP;
!
Incidence of adverse events of special interest (AESIs, defined in Protocol Section 8.3.4) post dose of 
IMP.
There are also other safety endpoints, including:
!
Deaths;
!
Laboratory evaluations;
!
Vital signs;
!
ECG evaluations;
!
Physical examinations.
All safety summaries will be presented by actual treatment group based on the SAF. Additional summaries may be 
presented by whether participants receive COVID-19 vaccination (Yes/No) during study and unblinding status 
(Yes/No) during study. Data will be presented using all the available data up to 15 month following the dose of IMP 
to the last assessment unless stated otherwise. There will be no statistical comparisons between the treatment groups 


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for safety data.
18.1. ADVERSE EVENTS
All AEs will be coded using the MedDRA dictionary, version 23.1 or higher.
Unless specified, event summary refers to the summary of number of participants with the corresponding adverse 
event.
Overall summaries of number and percentage of participants with an AE in the following categories will be provided 
by actual treatment group based on the SAF.
!
All AEs;
!
All SAEs;
!
Related SAEs;
!
AEs leading to study discontinuation;
!
Related AEs leading to study discontinuation;
!
MAAEs;
!
Related MAAEs;
!
AEs with outcome of death;
!
AESIs
Should a participant experience multiple events within a category, the participant will be counted only once for that 
category.
An overall summary of number and percentage of participants within categories of all SAEs, related SAEs, AEs 
leading to study discontinuation, related AEs leading to study discontinuation, MAAEs, AEs with outcome of death, 
and AESIs during the entire period of study will be provided by actual treatment group based on the SAF. 
18.1.1.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
AEs will be recorded from the time of IMP administration throughout the study up to and including the last visit.  
SAEs are those events recorded as “Serious” on the AE page of the eCRF. SAEs will be recorded from the time of 
signing of the informed consent form.
AEs and SAEs post the dose of IMP will be summarized by SOC and PT by actual treatment group. Specific AEs 
will be counted once for each participant for calculating percentages. The most frequent AEs, defined as AEs with 


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an incidence of at least 5% in either treatment group, will be summarized by PT by actual treatment group.
Summary of AEs and SAEs post the dose of IMP will be broken down further by maximum severity. If the same AE 
occurs multiple times for a particular participant, the highest/worst severity (i.e. from highest to lowest: fatal, life-
threatening, severe, moderate and mild). Separate summaries of related AEs and related SAEs will be provided by 
SOC and PT by actual treatment group.
Listings of AEs and SAE details will be provided. SAEs that started prior to the dose of IMP, and AEs and SAEs 
starting after Day 457 will only be presented in the listings. For SAEs with partial dates, if the known part of the 
date indicates that SAE stopped before the dose of IMP, it will be considered as an SAE prior to the dose of IMP. 
Otherwise, it will be considered as an SAE post dose of IMP. 
18.1.1.1.
Severity for AEs
Severity will be classified as mild, moderate, severe, potentially life-threatening or fatal (increasing severity) by 
using grading for AEs. Severity for AEs will be collected on the ‘Adverse Events’ form of the eCRF. Should a 
participant experience multiple events within a SOC or PT, only the participant’s worst severity food and drug 
association grade will be counted for that SOC or PT.
18.1.1.2.
Relationship to IMP/Other Medication/Study Procedure
Relationship to IMP/other medication/study procedure, as indicated by the Investigator, will be classified as not 
related or related.
Should a participant experience multiple events within a SOC or PT, the participant will be counted as related for 
that SOC or PT if one of those is related.
18.1.2. AES LEADING TO DISCONTINUATION OF IMP
AEs leading to permanent discontinuation of IMP are not expected due to this being a single dose study. Given the 
single dose is comprised of 2 sequential injections, the AE would need to occur immediately after the 1st injection 
and lead to discontinuation of the 2nd injection — this scenario is expected to be rare. Therefore, no summary will 
be prepared. 
A listing of all AEs leading to discontinuation of IMP will be provided, if data permit.  
18.1.3. AES LEADING TO DISCONTINUATION OF STUDY
A summary of AEs during the study leading to permanent discontinuation of study by SOC and PT will be prepared. 
A summary of related AEs leading to permanent discontinuation of study by SOC and PT will also be prepared. 
A listing of all AEs leading to permanent discontinuation of study will be provided.


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18.1.4. AES WITH OUTCOME OF DEATH
AEs with outcome of death are those AEs with “Fatal” outcome recorded on the “Adverse Event” form of the eCRF. 
A summary of AEs with outcome of death by SOC and PT will be prepared. 
18.1.5.
MEDICALLY ATTENDED ADVERSE EVENTS
MAAEs are AEs leading to medically attended visits that were not routine visits for physical examination or dosing, 
such as an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) 
for any reason. AEs, including abnormal vital signs, identified on a routine study visit or during the scheduled 
Illness Visits will not be considered MAAEs. MAAEs will be recorded from Day 1, post dose, through the last 
participant contact.
A summary of MAAEs by SOC and PT by actual treatment group will be prepared. Should a participant experience 
multiple events within a SOC or PT, the participant will be counted only once for that SOC or PT. A summary of 
related MAAEs by SOC and PT will also be prepared.
18.1.6.
ADVERSE EVENTS OF SPECIAL INTEREST
AESIs are:
!
Anaphylaxis and other serious hypersensitivity reactions, including immune complex disease;
!
Injection site reactions.
AESIs are indicated on the eCRF and will be recorded from Day 1, post dose, through the last participant contact. A 
summary of AESIs by AESI category and PT by actual treatment group will be prepared.  Should a participant
experience multiple events within an AESI category or PT, the participant will be counted only once for that SOC or 
PT.
A listing of all AESIs will be provided.
18.2. DEATHS
COVID-19 related deaths and the all-cause mortality rate are summarized as secondary efficacy endpoints, see 
Sections 16.2.3.2 and 16.2.3.3. In addition, the number and percentage of participants with death related to COVID-
19 and those with other deaths will be summarized by actual treatment group based on the SAF. Data will be taken 
from the “Death Details” page of the eCRF. All death data will be listed.
18.3. LABORATORY EVALUATIONS
A urine pregnancy test will be performed at screening and per the schedule of events (refer to protocol, Section 1.3).


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If urine tests positive or indeterminate, a serum test will be performed for confirmation. Chemistry, hematology, 
coagulation and urinalysis will be performed as per the schedule of events (refer to protocol, Section 1.3).  A list of 
laboratory parameters to be included in the outputs is included in APPENDIX 3.
Quantitative laboratory parameters reported as “< X”, i.e. below the lower limit of quantification (BLQ) or “> X”, 
i.e. above the upper limit of quantification, will be converted to X for the purpose of quantitative summaries, but 
will be presented as recorded, i.e. as “< X” or “> X” in the listings.  
The following summaries will be provided by actual treatment group based on the SAF for each of chemistry,
hematology, coagulation, and urinalysis laboratory parameter:
!
Observed and change from baseline in Standard International (SI) units by visit (for quantitative 
parameters);
!
Observed and change from baseline for Illness Visits as defined in Section 6.5 (for coagulation 
parameters) in SI units by Illness Visit (the Illness Visits corresponding to positive RT-PCR test will 
be used in the summary);
!
Number and percentage of participants in each laboratory parameter category by visit (for categorical 
parameters);
!
Shift from baseline to the worst post-baseline observed value according to the Common Terminology 
Criteria for Adverse Events (CTCAE) toxicity grades (for quantitative parameters with available 
CTCAE toxicity grades; refer to Section 18.3.1);
!
Shifts from baseline to the maximum/minimum post-baseline observed value according to normal 
range criteria (for quantitative parameters without CTCAE toxicity grades; refer to Section 18.3.2);
!
Maximum post-baseline alanine aminotransferase/transaminase (ALT)/ aspartate 
aminotransferase/transaminase (AST) observed value categorized as < 3 x upper limit of normal 
(ULN), ≥3 to < 5 x ULN, ≥5 to < 10 x ULN or ≥10 ULN by maximum post-baseline total bilirubin 
(TBL) observed value categorized as < 2 x ULN or ≥2 x ULN.
All lab data will be listed.
18.3.1.
CTCAE TOXICITY GRADES
Quantitative laboratory parameters with available CTCAE toxicity grades will be categorized as follows where 
higher grades representing a more severe toxicity (refer to APPENDIX 1 for each parameter toxicity grade criteria): 
!
Grade 1 (i.e., mild);
!
Grade 2 (i.e., moderate);
!
Grade 3 (i.e., severe);


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!
Grade 4 (i.e., life-threatening);
!
Grade 5 (i.e., death).
Although not defined in the CTCAE toxicity grading system, version 5, non-missing laboratory parameter results 
not meeting any of the 5 grades defined in the CTCAE toxicity grading system will be categorized as ‘No Event’ for 
the purpose of the shift from baseline summaries.
18.3.2.
LABORATORY NORMAL RANGES
Quantitative laboratory parameters will be compared with the relevant central laboratory normal ranges in SI units 
and categorized as:
!
Low: Below the lower limit of the laboratory normal range;
!
Normal: Within the laboratory normal range (upper and lower limit included);
!
High: Above the upper limit of the laboratory normal range.
18.4. VITAL SIGNS
The following vital sign parameters will be collected for this study as per the schedule of events (refer to protocol, 
Section 1.3):
!
Systolic blood pressure (SBP) (mmHg);
!
Diastolic blood pressure (DBP) (mmHg);
!
Heart rate (beats per minute [bpm]);
!
Body temperature (C);
!
Oxygen saturation (%);
!
Respiratory rate (breaths/min).
For severity grades of abnormal Vital Signs refer to APPENDIX 5. 
The following summaries will be provided by actual treatment group based on the SAF for each vital sign
parameter:
!
Observed and change from baseline by visit;
!
Observed and change from baseline (as defined in Section 6.5) by Illness Visit (the first illness 
episode with positive RT-PCR test result will be used for the summary);


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!
Number and percentages of participants with at least one abnormal post-baseline observed value 
(refer to APPENDIX 5).
All vital sign data will be listed. Indicators will be included for illness visits to distinguish those with positive RT-
PCR results from those with negative RT-PCR results.
18.5. ECG EVALUATIONS
The following electrocardiogram (ECG) parameters will be measured for this study as per the schedule of events 
(refer to protocol, Section 1.3):
!
Heart rate (bpm);
!
PR interval (msec);
!
RR interval (msec);
!
QRS interval (msec);
!
QT interval (msec);
!
QTc interval (msec);
!
QTcF interval (msec);
!
QTcB interval (msec);
!
Overall ECG interpretation (Investigator’s judgment):
o
Normal;
o
Abnormal, not clinically significant;
o
Abnormal, clinically significant.
Since triplicate ECGs will be performed for this study, the mean of the 3 measurements collected on a visit will be 
used in the by-visit summaries for that visit, but the worst of the 3 measurements collected on a visit will be used for 
the shift from baseline summaries for that visit. Should one or two of the triplicate measurements be missing at a 
specific visit, the mean of the available measurements will be used in the by-visit summaries for that visit. All 
individual measurements will be listed.
The following summaries will be provided by actual treatment group for each ECG parameter:
!
Observed and change from baseline by visit (for quantitative parameters);
!
Number and percentages of participants with at least one markedly abnormal post-baseline observed 


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value/change from baseline (for quantitative parameters; refer to Section 18.5.1);
18.5.1.
ECG MARKEDLY ABNORMAL CRITERIA
Markedly abnormal quantitative ECG parameters will be identified in accordance with the following predefined 
markedly abnormal criteria:
!
Observed values for QTc, QTcF, and QTcB intervals will be classified as:
o
> 450 msec;
o
> 480 msec;
o
> 500 msec.
!
Change from baseline for QTc, QTcF, and QTcB intervals will be classified as:
o
>30 msec increase from baseline;
o
>60 msec increase from baseline.
It is to be noted that the previous categories are not mutually exclusive, but cumulative. For example, if a 
participant’s worst post-baseline QTc post-baseline observed value is 490 mmHg, then this participant will be 
reported once under QTc > 450 msec and once under QTc > 480 msec.
18.6. PHYSICAL EXAMINATION
Physical examinations will be conducted as per the schedule of events (refer to protocol Section 1.3).  Clinically 
significant findings at screening will be recorded on the Medical History form of the eCRF while clinically 
significant changes from screening will be recorded on the Adverse Events form of the eCRF for the post-screening 
visits.  Hence, clinically significant findings/changes will be summarized though the Medical history summary (refer 
to Section 11) or AE summaries (refer to Section 18.1), as appropriate.  That is, no summaries will be specifically 
provided for the general physical examination.
19.
OTHER DATA COLLECTED
The following data collected on the eCRF will be summarized in listings only:
!
Pregnancy test and report;
!
Weekly telephone contact for safety monitoring;
!
Medication Error.


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20.
REFERENCES 
CDC. (Centers for Disease Control and Prevention). Coronavirus Disease 2019 (COVID-19), Symptoms of 
Coronavirus. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html. Published 2020. 
Accessed 01 July 2020.
Little, R. J. A. and Rubin, D. B. Statistical Analysis with Missing Data, 2nd Edition, Hoboken, NJ: John Wiley & 
Sons 2002; 257.
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4(2):213-26.
Zou, G. A Modified Poisson Regression Approach to Prospective Studies with Binary Data. Am J Epidemiol 2004; 
159:702–706.


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APPENDIX 1.
PARTIAL DATE CONVENTIONS
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS
START DATE
STOP DATE
ACTION
Known
Known or 
ongoing
If medication stop date < date of dose of IMP, assign as prior;
If medication start date < date of dose of IMP and medication stop date ≥
date of dose of IMP, assign as concomitant;
If date of dose of IMP ≤medication start date, assign as concomitant.
Partial
If known components of medication stop date show that medication stopped 
before date of dose of IMP, assign as prior;
If medication start date < date of dose of IMP and (known components of 
medication stop date show that medication stopped on or after date of dose 
of IMP), assign as concomitant;
If date of dose of IMP ≤medication start date, assign as concomitant.
Missing, not 
ongoing
If medication stop date is missing, then it can never be assigned as prior 
only;
If medication start date < date of dose of IMP, assign as concomitant;
If date of dose of IMP ≤medication start date, assign as concomitant.
Partial
Known or 
ongoing
If medication stop date < date of dose of IMP, assign as prior;
If (known components of medication start date show that medication started 
before date of dose of IMP) and (medication stop date ≥date of dose of 
IMP), assign as concomitant;
If known components of medication start date show that medication started 
on or after date of dose of IMP, assign as concomitant.


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START DATE
STOP DATE
ACTION
Partial
If known components of medication stop date show that medication stopped 
before date of dose of IMP, assign as prior;
If (known components of medication start date show that medication started 
before date of dose of IMP) and (known components of medication stop date 
show that medication stopped on or after date of dose of IMP), assign as 
concomitant;
If known components of medication start date show that medication started 
on or after date of dose of IMP, assign as concomitant.
Missing, not 
ongoing
Cannot be assigned as prior only;
If known components of medication start date show that medication started 
before study drug start date, assign as concomitant;
If known components of medication start date show that medication started 
on or after date of dose of IMP, assign as concomitant.
Missing
Known or
ongoing
If medication stop date < date of dose of IMP, assign as prior;
If medication stop date >= date of dose of IMP, assign as concomitant.
Partial
If known components of medication stop date show that medication stopped 
before date of dose of IMP, assign as prior;
If known components of medication stop date show that medication stopped 
on or after date of dose of IMP, assign as concomitant.
Missing, not 
ongoing
Assign as concomitant.


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APPENDIX 2.
PROGRAMMING CONVENTIONS FOR OUTPUTS
DATES & TIMES
Depending on data available, dates and times will take the form yyyy-mm-dd hh:mm:ss.
SPELLING FORMAT
English US. 
PAPER SIZE, ORIENTATION, AND MARGINS
The size of paper will be letter and the page orientation will be landscape. Margins will provide at least 1 inch (2.54 
centimeters) of white space all around the page.
FONTS
The font type ‘Courier New’ will be used, with a font size of 8.  The font color will be black with no bolding, 
underlining, italics or subscripting.
PRESENTATION OF TREATMENT GROUPS
For outputs, treatment groups will be represented as follows and in the given order:
Treatment Group
Tables and Graphs
Listings
AZD7442
1
1
Placebo
2
2
Total [1]
5
n/a
Randomized, Not Dosed
n/a
3
Screen Failure
n/a
4
[1] Not applicable for efficacy tables, safety tables and graphs.
PRESENTATION OF PK ANALYSES
Groups will be represented as follows and in the given order for participants who receive AZD7442 only: 


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Treatment Group
Tables and Graphs
Listings
AZD8895
1
1
AZD1061
2
2
PRESENTATION OF NOMINAL VISITS
For outputs, analysis visits will be represented as follows and in that order:
Long Name (default)
Short Name 
Screening
Scrn
Rescreening
RScrn
Day 1
D1
Day 8
D8
Day 29
D29
Day 58
D58
Day 92
D92
Day 183
D183
Day 366
D366
Day 457
D457
For outputs, analysis visits regarding Illness Visit will be represented as follows and in that order:
Long Name (default)
Short Name 
Episode 1 Illness Visit Day X, 
X=1,3,5,8,11,14,21,28
1IL-DXX,
X=1,3,5,8,11,14,21,28
Episode 2 Illness Visit Day X, 
X=1,3,5,8,11,14,21,28
2IL-DXX,
X=1,3,5,8,11,14,21,28


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Long Name (default)
Short Name 
Episode Y Illness Visit Day X, 
X=1,3,5,8,11,14,21,28
Y = 1, 2, 3, and so on, as applicable
YIL-DXX,
X=1,3,5,8,11,14,21,28
Y = 1, 2, 3, …
DESCRIPTIVE STATISTICS
If the original data has N decimal places, then the summary statistics will have the following decimal places:
!
Minimum and maximum: N;
!
Mean, median, Q1, Q3, lower and upper bounds of two-sided 95% CI: N + 1;
!
SD: N + 2
PERCENTAGES
Percentages will be reported to one decimal place.  Rounding will be applied, except for percentages < 0.1 but > 0.0 
which will be presented as ‘< 0.1’ and percentages < 100.0 but >99.9 which will be presented as ‘>99.9’.
Where counts are zero, no percentages will appear in the output.
P-VALUES
p-values will be reported to four decimal places.  Rounding will be applied, except for the p-values < 0.0001 which 
will be presented as ‘< 0.0001’ and p-values < 1.0000 but > 0.9999 which will be presented as ‘> 0.9999’.
LISTINGS
All listings will be ordered by the following (unless otherwise indicated in the output template):
! Randomized (planned) treatment group (or actual treatment received if it’s a safety output);
! Participant ID;
! Parameter, when applicable;
! Date/Time, when applicable;
! Timepoint, when applicable


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APPENDIX 3.
LABORATORY ASSESSMENTS
Chemistry (SI unit)
!
Alkaline phosphatase (ALP) (U/L)
!
Creatinine (μmol/L)
!
Alanine aminotransaminase (ALT) (U/L)
!
Glucose (mmol/L)
!
Aspartate aminotransaminase (AST) (U/L)
!
Creatine kinase (CK) (U/L)
!
Total bilirubin (μmol/L)
!
Sodium (mmol/L)
!
Conjugated bilirubin (μmol/L)
!
Potassium (mmol/L)
!
Gamma glutamyl transferase (GGT) (U/L)
!
Calcium (mmol/L)
!
C-Reactive protein (CRP) (nmol/L)
!
Phosphate (mmol/L)
!
Albumin (g/L)
!
Urea (mmol/L)
Hematology (SI unit)
!
Hemoglobin (g/L)
!
Absolute neutrophils count (x10E9/L)
!
Hematocrit
!
Absolute lymphocyte count 
(x10E9/L)
!
Mean corpuscular volume (MCV) (fL)
!
Absolute monocyte count (x10E9/L)
!
Red blood cells (RBC) count total
(x10E12/L)
!
Absolute eosinophils count 
(x10E9/L)
!
White blood cell (WBC) count total 
(x10E9/L)
!
Absolute basophils count (x10E9/L)
!
Mean corpuscular hemoglobin (MCH) (pg)
!
Absolute reticulocyte count 
(x10E9/L)
!
Mean corpuscular hemoglobin 
concentration (MCHC) (g/L)
!
Platelet count (x10E9/L)
Coagulation (SI unit)
!
International normalized ratio (INR)
!
Prothrombin time (PT) (s)
!
Activated partial thrombin time (aPTT) (s)
Urinalysis (SI unit)
Dip stick
Microscopy
!
Blood
!
White blood cells
!
Protein
!
Red blood cells
!
Glucose
!
Casts


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APPENDIX 4.
CTCAE TOXICITY GRADE, VERSION 5.0
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (accessed on 22-Apr-2020)
CTCAE Term
Laboratory Test
No Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Anemia
Hemoglobin (g/L)
≥ LLN
≥ 100 g/L -
< LLN
≥ 80 -
< 100 g/L
< 80 g/L
n/a
n/a
Hemoglobin increased
Hemoglobin (g/L)
No increase 
from baseline
Increase from 
baseline > 0 - ≤ 
20 g/L
Increase from 
baseline > 20 -
≤ 40 g/L
Increase from 
baseline 
> 40 g/L
n/a
n/a
Platelet count decreased
Platelet count 
(x10E9/L)
≥ LLN
≥75 x 10E9/L 
– < LLN
≥50 -
< 75 x 10E9/L
≥25 -
< 50 x 10E9/L
< 25 x 10E9/L
n/a
White blood cell (WBC) 
decreased
WBC (x 10E9/L)
≥ LLN
≥3.0 x 10E9/L 
– < LLN
≥2.0 -
< 3.0 x 10E9/L
≥1.0 - < 2.0 x 
10E9/L
< 1.0 x 10E9/L
n/a
Leukocytosis
WBC (x 10E9/L)
≤ 100 x 
10E9/L
n/a
n/a
> 100 x 10E9/L
n/a
n/a
Absolute neutrophils 
count decreased
Absolute neutrophils 
count (x 10E9/L)
≥ LLN
≥1.5 x 10E9/L 
– < LLN
≥1.0 -
< 1.5 x 10E9/L
≥0.5 - < 1.0 x 
10E9/L
< 0.5 x 10E9/L
n/a
Absolute lymphocytes 
count decreased
Absolute lymphocytes 
count (x 10E9/L)
≥ LLN
≥0.8 x 10E9/L 
– < LLN
≥0.5 -
< 0.8 x 10E9/L
≥0.2 -
< 0.5 x 10E9/L
< 0.2 x 10E9/L
n/a
Absolute lymphocytes 
count increased
Absolute lymphocytes 
count (x 10E9/L)
≤ 4 x 10E9/L
n/a
> 4 –
≤20 x 10E9/L
> 20 x 10E9/L
n/a
n/a
Eosinophilia
Absolute eosinophils
≤ ULN or
≤ Baseline
> ULN and
> Baseline
n/a
n/a
n/a
n/a
Hypernatremia
Sodium (mmol/L)
≤ ULN
> ULN – ≤150 
mmol/L
> 150 –
≤155 mmol/L
> 155 –
≤160 mmol/L
> 160 mmol/L
n/a
Hyponatremia
Sodium (mmol/L)
≥ LLN
≥130 mmol/L 
– < LLN
≥125 -
< 130 mmol/L
≥120 -
< 125 mmol/L
< 120 mmol/L
n/a


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CTCAE Term
Laboratory Test
No Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Hyperkalemia
Potassium (mmol/L)
≤ ULN
> ULN –
≤5.5 mmol/L
> 5.5 –
≤6.0 mmol/L
> 6.0 –
≤7.0 mmol/L
> 7.0 mmol/L
n/a
Hypokalemia
Potassium (mmol/L)
≥ LLN
≥3.0 mmol/L –
< LLN
n/a
≥2.5 -
< 3.0 mmol/L
< 2.5 mmol/L
n/a
Hypercalcemia
Ionized calcium 
(mmol/L)
≤ ULN
> ULN –
≤1.5 mmol/L
> 1.5 –
≤1.6 mmol/L
> 1.6 –
≤1.8 mmol/L
> 1.8 mmol/L
n/a
Hypocalcemia
Ionized calcium 
(mmol/L)
≥ LLN
≥1.0 mmol/L –
< LLN
≥0.9 -
< 1.0 mmol/L
≥0.8 -
< 0.9 mmol/L
< 0.8 mmol/L
n/a
Hypermagnesemia
Magnesium (mmol/L)
≤ ULN
> ULN –
≤1.23 mmol/L
n/a
> 1.23 –
≤3.30 mmol/L
> 3.30 mmol/L
n/a
Hypomagnesemia
Magnesium (mmol/L)
≥ LLN
≥0.5 mmol/L –
< LLN
≥0.4 -
< 0.5 mmol/L
≥0.3 -
< 0.4 mmol/L
< 0.3 mmol/L
n/a
Hypoglycemia
Glucose (mmol/L)
≥ LLN
≥3.0 mmol/L –
< LLN
≥2.2 -
< 3.0 mmol/L
≥1.7 -
< 2.2 mmol/L
< 1.7 mmol/L
n/a
Creatinine increased
Creatinine (μmol/L)
≤ ULN
> ULN –
≤1.5 x ULN
> 1.5 –
≤3.0 x ULN 
or
> 1.5 – ≤3.0 x 
baseline
> 3.0 –
≤6.0 x ULN 
or
> 3.0 x baseline
> 6.0 x ULN
n/a
Alkaline phosphatase 
(ALP) increased
ALP (U/L)
≤ ULN if 
baseline 
normal; 
≤ 2.0 x 
baseline if 
baseline 
abnormal
> ULN –
≤2.5 x ULN if 
baseline 
normal; 
> 2.0 -
≤2.5 x baseline 
if baseline 
abnormal
> 2.5 –
≤5.0 x ULN if 
baseline 
normal;
> 2.5 –
≤5.0 x baseline 
if baseline 
abnormal
> 5.0 –
≤20.0 x ULN if 
baseline 
normal;
> 5.0 – ≤ 20.0 x 
baseline if 
baseline 
abnormal
> 20.0 x ULN if 
baseline 
normal;
> 20.0 x 
baseline if 
baseline 
abnormal
n/a


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CTCAE Term
Laboratory Test
No Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Alanine transaminase 
(ALT) increased
ALT (U/L)
≤ ULN if 
baseline 
normal; 
≤ 1.5 x 
baseline if 
baseline 
abnormal
> ULN –
≤3.0 x ULN if 
baseline 
normal; 
> 1.5 - ≤ 3.0 x 
baseline if 
baseline 
abnormal
> 3.0 –
≤5.0 x ULN if 
baseline 
normal;
> 3.0 – ≤ 5.0 x 
baseline if 
baseline 
abnormal
> 5.0 – ≤ 20.0 x 
ULN if baseline 
normal;
> 5.0 – ≤ 20.0 x 
baseline if 
baseline 
abnormal
> 20.0 x ULN if 
baseline 
normal;
> 20.0 x 
baseline if 
baseline 
abnormal
n/a
Aspartate transaminase 
(AST) increased
AST (U/L)
≤ ULN if 
baseline 
normal; 
≤ 1.5 x 
baseline if 
baseline 
abnormal
> ULN –
≤3.0 x ULN if 
baseline 
normal; 
> 1.5 - ≤ 3.0 x 
baseline if 
baseline 
abnormal
> 3.0 –
≤5.0 x ULN if 
baseline 
normal;
> 3.0 – ≤ 5.0 x 
baseline if 
baseline 
abnormal
> 5.0 – ≤ 20.0 x 
ULN if baseline 
normal;
> 5.0 – ≤ 20.0 x 
baseline if 
baseline 
abnormal
> 20.0 x ULN if 
baseline 
normal;
> 20.0 x 
baseline if 
baseline 
abnormal
n/a
Blood bilirubin 
increased
Total bilirubin
(μmol/L)
≤ ULN if 
baseline 
normal; 
≤ baseline if 
baseline 
abnormal
> ULN –
≤1.5 x ULN if 
baseline 
normal; 
> baseline - ≤ 
1.5 x baseline 
if baseline 
abnormal
> 1.5 –
≤3.0 x ULN if 
baseline 
normal; 
> 1.5 - ≤ 3.0 x 
baseline if 
baseline 
abnormal
> 3.0 – ≤ 10.0 x 
ULN if baseline 
normal; 
> 3.0 - ≤ 10.0 x 
baseline if 
baseline 
abnormal
> 10.0 x ULN if 
baseline 
normal; 
> 10.0 x 
baseline if 
baseline 
abnormal
n/a


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CTCAE Term
Laboratory Test
No Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Gamma glutamyl 
transferase (GGT) 
increased
GGT (U/L)
≤ ULN if 
baseline 
normal; 
≤ 2.0 x 
baseline if 
baseline 
abnormal
> ULN –
≤2.5x ULN if 
baseline 
normal; 
> 2.0 -
≤2.5 x baseline 
if baseline 
abnormal
> 2.5 –
≤5.0 x ULN if 
baseline 
normal; 
> 2.5 -
≤5.0 x baseline 
if baseline 
abnormal
> 5.0 – ≤ 20.0 x 
ULN if baseline 
normal; 
> 5.0 - ≤ 20.0 x 
baseline if 
baseline 
abnormal
> 20.0 x ULN if 
baseline 
normal; 
> 20.0 x 
baseline if 
baseline 
abnormal
n/a
Hypoalbuminemia
Albumin (g/L)
≥ LLN
≥ 30 g/L - < 
LLN
≥ 20 - < 30 g/L
< 20 g/L
n/a
n/a
CPK increased
Creatine kinase (U/L)
≤ ULN
> ULN –
≤2.5 x ULN
> 2.5 –
≤5 x ULN
> 5 –
≤10 x ULN
> 10 x ULN
n/a
International normalized 
ratio (INR) increased
INR
≤ 1.2 if not on 
anticoagulant;
≤ baseline if 
on 
anticoagulant
> 1.2 – ≤1.5 if 
not on 
anticoagulant;
> baseline -
≤1.5 x baseline 
if on 
anticoagulant
> 1.5 – ≤2.5 if 
not on 
anticoagulant;
> 1.5 - ≤ 2.5 x 
baseline if on 
anticoagulant
> 2.5 if not on 
anticoagulant;
> 2.5 x baseline 
if on 
anticoagulant
n/a
n/a


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APPENDIX 5.
CLINICAL ABNORMALITIES: VITAL SIGNS
Vital Signs a
Vital Signs Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening (Grade 4)
Fever (℃) b
(℉) b
37.9-38.4
100.1-101.1
38.5-38.9
101.2-102.0
39.0-40
102.1-104
> 40
> 104
Tachycardia 
(beats/minute)
101-115
116- 130
> 130
ER visit or hospitalization 
for arrhythmia
Bradycardia 
(beats/minute) c
50-54
45-49
< 45
ER visit or hospitalization 
for arrhythmia
Hypertension; systolic 
(mm Hg)
141-150
151-155
> 155
ER visit or hospitalization 
for malignant hypertension
Hypertension; diastolic 
(mm Hg)
91-95
96-100
> 100
ER visit or hospitalization 
for malignant hypertension
Hypotension; systolic 
(mm Hg)
85-89
80-84
< 80
ER visit or hospitalization 
for hypotensive shock
Respiratory rate 
(breaths/minute)
17-20
21-25
> 25
Intubation
Note: Record vital signs as adverse events only if clinically relevant and changed from baseline.
a
Participant should be at rest for vital signs measurements.
a
No recent hot or cold beverages or smoking.
b
Use clinical judgment when characterizing bradycardia among some healthy participant populations, for 
example, conditioned athletes.
ER = emergency room; Hg = mercury.


Statistical Analysis Plan
AstraZeneca
D8850C00003 V3.1
07-Apr-2021
CONFIDENTIAL AND PROPRIETARY
74 of 74
APPENDIX 6.
HIGH RISK OF SEVERE COVID-19 AT BASELINE
High Risk of Severe 
COVID- 19 Condition
Description
History of Obesity: 
(eCRF)
COVID Co-Morbidities eCRF: “Does the subject have a history of Obesity -- those 
with a BMI greater than 30”
Programming example: MHDIAGYN4=”Yes”
Morbid Obesity: 
BMI>=40 (Derived)
Derived from the subjects reported hight and weight at baseline
Obese:
BMI>=30 (Derived)
Derived from the subjects reported hight and weight at baseline
CKD
COVID Co-Morbidities eCRF: “Does the subject have a history of Chronic kidney 
disease?”
Programming example: MHDIAGYN1=”Yes”
Diabetes
COVID Co-Morbidities eCRF: “Does the subject have a history of Type 1 diabetes?”
“Does the subject have a history of Type 2 diabetes?”
Programming example: MHDIAGYN15=”Yes” or MHDIAGYN7=”Yes”
Immunosuppressive 
disease
From reported Medical History Term
Programming example: SOC_NAME=” IMMUNE SYSTEM DISORDERS” and 
HLGT different than 'ALLERGIC CONDITIONS' 
Immunosuppressive 
treatment
From reported Concomitant medications identified as prior and ongoing with ATC2 is 
'L01' or 'L04'.
CV disease
COVID Co-Morbidities eCRF: “Does the subject have a history of Serious heart 
conditions like heart failure and coronary artery disease”
Programming example: MHDIAGYN5=”Yes”
COPD
COVID Co-Morbidities eCRF: “Does the subject have a history of Chronic obstructive 
pulmonary disease (COPD), like emphysema?”
Programming example: MHDIAGYN2=” Yes”
Chronic liver disease
COVID Co-Morbidities eCRF: “”
Programming example: MHDIAGYN13=” Yes”
Hypertension
COVID Co-Morbidities eCRF: “Does the subject have a history of High blood 
pressure?”
Programming example: MHDIAGYN12=” Yes”
Asthma
COVID Co-Morbidities eCRF: Does the subject have a history of Asthma?
Programming example: MHDIAGYN8=”Yes”
Cancer
From ongoing Medical History terms where SOC NAME='NEOPLASMS BENIGN, 
MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)' and PT 
name different than 'UTERINE LEIOMYOMA'
Smoking
COVID Co-Morbidities, specific question: What is the subject’s smoking history?
MHDIAGYN17=”1” (“Current”)
Sickle cell disease
COVID Co-Morbidities eCRF: Does the subject have a history of Sickle cell disease?
Programming example:MHDIAGYN6=” Yes”
Note: Final programming logic may differ to address the specific data elements such as additional fields, different 
field name or levels.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d8850c00003-sap-v-3-1
Document Title:
D8850C00003 Statistical Analysis Plan Version 3.1
07Apr2021
Document ID:
Doc ID-004448168
Version Label:
7.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
07-Apr-2021 18:45 UTC
Content Approval
07-Apr-2021 17:30 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD